Specific Adverse Events Research Articles

Could tocilizumab be used in familial Mediterranean Fever? A systematic review.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease characterized by recurrent fever and serosal inflammation. Although colchicine is the primary treatment, around 10% of FMF patients do not respond to it, necessitating alternative therapies. Biologic treatments, such as interleukin-1β (IL-1β), TNF-α, and interleukin-6 (IL-6) inhibitors, have been considered. However, the accessibility and cost of IL-1β inhibitors may limit their use in certain regions. Tocilizumab (TCZ), an IL-6 receptor inhibitor, offers an alternative, but its efficacy in FMF is not well-documented. To evaluate the efficacy and safety of tocilizumab in the treatment of FMF. Following PRISMA guidelines, we identified 237 articles on the use of TCZ in FMF. After selection, 14 articles were included: 2 double-blind RCTs, 2 retrospective studies, and 10 case reports. Multicentre double-blind RCTs reported mixed results in FMF patients without AA amyloidosis due to genetic/classification heterogeneity of the available studies, possible misdiagnosed FMF patients and study design. Retrospective studies suggest that TCZ may benefit FMF patients with established renal AA amyloidosis, potentially preventing progression and managing flares more effectively. TCZ showed a safe profile with no specific adverse events, but data on its use during pregnancy or breastfeeding are lacking. There was no available data on the use of TCZ in pediatric FMF. This review summarizes the current state of research, safety and efficacy of TCZ in FMF. While IL1β inhibitors remain the first choice for colchicine-resistant or intolerant FMF patients, TCZ might be of interest in some selected FMF patients with established AA amyloidosis and resistance to colchicine and interleukin 1 inhibitors.

Exploring the clinical significance of specific immune-related adverse events in melanoma patients undergoing immune checkpoint inhibitor therapy.

Several studies have demonstrated that patients who experience immune-related adverse events (irAE) as a result of immunotherapy treatment, exhibit significantly improved outcomes compared to patients without toxicity. Data regarding the impact of specific irAE is, however, currently lacking. This is a real-world single-site cohort of 415 advanced melanoma patients who were treated with immunotherapy as first-line between 2014 and 2020, with a median follow-up of 24.5 months. The most frequent irAEs were cutaneous (classified as non-vitiligo, n = 110, 26.5% and vitiligo, n = 48, 11.6%), rheumatologic ( n = 68, 16.4%), gastrointestinal ( n = 66, 15.9%), endocrine ( n = 61, 14.7%), and hepatitis ( n = 50, 12%). Specific irAE that were significantly associated with survival benefit were rheumatologic (hazard ratio 0.34 for PFS, P < 0.001; hazard ratio 0.38 for OS, P < 0.001), non-vitiligo cutaneous (hazard ratio 0.58 for PFS, P < 0.001; hazard ratio 0.54 for OS, P = 0.001), vitiligo (hazard ratio 0.30 for PFS, P < 0.001; hazard ratio 0.29 for OS, P < 0.001), and endocrine (hazard ratio 0.6 for PFS, P = 0.01; hazard ratio 0.52 for OS, P < 0.001). Other types of irAEs, such as colitis, hepatitis and others - do not present this correlation. The occurrence of these specific irAEs may reflect a hyperactivated immune response and thus can serve as meaningful clinical biomarkers.

Benefits from catheter ablation in patients with pulmonary hypertension: Recent advances.

Supraventricular tachycardia (SVT) is a frequent complication of pulmonary hypertension (PH). The most prevalent SVTs are atrial fibrillation (AF) and typical atrial flutter (AFL), followed by focal and macroreentrant atrial tachycardia (AT) and nodal arrhythmia (AV nodal reentry tachycardia or AV reentry tachycardia). SVT is frequently associated with functional deterioration and right ventricular failure in PH patients. According to some data, reestablishing sinus rhythm is associated with clinical improvement. Catheter ablation of typical AFL, nodal tachyarrhythmias, or other less complex focal ATs have been shown to be feasible, acutely effective, and safe in patients with PH. However, the long-term clinical outcome is modified by the recurrence of index arrhythmia and the onset of a new SVT. Due to right atrial dilatation, technical issues can arise when ablation is carried out. The role of catheter ablation in patients with AF or more complex AT is even less effective. The results mirror the success rate in the general AF population with non-paroxysmal AF. However, the data is limited, and electrophysiological procedures are also more often complicated by specific adverse events in a severely frail population. Despite these limitations, catheter ablation is the treatment of choice in less complex SVT, but the indications for AF ablation must be more individualized.

