Citations

The objective of this study was to compare drug response of uveal melanoma patient-derived cell lines (PDLs) and patient-derived organoids (PDOs) with response of commercially available cell lines and contextualize laboratory outputs in terms of clinical trial results. Uveal melanoma commercial cell lines, PDLs, and PDOs were treated with drugs that were ultimately utilized in clinical trials. Four treatments were chosen for promising laboratory results that failed to yield clinical response, while darovasertib was a surrogate positive control given initial favorable clinical trial data in the neoadjuvant setting. Drug concentrations were matched to laboratory work that supported progression to clinical trials. Viability was measured using PrestoBlueHS Cell Viability Reagent. Commercial cell lines showed promising viability reduction similar to prior laboratory results with treatments, including 5-μM darovasertib, 700-nM selumetinib, 700-nM selumetinib + 1000-nM MK-2206, 500-nM sotrastaurin + 1000-nM alpelisib, and 100-nM trametinib, with overall viability reduced to 32.5% for all drugs. However, PDLs (viability 52.8%) and PDOs (viability 80.4%) showed more treatment resistance ( P < 0.05), better simulating ultimate lack of efficacy found in clinical trials. While uveal melanoma with BAP1 loss demonstrated greater treatment resistance under some conditions, other factors such as cell morphology or culture in a three-dimensional environment appeared to be more consistent drivers of therapeutic sensitivity. PDLs and PDOs may more accurately represent uveal melanoma clinical response. Demonstrating efficacy of novel therapeutics in these models could improve the likelihood of successful translation for future clinical trials, but future studies are needed to define clinically meaningful in-vitro response thresholds.

Summary Renal response (RenR) in light‐chain (AL) amyloidosis is associated with a lower risk of end‐stage kidney disease and improved survival. However, substantial variation exists in the time to and depth of RenR. We investigated variables associated with RenR in a retrospective study of newly diagnosed AL amyloidosis patients ( n = 350) assessable for RenR between 2010 and 2022. RenRs were recorded at 6, 12 and 24 months and best response. Deep RenR was defined as a ≥renal very good partial response (RenVGPR, >60% reduction in 24‐h proteinuria or ≤200 mg). Logistic regression and competing risk methods were used to examine variables associated with RenR. The median age was 64 years, and median follow‐up was 5.5 years. On multivariable logistic regression, obtaining ≥HemVGPR within 6 months, kappa isotype, high baseline difference between involved and uninvolved free light chains (dFLC ≥40 mg/dL), renal stage and autologous haematopoietic stem cell transplant (AHSCT) were significantly associated with deep RenR. Cumulative incidence rates for deep RenR, treating death or renal progression as a competing event, demonstrated that early HemR, first‐line AHSCT, lower renal stage and dFLC ≥40 mg/dL significantly increased the likelihood of deep RenR. Specific clonal plasma cell features, namely light‐chain isotype and baseline dFLC levels, independently influence the timing and depth of RenRs in AL amyloidosis following treatment, in addition to renal stage and HemR.

Abstract Objective To evaluate whether postoperative intracranial pressure–lowering interventions reduce recurrence of lateral skull base spontaneous cerebrospinal fluid leaks after surgical repair. Data Sources Ovid MEDLINE, Embase, Cochrane CENTRAL, Web of Science Core Collection, and Scopus were searched from inception through April 7, 2025. Review Methods The review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines and included studies of adults with lateral skull base spontaneous cerebrospinal fluid leaks undergoing primary repair where postoperative intracranial pressure–lowering interventions were specified. Pooled recurrence rates were calculated by intervention type and compared with cohorts that did not receive intracranial pressure–lowering therapy. Results Thirty‐six studies including 687 patients (737 cases) met inclusion criteria. Six comparative cohorts (34 treated, 155 untreated) showed no significant difference in recurrence (risk ratio 1.16, 95% confidence interval [CI]: 0.14–9.76; I 2 = 0%). Across 82 intervention‐only cases, recurrence occurred in three (pooled proportion 0.10, 95% CI: 0.04–0.26; I 2 = 0%). Among 650 control‐only cases, 45 recurred (pooled proportion 0.09, 95% CI: 0.07–0.12; I 2 = 0%). No heterogeneity was observed across pooled analyses. Conclusion Available evidence does not support universal postoperative intracranial pressure–lowering therapy after lateral skull base spontaneous cerebrospinal fluid leak repair. Limited observational data suggest acetazolamide may be associated with lower recurrence, whereas lumbar drainage has not demonstrated sustained benefit. Given the heterogeneity in patient selection and intervention practices, postoperative management should be individualized. Future prospective studies are needed to better define the role of targeted therapy in high‐risk patients.

