Environmental Triggers of Autoreactive Responses: Induction of Antiphospholipid Antibody Formation.

Front Immunol. 2019;10:1609

Authors: Martirosyan A, Aminov R, Manukyan G

Abstract
Antiphospholipid antibodies (aPLs) comprise a diverse family of autoantibodies targeted against proteins with the affinity toward negatively charged phospholipids or protein-phospholipid complexes. Their clinical significance, including prothrombotic potential of anti-cardiolipin antibodies (aCLs), anti-β2-glycoprotein I antibodies (aβ2-GPIs), and lupus anti-coagulant (LA), is well-established. However, the ontogeny of these pathogenic aPLs remains less clear. While transient appearance of aPLs could be induced by various environmental factors, in genetically predisposed individuals these factors may eventually lead to the development of the antiphospholipid syndrome (APS). Since the first description of APS, it has been found that a wide variety of microbial and viral agents influence aPLs production and contribute to clinical manifestations of APS. Many theories attempted to explain the pathogenic potential of different environmental factors as well as a phenomenon termed molecular mimicry between β2-GPI molecule and infection-relevant structures. In this review, we summarize and critically assess the pathogenic and non-pathogenic formation of aPLs and its contribution to the development of APS.

PMID: 31354742 [PubMed - indexed for MEDLINE]

A Quality Improvement Approach to External Infliximab Infusions in Pediatric Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr. 2019 11;69(5):544-550

Authors: Gupta SR, Crandall WV, Donegan A, Johnson M, Drobnic B, Oates M, Boyle B, Maltz RM, Dotson JL

Abstract
OBJECTIVES: We used a quality improvement (QI) approach to improve access and reduce barriers to care by increasing the number of external infliximab infusions at our pediatric inflammatory bowel disease center.
METHODS: Using an iterative QI strategy, pediatric patients ≥12 years of age with inflammatory bowel disease were offered the opportunity to receive infliximab infusions at home/an external infusion center. They were required to first have >5 infusions at the hospital without any significant infusion reactions. Data were collected and tracked monthly using P-charts. Comparisons between control chart centerlines were analyzed using the Fisher exact test.
RESULTS: Fifty-four patients received external infusions, 87% had Crohn disease, 63% boys, average age 17.6 ± 2.9 years, and 89% with private insurance. From September 2016 to January 2018, the percentage of eligible patients receiving external infusions was approximately 7%, increasing to approximately 30% by January 2018. A centerline shift, representing a statistically significant change, occurred in October 2016 and June 2017 (P < 0.001). No serious safety concerns have occurred.
CONCLUSIONS: Through a multidisciplinary team of stakeholders using QI strategies, we now offer external infusion service options to all appropriate patients as routine practice. Home infusions are a viable option to reduce barriers to care, and our patients did not experience any safety events.

PMID: 31219936 [PubMed - indexed for MEDLINE]

Increasing Prevalence of Orthostatic Hypotension as a Cause of Syncope With Advancing Age and Multimorbidity.

J Am Med Dir Assoc. 2019 05;20(5):586-588

Authors: Ceccofiglio A, Mussi C, Rafanelli M, Rivasi G, Bo M, Mossello E, Martone AM, Abete P, Ungar A

PMID: 30926410 [PubMed - indexed for MEDLINE]

Mirabegron versus Placebo Add-on Therapy in Men with Overactive Bladder Symptoms Receiving Tamsulosin for Underlying Benign Prostatic Hyperplasia: a Safety Analysis from the Randomized, Phase 4 PLUS Study.

