Citations

Abstract Introduction There is convincing evidence that overall adiposity increases the risks of several cancers. Whether the distribution of adiposity plays a similar role is unclear. Methods We used 2-sample Mendelian randomization (MR) to examine causal relationships of 5 adiposity distribution traits (abdominal subcutaneous adipose tissue (ASAT); visceral adipose tissue (VAT); gluteofemoral adipose tissue (GFAT); liver fat; and pancreas fat) with the risks of 12 obesity-related cancers (endometrial, ovarian, breast, colorectal, pancreas, multiple myeloma, liver, kidney (renal cell), thyroid, gallbladder, esophageal adenocarcinoma, and meningioma). Results Sample size across all genome-wide association studies (GWAS) ranged from 8407 to 728 896 (median: 57 249). We found evidence that higher genetically predicted ASAT increased the risks of endometrial cancer, liver cancer, and esophageal adenocarcinoma (odds ratios (OR) and 95% confidence intervals (CI) per standard deviation (SD) higher ASAT = 1.79 (1.18 to 2.71), 3.83 (1.39 to 10.53), and 2.34 (1.15 to 4.78), respectively). Conversely, we found evidence that higher genetically predicted GFAT decreased the risks of breast cancer and meningioma (ORs and 95% CIs per SD higher genetically predicted GFAT = 0.77 (0.62 to 0.97) and 0.53 (0.32 to 0.90), respectively). We also found evidence for an effect of higher genetically predicted VAT and liver fat on increased liver cancer risk (ORs and 95% CIs per SD higher genetically predicted adiposity trait = 4.29 (1.41 to 13.07) and 4.09 (2.29 to 7.28), respectively). Discussion Our analyses provide novel insights into the relationship between adiposity distribution and cancer risk. These insights highlight the potential importance of adipose tissue distribution alongside maintaining a healthy weight for cancer prevention.

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of NSCLC. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines, with a focus on systemic therapy options for the treatment of patients with nonmetastatic NSCLC and the corresponding molecular testing considerations.

Objectives: A framework of high-reliability principles was used to identify, investigate, and mitigate infusion pump safety concerns at a large, multisite health care system. We developed a systematic approach to address challenges associated with overinfusions, underinfusions, and the inability to clear upstream occlusion alarms. We identified 112,875 upstream occlusion events for 389,604 infusion starts (failure rate, 29%) within 6 months. Methods: Five high-reliability principles were applied to infusion pump management. Preoccupation with failure emphasized reporting safety concerns and performing appropriate clinical and bench tests. Deference to expertise prompted the development of a multidisciplinary team with internal and external partners. Sensitivity to operations prompted assessment of human factors design, with simulations and analysis of medication-specific factors (e.g., viscosity; infusion rates). Reluctance to simplify prompted assessment of tubing characteristics (e.g., concentricity; wall thickness) with micro–computed tomography and process development for removing faulty equipment. Practice of resilience ensured ongoing engagement and commitment to a culture of safety and patient advocacy. Results: The multidisciplinary oversight team prompted a national recall, removal of malfunctioning pumps, and development of system-wide training and mitigation protocols. Despite ongoing pump challenges, our team optimized internal patient safety systems and processes. The cause of these malfunctions remains under investigation, but serious patient harm has been prevented. Conclusions: Key strategies for enhancing patient safety were continuous vigilance, interdisciplinary collaboration, and embracing complexity in a large health care organization. Future directions involve deeply integrating these high-reliability principles across all aspects of health care delivery to continue improving safety and quality outcomes.

Abstract Home parenteral nutrition (HPN) is a life‐sustaining therapy traditionally used as a bridge to enteral autonomy or intestinal transplantation. Increasingly, it is used for intractable feeding intolerance (IFI), which can occur near the end of life (EOL) in children with severe neurological impairment (SNI). In these cases, HPN use differs from its historical role and requires tailored outpatient planning. We report a retrospective case series of four children with SNI who developed IFI and received HPN as part of their EOL care. The pediatric palliative care team (PPCT) was involved in all cases during HPN decision‐making and planning. The pediatric nutrition support team (PNST) and PPCT collaborated to provide individualized, goal‐directed care. Patients ranged from 1 to 12 years old, with HPN durations between 5 weeks and 2 years. All were enrolled in hospice while receiving HPN. Plans were made through shared decision‐making, reflecting each family's values, and included tailored approaches to laboratory monitoring, febrile episodes, line care, growth assessment, and follow‐up. HPN at EOL requires careful ethical consideration, particularly of autonomy because families often find comfort in providing nutrition. IFI is often unanticipated, and prognoses are uncertain. With the combined expertise of PNST and PPCT, HPN can be used meaningfully at EOL, supporting family values, easing suffering, and creating space for peace and connection.

