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PURPOSE Patients with advanced, well-differentiated extrapancreatic neuroendocrine tumors (epNETs) have limited systemic treatment options. Pazopanib, an oral multikinase inhibitor with activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, PDGFR-alpha and-beta, and c-Kit, was tested for efficacy in epNET. PATIENTS AND METHODS We conducted a multicenter, randomized, double-blind, phase II study of pazopanib (800 mg once daily) versus placebo in low- to intermediate-grade epNET with radiologic progressive disease (PD) within 12 months of study entry. Previous somatostatin analog (SSA) was required for midgut tumors, and concurrent SSA was allowed. The primary end point was progression-free survival (PFS) by blinded independent central review. Unblinding and crossover were allowed if PD was confirmed by central review. RESULTS One hundred seventy-one patients (97 pazopanib and 74 placebo) were randomly assigned between September 2013 and October 2015. The majority had a midgut primary site (75%) and previous SSA treatment (93%). About half (49%) of the patients had functional tumors. The median follow-up was 61 months (95% CI, 60 to 63). Median PFS was 11.8 versus 7.6 months in pazopanib versus placebo, respectively (hazard ratio, 0.54 [95% CI, 0.37 to 0.79]; P < .001); 49 placebo patients crossed over to pazopanib. There was no significant difference in overall survival between the treatment arms. Rates of grade 3 or greater adverse events (regardless of attribution) were higher in pazopanib versus placebo (84% v 47%; P < .001), as were grade 5 death events (8% v 0%, P = .017). CONCLUSION Pazopanib compared with placebo significantly improves PFS in patients with progressive epNET, confirming that the VEGF signaling pathway is a valid target for therapy in epNET. However, after integrating the associated risks relative to the benefits, further development of pazopanib in this clinical context is not planned.

Abstract We investigated the influence of 55 583 autophagy-related single-nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across 4 independent populations comprising 5472 CLL cases and 726 465 controls. We also examined their impact on overall survival (OS), time to first treatment (TTFT), autophagy flux, and immune responses. A meta-analysis of the 4 populations identified, to our knowledge, for the first time, significant associations between CDKN2A (rs3731204) and BCL2 (rs4940571, rs12457371, and rs1026825) SNPs and CLL risk, with CDKN2A showing the strongest association (P = 1.57 × 10−12). We also validated previously reported associations for FAS, BCL2, and BAK1 SNPs with CLL risk (P = 4.73 × 10−21 to 3.39 × 10−9). The CDKN2Ars3731204 and FASrs1926194 SNPs associated with increased CDKN2A and ACTA2 messenger RNA expression levels in the whole blood and/or lymphocytes (P = 5.1 × 10−7, P = 1.58 × 10−21, and P = 7.8 × 10−41), although no significant effect on autophagy flux was observed. However, associations were found between CDKN2A, BCL2, and FAS SNPs and various T-cell subsets, cytokine production, and circulating concentrations of interferon gamma, tumor necrosis factor–related apoptosis-inducing ligand, CD40, chemokine ligand 20, and interleukin-2 receptor subunit β proteins (P ≤ .005). No significant association was detected between autophagy variants and OS or TTFT, suggesting that these variants drive disease initiation rather than progression. In conclusion, this study identified 4 novel associations for CLL and provided insights into the biological pathways that influence CLL development.

Objective To update, synthesise and provide meta-analytical evidence of the associations between domain-specific physical activity (PA) and mental health and mental ill-health outcomes. Design Systematic review and multilevel meta-analysis. Data sources In March 2024, we systematically searched five databases. Eligibility criteria Methods employed replicated those of a previous review in 2017. All studies examining associations between domain-specific PA and specified mental health outcomes were included. Results 372 studies met inclusion criteria and 361 were included in the meta-analysis. Across the 372 studies (combined sample size of 3 323 711), 338 examined leisure-time PA, 54 work-related PA, 72 transport-related PA, 44 household PA, 5 school sport and 8 physical education. Multilevel meta-analyses showed that leisure-time PA (r=0.205, 95% CI 0.157 to 0.253), transport-related PA (r=0.138, 95% CI 0.042 to 0.231) and household PA (r=0.096, 95% CI 0.025 to 0.165) were positively associated with mental health . Leisure-time PA (r=−0.149, 95% CI −0.189 to –0.11) and school sport (r=−0.096, 95% CI −0.115 to –0.077) were inversely associated with mental ill health . However, work-related PA (r=0.134 95% CI 0.069 to 0.199) was positively associated with mental ill health . Conclusion The direction of the association between PA and mental health/mental ill health is dependent on the domain in which PA occurs. Promoting PA for leisure purposes is likely to yield the greatest benefits for both promoting mental health and preventing mental ill health. As such, leisure-time PA should be prioritised in messaging, guidelines and interventions/programmes designed to support mental health through PA. PROSPERO registration number CRD42024510303.