Urology. 2020 Oct 09;:

Authors: Herschorn S, McVary KT, Santos JC, Foley S, Kristy RM, Choudhury N, Hairston J, Kaplan SA

Abstract
OBJECTIVES: To analyze the safety of mirabegron add-on therapy in men with overactive bladder symptoms concurrently receiving tamsulosin for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).
METHODS: The Phase 4 PLUS study comprised a 4-week run-in period (tamsulosin [0.4 mg]) and a 12-week randomized treatment period (add-on treatment: mirabegron [25 mg] or placebo). Doses were increased to mirabegron 50 mg or matched placebo after 4 weeks. Safety assessments: treatment-emergent adverse events (TEAEs), vital signs, 12-lead electrocardiograms (ECGs), and changes in post-void residual (PVR) volume and maximum urinary flow (Qmax).
RESULTS: The safety analysis set included 352 tamsulosin plus mirabegron (TAM+MIRA) and 354 tamsulosin plus placebo (TAM+PL) patients. The frequency of overall TEAEs was higher with TAM+PL, although a higher incidence of drug-related TEAEs was observed with TAM+MIRA. Most TEAEs were mild or moderate in severity. Drug-related serious TEAEs were reported for three patients (two TAM+MIRA patients: acute myocardial infarction with cerebral infarction and angina pectoris, one TAM+PL patient: lacunar stroke). Hypertension, headache, and nasopharyngitis were the most common TEAEs. Special interest TEAEs were infrequently reported. The most common was urinary retention and two TAM+MIRA patients required catheterization (neither led to discontinuation). No major changes in blood pressure or pulse rate were noted and similar ECG parameters were observed for both groups. Changes in mean PVR volume and Qmax were not clinically meaningful.
CONCLUSION: No unexpected safety concerns were noted in men receiving tamsulosin for LUTS associated with BPH who subsequently received mirabegron add-on therapy.

PMID: 33045287 [PubMed - as supplied by publisher]

Pentosan Polysulfate Maculopathy: What Urologists Should Know in 2020.

Urology. 2020 Oct 09;:

Authors: Mogica JAP, De EJB

Abstract
OBJECTIVE: To conduct a review of current literature to assess whether an association exists between Pentosan Polysulfate Sodium and the development of macular disease, as it is the only oral medication approved by the Food and Drug Administration for the management of interstitial cystitis.
MATERIALS AND METHODS: A systematic review was conducted by the authors separately, with review methods established prior to the conduct of the review. Databases searched included PubMed, Ovid, Medline, EBSCO, and Google Scholar. A search was conducted for the terms "Pentosan Polysulfate Maculopathy", "Pentosan Polysulfate Retinopathy" and "Interstitial Cystitis Maculopathy". All papers reporting on primary data were included.
RESULTS: A total of 14 papers reporting on primary data were identified. Most papers reported on the development of macular disease in the setting of chronic Pentosan Polysulfate Sodium exposure. No randomized controlled trials have been performed to date and data was insufficient to perform a meta-analysis. Nevertheless, patients with interstitial cystitis were more likely to receive a diagnosis of maculopathy after several years of the medication use.
CONCLUSIONS: Although the nature of the published studies renders them prone to confounders, currently available data suggest an increased risk for developing maculopathy after years of Pentosan Polysulfate Sodium use. In light of this, and the marginal effectiveness of the medication for the average individual, we suggest that education be provided as to the possible association and that regular ophthalmic evaluation be recommended for patients who are continued on chronic Pentosan Polysulfate Sodium.

PMID: 33045286 [PubMed - as supplied by publisher]

Mass balance, metabolic disposition, and pharmacokinetics of [14C]ensartinib, a novel potent anaplastic lymphoma kinase (ALK) inhibitor, in healthy subjects following oral administration.

Cancer Chemother Pharmacol. 2020 Oct 12;:

Authors: Zhou S, Liu W, Zhou C, Zhang L, Xie L, Xu Z, Wang L, Zhao Y, Guo L, Chen J, Ding L, Mao L, Tao Y, Zhang C, Ding S, Shao F