Abstract Importance and Objective Pancreatic cancer can lead to severe stenosis of the portomesenteric venous (PV/SMV) confluence due to extrinsic compression or direct invasion. This can result in venous hypertension associated with post-prandial abdominal pain, gastrointestinal bleeding, and ascites. In patients with unresectable tumors, transhepatic PV/SMV stenting has been reported; however, its safety and efficacy are poorly understood. Design, Setting and Participants All unresectable pancreatic cancer patients referred to Interventional Radiology to undergo palliative transhepatic PV/SMV stenting (2011–2024) were collected. Patient demographics, CT scans, transhepatic venograms, and clinical outcomes were reviewed. Intervention, Main Outcomes and Results In total, 129 patients were included; 92% had pancreatic ductal adenocarcinoma. Tumors were unresectable due to unreconstructable vascular involvement, metastatic disease, or poor performance status. Nearly 81% were symptomatic, while the remaining 24 asymptomatic patients presented with significant venous hypertensive varices and collaterals on imaging. Complete venous occlusion was seen in 39% of patients at the PV, the SMV, or the PV/SMV confluence; 97% of procedures were successful, with 4 technical failures at obtaining distal venous wire access. Adverse events occurred in 4 patients. Radiological follow-up was available in 94% of patients. Post-procedural primary stent patency was 80% at a median follow-up time of 20 months. Follow-up was available in 102 of the 105 symptomatic patients, with 85% reporting an improvement in symptoms. Conclusions and Relevance Palliative transhepatic PV/SMV stenting is a technically feasible and safe procedure in well-selected patients. Symptoms improvement can be seen in most patients. High-volume centers should consider this technique for patients with unresectable tumors who present with symptomatic stenosis or short segment occlusion.

ABSTRACT Aims The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across LVEF categories. Methods and results Patients with severe isolated TR from the TRIGISTRY, a multicentre international registry, were categorized based on LVEF (preserved ejection fraction [pEF]: ≥50%, mildly reduced ejection fraction [mrEF]: 41–49%, and reduced ejection fraction [rEF]: ≤40%). We assessed the impact of treatment modality and procedural success (mild-to-moderate or lower residual TR) on 2-year survival within each LVEF category. Among 2384 patients, 1383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery (p < 0.0005) and TTVI (p < 0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF (p = 0.28 for both), nor in those with rEF (p = 0.76 and p = 0.22, respectively). Similar results were obtained when surgical and transcatheter interventions were grouped (p < 0.0001, p = 0.17 and p = 0.29 in patients with pEF, mrEF and rEF, respectively). Patients with residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories (p = 0.47, p = 0.33 and p = 0.008 in pEF, mrEF and rEF, respectively). Conclusions Transcatheter tricuspid valve intervention, whether surgical or transcatheter-based, was associated with improved survival in patients with pEF but not in those with mrEF or rEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering TTVI in individuals with rEF.

