piperidines and Brain-Neoplasms

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Bing-Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS-penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS.

Topics: Adenine; Amino Acid Substitution; Brain Neoplasms; Humans; Magnetic Resonance Imaging; Mutation, Missense; Myeloid Differentiation Factor 88; Neoplasm Proteins; Piperidines; Pyrazoles; Pyrimidines; Waldenstrom Macroglobulinemia

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cranial Irradiation; Crizotinib; Disease Management; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Meningeal Neoplasms; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Neurocognitive Disorders; Observational Studies as Topic; Oncogene Proteins, Fusion; Pemetrexed; Piperidines; Protein Kinase Inhibitors; Radiosurgery

Anaplastic lymphoma kinase (ALK) gene rearrangements as driver genetic alterations occur in approximately 2-4% of non-small-cell lung cancer (NSCLC) patients. Alectinib, a next generation ALK inhibitor, recently demonstrated, in two separate Phase III trials, superior efficacy to crizotinib, the first ALK inhibitor to demonstrate clinical efficacy in ALK-positive NSCLC patients. Alectinib also demonstrated superior efficacy in the CNS. The data from these two Phase III studies suggest that the efficacy of starting with alectinib is superior to the overall clinical efficacy of starting with crizotinib followed by switching to alectinib at the time of disease progression. These results have changed the standard of care to alectinib as front-line therapy for advanced ALK-positive NSCLC patients. Areas covered: this paper reviews the available data on alectinib as front-line therapy in patients with ALK-positive NSCLC patients including its activity against brain metastases. In addition, the paper will review the data with other ALK inhibitors as front-line therapy.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Survival Rate; Treatment Outcome

Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment.

Topics: Adenine; Animals; Blood-Brain Barrier; Brain Neoplasms; Drug Delivery Systems; Glioblastoma; Mice; Pericytes; Piperidines; Pyrazoles; Pyrimidines; Tumor Microenvironment; Xenograft Model Antitumor Assays

Crizotinib is an anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) that represents the standard first-line treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). In this setting, crizotinib has demonstrated a response rate of roughly 75% and a median progression-free survival just under one year. However, acquired resistance will emerge in virtually all crizotinib-treated patients, whose management may require a diversified approach according to the pace of the disease and/or the site(s) of disease progression. Crizotinib beyond disease progression is an option in patients with oligoprogressive disease, especially in presence of isolated central nervous system (CNS) relapse, provided that local ablative therapy (mainly radiotherapy) to the brain is administered. On the other hand, novel more potent and highly selective ALK-TKIs with demonstrated anti-tumor activity (CNS included) in crizotinib-refractory patients have been made available in recent years. Therefore, clinicians may well consider switching to a second-generation ALK-TKI as treatment option in case of progression on crizotinib. Therapeutic chances are more limited for patients who progress after crizotinib and a second-generation ALK-TKI, for whom both a third-generation ALK-TKI or pemetrexed-based chemotherapy could prove beneficial, while evidence in support of the use of immunotherapy in patients pretreated with ≥1 ALK-TKI is lacking.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Immunotherapy; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

With therapeutic approaches based on oncogene addiction offering significant anticancer benefit, the identification of anaplastic lymphoma kinase (ALK) rearrangements is a key aspect of the management of lung cancers. The EML4-ALK gene fusion is detected in 4-8% of all lung cancers, predominantly in light smokers or nonsmokers. Crizotinib, the first agent to be approved in this indication, is associated with a median progression-free survival of 10.9 months when given as first-line treatment and 7.7 months when administered after chemotherapy. Median overall survival with crizotinib in the second-line setting is 20.3 months. Second-generation ALK inhibitors are currently being evaluated, with early studies giving impressive results, notably in patients resistant to crizotinib or with brain metastases. Among available chemotherapies, pemetrexed appears to be particularly active in this population. Despite this progress, several questions remain unanswered. What detection strategies should be favoured? What underlies the mechanisms of resistance and what options are available to overcome them? What are the best approaches for progressing patients? This review provides an overview of current data in the literature and addresses these questions.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Crizotinib; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Neoplasm Metastasis; Piperidines; Predictive Value of Tests; Prognosis; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Smoking; Sulfones

During the past several years, targeted therapies have significantly improved outcomes in advanced basal cell carcinoma, psoriasis, and metastatic melanoma. This article reviews how advances in our understanding of the molecular pathogenesis of these diseases led to the development of targeted therapies and how these therapies are improving outcomes. Research is ongoing to address continuing challenges of drug resistance, adverse effects, and how best to use the new medications.

Topics: Adult; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azetidines; Brain Neoplasms; Carcinoma, Basal Cell; Dermatologic Agents; Dermatology; Etanercept; Female; Humans; Imidazoles; Indoles; Interleukin-17; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Psoriasis; Pyridines; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Tumor Necrosis Factor-alpha; Ustekinumab; Vemurafenib

Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity through its rearrangement in non-small cell lung cancer (NSCLC), and patients (pts) with ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib, and ceritinib, than with chemotherapy. Despite the excellent efficacy of ALK inhibitors, resistance to these drugs is inevitably encountered in most ALK-rearranged pts. Cases of resistance are subtyped into three groups, i.e., systemic, oligo, and central nervous system (CNS) types, with the CNS being used to be considered a sanctuary. With regard to the management of CNS lesions in pts with ALK+ NSCLC, a growing body of evidence has gradually demonstrated the intracranial (IC) efficacy of ALK inhibitor (ALKi) in ALK+ NSCLC pts with brain metastases (BMs). Although the efficacy of crizotinib for the CNS lesions remains controversial, a recent retrospective investigation of ALK+ pts with BM enrolled in PROFILE 1005 and PROFILE 1007 demonstrated that crizotinib is associated with a high disease control rate for BM. However, BM comprises the most common site of progressive disease in pts with or without baseline BMs, which is a serious problem for crizotinib. Furthermore, alectinib can be used to achieve strong and long-lasting inhibitory effects on BM. In addition to alectinib, the IC efficacy of other next-generation ALK inhibitors, such as ceritinib, AP26113 and PF-06463922, has been demonstrated. In this article, we review the latest evidence regarding the BM and IC efficacy of ALK inhibitors in pts with ALK+ NSCLC.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes.

Topics: Adolescent; Adult; Age Factors; Antimetabolites, Antineoplastic; Attention; Benzhydryl Compounds; Brain Neoplasms; Central Nervous System Stimulants; Child; Child, Preschool; Cognitive Dysfunction; Comorbidity; Cranial Irradiation; Donepezil; Early Intervention, Educational; Education, Special; Head and Neck Neoplasms; Human Growth Hormone; Humans; Indans; Infant; Injections, Spinal; Memory, Short-Term; Methotrexate; Methylphenidate; Modafinil; Neoplasms; Neurosurgical Procedures; Nootropic Agents; Patient Education as Topic; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Psychomotor Performance; Quality of Life; Radiotherapy Dosage; Risk Factors; Severity of Illness Index; Sex Factors; Survivors; Thinking; Wakefulness-Promoting Agents; Young Adult

Topics: Animals; Biomarkers; Brain Neoplasms; Cholinesterase Inhibitors; Cognition Disorders; Cytokines; Donepezil; Humans; Hyperbaric Oxygenation; Indans; Magnetic Resonance Imaging; Neuropsychological Tests; Oxidative Stress; Piperidines; Radiosurgery; Radiotherapy; Radiotherapy, Conformal

Topics: Antineoplastic Agents; Benzamides; Brain Neoplasms; Drug Delivery Systems; Drug Design; Drug Resistance, Neoplasm; Drug Therapy, Combination; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Glioma; Humans; Imatinib Mesylate; Intracellular Signaling Peptides and Proteins; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Piperidines; Protein Kinases; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Anesthesia; Anesthetics, Intravenous; Brain Neoplasms; Conscious Sedation; Craniotomy; Female; Hemodynamics; Humans; Male; Monitoring, Intraoperative; Piperidines; Propofol; Remifentanil

Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non-small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups.. This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity.. 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7-53.0]. Patients aged <75 (n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7-60.0) and 39.7% (95% CI: 28.0-52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9-57.4) vs. 44.6% (33.7-55.9); median duration of response (95% CI): 10.8 (6.9-not estimable) vs. 11.1 (9.5-18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies.. Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations. See related commentary by Rosner and Spira, p. 1055.

Topics: Aged; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Exons; Humans; Lung Neoplasms; Piperidines; Pyridazines; Pyrimidines; Retrospective Studies

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

At the prior data cutoff (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p < 0.001). The median PFS in the alectinib arm was not reached versus 11.1 months with crizotinib. Retrospective analyses suggest that the echinoderm microtubule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cutoff December 1, 2017).. Patients were randomized to receive twice-daily alectinib, 600 mg, or crizotinib, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined by the investigators. Baseline plasma and tissue biomarker samples were analyzed by using hybrid-capture, next-generation sequencing to determine EML4-ALK variant.. Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectinib and 10.9 months with crizotinib. EML4-ALK fusions were detectable in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/ab did not affect PFS, objective response rate, or duration of response. Investigator-assessed PFS was longer for alectinib than for crizotinib across EML4-ALK variants 1, 2, and 3a/b in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectinib versus 10.8 months in the case of crizotinib), the safety of alectinib compared favorably with that of crizotinib.. Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.

Topics: Adolescent; Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Crizotinib; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Prognosis; Survival Rate; Young Adult

Despite improved progression-free survival, most patients treated with the first generation ALK inhibitor crizotinib ultimately experience central nervous system (CNS) progression. Brain metastases (BM) are associated with high clinical burden in patients with advanced anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). In this study we estimate the real-world economic burden of BM in newly diagnosed ALK+ NSCLC patients and investigate whether alectinib, a second generation ALK inhibitor that delays CNS progression, may help reduce healthcare costs in patients with ALK+ NSCLC.. Cost of BM was measured in ALK+ NSCLC patients identified from a stacked PharMetrics Plus and MarketScan claims database from January 2008 to March 2016 and December 2015, respectively. Per patient per month (PPPM) cost of BM was calculated as the difference in baseline-adjusted total costs in patients with and without BM over a variable follow-up period of up to 24 months. Cumulative incidence of new BM was derived from 88 alectinib-treated and 93 crizotinib-treated patients without baseline BM in a randomized phase III clinical trial, ALEX (NCT02075840). Costs of BM per patient were then calculated by applying the PPPM BM cost to the number of incident BM patients in each treatment cohort.. 207 patients with no BM and 198 with BM were selected from the claims database. Total cost of BM was estimated at $6,029 PPPM. 24-month cumulative incidence rates of BM from the clinical trial were 7.2% and 45.3% for alectinib and crizotinib, respectively. Over follow-up, alectinib was estimated to reduce BM-related costs by $41,434 per patient compared to crizotinib.. BM is associated with substantial economic burden. Alectinib was estimated to reduce BM-related costs by preventing or delaying the occurrence of BM compared to crizotinib.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cost of Illness; Crizotinib; Follow-Up Studies; Humans; Incidence; Lung Neoplasms; Neoplasm Metastasis; Piperidines; United States

Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations.. Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.. LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.. These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Topics: Adult; Brain Neoplasms; Carbazoles; Carcinoma, Neuroendocrine; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Piperidines; Proof of Concept Study; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Thyroid Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX.. Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression.. In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not.. Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy.. ClinicalTrials.gov NCT02075840.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Brain; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Crizotinib; Disease Progression; Female; Humans; Lung; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Treatment Outcome; Tumor Burden; Young Adult

Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib.. J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316).. Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17-0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3-not estimated) and was 10·2 months (8·2-12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group.. These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study.. Chugai Pharmaceutical Co, Ltd.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Neoplasm Grading; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Single-Blind Method

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; 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Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases.. In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials.. Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6-5.6) in the vandetanib group and 2.5 months (90% CI: 0.2-4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6-6.3) and 2.5 months (90% CI: 0.2-7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments.. The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Brain; Brain Neoplasms; Combined Modality Therapy; Disease-Free Survival; Double-Blind Method; Female; Humans; Male; Melanoma; Middle Aged; Piperidines; Quinazolines; Radiation-Sensitizing Agents; Radiotherapy

Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cohort Studies; Disease-Free Survival; Female; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Quinazolines; Sirolimus

Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function.. A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated.. Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment.. Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Cholinesterase Inhibitors; Cognition Disorders; Combined Modality Therapy; Donepezil; Double-Blind Method; Female; Humans; Indans; Learning; Male; Memory; Middle Aged; Neoplasm Metastasis; Neuropsychological Tests; Piperidines; Treatment Outcome; Young Adult

Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib.. We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028.. 47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent.. Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2.. Chugai Pharmaceuticals, F Hoffmann La-Roche.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gene Rearrangement; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Patient Selection; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Risk Assessment; Survival Analysis; Treatment Outcome

The aim of this study was to investigate clinical application of remifentanil in local anesthesia for resection of tumors in functional brain area.. Twenty-four patients were randomly divided into two groups: control group and remifentanil group. In remifentanil group remifentanil was infused intravenously with micro pump in 0.05-0.1 µg·kg-1·min-1. The hemodynamic changes and complications during operation were monitored.. The satisfactory degree for surgical procedure was evaluated. The surgery of two groups could be completed in a conscious state. Mean artery pressure (MAP), heart rate (HR) in remifentanil group during opening or closing skull or intra- cranial period were significantly lower than control group (p < 0.05). There were no conspicuous complications in two groups such as respiratory depression, nausea, vomitting and dysphoria. Satisfaction rate of remifentanyl group was significantly higher than control group (p < 0.05).. Awake brain tumor surgery could be completed in rational use of remifentanil on the base of good local anesthesia, and hemodynamics were stable and the patients were well tolerated.

Topics: Adult; Analgesics, Opioid; Anesthesia, Local; Anesthetics, Intravenous; Brain Neoplasms; Female; Glioma; Heart Rate; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Young Adult

To determine the maximum tolerated dose (MTD) of vandetanib with fractionated stereotactic radiosurgery (SRS) in patients with recurrent malignant gliomas.. Patients with a recurrent malignant glioma and T1-enhancing recurrent tumor ≤ 6 cm were eligible. Vandetanib was given orally, once per day, 7 days a week, starting at least 7 days before SRS and continued until a dose-limiting toxicity (DLT) or disease progression. The planned vandetanib daily dose was 100 mg, 200 mg, and 300 mg for the cohorts 1, 2, and 3, respectively, and was escalated using a standard 3+3 design. A total SRS dose of 36 Gy, 12 Gy per fraction, was delivered over 3 consecutive days. The MTD was defined as the dose of vandetanib at which less than 33% of patients developed DLTs, defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3 as any Grade 3 or greater nonhematologic toxicity and Grade 4 or greater hematologic toxicity.. Ten patients were treated, 6 on cohort 1 and 4 on cohort 2. Treatment characteristics were: 7 men, 3 women; median age, 40 years (range, 22-72); 7 GBM, 3 anaplastic astrocytoma (AA); median initial radiation (RT) dose, 60 Gy (range, 59.4-70); median interval since initial RT, 14.5 months (range, 7-123); All patients received SRS per protocol. The median follow-up time was 4 months (range, 1-10 months). Median time on vandetanib was 3 months (range 1-11). One of 6 patients in the first cohort developed a DLT of Grade 3 hemothorax while on anticoagulation. The MTD was reached when 2 of the 4 patients enrolled in the second cohort developed DLTs. Six patients had radiographic response, 2 with stable disease.. The MTD of vandetanib, with SRS in recurrent malignant glioma, is 100 mg daily. Further evaluation of safety and efficacy is warranted.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Camptothecin; Carboplatin; Cohort Studies; Combined Modality Therapy; Dacarbazine; Dexamethasone; Drug Administration Schedule; Female; Glioma; Glucocorticoids; Humans; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Prospective Studies; Quinazolines; Radiosurgery; Radiotherapy Dosage; Temozolomide; Tumor Burden; Vincristine; Young Adult

Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma.

Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Glioma; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Quinazolines; Young Adult

We conducted a phase I clinical trial of the combination of SCH 66336 with temozolomide administered on the standard 5-day dosing schedule. The primary objective was to determine the maximum tolerated dose and dose limiting toxicity (DLT) of twice daily SCH 66336 when administered with temozolomide to adults with malignant glioma previously treated with radiation therapy. Patients were enrolled to two strata: stratum A, patients not on enzyme-inducing antiepileptic drugs (EIAEDs); stratum B, patients receiving EIAEDs. Temozolomide was administered at a dose of 150 mg/m(2) daily for five days for the first 28-day cycle and escalated to 200 mg/m(2), during subsequent cycles. SCH 66336 was administered twice daily on a continuous daily dosing schedule. The starting dose of SCH 66336 was 75 mg twice daily for stratum A and 125 mg twice daily for stratum B. Cohorts of 3-6 patients were treated per dose level until DLT was observed. Thirty six patients were enrolled on study, including 21 patients on stratum A and 15 on stratum B. All DLTs were grade 3 events and included hepatic, gastrointestinal, renal, thrombotic and constitutional events. No grade 4 or 5 toxicities were observed. The phase II dose of SCH 66336 when combined with temozolomide is 150 mg twice daily for patients not on EIAEDs and 175 mg twice daily for patients on EIAEDs.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carotenoids; Dacarbazine; Disease-Free Survival; Drug Combinations; Enzyme Inhibitors; Fatty Acids, Unsaturated; Female; Glioma; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Grading; Piperidines; Pyridines; Temozolomide; Vitamin E

Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ).. A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard "3 + 3" dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of >or=60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs.. Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT.. Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Diverticulitis; Drug Administration Schedule; ErbB Receptors; Female; Gastrointestinal Hemorrhage; Glioblastoma; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neutropenia; Piperidines; Quinazolines; Temozolomide; Thrombocytopenia; Vascular Endothelial Growth Factor Receptor-2

Vandetanib is a once-daily oral agent that selectively inhibits vascular endothelial growth factor receptor, epidermal growth factor receptor, and RET (REarranged during Transfection) signaling.. This Phase I study investigated the safety, tolerability, and pharmacokinetics of vandetanib when administered with either gemcitabine plus cisplatin (GC) or vinorelbine plus cisplatin (VC) in patients with previously untreated locally advanced or metastatic non-small cell lung cancer.. Seventeen patients received vandetanib 100 mg/d plus VC (n = 9) or GC (n = 8). Three dose-limiting toxicities were reported in each treatment group: vandetanib + VC (pulmonary artery thrombosis and asymptomatic QTc prolongation [n = 2]); vandetanib + GC (peripheral ischemia [due to arterial occlusion], pulmonary embolism, and limb venous thrombosis). The protocol definition of a tolerable dose was not met, and no patients were recruited to receive vandetanib 300 mg plus VC or GC. There was no apparent pharmacokinetic interaction between vandetanib and vinorelbine or gemcitabine, but there was an approximate 30% increase in the exposure to cisplatin, which may be due to accumulation of total platinum and/or an interaction with vandetanib.. In this study, in patients with previously untreated advanced non-small cell lung cancer, vandetanib 100 mg/d in combination with either VC or GC was not tolerated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Deoxycytidine; Female; Gemcitabine; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Piperidines; Quinazolines; Survival Rate; Tissue Distribution; Treatment Outcome; Vinblastine; Vinorelbine

In neuroanesthesia practice, muscle relaxants may at times need to be avoided to facilitate intraoperative motor pathway monitoring. Our study's objective was to determine the optimal dose of remifentanil required to prevent movement after neurosurgical stimulation.. After Institutional Review Board approval and written informed consent, 132 patients undergoing elective craniotomy randomly received one of 12 remifentanil dose regimens (0.10 to 0.21 microg/kg/min). Remifentanil was started before induction with propofol and succinylcholine. Anesthesia was maintained with isoflurane (0.6% end-tidal) in air/oxygen. During the study, movement was assessed on predetermined criteria by the anesthesiology, nursing, and neurosurgical teams. Heart rate and blood pressure were recorded every 5 minutes. We assessed the relationship between movement, hypotension, bradycardia, and dose using probit analysis and logistic regression.. Sixty-five percent of the patients moved in response to surgical stimuli [95% confidence interval (CI): 49%-79%] at a remifentanil infusion rate of 0.10 microg/kg/min, and movement decreased to 21% (95% CI: 11-35) at 0.21 microg/kg/min. The probability of movement was 50% at an infusion rate (95% CI) of 0.13 (0.10 to 0.15) microg/kg/min remifentanil and decreased to 25% at an infusion rate of 0.19 (0.17 to 0.29) microg/kg/min. The probability of hypotension and bradycardia was 50% at 0.13 (0.10 to 0.15) microg/kg/min and 0.17 (0.15 to 0.21) microg/kg/min, respectively.. Higher doses of remifentanil lessen the risk of movement in the absence of muscle relaxants with surgical stimulation for elective craniotomy. Hypotension and bradycardia were common at higher doses. Even at the maximum dose (0.21 mcg/kg/min) there was a 20% chance of movement. Adjunctive therapy is needed to ablate movement reliably, and to counteract the hypotensive effect of remifentanil. These findings may be helpful for clinicians administering remifentanil and isoflurane during procedures, where muscle relaxants may not be desirable.