Abstract
PURPOSE: Ensartinib is a novel, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK) that has promising clinical activity and low toxicity in patients with ALK-positive non-small cell lung cancer. This study was conducted to investigate the pharmacokinetics, metabolism and excretion of ensartinib following a single 200 mg/100 μCi oral dose of radiolabeled ensartinib to healthy subjects.
METHODS: Six healthy male subjects were enrolled and administrated an oral suspension in a fasted state. Blood, urine and feces were collected. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of ensartinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and characterization.
RESULTS: The mean total recovery was 101.21% of the radiolabeled dose with 91.00% and 10.21% excreted in feces and urine, respectively. Unchanged ensartinib was the predominant drug-related component in urine and feces, representing 4.39% and 38.12% of the administered dose, respectively. Unchanged ensartinib and its metabolite M465 were the major circulating components, accounting for the same 27.45% of the plasma total radioactivity (AUC0-24h pool), while other circulating metabolites were minor, accounting for less than 10%. Mean Cmax, AUC0-∞, T1/2 and Tmax values for ensartinib in plasma were 185 ng/mL, 3827 h ng/mL, 18.3 h and 3.25 h, respectively. The total radioactivity in plasma was cleared with terminal half-life of 27.2 h. Treatment with ensartinib was well tolerated, and no serious adverse events were reported.
CONCLUSION: It was well tolerated in the six healthy male subjects following a single oral administration of 200 mg/100 μCi dose of ensartinib. Besides unchanged ensartinib, metabolite of M465 was the predominant circulating drug-related component. The drug was primarily eliminated in feces.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03804541.

PMID: 33044566 [PubMed - as supplied by publisher]

Vesatolimod, a toll-like receptor 7 agonist, induces immune activation in virally suppressed adults with HIV-1.

Clin Infect Dis. 2020 Oct 12;:

Authors: Riddler SA, Para M, Benson CA, Mills A, Ramgopal M, DeJesus E, Brinson C, Cyktor J, Jacobs J, Koontz D, Mellors J, Laird GM, Wrin T, Patel H, Guo S, Wallin J, Boice J, Zhang L, Humeniuk R, Begley R, German P, Graham H, Geleziunas R, Brainard DM, SenGupta D

Abstract
BACKGROUND: Treatment with vesatolimod, an investigational oral toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a phase 1 study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with HIV-1.
METHODS: In this double-blind, multicentre, placebo-controlled trial (ClinicalTrials.gov NCT02858401), participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose escalation cohorts. Primary study objectives included safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives.
FINDINGS: A total of 48 individuals were randomly assigned to vesatolimod (n=36) or placebo (n=12). Vesatolimod was generally well tolerated with no study drug-related serious adverse events or adverse events leading to study discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups compared to placebo.Vesatolimod plasma exposures increased dose-proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours post 6 mg dose were >3·9-fold for IP-10, IL-1Ra, and ITAC when compared to baseline values.
INTERPRETATION: Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation observed at doses above 4 mg, providing rationale for future combination trials in people with HIV.

PMID: 33043969 [PubMed - as supplied by publisher]

Acceptability of pharmacist-led interventions to resolve drug-related problems in patients with chronic myeloid leukaemia.

