piperidines and Skin-Neoplasms

The treatment of metastatic melanoma has been revolutionized by the introduction of immune checkpoint inhibitors and BRAF/MEK inhibition. Nevertheless, almost half of patients will progress or show primary resistance to treatment. The combination of BRAF/MEK and immune checkpoint inhibition might achieve higher response rates and improve long-term disease control. The IMspire150 trial investigated the combination of atezolizumab, cobimetinib and vemurafenib versus cobimetinib and vemurafenib alone.. This review covers the efficacy and safety of atezolizumab, cobimetinib and vemurafenib for patients with advanced or metastatic BRAF mutant melanoma. The combination is compared with the current standard of care including BRAF/MEK inhibition and treatment with immune checkpoint inhibitors.. Atezolizumab plus cobimetinib and vemurafenib showed superior progression-free survival in metastatic melanoma compared to cobimetinib and vemurafenib alone. Triplet therapy might be an option in situations of urgent need for disease control, when oncologists choose BRAF/MEK inhibition over immune checkpoint inhibition as first line treatment. At this time results are not mature yet, and longer follow-up including overall survival data is needed. The future role of this combination will also be determined by a comparison with the combination of ipilimumab and nivolumab.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Immune Checkpoint Inhibitors; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival in patients with BRAF V600-mutated melanoma. BRAF mutations are also frequently detected driver mutations in other tumor types, including thyroid carcinoma. Since thyroid carcinoma is not a labeled indication for BRAF/MEKi, a cohort for patients with BRAF V600-mutated thyroid carcinoma was opened within the Drug Rediscovery Protocol (DRUP), a national ongoing pan-cancer multi-drug trial, in which patients receive off-label treatment with approved drugs based on their molecular tumor profile.. Here, we present two patients with BRAF-mutated thyroid carcinoma, who were successfully treated with vemurafenib/cobimetinib administered via a feeding tube. Plasma concentrations of vemurafenib and cobimetinib were determined. A partial response was observed in both patients, but they experienced significant toxicity.. Our cases show that vemurafenib/cobimetinib treatment is effective in BRAF V600-mutated thyroid carcinoma, also when administered via a feeding tube. Although serious side effects occurred in both patients, we hypothesize that this was not attributable to the administration route. Therefore, administration of vemurafenib/cobimetinib by feeding tube is feasible and effective.. Clinical trial identification: NCT02925234.

Topics: Antineoplastic Agents; Azetidines; Humans; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Thyroid Neoplasms; Vemurafenib

The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination.

Topics: Antibodies, Monoclonal, Humanized; Azetidines; Dermatitis, Atopic; Humans; Interleukins; Janus Kinases; Lymphoma; Lymphoma, Primary Cutaneous Anaplastic Large Cell; Nitriles; Piperidines; Purines; Pyrazoles; Pyrimidines; Signal Transduction; Skin Neoplasms; STAT Transcription Factors; Sulfonamides; Tumor Microenvironment

We sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS.. Recursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAF. RPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3-16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8-2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments.. A combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment. Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dacarbazine; Humans; Melanoma; Mutation; Piperidines; Prognosis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety.. A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments.. The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).. Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Cancer Vaccines; Carboplatin; Dacarbazine; gp100 Melanoma Antigen; Humans; Hydrazines; Imidazoles; Interleukin-2; Ipilimumab; Lenalidomide; Melanoma; Network Meta-Analysis; Nitrosourea Compounds; Nivolumab; Organophosphorus Compounds; Oximes; Paclitaxel; Piperidines; Progression-Free Survival; Proportional Hazards Models; Pyridones; Pyrimidinones; Skin Neoplasms; Sorafenib; Survival Rate; Temozolomide; Treatment Outcome; Vemurafenib

With a rapidly evolving complement of advanced targeted therapies in inflammatory bowel disease, additional safety and side effect concerns emerge. It is the purpose of this review to consider various risks with biologic therapies in inflammatory bowel disease and discuss mitigating strategies.. Two recently approved monoclonal antibodies (vedolizumab and ustekinumab) and a Janus kinase inhibitor small molecule (tofacitnib) have introduced a number of novel safety and risk considerations. We review the clinical trial and real-world safety data to date on these agents as well as review new data and considerations with anti-tumor necrosis factor agents. New vaccines for varicella zoster virus, hepatitis B virus, and high-dose influenza have been studied, and we discuss the clinical importance of these findings. Lastly, we make management recommendations in the event of particular side effects or complications. Understanding the risks of new agents in inflammatory bowel disease, potential mitigating strategies, and management considerations is important to achieving and maintaining clinical outcomes in IBD patients.

Topics: Antibodies, Monoclonal, Humanized; Biological Products; Demyelinating Diseases; Deprescriptions; Drug Substitution; Gastrointestinal Agents; Humans; Infections; Inflammatory Bowel Diseases; Lymphoma; Melanoma; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk; Risk Assessment; Skin Neoplasms; Tumor Necrosis Factor-alpha; Ustekinumab

Approximately 50% of cutaneous melanomas harbor activating mutations of the BRAF-oncogene, making BRAF inhibitors (BRAFi) the standard treatment for this disease. However, disease responses are limited in duration mainly due to acquired resistance. Dual MAPK pathway inhibition with addition of a MEK inhibitor (MEKi) to a BRAFi improved the efficacy and tolerability compared with BRAFi alone. Cobimetinib (Cotellic

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; MAP Kinase Kinase 1; MAP Kinase Signaling System; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Survival Analysis; Time Factors; Treatment Outcome

New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Humans; Imidazoles; Immunologic Factors; Indoles; Ipilimumab; Melanoma; Molecular Targeted Therapy; Nivolumab; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

The use of biologics such as anti-tumor necrosis factor and oral Janus kinase inhibitors have revolutionized the treatment of rheumatoid arthritis (RA). The risk of malignancies such as lymphomas, lung cancer, and nonmelanoma skin cancers (NMSCs) is greater in patients with RA compared with the general population. The incidence of all malignancy (excluding NMSC) was similar in tofacitinib users compared with the general population. The rates of overall and site-specific malignancies in patients with RA treated with tofacitinib are similar to what is expected in the RA population and not different from disease-modifying antirheumatic drugs and biologics.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Incidence; Janus Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms

Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations. Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT. Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.

Topics: Benzamides; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Piperidines; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-kit; Pyridines; Skin Neoplasms; Sulfonamides; Thiazoles

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; 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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; 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

Background CD30+ lymphoproliferative disorders are rare and may feature a wide variety of presentations that mimic other conditions. Purpose A man with metastatic papillary thyroid carcinoma to skin who subsequently developed cutaneous anaplastic large cell lymphoma is described. Methods The PubMed medical database was used to search the following terms separately and in combination: ALCL, anaplastic large cell lymphoma ALCL, cutaneous anaplastic large cell lymphoma CALCL, cutaneous t-cell lymphoma CTCL, large t-cell lymphoma LTCL, lymphoproliferative, lymphomatoid papulosis LyP, mimic, papillary, thyroid cancer. Results CD30+ cutaneous anaplastic large cell lymphoma was diagnosed in a man with metastatic papillary thyroid carcinoma based on the temporal, histologic, and immunochemical features of an enlarging lesion. To the best of our knowledge, this is the initial description of a CD30+ lymphoproliferative disorder occurring in a patient with primary carcinoma of the thyroid. Conclusion Cutaneous lesions may present with various morphologies. Our patient had a previous history of metastatic papillary thyroid carcinoma to skin. His new chest lesion was originally suspected to be either an infection or a cutaneous metastasis. Multiple biopsies, not only for microscopic evaluation but also cultures for infectious organisms, were performed. Unexpectedly, a CD30+ lymphoproliferative disorder was diagnosed; subsequently the tumor spontaneously resolved. Therefore, when skin lesions appear that have more than one clinical presentation, it may be prudent for the clinician to collect representative samples of each distinct morphology to assure that an accurate diagnosis is established.

Topics: Aged; Carcinoma; Carcinoma, Papillary; Humans; Immunohistochemistry; Ki-1 Antigen; Lymphoma, Large-Cell, Anaplastic; Lymphoproliferative Disorders; Male; Neoplasms, Multiple Primary; Piperidines; Quinazolines; Skin Neoplasms; Thoracic Wall; Thyroid Cancer, Papillary; Thyroid Neoplasms

Cobimetinib combined with vemurafenib is a new approved MEK inhibitor for first line treatment of metastatic melanoma patients with BRAF V600 mutations. It improves tumor response rates and progression free survival compared to vemurafenib alone, while decreasing toxicities due to the paradoxical activation of the MAPK signaling pathway.. This review covers the pharmacology, efficacy, and toxicity data derived from clinical and preclinical studies on cobimetinib. It also reports ongoing trials evaluating cobimetinib to better understand future developments for this drug.. The combination of cobimetinib and vemurafenib seems to be more toxic than the combination therapy dabrafenib and trametinib even if these four drugs have never been compared in a randomized trial. The future of this combination depends on its capacity to be combined simultaneously or sequentially with immune based therapies to improve the durability of responses.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Indoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Melanoma causes the majority of skin cancer-related deaths. The outcome of melanoma depends on its stage at diagnosis. Currently, for patients with advanced melanoma, two MEK inhibitors (trametinib and cobimetinib) have been authorized by the European Medicines Agency. The main objective of this study was to compare the relative efficacy of trametinib-dabrafenib and cobimetinib-vemurafenib in patients with advanced melanoma through adjusted indirect treatment comparisons (ITCs).. A search was made up to the 3rd of November 2015. Databases consulted were MEDLINE, the Cochrane Library and the Centre for Reviews and Dissemination. Randomized controlled trials (RCTs) which compared the efficacy of trametinib-dabrafenib or cobimetinib-vemurafenib versus a common treatment comparator, in which outcomes of overall survival, progression-free survival (PFS) and overall response rate (ORR) were considered. ITCs were carried out using the method proposed by Bucher et al.. Two RCTs were included (one for each drugs combination). The results of the adjusted ITCs showed that there were no statistically significant differences between the two combinations in terms of PFS and ORR.. The ITCs indicate no difference in efficacy between both treatments. However, there should be an independent, head-to-head trial of both combinations to confirm the results.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Disease-Free Survival; Humans; Imidazoles; Indoles; Melanoma; Neoplasm Staging; Oximes; Piperidines; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Skin Neoplasms; Sulfonamides; Survival Rate; Treatment Outcome; Vemurafenib

In the recent years, melanoma patients' outcome and survival improved, mainly because of systemic treatment improvement with targeted therapy and checkpoint blockade. Targeted therapy with BRAF and MEK inhibitors was approved to treat patients with unresectable or metastatic melanoma, harboring BRAF V600 mutations. This paper addresses the safety and efficacy of cobimetinib, when used in combination with vemurafenib, in the previous mentioned setting.. This article presents an overview on the rationale for clinical development of cobimetinib, as well as the mechanism of action, the efficacy and safety, and the most important trials that led to the approval of the combination therapy with vemurafenib. We searched the PubMed for published papers related to safety and efficacy of cobimetinib, and resistance mechanisms to BRAF inhibition. The abstract databases of the American Society of Clinical Oncology and European Society for Medical Oncology were also searched for updates on the mentioned clinical trials. Expert commentary: Patients treated with targeted therapy experience a rapid tumor response. However, virtually all patients will develop resistance to treatment. Therapeutic combinations to overcome resistance mechanisms are currently addressed. In the future, targeted therapy strategy will include three or more drugs, probably from different therapeutic classes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Resistance, Neoplasm; Humans; Indoles; Melanoma; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

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

Genentech (a subsidiary of Roche) and Exelixis are developing cobimetinib, an orally available small molecule, for the treatment of various cancers, including malignant melanoma and breast cancer. Cobimetinib inhibits the MEK (mitogen-activated protein kinase) component of the MAPK/ERK signalling pathway, which is frequently over-activated in human tumours. The product has been approved in Switzerland in combination with vemurafenib for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma, and is under regulatory review for the same indication in several countries, including the USA and the EU. This article summarizes the milestones in the development of cobimetinib leading to this first approval for unresectable or metastatic BRAF V600 mutation-positive melanoma melanoma.

Topics: Animals; Antineoplastic Agents; Azetidines; Drug Approval; Humans; MAP Kinase Signaling System; Melanoma; Melanoma, Cutaneous Malignant; Mitogen-Activated Protein Kinases; Piperidines; Skin Neoplasms

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program.. Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis.. Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years' treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors.. For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Skin Neoplasms

Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance.. In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1).. Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6-18.4 months) and a median overall survival of 31.0 months (range: 19.8-42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0-8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP.. Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. Vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment.. The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Cell Cycle Proteins; GPI-Linked Proteins; Humans; Interferons; Melanoma; Mice; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses.. We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930).. Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets.. Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Female; Humans; Interleukin-2; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Piperidines; Skin Neoplasms

The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.. Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).. 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.. Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Follow-Up Studies; Humans; Melanoma; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Prognostic groups defined by lactate dehydrogenase concentration and number of organ sites containing metastases have been reported for patients treated with dabrafenib and trametinib for advanced melanoma. We aimed to validate these prognostic groups for patients treated with vemurafenib and cobimetinib in the coBRIM and BRIM-3 clinical studies. Eight hundred nine patients were included, 240 treated with vemurafenib plus cobimetinib and 569 with vemurafenib. For patients treated with vemurafenib and cobimetinib, both overall survival (P < 0.001, c-statistic = 0.72) and progression-free survival (P < 0.001, c-statistic = 0.65) differed markedly between prognostic groups. Two-year progression-free survival ranged from 3 (lactate dehydrogenase ≥2 times the upper limit of normal) to 50% (normal lactate dehydrogenase and ≤3 sites), and two-year overall survival ranged from 7 to 71%. For patients treated with vemurafenib monotherapy, overall survival (P < 0.001, c-statistic = 0.66) and progression-free survival (P < 0.001, c-statistic = 0.62) also differed significantly between prognostic groups. In conclusion, prognostic groups identified for patients treated with dabrafenib and trametinib are also applicable to patients treated with vemurafenib and cobimentinib.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers; Female; Humans; Imidazoles; L-Lactate Dehydrogenase; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Oximes; Piperidines; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Vemurafenib

To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study.. Median OS was 31.8 months [95% confidence interval (CI), 24.5-not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy-PD cohort, the median OS was 8.5 months (95% CI, 6.7-11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events.. A subset of patients with advanced

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Cohort Studies; Disease-Free Survival; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Mutation; Patient Safety; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Treatment Outcome; Vemurafenib; Young Adult

Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF. In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms.. Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014).. Cobimetinib treatment was associated with serous retinopathy in patients with BRAF

Topics: Adult; Aged; Azetidines; Central Serous Chorioretinopathy; Female; Humans; Indoles; Male; Melanoma; Middle Aged; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Recurrence; Skin Neoplasms; Sulfonamides; Time Factors; Vemurafenib

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

Topics: Acrylamides; Adult; Aged; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Patient Safety; Piperidines; Prognosis; Risk Assessment; Skin Neoplasms; Survival Analysis; Treatment Outcome

The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.. In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.. Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.. These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma.. F Hoffmann-La Roche-Genentech.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers, Tumor; Double-Blind Method; Female; Follow-Up Studies; Humans; Indoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Piperidines; Prognosis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Survival Rate; Vemurafenib; Young Adult

This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients.. Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0-3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings.. No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement.. The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cell Cycle Proteins; Drug Administration Schedule; Endothelin B Receptor Antagonists; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Injections, Intralesional; Male; Melanoma; Middle Aged; Minor Histocompatibility Antigens; Oligopeptides; Piperidines; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Receptor, Endothelin B; Skin Neoplasms; Treatment Outcome

Addition of a MEK inhibitor to a BRAF inhibitor enhances tumour growth inhibition, delays acquired resistance, and abrogates paradoxical activation of the MAPK pathway in preclinical models of BRAF-mutated melanoma. We assessed the safety and efficacy of combined BRAF inhibition with vemurafenib and MEK inhibition with cobimetinib in patients with advanced BRAF-mutated melanoma.. We undertook a phase 1b study in patients with advanced BRAF(V600)-mutated melanoma. We included individuals who had either recently progressed on vemurafenib or never received a BRAF inhibitor. In the dose-escalation phase of our study, patients received vemurafenib 720 mg or 960 mg twice a day continuously and cobimetinib 60 mg, 80 mg, or 100 mg once a day for either 14 days on and 14 days off (14/14), 21 days on and 7 days off (21/7), or continuously (28/0). The primary endpoint was safety of the drug combination and to identify dose-limiting toxic effects and the maximum tolerated dose. Efficacy was a key secondary endpoint. All patients treated with vemurafenib and cobimetinib were included in safety and efficacy analyses (intention-to-treat). The study completed accrual and all analyses are final. This study is registered with ClinicalTrials.gov, number NCT01271803.. 129 patients were treated at ten dosing regimens combining vemurafenib and cobimetinib: 66 had recently progressed on vemurafenib and 63 had never received a BRAF inhibitor. Dose-limiting toxic effects arose in four patients. One patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 80 mg once a day 14/14 had grade 3 fatigue for more than 7 days; one patient on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg once a day 21/7 had a grade 3 prolongation of QTc; and two patients on a schedule of vemurafenib 960 mg twice a day and cobimetinib 60 mg 28/0 had dose-limiting toxic effects-one developed grade 3 stomatitis and fatigue and one developed arthralgia and myalgia. The maximum tolerated dose was established as vemurafenib 960 mg twice a day in combination with cobimetinib 60 mg 21/7. Across all dosing regimens, the most common adverse events were diarrhoea (83 patients, 64%), non-acneiform rash (77 patients, 60%), liver enzyme abnormalities (64 patients, 50%), fatigue (62 patients, 48%), nausea (58 patients, 45%), and photosensitivity (52 patients, 40%). Most adverse events were mild-to-moderate in severity. The most common grade 3 or 4 adverse events were cutaneous squamous-cell carcinoma (12 patients, 9%; all grade 3), raised amounts of alkaline phosphatase (11 patients, 9%]), and anaemia (nine patients, 7%). Confirmed objective responses were recorded in ten (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2·8 months (95% CI 2·6-3·4). Confirmed objective responses were noted in 55 (87%) of 63 patients who had never received a BRAF inhibitor, including six (10%) who had a complete response; median progression-free survival was 13·7 months (95% CI 10·1-17·5).. The combination of vemurafenib and cobimetinib was safe and tolerable when administered at the respective maximum tolerated doses. The combination has promising antitumour activity and further clinical development is warranted in patients with advanced BRAF(V600)-mutated melanoma, particularly in those who have never received a BRAF inhibitor; confirmatory clinical testing is ongoing.. F Hoffmann-La Roche/Genentech.

Topics: Adult; Aged; Azetidines; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Indoles; Infusions, Intravenous; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Risk Assessment; Skin Neoplasms; Sulfonamides; Survival Rate; Treatment Outcome; Vemurafenib

No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting.. In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095.. Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group).. Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted.. AstraZeneca.

Topics: Adenocarcinoma, Follicular; Adolescent; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Carcinoma, Papillary; Diarrhea; Disease-Free Survival; Double-Blind Method; Electrocardiography; ErbB Receptors; Female; Heart Conduction System; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Skin Neoplasms; Survival Analysis; Thyroid Cancer, Papillary; Thyroid Neoplasms; Young Adult

In patients with ulcerative colitis (UC), risks of infection and malignancies increase with age. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. This analysis assessed age as a risk factor for adverse events of special interest (AESI) in the tofacitinib UC clinical program.. Data were from phase 2 and 3 induction studies, a phase 3 maintenance study, and an open-label, long-term extension study. Efficacy and/or safety outcomes were analyzed in the Induction, Maintenance, and Overall Cohorts (patients who received ≥ 1 dose of tofacitinib), stratified by age. The effects of baseline demographic and disease-related factors on AESI incidence were assessed by Cox proportional-hazards regression analysis.. In the Overall Cohort (1157 patients with ≤ 6.8 years' tofacitinib treatment), age was a statistically significant predictor of herpes zoster (HZ), malignancies excluding nonmelanoma skin cancer (NMSC), and NMSC. Other statistically significant predictors included prior tumor necrosis factor inhibitor failure for HZ, NMSC, and opportunistic infection events, and prior duration of UC for malignancies excluding NMSC. In the Induction and Maintenance Cohorts, a higher proportion of tofacitinib-treated than placebo-treated patients (numerical difference) achieved the efficacy endpoints (endoscopic improvement, clinical remission, clinical response) across all age groups.. Older individuals receiving tofacitinib as induction and maintenance therapy to treat UC may have an increased risk of HZ, malignancies (excluding NMSC), and NMSC versus similarly treated younger patients, consistent with findings from the general population. Across all age groups, tofacitinib demonstrated greater efficacy than placebo as an induction and maintenance therapy.. NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.. Age was assessed as a risk factor for adverse events of special interest in the tofacitinib ulcerative colitis clinical program. Older individuals receiving tofacitinib may have an increased risk of herpes zoster, malignancies (excluding nonmelanoma skin cancer), and nonmelanoma skin cancer versus similarly treated younger patients.

Topics: Colitis, Ulcerative; Herpes Zoster; Herpesvirus 3, Human; Humans; Janus Kinase Inhibitors; Piperidines; Skin Neoplasms

5-aminolevulinic acid-mediated PDT (ALA-PDT) has been used in a variety of skin diseases including cSCC (cutaneous squamous cell carcinoma). Halofuginone (HL) is a less-toxic febrifugine derivative and has inhibitory effects on a variety of cancer cells. For now, there are no published study focusing on the combination use of ALA-PDT with HL to improve clinical efficacy of cSCC.. In this study, we will examine the effectiveness of combined treatment of ALA-PDT and HL in cSCC as well as its underlying mechanism.. The human epidermoid carcinoma cell line SCL-1 was treated with ALA-PDT or/ and HL, and cell viability, cell migration, ROS production, apoptosis were evaluated by CCK-8, colony formation, scratch assay, DCFH-DA probe, flow cytometry, respectively. The protein expression of NRF2 signaling was examined by western blot.. HL strengthened ALA-PDT's inhibition of SCL-1 cell viability, migration, as well as NRF2 related β-catenin, p-Erk1/2, p-Akt and p-S6K1 expression. Overexpression of NRF2 conferred resistance to co-treatment's effects on c-Myc, Cyclin D1, Bcl-2, as well as cell proliferation. HL also strengthened ALA-PDT's inhibition of tumor volume in cSCC mouse model and elevated ROS generation of ALA-PDT.. HL enhances the anti-tumor effect of ALA-PDT in vitro and in vivo. HL has the potential to enhance the anti-tumor effect of ALA-PDT in cSCC via inhibiting NRF2 signaling.

Topics: Aminolevulinic Acid; Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Mice; NF-E2-Related Factor 2; Photochemotherapy; Photosensitizing Agents; Piperidines; Quinazolinones; Skin Neoplasms

Topics: Adenine; Adverse Drug Reaction Reporting Systems; Humans; Pharmacovigilance; Piperidines; Skin Neoplasms; United States; United States Food and Drug Administration

Topics: Anemia; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Stevens-Johnson Syndrome; Vemurafenib

Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC

Topics: Apoptosis; Azetidines; Cell Line; Humans; Melanoma; Naphthoquinones; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

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

Cancers have a strong relationship with immune cells in their microenvironment, which significantly influences tumor proliferation and progression. Thus, pharmacological strategies that stimulate the immune system to combat tumor cells are promising for better therapeutic efficacy. Deregulated expression of the splicing regulatory serine arginine protein kinases (mostly SRPK1 and SRPK2) has been found in different cancer types, leading to the expression of isoforms related to tumor growth and metastasis. The microenvironment of melanoma exhibits a strong presence of immune cells, which significantly influences tumor progression, and around 50% of cutaneous melanoma patients benefit from targeted immunotherapy. Here, we analyzed human malignant melanoma single-cell gene expression data and observed that SRPK1/2 overexpression correlates with immune system pathway alterations. In further analysis, we observed an increased presence of immune cells in biopsies from mice bearing metastatic melanoma treated with SRPIN340, a well-known SRPK1/2 pharmacological inhibitor. Local treatments increased the expression of proinflammatory cytokines at the tumor lesions and the activity of the spleen, accompanied by reduced pulmonary metastasis foci, edema formation, and alveolar congestion. In in vitro assays, SRPIN340 also potentiated immunological susceptibility, by increasing the expression of the antigen presenting MHCI and MHCII molecules and by increasing the ability of B16F10 cells to attract splenic cells in transwell assays. Taken together, these results reveal that the antimetastatic effect of SRPIN340 can also involve an increased immune response, which suggests additional functional clues for SRPKs in tumor biology.

Topics: Animals; Humans; Immunity; Melanoma; Mice; Niacinamide; Piperidines; Protein Serine-Threonine Kinases; Skin Neoplasms; Tumor Microenvironment

Skin cancer is one of the most dangerous diseases, leading to massive losses and high death rates worldwide. Topical delivery of nutraceuticals is considered a suitable approach for efficient and safe treatment of skin cancer. Nobiletin; a flavone occurring in citrus fruits has been reported to inhibit proliferation of carcinogenesis since 1990s, is a promising candidate in this regard. Nobiletin was loaded in various vesicular systems to improve its cytotoxicity against skin cancer. Vesicles were prepared using the thin film hydration method, and characterized for particle size, zeta potential, entrapment efficiency, TEM, ex-vivo skin deposition and physical stability. Nobiletin-loaded composite penetration enhancer vesicles (PEVs) and composite transfersomes exhibited particle size 126.70 ± 11.80 nm, 110.10 ± 0.90 nm, zeta potential + 6.10 ± 0.40 mV, + 9.80 ± 2.60 mV, entrapment efficiency 93.50% ± 3.60, 95.60% ± 1.50 and total skin deposition 95.30% ± 3.40, 100.00% ± 2.80, respectively. These formulations were selected for cytotoxicity study on epidermoid carcinoma cell line (A431). Nobiletin-loaded composite PEVs displayed the lowest IC

Topics: Animals; Anthracenes; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Carriers; Drug Compounding; Flavones; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Male; Mice; MicroRNAs; Particle Size; Piperidines; Skin Neoplasms; Xenograft Model Antitumor Assays

A series of novel ibrutinib analogues was synthesized, and their proliferation inhibitory activities against various B lymphoma cell lines (DaudiB and Raji) and solid tumor cells (B16, CT26, HepG2 and 4T1) were evaluated. The most potent compound, YL7, exhibited strong antiproliferative activity in all cell lines, and its IC

Topics: Adenine; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Melanoma; Melanoma, Cutaneous Malignant; Mice; Molecular Structure; Piperidines; Skin Neoplasms; Structure-Activity Relationship

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]).. Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated.. The overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46-1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time.. In the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

Topics: Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms; Treatment Outcome

The outcomes of patients with metastatic melanoma (MM) have significantly improved after the introduction of BRAF-specific inhibitors. Herein is reported a patient with MM and non-V600-BRAF mutation who responded to iBRAF/iMEK therapy. In July 2014, a 63-year-old man presented with a 4.1mm-thick V600E-BRAF wild type melanoma on the back. Metastases were identified in one sentinel node and two of 11 subsequently excised lymph nodes, with no signs of distant metastatic disease. In September 2017, lung metastasis was observed and pembrolizumab was started. Progressive disease was apparent at cycle 10 and therapy was switched to ipilimumab. After four cycles, an asymmetric response was observed. In November 2017, next generation sequencing genomic profiling disclosed a rare L597K-BRAF mutation and vemurafenib plus cobimetinib therapy was initiated in January 2018. Seven days after treatment start, a remarkable clinical improvement was observed. In April 2018, the patient achieved partial response, which was sustained until October 2018. Cases of patients with non-V600-BRAF mutations responding to iBRAF/iMEK therapy have been reported over the last years. To the best of our knowledge, this is the first case reporting response to combined iBRAF/iMEK therapy in a patient with metastatic melanoma harboring L597K mutation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Back; Dacarbazine; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers, Tumor; Female; Gene Fusion; Humans; Immune Checkpoint Inhibitors; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

Skin cancer is an alarming concern due to increased radiation and chemical exposure. Doxorubicin is a drug prescribed for various cancers by parenteral route. Apart from the pharmaceutical challenge of being a biopharmaceutical classification system (BCS) Class III drug, the side effects of doxorubicin are also a great concern. With an aim to enhance its safety and bioavailability, a phospholipid-based micellar system was developed. The developed nanometric and symmetric carriers not only offered substantial drug loading, but also offered a temporal drug release for longer durations. The pH-dependent drug release assured the spatial delivery at the target site, without loss of drug in the systemic circulation. The cancer cell toxicity studies along with the in vivo anti-tumor studies established the superior efficacy of the developed system. The blood profile studies and the biochemical estimations confirmed the safety of the developed nanocarriers. Lesser amount of drug was available for the microsomal degradation, as inferred by the biodistribution studies. The findings provide a proof of concept for the safer and effective doxorubicin delivery employing simple excipients like phospholipids for the management of skin cancer.

