tretinoin and Infections

Acute myeloid leukaemia (AML) is the most common acute leukaemia affecting adults. Most patients diagnosed with AML are at advanced age and present with co-morbidities, so that intensive therapy such as stem cell transplantation (SCT) is impossible to provide or is accompanied by high risks for serious adverse events and treatment-related mortality. Especially for these patients, it is necessary to find out whether all-trans retinoic acid (ATRA), an intermediate of vitamin A inducing terminal differentiation of leukaemic cell lines, added to chemotherapy confers increased benefit or harm when compared with the same chemotherapy alone.. This review aims to determine benefits and harms of ATRA in addition to chemotherapy compared to chemotherapy alone for adults with AML (not those with acute promyelocytic leukaemia (non-APL)).. We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, study registries and relevant conference proceedings up to July 2018 for randomised controlled trials (RCTs). We also contacted experts for unpublished data.. We included RCTs comparing chemotherapy alone with chemotherapy plus ATRA in patients with all stages of AML. We excluded trials if less than 80% of participants were adults or participants with AML, and if no subgroup data were available. Patients with myelodysplastic syndrome (MDS) were included, if they had a refractory anaemia and more than 20% of blasts.. Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. We used hazard ratios (HR) for overall survival (OS) and disease-free survival (DFS; instead of the pre-planned event-free survival, as this outcome was not reported), and we calculated risk ratios (RR) for the other outcomes quality of life, on-study mortality and adverse events. We presented all measures with 95% confidence intervals (CIs). We assessed the certainty of evidence using GRADE methods.. Our search resulted in 2192 potentially relevant references, of which we included eight trials with 28 publications assessing 3998 patients. Overall, we judged the potential risk of bias of the eight included trials as moderate. Two of eight trials were published as abstracts only. All the included trials used different chemotherapy schedules and one trial only evaluated the effect of the hypomethylating agent decitabine, a drug know to affect epigenetics, in combination with ATRA.The addition of ATRA to chemotherapy resulted in probably little or no difference in OS compared to chemotherapy only (2985 participants; HR 0.94 (95% confidence interval (CI) 0.87 to 1.02); moderate-certainty evidence). Based on a mortality rate at 24 months of 70% with chemotherapy alone, the mortality rate with chemotherapy plus ATRA was 68% (95% CI 65% to 71%).For DFS, complete response rate (CRR) and on-study mortality there was probably little or no difference between treatment groups (DFS: 1258 participants, HR 0.99, 95% CI 0.87 to 1.12; CRR: 3081 participants, RR 1.02, 95% CI 0.96 to 1.09; on-study mortality: 2839 participants, RR 1.02, 95% CI 0.81 to 1.30, all moderate-certainty evidence).Three trials with 1428 participants reported the adverse events 'infection' and 'cardiac toxicity': There was probably no, or little difference in terms of infection rate between participants receiving ATRA or not (RR 1.05, 95% CI 0.96 to 1.15; moderate-certainty evidence). We are uncertain whether ATRA decreases cardiac toxicity (RR 0.46, 95% CI 0.24 to 0.90; P = 0.02, very low certainty-evidence, however, cardiac toxicity was low).Rates and severity of diarrhoea and nausea/vomiting were assessed in two trials with 337 patients and we are uncertain whether there is a difference between treatment arms (diarrhoea: RR 2.19, 95% CI 1.07 to 4.47; nausea/vomiting: RR 1.46, 95% CI 0.75 to 2.85; both very low-certainty evidence).Quality of life was not reported by any of the included trials.. We found no evidence for a difference between participants receiving ATRA in addition to chemotherapy or chemotherapy only for the outcome OS. Regarding DFS, CRR and on-study mortality, there is probably no evidence for a difference between treatment groups. Currently, it seems the risk of adverse events are comparable to chemotherapy only.As quality of life has not been evaluated in any of the included trials, further research is needed to clarify the effect of ATRA on quality of life.

Topics: Adult; Antineoplastic Agents; Decitabine; Diarrhea; Disease Progression; Heart; Humans; Infections; Leukemia, Myeloid, Acute; Nausea; Recurrence; Tretinoin; Vomiting

Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology.

Topics: Adaptive Immunity; Animals; Cell Movement; Humans; Immune Tolerance; Immunity, Mucosal; Immunoglobulin A; Infections; Signal Transduction; T-Lymphocytes, Regulatory; Tretinoin; Vitamin A

Sweet syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by tender, red inflammatory nodules or papules that occur in association with infection, malignancy, connective tissue disease, or following exposure to certain drugs. Although drug-induced Sweet syndrome is rare, granulocyte colony-stimulating factor, all-trans-retinoic acid, and miscellaneous drugs have been implicated in causing this disorder in adults. In pediatric patients, granulocyte colony-stimulating factor, all-trans-retinoic acid, trimethoprim-sulfamethoxazole, and azathioprine have been implicated as potential causes of drug-induced Sweet syndrome. To date, six cases, including the patient reported here, have been reported in children.