Discontinuation Rate of Lurasidone and Quetiapine Extended Release in Bipolar Depression.

Lurasidone (LUR) was compared with quetiapine extended release (QUE-ER) regarding 1-year discontinuation in patients with bipolar depression (n=317). This is a retrospective cohort study. Although the time to all-cause discontinuation was estimated using the Kaplan-Meier survival curve with log-rank tests to compare treatment groups, no difference was found (p=0.317). The Cox proportional hazard model revealed that only the presence of adverse events (AEs) is associated with increased treatment discontinuation (p<0.0001). The most common AEs were akathisia for LUR (17.7%) and somnolence for QUE-ER (34.7%). In other Cox models divided by LUR or QUE-ER, the presence of akathisia or somnolence was associated with increased LUR (p=0.0205) or QUE-ER (p<0.0001) discontinuation, respectively. The acceptability of both antipsychotics to bipolar depression in clinical practice may be similar. However, specific AEs for each antipsychotic (LUR: akathisia and QUE-ER: somnolence) were associated with high treatment discontinuation.

Post-marketing safety of lorlatinib: a real-world study based on the FDA adverse event reporting system.

Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish the safety profile of lorlatinib based on the Food and Drug Administration Adverse Event Reporting System (FAERS). Reports from the FAERS between 2019 and 2023 were collected to conduct the disproportionality analysis. Reporting odds ratio (ROR) was employed to detect the potential adverse events (AEs) related to lorlatinib. The clinical characteristics, age and gender differences, time to onset of AEs were also investigated. A total of 2,941 AE reports were found to be associated with lorlatinib among the 8,818,870 AE reports obtained from the FAERS database. 167 lorlatinib-related AE signals were identified. The frequently reported AEs including hypercholesterolemia, oedema, and cognitive disorder were in line with those observed in clinical trials and drug instruction. However, AEs such as interstitial lung disease and AV block indicated in the drug label require further evaluation. More attention should be paid to the new potential unexpected AEs including pulmonary arterial hypertension and radiation necrosis. Furthermore, we examined the specific high-risk AEs of different ages and genders. In addition, majority of AEs occurred within the first 2months after lorlatinib initiation with a median onset time of 51days. Our study provides valuable insight into the post-marketing safety profile of lorlatinib, which can potentially benefit the rational and safe administration of lorlatinib in the clinic. Further prospective studies are needed to validate the associations between lorlatinib and the identified AEs.

Total Hip Arthroplasty in Patients Who Have Factor V Leiden: Elevated Risks Isolated to Venous Thromboembolism Events

BackgroundTotal hip arthroplasty (THA) is a common procedure that requires consideration of preexisting comorbidities. Factor V Leiden (FVL), an inherited thrombophilia, is one such condition that predisposes patients to venous thromboembolism (VTE, deep vein thrombosis, and pulmonary embolism). The present study aimed to characterize the risks associated with FVL patients undergoing THA and evaluate the effect of VTE chemoprophylactic agents on these risks. MethodsA total of 544,022 adult patients who underwent primary THA for osteoarthritis indications between 2010 and October 2021 were identified in an administrative claims database. Of these, FVL was identified in 1,138 (0.21%). Patients who had and did not have FVL were matched at a 1:4 ratio (1,131 with FVL and 4,519 without FVL) based on age, sex, and Elixhauser comorbidity index. Univariable and multivariable analyses were assessed for 90-day complications. Implant survival at 5 years was assessed and compared with log-rank tests. The relative use of different chemoprophylactic agents, including aspirin, warfarin, heparin, or direct oral anticoagulant (DOAC), was assessed. Bleeding events and VTE were compared for those prescribed either aspirin or warfarin, heparin, or DOAC. A Bonferroni correction was applied. ResultsOn multivariable analysis, FVL patients were found to have increased odds of 90-day deep vein thrombosis (odds ratio (OR) = 9.20), pulmonary embolism (OR = 6.89), and aggregated severe and all adverse events (OR = 4.74 and 1.98, respectively), but not elevated risk of other perioperative adverse events or 5-year reoperations. More potent chemoprophylactic agents (warfarin, heparin, DOAC) reduced, but did not completely eliminate, the increased VTE risks (without increasing bleeding events). ConclusionsThis study quantified the significantly elevated VTE risk associated with FVL patients undergoing THA. The lack of difference in other specific adverse events and 5-year reoperations is reassuring. Clearly, chemoprophylactic agents are important in this population and may need further attention.