Topics: Adult; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Blood Pressure; Bradycardia; Brain Neoplasms; Craniotomy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Rate; Humans; Hypotension; Intraoperative Complications; Intraoperative Period; Intubation, Intratracheal; Isoflurane; Male; Middle Aged; Movement; Neuromuscular Blockade; Neurosurgical Procedures; Piperidines; Prospective Studies; Remifentanil

In this study we compared the effectiveness of the use of remifentanil to fentanyl in conjunction with propofol in providing conscious sedation for awake craniotomy for tumor surgery and to assess patient satisfaction with both techniques. The ability to maintain appropriate levels of sedation, adequate analgesia, and hemodynamic stability was assessed in 50 patients randomized to receive either fentanyl or remifentanil. All complications were documented. Patients were interviewed at 1 h, 4 h, and 24 h after surgery to note their recall of procedure and pain and their overall satisfaction. There were no differences in sedation and pain scores or in hemodynamic and respiratory variables between the two groups. The incidence of intraoperative complications was not different (fentanyl, 14; remifentanil, 16). Respiratory complications occurred in 9 (18%) patients (fentanyl 6, remifentanil 3). The recall and satisfaction scores were not different; 93% of all patients were completely satisfied at all interview times. The use of remifentanil infusion in conjunction with propofol is a good alternative to fentanyl and propofol for conscious sedation for the awake craniotomy and these techniques are both well accepted by the patient.

Topics: Adult; Aged; Brain Neoplasms; Craniotomy; Drug Therapy, Combination; Female; Fentanyl; Humans; Male; Middle Aged; Patient Satisfaction; Piperidines; Propofol; Remifentanil; Wakefulness

A prospective, open-label phase II study was conducted to determine whether donepezil, a US Food and Drug Administration-approved reversible acetylcholinesterase inhibitor used to treat mild to moderate Alzheimer's type dementia, improved cognitive functioning, mood, and quality of life (QOL) in irradiated brain tumor patients.. Thirty-four patients received donepezil 5 mg/d for 6 weeks, then 10 mg/d for 18 weeks, followed by a washout period of 6 weeks off drug. Outcomes were assessed at baseline, 12, 24 (end of treatment), and 30 weeks (end of wash-out). All tests were administered by a trained research nurse.. Of 35 patients who initiated the study, 24 patients (mean age, 45 years) remained on study for 24 weeks and completed all outcome assessments. All 24 patients had a primary brain tumor, mostly low-grade glioma. Scores significantly improved between baseline (pretreatment) and week 24 on measures of attention/concentration, verbal memory, and figural memory and a trend for verbal fluency (all P < .05). Confused mood also improved from baseline to 24 weeks (P = .004), with a trend for fatigue and anger (all P < .05). Health-related QOL improved significantly from baseline to 24 weeks, particularly, for brain specific concerns with a trend for improvement in emotional and social functioning (all P < .05).. Cognitive functioning, mood, and health-related QOL were significantly improved following a 24-week course of the acetylcholinesterase inhibitor donepezil. Toxicities were minimal. We are planning a double blinded, placebo-controlled, phase III trial of donepezil to confirm these favorable results.

Topics: Adult; Affect; Aged; Anger; Brain Neoplasms; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Fatigue; Female; Glioma; Humans; Indans; Male; Memory; Middle Aged; Piperidines; Prospective Studies; Quality of Life; Radiation Injuries

Total intravenous anaesthesia (TIVA) is increasingly used in diagnostic surgery such as stereotactic biopsy of the brain. TIVA could lead to a faster recovery of cerebral function, which may lead to a better behavior and advantages in the postoperative management. The aim of this prospective, single-blind study was to compare the hemodynamics, the postoperative recovery period, the side-effects and the need for additional cardiovascular medication during and after the operation between the three study groups.. After giving informed consent and approval by the ethical committee of our hospital, 51 patients (ASA I and II) undergoing stereotactic biopsy of a brain tumor were randomized to receive either propofol via the TCI-system (group 1: TCI-TIVA), propofol by a manual technique (group 2: MAN-TIVA) or methohexitone-sevoflurane (group 3: BAL-SEVO). Remifentanil was used as the analgetic component in all groups. Systolic and diastolic blood pressure, heart rate und transcutaneous oxygen saturation were noted before and after induction and before and after the end of anaesthesia. The time until return of complete orientation relative to person, location and time were measured. The patients' ranking of their satisfaction with the anaesthesia was questioned 60 min and 24 hours after the end of the procedure (VAS). Undesirable side-effects (i. e. PONV, shivering, pain, dysphoria, tiredness) were noted, whenever they occurred. The number of hemodynamic interventions by the anaesthesiologist was counted, and the total doses of remifentanil and propofol were quoted. Depth of anaesthesia was monitored by using a BIS-system, a range between 40 and 50 was thought to be adequate. Besides this, the total doses of remifentanil, propofol and sevoflurane were ruled out and the costs of the three regimens were ranked.. Heart rate dropped markedly in all groups with a maximum in the TIVA-collective. Systolic and diastolic pressure also fell in the groups. In the SEVO-group, the difference was statistically significant only at the end of anaesthesia. After extubation, the three groups reached their hemodynamic starting-point with a slight overshoot in the SEVO-group. The number of required hemodynamic interventions was two (TCI-TIVA) vs. 7 (MAN-TIVA) vs. 8 (BAL-SEVO) in each group, respectively. The difference scarcely failed to get significance. The remifentanil requirements were similar between the collectives, group 1 needed more propofol per time than group 2. The number of side-effects was very little after the different regimens. There were no differences with regard to the other measured parameters between the groups. The use of TCI-TIVA was more expensive than manual TIVA (18,85 euro vs. 12,50 euro). Surprisingly, balanced anaesthesia using Sevoflurane was the most expensive method during the first hour, mainly due to the use of methohexitone as the induction agent (23,90 euro).. Each of the three techniques compared in our study is suitable for anaesthesia in diagnostic neurosurgery. Since fast recovery of vigilance is important to justify the neurological outcome, none of the methods seems to be superior to the others. The hemodynamics were largely stable with a strong trend towards minor necessity for hemodynamic intervention in the TCI-TIVA group. This is also the best method from the subjective point of view of the anaesthesiologist due to the easy handling and the low number of interventions. The use of newer TCI-systems (e. g. fm-controller, Braun, Melsungen) not operating with special application syringes will cheapen TCI-TIVA.

Topics: Analgesics; Anesthesia, Intravenous; Anesthetics, Intravenous; Biopsy; Blood Pressure; Brain Neoplasms; Heart Rate; Hemodynamics; Humans; Methohexital; Methyl Ethers; Oxygen; Patient Satisfaction; Piperidines; Propofol; Remifentanil; Sevoflurane

Adequate analgesia and sedation with adequate respiratory and hemodynamic control are needed during brain surgery in awake patients. In this study, a protocol using clonidine premedication, intraoperative propofol, remifentanil, and labetalol was evaluated prospectively in 25 patients (aged 50 +/- 16). In all but one patient, no significant problems regarding cooperation, brain swelling, or loss of control were noticed, and it was not necessary to prematurely discontinue any of the procedures. One patient, who was uncooperative and hypertensive, became apneic with increasing sedation, and needed a laryngeal mask airway inserted. Patients were hemodynamically stable; elevated systolic blood pressure (>or= 150 mm Hg) was measured infrequently, and there were no events of significant hypotension, tachycardia, or bradycardia. Events of hypoxemia (SAO2

Topics: Analgesics, Opioid; Anesthesia, Intravenous; Anesthetics, Intravenous; Blood Pressure; Brain Mapping; Brain Neoplasms; Craniotomy; Electrocardiography; Female; Hemodynamics; Humans; Intraoperative Complications; Male; Middle Aged; Monitoring, Intraoperative; Oximetry; Piperidines; Propofol; Remifentanil; Respiratory Mechanics; Wakefulness

Central nervous system-penetrant therapies with intracranial efficacy against non-small cell lung cancer (NSCLC) brain metastases are urgently needed. We report preclinical studies investigating brain penetration and intracranial activity of the MET inhibitor tepotinib. After intravenous infusion of tepotinib in Wistar rats (n = 3), mean (±standard deviation) total tepotinib concentration was 2.87-fold higher in brain (505 ± 22 ng/g) than plasma (177 ± 20 ng/mL). In equilibrium dialysis experiments performed in triplicate, mean tepotinib unbound fraction was 0.35% at 0.3 and 3.0 µM tepotinib in rat brain tissue, and 4.0% at 0.3 and 1.0 µM tepotinib in rat plasma. The calculated unbound brain-to-plasma ratio was 0.25, indicating brain penetration sufficient for intracranial target inhibition. Of 20 screened subcutaneous patient-derived xenograft (PDX) models from lung cancer brain metastases (n = 1), two NSCLC brain metastases models (LU5349 and LU5406) were sensitive to the suboptimal dose of tepotinib of 30 mg/kg/qd (tumor volume change [%TV]: -12% and -88%, respectively). Molecular profiling (nCounter®; NanoString) revealed high-level MET amplification in both tumors (mean MET gene copy number: 11.2 and 24.2, respectively). Tepotinib sensitivity was confirmed for both subcutaneous models at a clinically relevant dose (125 mg/kg/qd; n = 5). LU5349 and LU5406 were orthotopically implanted into brains of mice and monitored by magnetic resonance imaging (MRI). Tepotinib 125 mg/kg/qd induced pronounced tumor regression, including complete or near-complete regressions, compared with vehicle in both orthotopic models (n = 10; median %TV: LU5349, -84%; LU5406, -63%). Intracranial antitumor activity of tepotinib did not appear to correlate with blood-brain barrier leakiness assessed in T1-weighted gadolinium contrast-enhanced MRI.

Topics: Animals; Brain; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Heterografts; Humans; Lung Neoplasms; Piperidines; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines; Rats; Rats, Wistar; Xenograft Model Antitumor Assays

Cobimetinib combined with vemurafenib was available in France in 2015 through a 'Temporary Authorization for Use' program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5-20.7). Brain metastasis ( P < 0.001), ECOG index ≥2 ( P = 0.007), and hepatic impairment ( P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2-8.4). ECOG index ≥2 ( P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Humans; Melanoma; Mice; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Stroke Volume; Vemurafenib; Ventricular Function, Left

This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non-small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1-5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0-1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Glioblastoma multiforme (GBM) cancer stem cells (GSCs) are one of the strongest contributing factors to treatment resistance in GBM. Identification of biomarkers capable of directly affecting these cells within the bulk tumor is a major challenge associated with the development of new targeting strategies. In this study, we focus on understanding the potential of the multifunctional extraordinaire survivin as a biomarker for GSCs. We analyzed the expression profiles of this gene using various publicly available datasets to understand its importance in stemness and other cancer processes. The findings from these studies were further validated using human GSCs isolated from a GBM cell line. In these GSCs, survivin was inhibited using the dietary phytochemical piperine (PIP) and the subsequent effects on stemness, cancer processes and Temozolomide were investigated. In silico analysis identified survivin to be one of the most significant differentially regulated gene in GSCs, in comparison to common stemness markers. Further validation studies on the isolated GSCs showed the importance of survivin in stemness, cancer progression and therapy resistance. Taken together, our study identifies survivin as a more consistent GSC marker and also suggests the possibility of using survivin inhibitors along with standard of care drugs for better therapeutic outcomes.

Topics: Alkaloids; Benzodioxoles; Brain Neoplasms; Cell Line, Tumor; Cytochrome P-450 Enzyme Inhibitors; Glioblastoma; Humans; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Survivin

Anaplastic lymphoma kinase ( ALK ) rearrangement defines a unique nonsmall cell lung cancer (NSCLC) molecular subtype, of which the patients could potentially benefit from anti- ALK therapies. So far, the outcomes of the canonical echinoderm microtubule-associated protein-like ( EML-ALK ) patients subjected to ALK inhibitors are well established. However, given the increasing complexity of ALK fusion partners, as detected by high-throughput sequencing, the responses of those with rare ALK fusion events remain to be explored. Here, we report a lung adenocarcinoma patient with brain metastasis harboring an ARHGAP5 downstream intergenic region ALK fusion, as detected by using DNA-based next-generation sequencing, who experienced a partial response to alectinib treatment. While whole- transcriptome RNA sequencing (RNA-seq) failed to identify potential ALK fusion transcripts, subsequent targeted deep RNA-seq revealed the expression of EML4-ALK transcripts in the tumor tissue. Given the increasing application of the ALK-tyrosine kinase inhibitors (TKIs), it is extremely crucial to define the patients who could be suitable for this treatment in clinic. The present case has provided supporting evidence that noncanonical ALK rearrangements on the genomic level are often functionally relevant and targetable by ALK-TKI, particularly in cases with sub-optimal quantity and quality for RNA validation.

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; DNA, Intergenic; Humans; Lung Neoplasms; Microtubule-Associated Proteins; Piperidines; Protein Kinase Inhibitors; RNA

In May 2020 and February 2021, capmatinib and tepotinib, respectively were approved by the Food and Drug Administration (FDA) for the treatment of metastatic non-small cell lung carcinoma harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. Herein, we present a case of intolerable peripheral edema caused by tepotinib, in which MET inhibitor could be continued by switching to capmatinib. Peripheral edema has been identified as one of the most common adverse events in capmatinib and tepotinib; however, there is no unified management for this adverse event. This is the first report that two MET inhibitors have different effects on the development of peripheral edema, and that the MET inhibitors can be continued by switching these drugs.

Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Agents; Benzamides; Brain Neoplasms; Edema; Extremities; Humans; Imidazoles; Lung Neoplasms; Male; Piperidines; Pyridazines; Pyrimidines; Triazines

Epithelial-to-mesenchymal transition (EMT) recapitulates metastasis and can be induced in vitro through transforming growth factor (TGF)-β signaling. A role for MMP activity in glioblastoma multiforme has been ascribed to EMT, but the molecular crosstalk between TGF-β signaling and membrane type 1 MMP (MT1-MMP) remains poorly understood. Here, the expression of common EMT biomarkers, induced through TGF-β and the MT1-MMP inducer concanavalin A (ConA), was explored using RNA-seq analysis and differential gene arrays in human U87 glioblastoma cells. TGF-β triggered SNAIL and fibronectin expressions in 2D-adherent and 3D-spheroid U87 glioblastoma cell models. Those inductions were antagonized by the TGF-β receptor kinase inhibitor galunisertib, the JAK/STAT inhibitors AG490 and tofacitinib, and by the diet-derived epigallocatechin gallate (EGCG). Transient gene silencing of MT1-MMP prevented the induction of SNAIL by ConA and abrogated TGF-β-induced cell chemotaxis. Moreover, ConA induced STAT3 and Src phosphorylation, suggesting these pathways to be involved in the MT1-MMP-mediated signaling axis that led to SNAIL induction. Our findings highlight a new signaling axis linking MT1-MMP to TGF-β-mediated EMT-like induction in glioblastoma cells, the process of which can be prevented by the diet-derived EGCG.

Topics: Brain Neoplasms; Catechin; Cell Line, Tumor; Concanavalin A; Epithelial-Mesenchymal Transition; Fibronectins; Glioblastoma; Humans; Matrix Metalloproteinase 14; Piperidines; Pyrazoles; Pyrimidines; Quinolines; Receptors, Transforming Growth Factor beta; Signal Transduction; Snail Family Transcription Factors; STAT3 Transcription Factor; Transforming Growth Factor beta1; Tyrphostins

Topics: Adult; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Radiosurgery; Treatment Outcome

Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial-mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis.

Topics: Aminopyridines; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Survival; Down-Regulation; Epithelial-Mesenchymal Transition; Humans; Lactams; Lung Neoplasms; Matrix Metalloproteinases; Piperidines; Pyrazoles; Tumor Cells, Cultured

Endometrial cancer (EC) is the second most common gynecologic malignancy in China, and the incidence and mortality rates have increased in recent years. Brain metastasis from EC is extremely rare, affecting only 0.3-1.16% of EC patients. The prognosis for patients with brain metastasis from EC is poor, with a median survival time of 3.5-6.5 months from the diagnosis of brain metastasis. Niraparib is a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (BRCA). Niraparib is recommended as a maintenance treatment for ovarian cancer patients with platinum-sensitive relapse and has been shown to increase progression-free survival. Niraparib was found to enter the brain via the blood-brain barrier, which resulted in a higher concentration of the drug in the brain tissues and better tumor-suppressing effects. There was none report about the applications of PARP inhibitor for endometrial cancer with brain metastases. Here, we present the case of a 62-year-old woman whose Peripheral blood gene detection had shown BRCA1 mutation with brain metastases from high-grade serous carcinoma of the endometrium who was successfully treated with Niraparib and remained free of disease progression for 6 months.

Topics: Brain Neoplasms; China; Endometrial Neoplasms; Female; Humans; Indazoles; Middle Aged; Piperidines

Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase-dependent/-independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM.