Topics: Adult; Azathioprine; Child; Connective Tissue Diseases; Erythema; Fever; Granulocyte Colony-Stimulating Factor; Humans; Infections; Sweet Syndrome; Tretinoin; Trimethoprim, Sulfamethoxazole Drug Combination

Adaptive Foxp3(+)CD4(+) regulatory T (iTreg) cells develop outside the thymus under subimmunogenic antigen presentation, during chronic inflammation, and during normal homeostasis of the gut. iTreg cells are essential in mucosal immune tolerance and in the control of severe chronic allergic inflammation, and most likely are one of the main barriers to the eradication of tumors. The Foxp3(+) iTreg cell repertoire is drawn from naive conventional CD4(+) T cells, whereas natural Treg (nTreg) cells are selected by high-avidity interactions in the thymus. The full extent of differences and similarities between iTreg and nTreg cells is yet to be defined. We speculate that iTreg cell development is driven by the need to maintain a noninflammatory environment in the gut, to suppress immune responses to environmental and food allergens, and to decrease chronic inflammation, whereas nTreg cells prevent autoimmunity and raise the activation threshold for all immune responses.

Topics: Animals; Cell Differentiation; Dendritic Cells; Forkhead Transcription Factors; Humans; Immune Tolerance; Infections; Inflammation; Interleukin-15; Interleukin-2; Neoplasms; STAT Transcription Factors; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Thymus Gland; Transforming Growth Factor beta; Tretinoin

Vaccines are not presently available to prevent adherence and transmission of many common pathogens at mucosal surfaces. As a result, sexually transmitted diseases were one of the most commonly reported infections in the US in 1999. New methods are needed to reduce the spread of mucosal infections. Providing nonspecific protective factors, such as lipids and retinoids found in human milk to mucosal surfaces could reduce mucosal infection caused by viruses, e.g., herpes simplex virus-1 (HSV-1) and bacteria, e.g., Pseudomonas aeruginosa. Human milk lipids enzymatically modified to produce monoglycerides were antimicrobial and inactivated enveloped viruses, as well as gram-positive and gram-negative bacteria. Enveloped viruses were inactivated in seconds following contact with antimicrobial lipids, and P. aeruginosa infectivity was reduced by 99.9% after 2 hours. Transmission of pathogens at mucosal surfaces can also be prevented using retinoids that inhibit viral replication. In a human embryonic intestinal cell line the retinoic acid (RA) derivatives all-trans-RA and 9-cis-RA (10 microg/mL) decreased the production of HSV-1 and Echo-6 viruses by 1-2 log10 over a 48-hour period. In addition, all-trans-RA inhibited HSV-1 replication in Vero cells as effectively as interferon beta, reducing viral production by 2.5log10. These studies indicate that lipids and retinoids could be part of a topical microbicide to prevent mucosal infections.

Topics: Anti-Infective Agents, Local; Antiviral Agents; Delivery, Obstetric; Female; Humans; Infections; Infectious Disease Transmission, Vertical; Milk, Human; Sexually Transmitted Diseases; Tretinoin; Vaginal Diseases; Vaginosis, Bacterial; Virus Diseases

Vitamin A, an unsaturated 20 carbon cyclic alcohol, subserves a number of important physiological functions. However, the biochemical basis of these roles is not well understood. The main sources of retinol are liver, egg yolk and milk fat. Several carotenoids show vitamin A activity. The conversion of beta-carotene to retinol is affected by copper-containing dioxygenase and zinc-containing retinene reductase. The efficiency of conversion varies in different species. The latter is defined in units as the daily dose required to produce a weight gain of 3 g/week in young rats between the 4th and 8th week. Retinol is unstable on exposure to light or heat, particularly in the presence of heavy metal ions and water. Much recent work has focused on the absorption, metabolism and excretion of vitamin A. It is now recognized that plasma vitamin A levels do not reflect the nutritional status except in severe hypo- and hypervitaminosis A. Also, many dietary factors may influence vitamin A metabolism. These basic and applied aspects of vitamin A are reviewed.

