Elife. 2024 Apr 12;12:RP87288. doi: 10.7554/eLife.87288.

ABSTRACT

Anticancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

PMID:38607373 | PMC:PMC11014725 | DOI:10.7554/eLife.87288

Asia Pac J Clin Oncol. 2024 Apr 12. doi: 10.1111/ajco.14059. Online ahead of print.

ABSTRACT

BACKGROUND: Immune-checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs). The spectrum of irAEs and their managements has been partially clarified, however the knowledge on time-course of irAEs is not well understood.

METHODS: A retrospective study based on the medical record was performed. The study subjects were consisting of patients with various types of solid tumors for whom ICIs (nivolumab, pembrolizumab, durvalumab, atezolizumab, nivolumab plus ipilimumab) were used between April 2016 and October 2021. We focused on irAEs developed more than 1-year after commencement ICIs (delayed irAE group) and compared with irAEs developed within 1-year (non-delayed irAE group) in terms of types and severity of irAEs.

RESULTS: A total of 336 patients were enrolled in the study. Eighty-eight patients (26.2%) developed irAEs and 248 did not. Most of the patients developing irAEs were treated using PD-L1/PD-1 inhibitors. Eighty-one patients (24.1%) in non-delayed irAE group and 7 patients (2.1%) in delayed irAE group developed irAEs. The median onset of irAEs in the delayed irAE group was 18.6 months (range: 13.5-24.3). The types of irAEs observed in delayed irAE group were dermatitis (2 cases), pneumonitis (2 cases), nephritis (1 case), arthritis (1 case), and gastritis (1 case). The severity of irAEs was almost mild (≤G2), but one patient (.3%) developed G3 nephritis.

CONCLUSION: PD-L1/PD-1 inhibitors frequently caused various irAEs but their severities were mostly tolerable. Few patients developed delayed irAE with mild toxities.

PMID:38608154 | DOI:10.1111/ajco.14059

Brain. 2024 Apr 12:awae109. doi: 10.1093/brain/awae109. Online ahead of print.

ABSTRACT

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger containing (PIKfyve) inhibitor with favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis models. In this amyotrophic lateral sclerosis clinical trial, the safety, tolerability, CNS penetrance, and modulation of pharmacodynamic target engagement biomarkers were evaluated. This Phase 2a, randomized, double-blind, placebo-controlled, biomarker-endpoint clinical trial was conducted in four USA centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansion were randomly assigned (2:1) to receive twice-daily oral treatment of 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent adverse or serious adverse events attributable to study drug, and tolerability as trial completion on treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition (soluble glycoprotein nonmetastatic melanoma protein B [sGPNMB] upregulation) and disease-specific CNS target engagement (poly[GP]). Between Dec 16, 2021, and Jul 7, 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance (N=9 [90%] apilimod dimesylate; N=5 [100%] placebo). At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/mL (SD: 0.937). At Week 12, apilimod dimesylate increased plasma sGPNMB by > 2.5-fold (p < 0.001) indicating PIKfyve inhibition and lowered CSF poly(GP) protein levels by 73% (p < 0.001) indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker endpoints in this Phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to have the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

PMID:38606777 | DOI:10.1093/brain/awae109

Ther Adv Urol. 2024 Apr 10;16:17562872241241864. doi: 10.1177/17562872241241864. eCollection 2024 Jan-Dec.

ABSTRACT

BACKGROUND: Oral testosterone undecanoate (TU) formulations may provide effective, safe, and easily titratable testosterone replacement therapy.

OBJECTIVE: Demonstrate efficacy and safety of a novel oral TU formulation.

DESIGN: An open-label, single-arm, multi-center trial treated 155 hypogonadal men for 180 days. Treatment began at 200 mg TU twice daily with meals; doses were titrated over two 28-day cycles to between 100 and 800 mg TU daily, measuring average testosterone (T Cavg) after 90 days. Ambulatory blood pressure monitoring (ABPM) occurred at baseline, 120, and 180 days.

METHODS: Titrations used a randomized blood sample taken 3-, 4-, or 5-h post-morning dose. Outcomes used sodium fluoride/ethylenediaminetetraacetate plasma testosterone (T) values; serum results were also reported. Blood pressure (ABPM and in-clinic) was evaluated for change from baseline.