Topics: Animals; Anthracenes; Antibiotics, Antineoplastic; Carcinogens; Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Delivery Systems; Female; Humans; Mice; Mice, Inbred BALB C; Micelles; Nanostructures; Particle Size; Phospholipids; Piperidines; Skin Neoplasms; Tissue Distribution

Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.. This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.. In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).. In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Cardiovascular Diseases; Colonic Neoplasms; Cross-Sectional Studies; Female; Heart Failure; Humans; Hypertension; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Registries; Regression Analysis; Skin Neoplasms; Sulfonamides; Vemurafenib; Venous Thromboembolism; Young Adult

To investigate efficacy of masitinib mesylate for the treatment of advanced malignant melanoma in dogs.. Prospective clinical trial on 17 dogs with stage III and IV malignant melanoma (two digital, one anal and 14 oral mucosal). Only dogs with advanced gross disease for which the owner declined conventional treatment or dogs with progressive tumour despite conventional treatment were included.. There was a partial response in two dogs, stable disease in seven and tumour progression in eight dogs. Median survival time for all 17 dogs was 119 days (range 21-255). Masitinib was generally well-tolerated but grade 2 anaemia, grade 1 neutropenia, grade 1 diarrhoea and grade 2 anorexia were observed in one dog each.. There was only mild effectiveness in end-stage disease, indicating that masitinib mesylate is not an appropriate sole-agent option for treatment of advanced malignant melanoma in dogs.

Topics: Animals; Benzamides; Dog Diseases; Dogs; Melanoma; Piperidines; Prospective Studies; Pyridines; Skin Neoplasms; Thiazoles

Gain-of-function mutations in KIT are driver events of oncogenesis in mast cell tumours (MCTs) affecting companion animals. Somatic mutations of KIT determine the constitutive activation of the tyrosine kinase receptor leading to a worse prognosis and a shorter survival time than MCTs harbouring wild-type KIT. However, canine MCTs carrying KIT somatic mutations generally respond well to tyrosine kinase inhibitors; hence their presence represents a predictor of treatment effectiveness, and its detection allows implementing a stratified medical approach. Despite this, veterinary oncologists experience treatment failures, even with targeted therapies whose cause cannot be elucidated. The first case of an MCT-affected dog caused by a secondary mutation in the tyrosine kinase domain responsible for resistance has recently been reported. The knowledge of this and all the other mutations responsible for resistance would allow the effective bedside implementation of a deeply stratified and more effective medical approach.. The second case of a canine MCT carrying a different resistance mutation is herein described. The case was characterised by aggressive behaviour and early metastasis unresponsive to both vinblastine- and masitinib-based treatments. Molecular profiling of the tumoural masses revealed two different mutations; other than the already known activating mutation p.Asn508Ile in KIT exon 9, which is tyrosine kinase inhibitor-sensitive, a nearly adjacent secondary missense mutation, p.Ala510Val, which had never before been described, was detected. In vitro transfection experiments showed that the secondary mutation did not cause the constitutive activation by itself but played a role in conferring resistance to masitinib.. This study highlighted the importance of the accurate molecular profiling of an MCT in order to improve understanding of the molecular mechanism underlying tumourigenesis and reveal chemoresistance in MCTs for more effective therapies. The detection of the somatic mutations responsible for resistance should be included in the molecular screening of MCTs, and a systematic analysis of all the cases characterised by unexpected refractoriness to therapies should be investigated in depth at both the genetic and the phenotypic level.

Topics: Animals; Antineoplastic Agents; Benzamides; Dog Diseases; Dogs; Drug Resistance, Neoplasm; Female; Gain of Function Mutation; HEK293 Cells; Humans; Mastocytosis, Cutaneous; Piperidines; Proto-Oncogene Proteins c-kit; Pyridines; Skin Neoplasms; Thiazoles; Vinblastine

Rash is one of the most common severe adverse events associated with use of vemurafenib for the treatment of melanoma, either as monotherapy or in combination with cobimetinib. The study aimed to identify pre-treatment patient characteristics predictive of developing severe rash with vemurafenib therapy.. This was a secondary pooled analysis of individual patient data from the BRIM-2, BRIM-3 and coBRIM clinical trials, including all patients treated with vemurafenib alone and vemurafenib plus cobimetinib. Patient age, sex, performance status, body weight, body mass index, liver function markers and estimated glomerular filtration rate were assessed for association with development of severe (grade 3 or 4) rash using logistic regression.. Of 962 patients treated with vemurafenib, 150 (16%) patients experienced severe rash. Female sex was identified as a significant risk factor for severe rash development (P < 0.001), having a two-fold increased risk compared to males (22% vs 11%, odds ratio [OR] 2.17; 95% CI 1.52 to 3.09). Low body weight was also associated with increased risk of severe rash (P = 0.002), but this association was not significant after adjustment for sex. The association between sex and risk of severe rash was consistent across clinical trials and treatments (vemurafenib monotherapy, vemurafenib plus cobimetinib).. Females had approximately two-fold increased risk of developing severe rash compared to males in clinical trials of vemurafenib alone or in combination with cobimetinib.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Australia; Azetidines; Clinical Trials as Topic; Exanthema; Female; Humans; Incidence; Male; Melanoma; Middle Aged; Neoplasm Staging; Piperidines; Risk Factors; Sex Factors; Skin Neoplasms; Vemurafenib

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biopsy; Drug Hypersensitivity Syndrome; Female; Glucocorticoids; Humans; Lung; Lung Neoplasms; Melanoma; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Skin; Skin Neoplasms; Treatment Outcome; Vemurafenib

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Hypersensitivity Syndrome; Female; Humans; Imidazoles; Melanoma; Neoplasms, Multiple Primary; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

Advanced cutaneous squamous cell carcinoma (SCC) responds poorly to chemotherapy, leading to significant morbidity or death. Overexpression of epidermal growth factor receptor (EGFR) is frequently observed in advanced cutaneous SCC. Vandetanib is a multiple tyrosine kinase targeting vascular endothelial growth factor receptor-2 (VEGFR2), EGFR, and the rearranged during transfection (RET) proto-oncogene. Vandetanib has been reported to inhibit tumor growth in head and neck SCC. However, the efficacy of vandetanib against cutaneous SCC has not been thoroughly investigated. The aim of this study is to evaluate the efficacy of vandetanib against cutaneous SCC in vitro and in vivo. Vandetanib is found to inhibit the proliferation of cutaneous SCC cells as assessed by cell viability and clonogenic assay. Cell death analysis indicates that vandetanib induces cell death in SCC cells but not in normal human keratinocytes or fibroblasts. The in vivo anti-tumor effect of vandetanib is shown in xenograft tumor models using A431 SCC cells. Mechanistically, vandetanib suppresses the phosphorylation of EGFR in SCC cells. Clinically, EGFR expression levels are elevated in cutaneous SCC specimens, relative to normal epidermis. In conclusion, we identified vandetanib as a novel therapeutic option for cutaneous SCC, especially in tumors with high EGFR expression.

Topics: Aged; Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Female; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Piperidines; Proto-Oncogene Mas; Quinazolines; Skin Neoplasms

PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts.. Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays.. Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors.. Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.

Topics: Apoptosis; Cell Survival; Chemoradiotherapy; Drug Interactions; Fibroblasts; G2 Phase Cell Cycle Checkpoints; Homologous Recombination; Humans; Indazoles; Melanoma; Phthalazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Primary Cell Culture; Skin; Skin Neoplasms; Tumor Cells, Cultured

This study aimed to assess whether dabrafenib/trametinib and vemurafenib/cobimetinib treatments are associated with a change in skeletal muscle area (SMA) and total fat-free mass (FFM) assessed by computed tomography (CT), and to compare the efficacy and safety profile of these treatments in patients with metastatic melanoma. Thirty-one patients treated with B-Raf proto-oncogene, serine/threonine kinase/MAPK extracellular receptor kinase inhibitors were included between 2016 and 2019. Eighteen patients received dabrafenib/trametinib and remaining patients received vemurafenib/cobimetinib. CT scans were performed at baseline and at 4-6 months of follow-up to measure cross-sectional areas of SMA. FFM and skeletal muscle index (SMI) values were calculated. Of the patients, including 18 treated with dabrafenib/trametinib (58.1%) and 13 with vemurafenib/cobimetinib (41.9%); 58.1% were male, 41.9% were female and median age was 52 years. A significant decrease in SMA was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). A significant decrease in FFM values was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). Dose-limiting toxicity (DLT) was observed in 35.9% of the patients with sarcopenia. No significant difference was seen between the dabrafenib/trametinib and vemurafenib/cobimetinib groups in median progression-free survival (PFS) (11.9 vs. 7.3 months, respectively, P = 0.28) and in median overall survival (OS) (25.46 vs. 13.7 months, respectively, P = 0.41). Baseline sarcopenia was not significantly associated with PFS or OS (P = 0.172 and P = 0.326, respectively). We found a significant decrease in SMI values determined at 4-6 months compared to the values before treatment both in dabrafenib/trametinib and vemurafenib/cobimetinib groups. DLT was similar with both treatments. Baseline sarcopenia was not significantly associated with PFS or OS.

Topics: Azetidines; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

Free radical involvement in initiation, promotion and progression of carcinogenesis, implicates that scavengers of free radicals may act as inhibitors in the carcinogenic process. Melatonin, an antioxidant was used in the present study to evaluate its effectiveness on skin carcinogenesis induced by DMBA both with and without chronic restraint stress (CRS). Fifty Swiss albino young male rats were divided into five groups of 10 rats each as controls, topical DMB alone, Pre CRS-DMBA, melatonin DMBA and Pre-CRS-DMBA-melatonin treated groups. After 18 weeks blood was collected along with liver and skin samples. These were used for antioxidant enzyme assay, DNA damage and fluorescent spectra analysis. Melatonin showed antioxidant potential in combatting DMBA induced skin carcinogenesis measured by free radical scavenging enzymes and in vivo antioxidant status, DNA damage. Sensitive detection of the DMBA induced micro biochemical changes was possible by fluorescent spectroscopy from the transformed ratio of fluorescent intensity (F1 530 nm/630 nm) otherwise found constant for normal tissues. By melatonin treatment this ratio was similar to control values. The decreased antioxidant biochemical parameters depicting oxidative stress were comparable to comet assay and fluorescent studies, endorsing the chemo-preventive efficacy of melatonin against skin carcinogenesis caused by DMBA. CRS pre-exposure diminished the chemo-preventive/antioxidant ability of melatonin and the results were same as DMBA alone treatment, showing stress affected both cancer development and chemoprevention. CRS decreased the antioxidant potential of melatonin. Hence, managing stress could be perceived in cancer chemoprevention. Further studies focusing on stress reduction are needed.

Topics: Animals; Anthracenes; Antioxidants; Carcinogenesis; Carcinogens; Male; Melatonin; Oxidative Stress; Piperidines; Rats; Restraint, Physical; Skin Neoplasms; Stress, Psychological

Therapeutic approaches for cutaneous melanoma are flourishing, but despite promising results, there is an increasing number of reported primary or secondary resistance to the growing sets of drugs approved for therapy in the clinics. Combinatorial approaches may overcome resistance, as they may tackle specific weaknesses of melanoma cells, not sufficient on their own, but effective in combination with other therapies. The transgenic zebrafish line kita:ras develops melanoma with high frequency. At 3 dpf, transgenic kita:ras larvae show a hyperpigmentation phenotype as earliest evidence of abnormal melanocyte growth. Using this model, we performed a chemical screen based on automated detection of a reduction of melanocyte number caused by any of 1280 FDA or EMA approved drugs of the library. The analysis showed that 55 molecules were able to reduce by 60% or more the number of melanocytes per embryo. We further tested two compounds for each of the 5 classes, and a farnesyltransferase inhibitor (Lonafarnib), that inhibits an essential post-translational modification of HRAS and suppresses the hyperpigmentation phenotype. Combinations of Clotrimazole and Lonafarnib showed the most promising results in zebrafish embryos, allowing a dose reduction of both drugs. We performed validation of these observations in the metastatic human melanoma cell line A375M, and in normal human epithelial melanocytes (NHEM) in order to investigate the mechanism of action of Clotrimazole in blocking the proliferation of transformed melanocytes. Viability assay and analysis of energy metabolism in Clotrimazole treated cells show that this drug specifically affects melanoma cells in vitro and transformed melanocytes in vivo, having no effects on NHEM or wild type larvae. Similar effects were observed with another hit of the same class, Miconazole. Furthermore, we show that the effects of Clotrimazole are mediated by the inhibition of hexokinase activity, which is lethal to the abnormal metabolic profile of melanoma cells in vitro and in vivo. Thus, our study shows that the zebrafish can provide a phenotype-rich assay for fully automated screening approaches to identify drugs for synthetic lethal treatment in melanoma and suggest further testing of Clotrimazole in combinatorial treatments.

Topics: Animals; Animals, Genetically Modified; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Clotrimazole; Disease Models, Animal; Drug Screening Assays, Antitumor; Farnesyltranstransferase; Humans; Melanocytes; Melanoma; Melanoma, Cutaneous Malignant; Miconazole; Piperidines; Pyridines; Skin Neoplasms; Zebrafish

New primary melanomas (NPMs) in the era of combination treatments for melanoma constitute a challenge for physicians, especially due to the increased incidence of NPMs in patients treated with BRAF inhibitors. We present the unique case of a patient that developed an invasive NPM while under treatment with a combination of vemurafenib, cobimetinib, and atezolizumab. A 39-year-old white male was treated with vemurafenib, cobimetinib, and atezolizumab for a stage IV (T0, N3, M1) BRAF-V600E mutated malignant melanoma in the context of a clinical trial. Eight months from treatment initiation he was diagnosed with an NPM on his back that was found to be BRAF-wild type and neuroblastoma ras mutated, while he was in complete remission. Wide excision of the lesion followed, and the patient was not withdrawn from study treatment. Twenty-two months from treatment initiation, he is still in complete remission. NPMs are a well-known adverse effect of BRAF inhibitors and pose a challenge for the treating physician since these lesions are BRAF-wild type and usually have aggressive biologic behaviour. Invasive NPMs require an aggressive management strategy with clear guidelines to prevent the emergence of advanced or metastatic disease. The emergence of invasive NPMs in patients treated with triple regimens with BRAF/mitogen-activated protein kinase kinase inhibitors and PD1/PDL1 inhibitors is at least unexpected and constitutes a therapeutic stalemate for the physician. Through this case report, we aim to increase awareness about the diagnosis and management of patients with NPM and to express our concerns regarding further management of NPMs in patients under triple combination treatment.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Male; Melanoma; Neoplasm Metastasis; Piperidines; Skin Neoplasms; Vemurafenib

Topics: Adenine; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Humans; Leg; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Piperidines; Prednisone; Pyrazoles; Pyrimidines; Rituximab; Skin Neoplasms; Vincristine

Topics: Aged; Azetidines; Female; Granuloma; Humans; Melanoma; Middle Aged; Piperidines; Protein Kinase Inhibitors; Sarcoidosis; Skin Neoplasms; Vemurafenib

A 38-year-old man with a diagnosis of BRAF-mutated metastatic melanoma was referred to our clinic. He had been under treatment with 60-mg oral cobimetinib daily for 21 days/7 day off in combination with 960 mg vemurafenib twice daily. The patient had symptoms of blurred vision and photophobia in his right eye. A slit-lamp examination revealed bilateral central corneal stromal opacity and epithelial microcystic edema Involvement was more severe in the right eye compared with the left eye. Fourteen days after the first visit, the patient's symptoms and slit-lamp findings were largely resolved. We suggest that endothelium pump failure was involved in this acute corneal decompensation case similar to the mechanism in retinal pigment epithelium.