Topics: Absorption; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Artiodactyla; beta Carotene; Biological Availability; Biological Transport; Bone Development; Carotenoids; Chemical Phenomena; Chemistry; Drug Stability; Epithelium; Female; Fish Oils; Growth; Humans; Infections; Intestinal Absorption; Intracranial Pressure; Liver; Male; Neoplasms; Nutritional Requirements; Oxidation-Reduction; Reproduction; Silage; Structure-Activity Relationship; Tretinoin; Vision, Ocular; Vitamin A

An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction failure in a series of 732 patients of all ages (range, 2-83 years) with newly diagnosed APL who received all-trans retinoic acid (ATRA) plus idarubicin as induction therapy in 2 consecutive studies of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group. Complete remission was attained in 666 patients (91%). All the 66 induction failures were due to induction death. Hemorrhage was the most common cause of induction death (5%), followed by infection (2.3%) and differentiation syndrome (1.4%). Multivariate analysis identified specific and distinct pretreatment characteristics to correlate with an increased risk of death caused by hemorrhage (abnormal creatinine level, increased peripheral blast counts, and presence of coagulopathy), infection (age>60 years, male sex, and fever at presentation), and differentiation syndrome (Eastern Cooperative Oncology Group [ECOG] score>1 and low albumin levels), respectively. These data furnish clinically relevant information that might be useful for designing more appropriately risk-adapted treatment protocols aimed at reducing the considerable problem of induction mortality in APL.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Child; Child, Preschool; Creatinine; Disease-Free Survival; Female; Hemorrhage; Humans; Idarubicin; Infections; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Risk Factors; Sex Factors; Survival Rate; Syndrome; Treatment Failure; Tretinoin

Various methods of intensive chemotherapy have contributed to an improved survival in pediatric acute myeloid leukemia (AML). We here report the long-term results of the two consecutive trials of Tokyo Children's Cancer Study Group (TCCSG), incorporating repetitive use of high-dose cytarabine (HD-Ara-C) based combination chemotherapy in post-remission phase.. A total of 216 eligible children with newly diagnosed AML were treated in the two consecutive multi-center trials of TCCSG, M91-13 and M96-14, from August 1991 to September 1998. In M91-13 trial, patients received eight courses of intensive post-remission chemotherapy, including six HD-Ara-C containing courses, after remission-induction therapy. Autologous hematopoietic stem cell transplantation (HSCT) could be selected by physician's choice, and allogeneic HSCT was allocated if donor was available. In M96-14 trial, the last two HD-Ara-C courses were omitted from the chemotherapy arm.. The remission-induction rate was 88.8% and probability of 5-year Overall survival (OS) and event-free survival (EFS) were 62% (56-69% with 95% Confidence intervals (CIs)) and 56% (49-62%), respectively. Treatment-related mortality (TRM) was 7.8%. Among patients without Down syndrome (DS) or acute promyelocytic leukemia (APL), the presence of t(8;21) or inv(16) was a significant good prognostic factor both in the univariate and multivariate analyses. Children with DS (N = 10) and APL (N = 14) also showed a good survival exceeding 70% in 5 years.. These results suggest that repetitive use of HD-Ara-C was effective and safe for childhood AML. However, further optimization of AML therapy is required.

Topics: Acute Disease; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Down Syndrome; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Hydrocortisone; Infant; Infections; Japan; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Methotrexate; Mitoxantrone; Remission Induction; Survival Analysis; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Tretinoin; Vincristine

Twenty-two patients with high-risk myelodysplastic syndrome (HRMDS) were treated with a 10-day course of oral all trans retinoic acid (45 mg/m2) and s.c. low-dose cytosine arabinoside (LDARAc) given at the dose of 20 mg twice per day. The courses were repeated monthly until response or progression, in the case of response, the therapy was administered until relapse. Morphologic diagnoses were refractory anemia with excess blasts (RAEB) in nine, RAEB in transformation (RAEB-t) in nine, and chronic myelomonocytic leukemia (CMMoL) in four patients; in all cases, bone-marrow blast infiltration was greater than 10% (median 20%, range 12-30%). When the international prognostic scoring system was applied, all the cases qualified as intermediate/high-risk categories. Nineteen patients were males and three were females; the median age was 69 years (range 25-90 years); three patients had previously been treated with conventional chemotherapy, and one of them had also undergone autologous bone-marrow transplantation. The criteria of response were defined as follows: (1) complete response: normalization of blood counts and bone-marrow blasts (<5%), and (2) partial response: decrease in bone-marrow blast infiltration by 50%, and two of the following parameters - improvement in hemoglobin level by 1.5 g/dl or decrease by 50% in transfusional requirement, increase by 50% in absolute neutrophil count, and increase by 50% in platelet count. Overall, 7 (32%) of 22 patients achieved a response, with 5 (23%) being classified as complete responders and 2 (9%) as partial responders. Fifteen (68%) patients did not achieve any response, and 14 died of progressive disease or infectious disease. The overall median survival was 8 months (range 1-27 months), whereas the median survival of responders was 16 months (range 8-27 months); the median duration of response was 11 months (range 2-21 months). Moderate to severe hematological toxicity and infections were the most common side effects. In conclusion, it seems that the association of ATRA and LDARA-C may be effective in approximately 30% of HRMDS patients. Optimizing this approach might be pursued by selecting, on a biological basis, those cases more likely to respond or by incorporating other differentiating agents or growth factors.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Cytarabine; Dose-Response Relationship, Drug; Female; Humans; Hypertriglyceridemia; Infections; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Thrombocytopenia; Tretinoin