RESULTS: After titration, 87.8% of KYZATREX™ treated participants (worse-case scenario) and 96.1% of 90-day completers achieved eugonadal mean plasma T values. Serum T Cavg was 452 ng/dL and maximum T concentrations (T Cmax) met all FDA criteria. Participant eugonadal percentages were comparable across subgroups for age, weight, and body mass index. Diet had no effect on participant eugonadal percentages. KYZATREX was well tolerated, with no drug-related serious adverse events (SAE) and one adverse drug reaction (hypertension) observed in 2% or more of participants. Systolic ambulatory blood pressure increased 1.7 mmHg (95% confidence interval: 0.3-3.1). At baseline, 36% of 155 participants were receiving anti-hypertensive medication and 22% were diabetic. No dose increases occurred in existing anti-hypertensive medication; five participants (3.2%) started anti-hypertensive medication.

CONCLUSION: KYZATREX provided safe and effective testosterone levels within the normal range in hypogonadal male study participants.

CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ unique identifier NCT04467697, conducted under NCT03198728. Post-completion, clinicaltrials.gov requested creation of the separate NCT04467697 identifier. All subjects were recruited under NCT03198728.

PMID:38606384 | PMC:PMC11008350 | DOI:10.1177/17562872241241864

Cureus. 2024 Mar 11;16(3):e55986. doi: 10.7759/cureus.55986. eCollection 2024 Mar.

ABSTRACT

Leprosy is known for its diverse pathophysiologic involvement and resulting multisystemic manifestation and morbidities. Despite global efforts to eliminate this public health illness, it is still prevalent in some Asian and European countries. Perioperative management of a leprosy patient is challenging owing to the indirect and direct involvement of the airway, respiratory, and cardiac systems; treatment-related side-effects involving the hepato-renal systems affecting the anesthesia techniques and drugs pharmacokinetic and pharmacodynamics. While anaesthesiologists are aware of such happenings and often tailor the anesthesia management for the concerning issues, immunological aspects of the disease and drug-related adverse events are less enquired about, such as type-2 lepra reaction, i.e., erythema nodosum leprosum (ENL), etc. Further, data on perioperative ENL management and prevention are still being determined. We report one case of a 52-year-old female who underwent gynecology surgery and developed ENL on the third postoperative day, which was managed using Steroids. Unfortunately, the patient had a surgical site infection, which required another surgery within the month, while the patient was still under the steroid successfully without any adverse events. Although a single case cannot provide causation or association, the case is presented to highlight the probable preventive action of steroids on the occurrence of postoperative ENL, where surgical stress is considered a risk factor.

PMID:38606250 | PMC:PMC11007188 | DOI:10.7759/cureus.55986

Clin Endosc. 2024 Apr 12. doi: 10.5946/ce.2023.198. Online ahead of print.

ABSTRACT

BACKGROUND/AIMS: Sedation has become a standard practice for patients undergoing gastrointestinal (GI) endoscopy. However, considering the serious cardiopulmonary adverse events associated with sedatives, it is important to identify patients at high risk. Machine learning can generate reasonable prediction for a wide range of medical conditions. This study aimed to evaluate the risk factors associated with sedation during GI endoscopy and develop a predictive model for hypoxia during endoscopy under sedation.

METHODS: This prospective observational study enrolled 446 patients who underwent sedative endoscopy at the Korea University Ansan Hospital. Clinical data were used as predictor variables to construct predictive models using the random forest method that is a machine learning algorithm.

RESULTS: Seventy-two of the 446 patients (16.1%) experienced life-threatening hypoxia requiring immediate medical intervention. Patients who developed hypoxia had higher body weight, body mass index (BMI), neck circumference, and Mallampati scores. Propofol alone and higher initial and total dose of propofol were significantly associated with hypoxia during sedative endoscopy. Among these variables, high BMI, neck circumference, and Mallampati score were independent risk factors for hypoxia. The area under the receiver operating characteristic curve for the random forest-based predictive model for hypoxia during sedative endoscopy was 0.82 (95% confidence interval, 0.79-0.86) and displayed a moderate discriminatory power.

CONCLUSIONS: High BMI, neck circumference, and Mallampati score were independently associated with hypoxia during sedative endoscopy. We constructed a model with acceptable performance for predicting hypoxia during sedative endoscopy.

