Citations

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of 13.3%. First-line treatment relies on two chemotherapy regimens, FOLFIRINOX (FOLFNX) or gemcitabine plus nab-paclitaxel (GEMPAC). However, direct clinical comparisons between these regimens have yielded inconsistent results across survival and toxicity endpoints, and the molecular basis of heterogeneous treatment responses remains poorly defined. To investigate regimen-specific tumor-cell-intrinsic mechanisms, we performed quantitative proteomic profiling of a primary PDAC-derived MIA PaCa-2 cell line following treatment with FOLFNX or GEMPAC. Differentially expressed proteins were analyzed using Gene Ontology, KEGG, and Ingenuity Pathway Analysis to define pathway-level alterations, and findings were contextualized using TCGA transcriptomic data. Proteomic analyses revealed that FOLFNX and GEMPAC engage in distinct cytotoxic programs. FOLFNX predominantly suppressed ribosome biogenesis and mitochondrial translation, consistent with sustained metabolic and biosynthetic stress, whereas GEMPAC preferentially disrupted mitotic cytokinesis and phosphatidylinositol phosphate biosynthesis, consistent with mitotic failure. Integration with TCGA data showed that FOLFNX-altered proteins aligned with favorable prognostic expression signatures, whereas GEMPAC-associated proteins were enriched among adverse profiles, reflecting engagement of distinct tumor-intrinsic programs. Together, these findings provide mechanistic insight into differential chemotherapy responses and establish a foundation for proteomics-based biomarkers to guide personalized chemotherapy selection in PDAC.

OBJECTIVE To test the effect of physical activity on the gut microbiome and circulating short-chain fatty acids (SCFAs) among sedentary adults with prediabetes and overweight or obesity. RESEARCH DESIGN AND METHODS In a pilot and feasibility trial, we randomized 77 adults with prediabetes and a sedentary lifestyle into one of two groups: 1) intervention: invited to engage in home-based moderate-intensity walking 3×/week for 30 min/session in weeks 1–4 and for 45 min/session during weeks 5–8 of the 8-week intervention; or 2) control: maintained habitual physical activity levels. We performed metagenomic sequencing from stool collected at baseline, week 4, and week 8, with SCFAs measured from serum collected at baseline and week 8. Taxonomic and functional profiling was performed on the metagenomic reads; α-diversity metrics were subsequently derived. Linear regression assessed the difference in change between the intervention and control groups for α-diversity and SCFA levels. RESULTS We screened 1,533 participants for eligibility and consented 132. Of these, 87 entered the run-in phase, and 77 were randomized. Participants were mean (SD) 51.4 (8.9) years old, 87.7% female, and 74% non-Hispanic White. Mean fasting glucose was 103.3 (13.2) mg/dL, while mean BMI was 34.4 (5.7) kg/m2. Compared with the control group, the intervention group experienced decreased α-diversity as characterized by Shannon, Richness, and Faith diversity indices by intervention week 8 (P < 0.05). Changes in SCFA levels were not statistically significant different in intervention versus control. CONCLUSIONS Randomization to a walking intervention resulted in modest gut microbiome changes among adults with overweight or obesity and prediabetes.

ABSTRACT Background and Objectives Surgery is the mainstay of treatment for localized colorectal cancer (CRC); however, little is known about survival outcomes following CRC surgery in low‐ and middle‐income countries (LMICs). Here, we examine the available data on long‐term outcomes following CRC resections in LMICs. Methods A systematic review and meta‐analysis were conducted on primary research studies reporting survival data after CRC resection with curative intent in LMICs. Disease‐free survival (DFS) and overall survival (OS) data were extracted, and random effects modelling was used to estimate the pooled survival rates. Results One hundred and fifty‐four studies representing 20,589 CRC patients were analyzed. Notably, only 27 (20%) of the 137 LMICs were represented in the literature. The pooled 5‐year OS estimate was 88% (95% CI: 77–95), 76% (69–81), and 57% (49–64) for Stages I, II, and III, respectively. 5‐year DFS estimates were 82% (71–90), 76% (67–84), and 59% (51–65) for stages I, II, and III, respectively. Combined OS and DFS estimates for all three stages were 76% and 69%, respectively. Survival rates varied considerably across the included studies and between income groups. Conclusions With the rising incidence of CRC globally, our work highlights the dearth of data on long‐term outcomes following CRC operations in most LMICs and emphasizes the urgent need for research capacity building.

