Hepatocellular carcinoma (HCC) has high global morbidity and mortality. Advanced HCC depends on systemic therapies, but primary/acquired drug resistance severely limits patient survival, creating an urgent need for new targets. This review focuses on how lactylation modification drives HCC drug resistance. In recent years, lactylation, a novel type of post-translational modification (PTM) of proteins mediated by the metabolic product lactate, has been found to be widely involved in the regulation of malignant progression, maintenance of stem cell characteristics, and treatment resistance in HCC. Lactylation conjugates lactate to histones and non-histones, regulating gene expression. Key resistance pathways include: lactylated IGF2BP3 activating PCK2-NRF2 to counter lenvatinib-induced stress; ALDOA lactylation enhancing liver cancer stem cell self-renewal for chemoresistance; MOESIN lactylation in Regulatory T cells (Tregs) weakening anti-PD-1 efficacy. HCC lactylation levels are higher than normal tissues (correlating with poor prognosis); lactylation-related genes/models predict treatment responses. Therapeutically, 2-DG, AZD3965, or SIRT3 activators (reverse lactylation) restore drug sensitivity, alone or in combination. Despite limited specific detectors, lactylation is a promising target to overcome HCC drug resistance, aiding precision treatment.

The REGOTORI study showed that some metastatic colorectal cancer (mCRC) patients benefited from programmed death 1 (PD-1) antibody toripalimab plus anti-angiogenic tyrosine-kinase inhibitor regorafenib. However, biomarkers for this combined therapy in mCRC remain unclear. To address this gap, we performed an integrated multi-omics biomarker analysis in REGOTORI. Next-generation sequencing was performed on formalin-fixed, paraffin-embedded (FFPE) tissue and paired plasma samples. Multiplex immunohistochemistry was performed to analyze the tumor microenvironment (TME) on FFPE samples. Variant allele frequency, somatic alterations, tumor mutational burden (TMB), circulating tumor DNA (ctDNA), and TME markers were jointly assessed from both FFPE and plasma samples to explore their associations with clinical outcomes under regorafenib plus toripalimab. A total of 35 patients were included. Patients with lower ctDNA maximum somatic allele frequency (maxAF), high-allele-frequency blood-based TMB (HAF-bTMB), blood-based intratumor heterogeneity (bITH), or HAF-bITH had longer survival time than their respective counterparts. Somatic alterations in SMAD4 (progression-free survival: 2.4 vs 1.6 months; overall survival: not reached vs 5.1 months) or PIK3CA (overall survival: 15.5 vs 5.7 months) were associated with shorter survival time. ctDNA dynamics appeared related to treatment response. High positive rates of CD3+, CD3+CD8+, CD3+CD8-, and PD-1+CD3+ T cells in the stroma area correlated with prolonged progression-free survival and favorable disease control; however, neither the positive rate of PD-L1 cells nor the density of it in the tumor area was associated with survival and response. In this combination-therapy-focused multi-omics analysis integrating tissue genomics, ctDNA features/dynamics and TME profiling, we identified ctDNA maxAF, HAF-bTMB, bITH, HAF-bITH, mutational status of SMAD4 or PIK3CA and TME markers as predictive or prognostic biomarkers for regorafenib plus toripalimab in refractory mCRC.