PMID:38605689 | DOI:10.5946/ce.2023.198

Cancer Res Treat. 2024 Apr 9. doi: 10.4143/crt.2024.003. Online ahead of print.

ABSTRACT

PURPOSE: A "Smart Cancer Care" platform that integrates patient-reported outcomes (PROs) with management has been established in Korea. This study focused on improving health behaviors and connecting patients to welfare services by introducing and assessing the feasibility of "Smart Cancer Care 2.0," an enhanced version designed for monitoring complications post-cancer treatment.

MATERIALS AND METHODS: Smart Cancer Care 2.0 was developed by conducting a literature review and consulting with expert panels to identify symptoms or variables requiring monitoring and management guidelines based on the treatment type. Qualitative and quantitative surveys were conducted to assess the feasibility of the app and web system based on the experiences of patients with cancer and healthcare workers.

RESULTS: A total of 81 symptoms or variables (chemotherapy-, surgery-, radiotherapy-, rehabilitation-, and health management-related) were selected for management in Smart Cancer Care 2.0. PROs for these symptoms were basically categorized into three severity grades: (1) preventive management, (2) self-treatment, and (3) consultation with a healthcare worker or visit to a healthcare institution. The overall mean scores in the feasibility evaluation by patients and healthcare workers were 3.83 and 3.90 points, respectively, indicating high usefulness.

CONCLUSION: Smart Cancer Care 2.0 leverages the existing ICT-based platform, Smart Cancer Care, and further includes health behaviors and welfare services. Smart Cancer Care 2.0 may play a crucial role in establishing a comprehensive post-discharge management system for patients with cancer as it provides suitable interventions based on patients' responses and allows the regularly collected PROs to be easily viewed for streamlined care.

PMID:38605663 | DOI:10.4143/crt.2024.003

Sci Rep. 2024 Apr 11;14(1):8473. doi: 10.1038/s41598-024-57900-7.

ABSTRACT

Nearly half of the deaths among hospitalized human immuno deficiency virus-infected patients in the highly active antiretroviral therapy era have been attributed to liver disease. This may range from an asymptomatic mild increase of liver enzymes to cirrhosis and liver failure. Different works of literature elucidated both retroviral infection and the adverse effects of highly active antiretroviral therapy as a cause of hepatotoxicity. Individual adaptations to medications and environmental exposures, shaped by cultural norms and genetic predispositions, could potentially modulate the risk and progression of liver disease in this population. Therefore, this study aims to assess the predictors of severe hepatotoxicity in retroviral-infected adults receiving highly active antiretroviral therapy regimens within the Ilubabor Zone, Southwest Ethiopia. A facility-based cross-sectional study was conducted among adult retroviral-infected patients in five selected anti-retro virus therapy clinics from May1 to July 30/2022. A systematic sampling technique was used to select 457 study participants and Binary logistic regression statistical data analysis was used, P value < 0.05 was considered statistically significant. The prevalence of severe hepatotoxicity was 21.44% in the study population. CD+4 count < 200 cells/mm3 (AOR = 2.19, 95% CI 1.04-5.22, P = 0.01), human immunodeficiency virus co-infection with tuberculosis (AOR = 2.82, 95% CI 1.01-8.29, P = 0.03) and human immuno deficiency virus co-infection with hepatitis-B/hepatitis C virus (AOR = 5.02, 95% CI 1.82-16.41) were predictors of severe hepatotoxicity. The magnitude of severe hepatotoxicity was high among adult retroviral-infected patients on highly active anti-retroviral drug regimens. Co-infection of human immuno deficiency virus with hepatitis B virus or hepatitis C virus, tuberculosis and CD4+T-cell count below 200 cells/mm3 were predictors of severe hepatotoxicity. Therefore, HIV patients on highly active antiretroviral therapy require close attention and regular monitoring of their liver function.

PMID:38605149 | PMC:PMC11009247 | DOI:10.1038/s41598-024-57900-7

Epilepsy Res. 2024 Apr 3;202:107358. doi: 10.1016/j.eplepsyres.2024.107358. Online ahead of print.

ABSTRACT

BACKGROUND: Nonadherence to antiepileptic drugs (AEDs) is a prevalent issue in India, contributing to suboptimal seizure control, higher morbidity and mortality, increased hospitalization rates, and a substantial effect on the overall quality of life for individuals with epilepsy.

