Citations

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Background Strengthening emergency care systems could reduce death and disability in low- and middle-income countries (LMICs), yet many struggle to provide timely, high-quality care. LMICs also face growing risks from climate-related shocks and mass casualty events. This study identifies unmet emergency care needs in Nepal—one of the world’s most climate-vulnerable countries—using high-resolution geospatial data to estimate socioeconomic and climate-related inequalities. Methods We conducted a cross-sectional geospatial analysis using data from the 2022 Nepal Demographic and Health Survey (DHS), the 2021 DHS Service Provision Assessment and publicly available climate vulnerability data. Government hospitals were classified into three emergency care levels using World Health Organzation criteria: A (basic 24-hour services), B (A plus resuscitative capabilities) and C (B plus ≥50 beds and a surgeon). Household location and injury data were obtained from the DHS. Accessibility was defined as the proportion of the population within 1-hour and 2-hour travel times, estimated using AccessMod 5.8, incorporating road networks, rivers, land cover and elevation. Findings Most public hospitals (77.7%) met Level A criteria but only 49.3% met Level B and 10.8% met Level C. Nationally, 78.7% of households had 1-hour access to Level A care, 71.8% to Level B and 44.6% to Level C. Adjusted logistic regression showed rural, poorer and climate-vulnerable households had significantly lower 1-hour access compared with urban households, rural households had lower odds of access: Level A OR: 0.33 (95%CI 0.30 to 0.37), Level B OR: 0.33 (95%CI 0.30 to 0.36), Level C OR: 0.56 (95%CI 0.51 to 0.61). Households in high climate vulnerability areas had reduced access across all levels. Conclusions Substantial gaps and inequities in timely access to high-quality emergency care exist in Nepal. Rural, poorer and climate-vulnerable populations experience markedly lower access. Targeted, decentralised strengthening of emergency care capacity is essential both in Nepal and in other LMICs facing similar constraints.

Abstract Background Even for experienced operators, endovascular treatment of unruptured intracranial aneurysms involves intraoperative uncertainty that may lead to adjustments in strategy, prolong the procedure, and potentially cause inefficiency and device waste. This study aimed to evaluate whether pre-procedural testing (PPT) of endovascular treatment using patient-specific models was associated with increased operator confidence and perceived clinical utility, including improvements in procedural efficiency and reduced resource waste. Methods We enrolled a cohort of patients who underwent PPT before endovascular treatment for complex unruptured intracranial aneurysms and compared their outcomes with a control group treated without PPT. The primary outcome was the Training Fidelity Score, a composite of three operator-reported Likert items defined a priori. Secondary outcomes included perceived clinical utility, intraoperative strategy changes, procedural time, radiation exposure, device waste and safety. Results A total of 85 patients met the inclusion criteria (PPT=40; control=45). The Training Fidelity Score was high across the PPT group (median, 4.33/5). Perceived clinical utility was high and further increased significantly after the procedure. A significant reduction was observed in intraoperative strategy changes, with no changes recorded in the PPT group, compared to 6/45 in the control group (RR 0.09; p=0.027). Reductions in treatment time, radiation exposure and device waste were also noted. Conclusion PPT using patient-specific models was associated with increased operator confidence, fewer intraoperative strategy changes, improved procedural efficiency, and reduced device waste without compromising safety. These findings support its use in pre-interventional preparation, but require prospective multicenter validation.

Abstract Purpose The aim of this systematic review and meta‐analysis was to quantify and compare the evidence on the results obtained with the surgical treatments for meniscal lesions in athletes. Methods A literature search was conducted on PubMed, Cochrane and Web of Science in August 2025 according to the PRISMA guidelines. Inclusion criteria were clinical studies (randomised controlled trials [RCTs], non‐randomised comparative studies and case series), ≥6 patients, in the English language, on the surgical treatment of meniscal lesions in athletes. A meta‐analysis was conducted on the rate of patients returning to sport, the time to return to sport, and the rate of patients returning to the pre‐injury level of sport. Patient‐reported outcome measures, adverse events, failures and reoperation rates, as well as risk of bias and quality of evidence, were also documented. The risk of bias was assessed using the Cochrane RoB 2.0 tool, the Cochrane ROBINS‐I tool, and the JBI Critical appraisal checklist. The quality of evidence was assessed using a modified Coleman score and the GRADE tool. Result The mean time to return to sport was 2.1 months for meniscectomy, 5.8 months for meniscal repair, and 8.9 months for meniscal allograft transplantation (MAT). Statistically significant differences were observed between meniscectomy and repair and between meniscectomy and MAT (both p < 0.001). Meniscectomy showed a return to sport rate of 98.2%, meniscal repair of 96.9%, and MAT of 94.2%, while return to the same pre‐injury level of sport was reported as 84.4% for meniscectomy, 81.3% for meniscal repair, and 77.4% for MAT, with no statistically significant differences between groups. The mean modified Coleman Methodology Score for the included studies was 66.6 ± 7.0. Conclusion Meniscectomy, meniscal repair, and MAT are all able to provide high rates of return to sport in athletes. In the investigated treatment cohorts, meniscectomy presented the shortest pooled time to return to sport, followed by meniscal repair and MAT. Importantly, all treatments offered good rates of return to the same level of athletic performance. The treatment choice should be guided by an individualised, multidisciplinary approach aimed at providing a patient‐tailored treatment strategy to optimise both athletic recovery and joint preservation. Level of Evidence Level I.