Importance Sleep disordered breathing (SDB) is a well-established contributor to cardiovascular morbidity, mediated by intermittent hypoxemia, autonomic dysregulation, and endothelial dysfunction. Patients with hypertrophic cardiomyopathy (HCM) may be especially at risk for SDB, but the clinical impact of SDB in this population remains unclear. Objective To define the prevalence and subtypes of SDB in HCM and examine their association with echocardiographic parameters and cardiac biomarker expression. Design, Setting, and Participants A prospective cohort study was conducted between April 18, 2018, and January 15, 2024, at a single tertiary referral center specializing in HCM care. Adults with HCM (left ventricular wall thickness ≥15 mm or pathogenic variants) were recruited from an institutional registry. Patients diagnosed with SDB or current pregnancy were excluded. Patients underwent polysomnography, with comparative assessment of echocardiographic, electrocardiographic, and biomarker indices. Observers were blinded to polysomnographic results. Data analysis was performed from April 11, 2024, to July 25, 2024. Exposures SDB classified via polysomnography using apnea-hypopnea index thresholds, with subtypes including obstructive sleep apnea and central sleep apnea and with event severity, hypoxemia, and sleep architecture disruption quantified. Main Outcomes and Measures Echocardiographic indices, cardiac biomarker expression, functional status, apnea-hypopnea index, and overnight hypoxemia. Results Among 154 patients (median [IQR] age, 60 [48-68] years; 102 [66.2%] male), 91 (59.1%) were diagnosed with SDB. Those with SDB, compared with those without SDB, had higher left ventricular mass index (median [IQR], 128 [107-161] vs 109 [96-134] g/m 2 ; P = .03), E/e′ ratio (median [IQR], 12.5 [10.0-15.0] vs 10.0 [8.3-14.5]; P = .04), and baseline troponin-T level (median [IQR], 0.013 [0.009-0.022] vs 0.011 [0.007-0.015] ng/mL [to convert to micrograms per liter, multiply by 1]; P = .04) and greater overnight troponin-T level increases (change in median [IQR], 0.0021 [−0.0029 to 0.0062] vs 0.0002 [−0.0022 to 0.0026] ng/mL; P = .02). New York Heart Association class II or III symptoms were more common in those with SDB (48 [52.7%] vs 17 [27.0%]; P = .005). Hypertension and diabetes were more prevalent among patients with SDB than without SDB (hypertension: 67 [73.6%] vs 36 [57.1%]; P = .03; diabetes: 14 [15.4%] vs 3 [4.8%]; P = .04), whereas rates of atrial fibrillation and prior myectomy did not differ significantly between groups. Conclusions and Relevance This study suggests that undiagnosed SDB is highly prevalent in patients with HCM and that SDB is associated with adverse myocardial remodeling, greater diastolic dysfunction, and elevated troponin-T levels, indicating subclinical myocardial injury. SDB may contribute to HCM pathophysiology and symptom burden, supporting the rationale for randomized clinical trials to determine the impact of treating SDB on symptoms and clinical outcomes in patients with HCM.

A man in his mid-30s with a history of Crohn disease presented with several years of intermittent, nonexertional chest pressure. What would you do next?

Background: Glucagon-like peptide-1 receptor agonists (GLP-1) are approved for type 2 diabetes treatment. Given the link between diabetes-associated metabolic inflammation and increased carpal tunnel syndrome (CTS) risk, the aim of this study was to investigate development of CTS in diabetic patients who both were and were not taking GLP-1 therapy using a large claims database. Methods: A retrospective cohort study used a national claims database to identify diabetic patients. Those prescribed GLP-1 therapy were matched to controls by age, sex, comorbidity index, tobacco use, and obesity. Multivariable logistic regression evaluated the 2-year CTS incidence, controlling for various health conditions and socioeconomic factors. Secondary analysis also evaluated the rate of carpal tunnel release (CTR) after being diagnosed with CTS. Results: Glucagon-like peptide-1 therapy significantly reduced 2-year CTS diagnosis risk (odds ratio [OR] 0.49; 95% confidence interval [CI] 0.46-0.52; P < .001). Independent risk factors for increased CTS incidence included chronic obstructive pulmonary disease, osteoarthritis, coronary artery disease, depression, hypothyroidism, and rheumatoid arthritis (RA). Of patients who developed CTS, GLP-1 therapy was associated with increased odds of undergoing CTR (OR 1.23; 95% CI: 1.08-1.41; P = .002). Conclusions: Glucagon-like peptide-1 therapy is associated with decreased CTS risk in diabetic patients—potentially due to improved metabolic health—and increased odds of undergoing CTR once diagnosed. Further research is needed to clarify GLP-1 therapy’s role in reducing nervous system and musculoskeletal disease burden.

ABSTRACT Anaplastic lymphoma kinase‐positive large B‐cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of diffuse large B‐cell lymphoma with poor outcomes using standard chemotherapy. In this multi‐institutional retrospective study, we analyzed 39 cases of ALK+ LBCL identified at six US academic centers from 2002 to 2024, with treatment including conventional cytotoxic regimens in frontline and biologically informed and nonchemotherapy‐based strategies in the relapsed setting. Ninety‐two percent of patients received frontline anthracycline‐based chemotherapy; 43% received intensified regimens, and 15% underwent upfront autologous stem cell transplantation (ASCT). Despite these approaches, outcomes remained poor. At a median follow‐up of 5.4 years, median event‐free survival (EFS) was 0.6 years (95% CI, 0.4–0.9), and median overall survival (OS) was 1.5 years (95% CI, 1.3–NR). One‐ and five‐year EFS rates were 28% and 17%, while corresponding OS rates were 72% and 42%, respectively. Advanced stage and high IPI scores were associated with inferior outcomes. Twelve patients received ALK inhibitors, with alectinib showing more durable responses than crizotinib. Lenalidomide and immune checkpoint inhibitors also demonstrated activity, including durable complete responses. Five patients underwent allogeneic stem cell transplantation, with three achieving sustained remission. In conclusion, our findings highlight the limited benefit of chemotherapy, even when intensified or followed by ASCT, and support the integration of biologically targeted therapies, which may have contributed to improved OS in our cohort compared to historical outcomes. Prospective, collaborative studies are needed to better understand disease biology and define optimal use of modern therapies in this rare lymphoma.