The mitochondrial paradox.

Elife. 2020 06 25;9:

Authors: Penman SL, Jensen RL, Kiy RT, Chadwick AE

Abstract
A structural motif that is found in two cancer drugs may be responsible for their ability to tackle cancers and for the side-effects caused by the drugs.

PMID: 32583799 [PubMed - indexed for MEDLINE]

Predicting Adverse Drug Reactions on Distributed Health Data using Federated Learning.

AMIA Annu Symp Proc. 2019;2019:313-322

Authors: Choudhury O, Park Y, Salonidis T, Gkoulalas-Divanis A, Sylla I, Das AK

Abstract
Using electronic health data to predict adverse drug reaction (ADR) incurs practical challenges, such as lack of adequate data from any single site for rare ADR detection, resource constraints on integrating data from multiple sources, and privacy concerns with creating a centralized database from person-specific, sensitive data. We introduce a federated learning framework that can learn a global ADR prediction model from distributed health data held locally at different sites. We propose two novel methods of local model aggregation to improve the predictive capability of the global model. Through comprehensive experimental evaluation using real-world health data from 1 million patients, we demonstrate the effectiveness of our proposed approach in achieving comparable performance to centralized learning and outperforming localized learning models for two types of ADRs. We also demonstrate that, for varying data distributions, our aggregation methods outperform state-of-the-art techniques, in terms of precision, recall, and accuracy.

PMID: 32308824 [PubMed - indexed for MEDLINE]

Immunosuppressive agents in the treatment of IgA nephropathy: A meta-analysis of clinical randomized controlled literature.

Niger J Clin Pract. 2020 Apr;23(4):437-449

Authors: Zheng J, Gong X, Wu Z

Abstract
IgA nephropathy (IgAN) is the most common form of glomerulonephritis in the world. Immunosuppressive therapy has been widely used in IgAN patients at home and abroad. The present meta-analysis aimed to assess the efficacy and safety of different immunosuppressive agents in patients with biopsy proven IgAN, in order to provide guidance for the clinical treatment of IgAN treatment options. We conducted a meta-analysis of the published randomized controlled trials (RCTs). PubMed, EMBASE, Web of Science, Cochrane Library, Medline, WanFang, Weipu, and CNKI were searched for relevant RCTs published between 2000 and December 2017. Data were analyzed with the random effects model using Review Manager5.3 to evaluate the effect of immunosuppressive agents on IgAN. 52 RCTs were involving 2,930 patients were included in the review. Compared with steroids, immunosuppressive agents, including acetazolamide (AZA) [complete response (CR)/partial response (PR); relative risk (RR), 5.92; 95% confidence interval (CI) 3.07-11.44; P< 0.00001], leflunomide (LEF) (CR/PR; RR, 1.63; 95% CI,1.22-2.17; P = 0.0008), mycophenolate mofetil (MMF) (CR/PR; RR, 1.59; 95%CI, 1.02-2.49; P = 0.04), cyclophosphamide (CTX) (CR/PR; RR, 3.39; 95%CI, 1.03-11.14; P = 0.04), and Tacrolimus (TAC) (CR/PR; RR, 1.72; 95%CI, 0.99-2.96; P = 0.05) resulted in increased partial or complete proteinuria remission. There was no significant difference in the total effective rate between MMF and Placebo (CR/PR; RR, 0.92; 95% CI, 0.33-2.56; P = 0.87). Compared with CTX, MMF showed higher effectiveness (CR/PR; RR, 3.32; 95% CI, 1.83-6.01; P< 0.0001) and LEF showed higher effectiveness (CR/PR; RR, 1.85; 95% CI, 1.17C-2.92; P = 0.009) with a lower incidence of adverse events. The results showed that immunosuppressive agents are a promising strategy and should be investigated further. MMF is the safest, the best therapeutic result and the least side effects than the other immunosuppressive agents.

PMID: 32246648 [PubMed - indexed for MEDLINE]

Improving antibacterial prescribing safety in the management of COPD exacerbations: systematic review of observational and clinical studies on potential drug interactions associated with frequently prescribed antibacterials among COPD patients.