Topics: Acute Disease; Administration, Oral; Adult; Azetidines; Corneal Edema; Drug-Related Side Effects and Adverse Reactions; Humans; Male; MAP Kinase Kinase 1; Melanoma; Piperidines; Skin Neoplasms; Vision Disorders

Topics: Adult; Aged; Aged, 80 and over; Azetidines; Drug Hypersensitivity Syndrome; Drug Therapy, Combination; Female; Humans; Male; Melanoma; Middle Aged; Piperidines; Prognosis; Risk Assessment; Sampling Studies; Severity of Illness Index; Skin Neoplasms; Vemurafenib

A survival benefit was demonstrated by dabrafenib + trametinib for metastatic BRAF-mutated melanoma patients. Best response is a strong prognostic marker for survival.. The specific features associated with complete response (CR) were evaluated.. A total of 15/66 patients achieved CR. Median size of lesions was 3 cm (range: 0.5-10). Using that value as cut-off, the CR rate was 39.3% in patients with smaller lesions and 10.5% in patients with bigger size (p = 0.006). The clinical features associated with CR were the number of metastatic sites and the largest diameter of the biggest metastatic site.. The number of the metastases and the diameter of the largest metastatic site are associated with a higher CR rate.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

Bioactive derivatives from the camphor laurel tree, Cinnamomum camphora, are posited to exhibit chemopreventive properties but the efficacy and mechanism of these natural products are not fully understood. We tested an essential-oil derivative, camphor white oil (CWO), for anti-tumor activity in a mouse model of keratinocyte-derived skin cancer. Daily topical treatment with CWO induced dramatic regression of pre-malignant skin tumors and a two-fold reduction in cutaneous squamous cell carcinomas. We next investigated underlying cellular and molecular mechanisms. In cultured keratinocytes, CWO stimulated calcium signaling, resulting in calcineurin-dependent activation of nuclear factor of activated T cells (NFAT). In vivo, CWO induced transcriptional changes in immune-related genes identified by RNA-sequencing, resulting in cytotoxic T cell-dependent tumor regression. Finally, we identified chemical constituents of CWO that recapitulated effects of the admixture. Together, these studies identify T cell-mediated tumor regression as a mechanism through which a plant-derived essential oil diminishes established tumor burden.

Topics: Animals; Anthracenes; Camphor; Carcinoma, Squamous Cell; Cell Proliferation; Cells, Cultured; Female; Humans; Keratinocytes; Mice; NFATC Transcription Factors; Oils, Volatile; Piperidines; Skin Neoplasms; T-Lymphocytes, Cytotoxic

With the advent of immune-checkpoint inhibitors and targeted treatments (TT), there have been unprecedented response rates and survival in advanced melanoma, but the optimal sequencing of these two treatments modalities is unknown. Combining or sequencing these agents could potentially result in unique toxicities. Cutaneous adverse events (CAE) after sequential exposure to these agents represents one toxicity that needs further description.. After retrospectively reviewing charts of patients from 2015 to 2018, we identified six patients who experienced CAEs after recent exposure to sequential immunotherapy and TT or vice versa for the treatment for metastatic melanoma at the University of North Carolina, Chapel Hill. Skin biopsies were available in five patients.. Five patients received TT after immunotherapy, and one patient received immunotherapy after TT. TT consisted of vemurafenib/cobimetinib (V/C) in five patients with four patients starting V/C immediately before manifesting with a CAE. In patients receiving V/C after immunotherapy, the median time from beginning V/C to development of CAE was 14.5 days. The clinical presentation of diffuse morbilliform rash, fevers, hypotension, and end-organ damage raised concern for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. Histopathological features of lympho-eosinophilic infiltrate were supportive of a drug eruption. Immunotherapy or TT were re-initiated in five patients within 1-8 weeks after resolution of the index CAE. This resulted in two patients re-experiencing the CAE. Both of these patients were off prednisone at the time of therapy re-initiation, whereas none of the patients who were restarted on targeted therapy with a steroid overlap had a rash recurrence.. Sequential treatment using immunotherapy and TT, especially the sequence of V/C after immunotherapy appears to be the most common trigger for CAE with a median time to onset of approximately 2 weeks. Although the clinical presentation of these CAEs can be dramatic, they respond well to prednisone therapy. This unique presentation suggests that it may be reasonably safe to re-challenge certain patients with a steroid overlap after rash resolution.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Azetidines; Exanthema; Female; Humans; Immunotherapy; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Nivolumab; Piperidines; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Skin; Skin Neoplasms; Vemurafenib

Among the molecular signals underlying cutaneous inflammation is the transcription complex NF-κB, its upstream modulators, and cytokines and chemokines that are the downstream proinflammatory effectors. Central to NF-κB activation is IκB kinase (IKK), which phosphorylates IκBα, releasing NF-κB to the nucleus. In a screening of a kinase inhibitor library, we identified two IKK inhibitors that were high-affinity substrates for p-glycoprotein (ABCB1), the multidrug resistance protein known to facilitate transdermal drug delivery. ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridinecarbonitrile) and IKK 16 prevented both nuclear translocation of NF-κB and activation of a NF-κB reporter and reduced the induction of cytokine and chemokine transcripts in human or mouse keratinocytes by IL-1α, tumor necrosis factor-α, and phorbol myristate acetate. ACHP, but not IKK 16, was nontoxic to mouse or human keratinocytes at any dose tested. In mice, topical ACHP prevented the cutaneous inflammation induced by topical phorbol myristate acetate or imiquimod, reduced the inflammation from erythema doses of artificial sunlight, and lowered the tumor incidence of mice treated with 7,12-dimethyl benzanthracene when applied before phorbol myristate acetate. Topical ACHP also reduced the NF-κB and IL-17 inflammatory signature after multiple doses of imiquimod. Thus, ACHP and IKK 16 hit their NF-κB target in mouse and human keratinocytes, and ACHP is an effective topical nonsteroidal anti-inflammatory in mice.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Humans; Imiquimod; Inflammation; Keratinocytes; Mice; NF-kappa B; Nicotinic Acids; Nitriles; Piperidines; Pyrrolidines; Skin; Skin Neoplasms

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Female; Fibroma; Humans; Middle Aged; Neurofibromatosis 1; Piperidines; Pyrimidines; Pyrroles; Skin Neoplasms

Topics: Aged; Antineoplastic Agents; Azetidines; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Piperidines; Polyneuropathies; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

Undifferentiated sarcoma has been hypothesized as an intermediate step in the progression of malignant melanoma to rhabdomyosarcoma. The current report describes a new case of rhabdomyosarcomatous transformation in a malignant melanoma and documents the temporal progression of the malignant melanoma to rhabdomyosarcoma in different metastatic sites via undifferentiated sarcoma. A 65-year-old female with a past medical history of malignant melanoma presented with a new lung mass. A core biopsy revealed a malignant spindle cell neoplasm that was negative for all melanocytic markers, suggesting the possibility of a primary pulmonary sarcomatoid carcinoma or sarcoma. The subsequent lobectomy demonstrated an undifferentiated spindle cell neoplasm with areas of rhabdomyoblastic differentiation. Review of the skin lesion and lymph nodes confirmed the diagnosis of the primary cutaneous malignant melanoma, but also revealed that the nodal metastases had largely transformed into an undifferentiated sarcoma with similar morphology as the spindle cell neoplasm in the lung. Molecular studies demonstrated an identical

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers, Tumor; Cell Transformation, Neoplastic; Diagnosis, Differential; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Lung; Lung Neoplasms; Melanoma; Neoadjuvant Therapy; Piperidines; Pneumonectomy; Proto-Oncogene Proteins B-raf; Rhabdomyosarcoma; Skin; Skin Neoplasms; Vemurafenib

Piperine is a major pungent alkaloid present in black pepper (Piper nigrum L). This study investigated the potential anticancer effects of piperine on human melanoma cells and explored the potential pharmacological mechanisms in vitro and in vivo.. Studies were performed using the MTT assay, 4',6-diamidino-2-phenylindole (DAPI) staining, western blotting, a xenograft model, the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and immunohistochemistry.. Piperine inhibited the growth of melanoma cells. Several apoptotic events were observed following treatment, as revealed by DAPI staining. Piperine increased the expression of BCL2-associated X, apoptosis regulator (BAX), cleaved poly(ADP-ribose)polymerase, cleaved caspase-9, phospho-c-Jun N-terminal kinase and phospho-p38, and reduced that of B-cell lymphoma 2 (BCL2), X-chromosome-linked inhibitor of apoptosis, and phospho-extracellular signal-regulated protein kinase (ERK1/2) in a concentration-dependent manner. Treatment of mice for 4 weeks with piperine inhibited tumor growth without apparent toxicity. Piperine increased the expression of apoptotic cells and cleaved-caspase-3 protein and reduced the expression of phospho-ERK1/2 protein in melanoma tumors.. Piperine suppressed the growth of human melanoma cells by the induction of apoptosis via the inhibition of tumor growth of human melanoma cells and tumor xenograft models.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Benzodioxoles; Cell Line, Tumor; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinases; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Skin Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Radiation recall dermatitis is an uncommon inflammatory reaction of the skin appearing after several days to several years at the site of previous irradiation; it is precipitated by the use of triggering drugs, although rarely by BRAF or MEK inhibitors.. We report an unusual case of recall dermatitis induced 3 months after initiation of vemurafenib and cobimetinib therapy.. Radiation recall dermatitis is a cutaneous reaction that must be known and which in rare cases such as ours may occur a long time after the end of radiotherapy.

Topics: Adrenal Gland Neoplasms; Antineoplastic Agents; Azetidines; Ear Auricle; Ear Neoplasms; Facial Dermatoses; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Radiodermatitis; Skin Neoplasms; Vemurafenib

Topics: Azetidines; Erythema Multiforme; Female; Humans; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Vemurafenib

Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.

Topics: Adult; Aged; Antineoplastic Agents; Azetidines; Benzimidazoles; Databases, Factual; Enzyme Inhibitors; Female; Gastrointestinal Tract; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome

We conducted a retrospective analysis to evaluate the impact of concomitant acid-reducing agents (ARAs) and vemurafenib dose on the efficacy of vemurafenib in patients with BRAF. Data were pooled for patients treated with vemurafenib or cobimetinib plus vemurafenib in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. The primary end-points were progression-free survival and overall survival across patient subgroups defined by vemurafenib dose (full vs reduced) and concomitant ARA use (yes vs no). Objective response rate (ORR) was also analysed. Steady-state vemurafenib concentrations were evaluated according to vemurafenib dosing and concomitant ARA use across treatment cohorts in a subset of patients from BRIM-7 and coBRIM with available concentration data.. Efficacy analyses included 920 patients: 641 in the vemurafenib cohort and 279 in the cobimetinib plus vemurafenib cohort. Overall, no significant differences in survival outcomes were observed across subgroups according to vemurafenib dose and ARA use, with or without adjustment for known prognostic covariates, in both treatment cohorts. ORR was also similar across subgroups in both treatment cohorts. Steady-state vemurafenib concentrations were analysed in 389 patients (193 in the vemurafenib cohort and 196 in the cobimetinib plus vemurafenib cohort) and were generally similar across vemurafenib dose subgroups, regardless of ARA use in both treatment cohorts.. Results of this retrospective pooled analysis suggest that ARAs can be used concomitantly with vemurafenib, alone or in combination with cobimetinib, without compromising the efficacy of vemurafenib.