J Oncol Pharm Pract. 2020 Oct 12;:1078155220964539

Authors: Tan BK, Chua SS, Chen LC, Chang KM, Balashanker S, Bee PC

Abstract
PURPOSE: Chronic myeloid leukaemia (CML) patients on long-term tyrosine kinase inhibitor (TKI) therapy are susceptible to drug-related problems (DRPs). This study aimed to evaluate the acceptability and outcomes of pharmacist-led interventions on DRPs encountered by CML patients.
METHODS: This study included participants from the intervention arm of a randomised controlled trial which was conducted to evaluate the effects of pharmacist-led interventions on CML patients treated with TKIs. Participants were recruited and followed up in the haematology clinics of two hospitals in Malaysia from March 2017 to January 2019. A pharmacist identified DRPs and helped to resolve them. Patients were followed-up for six months, and their DRPs were assessed based on the Pharmaceutical Care Network Europe Classification for DRP v7.0. The identified DRPs, the pharmacist's interventions, and the acceptance and outcomes of the interventions were recorded. A Poisson multivariable regression model was used to analyse factors associated with the number of identified DRPs per participant.
RESULTS: A total of 198 DRPs were identified from 65 CML patients. The median number of DRPs per participants was 3 (interquartile range: 2, 4). Most participants (97%) had at least one DRP, which included adverse drug events (45.5%), treatment ineffectiveness (31.5%) and patients' treatment concerns or dissatisfaction (23%). The 228 causes of DRPs identified comprised the following: lack of disease or treatment information, or outcome monitoring (47.8%), inappropriate drug use processes (23.2%), inappropriate patient behaviour (19.9%), suboptimal drug selection (6.1%), suboptimal dose selection (2.6%) and logistic issues in dispensing (0.4%). The number of concomitant medications was significantly associated with the number of DRPs (adjusted Odds Ratio: 1.100; 95% CI: 1.005, 1.205; p = 0.040). Overall, 233 interventions were made. These included providing patient education on disease states or TKI-related side effects (75.1%) and recommending appropriate instructions for taking medications (7.7%). Of the 233 interventions, 94.4% were accepted and 83.7% were implemented by the prescriber or patient. A total of 154 DRPs (77.3%) were resolved.
CONCLUSIONS: The pharmacist-led interventions among CML patients managed to identify various DRPs, were well accepted by both TKI prescribers and patients, and had a high success rate of resolving the DRPs.

PMID: 33040675 [PubMed - as supplied by publisher]

Pneumonia caused by crizotinib: case report and review of literature.

Ann Palliat Med. 2020 Sep 22;:

Authors: Gou X, Yuan C, Bai Y, Shi L, Xing S, Ma H

Abstract
Crizotinib is the first-line drug for non-small cell lung cancer (NSCLC) patients who display anaplastic lymphoma kinase (ALK) rearrangement. With 60% overall response rate, crizotinib significantly prolongs median progression-free survival (ranged 8-10 months) of ALK rearrangement NSCLC patients. However, there are some adverse events from crizotinib, including diarrhea, weakness and nausea. Here, we describe a 47 years old woman with ALK-rearranged NSCLC who developed interstitial pneumonia (IP) induced by crizotinib. A female patient was diagnosed as the left lower lobe adenocarcinoma stage IV (T4N2M1, pleural metastasis) via lung biopsy and was detected wild-type EGFR and 18% ALK gene rearrangement from paraffin section. However, after going through 7 cycles of chemotherapy, she rejected chemotherapy because side effect and still experienced progression of the disease. Subsequently, crizotinib was prescribed as a targeted therapy. After 32 days, visible reduction in size was observed on the pulmonary mass and metastases found in brain and liver, but the patient presented drug-induced level 4 interstitial pneumonia. In a nutshell, the curative effect of crizotinib is worthy of note, but clinicians should also weigh the advantages and disadvantages, prior its usage.

PMID: 33040544 [PubMed - as supplied by publisher]

Quercetin, chrysin, caffeic acid and ferulic acid ameliorate cyclophosphamide-induced toxicities in SH-SY5Y cells.

Mol Biol Rep. 2020 Oct 10;:

Authors: Ayna A, Özbolat SN, Darendelioglu E

Abstract
Clinical use of cyclophosphamide (CP) causes apoptosis-induced cell death in the immune system, liver, heart and kidneys. To prevent the cells against side effects of CP and its metabolites, increasing antioxidant defence mechanism of the body with supplemental antioxidants is important. Therefore, there is a requirement for effective agents which could prevent the healthy cells from the harmful effects of drug-induced toxicities. Several antioxidants have been used in protecting or alleviating CP-induced cell death. However, no such study is reported in CP-induced SH-SY5Y cell toxicity. The aim of this study was to evaluate likelihood ameliorative effects of caffeic acid, chrysin, quercetin and ferulic acid against CP-induced toxicity in SH-SY5Y neuron cells. In this study protective effects of quercetin, chrysin, caffeic acid and ferulic acid against CP-induced cell toxicity in SH-SY5Y cells was evaluated by cell proliferation assay, lipid peroxidation (LPO) analysis to decipher antioxidant capacity, tunel assay and qRT-PCR experiments to examine anti-apoptotic activities of the antioxidants. The results showed that CP-induced cell toxicity in SH-SY5Y cells and treatments with the antioxidants suppressed the cell death. Our results suggests that these anti-oxidants protected SH-SY5Y cells via a decrease in LPO levels, downregulating the expression of Cas-3, Cyt c and Bax and upregulating expression of anti-apoptotic gene Bcl-2. The use of antioxidant as nutritional supplements, and in particular of caffeic acid, chrysin, quercetin and ferulic acid, reduce apoptotic effects of CP in SH-SY5Y cells that could add insight into therapeutic approaches to CP-induced cell injuries.