J Antimicrob Chemother. 2019 10 01;74(10):2848-2864

Authors: Wang Y, Bahar MA, Jansen AME, Kocks JWH, Alffenaar JC, Hak E, Wilffert B, Borgsteede SD

Abstract
BACKGROUND: Guidelines advise the use of antibacterials (ABs) in the management of COPD exacerbations. COPD patients often have multiple comorbidities, such as diabetes mellitus and cardiac diseases, leading to polypharmacy. Consequently, drug-drug interactions (DDIs) may frequently occur, and may cause serious adverse events and treatment failure.
OBJECTIVES: (i) To review DDIs related to frequently prescribed ABs among COPD patients from observational and clinical studies. (ii) To improve AB prescribing safety in clinical practice by structuring DDIs according to comorbidities of COPD.
METHODS: We conducted a systematic review by searching PubMed and Embase up to 8 February 2018 for clinical trials, cohort and case-control studies reporting DDIs of ABs used for COPD. Study design, subjects, sample size, pharmacological mechanism of DDI and effect of interaction were extracted. We evaluated levels of DDIs and quality of evidence according to established criteria and structured the data by possible comorbidities.
RESULTS: In all, 318 articles were eligible for review, describing a wide range of drugs used for comorbidities and their potential DDIs with ABs. DDIs between ABs and co-administered drugs could be subdivided into: (i) co-administered drugs altering the pharmacokinetics of ABs; and (ii) ABs interfering with the pharmacokinetics of co-administered drugs. The DDIs could lead to therapeutic failures or toxicities.
CONCLUSIONS: DDIs related to ABs with clinical significance may involve a wide range of indicated drugs to treat comorbidities in COPD. The evidence presented can support (computer-supported) decision-making by health practitioners when prescribing ABs during COPD exacerbations in the case of co-medication.

PMID: 31127283 [PubMed - indexed for MEDLINE]

Inappropriate Antibiotic Allergy Documentation in Health Records: A Qualitative Study on Family Physicians' and Pharmacists' Experiences.

Ann Fam Med. 2020 Jul;18(4):326-333

Authors: De Clercq K, Cals JWL, de Bont EGPM

Abstract
PURPOSE: It is hypothesized that 90% of antibiotic allergies documented in patients' health records are not actual, potentially life threatening, type I allergies mediated by IgE. This distinction is important because such documentation increases antibiotic resistance, as more second-choice and broad-spectrum antibiotics are then used. Evidence is lacking regarding causes of this inappropriate documentation. To develop interventions aimed at improving documentation, we explored experiences of family physicians and pharmacists in this area.
METHODS: We conducted a qualitative study among family physicians and pharmacists using focus group discussions, based on purposeful sampling and a naturalistic approach. Discussions were audio-recorded, transcribed verbatim, and analyzed in duplicate by means of constant comparative technique.
RESULTS: We conducted 4 focus group discussions among 34 family physicians and 10 pharmacists, from which 3 main themes emerged: (1) magnitude and awareness of the problem of inappropriate antibiotic allergy documentation, (2) origin of the problem, and (3) approaches for addressing the problem. Participants noted that the magnitude of contamination of medical files with inappropriate documentation leads to skepticism about current documentation. Major hindering factors are electronic health record systems and electronic communication. In addition, family physicians and pharmacists believed they had insufficient knowledge about antibiotic allergies and called for tools to rectify inappropriate allergy documentation and facilitate proper documentation going forward.
CONCLUSIONS: Family physicians and pharmacists perceive that few documented antibiotic allergies are in fact correct. Electronic health record barriers and communication barriers, as well as a lack of knowledge and facilitating tools, are main causes for numerous inappropriately documented antibiotic allergies and therefore targets for improving documentation in the future.

PMID: 32661033 [PubMed - in process]

Using PM-TOM for the Minimization of Adverse Drug and Gene Interactions in Therapies for Common Multi-Diseases.