Topics: Adult; Aged; Antacids; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Piperidines; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

Human malignant melanoma is one of the most aggressive cancers, accompanied with poor prognosis, metastatic evolution and high mortality. Many strategies have been developed using BRAF and MEK inhibitors in spite of the classic therapy with alkylating agents, but failure related to the ability of the tumor to activate alternative proliferation pathways occurred after promising initial successes. Poly(ADP-ribose) polymerase (PARP) enzymes are well known to be crucial for DNA damage response, and PARP inhibition results in the accumulation of DNA strand breaks that induce cell injury. For this reason, PARP-inhibitors (PARPi) have become promising tools to counteract many cancer types. One of the most used by clinicians is olaparib, that, however, showed again cancer resistance in patients. Thus, new generation molecules have been designed mainly to counteract this problem. Among them, we chose to test AZD2461 on the particularly aggressive human melanoma A375 cell line. This drug is a PARPi significantly less prone than olaparib to undergo the P-glycoprotein-mediated efflux mechanism, one of those responsible for resistance, that in turn is the main adversity in melanoma therapy. Then, we analysed AZD2461 also together with the enzyme onconase (ONC) on the same A375 cells, to investigate if the combination of drugs could possibly increase the in vitro antitumor activity. ONC is a small amphibian "pancreatic-type" ribonuclease that is able to exert a remarkable antitumor activity against many cancers, either in vitro or in vivo, principally because it can evade the ubiquitous ribonuclease cytosolic inhibitor thanks to its structural determinants. Hence, ONC became relevant in the use of protein-drug strategies against incurable cancers. The studies performed in this work showed that both drugs definitely affect A375 cells viability by inducing cytostatic and pro-apoptotic effects in a time- and dose-dependent manner, either if administered alone or in combination. Although we registered low synergistic effects with the combination of the two drugs, we found that AZD2461 did not induce resistance in A375 after two months treatment with high concentration of this molecule. Moreover, we underline that A375 cells treated for a prolonged time with AZD2461 were definitely more susceptible than parental A375 cells to the pro-apoptotic action of ONC. Considering also the different inhibitory effects of the two drugs on TNF-α gene expression and NF-κB DNA-binding, th

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Humans; Melanoma; Melanoma, Cutaneous Malignant; Phthalazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Ribonucleases; Skin Neoplasms

A recent hypothesis suggesting that the pharmacological target TRPV1 (transient receptor potential vanilloid subfamily, member 1) may function as a tumour suppressor, which potentially impacts the development of TRPV1 antagonist therapeutics for a range of conditions. However, little is known about the long-term physiologic effects of TRPV1 blockade in the skin. In vitro and in vivo studies suggested that the potent TRPV1 competitive antagonist AMG-9810 promoted proliferation in N/TERT1 cells (telomerase-immortalised primary human keratinocytes 1) and tumour development in mouse skin that was mediated through EGFR/Akt/mTOR signalling. We attempted to reproduce the reported in vitro and in vivo findings to further explore this hypothesis to understand the underlying mechanism and the risk associated with TRPV1 antagonism in the skin. In vitro proliferation studies using multiple methods and topical application with AMG-9810 and structurally similar TRPV1 antagonists such as SB-705498 and PAC-14028 were performed. Although we confirmed expression of TRPV1 in primary human epidermal keratinocytes (HEKn) and spontaneously immortalised human keratinocytes (HaCaT), we were unable to demonstrate cell proliferation in either cell type or any clear evidence of increased expression of proteins in the EGFR/Akt/mTOR signalling pathway with these molecules. We were also unable to demonstrate skin tumour promotion or underlying molecular mechanisms involved in the EGFR/Akt/mTOR signalling pathway in a single-dose and two-stage carcinogenesis mouse study treated with TRPV1 antagonists. In conclusion, our data suggest that inhibiting the pharmacological function of TRPV1 in skin by specific antagonists has not been considered to be indicative of skin tumour development.

Topics: Acrylamides; Animals; Anthracenes; Bridged Bicyclo Compounds, Heterocyclic; Capsaicin; Cell Line; Cell Proliferation; Cell Survival; Cocarcinogenesis; Female; Humans; Keratinocytes; Mice; Mice, Hairless; Piperidines; Primary Cell Culture; Pyridines; Pyrrolidines; Risk; Skin Neoplasms; TRPV Cation Channels; Urea

Cellular movement is controlled by small GTPases, such as RhoA. Although migration is crucial for cancer cell invasion, the specific role of RhoA in tumor formation is unclear. Inducing skin tumors in mice with a keratinocyte-restricted loss of RhoA, we observed increased tumor frequency, growth and invasion. In vitro invasion assays revealed that in the absence of RhoA cell invasiveness is increased in a Rho-associated protein kinase (ROCK) activation and cell contraction-dependent manner. Surprisingly, loss of RhoA causes increased Rho signaling via overcompensation by RhoB because of reduced lysosomal degradation of RhoB in Gamma-aminobutyric acid receptor-associated protein (GABARAP)+ autophagosomes and endosomes. In the absence of RhoA, RhoB relocalized to the plasma membrane and functionally replaced RhoA with respect to invasion, clonogenic growth and survival. Our data demonstrate for the first time that RhoA is a tumor suppressor in 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol 13-acetate skin carcinogenesis and identify Rho signaling dependent on RhoA and RhoB as a potent driver of tumor progression.

Topics: Animals; Anthracenes; Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Cells, Cultured; Humans; Keratinocytes; Lysosomes; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Piperidines; Prognosis; rho-Associated Kinases; rhoA GTP-Binding Protein; rhoB GTP-Binding Protein; rhoC GTP-Binding Protein; Signal Transduction; Skin Neoplasms; Transcriptional Activation; Up-Regulation

Topics: Alkaloids; Animals; Apoptosis; Bees; Brazil; Cell Line, Tumor; Cell Movement; Chromatography, High Pressure Liquid; G2 Phase Cell Cycle Checkpoints; Humans; Melanoma; Membrane Potential, Mitochondrial; Piperidines; Propolis; Reactive Oxygen Species; Skin Neoplasms; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Skin cancer is one of the most common malignancies in dermatology. Patient compliance and prognosis of skin cancer are poor. Ibrutinib, a Bruton's Tyrosine Kinase (BTK) inhibitor, is a new anticancer drug used to treat many cancers. Therefore, we aimed to explore the role of ibrutinib in the treatment of skin cancer.. Cell Counting Kit-8 (CCK8) and plate cloning assay were used to detect cell proliferation. Apoptosis was determined by flow cytometry. Western blotting analysis was used to analyze the expression of key proteins that regulated autophagy. Proliferation and apoptosis of skin cancer cells and induction of autophagy induced by ibrutinib were evaluated.. CCK8 plate cloning assays showed that ibrutinib can gradually inhibit the skin cancer cell proliferation as the treatment time and dose increased. Results of flow cytometry showed that apoptosis in skin cancer cells were induced after ibrutinib treatment. Western blot showed that autophagy in skin cancer cells was found induced by ibrutinib and also related to the time and concentration of ibrutinib treatment. Combination treatment of ibrutinib and 3MA for skin cancer cells can significantly increase apoptosis.. Ibrutinib has anti-tumor activity in skin cancer and can induce autophagy. Binding to autophagy inhibitors can promote ibrutinib's anti-skin cancer activity. Our experimental results provided new ideas for developing skin cancer drugs.

Topics: Adenine; Apoptosis; Autophagy; Autophagy-Related Protein 7; Cell Line, Tumor; Cell Proliferation; Humans; Microtubule-Associated Proteins; Piperidines; Pyrazoles; Pyrimidines; Skin Neoplasms

Topics: Administration, Topical; Back; Child; Dermatologic Agents; Humans; Lip Neoplasms; Male; Nevus, Halo; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an

Topics: Adenine; Aged, 80 and over; Antineoplastic Agents; CARD Signaling Adaptor Proteins; Disease Progression; Female; Genomic Instability; Guanylate Cyclase; Humans; I-kappa B Proteins; Interferon Regulatory Factors; Lymphatic Metastasis; Lymphoma, Large B-Cell, Diffuse; Mutation; Piperidines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Skin Neoplasms

Prognostic models may provide insight into clinical trial results and inform the clinical management of patients with BRAF V600-mutated metastatic melanoma.. To identify subgroups with distinct survival outcomes based on clinical and genomic characteristics and to assess survival in identified prognostic subgroups across cohorts treated with dacarbazine, vemurafenib, or cobimetinib plus vemurafenib.. This retrospective and exploratory recursive partitioning analysis (RPA) modeled associations between prespecified covariates and survival outcomes using pooled data from the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies.. Dacarbazine, vemurafenib, or cobimetinib plus vemurafenib.. Progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method.. The RPA included 1365 patients (783 men; 57.4%). Of these, 1032 (75.6%) were older than 65 years; 310 received cobimetinib plus vemurafenib; 717, vemurafenib alone; and 338, dacarbazine. Median follow-up was 14.1 months (interquartile range, 6.3-28.3 months). In the RPA that included all patients, baseline lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status (ECOG PS), presence or absence of liver metastases, and baseline sum of longest diameters of target lesions (SLDs) were significant prognostic factors for PFS: Median PFS was longest in patients with lower LDH (≤2 × upper limit of normal [ULN]), ECOG PS 0, and shorter SLD (≤44 mm) (11.1 months; 95% CI, 7.0-18.4 months), and shortest in those with elevated LDH (>2 × ULN) (3.5 months; 95% CI, 3.0-3.8 months). The subgroup with normal baseline LDH and no liver metastases had the longest median OS (22.7 months; 95% CI, 20.3-27.2 months). Similar PFS trends were observed when these prognostic subgroups were applied to the cobimetinib plus vemurafenib, vemurafenib alone, and dacarbazine cohorts. Baseline LDH, ECOG PS, and SLD were significant prognostic factors for OS: Median OS was longest in patients with normal LDH and shorter SLD (≤45 mm) (27.2 months; 95% CI, 22.1-32.1 months) and shortest in those with elevated LDH (>2 × ULN) (6.0 months; 95% CI, 5.3-6.8 months). Among patients in the most favorable subgroup (normal LDH and SLD ≤45 mm), 3-year OS rates were 53.3% (95% CI, 39.5%-67.1%) in the cobimetinib plus vemurafenib cohort, 35.6% (95% CI, 27.4%-43.8%) in the vemurafenib cohort, and 35.6% (95% CI, 24.8%-46.4%) in the dacarbazine cohort. Among patients with available gene expression data, RPA identified gene signature as a significant prognostic factor for PFS in those with normal LDH; 3-year PFS rates were 21.9%, (95% CI, 15.4%-28.4%) and 8.8% (95% CI, 3.6%-14.1%) in immune and cell cycle signature, respectively. The RPA for OS did not identify gene signature as a significant factor.. Baseline LDH, ECOG PS, disease burden, and gene signature appear to be key determinants of survival outcomes in patients with BRAF V600-mutated metastatic melanoma treated with BRAF and/or MEK inhibitors. These results are consistent with survival benefits of cobimetinib plus vemurafenib over vemurafenib alone observed in the coBRIM study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dacarbazine; Female; Humans; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Piperidines; Prognosis; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7-12 m. Long-term benefit from these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking. Data suggest that immune-related adverse events (irAEs) are associated with clinical benefit in patients treated with immunotherapy and that response to BRAF/MEK therapy may have an underlying immune mechanism. We hypothesised that AEs with an underlying immune mechanism may be associated with a durable response to targeted therapy. We retrospectively identified a cohort of 78 BRAF V600-mutant metastatic melanoma patients treated with BRAFi or BRAFi + MEKi between November 2010 and November 2013. Four treatment-related AEs including vitiligo, uveitis, erythema nodosum and keratitis sicca were defined as irAEs of interest. Retrospective analysis of AEs in relationship to progression-free survival (PFS), disease burden and LDH levels was performed. Median PFS (mPFS) for all patients was 7.5 months with responses ongoing in eight patients as of April 2017. Ten patients were identified with the AEs defined previously. Cox regression analysis revealed a very strong association between those AEs and PFS; mPFS was 42.8 m in patients with at least one AE versus 6.1 m in those without an AE (hazard ratio [HR] 0.22, p = 0.002). This association was independent of LDH levels and disease burden (HR 0.24, p = 0.035). This analysis demonstrates a strong association between immune AEs and durable response to targeted therapy and may provide a treatment-related biomarker to estimate the outcome of therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arthralgia; Azetidines; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Skin Neoplasms; Vemurafenib; Young Adult

Combined treatment with BRAF-V600 and MEK inhibitors has significantly improved progression-free and overall survival of patients with BRAF-mutated melanoma. Pattern of disease progression and outcomes in patients have not been fully characterized.. We conducted a single-center, retrospective, descriptive analysis of a cohort of 52 patients treated with BRAF-V600 + MEK inhibitors for advanced melanoma over a 12-month period. The aim of this study was to characterize disease progression, defined as metastatic pattern, disease kinetics, and response to subsequent therapies, in melanoma patients treated with BRAF-V600 + MEK inhibitors.. Disease progression was observed in 31/52 (59.6%) patients treated with BRAF-V600 + MEK inhibitors. Relapse of melanoma involved the CNS for 22/31 (70.9%) patients with disease progression, including 18/31 (58%) patients who had exclusive intracranial metastases. Sixteen patients died from disease progression. Among the 31 patients who had disease progression, the median time until a relapse was 8 months, and the median survival time after disease progression was 2 months.. Our study shows that, for patients treated with BRAF-V600 + MEK inhibitors who lose response, disease progression was aggressive and had poor outcomes. Most patients had CNS metastases and low rates of therapeutic response to any subsequent therapy.

Topics: Acrylonitrile; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Disease Progression; Female; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

We present a case report of an early-onset drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) induced by vemurafenib (BRAF inhibitor) in a middle-age man affected by a metastatic, BRAF mutant melanoma who was started on first-line metastatic treatment with vemurafenib and cobimetinib.After initiating the treatment, the patient presented an extensive cutaneous rash with eosinophilia and renal impairment. Due the constellation of signs and symptoms, a diagnosis of DRESS syndrome was made which strongly contraindicated the reintroduction of vemurafenib due to its hypersensibility reaction. Thus, vemurafenib was stopped immediately, and we started corticoid treatment with clinical improvement.Due to the contraindication to start vemurafenib again, after multidisciplinary view of the case and having balanced the risks and benefits, we successfully performed a switch to another BRAF inhibitor in a progressively ascending pattern, without any skin toxicity and with a good response of the metastatic melanoma.

Topics: Acute Kidney Injury; Adrenal Cortex Hormones; Azetidines; Drug Hypersensitivity Syndrome; Eosinophilia; Exanthema; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Protein Kinase Inhibitors; Skin Neoplasms; Treatment Outcome; Vemurafenib

A combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF.. To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France. We included 38 patients with metastatic BRAF-mutated melanomas treated by VMF and CB between March 2015 and June 2016. According to the NCI-CTCAE classification, AKI was defined as an increase in serum creatinine exceeding the baseline concentration by 1.5-fold. Serum creatinine was measured before treatment, then on a monthly basis during treatment, and 1 month after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-), and further subdivided into three groups according to AKI severity (stage 1-5).. Of 38 patients, 29 (76%) were AKI-, and all 9 AKI+ patients (24%) were diagnosed within the first trimester of treatment. Three-quarters of AKI (n = 7, 77%) had stage 1 AKI and the remaining 23% stage 2 AKI. Pre-treatment renal function was significantly better in AKI+ group: 105 vs. 80 ml/min/1.73m² AKI-, p = 0.009. Compared to previous results, the AKI incidence under the combined VMF-CB vs. VMF monotherapy was reduced by 60%.. We reported a reduced incidence and severity of nephrotoxicity of the association inhibitors of BRAF and MEK compared to a BRAF inhibitor monotherapy.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Creatinine; Disease-Free Survival; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Incidence; Indoles; Male; Melanoma; Middle Aged; Piperidines; Proto-Oncogene Proteins B-raf; Retrospective Studies; Skin Neoplasms; Sulfonamides; Vemurafenib

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

Therapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction. The clinical presentation comprised interscapular pain, axial fatigue with cervical hypotonia, CPK elevation, intense fluorine-18-fluorodeoxyglucose uptake in cervical muscles, and necrotizing myopathy was confirmed by muscle biopsy. Cobimetinib was temporarily discontinued, resulting in CPK normalization. Re-evaluation showed partial response, motivating continuation of combination therapy with a reduced dose of cobimetinib (40 mg/day). Because prescription of targeted therapies is likely to increase, this adverse event should be known.