PMID: 33040267 [PubMed - as supplied by publisher]

A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II.

Mol Ther. 2020 Sep 30;:

Authors: Okuyama T, Eto Y, Sakai N, Nakamura K, Yamamoto T, Yamaoka M, Ikeda T, So S, Tanizawa K, Sonoda H, Sato Y

Abstract
Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, single-arm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.

PMID: 33038326 [PubMed - as supplied by publisher]

Dabrafenib and trametinib induced pancreatitis: a case report and review of the literature.

Anticancer Drugs. 2020 Oct 07;:

Authors: Ogliari FR, Rodolfo Masera GL, Gueli R, Chini C

Abstract
Approximately 50% of melanomas are characterized by BRAF mutation (V600E in 90% of cases), that predicts more aggressive behaviour. This mutation is the target of dabrafenib, an anti-BRAF tyrosine-kinase inhibitor (TKI), that together with trametinib, anti-MEK TKI, is approved for first-line treatment of metastatic melanoma due to significant benefit in overall and progression-free survival. Most common treatment-related adverse events are pyrexia, chills, fatigue, rash, nausea, vomiting, and diarrhoea. This case report aims to present another less common adverse event of combined anti-BRAF and anti-MEK treatment. Our patient, after 4 months on target-therapy, experienced sudden deep abdominal pain. At the initial work-out at the emergency department, increase in serum lipase was detected and radiological findings were consistent with acute pancreatitis. Admitted to the hospital, other causes were ruled out and target-therapy was discontinued with symptoms improvement. Radiological and clinical follow-up was performed and a diagnosis of drug-induced pancreatitis was made. After few days of medical support with analgesia and antibiotic, the patient felt better and was discharged; target-therapy was permanently interrupted. Searching the literature, not so many cases of iatrogenic pancreatitis are described with this TKI combination, therefore, we have reported it as a rare but life-threatening adverse event that should be investigated whenever conceivable.

PMID: 33038084 [PubMed - as supplied by publisher]

Comparison of the efficacy and safety of different doses of nifekalant in the instant cardioversion of persistent atrial fibrillation during radiofrequency ablation.

Basic Clin Pharmacol Toxicol. 2020 Oct 09;:

Authors: Zhai Z, Xia Z, Xia Z, Hu J, Hu J, Zhu B, Xiong Q, Wu Y, Hong K, Chen Q, Yu J, Li J

Abstract
Nifekalant has been used in the treatment of atrial arrhythmia recently. However, there is no consensus on the preferable nifekalant dose to treat atrial fibrillation (AF). The purpose of this study was to explore efficacy and safety of different doses of nifekalant in the cardioversion of persistent AF. The study was a single-center, randomized controlled trial. All subjects received nifekalant or placebo intravenously, and the nifekalant was given at the dosage of 0.3, 0.4 or 0.5mg/kg. Primary efficacy endpoint: compared with 0.3mg group, the rate of cardioversion to sinus rhythm from AF in 0.4mg and 0.5mg group was higher. The 0.4mg/kg and 0.5mg/kg doses were associated with a similar magnitude of efficacy (P>0.05). Secondary efficacy endpoint: termination rates of AF in the group of 0.4mg and 0.5mg were higher than 0.3mg. Primary safety endpoint: the rate of Torsades de Pointes or ventricular fibrillation was numerically lower in the 0.4mg group than 0.5mg group (P=0.02). Secondary safety endpoint: The rates of the majority of other common drug-related adverse events in the group of 0.5mg and 0.4mg were higher than the 0.3mg group. A 0.4mg/kg dose of intravenous nifekalant may be recommended during the radiofrequency ablation for persistent AF considering the benefit-risk profile. (ClinicalTrials.gov number: NCT04209959).