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (topo1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate topo1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined topo1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a topo1 inhibitor via DS-8201a may reduce systemic toxicity, while maintaining synergistic cytotoxic activity in combination with olaparib (PARPi). DS-8201a + olaparib was evaluated in the ongoing CTEP #10355 trial (NCT04585958). Results from Dose Escalation are presented. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ or ERBB2 amplification by NGS or ISH (local testing allowed). DS-8201a was given Q3W across all dose escalation regimens. Olaparib dosing in continuous (Module 1 D1-21) and intermittent schedules (Module 2 D8-14; Module 3 D3-9) were explored. A 3+3 dose escalation design was followed in Mod 1 & 2 and up to 6 pts in a safety cohort were planned for Mod 3. Primary endpoints included safety as graded by CTCAE v5 and determination of an RP2D. Results: As of Oct 26, 2025, 30 pts were enrolled and 28 pts were treated. 12 pts had uterine and 16 pts had ovarian cancer; mean age was 61.6 years, median number of prior therapies was 4 (range 1-10). HER2 expression by local testing was: 4 pts IHC 1+, 17 pts IHC 2+, 6 pts IHC 3+, 1 pt ERBB2 amplification (IHC not reported). 9/10 pts enrolled in Mod 1 (continuous olaparib) were DLT-evaluable: 1/7 pts at DL1 (DS-8201a 4.4mg/kg IV Q3W + olaparib 100mg BID D1-21) and 3/3 pts at DL2 (DS-8201a 5.4mg/kg IV Q3W + olaparib 100mg BID D1-21) experienced DLTs (G4 neutropenia, febrile neutropenia, WBC decrease, colitis), halting further Mod 1 enrollment. 12/16 pts enrolled to Mod 2 (intermittent olaparib) were DLT-evaluable and only 1 pt at the highest dose level (DL3, DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14) experienced a DLT (G3 colitis). Hematologic TRAEs were markedly attenuated in Mod 2 compared to Mod 1: 12% vs 30% G3 and 19% vs 50% G4 neutropenia; 25% vs 70% G3 anemia; 6% vs 20% G3 and 0% vs 20% G4 thrombocytopenia. 2/2 DLT-evaluable pts in Mod 3 (intermittent olaparib; DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D3-9) experienced DLTs (G3 diarrhea, G3 nausea & vomiting, G4 neutropenia), halting further Mod 3 enrollment. The Mod 2 DL3 regimen of DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14 was declared the RP2D and is under further investigation in an ongoing Dose Expansion cohort enrolling HER2 IHC 1+ platinum resistant ovarian cancer. Objective responses were observed across all modules and dose levels. Conclusions: In pts with HER2-expressing advanced solid tumors, DS-8201a in combination with intermittently-dosed olaparib was tolerable. DS-8201a 5.4mg/kg IV Q3W + olaparib 300mg BID D8-14 was selected as the RP2D for further evaluation in Dose Expansion. Additional endpoints of clinical activity will be presented. Citation Format: Elizabeth K. Lee, Andrea Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Yinglu Zhou, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. CTEP #10355 A phase 1 trial of DS-8201a and olaparib in HER2-expressing malignancies: Results from dose escalation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT035.

Abstract Introduction: Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment. Methods: We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacitidine in 34 women with PROC (NCT02900560). Key eligibility criteria included age ≥ 18 years, ECOG performance status of 0-1, measurable disease and platinum-resistant, histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Primary endpoints included safety, tolerability, overall response rate (ORR), and disease control rate (DCR). Secondary endpoints included CA-125 response. The effect of combined epigenetic modulation and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors. Target gene expression analyses were used to identify differentially expressed genes and pathways, and bulk RNA sequencing was used for gene set enrichment analyses (GSEA) and to infer T cell receptor (TCR) assemblies. Results: The combination of azacitidine and pembrolizumab was moderately well tolerated, and the most common grade 3-4 adverse events were gastrointestinal side effects and anemia. ORR was 2.9% and DCR was 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses revealed an upregulation of inflammatory and cytolytic genes (FDR-adjusted p=0.005) and co-inhibitory checkpoints (p=0.005) 6 weeks on-therapy. Upregulation of interferon signaling (p=0.006), antigen presentation (p=0.003), costimulatory signaling (p=0.002), and immune cell adhesion and migration (p=0.005) pathways were prominent on-therapy, together with an increase in CD8+ T-cell density (p=0.05). GSEA analyses were concordant with these findings, showing enrichment of immune and inflammatory gene sets on-therapy and upregulation of gene sets linked to IFN-γ response, natural killer cell-mediated cytotoxicity, and immunoregulatory interactions (p &lt; 10e-13). Findings were not confounded by histological subtype. TCR abundance analyses evaluating significant TCR clonotypic expansions and regressions showed that intra-tumoral TCR repertoires were reshaped on-therapy. Furthermore, patients with a CA-125 and/or clinical response showed enrichment of hallmark inflammatory gene sets at baseline (p &lt; 10e-10) and of adaptive and conserved immune response gene sets on therapy (p &lt; 10e-09). Conclusions: Our findings highlight the potential of epigenetic modulators to reshape the tumor microenvironment of PROC toward a more inflammatory phenotype and may point to approaches to augment immunotherapy response. Citation Format: Blair V. Landon, Julia L. Boland, Andrea E. Wahner Hendrickson, Deborah K. Armstrong, Boris Winterhoff, Jaime Wehr, Akshaya V. Annapragada, Christopher Cherry, Archana Balan, Guneet Kaleka, Victor E. Velculescu, Stephen B. Baylin, Cynthia A. Zahnow, Dennis J. Slamon, Gottfried E. Konecny, John A. Glaspy, Valsamo (Elsa) Anagnostou. Pembrolizumab and epigenetic modification with azacitidine reprogram the tumor microenvironment of platinum-resistant epithelial ovarian cancer: clinical and translational findings from a phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT260.

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.