Stud Health Technol Inform. 2020 Jun 26;272:205-208

Authors: Kulenovic A, Lagumdzija-Kulenovic A

Abstract
Multiple studies show that therapies for multi-diseases can lead to dangerous reactions and high healthcare costs due to their adverse drug-drug, drug-gene, and drug-condition interactions. In this paper, we present the results of using PM-TOM (Personalized Medicine Therapy Optimization Method) for finding therapies that minimize these interactions. The testing of the method was performed on the repository of electronic medical records of the Harvard Personal Genome Project (PGP), and the public databases of the drug and genetic information: DrugBank and Comprehensive Toxicogenomics Database (CTD). The results presented in this paper showed a significant potential of PM-TOM for reducing the cumulative adverse drug interactions in therapies for common multi-diseases.

PMID: 32604637 [PubMed - indexed for MEDLINE]

Signal detection of oral drug-induced dementia in chronic kidney disease patients using association rule mining and Bayesian confidence propagation neural network.

Pharmazie. 2019 09 01;74(9):570-574

Authors: Noguchi Y, Nagasawa H, Tachi T, Tsuchiya T, Teramachi H

Abstract
Among the mechanisms responsible for cognitive dysfunction in chronic kidney disease (CKD) are albuminuria and oxidative stress. However, there may be other causes not yet identified. In fact, the full relevance of CKD patient drug use and its relationship to dementia has hardly been barely investigated. We identified drugs affecting cognitive function in CKD patients by analyzing the spontaneous reporting system in Japan using Association rule mining (ARM) and Bayesian confidence propagation neural network (BCPNN). The signal detection criterion used were as follows: case ≥ 3, lift > 1, conviction > 1 (ARM) and IC025 >0 (BCPNN). Drugs with more than 20 cases were valaciclovir (lift: 11.21, conviction: 1.28, IC025: 3.12), amantadine (lift: 19.69, conviction: 1.68, IC025: 3.05), nalfurafine (lift: 8.35, conviction: 1.19, IC025: 2.18), pregabalin (lift: 6.05, conviction: 1.12, IC025: 1.78), and acyclovir (lift: 5.89, conviction: 1.12, IC025: 1.68). This study is the first report to use a large-scale medical database to identify drugs related to oral drugs-induced dementia in CKD.

PMID: 31484600 [PubMed - indexed for MEDLINE]

10 ways to improve medication safety in community pharmacies.

J Am Pharm Assoc (2003). 2019 Jul - Aug;59(4):474-478

Authors: Rupp MT

Abstract
DATA SOURCES: Not applicable.
SUMMARY: Since at least the time of Hippocrates, health care providers have recognized their responsibility to protect patients from potential harm resulting from the care they provide. In pharmacy, such harm typically results from a violation of any of the "5 rights" of safe medication use. However, a memorable adage stops short of providing operational guidance to improve medication safety. Specific actionable recommendations are needed to identify changes that, if implemented, would significantly improve the safety of medication delivery and use.
CONCLUSION: Most threats to medication safety result from weaknesses or failures in one or more of the key system elements identified by the Institute for Safe Medication Practices. Pharmacists should be advocates for implementing targeted recommendations to strengthen their practice systems and improve medication safety.

PMID: 31109811 [PubMed - indexed for MEDLINE]

Linguistic Validation of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events in Korean.