Temporal Association Rule Mining: Race-Based Patterns of Treatment-Adverse Events in Breast Cancer Patients Using SEER-Medicare Dataset.

Disparities in the screening, treatment, and survival of African American (AA) patients with breast cancer extend to adverse events experienced with systemic therapy. However, data are limited and difficult to obtain. We addressed this challenge by applying temporal association rule (TAR) mining using the SEER-Medicare dataset for differences in the association of specific adverse events (AEs) and treatments (TRs) for breast cancer between AA and White women. We considered two categories of cancer care providers and settings: practitioners providing care in the outpatient units of hospitals and institutions and private practitioners providing care in their offices. We considered women enrolled in the Medicare fee-for-service option at age 65 who qualified by age and not disability, who were diagnosed with breast cancer with attributed patient factors of age and race, marital status, comorbidities, prior malignancies, prior therapy, disease factors of stage, grade, and ER/PR and Her2 status and laterality. We included 141 HCPCS drug J codes for chemotherapy, biotherapy, and hormone therapy drugs, which we consolidated into 46 mechanistic categories and generated AE data. We consolidated AEs from ICD9 codes into 18 categories associated with breast cancer therapy. We applied TAR mining to determine associations between the 46 TR and 18 AE categories in the context of the patient categories outlined. We applied the spark.mllib implementation of the FPGrowth algorithm, a parallel version called PFP. We considered differences of at least one unit of lift as significant between groups. The model's results demonstrated a high overlap between the model's identified TR-AEs associated set and the actual set. Our results demonstrate that specific TR/AE associations are highly dependent on race, stage, and venue of care administration. Our data demonstrate the usefulness of this approach in identifying differences in the associations between TRs and AEs in different populations and serve as a reference for predicting the likelihood of AEs in different patient populations treated for breast cancer. Our novel approach using unsupervised learning enables the discovery of association rules while paying special attention to temporal information, resulting in greater predictive and descriptive power as a patient's health and life status change over time.

Possible complications associated with the use of cyanoacrylate obliteration in patients with varicose veins

The problem of finding an ideal method for the correction of vertical venous reflux in lower extremity varicose disease is highly relevant due to the rapid development of technologies and the opening of new treatment methods, including minimally invasive ones. According to many researchers, the main parameters for choosing the optimal surgical technique should be low invasiveness, compliance with the anatomical, including ultrasound, picture, the possibility of using local anesthesia, taking into account concomitant pathology and individual intolerance of various drugs by patients, effectiveness of venous vessel obliteration, and minimal risk of possible complications. The review considers a comparative characterization of endovascular treatment methods for varicose disease, as well as lists the main possible complications of each of them. In terms of obliteration effectiveness and the least pronounced complications, the leading position is occupied by the method of cyanoacrylate obliteration. There is an increasing amount of information in the literature about the use of cyanoacrylate composite in the treatment of lower extremity varicose disease. Since this method is relatively new, the number of publications describing complications of this procedure is increasing. We describe a number of specific adverse events that occur during this surgery (extravasation of cyanoacrylate composite with the formation of aseptic granulomas and, in some cases, phlebitis-like phenomena, formation of rigid subcutaneous bands limiting mobility in the knee joint, migration of cyanoacrylate into the deep venous system of the lower extremities), possible mechanisms of their occurrence, and various approaches to treatment. Special attention is paid to proximal migration of cyanoacrylate composite into the area of the saphenofemoral junction, with a description of a specific clinical case and a discussion of further management tactics for this category of patients.

Simplified supine modified park bench / lateral decubitus position using a shoulder pad and a Mayfield head clamp for neurosurgical approach to lesions located in the occipital lobe or the posterior fossa: technical note.