Abstract Aims SCN5A-E1784K (c.5350G&gt;A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

Abstract Context Prior reports of plasma estradiol concentrations and their reference ranges in postmenopausal women identified marked variation, in part due to assay method and body mass index (BMI). Objective To develop an international reference range for plasma estradiol in postmenopausal women, support accurate assessment of concentrations during systemic and local (eg, vaginal) estradiol therapy, and improve risk prediction for diseases, including osteoporosis, breast, and endometrial cancers. Methodology Estradiol concentrations were measured using primarily liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays in 5 international cohorts of community-dwelling, postmenopausal women of primarily European ancestry aged 38-100 years who were not using exogenous estrogens (n = 7206). Measurements were harmonized to the Centers for Disease Control and Prevention (CDC) reference measurement procedure (RMP) by re-assaying a subset of samples for each cohort and generating recalibration equations. Reference intervals were determined for all women, non-obese women, and specific BMI categories. Results Estradiol concentrations from separate LC-MS/MS assays correlated closely with the CDC RMP, and harmonization minimized inter-assay variability. Estradiol concentrations correlated with BMI but not with chronological age. The reference range (2.5th-97.5th percentile) was 1.1-18.2 pg/mL (4.0-66.8 pmol/L) with median of 4.9 pg/mL (18.0 pmol/L) for all postmenopausal women and 1.1-12.5 pg/mL (4.0-45.9 pmol/L) with median of 4.1 pg/mL (15.1 pmol/L) for non-obese women (BMI &lt; 30). Reference ranges increased progressively with higher BMI categories. Conclusion Cross-calibration of estradiol measurements with the CDC RP enabled the development of harmonized plasma estradiol reference ranges for postmenopausal women who were not using exogenous estrogens, suitable for future studies to establish clinical utility. Increasing obesity in postmenopausal women was associated with increasing estradiol concentration and BMI category-specific reference ranges.

Abstract Concurrent thyrotropin (TSH) secreting and growth hormone (GH) secreting pituitary adenomas are rare entities. Although tumors of the PIT-1 lineage may coexpress TSH and GH, concurrent biologically active secretion resulting in central hyperthyroidism and acromegaly is uncommon. We report the case of a 42-year-old woman presenting with weight loss, palpitations, amenorrhea, and progressive acromegalic features. Biochemical evaluation revealed central hyperthyroidism with elevated free T4 and inappropriately normal TSH, markedly elevated insulin-like growth factor 1 (IGF-1) and GH, hyperprolactinemia, and elevated α-subunit. Pituitary magnetic resonance imaging demonstrated a 2.7-cm macroadenoma with cavernous sinus extension. She underwent transsphenoidal resection without complications. Pathology confirmed a mature plurihormonal PIT-1 lineage adenoma immunopositive for TSH, GH, and prolactin with a Ki-67 of 3%. Immediately postoperatively, thyrotoxicosis and hyperprolactinemia resolved, IGF-1 levels declined, acromegalic features improved, and menses resumed. Over the ensuing months, thyroid and prolactin tests remained within normal range, but the IGF-1 level remained elevated. This case illustrates the rare presentation of a PIT-1 lineage adenoma secreting biologically active TSH, GH, and prolactin. Comprehensive hormonal evaluation and long-term biochemical and radiologic surveillance are essential, given the risk of incomplete remission despite apparent surgical cure.

Abstract Background and Aims Burnout affects millions of healthcare workers worldwide, from food service and nurses to physicians and leaders, impairing worklives and threatening health system stability. Methods An international collaborative, PREVAIL, was created to reduce burnout globally. Leaders from six continents shared structured insights into the local state of wellness and burnout contributors and mitigators, which were then subjected to a formal thematic (qualitative) analysis to identify common and region-specific themes. Results Across continents, findings showed the global state of well-being was in danger, though threats varied by region: long shifts in Africa, heavy workloads in Asia, austerity-prone environments in Europe and financially driven care in North America. Vulnerable worker groups included women, nurses, and primary care. Mitigators included workload and schedule adjustments (Africa), shift policies with fair pay (Asia), leader support and regular well-being assessments (Australia), improved psychosocial services (Europe), organizational wellness support and career development (North America), and trainee support (South America). Conclusions A proposed “common pathway” framework explains shared drivers of poor workforce well-being and provides actionable steps for promoting compassionate, supportive environments worldwide. Implications/Learning Points Adopting a coordinated international approach may prevent devastating workforce shortages over the comingdecades. Burnout assessment and reduction in the global workforce is a high priority.