OBJECTIVES: This study aimed to measure the prevalence of medication adherence among individuals with epilepsy in India and to identify factors associated with nonadherence.

METHODS: Following PRISMA guidelines, we searched PubMed, Scopus, Embase, and Google Scholar for studies on AED adherence in India. Quality assessment employed Newcastle Ottawa Scale adapted for cross-sectional studies. Pooled prevalence was ascertained using a random-effects model in R software (version 4.2.2), with a 95% confidence interval. Heterogeneity was estimated with the I2 statistic, and publication bias was appraised via a funnel plot. Subgroup analyses, based on study region and adherence measurement tool, were done to investigate heterogeneity.

RESULTS: Nine cross-sectional studies with 1772 participants were analyzed. The pooled prevalence of adherence to AEDs in India stood at 49.9% (95% CI: 39.8%-60.1%). Subgroup analyses showed comparable adherence rates in the South (50.9%) and North (46.5%) regions of India. However, adherence rates varied substantially based on the measurement tool: Morisky Medication Adherence Scale-4 (MMAS-4) reported 71.3%, MMAS-8 indicated 45.9%, and Morisky Green Levine (MGL) adherence scale exhibited 42.0%. Factors contributing to non-adherence to antiepileptic therapies involved poor socioeconomic status, lower education levels, polytherapy, drug-related side effects, and substance abuse.

CONCLUSIONS: Almost half of persons with epilepsy in India were non-adherent to their AEDs. This underscores the importance for healthcare professionals to pay greater attention to improving the adherence rate to AEDs within the healthcare service.

PMID:38603915 | DOI:10.1016/j.eplepsyres.2024.107358

Proc ACM Int Conf Inf Knowl Manag. 2023 Oct;2023:4724-4730. doi: 10.1145/3583780.3615490. Epub 2023 Oct 21.

ABSTRACT

Predicting adverse drug reactions (ADRs) of drugs is one of the most critical steps in drug development. By pre-estimating the adverse reactions, researchers and drug development companies can greatly prevent the potential ADR risks and tragedies. However, the current ADR prediction methods suffer from several limitations. First, the prediction results are based on pure drug-related information, which makes them impossible to be directly applied for the personalized ADR prediction task. The lack of personalization of models also makes rare adverse events hard to be predicted. Therefore, it is of great interest to develop a new personalized ADR prediction method by introducing additional sources, e.g., patient health records. However, few methods have tried to use additional sources. In the meantime, the variety of different source formats and structures makes this task more challenging. To address the above challenges, we propose a novel personalized multi-sourced-based drug adverse reaction prediction model named pADR. pADR first works on every single source to transform them into proper representations. Next, a hierarchical multi-sourced Transformer is designed to automatically model the interactions between different sources and fuse them together for the final adverse event prediction. Experimental results on a new multi-sourced ADR prediction dataset show that PADR outperforms state-of-the-art drug-based baselines. Moreover, the case and ablation studies also illustrate the effectiveness of our proposed fusion strategies and the reasonableness of each module design.

PMID:38601743 | PMC:PMC11005853 | DOI:10.1145/3583780.3615490

Can J Hosp Pharm. 2024 Apr 10;77(2):e3491. doi: 10.4212/cjhp.3491. eCollection 2024.

ABSTRACT

BACKGROUND: Expansion of the scope of pharmacists' activities in hospital is associated with reductions in adverse events and drug-related readmissions. However, the breadth of hospital pharmacists' clinical activities varies widely across Ontario due to provisions in the provincial Public Hospitals Act. Few data exist defining expanded scope in institutions across Ontario.

OBJECTIVES: The primary objective was to describe the scope of practice of hospital pharmacists in Ontario who were undertaking expanded clinical activities based on policies or medical directives. The secondary objectives included determining benefits, limitations, facilitators, and barriers associated with implementing these activities.

METHODS: A survey was sent to the pharmacy leadership of Groups A and B public hospitals across Ontario. The survey contained quantitative and qualitative questions focused on 3 domains of expanded-scope activities: adaptation, discontinuation, and renewal of medication orders; prescriptive authority; and drug monitoring.

