Gallbladder and Pancreas

Introduction Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer and carries a poor prognosis even after curative surgery. Recurrence rates exceed 50%, particularly in patients with high-risk features such as large tumours (>5 cm), vascular invasion, multifocal disease, lymph-node involvement, or elevated CA19-9. Until now, no neoadjuvant therapy has been established as standard treatment for resectable high-risk iCCA. The GOLP regimen—a combination of gemcitabine–oxaliplatin chemotherapy, lenvatinib (an anti-angiogenic agent), and the PD-1 inhibitor toripalimab—has shown encouraging activity in advanced biliary tract cancers. This phase 2–3 randomised trial evaluated whether neoadjuvant GOLP before surgery could improve outcomes in patients with resectable high-risk iCCA. Summary In this multicenter randomised trial, 178 patients with resectable high-risk intrahepatic cholangiocarcinoma were assigned to either: Neoadjuvant GOLP therapy followed by surgery and adjuvant capecitabine Upfront surgery followed by adjuvant capecitabine (control group) At a median follow-up of 16.9 months, the median event-free survival was significantly longer with neoadjuvant therapy (18.0 months) compared with the control group (8.7 months, P<0.001). Two-year overall survival was 79% in the neoadjuvant group versus 61% in the control group, suggesting a survival advantage, although the predefined statistical threshold was not met. The objective response rate to neoadjuvant therapy was approximately 55%, with major pathological response in 19% and pathological complete response in 5% of patients. Adverse events occurred in 97% of patients receiving GOLP, with grade ≥3 toxicity in 28%, mainly hematologic, but no treatment-related deaths were reported. Key Message Neoadjuvant GOLP therapy significantly improves event-free survival in patients with resectable high-risk intrahepatic cholangiocarcinoma, suggesting a promising strategy to reduce early recurrence and potentially improve long-term outcomes.

Introduction Cholangiocarcinoma (CCA) is the second most common primary liver cancer and is associated with poor prognosis due to late diagnosis and aggressive tumour biology. Increasing evidence links diabetes mellitus and chronic hyperglycemia with both the development and progression of CCA. Tumour cells demonstrate a strong dependence on glucose metabolism—a phenomenon termed “glucose addiction.” CCA cells frequently upregulate glucose transporters (GLUTs) and glycolytic enzymes, allowing them to utilise glucose for rapid energy generation through aerobic glycolysis (Warburg effect). Beyond energy production, glucose also fuels multiple biosynthetic and signalling pathways that support tumour proliferation, invasion, and resistance to therapy. Summary This review highlights how high glucose environments promote cholangiocarcinoma progression through metabolic and signalling mechanisms. Key mechanisms include: Enhanced glycolysis (Warburg effect): Upregulation of GLUT1, PKM2, HK2, PFK1, and LDHA increases glucose uptake and glycolytic flux, supporting rapid tumour growth. Activation of oncogenic pathways: Hyperglycemia stimulates signaling cascades such as PI3K–AKT–mTOR, HIF-1α, and MYC, which further drive tumor proliferation and metabolic reprogramming. Alternative glucose pathways: Glucose metabolites feed into the pentose phosphate pathway (PPP) and hexosamine biosynthetic pathway (HBP), generating nucleotides, lipids, and glycosylated proteins essential for cancer progression. Tumor microenvironment changes: Increased lactate production leads to acidic microenvironments, enhancing tumor invasion and immune evasion. Importantly, this metabolic dependency may represent an Achilles’ heel of CCA cells. Targeting glucose metabolism—through glycolytic inhibitors, GLUT blockade, or metabolic pathway inhibitors—offers promising therapeutic opportunities for future CCA treatment strategies.

Introduction Acute pancreatitis (AP) is often considered a self-limited illness once the acute episode resolves, with survival exceeding 95%. However, increasing evidence suggests that AP frequently initiates a cascade of long-term pancreatic complications, including recurrent acute pancreatitis (RAP), early chronic pancreatitis (ECP), chronic pancreatitis (CP), and progressive endocrine dysfunction such as prediabetes and diabetes mellitus. The Goulash-Plus study, a prospective multicenter cohort from the Hungarian Pancreatic Study Group, was designed to longitudinally track structural pancreatic changes and endocrine outcomes following AP, aiming to clarify when disease progression occurs and identify critical periods for monitoring. Summary In this ongoing prospective cohort study, 360 patients with AP were followed for four years. At baseline, most patients (74.7%) had a single AP episode without morphologic pancreatic changes. Over time, structural progression was substantial: the proportion of patients with RAP, ECP, or CP increased from 25.3% at baseline to 55.1% at 4 years. Among patients with a single AP episode initially, 35.1% developed morphologic progression. Endocrine dysfunction progressed even more dramatically. At baseline, 59% had normal glucose metabolism, but by four years, prediabetes or diabetes occurred in 76.4%, and diabetes alone increased from 13.6% to 39.2%. Notably, most progression—both structural and endocrine—occurred within the first two years after AP. These findings highlight AP as a major risk factor for chronic pancreatic disease and metabolic dysfunction, supporting structured follow-up with pancreatic imaging and glucose testing during the first two years after AP.