Top 5 Papers
#1
Source: Gut | Authors: Soriano, Sherwood, Ward, et al.; senior author Ian Tomlinson (Oxford, Edinburgh, Uppsala, Birmingham) | Published: September 11, 2026
Score: 9/20 — Base: Gut (7) + large genetic-epidemiology cohort with tumour sequencing (+1) + biomarker-guided risk stratification (+1) = 9. Leads the edition as the only paper here that could change who gets offered germline testing and surveillance.
MSH3 and MLH3 are non-canonical mismatch repair genes handling insertion-deletion errors, and until now only bi-allelic carriers were clearly linked to colorectal cancer. Studying roughly 12,000 CRC and multiple-polyp cases against 460,000 controls, with cancer genome sequencing in 2,023 patients, the authors show that simple heterozygotes are also at risk: 2.2-fold for MSH3 and 1.6-fold for MLH3 (p=0.028). The mechanism is classical two-hit tumour suppression — somatic second hits inactivate the wild-type allele, and a single second hit sometimes knocks out both MSH3 and the neighbouring gene. The resulting cancers are microsatellite-stable yet hypermutant, with deletions of at least 2 bp enriched roughly 12-fold and mutational signature ID4 usually present (p<0.0001); tumours from heterozygotes without a second hit showed no hypermutation at all. This is the first causal link between specific gene defects and ID4 in human tumours, and it gives these carriers a phenotype that resembles MSH6-mutant Lynch syndrome with incomplete penetrance.
Post angle: MSS but hypermutant is the phrase to remember. Heterozygous MSH3/MLH3 carriers aren't Lynch, but they aren't background risk either. #CRC #GIOnc #PrecisionMedicine
#2
Source: Communications Medicine | Authors: Kagawa and Kotani (co-first), senior author Takayuki Yoshino; 19+ Japanese sites (REMARRY/PURSUIT) | Published: September 9, 2026
Score: 8/20 — Base: Communications Medicine (5, defaults to Other) + Phase II (+2) + biomarker-guided precision (+1) = 8. Scored on the trial, not the journal — a prospective multicentre phase II linked to a 185-patient ctDNA monitoring cohort punches well above its masthead.
Anti-EGFR rechallenge is standard-of-thinking in late-line RAS/BRAF wild-type mCRC, but the field has relied on a single plasma RAS check immediately before rechallenge. PURSUIT linked the 185-patient REMARRY monitoring cohort to a multicentre single-arm phase II trial: 51 patients enrolled, 50 treated with panitumumab plus irinotecan every 2 weeks, all plasma RAS-negative before rechallenge with an anti-EGFR-free interval of at least 4 months. Confirmed ORR was 14.0% and DCR 80.0%, with median PFS 3.6 months and median OS 12.0 months — real activity in a chemorefractory population. The finding that matters is the negative one: no patient with detectable plasma RAS immediately after progression on prior anti-EGFR therapy responded (0/7), even though all of them had cleared to RAS-negative by the time of rechallenge. Plasma RAS positivity at cycle 3 also tracked with shorter PFS and OS.
Post angle: A clean pre-rechallenge ctDNA result can be a false reassurance. The sample taken at progression carries information the later one has lost. #CRC #ctDNA #GIOnc
#3
Source: Clinical Gastroenterology and Hepatology | Authors: Barakat, Maranki, Irani, Chahal — AGA Institute Clinical Practice Updates Committee | Published: September 9, 2026
Score: 7/20 — Base: major society clinical practice guideline, AGA (7) = 7. Placed in the Top 5 over equally-scored papers because it is GI-primary and immediately actionable at the endoscopy unit, where a mixed-tumour phase 1b is neither.
Ampullary neoplasia is rare — 0.6% to 0.8% of GI cancers — but incidence in young adults has climbed over 20 years and guidance has lagged well behind that for other pancreaticobiliary lesions. This AGA expert review issues 15 Best Practice Advice statements. The practical core: assess with a side-viewing duodenoscope rather than a forward-viewing gastroscope; take at least 6 biopsies, because 20% to 40% of ampullary adenomas already harbour malignancy; and use EUS for staging in any lesion potentially amenable to endoscopic resection. Lesions best suited to endoscopic papillectomy are well-demarcated, under 4-5 cm, non-friable, soft to probing, with intraductal extension of 1 cm or less. Avoid pre-papillectomy sphincterotomy, resect en bloc where feasible, and prevent post-procedure pancreatitis with prophylactic pancreatic duct stenting, rectal NSAIDs and lactated Ringer's. Surveillance runs at 3, 6 and 12 months and then annually for at least 5 years. Five-year survival still spans 20% to 75% depending on stage.