Neurosurgical approach to lesions located in the occipital lobes or in the posterior fossa require very specific and time-consuming patient installations, such as the park bench position, the prone position, or the sitting position. Nevertheless, each of these position present major drawbacks regarding specific installation-related adverse events and potentially serious neurosurgical complications such as venous air embolism, iatrogenic intracranial hypertension, and supratentorial remote hematoma just to cite a few. In order to provide neurosurgeons with a simpler, physiologically-respective, easily tolerated, less time-consuming, and less provider or specific adverse events patient installation, Ochiai (1979) introduced the supine modified park-bench / lateral decubitus position. Given that this patient position has not gained wide visibility among the neurosurgical community despite its obvious numerous advantages over its classic counterparts, we provide our experience using this installation for neurosurgical approach to lesions located in the occipital lobes and in the posterior fossa.

Adverse events in endoscopic ultrasound-guided choledochoduodenostomy with lumen-apposing metal stents: A systematic review and meta-analysis.

Several meta-analyses have analyzed the technical and clinical success of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) by using lumen-apposing metal stents (LAMS) in malignant biliary obstruction, but those concerning adverse events (AEs) are scarce. The current systematic review and meta-analysis was conducted to evaluate the AEs after EUS-CDS with LAMS. A comprehensive literature search of PubMed, Embase, Scopus, Web of Science, and the Cochrane Library was conducted for studies reporting the outcomes of EUS-CDS with LAMS. The main endpoints were the incidence of overall and specific AEs. Moreover, the stent dysfunction, and reintervention rates were evaluated independently. A total of 21 studies (n=1438) were included in the final meta-analysis. The pooled rate of technical and clinical success was 93.5% (95% confidence interval [CI]: 91.3-95.1) and 88.0% (95% CI: 83.9-91.1), respectively. After EUS-CDS with LAMS, the pooled incidence of overall AEs was 20.1% (95% CI: 16.0-24.9). The estimated rate of early AEs was 10.6% (95% CI: 7.9-14.2), and late AEs was 11.2% (95% CI: 8.2-15.2). Infection/cholangitis was the commonest AE, with a pooled incidence of 6.1% (95% CI: 3.7-10.1). The estimated incidence of stent dysfunction and reintervention was 10.5% (95% CI: 7.5-14.4), and 12.1% (95% CI: 9.3-15.7), respectively. Despite with a high technical and clinical success rate, EUS-CDS with LAMS may be associated with overall AEs and stent dysfunction in one-fifth and one-tenth of cases, respectively. Further efforts are required to optimize its safety and long-term stent patency.

Safety analysis of Oseltamivir and Baloxavir Marboxil after market approval: a pharmacovigilance study based on the FDA adverse event reporting system

Background and objectivesAmidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references.MethodsA meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug.ResultsIncorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01–9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74–9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15–32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98–57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43–52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26].ConclusionMonitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir’s potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.

Evaluating the efficacy and safety of nivolumab and ipilimumab combination therapy compared to nivolumab monotherapy in advanced cancers (excluding melanoma): a systemic review and meta-analysis

BackgroundNivolumab (Nivo) and ipilimumab (Ipi) have revolutionized cancer treatment by targeting different pathways. Their combination shows promising results in various cancers, including melanoma, but not all studies have demonstrated significant benefits. A meta-analysis was performed to assess the effectiveness and safety of Nivo-Ipi compared to Nivo alone in advanced cancer types (excluding melanoma).MethodsFollowing PRISMA guidelines, we conducted a meta-analysis up to September 30, 2023, searching databases for randomized controlled trials (RCTs). We focused on advanced solid malignancies (excluding melanoma) with specific Nivo and Ipi dosing. Primary outcomes were overall survival (OS), progression-free survival (PFS), grades 3–4 adverse events (AEs), and treatment-related discontinuations. Secondary outcomes included specific adverse events. Statistical analysis in Review Manager included hazard ratio (HR) and risk ratio (RR), assessing heterogeneity (Higgins I2).ResultsNine RCTs, involving 2152 patients covering various malignancies, were analyzed. The Nivo plus Ipi group exhibited a median OS of 12.3 months and a median PFS of 3.73 months, compared to monotherapy with 11.67 months and 3.98 months, respectively. OS showed no significant difference between Nivo and Ipi combination and Nivo alone (HR = 0.97, 95% CI: 0.88 to 1.08, p = 0.61). PFS had a slight improvement with combination therapy (HR = 0.91, 95% CI: 0.82 to 1.00, p = 0.04). Treatment-related cumulative grades 3–4 adverse events were higher with Nivo and Ipi (RR = 1.52, 95% CI: 1.30 to 1.78, p < 0.00001), as were treatment-related discontinuations (RR = 1.99, 95% CI: 1.46 to 2.70, p < 0.0001). Hepatotoxicity (RR = 2.42, 95% CI: 1.39 to 4.24, p = 0.002), GI toxicity (RR = 2.84, 95% CI: 1.44 to 5.59, p = 0.002), pneumonitis (RR = 2.29, 95% CI: 1.24 to 2.23, p = 0.008), dermatitis (RR = 2.96, 95% CI: 1.08 to 8.14, p = 0.04), and endocrine dysfunction (RR = 6.22, 95% CI: 2.31 to 16.71, p = 0.0003) were more frequent with Nivo and Ipi.ConclusionsCombining nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone in advanced cancers (except melanoma). However, it did show slightly better PFS at the cost of increased toxicity, particularly grades 3–4 adverse events. Specific AEs occurred more frequently in the combination group. Further trials are needed to fully assess this combination in treating advanced cancers.