RESULTS: Of 56 hospitals invited, 46 (82%) submitted a survey response, with 1 exclusion (due to no response on some mandatory questions). The most common expanded-scope activity was independent performance of therapeutic drug monitoring (71%, 32/45). Pharmacists had the authority to independently adapt, discontinue, or renew inpatient medication orders in 60% (27/45) of hospitals, and could independently initiate medication orders in 20% (9/45). Barriers to implementing expanded-scope activities included limited time and staffing. Facilitators included proactive leadership, demonstrated clinical value, and strong rapport with other health care providers.

CONCLUSIONS: Many institutions in Ontario have established polices to expand pharmacists' clinical activities, but there is a great deal of variability in scope of practice. Advocacy at the provincial level to unify scope of practice will help to optimize patient outcomes.

PMID:38601132 | PMC:PMC10984262 | DOI:10.4212/cjhp.3491

Glomerular Dis. 2024 Mar 14;4(1):64-73. doi: 10.1159/000538255. eCollection 2024 Jan-Dec.

ABSTRACT

INTRODUCTION: Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end-stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD.

METHODS: We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs.

RESULTS: A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs.

DISCUSSION/CONCLUSION: Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.

PMID:38600955 | PMC:PMC11006409 | DOI:10.1159/000538255

Clin Cancer Res. 2024 Apr 15;30(8):1685-1695. doi: 10.1158/1078-0432.CCR-23-0914.

ABSTRACT

PURPOSE: Combination therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in a real-world setting.

EXPERIMENTAL DESIGN: We provide here a proof-of-concept study using 15 million patient records from the FDA Adverse Event Reporting System (FAERS). Complex adverse event frequencies of drugs or their combinations were visualized as heat maps onto a two-dimensional grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heat maps. In addition, statistical synergy analyses were performed on the basis of BLISS independence or χ2 testing.

RESULTS: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug-associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically.

CONCLUSIONS: Our study provides a framework for analyzing adverse events and suggests that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice.

PMID:38597991 | PMC:PMC11016889 | DOI:10.1158/1078-0432.CCR-23-0914

JAMA Netw Open. 2024 Apr 1;7(4):e245960. doi: 10.1001/jamanetworkopen.2024.5960.

ABSTRACT

IMPORTANCE: Psilocybin has been studied in the treatment of depression and anxiety disorders. Clinical studies have mainly focused on efficacy, with systematic reviews showing favorable efficacy; however, none have primarily focused on psilocybin safety.

OBJECTIVE: To evaluate the acute adverse effects of psilocybin at therapeutic doses in the treatment of depression and anxiety.

DATA SOURCES: MEDLINE via PubMed, Web of Science, and ClinicalTrials.gov were searched for publications available between 1966 and November 30, 2023.

STUDY SELECTION: Randomized, double-blind clinical trials that reported adverse effects of psilocybin in patients treated for depression and anxiety were screened.

DATA EXTRACTION AND SYNTHESIS: Data were independently extracted by 2 authors and verified by 2 additional authors following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. The inverse variance method with the Hartung-Knapp adjustment for the random-effects model was used, with a continuity correction of 0.5 for studies with 0 cell frequencies. Sensitivity analysis was conducted by sequentially removing 1 study at a time to assess the robustness of the results.

MAIN OUTCOMES AND MEASURES: The primary outcome was considered as the adverse effects of psilocybin at high and moderate (ie, therapeutic) dose regimens and compared with placebo, low-dose psilocybin, or other comparator in the treatment of depression and/or anxiety.

RESULTS: Six studies met the inclusion criteria with a total sample of 528 participants (approximately 51% female; median age 39.8 years; IQR, 39.8-41.2). Seven adverse effects were reported in multiple studies and included in the analysis. Among these, headache (relative risk [RR], 1.99; 95% CI 1.06-3.74), nausea (RR, 8.85; 95% CI, 5.68-13.79), anxiety (RR, 2.27; 95% CI, 1.11-4.64), dizziness (RR, 5.81; 95% CI, 1.02-33.03), and elevated blood pressure (RR, 2.29; 95% CI, 1.15- 4.53) were statistically significant. Psilocybin use was not associated with risk of paranoia and transient thought disorder.

CONCLUSIONS AND RELEVANCE: In this meta-analysis, the acute adverse effect profile of therapeutic single-dose psilocybin appeared to be tolerable and resolved within 48 hours. However, future studies need to more actively evaluate the appropriate management of adverse effects.

PMID:38598236 | DOI:10.1001/jamanetworkopen.2024.5960

Eur J Cancer. 2024 Mar 30;203:114039. doi: 10.1016/j.ejca.2024.114039. Online ahead of print.