Topics: Aged; Azetidines; Humans; Male; MAP Kinase Kinase 1; Melanoma; Muscular Diseases; Piperidines; Skin Neoplasms

Topics: Adenine; Aged; Aged, 80 and over; Humans; Male; Mohs Surgery; Piperidines; Postoperative Hemorrhage; Pyrazoles; Pyrimidines; Risk Factors; Skin Neoplasms

Vemurafenib ha probado ser una herramienta útil en el tratamiento de melanoma metastásico con mutación BRAF-V600E. Los efectos adversos incluyen artralgias, fatiga y toxicidad cutánea, siendo infrecuente la paniculitis. Presentamos el caso de una paciente de 43 años con melanoma metastásico que desarrolla lesiones subcutáneas dolorosas en miembros inferiores y superiores, asociadas a clínica sistémica después de 2 semanas de inicio de tratamiento con Vemurafenib + Cobimetinib. La histología demostró paniculitis linfocitaria septal y lobulillar. La paciente tuvo mala tolerancia al tratamiento anti diana a dosis plenas, requiriendo su ajuste, generando una corticodependencia para controlar sintomatología, y que finalmente obligó a la descontinuación de la terapia dirigida contra melanoma.  A la fecha, se han descrito 29 casos en la literatura de paniculitis asociada a vemurafenib, siendo la mayoría paniculitis neutrofílicas con adecuado control de sintomatología asociando antiinflamatorios no esteroidales y/o corticoides orales sin requerir en su mayoría modificación de la terapia contra melanoma; sin embargo hay que tener presente que pueden haber casos con mala evolución que obligan a la reducción de dosis de vemurafenib y descontinuar el tratamiento, como ha ocurrido en nuestro reporte.Vemurafenib has proven to be a useful tool in the treatment of metastatic melanoma with BRAF-V600E mutation. Adverse effects include arthralgia, fatigue, and skin toxicity; panniculitis is a rare complication. We present the case of a 43-year-old patient with metastatic melanoma who developed painful subcutaneous nodules of the lower and upper limbs and associated systemic clinical symptoms after 2 weeks of treatment with vemurafenib plus cobimetinib. Histology showed a septal and lobular lymphocytic panniculitis.The patient had poor tolerance of the full-dose treatment, requiring its adjustment. Systemic corticosteroids were required to control symptomatology, which finally forced the discontinuation of the medication.To date, 29 cases have been described in the literature of panniculitis associated with vemurafenib. Most of these have been neutrophilic panniculitis, but adequate control of symptoms is usually achieved with nonsteroidal anti-inflammatory drugs and/or oral corticosteroids without requiring modification of melanoma therapy. However, it must be borne in mind that there may be cases that force the reduction and discontinuation ofvemurafenib treatment. We beli

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Indoles; Melanoma; Panniculitis; Piperidines; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Animals; Anthracenes; Antigens, CD; Carcinogenesis; Gene Expression Regulation; Inflammation; Keratinocytes; Macrophage Migration-Inhibitory Factors; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; Piperidines; Pyridines; Receptors, CXCR; Skin; Skin Neoplasms

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain; Disease Progression; Humans; Indoles; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Melanoma; Piperidines; Posterior Leukoencephalopathy Syndrome; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Humans; Iris Neoplasms; Male; Melanoma; Piperidines; Protein Kinase Inhibitors; Remission Induction; Skin Neoplasms; Vemurafenib

Topics: Azetidines; Drug Interactions; Humans; MAP Kinase Kinase 1; Melanoma; Neoplasm Metastasis; Piperidines; Skin Neoplasms; Survival Rate

Topics: Antineoplastic Agents; Azetidines; Drug Interactions; Female; Humans; Male; Melanoma; Mitogen-Activated Protein Kinase Kinases; Piperidines; Pregnancy; Protein Kinase Inhibitors; Risk Factors; Signal Transduction; Skin Neoplasms; Treatment Outcome

Topics: Antineoplastic Agents; Azetidines; Central Serous Chorioretinopathy; Drug Therapy, Combination; Humans; Indoles; Male; Melanoma; Middle Aged; Piperidines; Recurrence; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib

Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor that promotes cell cycle arrest. We aimed to examine the anti-proliferative effects of the flavopiridol and oxaliplatin combination on p16INK4A deficient melanoma cells B16F10 and also its apoptotic effects on a subcutaneously injected B16F10 allograft melanoma tumor model. Flavopiridol and oxaliplatin treated B16F10 cell viability was determined by MTT assay. C57BL6 mice were injected with B16F10 cells and treated with flavopiridol after tumor implantation. BRAF and BCL2L1 mRNA expression levels were measured using reverse transcription-polymerase chain reaction (RT-PCR). Caspase 9 and caspase 3/7 activity were determined by activity assay kits. Proliferating cell nuclear antigen (PCNA) and B-cell lymphoma 2 (BCL-2) protein expression levels were analyzed immunohistochemically. Flavopiridol and oxaliplatin decreased cell death. Flavopiridol enhanced caspase 3/7 and caspase 9 activities in vitro and in vivo in a dose dependent manner via the mitochondrial apoptotic pathway. Even though there was a significant increase in Bcl-2 staining, PCNA staining was decreased in flavopiridol-administered mice. Decreased PCNA expression showed antiproliferative effects of flavopiridol which might be the result of cell-cycle arrest. Flavopiridol can be used as a cell cycle inhibitor.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Culture Techniques; Disease Models, Animal; Flavonoids; Melanoma; Mice; Mice, Inbred C57BL; Organoplatinum Compounds; Oxaliplatin; Piperidines; Proliferating Cell Nuclear Antigen; Skin Neoplasms; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents; Apoptosis; Azetidines; Carcinoma, Squamous Cell; Cell Line, Tumor; Cellular Senescence; Humans; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Xenograft Model Antitumor Assays

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Cell Transformation, Neoplastic; Dermoscopy; Female; Humans; Indoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Nevus, Pigmented; Piperidines; Signal Transduction; Skin Neoplasms; Sulfonamides; Vemurafenib

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Azetidines; Chemotherapy, Adjuvant; Drug Discovery; Drug Therapy, Combination; Humans; Imidazoles; Indoles; Ipilimumab; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Nivolumab; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

Medications in dermatology are used in a variety of different methods and dosages and for numerous different diseases entities that are not approved by the US Food and Drug Administration (FDA); however, there are medications that have only recently hit the market that require our attention, as they are either FDA approved for the intended dermatologic use or could be effective in treating conditions that previously have been poorly managed.

Topics: Aminolevulinic Acid; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arthritis, Psoriatic; Azetidines; Biphenyl Compounds; Carcinoma, Basal Cell; Cosmetic Techniques; Deoxycholic Acid; Dermatologic Agents; Drug Approval; Facial Dermatoses; Humans; Keratosis, Actinic; Melanoma; Oncolytic Virotherapy; Piperidines; Psoriasis; Pyridines; Scalp Dermatoses; Skin Neoplasms; United States; United States Food and Drug Administration

Masitinib mesylate is a tyrosine kinase inhibitor approved for the treatment of gross, non-metastatic grade II and III canine mast cell tumours (MCTs). This study evaluated the use of masitinib as a frontline and rescue agent for metastatic and non-metastatic canine MCTs. Identification of toxicities and prognostic factors in these dogs was of secondary interest. Twenty-six dogs were included in this study. The overall response rate to masitinib was 50%. The median survival time for dogs that responded to masitinib was 630 days versus 137 days for dogs that did not respond (P = 0.0033). Toxicity was recorded in 61.5% of treated dogs, but the majority of adverse events were mild and self-limiting. Response to masitinib, not tumour grade, stage or location, was the most significant prognostic factor for survival in dogs with MCTs.

Topics: Animals; Benzamides; Disease-Free Survival; Dog Diseases; Dogs; Female; Kaplan-Meier Estimate; Male; Mastocytosis, Cutaneous; Neoplasm Staging; Piperidines; Protein Kinase Inhibitors; Pyridines; Schools, Veterinary; Skin Neoplasms; Tennessee; Thiazoles

MEK inhibitors are being evaluated in clinical trials for treatment of different malignant neoplasms; trametinib dimethyl sulfoxide was approved by the US Food and Drug Administration for melanoma in 2013. We present 3 cases of patients receiving MEK inhibitors who developed an atypical eruption.. Three patients who were receiving different MEK inhibitors (selumetinib, cobimetinib, and trametinib) developed an eruption, all associated with unique duskiness. Drug hypersensitivity was confirmed by histopathologic testing in 2 of the 3 cases. The skin eruption responded well to corticosteroids and did not recur when treatment with the MEK inhibitor was restarted in 2 of the patients.. The typical skin reaction associated with MEK inhibitors is a papulopustular eruption. To our knowledge, the dusky erythema that occurred in the 3 patients described here has not previously been reported for this drug class.

Topics: Adult; Azetidines; Benzimidazoles; Drug Eruptions; Erythema; Female; Glucocorticoids; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

Topics: Adenine; Aged; Antineoplastic Agents; Fatal Outcome; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Retreatment; Skin Neoplasms

Human cutaneous melanoma is an aggressive and chemotherapy-resistant type of cancer. AM251 is a cannabinoid type 1 (CB1) receptor antagonist/inverse agonist with off-target antitumor activity against pancreatic and colon cancer cells. The current study aimed to characterize the in-vitro antimelanoma activity of AM251. The BRAF V600E mutant melanoma cell line, A375, was used as an in-vitro model system. Characterization tools included a cell viability assay, nuclear morphology assessment, gene expression, western blot, flow cytometry with Annexin V-FITC/7-AAD double staining, cell cycle analyses, and measurements of changes in intracellular cAMP and calcium concentrations. AM251 exerted a marked cytotoxic effect against A375 human melanoma cells with potency comparable with that observed for cisplatin without significant changes in the human dermal fibroblasts viability. AM251, at a concentration that approximates the IC50, downregulated genes encoding antiapoptotic proteins (BCL2 and survivin) and increased transcription levels of proapoptotic BAX, induced alteration of Annexin V reactivity, DNA fragmentation, chromatin condensation in the cell nuclei, and G2/M phase arrest.AM251 also induced a 40% increase in the basal cAMP levels, but it did not affect intracellular calcium concentrations. The involvement of GPR55, TRPA1, and COX-2 in the AM251 mechanism of action was excluded. The combination of AM251 with celecoxib produced a synergistic antitumor activity, although the mechanism underlying this effect remains to be elucidated. This study provides the first evidence of a proapoptotic effect and G2/M cell cycle arrest of AM251 on A375 cells. This compound may be a potential prototype for the development of promising diarylpyrazole derivatives to be evaluated in human cutaneous melanoma.

Topics: Antineoplastic Agents; Apoptosis; Calcium Channels; Celecoxib; Cell Line, Tumor; Cell Survival; Cyclic AMP; Cyclooxygenase 2; Drug Inverse Agonism; Drug Synergism; G2 Phase Cell Cycle Checkpoints; Humans; Melanoma; Mutation; Nerve Tissue Proteins; Piperidines; Proto-Oncogene Proteins B-raf; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Skin Neoplasms; Sulfonamides; Transient Receptor Potential Channels; TRPA1 Cation Channel

In view of the emergence of multidrug-resistant cancer cells, there is a need for therapeutic alternatives. Keeping this in mind, the present study was aimed at evaluating the synergism between nisin (an antimicrobial peptide) and doxorubicin (DOX) against DMBA-induced skin carcinogenesis. The possible tumoricidal activity of the combination was evaluated in terms of animal bioassay observations, changes in hisotological architecture of skin tissues, in situ apoptosis assay (TUNEL assay) and in terms of oxidant and antioxidant status of the skin tissues. In vivo additive effect of the combination was evidenced by larger decreases in mean tumour burden and tumour volume in mice treated with the combination than those treated with the drugs alone. Histological observations indicated that nisin-DOX therapy causes chromatin condensation and marginalisation of nuclear material in skin tissues of treated mice which correlated well with the results of TUNEL assay wherein a marked increase in the rate of apoptosis was revealed in tissues treated with the combination. A slightly increased oxidative stress in response to the adjunct therapy as compared to dox-alone-treated group was revealed by levels of lipid peroxidation (LPO) and nitrite generation in skin tissue-treated mice. An almost similar marginal enhancement in superoxide dismutase levels corresponding with a decrease in catalase activity could also be observed in nisin + DOX-treated groups as compared to nisin and dox-alone-treated groups. These results point towards the possible use of nisin as an adjunct to doxorubicin may help in developing alternate strategies to combat currently developing drug resistance in cancer cells.

Topics: Animals; Anthracenes; Apoptosis; Carcinogenesis; Doxorubicin; Humans; Lipid Peroxidation; Mice; Neoplasms, Experimental; Nisin; Oxidative Stress; Piperidines; Skin Neoplasms

Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.