Safety of marketed biosimilar monoclonal antibody cancer treatments in the US: a disproportionality analysis using the food and drug administration adverse event reporting system (FAERS) database

ABSTRACT Background By 31 December 2022, the United States Food and Drug Administration (FDA) has approved 12 biosimilar monoclonal antibody cancer treatments. This study detected disproportionate adverse event (AE) reporting signals and compared safety profile of individual biosimilars to their originator biologics and between each pair of biosimilars. Research design and methods The FDA Adverse Event Reporting System data (6/1/2018–12/31/2022) were used to identify AE reports for rituximab, bevacizumab, trastuzumab, and their marketed biosimilars. Reporting odds ratios and empirical Bayesian geometric mean were computed to detect reporting disproportionality in serious, death, and specific AEs between studied biologics/biosimilars and all other drugs. Results Significant AE reporting signals were identified: 1) death for biological rituximab, pruritus for biosimilar rituximab-pvvr, and infusion-related reactions for biological rituximab and biosimilar rituximab-pvvr (significantly higher ROR for rituximab-pvvr than biological rituximab, p < .0001); 2) death for biological bevacizumab and biosimilar bevacizumab-bvzr (significantly higher ROR for bevacizumab-bvzr than biological bevacizumab, p < .0001), hypertension, platelet count decreased (PCD), and proteinuria for biological bevacizumab and biosimilar bevacizumab-awwb (significantly higher ROR of PCD for bevacizumab-awwb than originator bevacizumab, p = .001); and 3) rash for biosimilar trastuzumab-anns. Conclusions Findings call for large, longitudinal studies to examine causality of certain AEs with rituximab-pvvr and bevacizumab biosimilars.

Psychosocial working conditions, perceived patient safety and their association in emergency medical services workers in Germany - a cross-sectional study.

Emergency medical service (EMS) workers face challenging working conditions that are characterized by high stress and a susceptibility to making errors. The objectives of the present study were (a) to characterize the psychosocial working conditions of EMS workers, (b) to describe the perceived quality of patient care they provide and patient safety, and (c) to investigate for the first time among EMS workers associations of psychosocial working conditions with the quality of patient care and patient safety. For this cross-sectional study, we carried out an online survey among 393 EMS workers who were members of a professional organization. Working conditions were measured by the Demand-Control-SupportQuestionnaire (DCSQ) and seven self-devised items covering key stressors. Participants reported how often they perceived work stress to affect the patient care they provided and we inquired to what extent they are concerned to have made a major medical error in the last three months. Additionally, we used parts of the Emergency Medical Services - Safety Inventory (EMS-SI) to assess various specific errors and adverse events. We ran descriptive analyses (objective a and b) and multivariable logistic regression (objective c). The most common stressors identified were communication problems (reported by 76.3%), legal insecurity (69.5%), and switching of colleagues (48.9%) or workplaces (44.5%). Overall, 74.0% reported at least one negative safety outcome based on the EMS-SI. Concerns to have made an important error and the perception that patient care is impaired by work stress and were also frequent (17.8% and 12.7%, respectively). Most psychosocial working conditions were associated with the perception that patient care is impaired due to work stress. Work stress in EMS staff is pronounced and negative safety outcomes or potential errors are perceived to occur frequently. Poor psychosocial working conditions were only consistently associated with perceived impairment of patient care due to work stress. It seems necessary to reduce communication problems and to optimize working processes especially at interfaces between emergency services and other institutions. Legal insecurity could be reduced by clarifying and defining responsibilities. Communication and familiarity between team colleagues could be fostered by more consistent composition of squads.

