Severe obesity (body mass index ≥ 40 kg/m2 or ≥ 35 kg/m2 with obesity-related comorbidities) is increasingly prevalent and independently associated with elevated perioperative morbidity and inferior oncologic outcomes in patients with colorectal cancer (CRC). Despite these risks, intentional preoperative weight optimization is not routinely incorporated into CRC management, owing to concerns regarding treatment delay, absence of guideline endorsement, and limited supporting evidence. A literature review was conducted using PubMed and Embase to evaluate the impact of severe obesity on morbidity, mortality, and oncologic outcomes in CRC. Peer-reviewed English-language studies involving adult human subjects were included, while conference abstracts, non-English publications, and studies unrelated to obesity and CRC were excluded. In the absence of published reports describing synchronized weight loss and CRC management in patients with severe obesity, three novel retrospective case examples were included to demonstrate feasibility during neoadjuvant treatment, with institutional review board approval obtained for all cases. Severe obesity complicates CRC staging due to limitations in cross-sectional imaging and anatomic delineation. Furthermore, severe and particularly visceral obesity is associated with increased rates of anastomotic leak, surgical site infection, and conversion to open surgery. Current CRC guidelines do not incorporate structured weight-loss strategies into standard treatment algorithms. Metabolic bariatric procedures, such as sleeve gastrectomy, achieve rapid and clinically meaningful weight reduction, often resulting in improved operative exposure and technical conditions for subsequent resection. Pharmacologic therapies, while more broadly accessible and less invasive, typically yield more modest reductions in visceral adiposity. Task force members report early experience across three distinct cases of locally advanced CRC in patients with severe obesity, demonstrating successful preoperative visceral fat reduction through multidisciplinary coordination incorporating metabolic bariatric surgery or pharmacologic therapy during neoadjuvant windows, followed by definitive oncologic resection. Severe obesity adversely influences CRC staging, operative complexity, and perioperative outcomes. Intentional metabolic optimization—through bariatric surgery or pharmacologic therapy—may represent a viable adjunct within multidisciplinary, patient-centered CRC care pathways. However, the absence of prospective short- and long-term outcome data underscores the need for systematic investigation to define optimal timing, safety parameters, and oncologic efficacy of weight-loss interventions in this high-risk population.
Type 1 diabetes is an autoimmune disease marked by the destruction of beta cells in pancreatic islets, with an incomplete picture of disease progression and a lack of a definitive cure. A recent finding linked pancreatic ductal cells of type 1 diabetic donors with elevated levels of human leukocyte antigen (HLA) class II molecules; however, the causal relationship and functional significance of this finding remain unknown. Because HLA class II molecules are typically expressed by professional antigen-presenting cells (APCs), this raises the possibility of ductal cells functioning as non-professional APCs. In this study, we test the hypothesis that ductal cells are responsive to type 1 diabetes-associated proinflammatory cytokines, TNF-α, IL-1β and IFN-γ, and can act as non-professional APCs. Pancreatic exocrine cells were obtained from cadaveric donors without diabetes following islet removal. Cells were cryopreserved and thawed into a defined culture medium tailored to support ductal cell survival in a 3D suspension culture system. Ductal cells were exposed to various doses of cytokines for 48 h and analysed for gene and protein expression, using quantitative PCR with reverse transcription, bulk RNA-seq, flow cytometry and western blot analyses. Correlation between cytokine response and APC-related gene expression was evaluated using publicly available single-cell RNA-seq datasets from 86 donors. The functional ability of cytokine-treated ductal cells to present an exogenous autoantigen (glutamic acid decarboxylase 65 kDa isoform [GAD65]) to T cells was tested using a GAD65-specific autoreactive CD4+ T cell clone (BRI-4.13) isolated from a type 1 diabetic donor. Within 48 h, a combination of TNF-α, IL-1β and IFN-γ stimulated mRNA and protein expression of HLA class II, co-stimulatory and antigen-processing molecules in non-diabetic ductal cells. Bulk RNA-seq analysis showed that cytokines significantly upregulated biological pathways in ‘antigen processing and presentation’ and ‘type 1 diabetes’. Single-cell RNA-seq analysis revealed a positive correlation between cytokine response and APC gene expression in human pancreatic ductal cells. Cytokine-treated ductal cells pulsed with exogenous GAD65 peptide activated and induced proliferation of BRI-4.13 T cells. Unexpectedly, 0.9