J Glob Oncol. 2019 03;5:1-10

Authors: Cho J, Yoon J, Kim Y, Oh D, Kim SJ, Ahn J, Suh GY, Nam SJ, Mitchell SA

Abstract
PURPOSE: The aim of this study was to translate and linguistically validate a Korean-language version of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
METHODS: All 124 PRO-CTCAE items were translated into Korean (PRO-CTCAE-Korean) using International Society for Pharmacoeconomics and Outcomes Research best practices and linguistically validated in a diverse sample of patients undergoing cancer treatment (n = 120) to determine whether the Korean translation captured the original concepts. During the cognitive interviews, participants first completed approximately 60 PRO-CTCAE-Korean questions and were then interviewed to evaluate the conceptual equivalence of the translation to the original PRO-CTCAE English-language source. Interview probes addressed comprehension, clarity, and ease of judgement. Three rounds of interviews were conducted. Items that met the a priori threshold of 10% or more of respondents with comprehension difficulties were considered for rephrasing and retesting.
RESULTS: A majority of PRO-CTCAE-Korean items were well comprehended in round 1; 14 items posed comprehension difficulties for at least 10% of respondents in round 1. Four symptom terms (mouth and throat sores, feeling like nothing could cheer you up, frequent urination, and pain, swelling, redness at drug injection or intravenous insertion site) were revised and retested in rounds 2 and 3. For the other 10 symptom terms, no suitable alternative phrasing was identified, and the terms were retested in rounds 2 and 3. After rounds 2 and 3, no item presented difficulties in 20% or more of participants.
CONCLUSION: PRO-CTCAE-Korean has been linguistically validated for use in Korean-speaking populations. Quantitative evaluation of this new measure to establish its measurement properties and responsiveness in Korean speakers undergoing cancer treatment is in progress.

PMID: 30917069 [PubMed - indexed for MEDLINE]

Challenges in pain assessment and management among individuals with intellectual and developmental disabilities.

Pain Rep. 2020 Jul-Aug;5(4):e821

Authors: Barney CC, Andersen RD, Defrin R, Genik LM, McGuire BE, Symons FJ

Abstract
Introduction: Intellectual and developmental disabilities (IDD) include conditions associated with physical, learning, language, behavioural, and/or intellectual impairment. Pain is a common and debilitating secondary condition compromising functional abilities and quality of life.
Objectives: This article addresses scientific and clinical challenges in pain assessment and management in individuals with severe IDD.
Methods: This Clinical Update aligns with the 2019 IASP Global Year Against Pain in the Vulnerable and selectively reviews recurring issues as well as the best available evidence and practice.
Results: The past decade of pain research has involved the development of standardized assessment tools appropriate for individuals with severe IDD; however, there is little empirical evidence that pain is being better assessed or managed clinically. There is limited evidence available to inform effective pain management practices; therefore, treatment approaches are largely empiric and highly variable. This is problematic because individuals with IDD are at risk of developing drug-related side effects, and treatment approaches effective for other populations may exacerbate pain in IDD populations. Scientifically, we are especially challenged by biases in self-reported and proxy-reported pain scores, identifying valid outcome measures for treatment trials, being able to adequately power studies due to small sample sizes, and our inability to easily explore the underlying pain mechanisms due to compromised ability to self-report.
Conclusion: Despite the critical challenges, new developments in research and knowledge translation activities in pain and IDD continue to emerge, and there are ongoing international collaborations.

PMID: 32656458 [PubMed]

Comments on: "A Systematic Review and Meta‑analysis of the Adverse Effects of Levonorgestrel Emergency Oral Contraceptive".

Clin Drug Investig. 2020 06;40(6):589-590

Authors: Ramnath R, Gossell-Williams M

PMID: 32372383 [PubMed - indexed for MEDLINE]

Oncolytic virotherapy, alone or in combination with immune checkpoint inhibitors, for advanced melanoma: A systematic review and meta-analysis.

Int Immunopharmacol. 2020 Jan;78:106050

Authors: Zou P, Tang R, Luo M

Abstract
BACKGROUND: Advanced melanoma, one of the most lethal forms of skin cancer, remains a difficult condition to treat, despite the substantial scientific progression in cancer treatment. Oncolytic virotherapy (OV), either alone or combined with immune checkpoint inhibitors (ICIs), has often been administrated in an attempt to cure this malignancy. However, the clinical outcomes dramatically vary among different reports.
METHODS: In this study, we performed a meta-analysis to evaluate the clinical efficacy and safety profile of OV, combined with ICIs in some cases, in advanced melanoma patients. The original clinical studies were identified based on the online query in PubMed, Cochrane, and Web of Science before December 30, 2018.
RESULTS: A total of 18 publications involving 1472 patients were included for the final meta-analysis. The data concerning objective response rate (ORR) and incidence rate of severe immune-related adverse events (irAEs) were extracted accordingly from the text or supplementary materials. The results illustrated that a single treatment of OV could generate a 25% ORR for advanced melanoma, and the ORR could be improved to 45% if combined with ICIs. Further analysis demonstrated that the introduction of ICIs in OV could increase the incidence rate of severe irAEs (AE ≥ 3) from 12% to 39%. However, the rate attributed to OV remains at 12% in the combination group.
CONCLUSION: The clinical efficacy of OV can be significantly improved by ICIs even though more onerous burden will be exerted simultaneously on the safety profile.

