Citations

Abstract Diffuse large B-cell lymphoma (DLBCL) poses a challenge in hematology given its varied symptoms, and the complex interplay between disease and treatment effects on health-related quality of life (HRQoL). The phase 3 POLARIX study demonstrated superior progression-free survival and a similar safety profile with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously untreated DLBCL. Here, we evaluate HRQoL through patient-reported outcome (PRO) instruments to fully characterize the patient experience in the POLARIX study. Changes from baseline in HRQoL, lymphoma symptoms, and gastrointestinal (GI) symptoms were assessed, as well as incidence and severity of common symptoms by PROs vs clinician-reported adverse events (AEs). Baseline characteristics of PRO-evaluable patients (N = 874) were consistent. Comparison between PROs and clinician-reported AEs revealed a notable discordance; patients generally reported a higher incidence of symptoms than clinicians, emphasizing the need for patient-centric tools to accurately capture the patient experience. Both treatments exhibited rapid and sustained improvements in HRQoL and lymphoma symptoms, with the most substantial improvements seen in global health status/QoL, lymphoma symptoms, fatigue, role, emotional, and social functioning. GI symptoms (diarrhea, constipation, nausea, and vomiting) were generally similar between treatment arms and returned to baseline levels after treatment completion. These HRQoL data underscore the complementarity of PROs, as an adjunct to clinician-reported AEs, in evaluating the efficacy and tolerability of new treatments, including Pola-R-CHP, which may represent a new benchmark for patient-reported HRQoL in previously untreated DLBCL. This trial was registered at www.clinicaltrials.gov as NCT03274492.

Abstract Introduction The lower urinary tract injury, although often not life-threatening, can result in devastating long-term morbidity and, in some cases, permanent disability. Male genital trauma adversely affects male sexual function. Aim This 5th International Consultation on Sexual Medicine guideline on male genitalia trauma evaluates urologic trauma literature to guide clinicians in the best-evidenced management with specific emphasis on preservation and optimization of male sexual function. Methods A systematic literature search was conducted to identify relevant English-language publications and contemporary guidelines using the PubMed database (search dates January 1, 1990 to June 1, 2024) on the following terms: “trauma,” “penis,” “urethra,” “testis,” and “scrotum.” The available literature was discussed, and selected articles with the highest evidence available were used to create consensus guideline statements, categorized based on the Grading of Recommendations Assessment, Development and Evaluation system. In the absence of sufficient evidence, additional information was provided as a Clinical Principle or Expert Opinion. Results Fourteen recommendations are provided with corresponding levels of evidence and grades of recommendation. Conclusions Treating clinicians should be mindful that both the male genitalia trauma itself and treatment outcomes invariably affect various male sexual functions. Optimal treatment of male genitalia trauma is essential and should incorporate patient tolerances, needs, and preferences to minimize long-term sexual dysfunction.

Abstract Background Completing adjuvant chemotherapy and reducing toxicities are critical for maximizing survival after a colon cancer diagnosis. Sex, as a biological variable, may affect colon cancer chemotherapy completion, toxicities, and survival differently. Methods From a National Cancer Institute–sponsored trial conducted among patients with stage III colon cancer (Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702), we included 2201 patients receiving the standard adjuvant chemotherapy regimen of fluorouracil, leucovorin, and oxaliplatin. We calculated relative dose intensity to indicate chemotherapy completion and considered reduced relative dose intensity (values <85%) as a clinically significant deviation from standard fluorouracil, leucovorin, and oxaliplatin. Using National Cancer Institute’s Common Terminology Criteria for Adverse Events, we defined severe adverse events (grade ≥3) as the occurrence of any following event, including neutrophil count decrease, nausea, platelet count decrease, hypertension, peripheral neuropathy, diarrhea, fatigue, gastritis, creatinine level increase, gastric ulcer, myocardial ischemia, and cerebral ischemia. The primary survival outcome was disease-free survival (time from enrollment to colon cancer recurrence or death from any cause), and secondary survival outcomes were recurrence-free and overall survival. Results Compared with men, women were at statistically significantly higher risks of experiencing reduced relative dose intensity (adjusted odds ratio = 1.59, 95% CI = 1.29 to 1.96; P < .001) and severe advance events (adjusted odds ratio = 1.72, 95% CI = 1.41 to 2.11; P < .001). Yet, women had statistically significantly better disease-free survival (adjusted hazard ratio = 0.72, 95% CI = 0.59 to 0.87; P < .001) as well as better recurrence-free and overall survival. Conclusions Our findings suggested that women with colon cancer are more likely to have worse chemotherapy completion rates and more severe adverse events, but they have better survival. Sex as a biological variable warrants further consideration in chemotherapy administration and survivorship management after colon cancer diagnosis.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