Abstract Radiotherapy is an established treatment for low-grade primary cutaneous B-cell lymphoma. Recommendations on its use differ internationally, which prompted our group to conduct this analysis. Twenty-two institutions participated in this international study. Patient eligibility required a diagnosis of limited (T1/T2) primary cutaneous marginal zone or follicle center lymphoma treated with radiotherapy between 1995 and 2023. Data were collected retrospectively until February 2024 within the framework of the International Lymphoma Radiation Oncology Group. Overall, 535 patients were analyzed. Predominant locations were the head (40%) and trunk (36%). Radiotherapy had a median dose of 24 Gy in fractions of 2 Gy. Complete responses were observed in 91% at a median time of 3.6 months following radiotherapy. There was no statistically significant difference between treatments ≤4 Gy and >4 Gy for complete or overall response rates (P = .077 and P = .056, respectively). However, there was an inferior duration of local control with ≤4 Gy (5-year local control 73% ± 12% vs 96% ± 2%; P< .001). Radiation dose was the main prognostic factor in the univariate and multivariable Cox analysis; however, higher doses did not translate into an overall survival benefit. Toxicities rarely exceeded grade 2 but were more frequent in the >4 Gy group. Radiotherapy remains an effective treatment option for indolent skin lymphoma with low toxicity. High response rates are observed with low doses of ≤4 Gy. In comparison to conventional doses, these treatments have a shorter duration of local control but a favorable toxicity profile.

ABSTRACT The local treatment of bladder and prostate rhabdomyosarcoma is a multidisciplinary decision, incorporating elements of patient age, tumor size and location, nodal involvement, and access to local expertise and technology. The relative absence of long‐term bladder and bowel function outcome data complicates discussions, particularly given improved survival rates and development of new surgical and radiotherapy techniques. These INSTRuCT guidelines, a collaboration of the Children's Oncology Group, Soft Tissue Sarcoma Committee, European Pediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe, reflect international expert consensus and are intended to inform practice, generate discussion, and highlight areas of future inquiry.

PURPOSE For patients with advanced biliary tract cancer (BTC), cancer-related time spent in health care systems, time toxicity, represents a critical but understudied burden affecting quality of life. This study aimed to quantify time toxicity in patients receiving first-line systemic therapy and evaluate whether the addition of durvalumab to gemcitabine plus cisplatin (GC) increases health care contact time. METHODS This international, multicenter, retrospective cohort study included patients with advanced BTC seen between January 2019 and April 2024 at Mayo Clinic Enterprise (US), and between January 2021 and April 2024 at Kyorin University Hospital (Japan), and Hospital Israelita Albert Einstein (Brazil). Patients received GC plus durvalumab (GCD) or GC. Time toxicity was recorded from treatment initiation until discontinuation or last follow-up during first-line systemic therapy. Multiple regression analysis identified factors associated with high time toxicity. RESULTS Among 193 patients (102 GCD, 91 GC; median age 65 years; 50% male; 49% Eastern Cooperative Oncology Group performance status [PS] 0), median time on treatment (TOT) was 156 days (95% CI, 122 to 190). The median proportion of total time toxicity was 14.4% (IQR, 10.9-20.6). Planned visits accounted for 11.9%, while unplanned visits were infrequent (1.8%). Time toxicity strongly correlated with TOT ( r = 0.824) and progression-free survival ( r = 0.827). Despite longer treatment in the GCD group than the GC group (212 v 134 days; P = .027), total time toxicity was similar (27 v 18 days; P = .19). Younger age and poor PS were independent factors of higher time toxicity. CONCLUSION Time toxicity represents a meaningful metric that allows for more comprehensive integration of the net benefit in patients with advanced BTC with a limited lifespan.

Abstract Forward genetic screens are powerful tools for novel biological discoveries because they do not require a priori knowledge of genes controlling a phenotype of interest. The Sleeping Beauty (SB) transposon system is one of many commonly employed genetic screen tools used to induce both gain and loss of gene function mutations via insertional mutagenesis. In the past, SB screens have been successfully utilized to discover several cancer driver genes that could serve as potential therapeutic targets. More recently, SB technologies have been extended to other applications, including the discovery of mechanisms contributing to drug resistance and novel targets for immunotherapy. Importantly, existing tools for SB screen data analysis do not support data-driven case–control comparisons capable of analyzing screens with this design. To this end, we developed a network-based common insertion site (NetCIS) analysis tool to robustly identify common insertion sites (CISes) in a case–control phenotype selection screen. NetCIS uses an efficient graph-based algorithm for discovering statistically significant CISes that differ between cases and controls. We benchmark NetCIS against other insertional mutagenesis analysis tools using a previously published SB dataset and show that NetCIS is able to prioritize previous biologically validated genes similarly or better than competing methods, is the only method that effectively utilizes a case–control experimental setup, and can identify CISes involving unannotated regions of the genome that are overlooked by existing methods. Code for NetCIS and an accompanying tutorial can be found at https://github.com/RogersLabGroup/NetCIS.

