Presentation Of Adverse Events Research Articles

Germinal and somatic genetic variants of NF1 in neuroblastoma: own experience and literature review

Introduction. Neuroblastoma (NB) is the most common embryonic extracranial malignant neoplasm in children. The contribution of the NF1 gene to the development of NB is discussed in the literature, but there is no evidence of the pathogenetic role of NF1 gene aberrations in NB. According to various literature sources, the occurrence of pathogenic variants in the NF1 gene in the general cohort of patients with NB does not exceed 1–6 %.Materials and methods. The molecular genetic examination by next generation sequencing (NGS) was performed in 77 patients with NB during the period from April 2019 to July 2021 in the Laboratory of Molecular Oncology Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology. The staging of patients was carried out within the framework of the international staging system, stratification into risk groups and therapy according to the protocol of the German Group for the study of NB GPOH NB-2004. International criteria of the response assessment system for patients with NB were used to assess the response to treatment. Calculations of event-free and overall survival by the Kaplan–Mayer method for the follow-up period up to 12.01.2022 were performed.Results and discussion. The cohort of patients included in the study was represented by patients with an initially unfavorable prognosis. Patients were divided into 3 groups: without pathogenic variants in genes belonging to the RAS-RAF-MEK pathway and TP53 – “RAS-/ TP53-” (n = 43), with clinically significant variants in the NF1 gene – “NF1+” (n = 12), clinically significant variants in the genes of RAS-RAF-MEK and TP53 pathway – “RAS+/TP53+” except NF1 (n = 22). The median age for the entire group of patients at the time of diagnosis was 41 months (0.1–173 months). Boys prevailed over girls with a ratio of 1.5:1. Patients with stage 4 of the disease according to the INSS classification prevailed – 81.8 % (63/77), high-risk groups according to the NB-2004 protocol – 77.9 % (60/77).In our study 13 clinically significant variants in NF1 were identified in 12 patients (15.6 %), of which 4 were germinal, 9 were somatic. The frequency of detection of pathogenic aberrations in the NF1 gene was much higher than the literature data, which can be associated with a selective cohort of studied patients with an unfavorable prognosis and patients with suspected hereditary genetic syndrome. The presentation of adverse events was observed in 83.3 % of patients, more often against the background of specific therapy (in 60 % of cases), which may be due to the rapid acquisition of NB chemoresistance, among other things. When comparing the three groups, it was shown that the frequency of objective responses to induction therapy was statistically significantly lower in the group of patients “NF1+”, when compared with other groups (p = 0.015; p = 0.024), which may also indicate the chemoresistance of NF1-aberrated NB. When analyzing survival there was no statistical difference between the compared groups.Conclusions. The data obtained by us do not allow us to consider the presence of genetic variants in NF1 separately as a prognostic factor, however, it can be assumed that a group of patients with an unfavorable prognosis may be enriched with cases with mutations in the NF1 gene. Refractory course of the disease/development of adverse events in the presence of genetic variants of NF1, causing the activation of the RASRAF- MEK signaling pathway, leads to the induction of tumor chemoresistance. The presence of clinical significance of aberrations in the NF1 gene does not lead to a statistically significant difference in prognosis when compared with patients with aberrations in other components of the RAS-RAF-MEK pathway, however, longer catamnestic follow-up of patients is necessary.Currently, there are no effective drugs for the treatment of NF1-associated NB in clinical practice that requires further study of the mechanisms of chemoresistance development in such patients. Understanding the molecular and genetic features of the course of NF1-associated NB can become the basis for the development of personalized therapy in the future.

Improving Clinical Governance of Kidney Transplantation: Review of a Ruling and of the Clinical Governance Process in the United Kingdom

The presentation of adverse events and negative outcomes is uncommon in scientific publications, particularly in a highly regulated and scrutinized practice such as solid organ transplantation. A ruling of a regulatory body of the pharmaceutical industry in the United Kingdom generates several considerations, in particular, regarding the governance process of kidney transplantation, as the events reported in the ruling are linked with high rejection rates and negative patient outcomes. This analysis offered a review of the current governance processes, while recognizing the relevant limitations of the system regulating kidney transplantation outcomes in the United Kingdom. The article identified some of the potential interventions that may contribute to delivering an improved governance, harmonizing contemporary practice, modern health care system, and establishing scientific knowledge.

Intravenous lipid emulsion as an antidote in clinical toxicology: a systematic review.