Topics: Administration, Oral; Anaplastic Lymphoma Kinase; Animals; Brain Neoplasms; Carbazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mice; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; STAT3 Transcription Factor; Sulfones; Temozolomide; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Ganglioglioma; Gene Fusion; Humans; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Vinculin

Topics: Animals; Brain Neoplasms; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Calcium-Binding Proteins; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Drug; Female; Glioblastoma; HeLa Cells; Humans; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; NFATC Transcription Factors; Piperidines; Urea; Xenograft Model Antitumor Assays

Cytoprotective agents are mainly used to protect the gastrointestinal tract linings and in the treatment of gastric ulcers. These agents are devoid of appreciable cytotoxic or cytostatic effects, and medicinal chemistry efforts to modify them into anticancer agents are rare. A drug repurposing campaign initiated in our laboratory with the primary focus of discovering brain cancer drugs resulted in drug-dye conjugate 1, a combination of the cytoprotective agent troxipide and heptamethine cyanine dye MHI 148. The drug-dye conjugate 1 was evaluated in three different patient-derived adult glioblastoma cell lines, commercially available U87 glioblastoma, and one paediatric glioblastoma cell line. In all cases, the conjugate 1 showed potent cytotoxic activity with nanomolar potency (EC

Topics: Antineoplastic Agents; Brain Neoplasms; Carbocyanines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Design; Drug Repositioning; Drug Therapy, Combination; Glioblastoma; Humans; Indoles; Molecular Structure; Piperidines; Temozolomide

Post-surgical management of low grade gangliogliomas is controversial with paucity of data for the use of chemotherapy. BRAF mutations are present in a number of glioma subtypes and offer an opportunity for treatment with targeted therapy.. A 32-year-old man with an unresectable, BRAF V600E mutant, WHO grade 1 ganglioglioma is commenced on combination BRAF and MEK inhibition (vemurafenib and cobimetinib). Partial radiological and clinical response was noted after 13 weeks of treatment. Treatment complication with grade 2 skin and liver toxicity was resolved with dose interruption and reduction.. Combination BRAF and MEK inhibition present a safe and feasible treatment strategy in unresectable BRAF V600E mutant low grade ganglioglioma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Ganglioglioma; Humans; Male; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

Since the first discovery of rearranged during transfection (RET) fusion in lung adenocarcinoma in 2011, two tyrosine kinase inhibitors, namely vandetanib and cabozantinib, are currently available. Despite favorable outcomes in systemic control, the intracranial therapeutic response remains insufficient. In this study, the clinical characteristics and outcomes of non-small cell lung cancer (NSCLC) patients with RET rearrangements were analyzed.. Patients with NSCLC harboring RET fusion who received treatment between January 2006 and January 2018 were analyzed. RET rearrangement was identified by FISH or NGS.. A total of 59 patients were identified. About half of the patients were female (47.5%) and never smokers (50.9%). Most patients had adenocarcinoma (89.8%). A total of 17 patients (28.8%) had an intracranial lesion at the initial diagnosis of stage IV disease, and 11 additional patients (18.6%) developed intracranial metastases during follow-up. The median time to development of intracranial metastases was 19.0 months (95% CI: 9.6-28.5), resulting in a >60% cumulative incidence of brain metastasis at 24 months. The systemic efficacy of pemetrexed-based regimens was favorable with progression-free survival of 9.0 (95% CI: 6.9-11.2) and OS of 24.1 (95% CI: 15.2-33.0) months. The median progression-free survival for vandetanib and immunotherapy was 2.9 (95% CI: 2.0-3.8) and 2.1 (95% CI: 1.6-2.6) months, respectively.. Given the likelihood of RET-rearranged NSCLC progressing to intracranial metastases and the absence of apparent clinical benefit of currently available targeted or immunotherapeutic agents, development of novel treatment with higher selectivity and better penetration of the blood-brain barrier remains a priority.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Gene Rearrangement; Genome, Human; Humans; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Piperidines; Proto-Oncogene Proteins c-ret; Quinazolines; Republic of Korea; Treatment Outcome

Anaplastic lymphoma kinase (ALK) rearranged metastatic non-small cell lung cancer (NSCLC) comprises 5%-7% of all lung cancer and carries a good prognosis with available ALK-inhibitors. Majority of registration trials in ALK-inhibitors did not include Indian patients. Hence, this study was planned to analyze the outcome of Indian patients treated with ALK-inhibitors and associated challenges.. This is a multi-center study in 5 major tertiary care cancer centers across India treating ALK-rearranged NSCLC patients from April 2013 to April 2019. ALK rearrangement was determined by Ventana immunohistochemistry with D5F3 clone and/or by break-apart FISH. Patients treated with ALK-inhibitors in any lines of treatment were included in this study. Patients were evaluated for clinicopathologic features, patterns of ALK-inhibitors use and outcome. Progression free-survival (PFS) and overall survival (OS) were calculated and data were censored on April 30, 2019.. A total of 274 patients were studied, out of which 250 patients received ALK inhibitor and were analyzed further for outcome. The median age was 50 years (range: 24-82) and male to female ratio of 1.17:1. ALK was evaluated by immunohistochemistry in majority of patients (97%), 3 patients by FISH and 3 more patients were evaluated by both methods. Sixty-five percent (n = 162) of the patients received ALK-inhibitor as first line therapy, 51 patients received ALK-inhibitor as switch maintenance therapy after initial chemotherapy. Crizotinib and Ceritinib were used in 88% and 12%, respectively. One patient received Alectinib. Forty-one percent of patients had CNS progression. After median follow up of 27 months (1-72 months), the median OS was 24.7 months with OS rate of 72%, 51%, and 18% at 1, 2, and 4-years respectively. Median OS was 21.2, 26, and 38 months in the first line ALK-inhibitors use (n = 162), switch maintenance group (n = 51) and second line ALK-inhibitors use (postchemotherapy progression) (n = 33), respectively. No baseline variable predicted PFS. Presence of brain metastasis (P = 0.039) and first line ALK-inhibitors use (P = 0.032) emerged as poor prognostic factor for OS on multivariate analysis. PFS rate was 70%, 47%, and 31% at 6, 12, and 18 months respectively.. This is one of the largest real-world data on outcome of ALK inhibitors in ALK-rearranged NSCLC from Asia. In absence of second line ALK inhibitor, initial chemotherapy followed by ALK-inhibitors (switch maintenance) had better outcome. This fact may be studied in individual patient data meta-analysis. Poor performance status and brain metastases at presentation are poor prognostic factors for overall survival. Second-line ALK inhibitor use crucial for better outcome and access to clinical trials are much needed in Indian patients.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Follow-Up Studies; Gene Rearrangement; Humans; India; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Pyrimidines; Retrospective Studies; Sulfones; Survival Rate; Young Adult

Topics: Adult; Age Factors; Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Comorbidity; Cost of Illness; Crizotinib; Female; Health Expenditures; Health Resources; Health Services; Humans; Insurance Claim Review; Lung Neoplasms; Male; Middle Aged; Patient Acceptance of Health Care; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Regression Analysis; Residence Characteristics; Retrospective Studies; Sex Factors; Socioeconomic Factors; Sulfones

Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand (

Topics: Animals; Autoradiography; Benzofurans; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Female; Fluorine Radioisotopes; Glioblastoma; Humans; Magnetic Resonance Imaging; Mice; Mice, Knockout; Mice, Nude; Molecular Imaging; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, sigma; Sigma-1 Receptor; Transplantation, Heterologous

Topics: Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Erythrocytes; Female; Hemolysis; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors

Cellular survival is dependent on the efficient replication and transmission of genomic information. DNA damage can be introduced into the genome by several different methods, one being the act of DNA replication. Replication is a potent source of DNA damage and genomic instability, especially through the formation of DNA double strand breaks (DSBs). DNA polymerase alpha is responsible for replication initiation. One subunit of the DNA polymerase alpha replication machinery is POLA2. Given the connection between replication and genomic instability, we decided to examine the role of POLA2 in DSB repair, as little is known about this topic. We found that loss of POLA2 leads to an increase in spontaneous DSB formation. Loss of POLA2 also slows DSB repair kinetics after treatment with etoposide and inhibits both of the major double strand break repair pathways: non-homologous end-joining and homologous recombination. In addition, loss of POLA2 leads to increased sensitivity to ionizing radiation and PARP1 inhibition. Lastly, POLA2 expression is elevated in glioblastoma multiforme tumors and correlates with poor overall patient survival. These data demonstrate a role for POLA2 in DSB repair and resistance to genotoxic stress.

Topics: Brain Neoplasms; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Damage; DNA Polymerase I; DNA Repair; Etoposide; Gene Expression Regulation, Neoplastic; Glioma; Humans; Indazoles; Piperidines; Radiation, Ionizing; Survival Analysis; Up-Regulation

Alterations in c-MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non-small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14-mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET-selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41-year-old woman with advanced NSCLC harboring an HLA-DRB1-MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. KEY POINTS: To our knowledge, this is the first report of a patient with non-small cell lung cancer harboring an HLA-DRB1-MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.

Topics: Adult; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Female; Gene Fusion; HLA-DRB1 Chains; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD

Topics: Acrylamides; Animals; Autophagy; B7-H1 Antigen; Brain Neoplasms; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Movement; Cyanides; Cytokines; Delayed-Action Preparations; Drug Carriers; Glioblastoma; Guanidines; Humans; Injections, Intralesional; Macrophages; Membrane Proteins; Mice; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines; Polymers; RNA, Messenger; Signal Transduction; Tumor Microenvironment; Up-Regulation

Anaplastic lymphoma kinase (ALK) rearrangement is identified in approximately 3-7% of all metastatic non-small cell lung cancer (NSCLC) patients, and ALK tyrosine kinase inhibitors (TKIs) have revolutionized the management of this subset of lung cancer cases.. This study aims to show alectinib (TKI) effectiveness and safety with focus on alectinib intracranial efficacy for ALK+ NSCLC patients.. Patient 1 was a 46-year-old woman diagnosed with non-small cell lung cancer with an echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (ALK+). She presented with intracranial and liver metastases and poor performance status of ECOG 3. Alectinib was initiated as a second line therapy, after whole brain irradiation and discontinuation of first line chemotherapy after two cycles, due to the central nervous system progression and liver metastases. Good response was consequently achieved, characterized with improved overall performance and without significant adverse events. Patient 2 was a 53-year old man with left sided lung adenocarcinoma surgically treated in 2017. Post-operative pTNM stage was IIB with a positive resection margin- R1. He received adjuvant chemotherapy and radiotherapy. In 2019, after two and half years of being disease free, he presented with severe cerebral symptoms leading to poor performance status. CT scan of the brain showed multiple brain metastases. He was treated with first line alectinib after completion of whole brain radiotherapy. In 5 months period he got significantly better and able for work again.. We recommend alectinib as a first and second line treatment approach for ALK+ NSCLC patients, in particular the ones with brain metastases at the time of diagnosis and poor PS.

Topics: Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) have transformed the standard of care in lung cancer. A number of TKIs have been discovered that specifically target oncogenes, including MET receptor tyrosine kinase. Second-generation MET TKIs are showing improved efficacy over first-generation TKIs. Herein, we report a case of a patient with metastatic lung adenocarcinoma harboring a

Topics: Adenocarcinoma of Lung; Aged; B7-H1 Antigen; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Class I Phosphatidylinositol 3-Kinases; Exons; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines

Ovarian cancer is the second the most common gynaecological malignancy in developed countries. 70% of patients relapse in the first 3 years following debulking surgery and first-line chemotherapy. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor which uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (

Topics: Aged; Brain Neoplasms; Cystadenocarcinoma, Serous; Disease-Free Survival; Female; Humans; Indazoles; Maintenance Chemotherapy; Neoplasm Grading; Ovarian Neoplasms; Piperidines; Treatment Outcome

Central nervous system (CNS) metastases represent a significant source of morbidity and mortality for patients with ALK tyrosine kinase gene (ALK)-positive NSCLC. Alectinib has demonstrated robust CNS activity in both crizotinib-naive and crizotinib-resistant settings. However, the CNS efficacy of alectinib has not been established in patients with untreated symptomatic, large CNS metastases.. In this retrospective study, patients were eligible if they had advanced ALK-positive NSCLC with large (defined as ≥1 cm) or symptomatic CNS metastases and received alectinib. Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1.. Of the 19 patients, 15 (79%) had measurable CNS disease at baseline and were evaluable for response. The CNS objective response rate in these patients was 73.3% (95% confidence interval [CI]: 44.9%-92.2%), the CNS disease control rate was 100.0% (95% CI: 78.2%-100.0%), and the median CNS duration of response was 19.3 months (95% CI: 14.3 months-not evaluable). In 18 evaluable patients with measurable and/or nonmeasurable baseline CNS disease, the CNS objective response rate was 72.2% (95% CI: 46.5%-90.3%), the CNS disease control rate was 100.0% (95% CI: 81.5%-100.0%), and the median CNS duration of response was 17.1 months (95% CI: 14.3 months-not evaluable). All eight patients with symptoms attributable to CNS metastases had clinical improvement upon starting alectinib therapy. Six patients (32%) eventually required salvage brain radiotherapy.. Alectinib demonstrated meaningful CNS efficacy in patients with ALK-positive NSCLC with untreated symptomatic or large brain metastases.

Topics: Adult; Aged; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Piperidines; Young Adult

Topics: Brain; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

Glioblastoma (GBM) is one of the major causes of brain cancer-related mortality worldwide. Temozolomide (TMZ) is an important agent against GBM. Acquired TMZ-resistance severely limits the chemotherapeutic effect and leads to poor GBM patient survival. To study the underlying mechanism of drug resistance, two TMZ resistant GBM cell lines, A172 and U87, were generated. In this study, the TMZ resistant cells have less apoptosis and cell-cycle change in response to the TMZ treatment. Western blot results revealed that cyclin E1 was upregulation in TMZ resistant cells. Inhibition or depletion of cyclin E1 re-sensitized the resistant cells to the TMZ treatment, which indicated the induction of cyclin E1 is the cause of TMZ resistance in GBM cells. Furthermore, we also found the expression of cyclin E1 stabilized the expression of Mcl-1, which contributes to the TMZ resistance in GBM cells. Finally, our in vivo xenograft data showed that the combination of flavopiridol, a cyclin E1/CDK2 inhibitor, overcomes the TMZ resistant by inducing higher apoptosis. Overall, our data provided a rationale to overcome the TMZ resistant in GBM treatment by inhibiting the cyclin E1 activity.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Brain Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin E; Drug Resistance, Neoplasm; Female; Flavonoids; Glioblastoma; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Transplantation; Oncogene Proteins; Piperidines; Protein Kinase Inhibitors; Temozolomide; Transplantation, Heterologous

There are limited effective drugs that can reach the brain to target brain tumors, in particular glioblastoma, which is one of the most difficult cancers to be cured from. Because the overexpression of the sigma-2 receptor is frequently reported in glioma clinical samples and associated with poor prognosis and malignancy, we herein studied the anti-tumor effect of the sigma-2 receptor agonist PB221 (4-cyclohexyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperidine) on an anaplastic astrocytoma tumor model based on previous encouraging results in pancreatic cancer and neuroblastoma SK-N-SH cells.. The expression of the sigma-2 receptor, transmembrane protein 97 (TMEM97), in ALTS1C1 and UN-KC6141 cell lines was measured by RT-PCR and quantitative RT-PCR. The binding of sigma-2 receptor fluorescent ligands PB385 (6-[5-[3-(4-cyclohexylpiperazin-1-yl)propyl]-5,6,7,8-tetrahydronaphthalen-5-yloxy]-N-(7-nitro-2,1,3-benzoxadiazol-4-yl)hexanamine) and NO1 (2-{6-[2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one-5-yloxy]hexyl}-5-(dimethylamino)isoindoline-1,3-dione) was examined by flow cytometry and the fluorescent plate reader. The antitumor activity of PB221 was initially examined in the murine brain tumor cell line ALTS1C1 and then in the murine pancreatic cell line UN-KC6141. The potential therapeutic efficacy of PB221 for murine brain tumors was examined by in vitro migration and invasion assays and in vivo ectopic and orthotopic ALTS1C1 tumor models.. The IC. This study demonstrates that the sigma-2 receptor agonist PB221 has the potential to be an alternative chemotherapeutic drug for brain tumors with comparable side effects as the current standard-of-care drug, temozolomide.

Topics: Animals; Astrocytoma; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Humans; Male; Membrane Proteins; Mice; Naphthalenes; Oxidative Stress; Piperidines; Tetrahydronaphthalenes; Xenograft Model Antitumor Assays

Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.

Topics: Animals; Apoptosis; Astrocytes; Biomarkers, Tumor; Brain; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Liberation; Glioma; Humans; Light; Liver; Male; Nanocapsules; Oxidative Stress; Piperidines; Polymers; Rats, Wistar; Thiazolidines; Thiobarbituric Acid Reactive Substances; Toxicity Tests; Weight Loss

Glioblastoma (GBM) is the most malignant primary brain tumor, with dismal median survival. Treatment of GBM is particularly challenging given the intrinsic resistance to chemotherapy and difficulty of drugs to reach the tumor beds due to the blood-brain barrier. Here, we examined the efficacy of SHP099, a potent, selective, and oral SHP-2 inhibitor for treating GBM with activated platelet derived growth factor receptor alpha (PDGFRα) signaling.. The effects of SHP099 on cell survival of neural progenitor cells (NPCs), GBM cell lines, and patient-derived glioma stem-like cells (GSCs) were evaluated. Brain and plasma pharmacokinetics of SHP099 and its ability to inhibit SHP-2 signaling were assessed. SHP099 efficacy as a single agent or in combination with temozolomide (TMZ) was assessed using transformed mouse astrocyte and GSC orthotopic xenograft models.. Activated PDGFRα signaling in established GBM cells, GSCs, and transformed mouse astrocytes was significantly inhibited by SHP099 compared with NPCs in vitro and in vivo through targeting SHP-2-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 in GBM. SHP099 treatment specifically inhibited expression of JUN, a downstream effector of PDGFR signaling, thereby attenuating cell cycle progression in GBM cells with activated PDGFRα. Moreover, SHP099 accumulated at efficacious concentrations in the brain and effectively inhibited orthotopic GBM tumor xenograft growth. SHP099 exhibited antitumor activity either as a single agent or in combination with TMZ and provided significant survival benefits for GBM tumor xenograft-bearing animals.. Our data demonstrate the utility and feasibility of SHP099 as a potential therapeutic option for improving the clinical treatment of GBM in combination with TMZ.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Proliferation; Female; Glioblastoma; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Piperidines; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Brain tumor has a low prognosis with only 15% survival rate (5 years after diagnosis). Many of the current therapeutics have limited activity due to their inability to cross the blood brain barrier which retards drug accumulation in tumor site and causes drug resistance. Piperine, a phytochemical drug with poor solubility, could be an alternative to current therapeutics after evading its solubility and permeability limitations. Piperine micellization was optimized to improve drug solubility. Positively charged trimethyl-chitosan was synthesized then electrostatically adsorbed onto piperine nanomicelles forming core-shell nanoparticles. Physicochemical and morphological characterizations, and in-vitro release were performed. Cytotoxicity on human brain cancer cell line (Hs683) was evaluated using IC50 determination, cell cycle arrest analysis, apoptosis and enzyme-linked immunosorbent assay. Optimum piperine-loaded core-shell nanoparticles were successfully fabricated with double-phase release model. Significant improvement in cytotoxicity than free drug was noted with increasing in G2/M-phase and pre-GI-phase population, apoptotic/necrotic rates and inhibition of CDK2a.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Benzodioxoles; Brain Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Chitosan; Drug Carriers; Drug Liberation; Humans; Inhibitory Concentration 50; Micelles; Nanoparticles; Piperidines; Polyunsaturated Alkamides; Solubility

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Drug Resistance, Neoplasm; Ganglioglioma; Humans; Male; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Disease Progression; Genetic Predisposition to Disease; Humans; Lung Neoplasms; Mutation; Phenotype; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Time Factors

Poly (ADP-ribose) polymerase (PARP) inhibitors are a relatively new class of anticancer agents that have attracted attention for treatment of glioblastoma because of their ability to potentiate temozolomide chemotherapy. Previous studies have demonstrated that sufficient brain penetration is a prerequisite for efficacy of PARP inhibitors in glioma mouse models. Unfortunately, however, most of the PARP inhibitors developed to date have a limited brain penetration due to the presence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) at the blood-brain barrier. AZD2461 is a novel PARP inhibitor that is unaffected by P-gp mediated resistance in breast cancer models and thus appears to have promising characteristics for brain penetration. We here use a comprehensive set of in vitro and in vivo models to study the brain penetration and oral bioavailability of AZD2461. We report that AZD2461 has a good membrane permeability. However, it is a substrate of P-gp and BCRP, and P-gp in particular limits its brain penetration in vivo. We show that AZD2461 has a low oral bioavailability, although it is not affected by P-gp and BCRP. Together, these findings are not in favor of further development of AZD2461 for treatment of glioblastoma.

Topics: Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Blood-Brain Barrier; Brain Neoplasms; Dogs; Drug Screening Assays, Antitumor; Glioblastoma; Madin Darby Canine Kidney Cells; Mice; Mice, Knockout; Neoplasm Proteins; Permeability; Phthalazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Glioblastomas (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutic options are urgently needed. A novel drug, Vacquinol-1 (Vac), a quinolone derivative, displays promising properties by inducing rapid cell death in GBM but not in non-transformed tissues. Features of this type of cell death are compatible with a process termed methuosis. Here we tested Vac on a highly malignant glioma cell line observed by long-term video microscopy. Human dental-pulp stem cells (DPSCs) served as controls. A major finding was that an exogenous ATP concentration of as little as 1 μM counter regulated the Vac-induced cell death. Studies using carvacrol, an inhibitor of transient receptor potential cation channel, subfamily M, member 7 (TRPM7), demonstrated that the ATP-inducible inhibitory effect is likely to be via TRPM7. Exogenous ATP is of relevance in GBM with large necrotic areas. Our results support the use of GBM cultures with different grades of malignancy to address their sensitivity to methuosis. The video-microscopy approach presented here allows decoding of signaling pathways as well as mechanisms of chemotherapeutic resistance by long-term observation. Before implementing Vac as a novel therapeutic drug in GBM, cells from each individual patient need to be assessed for their ATP sensitivity. In summary, the current investigation supports the concept of methuosis, described as non-apoptotic cell death and a promising approach for GBM treatment. Tissue-resident ATP/necrosis may interfere with this cell-death pathway but can be overcome by a natural compound, carvacrol that even penetrates the blood-brain barrier.