Post angle: Twenty to forty percent of ampullary adenomas already harbour cancer. Six biopsies minimum, and use the side-viewing scope. #GIOnc #Endoscopy #Pancreas
#4
Source: Clinical Cancer Research | Authors: Dhyani, Tezcan, Chou, et al.; senior author James J. Harding (MSKCC; Mater Misericordiae, Dublin) | Published: September 10, 2026
Score: 7/20 — Base: Clinical Cancer Research (6) + retrospective correlative cohort (+1) = 7. A deliberately negative result earns Top 5 placement here because it constrains how the ADC wave should be designed in biliary tract cancer.
With ADCs arriving across GI cancers, this MSKCC study asked the unglamorous prerequisite question: are the targets actually there, and do they mean anything? Tissue microarrays from 65 resected biliary tract cancers — 43% extrahepatic, 40% intrahepatic, 17% gallbladder — plus 18 paired metastatic samples were stained for CLDN18.2, c-MET, Nectin-4, TROP2 and HER2, with MSK-IMPACT sequencing in a subset. Every target was expressed, but the gap between any positivity and strong expression was wide: TROP2 83% positive yet only 26% at H-score 200 or above, c-MET 75%/26%, Nectin-4 66%/35%, CLDN18.2 46%/7.7%. HER2 overexpression appeared in just 3.1%. Agreement between primary and matched metastatic samples ran only 43% to 75%, highest for HER2 and TROP2 and lowest for c-MET, CLDN18.2 and Nectin-4. Commonly altered genes were TP53 (36%), SMAD4 (27%) and ELF3 (21%). Critically, the authors found no significant association between target expression and genomics, recurrence-free survival, or overall survival.
Post angle: Expression is not the same as a validated biomarker. In biliary tract cancer the ADC targets are present, heterogeneous, discordant between sites, and prognostically silent. #Cholangiocarcinoma #ADC #GIOnc
#5
Source: ESMO Gastrointestinal Oncology | Authors: Martínez Lago, Sánchez Ares, Carral Maseda, et al.; Complexo Hospitalario Universitario de Santiago de Compostela | Published: September 1, 2026
Score: 7/20 — Base: ESMO Gastrointestinal Oncology (5) + predefined retrospective molecular subanalysis (+1) + biomarker-guided precision (+1) = 7. Small (n=20) and explicitly exploratory, but it tests an under-asked question about who fails behind a good response rate.
dMMR/MSI-H status predicts benefit from checkpoint blockade, yet a subset of patients still does poorly, and this predefined molecular subanalysis asks whether a second driver explains it. Twenty patients with advanced MLH1-deficient dMMR/MSI-H GI tumours treated with pembrolizumab (9 CRC, 11 non-CRC) underwent RNA-based fusion profiling with pan-TRK immunohistochemistry and RET FISH. Secondary actionable fusions turned up in 4 of 9 CRC cases (44.4%) — mostly NTRK1, one RET — and in none of the non-CRC tumours. Response was strong overall: among 19 assessable patients, ORR was 84.2% and DCR 89.5%. But survival separated sharply. Median OS was not reached in fusion-negative CRC, 43.0 months in fusion-positive CRC, and 20.2 months in non-CRC disease; within CRC, OS differed by NTRK1 fusion status (log-rank p=0.034). With 20 patients this is hypothesis-generating and the authors say so, but it suggests a good response rate can mask a subgroup whose benefit does not last.
Post angle: An 84% response rate can still hide a group that does badly. In MLH1-deficient CRC, secondary NTRK1/RET fusions may mark who stops benefiting. #CRC #MSI #Immunotherapy #GIOnc
Additional Papers of Interest
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eBioMedicine — Dose escalation in 22 enrolled/18 treated patients (9 gastric, 3 pancreatic, 6 ovarian) across 45 PIPAC procedures found no dose-limiting toxicity; mPFS 3.5 mo and mOS 9.4 mo, with 5 GI patients surviving beyond a year.
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ESMO Gastrointestinal Oncology — 549 patients across 19 Spanish hospitals; mOS 10.8 mo, mPFS 5.0 mo, ORR 9.6%, DCR 51.9%, closely reproducing SUNLIGHT outside a trial population.
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Nature Communications — Across 2,616 CRCs in three independent cohorts, SBS_D is shown to be distinct from SBS18 rather than a decomposition artefact, and has been submitted to COSMIC as SBS111.
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JCO Oncology Practice — Across 15 studies and 4,320 patients, the neutropenic diet gave no reduction in major infections (RR 1.02), bacteremia/fungemia (RR 0.97), pneumonia, diarrhea or mortality; the lone signal was lower bacteremia in the RCT-only hematologic/HSCT subgroup (RR 0.67).
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