ABSTRACT

BACKGROUND: cemiplimab is an immunoglobulin G4 monoclonal antibody targeting the programmed cell death-1 receptor. A nominal use program is available in Italy in advanced cervical cancer (CC) patients treated with platinum based chemotherapy based on the results of EMPOWER-Cervical 1/GOG-3016/ENGOTcx9 trial. This real-world, retrospective cohort, multicenter study aimed at describing clinical outcomes of patients with advanced CC treated with cemiplimab in Italy.

METHODS: The primary objective of the study was to assess the feasibility and the replicability of the initial results in a real world setting of cemiplimab nominal use. The primary endpoint of our analysis was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and safety data.

RESULTS: From March 2022 to December 2023, 135 patients were treated in 12 Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) Centers. Forty-two percent of patients had one or more comorbidities, hypertension being the most common (23.4%). Median PFS was 4.0 months (range 3.0-6.0) and median OS was 12.0 months (12.0- NR) with no differences according to PD-L1 status. Complete response (CR) or no evidence of disease (NED) were observed in 8.6%; partial response (PR) in 21.1%, stable disease (SD) in 14.8% and progression was recorded in 44.5% of patients. Most common drug related adverse events (AEs) were anemia (39.1%) and fatigue (27.8%). Immune related AEs occurred in 18.0%.

CONCLUSIONS: This study confirms the feasibility and the replicability of the cemiplimab nominal use in advanced CC, in a real-world practice in Italy.

PMID:38598922 | DOI:10.1016/j.ejca.2024.114039

Trials. 2024 Apr 10;25(1):250. doi: 10.1186/s13063-024-08093-x.

ABSTRACT

BACKGROUND: Acute type A aortic dissection (aTAAD) is a critical and life-threatening condition. Previous research has demonstrated that the use of ketorolac not only reduces the progression, incidence, and severity of aortic aneurysms in animal models, but also decreases postoperative mortality and complications in patients undergoing open abdominal aortic aneurysm replacement. However, there is a lack of studies investigating the efficacy of ketorolac in treating aTAAD in humans. Therefore, we conducted a study to evaluate the safety and efficacy of ketorolac in patients with aTAAD. Our hypothesis was that ketorolac treatment for aTAAD patients would meet safety indicators and effectively improve patient prognosis.

METHODS/DESIGN: This study is a single-center, randomized, double-blinded, and placebo-controlled study. A total of 120 patients with aTAAD will be recruited and will be randomized into the ketorolac group and placebo group with a ratio of 1:1. Ketorolac tromethamine 60 mg per 2 ml will be intramuscularly injected within 2 h before surgery, followed by intramuscular injections of 30 mg per 1 ml BID. on the first and second postoperative days in the Ketorolac group, while 0.9% saline will be administered at the same dose, dosage form, and time in the placebo group. This study aims to evaluate the safety and efficacy of ketorolac in improving the prognosis of aTAAD. The primary endpoint is the composite endpoint event concerning drug-related adverse events. Secondary endpoints include drug-related adverse events, laboratory examination of blood, diagnostic imaging tests, clinical biomarkers, etc. DISCUSSION: This study has been approved by the Medical Ethics Committee of Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College (approval number: 2023-197-02). This study is designed to evaluate the safety and efficacy of ketorolac in patients with aTAAD. All participating patients will sign an informed consent form, and the trial results will be published in international peer-reviewed journals.

TRIAL REGISTRATION: The Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) ChiCTR2300074394. Registered on 4 October 2023.

PMID:38600561 | DOI:10.1186/s13063-024-08093-x

Int J Surg. 2024 Apr 10. doi: 10.1097/JS9.0000000000001397. Online ahead of print.

ABSTRACT

BACKGROUND: Thermal ablation is routinely used for solitary colorectal liver metastases (SCLM), but the added value of adjuvant systemic therapy in SCLM remains unclear. This study aimed to compare the long-term outcomes for SCLM treated by ablation alone (AB) versus ablation plus systemic therapy (AS).

METHODS: This multicenter retrospective study using nationwide data from fourteen institutions between October 2010 and May 2023, 369 patients with initial SCLM smaller than 5 cm, no extrahepatic metastases, and colorectal cancer R0 resection treated by thermal ablation were included. The crude analysis was used to analyze eligible cases between the two groups. The propensity score matching (PSM) to control for potential confounders in each matched group. Subgroup analyses were performed to identify specific survival benefits.