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study

BackgroundThis study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies.MethodsA retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status.ResultsGenotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users.ConclusionsNUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

Analysis of post-market adverse events of istradefylline: a real-world study base on FAERS database

Analyze the adverse event (AE) signals of istradefylline based on the FAERS database. By extracting large-scale data from the FAERS database, this study used various signal quantification techniques such as ROR, PRR, BCPNN, and MGPS to calculate and evaluate the ratio and association between istradefylline and specific AEs. In the FAERS database, this study extracted data from the third quarter of 2019 to the first quarter of 2023, totaling 6,749,750 AE reports. After data cleansing and drug screening, a total of 3633 AE reports related to istradefylline were included for analysis. Based on four calculation methods, this study unearthed 25 System Organ Class (SOC) AE signals and 82 potential preferred terms (PTs) related to istradefylline. The analysis revealed new AEs during istradefylline treatment, including reports of Parkinsonism hyperpyrexia syndrome (n = 3, ROR 178.70, PRR 178.63, IC 1.97, EBGM 165.63), Compulsions (n = 5, ROR 130.12, PRR 130.04, IC 2.53, EBGM 123.02), Deep brain stimulation (n = 10, ROR 114.42, PRR 114.27, IC 3.33, EBGM 108.83), and Freezing phenomenon (n = 60, ROR 97.52, PRR 96.76, IC 5.21, EBGM 92.83). This study provides new risk signals and important insights into the use of istradefylline, but further research and validation are needed, especially for those AE that may occur in actual usage scenarios but are not yet explicitly described in the instructions.

Retaliating against cyber-attacks: a decision-taking framework for policy-makers and enforcers of international and cybersecurity law

Cyber warfare is a reality taking on increasing importance. Governments, state-sponsored actors, and non-state sponsored actors have used cyber-attacks as the “weapon of choice” due to their specific characteristics. Cyber-attacks can be highly targeted and focused, even tailored to a specific unit or system, providing limited to no physical destruction (unlike a cruise missile) and potentially resulting in no loss of life. There are several incident response frameworks and approaches that an organization can implement to enhance its security posture. Usually, these will address specific adverse events such as computer security incidents, which in turn are limited in scope and coverage, typically within an organization. Nations have made limited effort in confronting severe cyber-attacks targeting and/or threatening them, as well as in preventing these attacks from being launched. In this work, we identify and discuss a decision-taking framework that may allow state actors to adopt new options against severe cyber-attacks, not always complying with international norms. Such options are neither encouraged nor supported. On the contrary, we discuss them so that the international community is made aware of such potential frameworks. More specifically, by defining clear thresholds, roles, and responsibilities, by introducing a structured chain of command, and by identifying the potential of certain actions, policy makers can recognize an extended decision space that may lead to unpredictable deterrence options against cyber-attacks.

Abstract 922: Comparison of adverse effects of different combination therapies of immune checkpoint inhibitors and radiotherapy: A systematic review and meta-analysis