Intravenous lipid emulsions (ILE) were developed many decades ago to supply nutritional requirements to patients unable to obtain adequate enteral nutrition. The utility of ILE was extended to therapeutics, facilitating the delivery of drugs. More recently, the potential for ILE to act as an antidote for inversion of drug toxicity has been recognized. This review aims to summarize the literature on ILE therapy as an antidote. Suggested mechanisms of action, safety profile, and recommendations on the administration of ILE in cases of drug intoxication are highlighted. A complete literature survey was performed using the PubMed database search to collect available information regarding mechanisms of ILE action as an antidote, ILE administration for drug toxicity, and presentation of adverse events. A total of 102 studies met the selection criteria for inclusion in the review. Mainly used for local anesthetics toxicity, ILE therapy has been expanded in clinical toxicology involving overdose treatment of drugs other than local anesthetics. Partitioning in a lipid phase of fat droplets is a mechanism named the lipid sink phenomenon that has primarily been described to explain this action of ILE and remains the most widely accepted. At the same time, recent research has also revealed several molecular mechanisms that may contribute to ILE efficacy. ILE therapy comprises a recognized approach in clinical toxicology. Due to the lack of randomized clinical trials, recommendations on administration are based on animal studies and published cases. Thus, the constantly increased knowledge about ILE therapy supports the need for a detailed appraisal.

Analysis and reporting of adverse events in randomised controlled trials: a review.

ObjectiveTo ascertain contemporary approaches to the collection, reporting and analysis of adverse events (AEs) in randomised controlled trials (RCTs) with a primary efficacy outcome.DesignA review of clinical trials of drug interventions from four high impact medical journals.Data sourcesElectronic contents table of the BMJ, the Journal of the American Medical Association (JAMA), the Lancet and the New England Journal of Medicine (NEJM) were searched for reports of original RCTs published between September 2015 and September 2016.MethodsA prepiloted checklist was used and single data extraction was performed by three reviewers with independent check of a randomly sampled subset to verify quality. We extracted data on collection methods, assessment of severity and causality, reporting criteria, analysis methods and presentation of AE data.ResultsWe identified 184 eligible reports (BMJ n=3; JAMA n=38, Lancet n=62 and NEJM n=81). Sixty-two per cent reported some form of spontaneous AE collection but only 29% included details of specific prompts used to ascertain AE data. Numbers that withdrew from the trial were well reported (80%), however only 35% of these reported whether withdrawals were due to AEs. Results presented and analysis performed was predominantly on ‘patients with at least one event’ with 84% of studies ignoring repeated events. Despite a lack of power to undertake formal hypothesis testing, 47% performed such tests for binary outcomes.ConclusionsThis review highlighted that the collection, reporting and analysis of AE data in clinical trials is inconsistent and RCTs as a source of safety data are underused. Areas to improve include reducing information loss when analysing at patient level and inappropriate practice of underpowered multiple hypothesis testing. Implementation of standard reporting practices could enable a more accurate synthesis of safety data and development of guidance for statistical methodology to assess causality of AEs could facilitate better statistical practice.

Pregabalin for essential tremor

Essential tremor is one of the most common movement disorders. Treatment primarily consists of pharmacological agents. While primidone and propranolol are well-established treatments in clinical practice, they may be ineffective in 25% to 55% of patients and can produce serious adverse events in a large percentage of them. For these reasons, it is worth evaluating the treatment alternatives for essential tremor. Some specialists have suggested that pregabalin could be a potentially useful agent, but there is uncertainty about its efficacy and safety. To assess the effects of pregabalin versus placebo or other treatment for essential tremor in adults. We performed a systematic search without language restrictions to identify all relevant trials up to December 2015. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, NICE, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We handsearched grey literature and examined the reference lists of identified studies and reviews. We included all randomised controlled trials (RCTs) of pregabalin versus placebo or any other treatments. We included studies in which the diagnosis of ET was made according to accepted and validated diagnostic criteria. We excluded studies conducted in patients presenting secondary forms of tremor or reporting only neurophysiological parameters to assess outcomes. Two reviewers independently collected and extracted data using a data collection form. We assessed the risk of bias of the body of evidence, and we used inverse variance methods to analyse continuous outcomes and measurement scales. We compared the mean difference between treatment groups, and we combined results for dichotomous outcomes using Mantel-Haenszel methods and risk differences We used Review Manager software for data management and analysis. We only found one study eligible for this review (22 participants). We assessed the risk of bias for most domains as unclear. We graded the overall quality of evidence as very low. Compared to placebo, patients treated with pregabalin showed no significant improvement of motor tasks on the 36-point subscale of the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) (MD -2.15 points; 95% CI -9.16 to 4.86) or on the 32-point functional abilities subscale of the TRS (MD -0.66 points; 95% CI -2.90 to 1.58).The limited evidence showed no difference in study withdrawal (Mantel-Haenszel RD -0.09; 95% CI -0.48 to 0.30) and presentation of adverse events between pregabalin and placebo (Mantel-Haenszel RD 0.18; 95% CI -0.13 to 0.50). The effects of pregabalin for treating essential tremor are uncertain because the quality of the evidence is very low. One small study did not highlight any effect of this treatment; however, the high risk of bias and the lack of other studies on this topic limit further conclusion.