Topics: Adenosine Triphosphate; Brain Neoplasms; Caspase 3; Caspase 7; Cell Death; Cell Line, Tumor; Cymenes; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Monoterpenes; Piperidines; Protein Serine-Threonine Kinases; Quinolines; TRPM Cation Channels

Awake craniotomy allows continuous monitoring of patients' neurological functions during open surgery. Anesthesiologists have to sedate patients in a way so that they are compliant throughout the whole surgical procedure, nevertheless maintaining adequate analgesia and anxiolysis. Currently, the use of α2-receptor agonist dexmedetomidine as the primary hypnotic-sedative medication is increasing.. Nine patients undergoing awake craniotomy were treated with refined monitored anesthesia care (MAC) protocol consisting of a combination of local anesthesia without scalp block, low-dose infusion of dexmedetomidine, propofol, and remifentanil, without the need of airways management.. The anesthetic protocol applied in our study has the advantage of decreasing the dose of each drug and thus reducing the occurrence of side effects. All patients had smooth and rapid awakenings. The brain remained relaxed during the entire procedure.. In our experience, this protocol is safe and effective during awake brain surgery. Nevertheless, prospective randomized trials are necessary to confirm the optimal anesthetic technique to be used.

Topics: Adult; Anesthesia, Local; Anesthetics, Local; Brain Neoplasms; Craniotomy; Dexmedetomidine; Female; Glioma; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Retrospective Studies; Wakefulness

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Demyelinating Diseases; Female; Guillain-Barre Syndrome; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Piperidines; Polyradiculoneuropathy; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Animals; Aspergillosis; Brain Neoplasms; CD79 Antigens; Drug Therapy, Combination; Enzyme Inhibitors; Female; Gene Knockout Techniques; Humans; Lymphoma; Male; Mice; Mice, Knockout; Middle Aged; Myeloid Differentiation Factor 88; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction

The awake brain surgery is an innovative approach in the treatment of tumors in the functional areas of the brain. There are various anesthetic techniques for awake craniotomy (AC), including asleep-awake-asleep technique, monitored anesthesia care, and the recent introduced awake-awake-awake method. We describe our first experience with anesthetic management for awake craniotomy, which was a combination of these techniques with scalp nerve block, and propofol/rémifentanil target controlled infusion. A 28-year-oldmale underwent an awake craniotomy for brain glioma resection. The scalp nerve block was performed and a low sedative state was maintained until removal of bone flap. During brain glioma resection, the patient awake state was maintained without any complications. Once, the tumorectomy was completed, the level of anesthesia was deepened and a laryngeal mask airway was inserted. A well psychological preparation, a reasonable choice of anesthetic techniques and agents, and continuous team communication were some of the key challenges for successful outcome in our patient.

Topics: Adult; Anesthetics; Brain Neoplasms; Craniotomy; Glioma; Hospitals, Military; Humans; Laryngeal Masks; Male; Morocco; Nerve Block; Piperidines; Remifentanil; Wakefulness

Malignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted therapeutics for glioma is urgently needed.. In this study, we examined the prognostic significance BTK expression in patients with glioma. Furthermore, we investigated the mechanism and therapeutic potential of ibrutinib in the treatment of human glioma in vitro and in vivo.. Our data demonstrate that high expression of BTK is a novel prognostic marker for poor survival in patients with glioma. BTK-specific inhibitor ibrutinib effectively inhibits the proliferation, migration and invasion ability of glioma cells. Furthermore, ibrutinib can induce G1 cell-cycle arrest by regulating multiple cell cycle-associated proteins. More importantly, we found that BTK inhibition significantly blocks the degradation of IκBα and prevents the nuclear accumulation of NF-κB p65 subunit induced by EGF in glioma cells.. Taken together, our study suggests that BTK is a novel prognostic marker and molecular therapeutic target for glioma. BTK is required for EGFR-induced NF-κB activation in glioma cells. These findings provide the basis for future clinical studies of ibrutinib for the treatment of glioma.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mice; Neoplasm Transplantation; NF-kappa B; Piperidines; Prognosis; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Survival Analysis; Transcriptional Activation; Up-Regulation

The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma (GBM). Disrupting the BTB is therefore highly desirable but complicated by the need to maintain the normal blood-brain barrier (BBB). Here we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupted the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing the chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly improve treatment of brain tumors.

Topics: Adenine; Animals; Blood-Brain Barrier; Brain Neoplasms; Capillary Permeability; Glioma; Humans; Mice; Neoplastic Stem Cells; Pericytes; Piperidines; Prognosis; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Survival Analysis; Tight Junctions; Treatment Outcome

Glioblastoma is the most malignant primary brain tumor, with a median survival of less than 2 years. More effective therapeutic approaches are needed to improve clinical outcomes.. Glioblastoma patient-derived cells (GPDC) were isolated from patient glioblastomas and implanted in mice to form xenografts. IHC was performed for human Ether-à-go-go-Related Gene (hERG) expression and tumor proliferation. Sphere-forming assays with the hERG blocker E-4031 were performed on a high and low hERG-expressing lines. A glioblastoma tissue microarray (TMA; 115 patients) was used to correlate hERG expression with patient survival. Clinical data were analyzed to determine whether patient survival was affected by incidental administration of hERG inhibitory drugs and the correlative effect of patient glioblastoma hERG expression levels.. hERG expression was upregulated in glioblastoma xenografts with higher proliferative indices. High hERG-expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared with low hERG-expressing GPDCs. Glioblastoma TMA analysis showed worse survival for glioblastoma patients with high hERG expression versus low expression-43.5 weeks versus 60.9 weeks, respectively (P = 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared with patients who did not (P = 0.0015). Subgroup analysis showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival (P = 0.0458). There was no difference in survival for low hERG-expressing glioblastoma patients who received hERG blockers (P = 0.4136).. Our findings suggest that hERG is a potential glioblastoma survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be repurposed as adjuvant glioblastoma therapy in high hERG-expressing glioblastoma patients. Clin Cancer Res; 23(1); 73-80. ©2016 AACRSee related commentary by Arcangeli and Becchetti, p. 3.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Proliferation; Disease Models, Animal; Ether-A-Go-Go Potassium Channels; Gene Expression; Glioblastoma; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Mice; Molecular Targeted Therapy; Piperidines; Pyridines; Spheroids, Cellular; Tissue Array Analysis; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

We describe a 71-year-old-patient receiving antiplatelet therapy and being attended by emergency medical services for psychomotor retardation and gait disturbance. An emergency computed tomographic scan showed a bilateral subacute hematoma. The patient reported a fall 2 weeks earlier. We performed bilateral drills and saw a solid mass that was biopsied. The patient had a history of mantle cell lymphoma (MCL) in complete remission (results of bone marrow biopsy and whole-body positron emission tomography-computed tomography scans were normal 6 months earlier). We diagnosed an intracranial MCL by immunohistochemistry, flow cytometry, and fluorescence in situ hybridization. We performed magnetic resonance imaging. The results of a new bone marrow biopsy were positive for recurrence of MCL. MCL constitutes approximately 5%-6% of non-Hodgkin lymphoma. The incidence of central nervous system (CNS) involvement between MCLs is 4.1%. After a review of the literatures we found small series comprising 3-5 cases and a multicenter study with 57 cases. Until now, the median survival was 3.7 months. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, has demonstrated efficacy and CNS penetration in relapsed or refractory MCL with rapid and complete response even after 1 year of follow-up. Our patient received ibrutinib and had a complete response at 3 months, which was maintained to the present (6 months). After a review of the literature, we found different pathologies that can mimic subdural hematomas. However, this is the first report of a lymphoma with CNS involvement mimicking bilateral subdural hematomas. This report contributes to the knowledge of lymphomas with CNS involvement. Its strange radiographic appearance and histologic type make it unique.

Topics: Adenine; Aged; Antineoplastic Agents; Brain Neoplasms; Diagnosis, Differential; Hematoma, Subdural; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Piperidines; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed

The invasive and lethal nature of Glioblastoma multiforme (GBM) necessitates the continuous identification of molecular targets and search of efficacious therapies to inhibit GBM growth. The GBM resistance to chemotherapy and radiation it is attributed to the existence of a rare fraction of cancer stem cells (CSC) that we have identified within the tumor core and in peritumor tissue of GBM. Since Notch1 pathway is a potential therapeutic target in brain cancer, earlier we highlighted that pharmacological inhibition of Notch1 signalling by γ-secretase inhibitor-X (GSI-X), reduced cell growth of some c-CSC than to their respective p-CSC, but produced negligible effects on cell cycle distribution, apoptosis and cell invasion. In the current study, we assessed the effects of Hes1-targeted shRNA, a Notch1 gene target, specifically on GBM CSC refractory to GSI-X. Depletion of Hes1 protein induces major changes in cell morphology, cell growth rate and in the invasive ability of shHes1-CSC in response to growth factor EGF. shHes1-CSC show a decrease of the stemness marker Nestin concurrently to a marked increase of neuronal marker MAP2 compared to pLKO.1-CSC. Those effects correlated with repression of EGFR protein and modulation of Stat3 phosphorylation at Y705 and S727 residues. In the last decade Stat3 has gained attention as therapeutic target in cancer but there is not yet any approved Stat3-based glioma therapy. Herein, we report that exposure to a Stat3/5 inhibitor, induced apoptosis either in shHes1-CSC or control cells. Taken together, Hes1 seems to be a favorable target but not sufficient itself to target GBM efficaciously, therefore a possible pharmacological intervention should provide for the use of anti-Stat3/5 drugs either alone or in combination regimen.

Topics: Apoptosis; Benzimidazoles; Brain Neoplasms; Carbamates; Cell Differentiation; Cell Proliferation; Dipeptides; ErbB Receptors; Glioblastoma; Humans; Microtubule-Associated Proteins; Neoplasm Invasiveness; Neoplastic Stem Cells; Phosphorylation; Piperidines; Receptor, Notch1; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; STAT5 Transcription Factor; Transcription Factor HES-1; Tumor Suppressor Proteins

We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis.. A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling.. Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001).. Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cranial Irradiation; Crizotinib; Disease-Free Survival; Female; Follow-Up Studies; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Karnofsky Performance Status; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Piperidines; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Radiosurgery; Receptor Protein-Tyrosine Kinases; Risk Assessment; Risk Factors; Smoking; Sulfones

Cognitive dysfunction is prevalent among brain tumor patients treated with radiotherapy (RT) and chemotherapy. However, there are no approved pharmacological interventions for cognitive dysfunction in cancer patients. The goal of this pilot study was to examine the efficacy of donepezil, an acetylcholinesterase inhibitor used to treat Alzheimer's disease, in improving cognitive functions in brain tumor patients previously treated with RT + chemotherapy or chemotherapy alone. Fifteen patients with a brain tumor received a single daily dose of donepezil for 24 weeks (5 mg for 4 weeks, then 10 mg for 20 weeks). Patients completed cognitive evaluations prior to initiating therapy (baseline), and about 12 weeks (mid-study) and 24 weeks (end-of-study) subsequent to initiation of donepezil therapy. The results of linear mixed models analysis, controlling for each patient's baseline cognitive test score, showed a significant post-baseline improvement in attention (WAIS-III digit span forward; p = 0.037), graphomotor speed (WAIS-III digit symbol; p = 0.035) and visual memory (BVMT-R-delay; p = 0.025). There was also an improvement in self-reported quality of life (FACT-Br, social well-being subscale; p = 0.01). The findings of this pilot study suggest that treatment with donepezil may improve some aspects of cognitive functions and quality of life in brain tumor patients. Similar findings were reported in two prior trials of donepezil in brain tumor survivors.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Cholinesterase Inhibitors; Cognition; Cognition Disorders; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Neoplasm Staging; Neuropsychological Tests; Pilot Projects; Piperidines; Prognosis; Survival Rate; Survivors

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis.

Topics: Adult; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Brain; Brain Neoplasms; Carbazoles; Crizotinib; Disease Progression; Humans; Lung Neoplasms; Male; Middle Aged; Necrosis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiation Injuries; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer. Bioinformatics data indicates that Btk is significantly higher in clinical glioma samples as compared to normal brain cells and Btk expression level is associated with stage progression. This prompts us to investigate the potential role of Btk as a therapeutic target for glioma. Here, we demonstrate Btk expression is associated with GBM tumorigenesis. Down-regulation of Btk in GBM cell lines showed a significantly reduced abilities in colony formation, migration and GBM sphere-forming potential. Mechanistically, Btk-silenced cells showed a concomitant reduction in the expression of CD133 and Akt/mTOR signaling. In parallel, Ibrutinib (a Btk inhibitor) treatment led to a similar anti-tumorigenic response. Using xenograft mouse model, tumorigenesis was significantly reduced in Btk-silenced or ibrutinib-treated mice as compared to control counterparts. Finally, our glioma tissue microarray analysis indicated a higher Btk staining in the malignant tumors than less malignant and normal brain tissues. Collectively, Btk may represent a novel therapeutic target for glioma and ibrunitib may be used as an adjuvant treatment for malignant GBM.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Animals; Brain Neoplasms; Cell Line, Tumor; Female; Glioma; Humans; Male; Mice; Middle Aged; Neoplastic Stem Cells; Phenotype; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Death; Cell Line, Tumor; Glioblastoma; Humans; Mice; Models, Molecular; Piperidines; Quinolines; Stereoisomerism; Zebrafish

The aims of this paper were to elucidate the difference in concentration among remifentanil blood, cerebrospinal fluid and cerebral extracellular fluid levels, and to verify the presumable existence of a correlation between arterial and cerebral remifentanil. We used brain microdialysis to shed light on this aspect of the pharmacokinetic and to correlate these findings with Minto's model.. The study population was formed by 9 patients scheduled for elective intracranial surgery for cerebral supratentorial neoplasia. All patients received general anaesthetic; 100 microliters of dialysate were collected. Furthermore, arterial blood samples of 3 mL each were collected, respectively one at the beginning and one at the end of the sampling period. We determined the concentration of remifentanil and its main metabolite, remifentanil acid, in the blood and in the brain. The predictive performance of the Minto pharmacokinetic parameter set was evaluated by examining the performance error.. The mean Performance Error was -45.13% (min -21.80, max -88.75) for the first series of arterial samples, -38.29% (min -6.57, max -79.17) for the second one and 67.73% (min 7, max -93.12) for the extra cellular fluid sample. The concentration of remifentanil set pumps was correlated with blood concentration for both series of samples. Neither the set concentration, nor the arterial samples were correlated with extra cellular fluid values.. There was a wide interindividual variability with regard both to blood and cerebral remifentanil concentration. Moreover, the ratio between arterial blood and cerebral remifentanil was not consistent among our patients in spite of a stable infusion rate of remifentanil; at the end we found a trend of over prediction in the ratio between the various compartments examined.

Topics: Adult; Anesthesia, Intravenous; Anesthetics, Intravenous; Brain Neoplasms; Extracellular Fluid; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neurosurgical Procedures; Piperidines; Predictive Value of Tests; Remifentanil

We report the case of an aborted awake craniotomy for a left frontotemporoinsular glioma due to ammonia encephalopathy on a patient taking Levetiracetam, valproic acid and clobazam. This awake mapping surgery was scheduled as a second-stage procedure following partial resection eight days earlier under general anesthesia. We planned to perform the surgery with local anesthesia and sedation with remifentanil and propofol. After removal of the bone flap all sedation was stopped and we noticed slow mentation and excessive drowsiness prompting us to stop and control the airway and proceed with general anesthesia. There were no post-operative complications but the patient continued to exhibit bradypsychia and hand tremor. His ammonia level was found to be elevated and was treated with an infusion of l-carnitine after discontinuation of the valproic acid with vast improvement. Ammonia encephalopathy should be considered in patients treated with valproic acid and mental status changes who require an awake craniotomy with patient collaboration.

Topics: Anesthesia, General; Anesthesia, Local; Anticonvulsants; Aphasia; Benzodiazepines; Brain Diseases; Brain Mapping; Brain Neoplasms; Carnitine; Clobazam; Conscious Sedation; Consciousness Disorders; Craniotomy; Dominance, Cerebral; Frontal Lobe; Glioma; Humans; Hyperammonemia; Hypnotics and Sedatives; Intraoperative Complications; Language; Levetiracetam; Male; Middle Aged; Piperidines; Piracetam; Propofol; Remifentanil; Seizures; Temporal Lobe; Valproic Acid

Crizotinib is a potent and specific small-molecule inhibitor of both anaplastic lymphoma kinase (ALK) and c-MET tyrosine kinases, and patients with ALK rearrangement tumor benefit from crizotinib treatment; however, its penetration into calculated cerebrospinal fluid (CSF) is considered to be poor. Alectinib is a highly selective, next-generation ALK inhibitor, and both preclinical and clinical studies have indicated that alectinib is also effective in crizotinib-resistant tumors. A recent in vitro study demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALK-positive non-small-cell lung cancer. In this paper, we report a first case alectinib was highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable.

Topics: Antineoplastic Agents; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Pyrazoles; Pyridines

EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Bone Neoplasms; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Crizotinib; Female; Humans; Lung Neoplasms; Male; Mice; Mice, SCID; Microtubule-Associated Proteins; Oncogene Proteins, Fusion; Piperidines; Pleural Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiography; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases

The failure of standard treatment for patients diagnosed with glioblastoma (GBM) coupled with the highly vascularized nature of this solid tumor has led to the consideration of agents targeting VEGF or VEGFRs, as alternative therapeutic strategies for this disease. Despite modest achievements in survival obtained with such treatments, failure to maintain an enduring survival benefit and more invasive relapsing tumors are evident. Our study suggests a potential mechanism by which anti-VEGF/VEGFR therapies regulate the enhanced invasive phenotype through a pathway that involves TGFβR and CXCR4. VEGFR signaling inhibitors (Cediranib and Vandetanib) elevated the expression of CXCR4 in VEGFR-expressing GBM cell lines and tumors, and enhanced the in vitro migration of these lines toward CXCL12. The combination of VEGFR inhibitor and CXCR4 antagonist provided a greater survival benefit to tumor-bearing animals. The upregulation of CXCR4 by VEGFR inhibitors was dependent on TGFβ/TGFβR, but not HGF/MET, signaling activity, suggesting a mechanism of crosstalk among VEGF/VEGFR, TGFβ/TGFβR, and CXCL12/CXCR4 pathways in the malignant phenotype of recurrent tumors after anti-VEGF/VEGFR therapies. Thus, the combination of VEGFR, CXCR4, and TGFβR inhibitors could provide an alternative strategy to halt GBM progression.