Abstract Aims Alcohol and its relationship with cardiovascular disease (CVD) remain contentious. Several observational studies have found cardioprotective associations, while Mendelian randomization studies have found null or harmful effects of moderate drinking. Biases, including abstainer misclassification and sick-quitter effects, may obscure true associations. It is widely understood that former drinkers are often sick quitters. However, removal of former drinkers from analyses addresses bias in the abstainer group but fails to account for induced survivorship among current drinkers. This study sought to determine whether adjusting for biases altered the association between alcohol and CVD by comparing conventional models with those using (i) occasional drinkers as the reference group instead of lifetime abstainers and (ii) ‘intention-to-treat’ reallocation of former drinkers based on past drinking patterns. Methods and results The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of 6814 participants aged 45–84 years between 2000 and 2002 without baseline CVD. A total of 6755 participants were included after excluding those with missing data. Alcohol consumption was self-reported and classified as lifetime abstainer, former, or current drinker [occasional (≤1 drink/week), light (2–7 drinks/week), moderate (8–14 drinks/week), heavy (&gt;14 drinks/week)]. Outcomes included coronary artery calcium (CAC; 0, 1–100, 101–300, and &gt;300) and clinical events [myocardial infarction (MI), stroke, cardiovascular mortality, composite major adverse cardiovascular events (MACEs), and heart failure]. Of 6755 participants, 20.6% were lifetime abstainers, 24.1% former drinkers, and 55.3% current drinkers. Adjusting for biases altered the observed relationship between alcohol and CVD, showing increased harm with light drinking, decreased protection with moderate drinking, and a dose–response relationship between alcohol and CAC, particularly CAC &gt;300 in adjusted models. Protective associations between moderate drinking and MI [hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.38–1.06] and cardiovascular mortality (HR: 0.81, 95% CI: 0.53–1.25) were attenuated and became non-significant. Light drinking shifted from null to increased risk for MI (HR: 1.46, 95% CI: 1.11–1.92), stroke (HR: 1.54, 95% CI: 1.17–2.03), MACE (HR: 1.33, 95% CI: 1.12–1.57), and heart failure (HR: 1.42, 95% CI: 1.10–1.84). Conclusion Associations between alcohol and CVD in observational studies are sensitive to methodologic variation. Results from models correcting for abstainer/sick-quitter biases may help explain discrepant results from previous studies.

Abstract Background Glioblastoma (GBM) is driven, in part, by glioma stem cells (GSCs), which sustain therapeutic resistance and recurrence. OLIG2 is a key regulator of GSC programs but the signaling pathways that cooperate with Oligodendrocyte transcription factor 2 (OLIG2) to maintain GSC states remain incompletely defined. Although Signal transducer and activator of transcription (STAT) signaling has been implicated in GSC biology, work to date has focused primarily on STAT3, and the contribution of STAT5 remains poorly defined. Here, we investigated whether STAT5B functionally cooperates with OLIG2 in sustaining GSC phenotypes. Methods Transcriptomic analyses, proximity ligation assays and biochemical studies were utilized to define OLIG2-STAT5B interactions in patient-derived GSCs. Functional consequences of OLIG2, STAT5B, BIRC5, and NUSAP1 suppression were assessed using small interfering RNA/short hairpin RNA-knockdown, stemness, and migration assays in EGFRvIII-expressing GSCs. In vivo tumor growth studies were performed using orthotopic xenograft models. Results OLIG2 and STAT5B expression were positively correlated in GBM datasets and patient-derived models. OLIG2 physically associated with STAT5B in EGFRvIII-expressing GSCs, and loss of OLIG2 reduced STAT5 activation, supporting a functional link between these factors. OLIG2 or STAT5B suppression induced convergent transcriptional changes, including downregulation of genes associated with GSC maintenance and proliferation, notably stemness regulators BIRC5 and NUSAP1. Silencing BIRC5 or NUSAP1 impaired GSC self-renewal and migration. In orthotopic models, STAT5B knockdown prolonged survival and phenocopied OLIG2 suppression and stemness loss. Conclusions These findings identify STAT5B as a functional partner of OLIG2 in GBM and define anOLIG2-STAT5B transcriptional axis that sustains GSC maintenance and malignant behavior. Targeting this axis may represent a therapeutic strategy to disrupt treatment-refractory glioma cell states.