PMID: 33037726 [PubMed - as supplied by publisher]

Comprehensive review of hepatotoxicity associated with traditional Indian Ayurvedic herbs.

World J Hepatol. 2020 Sep 27;12(9):574-595

Authors: Philips CA, Ahamed R, Rajesh S, George T, Mohanan M, Augustine P

Abstract
With growing antipathy toward conventional prescription drugs due to the fear of adverse events, the general and patient populations have been increasingly using complementary and alternative medications (CAMs) for managing acute and chronic diseases. The general misconception is that natural herbal-based preparations are devoid of toxicity, and hence short- and long-term use remain justified among people as well as the CAM practitioners who prescribe these medicines. In this regard, Ayurvedic herbal medications have become one of the most utilized in the East, specifically the Indian sub-continent, with increasing use in the West. Recent well-performed observational studies have confirmed the hepatotoxic potential of Ayurvedic drugs. Toxicity stems from direct effects or from indirect effects through herbal metabolites, unknown herb-herb and herb-drug interactions, adulteration of Ayurvedic drugs with other prescription medicines, and contamination due to poor manufacturing practices. In this exhaustive review, we present details on their hepatotoxic potential, discuss the mechanisms, clinical presentation, liver histology and patient outcomes of certain commonly used Ayurvedic herbs which will serve as a knowledge bank for physicians caring for liver disease patients, to support early identification and treatment of those who present with CAM-induced liver injury.

PMID: 33033566 [PubMed]

Efficacy and safety of trabectedin for patients with unresectable and relapsed soft-tissue sarcoma in Japan: A Japanese Musculoskeletal Oncology Group study.

Cancer. 2020 03 15;126(6):1253-1263

Authors: Kobayashi H, Iwata S, Wakamatsu T, Hayakawa K, Yonemoto T, Wasa J, Oka H, Ueda T, Tanaka S

Abstract
BACKGROUND: Although initial trabectedin (1.2 mg/m2 ) is safe and effective for patients with translocation-related sarcoma (TRS) in Japan, its efficacy in other types of soft-tissue sarcomas (STSs) remains unknown. This study retrospectively investigated its efficacy and safety through postmarketing surveillance of trabectedin in patients with unresectable and relapsed STS.
METHODS: One hundred forty patients received intravenous trabectedin (1.2 mg/m2 on day 1 every 21 days) over the course of 24 hours. The primary endpoint was the efficacy and safety of trabectedin.
RESULTS: Grade 3 or higher adverse events occurred in 100 patients (71%) and included hepatotoxicity (37.8%), neutropenia (32.8%), and rhabdomyolysis (3.6%). Patients at high risk for grade 3 or higher rhabdomyolysis (36%) were classified by height (≥170.3 cm) and age (≤32 years) through a classification and regression tree model (area under the curve, 0.9). The overall median progression-free survival (PFS) was 3.7 months; with respect to the histological type, the median PFS was 17.4 months for myxoid liposarcoma, 4.9 months for leiomyosarcoma, 5.6 months for synovial sarcoma, and 3.7 months for dedifferentiated liposarcoma. Histological type (liposarcoma/leiomyosarcoma [L-sarcoma] and TRS) and grade 3 neutropenia (but not grade 4) were associated with significantly improved PFS after trabectedin treatment (P = .003, P = .04, and P = .001). The median growth modulation index (GMI) was 0.91; 37 patients (36.7%) experienced a GMI > 1.33, and among patients with solitary fibrous tumors and undifferentiated pleomorphic sarcoma, 60% and 42.9%, respectively, had a GMI > 1.33. The median overall survival (OS) was 16.4 months. A GMI > 1.33 was associated with significantly improved OS (P = .0006).
CONCLUSIONS: Initial trabectedin at 1.2 mg/m2 has clinically meaningful benefits for patients with L-sarcoma and certain histological subtypes of TRS.

