Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, often associated with new-onset diabetes. The relationship between PDAC and diabetes, particularly type 3c diabetes, remains poorly understood. This study investigates whether PDAC-associated diabetes represents a distinct subtype by integrating transcriptomic and histological analyses. Whole-tumour RNA sequencing data from The Cancer Genome Atlas (TCGA) were analysed to compare gene expression profiles between PDAC patients with and without diabetes. Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) deconvolution was employed to assess immune cell populations. Histopathological evaluations of pancreatic tissues were conducted to assess fibrosis and islet morphology. Histological analysis revealed perivascular fibrosis and islet basement membrane thickening in both PDAC cohorts. Transcriptomic data indicated significant downregulation of islet hormone genes insulin (INS) and glucagon (GCG) but not somatostatin (SST) in PDAC-associated diabetes, consistent with a type 3c diabetes phenotype. Contrary to previous reports, no distinct immunogenic signature was identified in PDAC with diabetes, as key immune checkpoint genes (Programmed Cell Death Protein 1 (PDCD1), Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), Programmed Death-Ligand 1(PD-L1)) were not differentially expressed. The findings suggest that PDAC-associated diabetes arises through neoplastic alterations in islet physiology rather than immune-mediated mechanisms. The observed reductions in endocrine markers reinforce the concept of PDAC-driven β-cell dysfunction as a potential early indicator of malignancy. Given the poor response of PDAC to PD-L1 checkpoint inhibitors, further research is needed to elucidate alternative therapeutic strategies targeting tumour–islet interactions.

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with new-onset diabetes (NOD) in adults aged ≥ 50 years. Accordingly, NOD may serve as an early clinical marker for PDAC, although the causal links remain incompletely defined. This review synthesises clinical and experimental evidence into an islet-centric view in which tumour-derived signals and microenvironmental changes impair β-cell insulin secretion and disrupt α- and δ-cell regulation. We distinguish findings established in PDAC from mechanisms inferred from islet physiology and systemic metabolism. Key uncertainties include the timing of systemic versus local drivers, the clinical relevance of tumour-derived signals in driving dysglycaemia, the status of endocrine cell signalling and endocrine–exocrine crosstalk, and the effects of microvascular and matrix changes on endocrine–vascular exchange. This synthesis highlights mechanisms that remain incompletely defined and prioritises areas for further research.

Background: Durvalumab (anti-PD-L1) in combination with gemcitabine and cisplatin has become the first-line treatment for patients with locally advanced, surgically unresectable, or metastatic biliary tract cancer, following the survival benefit demonstrated in the TOPAZ-1 phase III trial. This study presents real-world data from UK centres in patients who received early access to the regimen via AstraZeneca’s scheme. The aim was to assess the safety and efficacy of this treatment approach in routine clinical practice and compare it to outcomes reported in the TOPAZ-1 trial. Method: This retrospective study included patients with locally advanced, surgically unresectable, or metastatic biliary tract adenocarcinoma who received durvalumab in combination with gemcitabine and cisplatin. Data were collected across ten UK centres. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), overall response rate (ORR), and safety outcomes, encompassing both chemotherapy and immunotherapy-related adverse events (AEs). Results: A total of 134 patients treated between April 2022 and December 2023 were included. The median follow-up was 12.8 months (95% CI: 11–16.8). The median PFS was 8.83 months (95% CI: 5.73–11.7), closely aligning with the 7.2 months reported in TOPAZ-1 (95% CI: 6.7–7.4). The median OS was 12 months (95% CI: 10.7–13.9), slightly below the 12.8 months observed in TOPAZ-1 (95% CI: 11.1–14.0). The ORR was 29.1% (TOPAZ-1: 26.7%), and the disease control rate was 61.2%. In terms of safety, 64 patients (52.3%) experienced any-grade AEs, and 9 patients (6.8%) had grade 3–4 AEs, representing a lower toxicity profile than TOPAZ-1. Immunotherapy-related AEs occurred in 25 patients (18.7%), with grade 3–4 events in 3%. Conclusions: These real-world findings from UK cancer centres support the outcomes of the TOPAZ-1 trial, demonstrating comparable efficacy and a favourable safety profile for durvalumab combined with gemcitabine-cisplatin as first-line treatment for advanced biliary tract cancer.

Cabozantinib is a commonly prescribed tyrosine kinase inhibitor for metastatic renal cell carcinoma (mRCC). Dose reductions may be required to manage side effects. Data was collected at University Hospitals Plymouth NHS Trust between 2020 and 2024 to investigate the dosing of Cabozantinib and its impact on cancer control. Starting at a reduced dose was common, with only 17% starting at full dose (60 mg). Only 9% completed their Cabozantinib course at 60 mg, with the majority (61%) ending up taking 20 mg. Dose reductions occurred early, with the vast majority ending up on their final dose at cycle two or three. Median progression-free survival was 7–10 months regardless of dose, and there was no statistically significant difference in PFS or OS according to dose.