Topics: Adult; Aged; Angiogenesis Inhibitors; Animals; Benzylamines; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cyclams; Female; Glioblastoma; Heterocyclic Compounds; Humans; Interleukin-2 Receptor alpha Subunit; Male; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Neoplasm Invasiveness; Piperidines; Protein Kinase Inhibitors; Quinazolines; Receptor Cross-Talk; Receptors, CXCR4; Receptors, Transforming Growth Factor beta; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Time Factors; Up-Regulation; Xenograft Model Antitumor Assays

Kinesin spindle protein (KSP) is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, as well as centrosome separation and maturation. Inhibition of KSP has the potential to provide anti-tumor activity while avoiding peripheral neuropathy associated with some microtubule-targeted drugs. Based on MK-0731 and related heterocyclic compounds targeting the KSP monastrol binding site, structurally constrained spiro-cyclic KSP inhibitors were designed. In particular, rapid evaluation and optimization of the novel spiro 1,3,4-thiadiazolines resulted in a series of potent KSP inhibitors demonstrating mechanism based activities in cells, including induction of the mitotic marker phospho-histone H3 and induction of monaster spindle formation. Further optimization of the pharmacokinetic (PK) properties afforded MK-8267 as a potent, orally bioavailable and brain penetrant KSP inhibitor which showed anti-tumor activity in preclinical xenograft models.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biomarkers; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Dogs; Drug Discovery; HCT116 Cells; Histones; Humans; Kinesins; Male; Mice; Permeability; Piperidines; Pyrimidines; Pyrroles; Rats; Spiro Compounds; Thiadiazoles; Thiones; Tubulin Modulators; Xenograft Model Antitumor Assays

Topics: Brain Neoplasms; Cognition Disorders; Female; Humans; Indans; Male; Piperidines

In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Everolimus; Female; Gene Amplification; Gene Rearrangement; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Neuroimaging; Oncogene Proteins, Fusion; Piperidines; Proto-Oncogene Proteins c-akt; Quinazolines

Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas. Functional studies, using U251MG glioma cells and primary tumor cell lines derived from glioma patients expressing different levels of CB1, highlighted SR141716 efficacy in inducing apoptosis via G1 phase stasis and block of TGF-β1 secretion through a mechanism that involves STAT3 inhibition. According to the multivariate role of STAT3 in the immune escape too, interestingly SR141716 lead also to the functional and selective expression of MICA/B on the surface of responsive malignant glioma cells, but not on NHA. This makes SR141716 treated-glioma cells potent targets for allogeneic NK cell-mediated recognition through a NKG2D restricted mechanism, thus priming them for NK cell antitumor reactivity. These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.

Topics: Animals; Antineoplastic Agents; Apoptosis; Astrocytes; Brain Neoplasms; Cell Line, Tumor; G1 Phase Cell Cycle Checkpoints; Glioma; Histocompatibility Antigens Class I; Humans; Killer Cells, Natural; Mice; Mice, Nude; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA Interference; RNA, Small Interfering; STAT3 Transcription Factor; Transforming Growth Factor beta1; Xenograft Model Antitumor Assays

Topics: Brain Neoplasms; Cognition Disorders; Female; Humans; Indans; Male; Piperidines

Topics: Brain Neoplasms; Cognition Disorders; Female; Humans; Indans; Male; Piperidines

Malignant melanoma in the gastrointestinal tract may be primary or metastatic. Mucosal melanoma is a quite rare and aggressive disease, growing hidden and diagnosed with a certain delay which makes treatment difficult.. The authors present the first patient with c-kit exon 11 mutated primary esophageal melanoma treated with oral tyrosine kinase inhibitor masitinib. A 55-year-old-man presented with esophageal melanoma metastising into visceral organs and to the brain. The patient showed objective and clinical significant therapeutic response to masitinib. After initiation of masitinib, dysphagia and odynophagia disappeared within 1 week. Following 1 month of treatment, computed tomography showed a regression in the number and size of brain metastatic lesions and regression in visceral lesions. This therapeutic response, despite the aggressive disease on treatment initiation, effectively enabled the patient to have 6 months of quality life.. This report corroborates the plausibility of treating advanced melanoma carrying a mutation of KIT with masitinib. It also raises the question of masitinib treatment beyond progression. Additionally, the observed masitinib treatment effect on the brain suggests accumulation of therapeutically relevant concentration of masitinib in the central nervous system. This observation has possible ramifications for treatment of intracranial neoplasms.

Topics: Benzamides; Brain Neoplasms; Esophageal Neoplasms; Exons; Fatal Outcome; Humans; Male; Melanoma; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Thiazoles

Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity relationship and analogs with increased potency, termed Vacquinols. Vacquinols stimulate death by membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture of GCs. The MAP kinase MKK4, identified by a shRNA screen, represents a critical signaling node. Vacquinol-1 displays excellent in vivo pharmacokinetics and brain exposure, attenuates disease progression, and prolongs survival in a GBM animal model. These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.

Topics: Animals; Brain Neoplasms; Cell Death; Glioblastoma; Heterografts; Humans; Hydroxyquinolines; MAP Kinase Kinase 4; Mice; Neoplasm Transplantation; Pinocytosis; Piperidines; Quinolines; Small Molecule Libraries; Vacuoles; Zebrafish

Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds (CPA-7 [trichloronitritodiammineplatinum(IV)], WP1066 [(S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, C17H14BrN3O], and ML116 [4-benzyl-1-{thieno[2,3-d]pyrimidin-4-yl}piperidine, C18H19N3S]) in cultured rodent and human glioma cells, including GBM cancer stem cells. Our results demonstrate a potent induction of growth arrest in GBM cells after drug treatment with a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor κ light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7-derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Chlorine Compounds; Drug Screening Assays, Antitumor; Glioma; HEK293 Cells; Heterocyclic Compounds, 2-Ring; Humans; Melanoma, Experimental; Mice; Piperidines; Platinum Compounds; Pyridines; Small Molecule Libraries; STAT3 Transcription Factor; Tissue Distribution; Tyrphostins

Attempts to treat cancer with drugs that target mutated proteins have met with mixed success. By screening for compounds that alter the phenotype of glioblastoma cells-an aggressive brain tumor-Kitambi et al. identify a potential new treatment of the disease and shed light on an unusual cell death mechanism.

Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Piperidines; Quinolines; Small Molecule Libraries

Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Piperidines; Quinolines; Small Molecule Libraries

In a recent Cell paper, Kitambi and colleagues identify a small molecule (Vacquinol-1) that has beneficial effects on a glioblastoma multiforme mouse model by oral administration. In glioblastoma cells, Vacquinol-1 targets macropinocytosis, a cellular process that will not lead to cell death in normal cells.

Topics: Animals; Brain Neoplasms; Glioblastoma; Humans; Piperidines; Quinolines; Small Molecule Libraries

Topics: Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Piperidines

Several previous reports have established the Pentax Airwayscope (Pentax AWS, S-100, HOYA-PENTAX, Tokyo, Japan) as an efficient tool for tracheal intubation in adult patients. The Pentax AWS is often successfully used with an INTLOCK blade; to date, however, INTLOCK blades have been released for neonatal and pediatric patients only. In this case, we performed tracheal intubation using a Pentax AWS attached to a pediatric-type INTLOCK blade (ITL-P) in an adult patient fitted with a Leksell Stereotactic frame (Elekta, Sweden). The patient weighed 45 kg and was 154 cm tall, and was scheduled for a tumor biopsy due to glioblastoma in the brain stem. The patient was preoperatively fitted with a Leksell frame on her head. The patient was not premedicated and was monitored with electrocardiography (ECG), noninvasive blood pressure, and pulse oximetry. Following pre-oxygenation, general anesthesia was induced using propofol 4.0 microg x ml with target-controlled infusion and remifentanil 0.25 microg x kg(-1) hr(-1). After loss of consciousness, we administered 30-mg rocuronium boluses. We initially attempted tracheal intubation first using a Macintosh laryngoscope and then a Pentax AWS, but we could not achieve tracheal intubation with either of these instruments. Upon switching to a Pentax AWS with an ITL-P, we successfully achieved tracheal intubation without any complications. Anesthesia was maintained uneventfully with 3.0 microg x ml(-1) propofol and remifentanil 0.10 to 0.25 microg x kg(-1) x hr(-1) in oxygen and air. Further study is needed to facilitate the effective use of the Pentax AWS and the ITL-P in such cases.

Topics: Adult; Anesthesia, General; Brain Neoplasms; Brain Stem; Female; Glioblastoma; Humans; Intubation, Intratracheal; Laryngoscopes; Piperidines; Propofol; Remifentanil

The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors.. We established intracranial tumor implantation mouse models of EML4-ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of (14)C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell.. Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration.. We established intracranial tumor implantation models of EML4-ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.

Topics: Anaplastic Lymphoma Kinase; Animals; Brain Neoplasms; Caco-2 Cells; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Luciferases; Luminescent Measurements; Lung; Lung Neoplasms; Mice, Nude; Mice, SCID; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Rats; Receptor Protein-Tyrosine Kinases; Tissue Distribution; Xenograft Model Antitumor Assays

A 7-year-old castrated border collie dog was anesthetised for surgical resection of a hippocampal mass. Anesthesia was maintained using a previously unreported TIVA protocol for craniectomy consisting of alfaxalone and remifentanil. Recovery was uneventful, and the patient was discharged from hospital. We describe the anesthetic management of this case.

Topics: Anesthetics, Intravenous; Animals; Brain Neoplasms; Decompressive Craniectomy; Dog Diseases; Dogs; Hippocampus; Male; Piperidines; Pregnanediones; Remifentanil

Topics: Adult; Anaplastic Lymphoma Kinase; Bone Neoplasms; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Crizotinib; Drug Resistance, Multiple; Female; Gene Fusion; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases

Aquatic microbes produce diverse secondary metabolites with interesting biological activities. Cytotoxic metabolites have the potential to become lead compounds or drugs for cancer treatment. Many cytotoxic compounds, however, show undesirable toxicity at higher concentrations. Such undesirable activity may be reduced or eliminated by using lower doses of the cytotoxic compound in combination with another compound that modulates its activity. Here, we have examined the cytotoxicity of four microbial metabolites [ethyl N-(2-phenethyl) carbamate (NP-1), Euglenophycin, Anabaenopeptin, and Glycolipid 652] using three in vitro cell lines [human breast cancer cells (MCF-7), mouse neuroblastoma cells (N2a), and rat pituitary epithelial cells (GH4C1)]. The compounds showed variable cytotoxicity, with Euglenophycin displaying specificity for N2a cells. We have also examined the modulatory power of NP-1 on the cytotoxicity of the other three compounds and found that at a permissible concentration (125 µg/mL), NP-1 sensitized N2a and MCF-7 cells to Euglenophycin and Glycolipid 652 induced cytotoxicity.

Topics: Adjuvants, Pharmaceutic; Animals; Antineoplastic Agents; Biological Products; Brain Neoplasms; Cell Line, Tumor; Glycolipids; Humans; Marine Toxins; MCF-7 Cells; Mice; Neuroblastoma; Peptides, Cyclic; Piperidines; Rats; Seawater; Thiazoles

Despite advances in clinical therapy, metastasis remains the leading cause of death in breast cancer patients. Mutations in mitochondrial DNA, including those affecting complex I and oxidative phosphorylation, are found in breast tumors and could facilitate metastasis. This study identifies mitochondrial complex I as critical for defining an aggressive phenotype in breast cancer cells. Specific enhancement of mitochondrial complex I activity inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORC1 activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by interfering with nicotinamide phosphoribosyltransferase expression rendered tumor cells more aggressive and increased metastasis. The results translate into a new therapeutic strategy: enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models, increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model. Thus, aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, while therapeutic normalization of the NAD+/NADH balance can inhibit metastasis and prevent disease progression.

Topics: Acrylamides; Animals; Autophagy; Autophagy-Related Protein 5; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cytokines; Disease Progression; Electron Transport Complex I; Female; Gene Knockdown Techniques; Humans; Lung Neoplasms; Mammary Neoplasms, Experimental; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred BALB C; Mice, SCID; Microtubule-Associated Proteins; Mitochondria; Multiprotein Complexes; NAD; Neoplasm Transplantation; Niacin; Niacinamide; Nicotinamide Phosphoribosyltransferase; Piperidines; Protein Transport; Proteins; Recombinant Proteins; Saccharomyces cerevisiae Proteins; TOR Serine-Threonine Kinases

Although diacylglycerol kinase α (DGKα) has been linked to several signaling pathways related to cancer cell biology, it has been neglected as a target for cancer therapy. The attenuation of DGKα activity via DGKα-targeting siRNA and small-molecule inhibitors R59022 and R59949 induced caspase-mediated apoptosis in glioblastoma cells and in other cancers, but lacked toxicity in noncancerous cells. We determined that mTOR and hypoxia-inducible factor-1α (HIF-1α) are key targets of DGKα inhibition, in addition to its regulation of other oncogenes. DGKα regulates mTOR transcription via a unique pathway involving cyclic AMP. Finally, we showed the efficacy of DGKα inhibition with short hairpin RNA or a small-molecule agent in glioblastoma and melanoma xenograft treatment models, with growth delay and decreased vascularity. This study establishes DGKα as a central signaling hub and a promising therapeutic target in the treatment of cancer.

Topics: Apoptosis; Brain Neoplasms; Cell Line, Tumor; Diacylglycerol Kinase; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Molecular Targeted Therapy; Piperidines; Pyrimidinones; Quinazolinones; RNA, Small Interfering; Thiazoles

The recent progress in chemotherapy for malignant gliomas is attributable to the introduction of the DNA-methylating agent temozolomide (TMZ); however, drug resistance remains a major issue. Previous studies have shown that TMZ induces prolonged arrest of human glioma cells in the G2/M phase of the cell cycle followed by a senescence-like phenomenon or mitotic catastrophe. These findings suggest that the G2 checkpoint is linked to DNA repair mechanisms. We investigated the effect of a cyclin-dependent kinase (Cdk) inhibitor flavopiridol (FP) that inhibits the action of Cdc2, a key protein in the G2 checkpoint pathway, on TMZ-treated glioma cells. Colony formation efficiency revealed that FP potentiated the cytotoxicity of TMZ in glioma cells in a p53-independent manner. This effect was clearly associated with the suppression of key proteins at the G2-M transition, accumulation of the cells exclusively at the G2 phase, and increase in a double-stranded DNA break marker (seen on performing immunoblotting). TMZ-resistant clones showed activation of the G2 checkpoint in response to TMZ, while FP treatment resensitized these clones to TMZ. FP also enhanced the cytotoxicity of TMZ in U87MG-AktER cells. Moreover, administration of TMZ and/or FP to nude mice with xenografted U87MG cells revealed that FP sensitized xenografted U87MG cells to TMZ in these mice. Our findings suggest that TMZ resistance could be promoted by enhanced DNA repair activity in the G2-M transition and that a Cdk inhibitor could suppress this activity, leading to potentiation of TMZ action on glioma cells.

Topics: Animals; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Cycle; Colony-Forming Units Assay; Comet Assay; Cyclin-Dependent Kinases; Dacarbazine; Drug Synergism; Female; Flavonoids; Fluorescent Antibody Technique; Glioma; Humans; Immunoblotting; Mice; Mice, Inbred BALB C; Piperidines; Protein Kinase Inhibitors; Temozolomide; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Poly(ADP-ribose) polymerases (PARPs) are recognized as key regulators of cell survival or death. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. The enzyme may be overactivated in response to inflammatory cues, thus depleting cellular energy pools and eventually causing cell death. Accordingly, PARP-1 inhibitors, acting by competing with its physiological substrate NAD(+), have been proposed to play a protective role in a wide range of inflammatory and ischemia/reperfusion-associated diseases. Recently, it has also been reported that PARP-1 regulates proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and enzymes (e.g., iNOS). Furthermore, PARP-1 has been shown to act as a coactivator of NF-κB- and other transcription factors implicated in stress/inflammation, as AP-1, Oct-1, SP-1, HIF, and Stat-1. To further substantiate this hypothesis, we tested the biomolecular effects of PARP-1 inhibitors DPQ and PJ-34 on human glioblastoma cells, induced to a proinflammatory state with lipopolysaccharide and Interferon-γ. PARP-1 expression was evaluated by laser scanning confocal microscopy immunofluorescence (LSM); nitrite production, LDH release and cell viability were also determined. LSM of A-172, SNB-19 and CAS-1 cells demonstrated that DPQ and PJ-34 downregulate PARP-1 expression; they also cause a decrease of LDH release and nitrite production, while increasing cell viability. Similar effects were caused in all three cell lines by N-mono-methyl-arginine, a well known iNOS inhibitor, and by L-carnosine and trehalose, two antioxidant molecules. These results demonstrate that, similar to other well characterized drugs, DPQ and PJ-34 reduce cell inflammation and damage that follow PARP-1 overexpression, while they increase cell survival: this suggests their potential exploitation in clinical Medicine.

Topics: Anti-Inflammatory Agents; Biomarkers; Brain Neoplasms; Carnosine; Cell Line, Tumor; Cell Survival; Coloring Agents; Down-Regulation; Fluorescent Antibody Technique; Glioblastoma; Humans; Isoquinolines; L-Lactate Dehydrogenase; Microscopy, Confocal; Nitrites; Phenanthrenes; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Tetrazolium Salts; Thiazoles; Trehalose

Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis.

Topics: Analysis of Variance; Animals; Brain Neoplasms; Breast Neoplasms; Chemoradiotherapy; Crizotinib; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Mice; Piperidines; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Radiation Tolerance; Real-Time Polymerase Chain Reaction; RNA, Small Interfering; Signal Transduction; Tumor Cells, Cultured

Neurocognitive deficits are a recognized late effect of curative brain tumor therapy. We evaluated the feasibility, tolerance, and impact of a pilot pharmacologic intervention with the acetylcholinesterase (AChe) inhibitor, donepezil, in pediatric brain tumor (BT) survivors at risk for neurocognitive dysfunction.. A single institution open-label pilot study was conducted in childhood BT survivors: ≥1 year from cancer treatment; and who received >23.5 Gy cranial radiation therapy (RT). Toxicity, adherence and neurocognitive outcomes were evaluated at baseline and serially during 24 weeks of donepezil, and following a 12-week washout period off drug.. From a pool of subjects, 13 were successfully contacted and screened, and 11 met all eligibility criteria to initiate donepezil at a median of 4.7 (1.9-11.9) years from RT. Seventy-two percent of patients completed the 24-week drug study visit. Despite transient gastrointestinal toxicity (vomiting and diarrhea) in 30% of patients there was no weight loss on donepezil. Significant improvement in performance was noted at 24 weeks on the Dellis-Kaplan Executive Function (D-KEF) Tower test (P < 0.001), the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML-2) Visual memory (P = 0.007), and the Number/Letter task (P = 0.018).. Donepezil was well tolerated among childhood BT survivors who had received substantial prior therapy. Based on improved executive function and memory performance in this pilot trial, a randomized placebo controlled trial of this pharmacologic agent is warranted to fully evaluate its efficacy in remediating neurocognitive dysfunction.

Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Child; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Executive Function; Female; Humans; Indans; Male; Memory; Neuropsychological Tests; Pilot Projects; Piperidines; Survivors; Treatment Outcome

Remifentanil, a mu-opioid receptor agonist, has important characteristics for neuroanesthesia, but data about its effects on postoperative recovery and mortality are currently lacking.. Using the Japanese Diagnosis Procedure Combination database in 2007, we selected patients who underwent elective brain tumor resection with open craniotomy under general anesthesia using either remifentanil or fentanyl and divided them into two categories: remifentanil patients and non-remifentanil patients. After propensity score matching for potential confounders, we compared the in-hospital mortality and postoperative length of stay (LOS) between the two groups. For comparison, the same endpoints were evaluated for patients underwent rectal cancer surgery under general anesthesia with intraoperative epidural anesthesia.. In patients who underwent brain tumor resection (936 pairs), remifentanil patients had significantly lower in-hospital mortality (1.5 % vs. 3.0 %; P = 0.029). Logistic regression analysis revealed that the odds ratio for use of remifentanil for in-hospital mortality was 0.47 (95 % confidence interval, 0.25-0.91; P = 0.025). Remifentanil patients also showed earlier discharge from hospital (median LOS, 17 vs. 19 days; hazard ratio, 1.19, 95 % confidence interval, 1.08-1.30; P < 0.001). In contrast, in 2,756 pairs of patients undergoing rectal cancer surgery, no significant difference was seen in either in-hospital morality (1.2 % vs. 1.3 %; P = 0.518) or median LOS (19 vs. 19 days; P = 0.148) between the two groups.. Our data suggest a possible association between use of remifentanil and better early postoperative recovery for patients undergoing neurosurgery with craniotomy. Further studies, including a randomized controlled trial, are required to confirm the present results.