Abstract Background: Numerous ongoing trials are investigating cancer treatment combinations based on the combination of radiotherapy and immune checkpoint inhibitors. Understanding the toxicity profile of treatment-related adverse events is crucial. The purpose of this study is to comprehensively investigate the incidence and overview of treatment-related adverse events in different combination therapies involving radiotherapy and immune checkpoint inhibitors. Methods: We conducted a systematic review and meta-analysis of different combination therapies involving radiotherapy and immune checkpoint inhibitors. We searched English-language articles published between January 1, 2000, and May 31, 2023, in Pubmed, Embase, and the Cochrane database, investigating globally approved therapies based on PD-1, PD-L1 inhibitors, or CTA-4. Only prospective trials reporting overall incidence rates or lists of treatment-related adverse events data were included, and studies recruiting fewer than 10 patients were excluded. Retrospective studies were also excluded to minimize the risk of bias. The primary outcomes were the overall incidence and overview of treatment-related adverse events of all grades and grade 3 or higher. Heterogeneity among studies was assessed using the I2 statistic. The summary measure for primary outcomes was incidence rate (95% CI). This protocol is registered in PROSPERO (CRD42023390147). Results: We identified 1300 records, of which 50 studies (1655 patients) met the inclusion criteria. The incidence of treatment-related adverse reactions in the concurrent group was 76.0% (95% CI 73.5-78.4), and the incidence of grade 3 or higher adverse events was 23.5% (21.1-25.9). In the sequential group, the incidence of treatment-related adverse reactions was 75.9% (70.8-80.6), and the incidence of grade 3 or higher adverse events was 22.5% (18.0-27.5). In the induction group, the incidence of treatment-related adverse reactions was 72.8% (65.0-79.8), and the incidence of grade 3 or higher adverse events was 37.1% (29.4-45.3). The most common specific adverse event in the concurrent group was Fatigue (27.8% [25.2-30.6]); in the sequential group, it was Fatigue (43.3% [33.3-53.7]); in the induction group, it was Fatigue (71.4% [56.7-83.4]). Grade 3 or higher adverse events in the concurrent group was Lymphocyte Count Decreased (7.2% [5.4-9.4]); in the sequential group, it was Pneumonitis (11.1% [5.7-19.0]); in the induction group, it was Fatigue (10.5% [5.6-17.7]). Conclusion: Our study provides comprehensive data on treatment-related adverse events in different combination therapies involving radiotherapy and immune checkpoint inhibitors. Our results provide an essential reference of toxicity profiles of radiotherapy combined with immune checkpoint inhibitors for clinicians in routine practice of cancer care. Citation Format: Haiyu Zhou, Zefeng Guo, Ting Wang, Liyu Cai, Peimeng You. Comparison of adverse effects of different combination therapies of immune checkpoint inhibitors and radiotherapy: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 922.

Feasibility study of micronutrient status and body mass index of newly diagnosed pediatric oncology patients: Research commentary.

We conducted a feasibility study to evaluate micronutrients and body mass index (BMI). Fat soluble vitamins A, D, E and trace elements copper (Cu), selenium (Se), and zinc (Zn) levels were evaluated. Weight, height, BMI, and Z-scores were recorded. Side effects or specific adverse events were documented. No patient had a Z-score for height, weight, or BMI of less than 2 SD or greater than 2 SD. Ninety percent of patients had one or more micronutrient levels below normal. These results suggest that micronutrient abnormalities are common despite no obvious evidence of malnutrition. Side effects of chemotherapy may be exacerbated by micronutrient depletion.

Assessing the application of barbed sutures in comparison to conventional sutures for surgical applications: a global systematic review and meta-analysis of preclinical animal studies.

Following an initiative published by Lancet in 2002 and an IDEAL-D framework, the value of preclinical animal studies has garnered increasing attention in recent research. Numerous preclinical animal experiments tried to generate evidence to guide the development of barbed sutures. However, discernible drawbacks and incongruities in outcomes have emerged between clinical and preclinical animal studies. Therefore, this meta-analysis aimed to review the preclinical animal experiments comparing barbed sutures with conventional sutures. The authors hope to facilitate clinical translation of barbed sutures by evaluating effectiveness, safety, and physical properties/reliability. A systematic search of PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov was conducted to identify controlled preclinical animal experiments comparing barbed sutures with conventional sutures. The risk of bias was assessed using SYRCLE. GRADE approach was used to evaluate evidence quality. Revman was applied to analyze all the data. Subgroup, sensitivity, and meta-regression analyses were also performed. A total of 62 articles were eligible with low to moderate quality, including 2158 samples from 10 different animal species across 27 surgical procedures. Barbed suture exhibited a significant reduction in suture time, limited change in Cross-Sectional Area (CSA), and decreased instances of tissue disruption (all P <0.05). Subgroup analyses, considering both clinical and research significance, indicated that barbed sutures might cause more specific adverse events and demonstrate suboptimal performance of physical properties/reliability. Meta-regression suggested that heterogeneity resulted from variations in studies and animal models. Although barbed suture demonstrated superiority in numerous surgeries for time efficiency, its safety and physical properties/reliability might be influenced by diverse preclinical models, sutures' brand, surgeries, and anatomical sites. Further evaluation, based on standardized and well-designed animal experiments, is essential for medical device development and applications in human beings.