The Adverse Event Profile in Patients Treated with Transferon<sup>TM</sup> (Dialyzable Leukocyte Extracts): A Preliminary Report

Background: Dialyzable leukocyte extracts (DLE) are heterogeneous mixtures of peptides less than 10 kDa in size that are used as immunomodulatory adjuvants in immune-mediated diseases. TransferonTM is DLE manufactured by National Polytechnic Institute (IPN), and is registered by Mexican health-regulatory authorities as an immunomodulatory drug and commercialized nationally. The proposed mechanism of action of TransferonTM is induction of a Th1 immunoregulatory response. Despite that it is widely used, to date there are no reports of adverse events related to the clinical safety of human DLE or TransferonTM. Objective: To assess the safety of TransferonTM in a large group of patients exposed to DLE as adjuvant treatment. Methods: We included in this study 3844 patients from our Clinical Immunology Service at the Unit of External Services and Clinical Research (USEIC), IPN. Analysis was performed from January 2014 to November 2014, searching for clinical adverse events in patients with immune-mediated diseases and treated with TransferonTM as an adjuvant. Results: In this work we observed clinical nonserious adverse events (AE) in 1.9% of patients treated with TransferonTM (MD 1.9, IQR 1.7 - 2.0). AE were 2.8 times more frequently observed in female than in male patients. The most common AE were headache in 15.7%, followed by rash in 11.4%, increased disease-related symptomatology in 10%, rhinorrhea in 7.1%, cough in 5.7%, and fatigue in 5.7% of patients with AE. 63% of adverse event presentation occurred from day 1 to day 4 of treatment with TransferonTM, and mean time resolution of adverse events was 14 days. In 23 cases, the therapy was stopped because of adverse events and no serious adverse events were observed in this study. Conclusion: TransferonTM induced low frequency of nonserious adverse events during adjuvant treatment. Further monitoring is advisable for different age and disease groups of patients.

Tratamiento con antipsicóticos de mantenimiento del paciente adulto con diagnóstico de esquizofrenia

ObjectivesTo determine the effectiveness and security of the antipsychotics available for the management of adult patients with schizophrenia in the maintenance phase. To develop recommendations of treatment for the maintenance phase of the disease. MethodsA clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Protección Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. The evidence of NICE guide 82 was adopted and updated. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. Results18 studies were included to evaluate the effectiveness and / or safety of different antipsychotic drugs first and second generation. Overall, antipsychotics (AP) showed superiority over placebo in relapse rate over 12 months (RR 0.59 95% CI 0.42, 0.82) and hospitalization rate over 24 months of follow-up (RR 0.38 95% 0.27, 0.55); its use is associated with increased risk of treatment dropout (RR 0.53 95% CI 0.46, 0.61) and adverse events such as weight gain, dystonia, extrapyramidal symptoms and sedation. There was no difference in the outcome of re hospitalizations, comparisons on quality of life, negative symptoms or weight gain between AP first and second generation. Continuous or standard dose regimens appear to be superior to intermittent or low doses in reducing the risk of abandonment of treatment regimes. ConclusionAdult patients diagnosed with schizophrenia should receive maintenance treatment with antipsychotics. The medication of choice will depend on the management of the acute phase, the patient's tolerance to it and the presentation of adverse events.

Morbidity and Mortality Conferences: Change You Can Believe In?

Morbidity and Mortality Conferences: Change You Can Believe In?

Reporting of adverse events in randomized controlled trials of highly active antiretroviral therapy: systematic review

Our objectives were to systematically assess the quality of reporting of adverse events (AEs) in publications of randomized trials of highly active antiretroviral therapy (HAART), and to examine whether reporting quality affects the effect estimates reported for AEs. We searched the PubMed, Cochrane library and EMBASE electronic databases up to December 2008. We included all published randomized controlled trials assessing HAART for treatment-naive adult HIV-infected individuals, with 48 weeks' follow-up. The quality of AE reporting was extracted according to CONSORT guidelines. We pooled the relative risks for AEs and compared results by sponsorship and different reporting methods. Forty-nine trials, including 19 882 patients, published between 2000 and 2008, met the inclusion criteria. Only one of the trials reported on AE collection methods. Twenty-six trials reported only AEs attributed to drugs, 17 of which did not refer to the attribution methods. AE reporting was nearly always selective and selection criteria were highly variable, based on severity grading or occurrence threshold. Presentation of AEs above an occurrence threshold was more common in studies sponsored by industry (30/31) than in studies sponsored by non-profit organizations (3/18). Moreover, we showed that differences in the methods of reporting AEs may affect the results reported for AEs. No significant improvement in AE reporting was seen over this period. We found substantial variability in AE reporting. Variability was influenced by sponsor identity and affected outcomes. These facts obstruct our ability to choose HAART based on currently published data.