BACKGROUND AND OBJECTIVES: The therapeutic approach for small- and medium-sized vestibular schwannoma (VS) with normal hearing function remains controversial, with limited comparative data regarding hearing outcomes after stereotactic radiosurgery (SRS) or observation (OBS). We evaluated the serviceable hearing preservation, loss of American Academy of Otolaryngology-Head and Neck Surgery class A hearing, and tumor control (TC) across individuals with Koos grade I and II VSs and normal hearing at presentation who underwent SRS or OBS. METHODS: In this multicenter international study, we retrospectively analyzed the hearing, radiological, and neurological outcomes of patients who underwent SRS (SRS group) or OBS (OBS group). The cohorts were matched using propensity scores based on age, sex, tumor volume, pure-tone average, and speech discrimination score at a 1:1 ratio without replacement. RESULTS: After matching, each group comprised 57 patients. The median follow-up was 49 and 37 months for the SRS and the OBS groups, respectively ( P = .3). The 5- and 9-year serviceable hearing preservation rates in the SRS group were 76.2% and 42.4% vs 56.1% and 16.8% in the OBS group ( P = .17). Class A preservation occurred in 57.9% (33/57) of the SRS and 52.6% (30/57) of the OBS cohorts ( P = .70). Regarding the TC rates, SRS was associated with significantly higher TC rates ( P < .0001). CONCLUSION: We found that SRS is significantly superior regarding TC and provided noninferior hearing outcomes compared with OBS in VS patients with American Academy of Otolaryngology-Head and Neck Surgery class A hearing at presentation. Therefore, we suggest performing SRS in individuals with VS and normal hearing function.

Importance Cardiovascular (CV) disease is the leading cause of death globally for both men and women, yet women remain historically underrepresented in CV clinical trials, despite facing a disproportionately high burden of morbidity and mortality in many forms of CV disease. Objective To determine the representation of women across a broad range of CV trials. Evidence Review The participation of women in CV trials registered on ClinicalTrials.gov from 2017 to 2023 was systematically determined through the extraction of publicly available information. Data were extracted to identify the country of study, disease type, trial size, clinical intervention, and age of the participants. The proportion of women and the ratio of number of female to male participants (F:M ratio) were calculated for each trial. The women’s participation:prevalence ratio (PPR) was estimated for each trial based on the relative prevalence of the disease by sex in the specified region. Findings A total of 1079 registered CV trials were identified, including 1 396 104 participants, of whom 571 641 (41.0%) were women. The F:M ratio was significantly lower for studies on arrhythmia (median [IQR], 0.5), coronary heart disease (median [IQR], 0.39 [0.33-0.70]), acute coronary syndrome (median [IQR], 0.32 [0.24-0.51]), and heart failure (median [IQR], 0.51 [0.32-0.87]) but higher for obesity (median [IQR], 1.44 [1.08-4.50]) and pulmonary hypertension (median [IQR], 2.86 [1.50-3.97]) trials. The F:M ratio was higher for trials on lifestyle interventions (median [IQR], 1.51 [0.77-3.24]) than for drug trials. PPRs were low for clinical trials on coronary heart disease (median [IQR], 0.66 [0.50-0.86]), acute coronary syndrome (median [IQR], 0.79 [0.51-0.87]), and stroke (median [IQR], 0.74 [0.61-0.95]). Representation of women in CV trials varied by disease state, region, intervention, and sponsor type. Conclusions and Relevance These findings highlight both progress and persistent challenges in representation of women within CV trials. These gaps not only limit the generalizability of trial outcomes but also perpetuate inequities in evidence-based care for women with CV conditions.

Abstract Background Acamprosate is an FDA-approved medication for the treatment of alcohol use disorder (AUD), however, only about 50% of patients will respond to acamprosate. Previously, we conducted an acamprosate trial (n=442), which is one of the largest acamprosate clinical studies ever conducted and currently the only study with multi-omics data. To date, no biological measures are utilized to predict response to acamprosate treatment. Aims & Objectives We set out to apply our established pharmaco-omics informed genomics strategy to identify potential biomarkers associated with acamprosate treatment response. Method Our open-label acamprosate clinical trial recruited 442 patients with AUD, all of whom were treated with acamprosate for three months. The primary outcomes were 1) relapse to alcohol use and 2) relapse to heavy drinking. Alcohol consumption was measured using the self-reported timeline follow back method. Plasma protein levels were measured using Olink proximity extension immunoassays. Results Our established “Pharmaco-Omics-informed genome-wide association study (GWAS)” research strategy identified 12 proteins, including interleukin-17 receptor B (IL17RB), that were associated with acamprosate treatment response. A GWAS for IL17RB concentrations identified several genome-wide significant signals. Specifically, the top hit single nucleotide polymorphism (SNP) rs6801605 with a minor allele frequency of 38% in the European American population mapped 4 kilobase (Kb) upstream of IL17RB, and intron 1 of the choline dehydrogenase (CHDH) gene on chromosome 3 (p: 4.8E-20). The variant genotype (AA) for the SNP rs6801605 was associated with lower IL17RB protein expression. In addition, we identified a series of genetic variants in IL17RB that were associated with acamprosate treatment outcomes. Furthermore, the variant genotypes for all of those IL17RB SNPs were protective against alcohol relapse. Finally, we demonstrated that the basal level of mRNA expression of IL17RB was inversely correlated with those of nuclear factor-κB (NF-κB) subunits, and a significantly higher expression of NF-κB subunits was observed in AUD patients who relapsed to alcohol use. Discussion & Conclusions This study illustrates that IL17RB genetic variants might contribute to acamprosate treatment outcomes. This series of studies represents an important step toward generating functional hypotheses that could be tested to gain insight into mechanisms underlying variation in acamprosate treatment response phenotypes.