Topics: Aged; Analgesics, Opioid; Anesthesia Recovery Period; Anesthesia, Epidural; Anesthesia, General; Brain Neoplasms; Craniotomy; Female; Fentanyl; Humans; Male; Middle Aged; Neurosurgical Procedures; Piperidines; Postoperative Period; Receptors, Opioid, mu; Rectal Neoplasms; Remifentanil; Retrospective Studies

The Notch pathway is dysregulated and a potential target in glioblastoma multiforme (GBM). Currently available Notch inhibitors block γ-secretase, which is necessary for Notch processing. However, Notch is first cleaved by α-secretase outside the plasma membrane, via a disintegrin and metalloproteinase-10 and -17. In this work, we used a potent α-secretase inhibitor (ASI) to test inhibition of glioblastoma growth and inhibition of Notch and of both novel and known Notch targets. Featured in this study are luciferase reporter assays and immunoblot, microarray analysis, chromatin immunoprecipitation (ChIP), quantitative real-time PCR, cell number assay, bromodeoxyuridine incorporation, plasmid rescue, orthotopic xenograft model, and local delivery of treatment with convection-enhanced delivery using nanoparticles, as well as survival, MRI, and ex vivo luciferase assay. A CBF1-luciferase reporter assay as well as an immunoblot of endogenous Notch revealed Notch inhibition by the ASI. Microarray analysis, quantitative real-time PCR, and ChIP of ASI and γ-secretase inhibitor (GSI) treatment of GBM cells identified known Notch pathway targets, as well as novel Notch targets, including YKL-40 and leukemia inhibitory factor. Finally, we found that local nanoparticle delivery of ASIs but not GSIs increased survival time significantly in a GBM stem cell xenograft treatment model, and ASI treatment resulted in decreased tumor size and Notch activity. This work indicates α-secretase as an alternative to γ-secretase for inhibition of Notch in GBM and possibly other cancers as well, and it identifies novel Notch targets with biologic relevance and potential as biomarkers.

Topics: Amyloid Precursor Protein Secretases; Animals; Apoptosis; Biomarkers, Tumor; Blotting, Western; Brain Neoplasms; Cell Cycle; Cell Proliferation; Chromatin Immunoprecipitation; Gene Expression Profiling; Glioblastoma; Humans; In Vitro Techniques; Luciferases; Magnetics; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; Piperidines; Real-Time Polymerase Chain Reaction; Receptors, Notch; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spiro Compounds; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors. We now report the in vitro and orthotopic in vivo results of combination therapy using radiation, temozolomide and lonafarnib (SCH66336), an oral farnesyl transferase inhibitor, in a murine model of glioblastoma. We examined the viability, proliferation, farnesylation of H-Ras, and activation of downstream signaling of combination-treated U87 cells in vitro. Lonafarnib alone or in combination with radiation and temozolomide had limited tumor cell cytotoxicity in vitro although it did demonstrate significant inhibition in tumor cell proliferation. In vivo, lonafarnib alone had a modest ability to inhibit orthotopic U87 tumors, radiation and temozolomide demonstrated better inhibition, while significant anti-tumor activity was found with concurrent lonafarnib, radiation, and temozolomide, with the majority of animals demonstrating a decrease in tumor volume. The use of tumor neurospheres derived from freshly resected adult human glioblastoma tissue was relatively resistant to both temozolomide and radiation therapy. Lonafarnib had a significant inhibitory activity against these neurospheres and could potentate the activity of temozolomide and radiation. These data support the continued research of high grade glioma treatment combinations of farnesyl transferase inhibitors, temozolomide, and radiation therapy.

Topics: Animals; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Dacarbazine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Glioma; Humans; Mice; Neoplasm Transplantation; Piperidines; Prenylation; Pyridines; Radiation, Ionizing; ras Proteins; Signal Transduction; Temozolomide; Time Factors

The 2009 TNM classification of lung cancer reclassified patients with pleural invasion from stage IIIB (T4) to stage IV (M+). However, the 2009 TNM separates patients with pleural metastases (M1a) from patients with others visceral metastases (M1b), the patients with stage M1a having the better prognosis.. Two cases are reported of patients with non-small cell lung cancer (NSCLC) metastatic to the pleura, having a long disease free survival (50 and 34 months).. Patients with pleural metastases from NSCLC seem to have a better prognosis than other patients with stage IV disease, maybe because of a subgroup of patients with long survival. This long survival is probably related to specific biological characteristics of certain pleural disorders that need to be identified. This would allow a more aggressive treatment of this subgroup of patients regarded today as incurable.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Piperidines; Pleural Neoplasms; Quinazolines; Radiotherapy; Receptor Protein-Tyrosine Kinases; Retreatment; Survivors; Thoracotomy

Currently available compounds that interfere with VEGF-A signalling effectively inhibit angiogenesis in gliomas, but influence diffuse infiltrative growth to a much lesser extent. Development of a functional tumour vascular bed not only involves VEGF-A but also requires platelet-derived growth factor receptor-β (PDGFRβ), which induces maturation of tumour blood vessels. Therefore, we tested whether combined inhibition of VEGFR and PDGFRβ increases therapeutic benefit in the orthotopic glioma xenograft models E98 and E473, both displaying the diffuse infiltrative growth that is characteristically observed in most human gliomas. We used bevacizumab and vandetanib as VEGF(R) inhibitors, and sunitinib to additionally target PDGFRβ. We show that combination therapy of sunitinib and vandetanib does not improve therapeutic efficacy compared to treatment with sunitinib, vandetanib or bevacizumab alone. Furthermore, all compounds induced reduction of vessel leakage in compact E98 tumour areas, resulting in decreased detectability of these mostly infiltrative xenografts in Gd-DTPA-enhanced MRI scans. These data show that inhibition of VEGF signalling cannot be optimized by additional PDGFR inhibition and support the concept that diffuse infiltrative areas in gliomas are resistant to anti-angiogenic therapy.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blood-Brain Barrier; Brain Neoplasms; Glioma; Humans; Indoles; Magnetic Resonance Imaging; Mice; Mice, Nude; Neovascularization, Pathologic; Piperidines; Pyrroles; Quinazolines; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Sunitinib; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

We have investigated in vitro effects of anticancer therapy with the histone deacetylase inhibitor (HDACi) 4-phenylbutyrate (4-PB) combined with receptor tyrosine kinase inhibitors (RTKi) gefitinib or vandetanib on the survival of glioblastoma (U343MGa) and medulloblastoma (D324Med) cells. In comparison with individual effects of these drugs, combined treatment with gefitinib/4-PB or vandetanib/4-PB resulted in enhanced cell killing and reduced clonogenic survival in both cell lines. Our results suggest that combined treatment using HDACi and RTKi may beneficially affect the outcome of cancer therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gefitinib; Glioblastoma; Histone Deacetylase Inhibitors; Humans; Models, Biological; Phenylbutyrates; Piperidines; Protein Kinase Inhibitors; Quinazolines; Receptor Protein-Tyrosine Kinases; Tumor Stem Cell Assay

A sensitive and precise LC-ESI-MS/MS method for the determination of vandetanib (ZD6474) in human plasma and cerebrospinal fluid (CSF) using [(13)C,d(3)]-ZD6474 as an internal standard (ISTD) was developed and validated. Sample preparation consisted of a simple liquid-liquid extraction with tert-butyl methyl ether containing 0.1% or 0.5% ammonium hydroxide. ZD6474 and ISTD were separated on a Kinetex C18 column (2.6 μm, 50 mm × 2.1 mm) at ambient temperature with an isocratic mobile phase (acetonitrile/10mM ammonium formate=50/50, v/v, at pH 5.0) delivered at 0.11 mL/min. The retention time of both compounds was at 1.60 min in a runtime of three min. Detection was achieved by an API-3200 LC-MS/MS system, monitoring m/z 475.1/112.1 and m/z 479.1/116.2 for vandetanib and ISTD, respectively. The method was linear in the range of 0.25-50 ng/mL (R(2) ≥ 0.990) for the CSF curve and from 1.0 to 3000 ng/mL (R(2) ≥ 0.992) for the plasma curve. The mean recovery for vandetanib was 80%. Within-day and between-day precisions were ≤ 8.8% and ≤ 5.9% for CSF and plasma, respectively. Within-day and between-day accuracies ranged from 95.0 to 98.5% for CSF, and from 104.0 to 108.5% for plasma. Analysis of plasma from six different sources showed no matrix effect for vandetanib (MF=0.98, %CV ≤ 4.97, n=6). This method was successfully applied to the analysis of pharmacokinetic samples from children with brain tumors treated with oral vandetanib.

Topics: Antineoplastic Agents; Brain Neoplasms; Chemical Fractionation; Child; Chromatography, Liquid; Drug Stability; Humans; Piperidines; Quinazolines; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

There is no general consensus about the best anesthesiologic approach to use during craniotomies with intraoperative brain mapping, and large prospective studies evaluating the complications associated with different approaches are lacking. Objective of this study was to prospectively collect and evaluate data about a large series of consecutive asleep-awake and asleep-asleep craniotomies.. We analyzed 238 consecutive procedures from January 2005 to December 2008. During asleep-awake procedures, patients were initially ventilated through a laryngeal mask which was removed to allow language testing. During asleep-asleep procedures, patients remained sedated and intubated to permit motor testing.. In asleep-awake craniotomies [n=135, age 42 y (range: 16 to 72 y), American Society of Anesthesiologists classification (ASA) 1 (1 to 3), and body mass index 24.2+/-3.7 kg/m], 43% of the procedures were free of complications. Most common complications were hypertension (27%) and brief clinical seizures (16%), but also hypotension (10%), vomiting (7%), brief periods of apnea (4%), and agitation (6%) were observed. In 7% of the procedures, seizures required pharmacologic treatment. Fifty-nine percent of the asleep-asleep procedures [n=103, age 51 y (range: 21 to 76 y), ASA 1 (1 to 3), body mass index 25.4+/-3.9 kg/m, P<0.05 vs. asleep-awake] were free of complications. Clinical seizures were observed in 31% of the cases. The administration of boluses of hypnotics was rarely necessary (6%) and safer because of secured airways.. With this study, we demonstrated the feasibility and safety of our protocols on large prospective case series. Asleep-awake protocol can be safely used when intraoperative language mapping is planned, whereas an asleep-asleep protocol with secured airway might be preferred when motor testing only is required.

Topics: Adolescent; Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Brain Mapping; Brain Neoplasms; Female; Hemodynamics; Humans; Infusions, Intravenous; Intraoperative Complications; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Propofol; Remifentanil; Young Adult

Patients with bilateral vestibular schwannomas associated with neurofibromatosis type 2 (NF2) experience significant morbidity such as complete hearing loss. We have recently shown that treatment with bevacizumab provided tumor stabilization and hearing recovery in a subset of NF2 patients with progressive disease. In the current study, we used two animal models to identify the mechanism of action of anti-vascular endothelial growth factor (VEGF) therapy in schwannomas. The human HEI193 and murine Nf2(-/-) cell lines were implanted between the pia and arachnoid meninges as well as in the sciatic nerve to mimic central and peripheral schwannomas. Mice were treated with bevacizumab (10 mg/kg/wk i.v.) or vandetanib (50 mg/kg/d orally) to block the VEGF pathway. Using intravital and confocal microscopy, together with whole-body imaging, we measured tumor growth delay, survival rate, as well as blood vessel structure and function at regular intervals. In both models, tumor vessel diameter, length/surface area density, and permeability were significantly reduced after treatment. After 2 weeks of treatment, necrosis in HEI193 tumors and apoptosis in Nf2(-/-) tumors were significantly increased, and the tumor growth rate decreased by an average of 50%. The survival of mice bearing intracranial schwannomas was extended by at least 50%. This study shows that anti-VEGF therapy normalizes the vasculature of schwannoma xenografts in nude mice and successfully controls the tumor growth, probably by reestablishing a natural balance between VEGF and semaphorin 3 signaling.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Brain Neoplasms; Cell Growth Processes; Cell Line, Tumor; Humans; Mice; Mice, Nude; Neovascularization, Pathologic; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Piperidines; Quinazolines; Vascular Endothelial Growth Factor A

The treatment of glioblastoma is unsatisfactory. Improved understanding of the biological effects of treatment, together with development of new tools to predict outcome of the initiated treatment are therefore of great need. Vandetanib (ZD6474) is mainly a vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) receptor tyrosine kinase inhibitor. This study investigated the pattern of protein expression in brain tumor and normal brain tissue, following treatment with vandetanib in a rat glioma model. BT4C-cells were stereotactically implanted into the brain of BD IX rats. The rats were divided into three different experiments. The treatment schedule for experiments one and two consisted of daily, oral doses of vandetanib from day 6 until day 12 or 20 after implantation, respectively. In the third experiment, each animal received a single dose of vandetanib on day 19 after implantation and was then sacrificed 2, 8 or 24 h thereafter. The protein expression profiles were analyzed by SELDI-TOF-MS and evaluated with multivariate statistical methods. Following treatment with vandetanib, we found significantly altered protein expression pattern in malignant glioma and normal brain. Analyzing protein spectra is an interesting option to assess biological effects induced in brain tissue by signal transduction inhibitors such as vandetanib.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Brain; Brain Neoplasms; Cell Line, Tumor; Drug Administration Schedule; ErbB Receptors; Glioma; Multivariate Analysis; Nerve Tissue Proteins; Piperidines; Protein Kinase Inhibitors; Proteomics; Quinazolines; Rats; Receptors, Vascular Endothelial Growth Factor; Reproducibility of Results; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Time Factors

To describe a patient with a history of epithelial basement membrane dystrophy who developed symptomatic corneal verticillata after vandetanib therapy for anaplastic astrocytoma.. Retrospective interventional case report.. A 48-year-old female patient with a history of anaplastic astrocytoma status post resection, external beam radiation, and chemotherapy presented with glare symptoms, decreased contrast sensitivity, and increased lacrimation after approximately 12 months of therapy with the anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor receptor 2 protein tyrosine kinase inhibitor, vandetanib. Ophthalmic examination revealed diffuse corneal verticillata and fine subepithelial opacities. Schirmer 1 testing was normal bilaterally. Therapy with carboxymethylcellulose, 5% sodium chloride ointment, and a decrease in the dose of vandetanib led to an improvement in the patient's ophthalmic symptoms despite persistence of the corneal findings. The patient remained under surveillance for tumor recurrence.. Vandetanib (ZD6474), a protein tyrosine kinase inhibitor with dual anti-EGFR and anti-vascular endothelial growth factor receptor 2 action, may have contributed to the formation of corneal verticillata in our patient. Inhibition of EGFR, which is involved with corneal epithelial cell migration and wound healing, may play a role in the pathogenesis underlying corneal vortex keratopathy and ocular surface conditions with significant epithelial turnover.

Topics: Astrocytoma; Brain Neoplasms; Cellulase; Corneal Diseases; Corneal Opacity; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; ErbB Receptors; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ointments; Piperidines; Quinazolines; Retrospective Studies; Sodium Chloride; Vascular Endothelial Growth Factor Receptor-2

We report two cases of awake craniotomy successfully managed using remifentanil. During the intraoperative awake period lasting 2 to 2.5 hours, the infusion of low doses of remifentanil (0.02-0.05 microg x kg(-1) min(-1)) with or without propofol kept the patients comfortable and sufficiently awake to conduct various tasks but did not produce excessive respiratory depression. Because remifentanil can be titrated rapidly due to its extremely short duration of action, it may be useful for awake craniotomy for which both analgesia and sedation have to be tuned carefully according to the patient's need.

Topics: Adult; Analgesics, Opioid; Anesthetics, Intravenous; Brain Neoplasms; Conscious Sedation; Craniotomy; Female; Frontal Lobe; Humans; Hypnotics and Sedatives; Intraoperative Care; Intraoperative Period; Male; Middle Aged; Piperidines; Remifentanil; Wakefulness

Proper delineation of gliomas using contrast-enhanced magnetic resonance imaging (CE-MRI) poses a problem in neuro-oncology. The blood brain barrier (BBB) in areas of diffuse-infiltrative growth may be intact, precluding extravasation and subsequent MR-based detection of the contrast agent gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA). Treatment with antiangiogenic compounds may further complicate tumor detection as such compounds can restore the BBB in angiogenic regions. The increasing number of clinical trials with antiangiogenic compounds for treatment of gliomas calls for the development of alternative imaging modalities. Here we investigated whether CE-MRI using ultrasmall particles of iron oxide (USPIO, Sinerem) as blood pool contrast agent has additional value for detection of glioma in the brain of nude mice. We compared conventional T1-weighted Gd-DTPA-enhanced MRI to T2*-weighted USPIO-enhanced MRI in mice carrying orthotopic U87 glioma, which were either or not treated with the antiangiogenic compound vandetanib (ZD6474, ZACTIMA). In untreated animals, vessel leakage within the tumor and a relatively high tumor blood volume resulted in good MRI visibility with Gd-DTPA- and USPIO-enhanced MRI, respectively. Consistent with previous findings, vandetanib treatment restored the BBB in the tumor vasculature, resulting in loss of tumor detectability in Gd-DTPA MRI. However, due to decreased blood volume, treated tumors could be readily detected in USPIO-enhanced MRI scans. Our findings suggest that Gd-DTPA MRI results in overestimation of the effect of antiangiogenic therapy of glioma and that USPIO-MRI provides an important complementary diagnostic tool to evaluate response to antiangiogenic therapy of these tumors.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Blood-Brain Barrier; Brain Neoplasms; Contrast Media; Dextrans; Ferrosoferric Oxide; Gadolinium DTPA; Glioma; Immunohistochemistry; Iron; Magnetic Resonance Imaging; Magnetite Nanoparticles; Mice; Mice, Inbred BALB C; Mice, Nude; Microcirculation; Oxides; Piperidines; Predictive Value of Tests; Quinazolines; Transplantation, Heterologous

Glioblastomas are highly aggressive primary brain tumors. Curative treatment by surgery and radiotherapy is generally impossible due to the presence of diffusely infiltrating tumor cells. Furthermore, the blood-brain barrier (BBB) in infiltrative tumor areas is largely intact, and this hampers chemotherapy as well. The occurrence of angiogenesis in these tumors makes these tumors attractive candidates for antiangiogenic therapies. Because antiangiogenic compounds have been shown to synergize with chemotherapeutic compounds in other tumor types, based on vessel normalization, there is a tendency toward such combination therapies for primary brain tumors also. However, vessel normalization in brain may result in restoration of the BBB with consequences for the efficacy of chemotherapeutic agents. In this study, we investigated this hypothesis. BALB/c nude mice with intracerebral xenografts of the human glioblastoma lines E98 or U87 were subjected to therapy with different dosages of vandetanib (an angiogenesis inhibitor), temozolomide (a DNA alkylating agent), or a combination (n>8 in each group). Vandetanib selectively inhibited angiogenic growth aspects of glioma and restored the BBB. It did not notably affect diffuse infiltrative growth and survival. Furthermore, vandetanib antagonized the effects of temozolomide presumably by restoration of the BBB and obstruction of chemodistribution to tumor cells. The tumor microenvironment is an extremely important determinant for the response to antiangiogenic therapy. Particularly in brain, antiangiogenic compounds may have adverse effects when combined with chemotherapy. Thus, use of such compounds in neuro-oncology should be reconsidered.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Dacarbazine; Disease Models, Animal; Humans; Mice; Neovascularization, Pathologic; Piperidines; Quinazolines; Temozolomide; Xenograft Model Antitumor Assays

The extensive neovascularisation of malignant glioma is mainly influenced by vascular endothelial growth factor (VEGF). The effect of ZD6474, a potent inhibitor of VEGF-receptor-2, was evaluated in combination with either radiotherapy or temozolomide.. The effects on glioma growth were investigated in the intracerebral BT4C rat glioma model. ZD6474 30 mg/kg was given alone or in combination with radiotherapy 12 Gy x 1 or with temozolomide 100 mg/kg for 3 days. Two different experiments were performed comparing ZD6474 to radiotherapy or temozolomide. For each experiment 28 animals were randomized into four groups.. ZD6474 in combination with radiotherapy significantly decreased tumour area by 66% compared with controls whereas the combination with temozolomide decreased tumour area by 74%.. ZD6474 in combination with two standard modalities in the treatment of malignant glioma, radiotherapy and chemotherapy, markedly decreased the growth of an intracerebral experimental glioma. These results justify further investigations of these therapies in combination.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Cell Line, Tumor; Combined Modality Therapy; Dacarbazine; ErbB Receptors; Glioma; Neoplasm Transplantation; Piperidines; Quinazolines; Rats; Receptors, Vascular Endothelial Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; Temozolomide

We retrospectively reviewed the first 25 planned cases of awake craniotomies using the 'asleep-awake' technique, an alternative to the often-used 'asleep-awake-asleep' technique.. The patients were anaesthetized using propofol/remifentanil anaesthesia, a laryngeal mask and controlled ventilation according to a protocol defined before the start of this series of patients. The patients were awakened before the brain mapping and were kept awake throughout the rest of the procedure allowing for additional mapping and modification of the resection of the tumour if symptoms should develop. A small dose of remifentanil was infused during this period if necessary.. Twenty-three patients were mapped as planned. One patient was not awakened due to protrusion of the brain during the awakening phase. Another patient was intubated preoperatively as it was impossible to obtain a tight laryngeal mask. All of the 23 patients were awake as from when the mapping session began and throughout the rest of the operation. In five cases the resection of the tumour was modified as symptoms emerged. These symptoms all subsided in due course. No case of hypoxia was recorded. In no case the respiratory rate was below 10 breaths min-1 in the awake period. Complications were comparable to other studies. The patients in the present study were all satisfied with the method.. Different methods of anaesthesia have been described, but no method has been shown to be superior. The presented method seems to be a rational and useful technique allowing for modification of tumour resection, if symptoms should develop. The method was well tolerated by the patients.