Topics: Cell Line, Tumor; Genes, Tumor Suppressor; Humans; Janus Kinase 3; Lymphoma, T-Cell, Cutaneous; MicroRNAs; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; STAT5 Transcription Factor; Transfection

RAS-driven malignancies remain a major therapeutic challenge. The two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) model of mouse skin carcinogenesis has been used to study mechanisms of epithelial tumor development by oncogenic Hras. We used mice with an Hras(G12V) knock-in allele to elucidate the early events after Hras activation, and to evaluate the therapeutic effectiveness of farnesyltransferase inhibition (FTI). Treatment of Caggs-Cre/FR-Hras(G12V) mice with TPA alone was sufficient to trigger papilloma development with a shorter latency and an ∼10-fold greater tumor burden than DMBA/TPA-treated WT-controls. Hras(G12V) allele copy number was increased in all papillomas induced by TPA. DMBA/TPA treatment of Hras(G12V) knock-in mice induced an even greater incidence of papillomas, which either harbored Hras(G12V) amplification or developed an Hras(Q61L) mutation in the second allele. Laser-capture microdissection of normal skin, hyperplastic skin and papillomas showed that amplification occurred only at the papilloma stage. HRAS-mutant allelic imbalance was also observed in human cancer cell lines, consistent with a requirement for augmented oncogenic HRAS signaling for tumor development. The FTI SCH66336 blocks HRAS farnesylation and delocalizes it from the plasma membrane. NRAS and KRAS are not affected as they are alternatively prenylated. When tested in lines harboring HRAS, NRAS or KRAS mutations, SCH66336 delocalized, inhibited signaling and preferentially inhibited growth only of HRAS-mutant lines. Treatment with SCH66336 also induced near-complete regression of papillomas of TPA-treated Hras(G12V) knock-in mice. These data suggest that farnesyl transferase inhibitors should be reevaluated as targeted agents for human HRAS-driven cancers, such as those of bladder, thyroid and other epithelial lineages.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Line, Tumor; Enzyme Inhibitors; Farnesyltranstransferase; Gene Dosage; Gene Knock-In Techniques; Genes, ras; Humans; Mice, Mutant Strains; Mutation; Papilloma; Piperidines; Pyridines; Skin Neoplasms; Tetradecanoylphorbol Acetate

Current therapies for metastatic melanoma are targeted either at cancer mutations driving growth (e.g., vemurafenib) or immune-based therapies (e.g., ipilimumab). Tumour progression also requires angiogenesis, which is regulated by VEGF-A, itself alternatively spliced to form two families of isoforms, pro- and anti-angiogenic. Metastatic melanoma is associated with a splicing switch to pro-angiogenic VEGF-A, previously shown to be regulated by SRSF1 phosphorylation by SRPK1. Here, we show a novel approach to preventing angiogenesis-targeting splicing factor kinases that are highly expressed in melanomas.. We used RT-PCR, western blotting and immunohistochemistry to investigate SRPK1, SRSF1 and VEGF expression in tumour cells, and in vivo xenograft assays to investigate SRPK1 knockdown and inhibition in vivo.. In both uveal and cutaneous melanoma cell lines, SRPK1 was highly expressed, and inhibition of SRPK1 by knockdown or with pharmacological inhibitors reduced pro-angiogenic VEGF expression maintaining the production of anti-angiogenic VEGF isoforms. Both pharmacological SRPK1 inhibitors and SRPK1 knockdown reduced growth of human melanomas in vivo, but neither affected cell proliferation in vitro.. These results suggest that selective blocking of pro-angiogenic isoforms by inhibiting splice-site selection with SRPK1 inhibitors reduces melanoma growth. SRPK1 inhibitors may be used as therapeutic agents.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Gene Knockdown Techniques; Humans; Melanoma; Mice; Mice, Nude; Molecular Targeted Therapy; Neovascularization, Pathologic; Niacinamide; Piperidines; Protein Serine-Threonine Kinases; RNA Splicing; Skin Neoplasms; Tumor Burden; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Topics: Azetidines; Female; Humans; Indoles; Male; Melanoma; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib

Eruptive melanocytic nevi (EMN) are characterized by the sudden onset of numerous melanocytic nevi and have been traditionally described in the setting of immunosuppression. Selective BRAF inhibitors such as vemurafenib cause multiple cutaneous adverse effects, including the formation of cutaneous squamous cell carcinoma, as well as EMN. We describe the first reported case, to our knowledge, of involution of BRAF inhibitor-induced EMN following the concomitant addition of a MEK inhibitor, cobimetinib.. A woman in her 20s with a history of metastatic melanoma developed EMN while receiving therapy with vemurafenib, a selective BRAF inhibitor. After disease progression, the patient was placed on a clinical trial that combined vemurafenib with a MEK inhibitor, cobimetinib. Within months, we noted clinical involution of many of her EMN. In addition, numerous preexisting nevi were noted to fade in color on the dual regimen. Over a year after initiating this combination therapy, most of the patient's EMN were no longer clinically evident.. Our case report describing the involution of EMN supports data from previous clinical trials indicating that combination BRAF and MEK inhibition may reduce cutaneous proliferative effects that arise on BRAF inhibitor monotherapy. Further studies are necessary to characterize the biological mechanisms underlying this phenomenon.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Interactions; Female; Humans; Indoles; MAP Kinase Kinase 1; Melanoma; Nevus, Pigmented; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib; Young Adult

BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) frequently cause cutaneous adverse events.. We sought to investigate the cutaneous safety profile of BRAFi versus BRAFi and MEKi combination regimens.. We performed a retrospective cohort study, collecting data from 44 patients with melanoma treated either with BRAFi (vemurafenib or dabrafenib) or BRAFi and MEKi combination regimens (vemurafenib + cobimetinib or dabrafenib + trametinib). Patient characteristics, and the occurrence and severity of cutaneous adverse events, are described.. The development of cutaneous adverse events was significantly less frequent (P = .012) and occurred after longer treatment time (P = .025) in patients treated with BRAFi and MEKi combination regimen compared with patients treated with BRAFi monotherapy. Among patients who received both BRAFi and the combination of BRAFi and MEKi at different time points during their treatment course, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent when they received the combination regimen (P = .008). Patients receiving vemurafenib developed more cutaneous adverse events (P = .001) and in particular more photosensitivity (P = .010) than patients who did not.. There were a limited number of patients.. Combination regimen with BRAFi and MEKi shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval compared with BRAFi monotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Humans; Imidazoles; Indoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Sulfonamides; Vemurafenib; Young Adult

Topics: Acrylamides; Cell Death; Cell Line, Tumor; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Nicotinamide Phosphoribosyltransferase; Piperidines; Skin Neoplasms

This study evaluated the in vitro activity of masitinib mesylate against canine hemangiosarcoma (HSA) cell lines after treatment with increasing concentrations of masitinib mesylate (0.01-100 µM) for 24, 48 and 72 h. Results indicated that masitinib mesylate caused a dose- and time-dependent decrease in HSA cell proliferation. The 50% inhibitory concentration (IC(50) ) at 72 h for three HSA cell lines (DEN, Fitz and SB) was found to be 8.56, 9.41 and 10.65 µM, respectively. Further investigation demonstrated that masitinib mesylate induced apoptosis in all HSA cell lines, including activation of caspase-3/7. Measurement of VEGF levels in cell supernatant found a statistically significant increased VEGF in close proximity to the IC(50) of each cell line followed by a decline back towards baseline. These findings indicate that masitinib mesylate causes dose-dependent HSA cell death in vitro and supports future clinical trials of masitinib for canine HSA.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Dogs; Dose-Response Relationship, Drug; Hemangiosarcoma; In Situ Nick-End Labeling; In Vitro Techniques; Neoplasms, Vascular Tissue; Piperidines; Protein-Tyrosine Kinases; Pyridines; Skin Neoplasms; Thiazoles; Vascular Endothelial Growth Factor A

Diacylglycerol (DAG) increases the melanin content of human melanocytes in vitro and increases the pigmentation of guinea pig skin in vivo, but the mechanism(s) underlying those effects remain unknown. In this study, we characterized the role of diacylglycerol kinase (DGK), which phosphorylates DAG to generate phosphatidic acid, in the regulation of pigmentation. Ten isoforms of DGK have been identified, and we show that DGKζ is the most abundant isoform expressed by human melanocytic cells. Melanin content, tyrosinase activity, and tyrosinase protein levels were significantly reduced by a DGK inhibitor, but tyrosinase and microphthalmia-associated transcription factor messenger RNA (mRNA) levels were not changed by that inhibition, and there were no effects on the expression of other melanogenesis-related proteins. Isoform-specific small interfering RNAs showed that knockdown of DGKζ decreased melanin content and tyrosinase expression in melanocytic cells. Overexpression of DGKζ increased tyrosinase protein levels, but did not increase tyrosinase mRNA levels. Glycosidase digestion revealed that inhibition of DGK reduced only the mature form of tyrosinase, and the decrease of tyrosinase resulting from DGK inhibition could be blocked partially by protease inhibitors. These results suggest that DGK regulates melanogenesis via modulation of the posttranslational processing of tyrosinase, which may be related with the protein degradation machinery.

Topics: Adenoviridae; alpha-MSH; Animals; Cell Line, Tumor; Diacylglycerol Kinase; Endoplasmic Reticulum; Enzyme Inhibitors; Epidermal Cells; Flavonoids; Gene Expression Regulation, Enzymologic; Hormones; Humans; Indoles; Maleimides; Melanins; Melanocytes; Melanoma, Experimental; Membrane Glycoproteins; Mice; Monophenol Monooxygenase; Oxidoreductases; Piperidines; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Quinazolinones; Skin Neoplasms

Farnesyl transferase inhibitors (FTIs) inhibit the farnesylation of proteins, including RAS and RHEB (Ras homolog enriched in brain). RAS signals to the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways, which have a major role in melanoma progression. RHEB positively regulates mammalian target of rapamycin (mTOR). We investigated the effects of the FTI lonafarnib alone and in combination with MAPK (mitogen-activated protein kinase) or AKT (acutely transforming retrovirus AKT8 in rodent T-cell lymphoma) pathway inhibitors on proliferation, survival, and invasive tumor growth of melanoma cells. Lonafarnib alone did not sufficiently inhibit melanoma cell growth. Combinations of lonafarnib with AKT pathway inhibitors did not significantly increase melanoma cell growth inhibition. In contrast, combinations of lonafarnib with MAPK pathway inhibitors yielded additional growth-inhibiting effects. In particular, the combination of the FTI lonafarnib with the pan-RAF inhibitor sorafenib synergistically inhibited melanoma cell growth, significantly enhanced sorafenib-induced apoptosis, and completely suppressed invasive tumor growth in monolayer and organotypic cultures, respectively. Apoptosis induction was associated with upregulation of the endoplasmic reticulum stress-related transcription factors p8 and CHOP (CAAT/enhancer binding protein (C/EBP) homologous protein), and downregulation of the antiapoptotic Bcl-2 (B-cell lymphoma-2) family protein Mcl-1(myeloid cell leukemia 1). Lonafarnib did not affect MAPK and AKT but did affect mTOR signaling. Together, these findings suggest that the FTI lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells and may therefore represent an effective alternative for melanoma treatment.

Topics: Antineoplastic Agents; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Benzenesulfonates; Cell Line, Tumor; Endoplasmic Reticulum; Farnesyltranstransferase; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Niacinamide; Phenylurea Compounds; Piperidines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Pyridines; Signal Transduction; Skin Neoplasms; Sorafenib; TOR Serine-Threonine Kinases; Transcription Factor CHOP

Grover's disease (GD), or transient acantholytic dermatosis, is a persistent recurrent dermatosis that usually occurs in men older than 50 years. Rare cases of GD and hematologic malignancy in the same cutaneous biopsy specimen have been reported. We report a case of GD in association with leukemia cutis. A 72-year-old man with a history of myelodysplastic syndrome presented with numerous pruritic papules on the torso, which were clinically diagnosed as GD. A skin biopsy revealed foci of suprabasal acantholysis and dyskeratosis consistent with GD and dense aggregates of mononuclear atypical cells in the superficial dermis consistent with leukemia cutis. Direct immunofluorescence was negative. This case illustrates the need to consider a diagnostic skin biopsy in any patient who presents with classic clinical findings of GD if there is any indication that the patient may be at higher risk for a hematologic malignancy.

Topics: Acantholysis; Aged; Antineoplastic Agents; Biopsy; Dermis; Fatal Outcome; Flavonoids; Humans; Hydroxamic Acids; Ichthyosis; Leukemia; Leukemic Infiltration; Male; Myelodysplastic Syndromes; Piperidines; Salvage Therapy; Skin Neoplasms; Vorinostat

The present study is designed to investigate the effect of piperine in modifying the carcinogenic process, as well as biochemical alterations at the molecular level during DMBA-induced hamster buccal pouch carcinogenesis by FT-IR spectroscopy. Specific changes were noticed in the FT-IR spectral features of DMBA-induced hamster buccal pouch carcinoma. These alterations include structural changes of proteins and possible increase of its content, an increase in the nuclear-to-cytoplasm ratio, an increase in the relative amount of DNA, an enhancement in the phosphorylation of proteins, a loss of hydrogen bonding of the C-OH groups in the amino acid residues of proteins and diminished lipid peroxidation which were accompanied by a significant reduction in the relative amount of lipids compared to untreated control animals. Administration of piperine significantly increased the levels of lipid peroxidation and decreased the levels of proteins and nucleic acid content that were found to increase in oral cancer bearing animals. In conclusion, the results of the present study suggest that piperine may exert its chemopreventive effect by modulating the biochemical changes at the molecular level during DMBA-induced hamster buccal pouch carcinogenesis which can be detected using FT-IR spectroscopic technique.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alkaloids; Animals; Antineoplastic Agents; Benzodioxoles; Cricetinae; Male; Mouth Mucosa; Piperidines; Polyunsaturated Alkamides; Skin Neoplasms

Tumors are complex tissues composed of neoplastic cells, soluble and insoluble matrix components and stromal cells. Here we report that in melanoma, turn-over of type I collagen (Col(I)), the predominant matrix protein in dermal stroma affects melanoma progression. Fibroblasts juxtaposed to melanoma cell nests within the papillary dermis display high levels of Col(I) mRNA expression. These nests are enveloped by collagen fibers. In contrast, melanoma-associated fibroblasts within the reticular dermis express Col(I) mRNA at a level that is comparable to its expression in uninvolved dermis and reduced amount of collagen protein can be observed. To determine the significance of Col(I) expression in melanoma, we pharmacologically inhibited its transcription in a porcine cutaneous melanoma model by oral administration of halofuginone. When administered before melanoma development, it reduced melanoma incidence and diminished the transition from microinvasive toward deeply invasive growth by limiting the development of a tumor vasculature. Whereas invasive melanoma growth has been correlated with increased blood vessel density previously, our data for the first time demonstrate that the proangiogenic effect of Col(I) expression by fibroblasts and vascular cells precedes the development of invasive melanomas in a de novo tumor model.