RESULTS: 61.2% (226/369) of eligible patients were treated with AS and 38.8% (143/369) with AB. During the median follow-up period of 8.8 years, 1-/3-/5-year DFS/OS rates did not differ between the two groups, when analyzed via PSM (P=0.52/0.08). Subgroup analysis revealed that AS was significantly associated with better OS than AB in patients with plasma CEA >5 ug/L (P=0.036), T (III-IV) category of primary cancer (P=0.034), or clinical risk score (1-2) (P=0.041). In each matched group, we did find a significant difference in drug-related adverse events (P<0.001) between AS group (24.1%, 28/116) and AB group (0.0%, 0/116).

CONCLUSIONS: For patients with plasma CEA >5 ug/L, T (III-IV) category of primary cancer, or clinical risk score (1-2), thermal ablation plus systemic therapy appeared to be associated with improved overall survival. Thermal ablation was equally effective in disease-free survival for treating solitary colorectal liver metastasis, whether with or without adjuvant systemic therapy.

PMID:38597399 | DOI:10.1097/JS9.0000000000001397

J Investig Med. 2024 Apr 10:10815589241247796. doi: 10.1177/10815589241247796. Online ahead of print.

ABSTRACT

Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both SSRI antidepressants, inhibit the NLRP3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and the incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs (VA) healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by ICD-9-CM or ICD-10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR=0.62, 95% CI=(0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.

PMID:38597272 | DOI:10.1177/10815589241247796

J Pediatr Pharmacol Ther. 2024 Apr;29(2):119-129. doi: 10.5863/1551-6776-29.2.119. Epub 2024 Apr 8.

ABSTRACT

OBJECTIVE: Care coordination for children and youth with special health care needs and medical complexity (CYSHCN-CMC), especially medication management, is difficult for providers, parents/caregivers, and -patients. This report describes the creation of a clinical pharmacotherapy practice in a pediatric long-term care facility (pLTCF), application of standard operating procedures to guide comprehensive medication management (CMM), and establishment of a collaborative practice agreement (CPA) to guide drug therapy.

METHODS: In a prospective case series, 102 patients characterized as CYSHCN-CMC were included in this pLTCF quality improvement project during a 9-month period.

RESULTS: Pharmacists identified, prevented, or resolved 1355 drug therapy problems (DTP) with an average of 13 interventions per patient. The patients averaged 9.5 complex chronic medical conditions with a -median length of stay of 2815 days (7.7 years). The most common medications discontinued due to pharmacist assessment and recommendation included diphenhydramine, albuterol, sodium phosphate enema, ipratropium, and metoclopramide. The average number of medications per patient was reduced from 23 to 20. A pharmacoeconomic analysis of 244 of the interventions revealed a monthly direct cost savings of $44,304 ($434 per patient per month) and monthly cost avoidance of $48,835 ($479 per patient per month). Twenty-eight ED visits/admissions and 61 clinic and urgent care visits were avoided. Hospital -readmissions were reduced by 44%. Pharmacist recommendations had a 98% acceptance rate.

CONCLUSIONS: Use of a CPA to conduct CMM in CYSHCN-CMC decreased medication burden, resolved, and prevented adverse events, reduced health care-related costs, reduced hospital readmissions and was well-accepted and implemented collaboratively with pLTCF providers.

PMID:38596413 | PMC:PMC11001202 | DOI:10.5863/1551-6776-29.2.119

Cureus. 2024 Mar 9;16(3):e55865. doi: 10.7759/cureus.55865. eCollection 2024 Mar.

ABSTRACT

Clozapine has become a widely popular and effective medication in the treatment of refractory schizophrenia and refractory bipolar disorder. Although the use of clozapine proves to be an effective resort, it has to be closely monitored due to its narrow therapeutic range and multiple dangerous adverse effects. In rare cases, clozapine has been known to cause an antagonistic myoclonic jerk that leads to knee buckling. Here, we present the case of a 29-year-old female who is being treated for schizoaffective disorder, bipolar, manic type, who reported two instances of knee buckling associated with falls while taking clozapine.

PMID:38595866 | PMC:PMC11002468 | DOI:10.7759/cureus.55865