PMID: 31825533 [PubMed - indexed for MEDLINE]

Selective reporting bias in randomised controlled trials from two network meta-analyses: comparison of clinical trial registrations and their respective publications.

BMJ Open. 2019 09 05;9(9):e031138

Authors: Wong EK, Lachance CC, Page MJ, Watt J, Veroniki A, Straus SE, Tricco AC

Abstract
OBJECTIVE: To determine (i) the difference in the frequency of serious adverse events (SAEs) reported in trial registrations and their respective primary publications and (ii) the effect of adding SAE data from registries to a network meta-analysis (NMA) in changing the surface under the cumulative ranking (SUCRA) curve values of interventions.
DESIGN: Secondary analysis of primary publications from two NMAs.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included randomised trials published in English after 2005 that were included in two NMAs of pharmacological interventions for Alzheimer's disease and chronic obstructive pulmonary disease.
DATA EXTRACTION: Two reviewers independently searched multiple international trial registries for registration status and abstracted data from the included study publications and ClinicalTrials.gov.
RESULTS: Of the 203 randomised trials included, 140 (69.0%) were registered with a trial registry and 72 (35.5%) posted results in the registry. The proportion of registered trials increased over time (38.5% in 2005 vs 78.6% in 2014). Of the publications with results posted in a trial registry, 14 (19.4%) had inconsistent reporting of overall SAEs; 7 (10.4%) studies did not report SAEs in the publication but did in the registry. In the 134 randomised trials with a prespecified primary outcome in the registry, 19 studies (9.4%) had a change in the primary outcome in the publication. Adding SAEs reported in registries to the NMAs did not affect the ranking of interventions.
CONCLUSION: We identified inconsistent reporting of SAEs in randomised trials that were included in two NMAs. Findings highlight the importance of including trial registries in the grey literature search and verifying safety data before incorporating it into NMAs.
STUDY REGISTRATION: osf.io/mk6dr.

PMID: 31492792 [PubMed - indexed for MEDLINE]

Immunotherapy-Related Adverse Effects When Treating Cancer #375.

J Palliat Med. 2019 Jun;22(6):724-725

Authors: Matts C, Beck A

PMID: 31158056 [PubMed - indexed for MEDLINE]

A safety update on sodium glucose co-transporter 2 inhibitors.

Diabetes Obes Metab. 2019 04;21 Suppl 2:34-42

Authors: Fitchett D

Abstract
Sodium glucose co-transporter 2 inhibitors (SGLT2is) are the first class of glucose lowering agent to be shown to reduce cardiovascular events. They are generally well tolerated with infrequent serious adverse events. The most frequent side effect is genital mycotic infections with candida species that are usually mild to moderate in severity, easily treated and infrequently recur. Urinary tract infections, although common in patients with diabetes, have not been shown to be increased in controlled studies with SGLT2i. Hypoglycaemia can occur when an SGLT2i is added to agents that cause hypoglycaemia, such as insulin or sulphonylureas. Volume depletion and hypotension is infrequent and can be minimized by adjusting diuretic and antihypertensive treatment in patients at risk. Acute renal failure or kidney injury was observed in early observational studies. However, in randomized controlled trials (RCTs) and in more recent observational studies a decreased incidence of acute kidney injury was observed in SGLT2-treated patients compared to those receiving either placebo or another class of glucose lowering agents. An increased incidence of amputation (largely feet and toes) was observed in the RCT with canagliflozin but not with the other SGLT2i. Observational studies have shown either an increased risk of amputation with other agents whereas another study showed no increase. Although the increased risk of amputation is very low, avoidance of SGLT2i in patients at high risk seems prudent. Increased incidence of fractures was observed with canagliflozin but not with SGLT2i nor in a meta-analysis that included canagliflozin, empagliflozin and dapagliflozin. No increased incidence of cancer has been observed in either RCTs or observational studies.