Topics: Angiogenesis Inhibitors; Animals; Collagen Type I; Humans; Immunohistochemistry; In Situ Hybridization; Melanoma; Neoplasm Invasiveness; Neovascularization, Pathologic; Piperidines; Quinazolinones; Reverse Transcriptase Polymerase Chain Reaction; Skin Neoplasms; Swine; Swine, Miniature

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

Poly(ADP-ribose) polymerase (PARP)-1, an enzyme that catalyzes the attachment of ADP ribose to target proteins, acts as a component of enhancer/promoter regulatory complexes. In the present study, we show that pharmacologic inhibition of PARP-1 with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) results in a strong delay in tumor formation and in a dramatic reduction in tumor size and multiplicity during 7,12-dimethylbenz(a)anthracene plus 12-O-tetradecanoylphorbol-13-acetate-induced skin carcinogenesis. This observation was parallel with a reduction in the skin inflammatory infiltrate in DPQ-treated mice and tumor vasculogenesis. Inhibition of PARP also affected activator protein-1 (AP-1) activation but not nuclear factor-kappaB (NF-kappaB). Using cDNA expression array analysis, a substantial difference in key tumor-related gene expression was found between chemically induced mice treated or not with PARP inhibitor and also between wild-type and parp-1 knockout mice. Most important differences were found in gene expression for Nfkbiz, S100a9, Hif-1alpha, and other genes involved in carcinogenesis and inflammation. These results were corroborated by real-time PCR. Moreover, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1alpha) was compromised by PARP inhibition or in PARP-1-deficient cells, as measured by gene reporter assays and the expression of key target genes for HIF-1alpha. Tumor vasculature was also strongly inhibited in PARP-1-deficient mice and by DPQ. In summary, this study shows that inhibition of PARP on itself is able to control tumor growth, and PARP inhibition or genetic deletion of PARP-1 prevents from tumor promotion through their ability to cooperate with the activation AP-1, NF-kappaB, and HIF-1alpha.

Topics: Animals; Carcinogens; Cell Transformation, Neoplastic; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Hypoxia-Inducible Factor 1, alpha Subunit; Isoquinolines; Mice; Mice, Inbred C57BL; NF-kappa B; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Reverse Transcriptase Polymerase Chain Reaction; Skin Neoplasms; Tetradecanoylphorbol Acetate; Transcription Factor AP-1

Endothelin receptor B (ETRB or EDNRB) is overexpressed in most human melanomas and is proposed to provide a marker of melanoma progression. We have shown previously that inhibition of ETRB leads to increased human melanoma cell death in vitro and in vivo, resulting in shrinkage of tumors grown in immunocompromised mice. In the present work, we analyzed the effects of ETRB inhibition on 10 human melanoma cell lines derived from tumors at distinct stages of progression. Our observations suggest that the ETRB antagonist BQ788 induces apoptosis most effectively in metastatic melanoma cells. Microarray analysis shows that BQ788 treatment leads to a reduction in the expression of the survival factor BCL-2A1 and the DNA repair factor poly(ADP-ribose) polymerase 3 that is more pronounced in cells derived from metastatic than primary melanoma. Decreased cell viability was observed to correlate with reduction in ETRB expression, and reduction in ETRB protein levels by small interfering RNA led to an increase in cell death. Interestingly, reduction of ETRB expression by BQ788 was accompanied by a strong induction of VEGF expression and repression of the angiogenic suppressor gravin. These changes in gene expression correlated with increased angiogenesis in tumors injected with ETRB antagonist in vivo. Taken together, our observations suggest that ETRB may provide a potential therapeutic target in high-grade melanomas and identify candidate pathways that may be implicated in the regulation of cell survival and tumor progression associated with ETRB signaling.

Topics: Apoptosis; Caspase 6; Caspases; Cell Cycle Proteins; Cell Line, Tumor; Disease Progression; Endothelin B Receptor Antagonists; Enzyme Activation; Humans; Lymphatic Metastasis; Melanoma; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Oligopeptides; Piperidines; Poly(ADP-ribose) Polymerases; Skin Neoplasms

Melanoma cell adhesion molecule (MCAM) is a cell-surface adhesion molecule expressed on over 70% of metastatic melanoma cells but not expressed in normal melanocytes invivo. Protein levels of MCAM correlate with aggressive invasive behavior of melanoma cells in vitro and invivo. Here we demonstrate that endothelin-1 (ET-1) upregulates MCAM protein in primary human melanocytes. MCAM upregulation by ET-1 occurs irrespective of degree of melanocyte pigmentation and is dose-responsive. The drug BQ788 is an endothelin-B (ET(B)) receptor antagonist and inhibits upregulation of MCAM by ET-1. In addition, endothelin-3 (ET-3) and N-succinyl-[Glu9, Ala11, 15]-ET-1-1620, both selective ET(B) agonists, are potent upregulators of MCAM. These demonstrate a critical role for the ET(B) receptor in the upregulation of MCAM by ET-1 and related isoforms. MCAM mRNA abundance is also increased by ET-1 stimulation, thus the mechanism of MCAM protein upregulation may occur at the level of transcription. Our previous studies have demonstrated that ET-1 downregulates E-cadherin in melanocytes and melanoma cells. Since E-cadherin is a melanoma invasion suppressor, and MCAM is a melanoma invasion promoter, ET-1 may promote melanoma invasion and metastasis through the regulation of adhesion molecule expression.

Topics: Antigens, CD; CD146 Antigen; Endothelin B Receptor Antagonists; Endothelin-1; Gene Expression; Humans; Kinetics; Melanocytes; Melanoma; Neural Cell Adhesion Molecules; Oligopeptides; Piperidines; RNA, Messenger; Skin Neoplasms; Tumor Cells, Cultured; Up-Regulation

The constitutive activity of a number of growth and cell survival pathways are thought to contribute to the inherent resistance of melanoma to chemotherapy and radiotherapy. Many of these pathways are driven through the small GTPase Ras. Novel drugs such as the farnesyl transferase inhibitors (FTIs) and farnesyl thiosalicylic acid (FTS) interfere with the signaling of oncogenic Ras. The aim of our study was to assess the anti-tumour activity of the FTI SCH66336 in melanoma and to assess whether SCH66336 and FTS could modulate chemoresistance in melanoma cells. SCH66336 had marked anti-proliferative activity in both human and mouse melanoma cell lines, but not in non-transformed NIH 3T3 cells. The anti-proliferative activity of SCH66336 was due to G1-phase cell cycle arrest and retinoblastoma protein inactivation, followed by apoptosis. Cisplatin, when administered alone, induced little apoptosis. In combination with cisplatin, both FTS and SCH66336 markedly enhanced the level of cisplatin-induced apoptosis, an effect that was associated with enhanced G2/M cell cycle arrest. Pharmacological inhibitors of either ERK or PI-3 kinase/Akt did not mimic the chemosensitising activity of either SCH66336 or FTS. In summary, our study demonstrates that SCH66336 has good in vitro anti-tumour activity in both human and mouse melanoma cell lines, and suggests that Ras antagonists could be useful in overcoming chemoresistance to cisplatin in melanoma.

Topics: 3T3 Cells; Actins; Alkyl and Aryl Transferases; Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Division; Cisplatin; Colony-Forming Units Assay; Drug Synergism; Enzyme Inhibitors; Farnesol; Farnesyltranstransferase; Humans; In Situ Nick-End Labeling; In Vitro Techniques; Melanoma; Mice; Microscopy, Confocal; Mitogen-Activated Protein Kinases; Piperidines; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyridines; Retinoblastoma Protein; Salicylates; Skin Neoplasms; Tumor Cells, Cultured

Flavopiridol is the first cyclin-dependent kinase inhibitor to enter clinical trials. Flavopiridol has been shown to mimic, in part, the effect of the cell cycle control gene p16, which is frequently lost or mutated in malignant melanoma, making it an ideal candidate for targeted therapy in this disease. In these studies we investigated the effect of flavopiridol, at various concentrations, on the growth and gene expression of nine human melanoma cell lines with intact, absent or mutated p16. A cytostatic effect of flavopiridol on the growth of six melanoma cell lines with a mutated or non-expressed p16 (p16-) was seen at low concentrations of flavopiridol (mean 50% inhibitory concentration [IC(50)] = 12.5 nM), while the three melanoma cell lines with intact p16 (p16+) required higher concentrations (mean IC(50) = 25 nM) to produce this effect. Apoptotic cell death increased with increasing concentrations of flavopiridol in both p16- and p16+ cells. Exposure of cells to high flavopiridol concentrations (>100 nM) resulted in decreased expression of genes downstream in the normal p16 cell cycle control pathway (Rb and E2F) and the anti-apoptotic gene BCL2. No change in BCL2 expression was found after exposure to IC(50) concentrations of flavopiridol. These data indicate that flavopiridol in low, clinically achievable concentrations may have significant cytostatic effects, particularly in p16- melanoma cells, and may provide new molecular-based therapies for melanoma, particularly when combined with agents that target anti-apoptotic mechanisms.

Topics: Antineoplastic Agents; Cell Cycle; Cyclin-Dependent Kinase Inhibitor p16; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavonoids; Gene Expression Regulation, Neoplastic; Genes, p16; Humans; Inhibitory Concentration 50; Melanoma; Piperidines; Skin Neoplasms; Tumor Cells, Cultured

Oral administration of TMK688 (1-([5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadien oyl] aminoethyl)-4-diphenylmethoxypiperidine: 30 mg/kg) at 6 h and 30 min prior to and at 30 min after a single topical application of 7,12-dimethylbenz[a]anthracene (DMBA) to dorsal skins of mice reduced both tumor incidence and number of tumors per mouse in the DMBA-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted two-stage mouse skin carcinogenesis. TMK688 and its active metabolite TMK777 (1-([5'-(3"-methoxy-4"- hydroxyphenyl)-2',4'-pentadienoyl]-aminoethyl)-4-diphenylmethox y piperidine) inhibited 3-methylchol-anthrene (MC)-induced epidermal aryl hydrocarbon hydroxylase (AHH) activity in a concentration-dependent manner. IC50 of TMK688 and TMK777 was 0.18 and 0.01 mumol/l, respectively. Oral administration of TMK688 (30 mg/kg) almost completely suppressed Cyp1a1 mRNA levels in mouse epidermis induced by a topical application of MC (40 mg/kg) or benzo[a]pyrene (200 nmol) to mouse skin. Oral administration of TMK688 (30 mg/kg) also almost completely inhibited induction of epidermal AHH activity caused by a topical application of MC. These results indicate that oral administration of TMK688 inhibited DMBA-caused skin tumor initiation at least in part by inhibiting Cyp1a1 mRNA induction and epidermal AHH activity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aryl Hydrocarbon Hydroxylases; Base Sequence; Benzo(a)pyrene; Carcinogens; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Enzyme Induction; Epidermis; Female; Gene Expression Regulation, Enzymologic; Lipoxygenase Inhibitors; Mice; Piperidines; RNA, Messenger; Skin Neoplasms

1-([5'-(3''-methoxy-4''-ethoxycarbonyloxyphenyl)-2',4'- pentadienoyl]aminoethyl)-4-diphenylmethoxypiperidine (TMK688) is a potent and orally active 5-lipoxygenase inhibitor having anti-histamine activity in its moiety. Recently, we have found that TMK688 also inhibits epidermal cyclooxygenase activity with a potency similar to its inhibiting 5-lipoxygenase. Oral administration of 30 mg/kg TMK688, a dose which markedly inhibits tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated LTB4 formation in mouse skin, markedly inhibited both TPA-promoted and a non-TPA-type tumor promoter anthralin-promoted skin tumor formation in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated CD-1 mice. The inhibitory effect of TMK688 was not due to any damage inflicted on the initiated cells but due to its antitumor-promoting activity. TMK688 not only inhibited two-stage skin carcinogenesis but also inhibited benzo[a]pyrene-caused complete skin carcinogenesis. Throughout the tumorigenesis experiment, the survival rate of animals was 100% and the TMK688-treated mice looked healthy. The body weight gain of TMK688-treated mice was not significantly different from that of non-treated mice. Both TMK688 and 1-([5'-(3''-methoxy-4''-hydroxyphenyl)-2',4'-pentadienoyl]amino eth yl]-4-diphenylmethoxypiperidine (TMK777), an active metabolite of TMK688 having more potent 5-lipoxygenase inhibitory activity and less potent cyclooxygenase inhibitory activity than TMK688, inhibited epidermal 8-lipoxygenase activity induced by a topical application of TPA to mouse skin. The 8-lipoxygenase inhibitory activity of TMK777 was approximately 5 times more potent than that of TMK688. Indomethacin, a typical cylcloxygenase inhibitor, in topical doses which almost completely inhibit epidermal PGE2 formation, failed to inhibit or only slightly inhibited DMBA-initiated and TPA-promoted skin tumor formation. These results suggest that the cyclooxygenase inhibitory effect of TMK688 is not essential for its anti-tumor promoting activity. Although at present a possible contribution of anti-histamine activity cannot be ruled out completely, the anti-tumor promoting action of TMK688 may most probably be related to its anti-lipoxygenase activity. TMK688 seems to be a promising agent for the prevention of skin carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Administration, Topical; Animals; Anticarcinogenic Agents; Arachidonate Lipoxygenases; Benzo(a)pyrene; Female; Indomethacin; Lipoxygenase Inhibitors; Mice; Mice, Inbred Strains; Piperidines; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate

Four N-Acetoxy-N-arylacetamides previously found to be local sarcomagens in the rat have been found to be initiators of tumorigenesis in mouse skin. The order of activity was: N-acetoxy-2-acetamidophenanthrene greater than N-acetoxy-4-acetamino-stilbene similar to N-acetoxy-2-acetamido-fluorene greater than N-acetoxy-4-acetamidobiphenyl. Two substituted N-benzoyloxypiperidines previously shown to yield nitrenium ions on solvolysis in methanol also had initiating activity in mouse skin.

Topics: Acetamides; Animals; Benzene Derivatives; Biphenyl Compounds; Female; Fluorobenzenes; Mice; Phenanthrenes; Piperidines; Precancerous Conditions; Skin Neoplasms; Stilbenes; Time Factors

Topics: Animals; Carcinogens; Chemical and Drug Induced Liver Injury; Cricetinae; Dose-Response Relationship, Drug; Female; Injections, Subcutaneous; Lung Neoplasms; Male; Morpholines; Neoplasms, Experimental; Nitrosamines; Nitroso Compounds; Nitrosourea Compounds; Nose Neoplasms; Piperidines; Sarcoma; Sarcoma, Experimental; Skin Neoplasms; Stomach Neoplasms; Tracheal Neoplasms

Topics: Animals; Azepines; Carcinoma, Squamous Cell; Facial Neoplasms; Female; Male; Mice; Mice, Inbred Strains; Mouth Mucosa; Mouth Neoplasms; Nasal Mucosa; Nitroso Compounds; Pharyngeal Neoplasms; Pharynx; Piperidines; Skin Neoplasms; Time Factors

Topics: Amines; Animals; Chromatography, Thin Layer; Fluorometry; Guinea Pigs; Histamine; Humans; Indicators and Reagents; Mice; Piperidines; Rats; Skin; Skin Neoplasms; Spectrophotometry; Spermine; Sweat; Ultraviolet Rays