This study aimed to evaluate the outcome and predictors of survival in hemodialysis patients of Hasheminejad Kidney Center where a comprehensive dialysis care program has been placed since 2004.. Data of 560 hemodialysis patients were used to evaluate 9-year survival rates and predictors of mortality. Cox regression models included comorbidities as well as averaged and 6-month-averaged time-dependent values of laboratory findings as independent factors.. Survival rates were 91.9%, 66.0%, 46.3%, and 28.5%,  at 1, 3, 5, and 9 years, respectively, in all patients and 90.8%, 61.6%, 42.1%, and 28.0% in 395 incident patients starting hemodialysis after 2004. Adjusted survival models demonstrated age, male sex, diabetes mellitus, cardiovascular disease, and high-risk vascular access as baseline predictors of mortality, as well as averaged low hemoglobin level (hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.36 to 2.90) and a single-pool KT/V < 1.2 (HR, 2.28; 95% CI, 1.60 to 3.26). The averaged high-density lipoprotein cholesterol (HR, 0.67; 95% CI, 0.55 to 0.81) and serum creatinine (HR, 0.71; 95% CI, 0.64 to 0.79) levels demonstrated protective effects. The adjusted time-dependent model further revealed the significant association of hypocalcemia (HR, 1.63; 95% CI, 1.13 to 2.34), hypercalcemia (HR, 1.50; 95% CI, 1.02 to 2.21), and hyperphosphatemia (HR, 1.68; 95% CI, 1.20 to 2.37) with death.. Our patients have relatively comparable survival rates with high-profile dialysis centers. Aiming to better achieve the recommended targets, especially hemoglobin and nutritional and bone metabolism factors, should be considered for optimal dialysis outcomes.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Cardiovascular Diseases; Cause of Death; Cerebrovascular Disorders; Child; Cholesterol, HDL; Creatinine; Diabetes Mellitus; Female; Humans; Hypercalcemia; Hyperphosphatemia; Hypocalcemia; Infections; Iran; Kidney Failure, Chronic; Male; Middle Aged; Mortality; Neoplasms; Proportional Hazards Models; Renal Dialysis; Retrospective Studies; Risk Factors; Sex Factors; Survival Rate; Time Factors; Tretinoin; Young Adult

In a pilot study to reduce the duration of treatment and potential long-term toxicities, 39 patients with acute promyelocytic leukemia in remission received a single cycle of intensive consolidation therapy, followed by intermittent ATRA maintenance. Consolidation therapy required prolonged hospitalization and was associated with a high incidence of mucositis (43% grade II or greater) and documented infection (45%). No deaths occurred during consolidation. Seven patients have relapsed; all other patients are in molecular remission (median follow-up, 2.75 years). Kaplan-Meier estimate of 3 year disease-free survival is 73% (95% confidence interval 55-91%). The relapse rate (0.06 relapses/patient-year of follow-up) is well within the range of larger published series that administer more prolonged consolidation. One patient has developed secondary myelodysplastic syndrome. These pilot data suggest that decreasing the total duration of consolidation chemotherapy did not compromise disease-free survival for APL patients induced with ATRA/anthracycline and given intermittent ATRA maintenance. However, the toxicity of the consolidation module and the development of secondary myelodysplasia despite decreased total therapy emphasize the need to further improve and refine curative therapy for APL.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Humans; Incidence; Infections; Leukemia, Promyelocytic, Acute; Middle Aged; Myelodysplastic Syndromes; Neoplasm Recurrence, Local; Pilot Projects; Receptors, Retinoic Acid; Remission Induction; Retinoic Acid Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; Stomatitis; Survival Analysis; Treatment Outcome; Tretinoin