Topics: Adult; Aged; Anesthesia, General; Anesthetics, Intravenous; Brain Mapping; Brain Neoplasms; Craniotomy; Humans; Middle Aged; Monitoring, Intraoperative; Patient Satisfaction; Piperidines; Propofol; Remifentanil; Retrospective Studies; Treatment Outcome; Wakefulness

We experienced anesthetic management using target-controlled infusion (TCI) of remifentanil for craniotomy in which monitoring of motor evoked potential (MEP) was performed. Anesthesia was induced and maintained by TCI of propofol and remifentanil. Vecuronium bromide was not administered except for facilitating tracheal intubation. Target effect-site concentrations (ESCs) of remifentanil during intubation, exposure, dura incision, microsurgery and closure were 6, 10, 8, 5 and 8 ng x ml(-1), respectively. Myogenic MEP was sufficiently elicited throughout the microsurgery without patient's body movement. Extubation was completed 10 min after the end of surgery with administration of remifentanil continued at a target ESC of 2 ng ml(-1) after surgery. Emergence from anesthesia was good without complaint of pain or respiratory disorder or new neurological deficit. It has been reported that remifentanil is suitable because of its wide dosage window with respect to recording MEP. ESC of remifentanil was fixed during continuous infusion, but its absolute value varies depending on lean body mass and/or age. The use of TCI enabled easy elimination of the above effects, adjustment of ESC to the expected value and maintenance of ESC of remifentanil at a constant level. TCI of remifentanil might be suitable for anesthesia with monitoring of MEP.

Topics: Anesthesia, Intravenous; Brain Neoplasms; Craniotomy; Evoked Potentials, Motor; Humans; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Propofol; Remifentanil

How and why tumors metastasize is still a matter of debate. The assumption is that mutations render tumor cells with a metastatic phenotype, enabling entrance in and transport through lymph or blood vessels. Distant outgrowth is thought to occur only in a suitable microenvironment (the seed and soil hypothesis). However, the anatomical location of most metastases in cancer patients suggests entrapment of tumor cells in the first microcapillary bed that is encountered. We here investigated how vascular endothelial growth factor-A (VEGF-A) attributes to the metastatic process. We describe here that VEGF-A enhances spontaneous metastasis by inducing intravasation of heterogeneous tumor cell clusters, surrounded by vessel wall elements, via an invasion-independent mechanism. These tumor clusters generate metastatic tissue embolisms in pulmonary arteries. Treatment of tumor-bearing mice with the antiangiogenic compound ZD6474 prevented the development of this metastatic phenotype. This work shows that tumors with high constitutive VEGF-A expression metastasize via the formation of tumor emboli and provides an alternative rationale for anti-VEGF-A therapy, namely to inhibit metastasis formation.

Topics: Angiogenesis Inhibitors; Animals; Brain Neoplasms; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins; Humans; Immunoenzyme Techniques; Lung Neoplasms; Lymphatic Metastasis; Male; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Piperidines; Pulmonary Embolism; Quinazolines; Skin Neoplasms; Transfection; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Different anesthetic techniques have been suggested for craniotomy with intraoperative awakening. We describe an asleep-awake-asleep technique with propofol and remifentanil infusions, with pharmacokinetic simulation to predict the effect-site concentrations and to modulate the infusion rates of both drugs, and bispectral index (BIS) monitoring. Five critical moments were defined: first loss of consciousness (LOC1), first recovery of consciousness (ROC1), final of neurologic testing (NT), second loss of consciousness (LOC2), and second recovery of consciousness (ROC2). At LOC1, predicted effect-site concentrations of propofol and remifentanil were, respectively, 3.6+/-1.2 microg/mL and 2.4+/-0.4 etag/mL. At ROC1, predicted effect-site concentrations of propofol and remifentanil were, respectively, 2.1+/-0.3 microg/mL and 1.8+/-0.3 etag/mL. At NT, predicted effect-site concentrations of propofol and remifentanil were, respectively, 0.9+/-0.3 microg/mL and 1.8+/-0.2 etag/mL. At LOC2, predicted effect-site concentrations of propofol and remifentanil were, respectively, 2.1+/-0.2 microg/mL and 2.5+/-0.2 etag/mL. At ROC2, predicted effect-site concentrations of propofol and remifentanil were, respectively, 1.2+/-0.5 microg/mL and 1.4+/-0.2 etag/mL (data are mean+/-SE). A significative correlation was found between BIS and predicted effect-site concentrations of propofol (r=0.547, P<0.001) and remifentanil (r=0.533, P<0.001). Multiple regression analysis between BIS and propofol and remifentanil predicted effect-site concentrations at the different critical steps of the procedure was done and found also significative (r=0.7341, P<0.001).

Topics: Adult; Anesthesia, General; Anesthetics, Combined; Anesthetics, Intravenous; Brain Neoplasms; Computer Simulation; Conscious Sedation; Craniotomy; Electroencephalography; Female; Humans; Intraoperative Period; Laryngeal Masks; Male; Monitoring, Intraoperative; Piperidines; Predictive Value of Tests; Propofol; Remifentanil; Retrospective Studies; Wakefulness

This prospective study was performed to compare the incidence of complications occurring after neurosurgical procedures in patients anesthetized with either sevoflurane-fentanyl or propofol-remifentanil anesthesia. We enrolled 162 American Society of Anesthesiologists (ASA) I to III patients (82 females and 80 males, Glasgow 15) undergoing elective neurosurgical procedures. Anesthesia was conducted using either propofol-remifentanil (T group; n=80 patients) or sevoflurane-fentanyl (S group; n=82 patients). All patients were monitored in the postanesthesia care unit for 6 hours after extubation. We analyzed and compared in both groups the incidence of high severity complications such as respiratory events (PaO2 <90 mm Hg; PaCO2 >45 mm Hg) and neurologic events (seizures, new motor or sensory deficit, unexpected delay of awakening) and the incidence of low severity complications such as hypertension (mean arterial pressure increase above 30% of baseline), hypotension (mean arterial pressure decrease below 30% of baseline), pain, shivering, nausea, and vomiting. A total of 162 complications occurred in 92 patients (57%) with 50 patients (31%) having had 1, 26 patients (16%) having had 2, and 16 patients (10%) having had 3 or more events. The most frequent complication was respiratory impairment (28%) which was frequently reported only in the first postoperative hour. Out of the total number of complicating events, 77 (48 %) were found in group S, and 85 (52%) in group T (P=ns). Severe complications were rarely reported and evenly distributed in the 2 anesthetic groups. Similarly, no difference could be demonstrated in the composite incidence of less serious complications between the 2 anesthetic regimens tested in this study. This study confirms that the recovery period after neurosurgical procedures remains a time of great potential danger to patients given the high incidence of postoperative complicating events independently from the anesthetic strategy.

Topics: Adult; Aged; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Brain; Brain Neoplasms; Endpoint Determination; Female; Fentanyl; Humans; Intracranial Aneurysm; Intracranial Arteriovenous Malformations; Male; Methyl Ethers; Middle Aged; Neurosurgical Procedures; Piperidines; Postoperative Care; Postoperative Complications; Propofol; Prospective Studies; Remifentanil; Respiratory Mechanics; Sevoflurane

Topics: Alzheimer Disease; Brain Neoplasms; Cognition Disorders; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Radiation Injuries; Radiotherapy

The aim of this study was to compare the effects of 3 different sedative-analgesic regimens in patients with intracranial mass lesions undergoing stereotactic brain biopsy. A 135 outpatients with American Society of Anesthesiologists I to II were divided into 3 groups: group A (n = 45) received a loading dose of IV alfentanil 7.5 microg/kg followed by infusion rate of 0.25 microg/kg/min; group F (n = 45) received a bolus dose of 1 microg/kg IV fentanyl and repeated as needed; and group R (n = 45) received infusion of 0.05 microg/kg/min remifentanil. Target level of sedation was 3 to 4 of the Ramsay Sedation Scale. Systolic and diastolic blood pressure, heart rate, respiratory rate, peripheric oxygen saturation (SpO2), and end-tidal carbon dioxide were recorded at different stages of the procedures. The patients in group F had significantly lower mean heart rate than those in groups A and R, but this was not in the limits of the bradycardia. The patients in group A had significantly lower mean SpO2 than those in the other groups, but mean SpO2 values did not drop below 94%. There were no significant differences in end-tidal carbon dioxide and respiratory rate values among the groups. Our results suggest that all 3 regimens have relatively similar hemodynamic and respiratory responses. The use of bolus fentanyl technique caused less hemodynamic stability. The continuous infusion technique of remifentanil or alfentanil provided better control on hemodynamic parameters.

Topics: Adult; Aged; Alfentanil; Anesthetics, Intravenous; Biopsy; Brain; Brain Neoplasms; Conscious Sedation; Female; Fentanyl; Hemodynamics; Humans; Male; Mental Recall; Middle Aged; Monitoring, Intraoperative; Nerve Block; Neurosurgical Procedures; Piperidines; Remifentanil; Respiratory Mechanics; Stereotaxic Techniques

We have carried out an in vitro study to investigate the ability of substance P to activate cell growth and the NK1 receptor antagonist L-733,060 to inhibit cell growth in the SKN-BE(2) neuroblastoma and GAMG glioma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)2-(4-sulfophenyl)-2H-tetrazolium], inner salt, colorimetric method to evaluate cell viability in this cytotoxicity assay. Nanomolar concentrations of substance P increased, and micromolar concentrations of L-733,060 inhibited the growth of both cell lines studied, with and without previous administration of substance P. In addition, we have demonstrated by immunoblot analysis that NK1 receptors are present in both cancer cell lines studied here. Thus, this study demonstrates that substance P acts as a mitogen in the SKN-BE(2) neuroblastoma and GAMG glioma cell lines, and that the antitumoural action of L-733,060 on both human cell lines occurs through the NK1 receptor. This action suggests that the NK1 receptor is a new and promising target in the treatment of human neuroblastoma and glioma.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Division; Cell Line, Tumor; Glioma; Humans; Mitogens; Neuroblastoma; Piperidines; Receptors, Neurokinin-1; Substance P

Endothelin-1 (ET-1), a vasoactive and mitogenic peptide mainly produced by vascular endothelial cells, may be involved in the progression of several human tumors. Here, we present an immunohistochemical analysis of the expression pattern of ET-1 receptor subtypes (ET(A)-R and ET(B)-R) and a functional study of their potential role in human oligodendrogliomas and oligoastrocytomas. By comparison, we assessed the corresponding expression patterns of glioblastomas. Interestingly, a nuclear localization of ET-1 receptor subtypes (associated or not with a cytoplasmic labeling) was constantly observed in tumor cells from all three glioma types. Moreover, we noted a distinct receptor distribution in the different gliomas: a nuclear expression of ET(B)-R by tumor cells was found to be restricted to oligodendrogliomas and oligoastrocytomas, while a nuclear expression of ET(A)-R was only detected in tumor cells from some glioblastomas. Using primary cultures of oligodendroglial tumor cells, we confirmed the selective expression of nuclear ET(B)-R, together with a plasma membrane expression, and further demonstrated that this receptor was functionally coupled to intracellular signaling pathways known to be involved in cell survival and/or proliferation: extracellular signal-regulated kinase and focal adhesion kinase activation, actin cytoskeleton reorganization. In addition, impairment of ET(B)-R activation in these cells by in vitro treatment with an ET(B)-R-specific antagonist induced cell death. These data point to ET-1 as a possible survival factor for oligodendrogliomas via ET(B)-R activation and suggest that ET(B)-R-specific antagonists might constitute a potential therapeutic alternative for oligodendrogliomas.

Topics: Actin Cytoskeleton; Antihypertensive Agents; Astrocytoma; Brain Neoplasms; Cell Membrane; Cell Nucleus; Cell Survival; Cytoplasm; Endothelin B Receptor Antagonists; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Glioblastoma; Humans; Immunohistochemistry; Oligodendroglioma; Oligopeptides; Piperidines; Protein-Tyrosine Kinases; Receptor, Endothelin A; Receptor, Endothelin B; Tumor Cells, Cultured

We performed this study to summarize drug dosing, physiologic responses, and anesthetic complications from an IV general anesthetic technique for patients undergoing craniotomy for awake functional brain mapping. Review of 98 procedures revealed "most rapid" IV infusion rates for remifentanil 0.05, 0.05-0.09 microg x kg(-1) x min(-1) and propofol 115, 100-150 microg x kg(-1) x min(-1). The infusions lasted for 78, 58-98 min. Intraoperative emergence from general anesthesia was 9 (6-13) min after discontinuing IV infusions to allow for brain mapping and was independent of infusion duration and duration of craniotomy before mapping. Spontaneous ventilation was generally satisfactory during drug infusion, as evidenced by Sao(2) = 95% (92%-98%) and Paco(2) = 50 (47-55) mm Hg. However, we recorded at least one 30-s epoch of apnea in 69 of 96 patients. Maximum systolic arterial blood pressure was 150 (139-175) mm Hg and minimal systolic arterial blood pressure was 100 (70-150) mm Hg during drug infusion. Three patients experienced intraoperative seizures. Two patients did not tolerate the awake state and required reinduction of general anesthesia. No patients required endotracheal intubation or discontinuation of surgery. This general anesthetic technique is effective for craniotomy with awake functional brain mapping and offers an alternative to continuous wakefulness or other IV sedation techniques.. An IV general anesthetic technique using remifentanil and propofol is an effective method allowing for reliable emergence for intraoperative awake functional brain mapping during craniotomy.

Topics: Adolescent; Adult; Aged; Anesthesia, General; Anesthetics, Intravenous; Brain Mapping; Brain Neoplasms; Child; Cognition; Craniotomy; Efferent Pathways; Female; Humans; Male; Middle Aged; Neurologic Examination; Piperidines; Propofol; Remifentanil; Retrospective Studies; Survival Analysis; Visual Perception; Wakefulness

Angiogenesis is a critical step required for sustained tumor growth and tumor progression. The stimulation of endothelial cells by cytokines secreted by tumor cells such as vascular endothelial growth factor (VEGF) induces their proliferation and migration. This is a prominent feature of high-grade gliomas. The secretion of VEGF is greatly upregulated under conditions of hypoxia because of the transcription factor hypoxiainducible factor (HIF)-1alpha, which controls the expression of many genes, allowing rapid adaptation of cells to their hypoxic microenvironment. Flavopiridol, a novel cyclin-dependent kinase inhibitor, has been attributed with antiangiogenic properties in some cancer cell lines by its ability to inhibit VEGF production. Here, we show that flavopiridol treatment of human U87MG and T98G glioma cell lines decreases hypoxia-mediated HIF-1alpha expression, VEGF secretion, and tumor cell migration. These in vitro results correlate with reduced vascularity of intracranial syngeneic GL261 gliomas from animals treated with flavopiridol. In addition, we show that flavopiridol downregulates HIF-1alpha expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1alpha. The potential to downregulate HIF-1alpha expression with flavopiridol treatment in combination with a proteasome inhibitor makes this an extremely attractive anticancer treatment strategy for tumors with high angiogenic activity, such as gliomas.

Topics: Animals; Blotting, Western; Boronic Acids; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Down-Regulation; Female; Flavonoids; Glioma; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Matrix Metalloproteinase 2; Mice; Neovascularization, Pathologic; Piperidines; Polymerase Chain Reaction; Protease Inhibitors; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; RNA, Messenger; Transcription Factors; Transcription, Genetic; Vascular Endothelial Growth Factor A

The mechanism of action of many chemotherapeutic agents targets the cell cycle. Recently, we demonstrated cytotoxic and other anti-tumor effects of flavopiridol, the first synthetic cyclin dependent kinase (CDK) inhibitor to enter clinical trials, on the murine GL261 glioma cell line in vitro (Newcomb et al., Cell Cycle 2003; 2:243). Given that flavopiridol has demonstrated anti-tumor activity in several human xenograft models, we wanted to evaluate it for anti-glioma activity in vivo in our established subcutaneous and intracranial GL261 experimental tumor models. In particular, the intracranial animal model recapitulates many of the histopathological and biological features of human high-grade glioma including both necrosis with pseudopalisading and invasion of the brain adjacent to tumor. Here we tested the activity of flavopiridol against tumors formed by GL261 cells, first as subcutaneous implants, and then in the intracranial model. We demonstrate efficacy of flavopiridol as a single modality treatment in delaying tumor growth in both animal models. We hypothesize that flavopiridol treatment induced tumor growth delay by two possible mechanisms involving growth arrest combined with recruitment of tumor cells to S-phase. Based on our findings, flavopiridol should be considered as a treatment approach for patients with high-grade glioma.