PMID: 31081590 [PubMed - indexed for MEDLINE]

OCULAR ADVERSE EVENTS ASSOCIATED WITH MEK INHIBITORS.

Retina. 2019 Aug;39(8):1435-1450

Authors: Méndez-Martínez S, Calvo P, Ruiz-Moreno O, Pardiñas Barón N, Leciñena Bueno J, Gil Ruiz MDR, Pablo L

Abstract
PURPOSE: Mitogen-activates protein kinase (MAPK) inhibitors, particularly MEK inhibitors, have shifted the treatment paradigm for metastatic BRAF-mutant cutaneous melanoma; however, oncologists, ophthalmologists, and patients have noticed different toxicities of variable importance. This review aims to provide an update of the ocular adverse events (OAEs), especially retinal toxicity, associated with the use of MEK inhibitors.
METHODS: We conducted a scientific literature search using the PubMed database up to July 2018 with the terms "MEK inhibitors" with a "review" filter and "MEK inhibitors" with a "clinical trials" filter. Phase I-III experimental studies and reviews were selected. Current principles and techniques for diagnosing and managing MEK inhibitor retinopathy and other OAEs are discussed.
RESULTS: In patients treated with MEK inhibitors, including asymptomatic patients, OAEs occur with an incidence of up to 90%. Mild to severe ophthalmic toxicities are described, including visual disturbances, a 2-line decrease in Snellen visual acuity, dry eye symptoms, ocular adnexal abnormalities, visual field defects, panuveitis, and retinal toxicities, such as different degrees of MEK-associated retinopathy, vascular injury, and retinal vein occlusion.
CONCLUSION: MEK inhibitors can lead to different degrees of retinal, uveal, and adnexal OAE, causing visual disturbances or discomfort. One of the most relevant OAE of MEK therapy is MEK inhibitor-associated retinopathy (MEKAR), which is usually mild, self-limited, and may subside after continuous use of the drug for weeks or months, or discontinuation, thereby restoring the normal visual function of the retina, with some exceptions. Ocular adverse events are often associated with other systemic adverse effects that can modify the dosage of treatment, so the communication with the oncologist is fundamental.

PMID: 30681641 [PubMed - indexed for MEDLINE]

Phase I study of the anti-PD-1 antibody spartalizumab (PDR001) in Japanese patients with advanced malignancies.

Cancer Sci. 2020 Oct 08;:

Authors: Minami H, Doi T, Toyoda M, Imamura Y, Kiyota N, Mitsuma A, Shimokata T, Naito Y, Matsubara N, Tajima T, Tokushige K, Ishihara K, Cameron S, Ando Y

Abstract
Spartalizumab is a humanized IgG4/κ monoclonal antibody directed against human PD-1. In this phase I study we investigated safety, pharmacokinetics, preliminary antitumor activity, and toxicity of spartalizumab in patients with advanced malignancies. Patients (n=18) with a range of tumor types received spartalizumab intravenously at doses of 1, 3, and 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or discontinuation at the discretion of the investigator or patient. Most patients (61%) had received ≥5 prior lines of therapy. No dose-limiting toxicities were reported and, hence, the maximum tolerated dose was ≥10 mg/kg. Pharmacokinetics in Japanese patients aligned with those reported in a global dose-escalation study. The safety profile was consistent with other approved anti-PD-1 monoclonal antibodies; the most common drug-related adverse events were maculopapular rash (22%), followed by malaise and increased blood alkaline phosphatase (11% each). Partial responses were reported in 2 patients (11%), one with transitional cell carcinoma and the other with hepatocellular carcinoma. In conclusion, this study confirmed the safety of spartalizumab administered at a dose of up to 10 mg/kg every 2 weeks in Japanese patients with cancers.

PMID: 33031626 [PubMed - as supplied by publisher]