PMID: 31812724 [PubMed - indexed for MEDLINE]

Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system.

J Immunother Cancer. 2019 11 06;7(1):286

Authors: Zhai Y, Ye X, Hu F, Xu J, Guo X, Zhuang Y, He J

Abstract
BACKGROUND: Immune-checkpoint inhibitors (ICIs) emerged as a novel class of drugs for the treatment of a broad spectrum of malignancies. ICIs can produce durable antitumor responses but they are also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs.
METHODS: This study aimed to quantify association of endocrine adverse events (AEs) and ICI therapy and also to characterize the profiles of ICI-related endocrine complications from real-world practice. Data from the first quarter of 2014 to first quarter of 2019 in FDA Adverse Event Reporting System (FAERS) database were gathered to conduct disproportionality analysis. The definition of endocrine AEs relied on the preferred terms (PTs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Two signal indices based on statistical shrinkage transformation, reporting odds ratios (ROR) and information component (IC), were used to evaluate correlations between ICIs and endocrine events. For ROR, it was defined a signal if the lower limit of the 95% confidence interval (ROR025) more than one, with at least 3 cases. For IC, lower end of the 95% confidence interval of IC (IC025) exceeding zero was deemed statistically significant.
RESULTS: A total of 29,294,336 records were involved, among these 6260 records related to endocrine AEs after ICIs treatment were identified. In general, male had a slightly lower reporting frequencies for ICIs-related endocrinopathies compared with female but not significant (ROR = 0.98 95%CI: 0.93-1.04) and the difference varied in several common endocrine AEs. Notably, in general, ICI drugs were significantly associated with over-reporting frequencies of endocrine complications, corresponding to IC025 = 2.49 and ROR025 = 5.99. For monotherapy, three strategies (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing endocrine events. Different reporting frequencies emerged when anti-CTLA-4 therapy was compared with anti-PD-1/PD-L1 medications for endocrine toxicities, corresponding to ROR = 1.68 (95%CI 1.55-1.83), ROR = 2.54 (95%CI 2.20-2.93), respectively. Combination therapy was associated with higher risk of endocrinopathies compared with monotherapy (ROR = 2.00, 95%CI 1.89-2.11). When further analysis, the spectrum of endocrine AEs differed in immunotherapy regimens. Hypothyroidism (N = 885,14.14%), adrenal insufficiency(N = 730,11.66%), hypophysitis (N = 688,10.99%) and hyperthyroidism (N = 472,7.54%) were top 4 ranked endocrine events after ICI therapy and their reporting frequency also differed in ICI immunotherapies.
CONCLUSION: Our pharmacovigilance analysis shows a high reporting frequency of endocrine AEs provoked by ICI monotherapy (especially anti-CTLA-4 therapy) and further reinforced by combination therapy. In addition, treatment with different ICI immunotherapies may result in a unique and distinct profile of endocrinopathies. Early recognition and management of ICI-related endocrine irAEs is of vital importance in clinical practice.

PMID: 31694698 [PubMed - indexed for MEDLINE]

Antibiotics prescription and guidelines adherence in elderly: impact of the comorbidities.