PURPOSE:We evaluated the role of complete cytoreductive surgery (CRS) for locoregional disease control in patients with colorectal cancer with peritoneal metastases (CRC-PM) and concurrent extraperitoneal metastases (EPM). METHODS:Institutional data identified patients with CC-0/1 CRS for CRC-PM. Patients with peritoneal disease only (PDO) were compared with those with concomitant EPM. Co-primary outcomes were progression-free survival (PFS) and peritoneal progression-free survival (p-PFS). The secondary outcome was overall survival (OS). Covariate imbalance was addressed using entropy balancing. Survival was analyzed using a weighted Cox proportional hazards model. Subgroup analyses were performed to identify favorable prognostic groups. RESULTS:In total, 83 patients were included: 31 (37.4%) had EPM. Baseline characteristics were comparable. Within the EPM cohort, liver-only metastases were most common (58%), followed by lung-only metastases (26%). EPM were managed at index CRS in 61%, before CRS in 19%, and deferred or untreated in 19% of patients. Unadjusted analyses demonstrated comparable median OS (PDO vs. EPM: 39 vs. 34 months, p = 0.551) and median p-PFS (PDO vs. EPM: 17 vs. 15 months, p = 0.346) but longer median PFS in the PDO group (14 vs. 5 months, p<0.001). After entropy balancing, patients with EPM had worse OS (31.6 vs. 38.7 months; hazard ratio [HR] 2.12; 95% confidence interval [CI] 1.02-4.37; p < 0.05) and PFS (5.0 vs.12.8 months; HR 2.7; 95% CI 1.58-4.5; p < 0.001) but similar p-PFS (13.4 vs.14.9 months; HR 1.10; 95% CI 0.58-1.77; p = 0.622). Subgroup analyses demonstrated comparable OS and p-PFS for patients with PDO and those with single-site liver or lung EPM. CONCLUSION:Complete CRS provides durable locoregional disease control in patients with EPM.
Menin inhibitors (MENINi) show promise for relapsed or refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2Ar) and NPM1 mutations (NPM1c). Outcomes after MENINi failure are poorly understood. To characterize the mutational landscape and subsequent outcomes, we conducted a multicenter retrospective study of adults from 4 U.S. centers with R/R AML after MENINi failure (relapse after response or primary refractory). The 84 patients (63% KMT2Ar, n=53; 23% NPM1c, n=19) who received MENINi were heavily pre-treated: 86% (n=72) had prior intensive chemotherapy (IC), 77% venetoclax (VEN, n=67), and 38% (n=32) allogeneic stem cell transplantation. After MENINi failure, 40% of patients (n=34) received supportive care. Of the 60% (n=50) that were treated, common regimens were hypomethylating agent (HMA)/VEN (26%, n=13), clinical trial (26%, n=13), and gilteritinib-based therapy (18%, n=9). The CR/CRi rate for non-trial therapies was 19% (n=7); ORR was 32% (n=12). All CR/CRi occurred with HMA/VEN (n=2, 15%), IC+VEN (n=4, 67%), or MENINi switching (bleximenib to revumenib, n=1, 50%). No FLT3-mutant patients responded to gilteritinib (0/6 gilteritinib-naïve). Median overall survival (mOS) from start of next therapy was 4.4 months; patients who achieved CR/CRi had mOS of 15.4 vs 3.4 months for non-responders (p=0.048). Outcomes after MENINi failure are poor, but responses occur with VEN-based regimens or MENINi switching. FLT3-ITD, WT1, and MEN1 mutations are associated with resistance.
BackgroundThe Lynch syndrome INtegrative Epidemiology And GEnetics (LINEAGE) consortium was established to address gaps in understanding genotype-specific cancer risks and risk-modifiers in contemporary North American Lynch syndrome (LS) populations. LINEAGE is a multi-center, longitudinal cohort to systematically collect data on risk factors, adherence to care, quality of surveillance, and patient-, provider-, and system-level factors associated with incident LS-associated cancers.MethodsLINEAGE recruits individuals with confirmed pathogenic or likely pathogenic variants in LS-associated genes from participating institutions. Data includes retrospective and prospective collection, encompassing clinical abstraction (demographics, surgical history, endoscopic data, treatments), patient-reported surveys (behavioral/lifestyle factors, quality of life, procedures), endoscopist-level data, and biosample metadata. A standardized REDCap database, data harmonization protocols, and a virtual biobank support reproducibility and linkage of clinical data and biosamples. Rigorous quality assurance/quality control processes are embedded for data integrity.ResultsParticipating centers will contribute data to determine gene-specific risks, and gene-environment interactions for Lynch-associated, and other cancers. We will evaluate associations with exposure to, and quality of cancer risk-reduction care, including endoscopic surveillance, risk-reduction surgery, and chemoprevention. The inclusion of provider-level variables, such as endoscopist training and experience, enables unique research into modifiers of post-endoscopy cancer risk. The linked biosample resources will further facilitate mechanistic studies and biomarker discovery.ConclusionsLINEAGE provides a robust platform for advancing LS research by integration of clinical, pathological, epidemiological and genetic data across institutions. Its standardized, collaborative framework enhances the validity and generalizability of risk estimates that will guide decision-making and policy for surveillance to ultimately reduce morbidity and mortality for individuals with Lynch syndrome.
