GI Oncology Daily Digest

Checkpoint inhibitors have never done much as monotherapy in biliary tract cancer, and the rationale for adding GM-CSF came from melanoma, where combining it with ipilimumab extended survival. This single-centre phase II gave pembrolizumab 200 mg every 21 days alongside two cycles of GM-CSF 250 µg subcutaneously on days 1–14, in 42 patients who had received prior chemotherapy but no prior checkpoint inhibitor; 67% had intrahepatic cholangiocarcinoma, 90% had stage IV disease, and 24% had underlying viral hepatitis. The confirmed objective response rate was 12% (95% CI, 4–26), which fell short of the pre-specified efficacy bar, though two patients achieved complete response and 26% remained progression-free at six months. Tolerability was good, with treatment-related grade 3–4 events in 7% and treatment-related serious adverse events in 10%. The correlative work is where the paper earns its place: tumour PD-L1 expression was present in 46% of patients and tracked with a higher six-month progression-free rate, and paired biopsies taken before and after GM-CSF showed upregulation of CD8+ T-cell populations and antigen-processing pathways. The combination did not work as designed, but it demonstrably moved the tumour immune microenvironment in the intended direction.

Pancreatic adenosquamous carcinoma is a rare variant that most centres treat as though it were conventional pancreatic ductal adenocarcinoma, largely because nobody has characterised it well enough to argue otherwise. This study assembles three layers of evidence to test that assumption: clinicopathologic features, treatment patterns and survival for 178 patients treated at Johns Hopkins between 2013 and 2023; a genomic comparison of 244 adenosquamous tumours against 29,021 conventional PDAC cases in the FoundationCore database; and Visium spatial transcriptomics on 11 resected adenosquamous tumours from 8 patients, benchmarked against a four-sample PDAC comparator. Outcomes were poor in both resected and advanced disease. Genomically, KRAS mutation frequency was similar to PDAC, but MTAP loss was more common and the low-frequency immune biomarkers — MSI-high, PD-L1 positivity, TMB ≥10 mutations/Mb — were all enriched. Spatial profiling found broadly comparable immune cell proportions but higher regulatory T-cell abundance, and distinct co-localisation patterns: immune infiltrates sat closest to squamous regions and farthest from glandular ones. Adenosquamous tumours showed increased squamous/basal lineage expression overall, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory and stress-response pathways relative to the glandular niche. Shared drivers, genuinely different disease.