Background: Ischemia–reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI). While the precise mechanisms of AKI are still incompletely defined, extensive evidence highlights tubular cell injury and death as key factors in its development. Necroptosis has recently emerged as a critical pathway in the pathogenesis of ischemia–reperfusion-induced AKI (IR-AKI). Although sex differences in susceptibility to IR-AKI have been reported, it remains unclear whether there are sex differences in necroptosis dynamics and whether these differences underlie the observed sexual dimorphism in kidney IRI. This study aimed to address these questions. Methods: male and female C57BL/6 J mice were subjected to AKI via ischemia induced by bilateral renal pedicle clamping for 18 min at 37 °C. Plasma, urine, and kidney samples were collected at 0 h, 3 h, 6 h, 12 h, 24 h, 48 h, and 72 h post-reperfusion. Kidney injury and function were assessed by measuring plasma creatinine (PCr), blood urea nitrogen (BUN) levels, and histological damage (PAS and cleaved caspase3 staining). Necroptosis activation was assessed by quantifying phosphorylated forms of key markers: p-RIPK1 and p-MLKL. To explore the role of sex hormones in regulating necroptosis dynamics, ovariectomized female mice were subjected to the same IR-AKI protocol, and their kidney injury and functional outcomes were compared with those of intact counterparts. Results: The PCr was 0.35 ± 0.04 and 0.32 ± 0.06 mg/dL for males and females, respectively, at 3 h of IR. The levels exponentially increased to 2.05 ± 0.18 at 48 h post-reperfusion in the males but only gradually to 0.94 ± 0.13 mg/dL in females. Necroptosis activation began as early as 3 h post-IR in males but was delayed until ~6 h in females. Males exhibited stronger and more sustained necroptosis activation than females, showing elevated phosphorylation levels of pRIPK1 and pMLKL in Western blot. Female sex hormone deficiency exacerbated the female response to IR-induced injury, which reduced the sex difference in the dynamic of the necroptotic activation and subsequent kidney injury. To our knowledge, this is the first study to characterize sex differences in the initiation and progression of necroptosis and subsequent injury in a mouse model of IR-AKI. Conclusions: Our findings reveal distinct temporal patterns of programmed cell death between sexes. Necroptosis-targeted therapies require early intervention in males, which can be delayed in females after IR-AKI, highlighting the need for sex-specific therapeutic windows.

AbstractElectronic patient-reported outcome measures (ePROMs) can improve care for people with cancer, but effectiveness hinges on well-supported integration in clinical settings.We evaluated clinician use of specific clinical decision support (CDS) tools in the electronic health record (EHR) designed to facilitate timely, clinically appropriate responses to ePROM scores for six symptoms commonly experienced by cancer patients.The parent pragmatic trial, which took place at Mayo Clinic (Rochester, Minnesota, United States) and its affiliated community health care system between March 2019 and January 2023, evaluated the population-level effectiveness and implementation of an ePROM surveillance and EHR-facilitated collaborative care symptom management intervention. The present evaluation used a case study approach with four data sources: (1) clinician interactions with CDS tools abstracted from the EHR; (2) clinician notes identified with an institution-specific textual search tool; (3) qualitative interviews and group discussions with care teams; and (4) administrative records reviewed to identify training and outreach to care teams.EHR metrics showed very low adoption of CDS tools including alerts and symptom-specific order sets, despite educational outreach and information technology support provided to clinical care teams. Qualitative findings revealed that CDS use was not easy to integrate into busy clinical workflows and highlighted clinician perceptions that the collaborative care intervention provided additional patient support that reduced clinicians' need to utilize CDS tools. They also highlight the importance of contextual factors, including institutional priorities and EHR changes.This pragmatic clinical trial case study found limited adoption of EHR CDS tools that had been developed to increase clinicians' awareness of and responses to ePROM data. Findings suggest the need to align clinician and organizational implementation strategies, simplify CDS tools to fit practice expectations, and identify and address contextual factors that could undercut strategies like education and peer support. This may be especially important for teams who aim to iteratively evaluate and refine CDS and implementation strategies for multicomponent interventions or introduce new strategies that are responsive to barriers while maintaining scalability.

This cross-sectional study analyzes patient-reported outcome findings from the Enhanced, Electronic Health Record–Facilitated Cancer Symptom Control (E2C2) trial to investigate level of symptom burden in adolescents and young adults with cancer.

Key Points Genetic testing of individuals suspected of monogenic urinary stone disease resolved 34% of families with 22 different genes detected. Resolved individuals had a lower baseline and last visit eGFR and earlier age of stone presentation than the unresolved group. Specific phenotypes and younger diagnostic age were associated with a monogenic cause, allowing refinement of future screenings. Background Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here, we present testing results from a large cohort with suspected MSD. Methods Patients with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. Results Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and two digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in ten or more families include the following: AGXT , HOGA1 , SLC34A3 , CYP24A1 , SLC3A1 , and CLCN5 . Compared with the unresolved group, MSD probands had a lower baseline and last visit eGFR, earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those <16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, patients with primary hyperoxaluria had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. Conclusions Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of patients with MSD were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.