IMPORTANCE Neoadjuvant chemoimmunotherapy has high rates of pathologic response and improved prognosis among solid tumors. Its role in head and neck squamous cell carcinoma (HNSCC) remains understudied. OBJECTIVE To summarize the efficacy associated with neoadjuvant chemoimmunotherapy regimens in HNSCC and to compare the efficacy associated with neoadjuvant chemoimmunotherapy vs immunotherapy alone in locoregionally advanced resectable HNSCC prior to definitive surgery. DATA SOURCES A librarian-led systematic review was conducted using multiple electronic databases, including Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus, following Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. Databases were queried from inception to October 2024. STUDY SELECTION Inclusion criteria included prospective interventional trials that have completed accrual, with results published in English. Only trials of resectable, treatment-naive HNSCC were included. Exclusion criteria included lack of reporting on pathologic response or Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 response. DATA EXTRACTION AND SYNTHESIS Two investigators independently conducted title, abstract, and full-text reviews per PRISMA guidelines. Primary outcomes extracted were major pathologic response (MPR) and complete pathologic response (CPR) at surgery and complete response (CR) on imaging by RECIST 1.1. Secondary outcomes included 1-year overall survival (OS) and toxic effects. MAIN OUTCOMES AND MEASURES A meta-analysis was performed using a binary random-effects model to determine the pooled proportion of primary outcomes in the immunotherapy and chemoimmunotherapy groups. Heterogeneity was reported as I 2 . RESULTS A total of 751 patients (502 [77%] male; age range, 27-87 years) across 23 studies were included in the meta-analysis, including 357 patients (47%) who underwent chemoimmunotherapy, 102 patients (14%) who underwent dual-agent immunotherapy, and 292 patients (39%) who underwent single-agent immunotherapy. Pooled rates of MPR plus CPR were 66% (95% CI, 58%-73%; I 2 = 0.59) for chemoimmunotherapy, 18% (95% CI, 6%-29%; I 2 = 0.65) for dual-agent immunotherapy, and 6% (95% CI, 3%-9%; I 2 < 0.01) for single-agent immunotherapy. Across all groups, 1-year OS rates ranged from 88% to 96% for single-agent immunotherapy, 88% to 96% for dual-agent immunotherapy, and 88% to 100% for chemoimmunotherapy. Grade 3 to 5 adverse events were reported in 61 of 210 patients (29%), 2 of 67 patients (3.0%), and 36 of 210 patients (17%) among the reporting studies in the single-agent immunotherapy, dual-agent immunotherapy, and chemoimmunotherapy groups, respectively. CONCLUSIONS AND RELEVANCE These findings suggest that neoadjuvant chemoimmunotherapy regimens were associated with higher pathologic and radiographic response rates compared with immunotherapy alone in locoregionally advanced HNSCC. These results call for phase 3 trials comparing these neoadjuvant regimens head to head.

ABSTRACT Recent advances in the diagnosis and management of reflux disease were the central focus of the inaugural Gatherings in Esophagology (GiE), which convened experts across gastroenterology, surgery, otolaryngology, pulmonology, and basic research. The sessions highlighted innovations in reflux monitoring—including high‐resolution manometry, wireless pH monitoring, and novel salivary biomarkers—while critically evaluating their diagnostic accuracy and clinical utility. Presentations explored the limitations of traditional proton‐pump inhibitor therapy, the emergence of potassium‐competitive acid blockers as a new class of acid suppressants, and the evolving role of adjunctive treatments such as mucosal protectants, reflux reducers, and neuromodulators for refractory symptoms. The discourse extended to advanced interventional procedures, including transoral incisionless fundoplication, magnetic sphincter augmentation, and the RefluxStop device, with discussion of patient selection, efficacy, and complication management. Discussants emphasized the pathophysiology and management of extraesophageal manifestations of reflux, the interplay between reflux and pulmonary disease, and the diagnostic challenges in pediatric populations. The meeting also addressed the integration of behavioral therapies, the role of the microbiome, and the application of artificial intelligence in reflux diagnostics. Collectively, these insights underscore a shift toward precision medicine in reflux disease, emphasizing individualized diagnostic strategies and tailored therapeutic approaches to improve patient outcomes.

Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitor (BCL2i)–containing regimens significantly improve survival outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Results from randomized clinical trials have demonstrated that time-limited treatment with BCL2i-containing regimens resulted in higher rates of undetectable measurable residual disease (uMRD) than BTKi monotherapy or chemoimmunotherapy (CIT). Pirtobrutinib (a noncovalent BTKi) and lisocabtagene maraleucel (CD19-directed CAR T-cell therapy) are newer options for relapsed or refractory disease after prior therapy with BTKi and BCL2i-contining regimens. Histologic transformation of CLL/SLL to diffuse large B-cell lymphoma (Richter transformation) is associated with a poor prognosis. Molecular analysis to determine whether there is clonal relationship between CLL/SLL and transformed diffuse large B-cell lymphoma is useful to select an appropriate treatment option. These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for the treatment of CLL/SLL and Richter transformation.