Topics: Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Cell Death; Cell Division; Female; Flavonoids; Glioma; Mice; Models, Animal; Piperidines; Tumor Cells, Cultured

We have performed an in vitro study of the growth-inhibitory capacity of the potent and long-acting NK1 receptor antagonist L-733,060, at concentrations ranging from 2.5 microM to 20 microM, against the neuroblastoma cell line SKN-BE(2) and 10 microM to 25 microM for glioma cell line GAMG. Coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)2-(4-sulfophenyl)-2H-tetrazolium], inner salt colorimetric method to evaluate cell viability in this cytotoxicity assay. L-733,060 inhibited the growth of the two cell lines studied in a dose-dependent manner. The IC 50 values were 11.6 microM (30h) and 10.2 microM (72h) for SKN-BE(2); and 21.3 microM (48h) and 19.9 microM (96h) for GAMG. These findings indicate that the NK1 receptor antagonist L-733,060 acts as a broad-spectrum antitumoural agent. This new action, reported here for the first time, suggests that the NK1 receptor antagonist L-733,060 could be a promising therapeutic drug for the treatment of human neuroblastoma and human glioma.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Glioma; Humans; Neuroblastoma; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Substance P

Malignant glioma is characterised by extensive neovascularisation, principally influenced by vascular endothelial growth factor (VEGF). ZD6474 is a potent inhibitor of VEGF-R2 tyrosine kinase activity, but with additional inhibitory effects on other growth factors. In this study, we have investigated the effects of ZD6474 with regard to tumour growth, neovascularisation, proliferation and apoptosis in the intracerebral rat glioma model, BT4C. ZD6474 (50 and 100 mg kg(-1)) was given as a daily oral gavage. Animals were killed on day 19 and tumour volume was measured. Sections were stained for factor VIII, Ki-67 and for apoptosis. The ability of ZD6474 to inhibit cell growth directly was examined in vitro, using the glioma cell line BT4C and the transformed rat brain endothelial cell line RBE4. Cell growth was analysed with fluorometric microculture cytotoxicity assay to quantify the cytotoxic effects. ZD6474 significantly decreased tumour volume compared to controls. Microvascular density increased after treatment with ZD6474, and tumour cell proliferation index was reduced. There was also an increase in tumour cell apoptosis. In vitro, the growth of both cell lines was significantly reduced. The results reported justify further experimental investigations concerning the effects of ZD6474 in malignant glioma alone or in combination with other modalities.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Division; Disease Models, Animal; Enzyme Inhibitors; Glioma; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Rats

In the brain, tumors may grow without inducing angiogenesis, via co-option of the dense pre-existent capillary bed. The purpose of this study was to investigate how this phenomenon influences the outcome of antiangiogenic therapy.. Mice carrying brain metastases of the human, highly angiogenic melanoma cell line Mel57-VEGF-A were either or not treated with different dosages of ZD6474, a vascular endothelial growth factor (VEGF) receptor 2 tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor. Effect of treatment was evaluated using contrast-enhanced magnetic resonance imaging (CE- MRI) and (immuno)morphologic analysis.. Placebo-treated Mel57-VEGF-A brain metastases evoked an angiogenic response and were highlighted in CE-MRI. After treatment with ZD6474 (100 mg/kg), CE-MRI failed to detect tumors in either prevention or therapeutic treatment regimens. However, (immuno)histologic analysis revealed the presence of numerous, small, nonangiogenic lesions. Treatment with 25 mg/kg ZD6474 also resulted in efficient blockade of vessel formation, but it did not fully inhibit vascular leakage, thereby still allowing visualization in CE-MRI scans.. Our data show that, although angiogenesis can be effectively blocked by ZD6474, in vessel-dense organs this may result in sustained tumor progression via co-option, rather than in tumor dormancy. Importantly, blocking VEGF-A may result in undetectability of tumors in CE-MRI scans, leading to erroneous conclusions about therapeutic efficacy during magnetic resonance imaging follow-up. The maintenance of VEGF-A-induced vessel leakage in the absence of neovascularization at lower ZD6474 doses may be exploited to improve delivery of chemotherapeutic agents in combined treatment regimens of antiangiogenic and chemotherapeutic compounds.

Topics: Angiogenesis Inhibitors; Animals; Brain; Brain Neoplasms; Cell Line, Tumor; Disease Progression; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Melanoma; Mice; Mice, Inbred BALB C; Necrosis; Neoplasm Metastasis; Neovascularization, Pathologic; Oligonucleotides, Antisense; Phenotype; Piperidines; Placebos; Quinazolines; RNA; Transfection; Treatment Outcome; Vascular Endothelial Growth Factor A

Flavopiridol is a synthetic flavone, which inhibits growth in vitro and in vivo of several solid malignancies such as renal, prostate, and colon cancers. It is a potent cyclin-dependent kinase inhibitor presently in clinical trials. In this study, we examined the effect of flavopiridol on a panel of glioma cell lines having different genetic profiles: five of six have codeletion of p16(INK4a) and p14(ARF); three of six have p53 mutations; and one of six shows overexpression of mouse double minute-2 (MDM2) protein. Independent of retinoblastoma and p53 tumor suppressor pathway alterations, flavopiridol induced apoptosis in all cell lines but through a caspase-independent mechanism. No cleavage products for caspase 3 or its substrate poly(ADP-ribose) polymerase or caspase 8 were detected. The pan-caspase inhibitor Z-VAD-fmk did not inhibit flavopiridol-induced apoptosis. Mitochondrial damage measured by cytochrome c release and transmission electron microscopy was not observed in drug-treated glioma cells. In contrast, flavopiridol treatment induced translocation of apoptosis-inducing factor from the mitochondria to the nucleus. The proteins cyclin D(1) and MDM2 involved in the regulation of retinoblastoma and p53 activity, respectively, were down-regulated early after flavopiridol treatment. Given that MDM2 protein can confer oncogenic properties under certain circumstances, loss of MDM2 expression in tumor cells could promote increased chemosensitivity. After drug treatment, a low Bcl-2/Bax ratio was observed, a condition that may favor apoptosis. Taken together, the data indicate that flavopiridol has activity against glioma cell lines in vitro and should be considered for clinical development in the treatment of glioblastoma multiforme.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; Blotting, Northern; Brain Neoplasms; Caspase 8; Caspase 9; Caspases; Cell Cycle Proteins; Cell Division; Cyclin-Dependent Kinases; Cytochrome c Group; Enzyme Inhibitors; Flavonoids; Flavoproteins; Flow Cytometry; Glioma; Humans; Immunoenzyme Techniques; Membrane Proteins; Microscopy, Electron; Nuclear Proteins; Piperidines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Retinoblastoma Protein; Tumor Cells, Cultured; Tumor Suppressor Protein p53

There are conflicting results concerning the receptor subtype(s) involved in calcium-mediated endothelin signaling in the glial cells. In order to elucidate the role of endothelin A and B receptors in these processes, we have studied the effect of a complex spectrum of endothelin receptor ligands on intracellular calcium concentration changes in proliferating and differentiated C6 rat glioma cells. Cell differentiation was induced by dibutyryl-cAMP and assessed by the glial fibrillar acidic protein content. Intracellular calcium changes were measured in cell suspensions using fluorescent probe Fura-2. The specific endothelin B receptor agonists sarafotoxin S6c and IRL-1620 did not influence the intracellular calcium concentration. However, calcium changes induced by endothelin-1 and especially by endothelin-3 after the pretreatment of cells with one of these endothelin B receptor specific agonists were significantly enhanced even above the values attained by the highest effective endothelin concentrations alone. Such endothelin B-receptor ligand-induced sensitization of calcium signaling was not observed in differentiated C6 cells. Moreover, endothelin-induced calcium oscillations in differentiated C6 cells were less inhibited by BQ-123 and BQ-788 than in their proliferating counterparts. In conclusion, the specific activation of endothelin B receptor in C6 rat glioma cells does not affect intracellular calcium per se, but probably does so through interaction with the endothelin A receptor. The pattern and/or functional parameters of endothelin receptors in C6 rat glioma cells are modified by cell differentiation.

Topics: Animals; Brain Neoplasms; Calcium; Cell Differentiation; Endothelin-1; Endothelin-3; Fluorescent Dyes; Fura-2; Glioma; Oligopeptides; Piperidines; Rats; Receptor Cross-Talk; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Signal Transduction; Tumor Cells, Cultured; Viper Venoms

Previous studies have demonstrated that astrocytomas express elevated levels of activated Ras.GTP despite the absence of activating Ras mutations. Farnesyl transferase inhibitors (FTIs) exert their antitumor effect in part through inhibition of Ras-mediated signaling. SCH66336 is a potent FTI presently undergoing clinical trials in patients with solid tumors. We evaluated the efficacy of SCH66336 against a panel of eight human astrocytoma cell lines and three human astrocytoma explant xenograft models in NOD-SCID mice. SCH66336 demonstrated variable antiproliferative effects against the cell lines, with IC(50) ranging from 0.6 microM to 32.3 microM. Two of the three human glioblastoma multiforme (GBM) xenografts demonstrated substantial growth inhibition in response to SCH66336, with up to 69% growth inhibition after 21 days of treatment. Drug efficacy could be accurately predicted using a combination of the H-, K-, and N-isotype-specific Ras.GTP levels. These data indicate that the absence of Ras mutations does not preclude chemotherapeutic efficacy by FTIs, that Ras is likely a major target of FTIs regardless of Ras mutational status, and that isotype-specific Ras.GTP levels are a promising marker of drug efficacy.

Topics: Alkyl and Aryl Transferases; Animals; Astrocytoma; Brain Neoplasms; Cell Division; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Glioblastoma; Guanosine Triphosphate; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Monomeric GTP-Binding Proteins; Mutation; Piperidines; Pyridines; ras Proteins; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The development of new therapeutic strategies is essential for the management of gliomas, one of the most malignant forms of cancer. We have shown previously that the growth of the rat glioma C6 cell line is inhibited by psychoactive cannabinoids (I. Galve-Roperh et al., Nat. Med., 6: 313-319, 2000). These compounds act on the brain and some other organs through the widely expressed CB(1) receptor. By contrast, the other cannabinoid receptor subtype, the CB(2) receptor, shows a much more restricted distribution and is absent from normal brain. Here we show that local administration of the selective CB(2) agonist JWH-133 at 50 microg/day to Rag-2(-/-) mice induced a considerable regression of malignant tumors generated by inoculation of C6 glioma cells. The selective involvement of the CB(2) receptor in this action was evidenced by: (a) the prevention by the CB(2) antagonist SR144528 but not the CB(1) antagonist SR141716; (b) the down-regulation of the CB(2) receptor but not the CB(1) receptor in the tumors; and (c) the absence of typical CB(1)-mediated psychotropic side effects. Cannabinoid receptor expression was subsequently examined in biopsies from human astrocytomas. A full 70% (26 of 37) of the human astrocytomas analyzed expressed significant levels of cannabinoid receptors. Of interest, the extent of CB(2) receptor expression was directly related with tumor malignancy. In addition, the growth of grade IV human astrocytoma cells in Rag-2(-/-) mice was completely blocked by JWH-133 administration at 50 microg/day. Experiments carried out with C6 glioma cells in culture evidenced the internalization of the CB(2) but not the CB(1) receptor upon JWH-133 challenge and showed that selective activation of the CB(2) receptor signaled apoptosis via enhanced ceramide synthesis de novo. These results support a therapeutic approach for the treatment of malignant gliomas devoid of psychotropic side effects.

Topics: Animals; Antineoplastic Agents; Apoptosis; Astrocytoma; Benzoxazines; Brain Neoplasms; Camphanes; Cannabinoids; Cell Division; Ceramides; Glioma; Growth Inhibitors; Humans; Mice; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Cannabinoids affect prostaglandin (PG) formation in the central nervous system through as yet unidentified mechanisms. Using H4 human neuroglioma cells, the present study investigates the effect of R(+)-methanandamide (metabolically stable analogue of the endocannabinoid anandamide) on the expression of the cyclooxygenase-2 (COX-2) enzyme. Incubation of cells with R(+)-methanandamide was accompanied by concentration-dependent increases in COX-2 mRNA, COX-2 protein, and COX-2-dependent PGE(2) synthesis. Moreover, treatment of cells with R(+)-methanandamide in the presence of interleukin-1beta led to an overadditive induction of COX-2 expression. The stimulatory effect of R(+)-methanandamide on COX-2 expression was mimicked by the structurally unrelated cannabinoid Delta(9)-tetrahydrocannabinol. Stimulation of both COX-2 mRNA expression and subsequent PGE(2) synthesis by R(+)-methanandamide was not affected by the selective CB(1) receptor antagonist AM-251 or the G(i/o) protein inactivator pertussis toxin. Enhancement of COX-2 expression by R(+)-methanandamide was paralleled by time-dependent phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK. Consistent with the activation of both kinases, R(+)-methanandamide-induced COX-2 mRNA expression and PGE(2) formation were abrogated in the presence of specific inhibitors of p38 MAPK (SB203580) and p42/44 MAPK activation (PD98059). Together, our results demonstrate that R(+)-methanandamide induces COX-2 expression in human neuroglioma cells via a cannabinoid receptor-independent mechanism involving activation of the MAPK pathway. In conclusion, induction of COX-2 expression may represent a novel mechanism by which cannabinoids mediate PG-dependent effects within the central nervous system.

Topics: Analgesics, Non-Narcotic; Arachidonic Acids; Blotting, Western; Brain Neoplasms; Cannabinoid Receptor Modulators; Cell Line; Central Nervous System; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Dronabinol; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Glioma; Humans; Imidazoles; Interleukin-1; Isoenzymes; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Pertussis Toxin; Phosphorylation; Piperidines; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Pyridines; Receptors, Cannabinoid; Receptors, Drug; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Tumor Cells, Cultured; Virulence Factors, Bordetella

Remifentanil hydrochloride is a new opioid rapidly metabolized by blood and tissue esterases. The swift degradation accounts for the elimination half-life (t1/2 beta) of < 10 min. An anesthetic agent allowing more rapid postoperative assessment of the neurosurgical patient would be beneficial. This study examined the effect of remifentanil on cerebral blood flow (CBF) reactivity to changes in the arterial pressure of carbon dioxide (PaCO2). Cerebral blood flow was measured with intravenous 133-Xenon during remifentanil/ nitrous oxide (N2O) anesthesia in 10 patients undergoing craniotomy. Cerebrovascular reactivity was determined by repeating CBF measurements after the addition of carbon dioxide (CO2) to the inspired gas mixture. The CBF increased from 21 +/- 6 to 31 +/- 7 ml/100 g/min as the PaCO2 increased from 27 +/- 4 to 36 +/- 3 mm Hg. The relative CBF reactivity was 3.6 +/- 1.2%/mm Hg CO2. During the CBF determinations, the doses of remifentanil administered were not significantly different (0.38 +/- 0.18 microgram/kg/min at hypocapnia vs. 0.34 +/- 0.16 microgram/kg/min at normocapnia). Electroencephalographic monitoring showed a spectral edge frequency of 26 +/- 1 Hz before induction, 25 +/- 1 Hz during maintenance of the remifentanil/N2O anesthetic (0.32 +/- 0.15 microgram/kg/ min), 24 +/- 1 Hz during hypocapnic CBF determination, and 24 +/- 2 Hz during normocapnic CBF determination. At the completion of the procedure, the patients responded to commands within 3.6 +/- 2.5 min and were extubated 7.2 +/- 4.5 min after the remifentanil/N2O was discontinued. In conclusion, absolute CBF values during remifentanil/N2O are similar to previously reported CBF values during fentanyl/N2O and isoflurane/N2O anesthesia, and cerebrovascular reactivity to CO2 remains intact.

Topics: Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Blood Pressure; Brain; Brain Neoplasms; Carbon Dioxide; Cerebrovascular Circulation; Craniotomy; Electroencephalography; Female; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Monitoring, Intraoperative; Nitrous Oxide; Partial Pressure; Piperidines; Regional Blood Flow; Remifentanil; Xenon Radioisotopes

1. The relationships between the K+ inward rectifier current present in neuroblastoma cells (IIR) and the current encoded by the human ether-á-go-go-related gene (HERG), IHERG, and the rapidly activating repolarizing cardiac current IK(r), were investigated in a rat dorsal root ganglion (DRG) x mouse neuroblastoma hybrid cell line (F-11) using pharmacological and biophysical treatments. 2. IIR shared the pharmacological features described for IK(r), including the sensitivity to the antiarrhythmic drugs E4301 and WAY-123,398, whilst responding to Cs+, Ba2+ and La3+ in a similar way to IHERG. 3. The voltage-dependent gating properties of IIR were similar to those of IK(r) and IHERG, although IIR outward currents were negligible in comparison. 4. In high K+ extracellular solutions devoid of divalent cations, IIR deactivation kinetics were removed resulting in long-lasting currents apparently activated in hyperpolarization, with a marked (2.7-fold) increase in conductance, as recorded from the instantaneous linear current-voltage relationship at -120 mV. Re-addition of Ca2+ restored the original closure of the channel whereas re-addition of Mg2+ reduced the peak current. 5. The IIR described here, the heart IK(r) and the IHERG could be successfully predicted by a unique kinetic model where the voltage dependencies of the activation/inactivation gates were properly voltage shifted. On the whole, IIR seems to be the first example of a HERG-type current constitutively expressed and operating in mammalian cells of the neuronal lineage.

Topics: Animals; Anti-Arrhythmia Agents; Benzimidazoles; Brain Neoplasms; Cation Transport Proteins; Cations, Divalent; DNA-Binding Proteins; Electrophysiology; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Ganglia, Spinal; Hybrid Cells; Ion Channel Gating; Kinetics; Membrane Potentials; Mice; Models, Biological; Neuroblastoma; Patch-Clamp Techniques; Piperidines; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Rats; Sulfanilamides; Trans-Activators

The effects of muscarine on whole-cell Ca2+ channel currents in SH-SY5Y cells were studied using conventional and perforated-patch-clamp techniques, with 10 mM Ba2+ as charge carrier. Muscarine (10-300 microM) caused concentration-dependent inhibitions of Ca2+ channel currents which were only reversible when perforated-patch recordings were used. Inhibition of currents was associated with slowing of activation kinetics in approximately 50% of cells. In the presence of 5 microM nifedipine, muscarine was still able to inhibit currents, but after pre-exposure of cells to 1 microM omega-conotoxin GVIA the inhibitory effects of muscarine were almost completely lost. In the presence of 100 microM muscarine, Bay K 8644 (5 microM) was still able to enhance current amplitudes. Pre-treatment of cells with pertussis toxin (250 ng/ml for 16-24 hr) or inclusion of 1 mM GDP-beta-S in the patch-pipette prevented the inhibitory actions of muscarine. Hexahydrosiladifenidol (0.1-1 microM) antagonized the actions of muscarine (calculated pA2 7.1) but the presence of 10 microM pirenzipine or 0.1 microM methoctramine in the bath solution did not alter the degree of current inhibition caused by 100 microM muscarine. In summary, these results indicate that muscarine in SH-SY5Y cells causes inhibition of N-type Ca2+ channels via a M3 receptor coupled to a pertussis toxin-sensitive G-protein.

Topics: Brain Neoplasms; Calcium Channel Blockers; GTP-Binding Proteins; Humans; Muscarine; Muscarinic Agonists; Neuroblastoma; Parasympatholytics; Patch-Clamp Techniques; Pertussis Toxin; Piperidines; Receptors, Muscarinic; Tumor Cells, Cultured; Virulence Factors, Bordetella

1. The aim of this study was to provide evidence that anpirtoline, which is an agonist at 5-HT1B and 5-HT1D receptors and also displays submicromolar affinity for 5-HT1A recognition sites, in addition, acts as an antagonist at 5-HT3 receptors. 2. In radioligand binding studies on rat brain cortical membranes, anpirtoline inhibited specific binding of [3H]-(S)-zacopride to 5-HT3 receptor recognition sites (pKi: 7.53). 3. In N1E-115 neuroblastoma cells in which [14C]-guanidinium was used as a tool to measure cation influx through the 5-HT3 receptor channel, the 5-HT-induced influx was concentration-dependently inhibited by anpirtoline. In this respect, anpirtoline mimicked other 5-HT3 receptor antagonists; the rank order of potency was ondansetron > anpirtoline > metoclopramide. 4. The concentration-response curve for 5-HT as a stimulator of [14C]-guanidinium influx was shifted to the right by anpirtoline (apparent pA2: 7.78). 5. In urethane-anaesthetized rats, anpirtoline inhibited (at lower potency than zacopride and tropisetron) the 5-HT- or phenylbiguanide-induced bradycardia (Bezold-Jarisch reflex), but did not induce this reflex by itself. 6. Intravenous infusion of cisplatin in the domestic pig caused a consistent emetic response which was antagonized by anpirtoline. 7. It is concluded that anpirtoline, which was previously characterized as a 5-HT1 receptor agonist also proved to be a 5-HT3 receptor antagonist in several experimental models and, hence, exhibits a unique pattern of properties at different 5-HT receptors.

Topics: Animals; Antidepressive Agents; Antiemetics; Brain Neoplasms; Cisplatin; Entorhinal Cortex; In Vitro Techniques; Male; Mice; Neuroblastoma; Piperidines; Pyridines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Reflex; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Swine; Tumor Cells, Cultured

Topics: Adolescent; Adult; Aged; Amygdala; Astrocytoma; Brain Neoplasms; Central Nervous System Diseases; Cerebral Cortex; Chronic Disease; Electroencephalography; Electrophysiology; Epilepsy, Temporal Lobe; Female; Humans; Male; Mental Disorders; Middle Aged; Parasympatholytics; Piperidines; Temporal Lobe