BMC Geriatr. 2019 10 29;19(1):291

Authors: Dylis A, Boureau AS, Coutant A, Batard E, Javaudin F, Berrut G, de Decker L, Chapelet G

Abstract
BACKGROUND: Although the interest of antibiotics is well known, antibiotics prescription is associated with side effect, especially in patients with multiples comorbidities. One way to reduce the incidence of side effects is to respect antibiotics prescriptions guidelines. Our objective was to investigated the factors associated with guidelines adherence in elderly patients with multiples comorbidities.
METHODS: From October 2015 to December 2016, antibiotics prescription and guidelines adherence were analyzed in two post-acute care and rehabilitation services of a 2600-bed, university-affiliated center.
RESULTS: One hundred and twenty-eight patients were included, fifty-nine (46%) patients had antibiotics prescription according to guidelines. In Multivariable logistic regression analysis, prescription of 2 antibiotics or more (OR = 0.168, 95% IC = 0.037-0.758, p < 0.05), 85 years of age and more (OR = 0.375, 95% IC = 0.151-0.931, p < 0.05) and the Charlson comorbidity index score (OR = 0.750, 95% IC = 0.572-0.984, p < 0.05) were negatively associated with antibiotics prescriptions according to guidelines.
CONCLUSIONS: High comorbidity in the elderly was negatively associated with the guidelines adherence of antibiotiсs prescriptions. These criteria should be considered to optimize antibiotics prescriptions in elderly patients.

PMID: 31664914 [PubMed - indexed for MEDLINE]

Assessing clinical and psychological features: who are patients showing a nocebo re-action during the drug challenge test?

Eur Ann Allergy Clin Immunol. 2019 11;51(6):258-265

Authors: Bizzi F, Voltolini S, Fiaschi MD, Cavanna D

Abstract
Summary: The nocebo reaction, namely the undesirable effect of an inert substance (placebo), is a phenomenon rarely investigated in literature. A better knowledge of this reaction may help clinicians in the management of these patients in clinical practice. Patients with drug adverse reactions (ADR) undergoing the drug challenge test are an ideal model for studying the nocebo effect, and the study aims to investigate their clinical and psychological features. One hundred and twenty patients (Mage = 46.59, SD = 15.5; 82% female), of which 90 non responders and 30 with nocebo reactions (25%) were recruited, and completed a battery of psychological measures: State-Trait Anxiety Inventory X1-X2, Beck Depression Inventory II, Symptoms Checklist-90-R, Difficulties in Emotion Regulation Scale, Toronto Alexithymia Scale. Clinical features (individual characteristics and ADR clinical history) were collected by clinicians. The results show that older age (p = 0.002), low level of education (p = 0.039) and a depressive tendency (p = 0.030) appear to be potential risk factors for nocebo effects. Although none of the features related to the previous clinical history appear to represent a risk factor for the nocebo reactions (p minor 0.05), significant correlations between some of the clinical and psychological characteristics considered (p values from 0.005 to 0.042) help to better delineate the profile of these reactive patients. A specific training of the sanitary team about psychological aspects is recommendable.

PMID: 31594299 [PubMed - indexed for MEDLINE]

Fatal adverse events in two thymoma patients treated with anti-PD-1 immune check point inhibitor and literature review.

Lung Cancer. 2019 09;135:29-32

Authors: Konstantina T, Konstantinos R, Anastasios K, Anastasia M, Eleni L, Ioannis S, Sofia A, Dimitris M

Abstract
OBJECTIVES: Thymomas, as well as thymic carcinomas, are extremely rare tumors that arise from the thymus. The management of these tumors is primarily the complete surgical resection, however when there is tumor progression or metastatic unresectable disease, palliative platinum-based chemotherapy is the standard of care. On this setting, alternative options are emerging including immune checkpoints inhibitors. Based on that, PDL-1 expression was measured in thymic tumors as a potential predictive biomarker of response to anti-PD1 and anti-PDL1 immune inhibitors. Our objective is to report the first two cases of fatal toxicity due to anti- PD1 therapy in thymoma patients.
MATERIALS AND METHODS: Here, we report two cases of metastatic B2/B3 thymomas refractory to initial standard chemotherapy treatment, with high PDL1 expression (>50%), that were treated with the anti-PD1 agent, pembrolizumab.
RESULTS: The administration of anti- PD1 immune check point inhibitor resulted in a storm of immune related adverse events including myositis, myocarditis and myasthenia gravis and death after administration of the first treatment cycle.
CONCLUSION: In thymomas, the administration of PD1 inhibitors seems to be associated with a high percentage of severe immune related adverse events, thus requiring special caution on the usage of these agents in thymomas.

