Early-onset cancer (EOC) of the oesophagus, stomach, colorectum, biliary tract, liver, pancreas, kidney, prostate, uterine corpus, breast, bone marrow, and head and neck has shown an increasing incidence worldwide. This Review summarizes current evidence for epidemiological and molecular pathological features of rising EOC overall and in each organ-specific cancer type, underscoring not only their shared aetiologies but also their dissimilarities. Although the contributions of enhanced screening, diagnostics and early detection to the rise of EOC are difficult to quantify, a genuine increase in EOC development seems likely in certain EOC types exhibiting mortality increases or aggressive tumoural features compared to later-onset counterparts. Evidence suggests that this trend reflects decades-long influences of environmental, lifestyle, systemic and metabolic factors that begin in early life. Polygenic influences with associated gene–environment interactions on cancer risks appear more pronounced in younger ages. However, identifying specific aetiological factors remains difficult due to prolonged latency, confounding and limited availability of long-term exposure data. Nonetheless, EOC tumour profiling efforts provide pathogenic clues to genomic, epigenomic, microbial and immune contributions. Integrative research frameworks, such as molecular pathological epidemiology, combined with the prospective cohort incident-tumour biobank method, comprehensive biorepositories and artificial intelligence-empowered analytical tools, offer promising opportunities to clarify pathophysiological mechanisms. Early-onset cancer of many body sites and organ systems is increasing worldwide; this Review outlines the potential causes.

Endoscopic retrograde cholangiopancreatography (ERCP) is essential for pancreatobiliary diseases but carries a risk of post-ERCP pancreatitis (PEP). Early prediction of PEP is crucial; thus, urinary trypsinogen-2 (UT2) is a potential biomarker, but its role and optimal measurement timing remain unclear. This single-center prospective study enrolled consecutive patients undergoing their first ERCP at our institution between February 2022 and June 2024. Patients with choledochojejunostomy, biliary pancreatitis, or hemodialysis were excluded. The diagnostic performance of UT2 was evaluated immediately, 1 h, and 3 h after ERCP, and compared with serum amylase (AMY) measured 3 h after ERCP. Of 521 patients screened, 337 were analyzed (median age 74 years, 64

BACKGROUND & AIMS:The optimal timing for direct endoscopic necrosectomy (DEN) after endoscopic ultrasound (EUS)-guided transmural drainage of symptomatic necrotizing pancreatitis remains unknown. We hypothesized that immediate DEN after EUS-guided drainage might reduce the time to disease resolution compared with a drainage-oriented step-up approach. METHODS:This study was a multicenter, open-label, superiority randomized trial (WONDER-01). Among patients who received EUS-guided treatment for symptomatic necrotizing pancreatitis, eligible patients were randomly assigned 1:1 to receive either immediate DEN or the drainage-oriented step-up approach. The primary endpoint was the time from randomization to clinical success, defined as a decrease in collection size to ≤3 cm and an improvement in inflammatory markers. RESULTS:Seventy patients were enrolled in this study: 33 in the immediate DEN arm and 37 in the step-up arm. Immediate DEN was associated with a shorter time to clinical success than the step-up approach (P = .009), with median times (95% confidence interval) of 29 (19-34) and 44 (38-52) days, respectively. All patients in the immediate DEN arm received DEN compared with 46% in the step-up approach arm, but the rates of procedure-related adverse events were comparable (24% vs 22%, respectively; P = .79). No significant differences were noted between the treatment arms in terms of technical success (100% vs 97%; P > .99) and mortality (12% vs 5.4%; P = .41). CONCLUSIONS:Compared with the step-up approach, immediate DEN after EUS-guided drainage of necrotizing pancreatitis reduced time to clinical success without increasing adverse outcomes but required more DEN procedures (ClinicalTrials.gov, NCT05451901).

Prognostication for pancreatic ductal adenocarcinoma (PDAC) using histologic images is difficult due to tumor heterogeneity. We developed an artificial intelligence (AI) model to predict postoperative recurrence using histologic image patches. We included 591 patients with resected PDAC to train an AI model for recurrence prediction at 12 or 24 months and validated it using external cohorts (n = 302 in total). Image patches from hematoxylin and eosin-stained slides were clustered via uniform manifold approximation and projection (UMAP) and used to train a random forest model. Predictive performance was evaluated using area under the receiver operating characteristic curve (AUC). Gene expression analysis was conducted to characterise survival-related clusters. Seventeen patch clusters were identified. Two were linked to high recurrence risk, and one to low risk. In external validation, the model achieved an AUC of up to 0.792. The random forest score independently predicted recurrence. Greater heterogeneity in patch composition correlated with shorter time to recurrence (P < 0.01). High-risk clusters showed elevated CSF3R expression; the low-risk cluster showed increased IGFBP3 expression. Our AI model, using only archival histologic slides, accurately predicted postoperative recurrence in PDAC and revealed image features linked to outcomes and gene expression.

BACKGROUND:Adiposity may promote the progression of different types of cancer. The prognostic significance of visceral and subcutaneous adipose tissue has not been thoroughly investigated in patients with advanced biliary tract cancer. METHODS:Using a single-institutional series of 386 patients with unresectable or recurrent biliary tract cancer, we measured visceral and subcutaneous adipose tissue areas (both normalized by body height) based on abdominal computed tomography images. Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) according to adipose tissue areas. RESULTS:Neither visceral nor subcutaneous adipose tissue area was associated with PFS or OS (Ptrend > 0.02 at the α level of 0.005 accounting for multiple comparisons). The multivariable HRs for PFS comparing the highest to lowest quartiles were 1.01 (95% CI, 0.71-1.45) and 0.95 (95% CI, 0.67-1.36) for visceral and subcutaneous adipose tissue, respectively. The corresponding HRs for OS were 0.84 (95% CI, 0.61-1.16) and 0.71 (95% CI, 0.52-0.96), respectively. Null survival associations were also observed for total adipose tissue area and visceral-to-subcutaneous adipose tissue area ratio (Ptrend > 0.06). CONCLUSIONS:The adipose tissue area was not significantly associated with survival outcomes of patients with advanced biliary tract cancer. Our data suggest a minimal role of adiposity status in determining tumor progression and patient survival in this population.