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that is caused by mutations in PKD genes. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (GLP‐1RAs) are a class of medications that mimic the actions of the hormone GLP‐1, conferring beneficial effects on weight management and other metabolic conditions. However, whether GLP‐1RA plays a kidney‐protective action in ADPKD remains unknown. In this study, we define the role and mechanisms of one of the most popular GLP‐1RA agonists, Semaglutide, in ADPKD. We show that the expression of GLP‐1R is decreased in Pkd1 mutant renal epithelial cells and kidneys. Treatment with Semaglutide delays cyst growth in aggressive and long‐lasting Pkd1 mutant mouse models. Treatment with Semaglutide (1) decreases glucose uptake, ATP generation, and glycolysis, (2) deactivates PKD‐associated signaling pathways, including Rb, S6, and Stat3, resulting in a decrease in cell proliferation, (3) deactivates NF‐kB signaling pathways, resulting in a decrease in the expression of cytokines and the recruitment of macrophages, (4) normalizes mitochondrial morphology and function, (5) induces Pkd1 mutant renal epithelial cell death, (6) induces ketosis characterized by an increase in serum level of beta‐hydroxybutyrate (BHB) and the activation of AMPK, and (7) alleviates renal fibrosis through deactivation of TGF‐b signaling in Pkd1 mutant mouse kidneys. This study highlights the potential of GLP‐1R agonists as a novel therapeutic strategy for ADPKD treatment.

BACKGROUND AND OBJECTIVES: Single-session stereotactic radiosurgery (SRS) has limited role for large arteriovenous malformations (AVM). Volume-staged SRS (VS-SRS) is used to optimize outcomes, but studies reporting results are limited. METHODS: This multicenter retrospective cohort of 378 patients from 21 centers reports results of VS-SRS for the entire AVM nidus. We report favorable outcome, obliteration, hemorrhage, and permanent symptomatic adverse radiation effect rates. RESULTS: The median age was 31 years (IQR: 19-44) at the first volume stage, with patients treated in 2–4 stages. The median total nidus volume was 21 cm 3 (IQR: 13.9-30.1 cm 3 ), and a median prescription dose of 17 Gy (IQR: 16-18 Gy) was used. The median radiographic and clinical follow-up were 48 and 55 months, respectively. Seventy-seven patients (20.4%) had a favorable outcome, with the 3-year and 5-year rates being 3.9% and 18%, respectively. 127 patients (33.6%) achieved obliteration, with the 3-year and 5-year rates being 6.8% and 26%, respectively. Obliteration rates of AVMs <15 cm 3 were 81% and 31%, respectively. The latency period hemorrhage incidence rate was 3.02 cases per 100 patient-years; 52 patients (13.8%) had a bleed. Seventy-two patients (19%) had symptomatic adverse radiation effect; in 38 patients (10.1%), these were permanent. Total nidus volume, prescription dose at first stage, diffuse nidus, and prior hemorrhage were all independent affecting outcome rates. CONCLUSION: VS-SRS can be used to treat large AVMs as a standalone treatment. Obliteration rates and favorable outcomes are lower than that with smaller AVMs, and repeat treatment is often required. Optimizing treatment plans, by increasing prescription doses, reducing treatment volume at each stage, and increasing the number of stages, may lead to better outcomes.

Effective healthcare referral triage poses a significant challenge, especially extracting referral notes on time for scheduling. To offset this issue, this study aims to develop an optimized Random Forest classifier to recreate the referral notes content and identify patients requiring Spinal Cord Stimulation procedures. A performance index was introduced to improve accuracy, while a consistency index was designed to prevent overfitting. The optimized classifier, with the optimal selection at the number of estimates being 5 trees and tree depth being 4, achieved an accuracy of 0.74 with a lower standard deviation, demonstrating its reliability and effectiveness.