PMID: 31446999 [PubMed - indexed for MEDLINE]

The importance of drug safety and tolerability in the development of new immunosuppressive therapy for transplant recipients: The Transplant Therapeutics Consortium's position statement.

Am J Transplant. 2019 03;19(3):625-632

Authors: Stegall MD, Troy Somerville K, Everly MJ, Mannon RB, Gaber AO, First MR, Agashivala N, Perez V, Newell KA, Morris RE, Sudan D, Romero K, Eremenco S, Mattera M, Spear N, Porter AC, O'Doherty I

Abstract
The Transplant Therapeutics Consortium (TTC) is a public-private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug-development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug-development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process-accelerating tools. The TTC has identified 2 major areas of emphasis: new biomarkers or endpoints for determining the efficacy of new therapies and new tools to assess the safety or tolerability of new therapies. This article presents the rationale and planned approach to develop new tools to assess safety and tolerability of therapies for transplant patients. We also discuss how similar efforts might support the continued development of patient-reported outcome measures in the future.

PMID: 30549395 [PubMed - indexed for MEDLINE]

Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial.

EBioMedicine. 2020 Jul 01;:102844

Authors: Camu W, Mickunas M, Veyrune JL, Payan C, Garlanda C, Locati M, Juntas-Morales R, Pageot N, Malaspina A, Andreasson U, Kirby J, Suehs C, Saker S, Masseguin C, De Vos J, Zetterberg H, Shaw PJ, Al-Chalabi A, Leigh PN, Tree T, Bensimon G

Abstract
BACKGROUND: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects.
METHODS: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759.
FINDINGS: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3-4·9) and 1 MIU ES=3·5 (IC95%: 2·1-4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels.
INTERPRETATION: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression.
FUNDING: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).

PMID: 32651161 [PubMed - as supplied by publisher]

Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets.

Cancers (Basel). 2020 Jul 07;12(7):

Authors: Alard E, Butnariu AB, Grillo M, Kirkham C, Zinovkin DA, Newnham L, Macciochi J, Pranjol MZI

Abstract
Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient's own immune system to selectively kill cancer cells. The immune system is the body's main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response.

PMID: 32645977 [PubMed]

Methanolic extract of Ephedra alata ameliorates cisplatin-induced nephrotoxicity and hepatotoxicity through reducing oxidative stress and genotoxicity.

Environ Sci Pollut Res Int. 2020 Apr;27(11):12792-12801

Authors: Sioud F, Ben Toumia I, Lahmer A, Khlifi R, Dhaouefi Z, Maatouk M, Ghedira K, Chekir-Ghedira L

Abstract
Cisplatin (CP) is a powerful anticancer agent used in the treatment of a diverse type of cancers. Oxidative stress is one of the most important side effects limiting the use of cisplatin. The protective effects of methanolic extract (ME) and ephedrine (EP), major compound, of Ephedra alata on CP-induced damages were here assessed. Treatment with CP-induced nephrotoxicity and hepatotoxicity characterized by biochemical alterations. In fact, using CP reduced significantly glutathione (GSH) levels, enzymatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and increased malondialdehyde (MDA) content. Nonetheless, CP-treatment induced DNA damage at renal, hepatic, and blood cells and increased interferon gamma (IFNγ) level in serum. Co-treatments of mice with ME normalized relative kidney/body weight, restored biochemical and oxidative stress parameters, reduced DNA damage and IFNγ level. In conclusion, ME exhibited the best protective effect against CP damage compared with ephedrine. This is could be attributed to the presence of polysaccharides, organic acids, flavonoids, and tannins in addition to ephedrine alkaloids. These compounds were reported to play a major role in inhibiting and scavenging free radicals, providing an effective protection against CP- induced oxidative damage. Graphical abstract.

PMID: 32008195 [PubMed - indexed for MEDLINE]