Whether physical activity and restricted sedentary behaviour can maintain pancreas health remains inconclusive. We aimed to comprehensively investigate the associations of physical activity and sedentary behaviour with exocrine and endocrine pancreatic diseases in a prospective cohort study and further verify these associations by using Mendelian randomization (MR). The prospective study included 437,131 UK Biobank participants free of pancreatic diseases at baseline. We used moderate-to-vigorous physical activity (MVPA) to indicate physical activity and leisure screen time (LST) to indicate sedentary behaviour. Outcomes included five diseases related to pancreatic secretory functions. We conducted Cox proportional hazards regression and mediation analyses to examine the mediating role of body mass index (BMI). MR analysis was used to assess the robustness of the observational findings. During a mean follow-up of 14 years, we identified 2,548 acute pancreatitis (AP), 638 chronic pancreatitis (CP), 1,711 pancreatic cancer (PC), 1,705 type 1 diabetes mellitus (T1DM), and 19,371 type 2 diabetes mellitus (T2DM) cases. Increasing MVPA was associated with AP, CP, T1DM, and T2DM risk in a U-shaped manner, with the lowest risk at ∼3,000 metabolic equivalent tasks-minutes/week (all P-nonlinearity < 0.05). BMI partially mediated associations of MVPA with AP, T1DM, and T2DM. LST was associated with an increased risk of AP, CP, PC, T1DM, and T2DM, with significant linear trends for CP, PC, and T1DM (all P-nonlinearity > 0.05). BMI partially mediated the associations of LST with AP, PC, T1DM, and T2DM. MR confirmed the associations of MVPA with AP and CP and of LST with AP, CP, and T2DM. Moderate MVPA and strict restriction of LST can serve as effective and practical strategies for preventing AP, CP, and T2DM.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), follow heterogeneous clinical trajectories. Although therapeutic options have expanded substantially over the past two decades, the extent to which modern treatment modifies long-term structural outcomes remains uncertain. We performed a targeted review focusing on high-quality population-based inception cohorts and large registries that report long-term outcomes in adult- and pediatric-onset IBD. Outcomes of interest included phenotype or extent progression, surgery, extraintestinal manifestations (EIMs), and colorectal neoplasia. CD consistently emerged as the more structurally progressive condition. Approximately one third of adults' progress from inflammatory to stricturing or penetrating disease within 5 years, and around half do so over longer follow-up. Perianal disease develops in 10%-20% of patients, with higher rates in pediatric-onset CD. Despite declines in surgical rates in the biologic era, intestinal resection remains frequent. In UC, proximal extension is the dominant progression pattern, affecting roughly one third of patients with limited disease over the first decade; pediatric UC shows even higher extension rates. Colectomy risks have markedly decreased in contemporary cohorts, and colorectal cancer incidence has declined compared with historical estimates, reflecting improved inflammation control and surveillance. Across IBD, EIMs occur in approximately one quarter of patients and cluster with extensive colonic involvement and higher systemic inflammatory burden. Population-based evidence reveals that IBD remains progressive in a substantial subset of patients, with notable differences between CD and UC and between adult and pediatric disease. Declining surgical and colorectal cancer rates suggest a measurable therapeutic era effect, supporting the importance of early, sustained inflammation control. However, high-quality prospective disease-modification trials are still needed to further characterize how current strategies can durably alter the natural history of IBD.

Liver transplantation (LT) is the most effective curative therapy for selected patients with hepatocellular carcinoma (HCC). However, rising LT demand, limited graft availability, and evolving HCC epidemiology complicate selection of candidate and prediction of pre- and post-LT outcomes. This review summarizes current evidence on patient selection, downstaging strategies, risk stratification, and post-LT surveillance in HCC treated with LT. Recent LT selection criteria increasingly integrate tumor morphology with biological markers and dynamic treatment response. Alpha-fetoprotein (AFP)-based models, such as Metroticket 2.0 and the French AFP criteria, improve prognostication compared with morphology alone. Downstaging using locoregional therapies can effectively decrease a larger tumor burden to LT eligibility criteria, although dropout rates remain higher for patients with larger or 'all-comers' tumors. Immune checkpoint inhibitors (ICIs) show promise for downstaging and may improve post-LT outcomes by eliminating micrometastases, but their rejection risk necessitates a roughly 3-month washout, and further evidence is required before routine use. Risk stratification models combining explant pathology, morphological and biological markers, like RETREAT, MORAL, and emerging tools, like circulating tumor DNA and radiomics/artificial intelligence, allow risk-adaptive surveillance and earlier recurrence detection. Post-LT imaging with AFP monitoring is suggested every 3 to 4 months in year 1, every 6 months in year 2, and every 6 to 12 months in years 3 to 5, with more frequent checks for high-risk patients. Future multicenter prospective studies should standardize downstaging algorithms, establish safe pre-LT ICI protocols, and validate integrated biomarker-imaging surveillance strategies to reduce recurrence and improve graft and patient outcomes.

The steatotic liver disease (SLD) landscape has seen a paradigm shift in recent years with a revitalization of the nomenclature following a multi-society Delphi consensus. The terms metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) were introduced to address several of the challenges and limitations associated with the former terminology. By transitioning away from stigmatizing and ambiguous terms, the nomenclature has adopted inclusionary language that emphasizes the underlying risk factors that drive disease progression and are accompanied by distinct diagnostic criteria. With SLD prevalence steadily increasing over the past few decades, affecting over 30% of the global population, accurate classification of the spectrum of conditions that fall under this overarching term is essential. Most importantly, the introduction of combined metabolic and alcohol-associated liver disease (MetALD) as a novel subclassification of SLD has shifted the diagnostic approach, raised awareness of disease prevalence, and paved the way for therapeutic management and multidisciplinary approaches to patient care. By recognizing the distinct clinical entity that is MetALD and the synergistic interplay between the cardiometabolic risk factors and alcohol use, clinicians are better equipped to effectively care for this patient population. In this review, we aim to discuss the catalysts for the SLD nomenclature changes, the dynamic nature of its subclasses, the natural history and disease burden, and the implications for clinical practice and research, with a particular focus on MetALD.

BackgroundMismatch repair–proficient rectal cancer (pMMR RC) is characterized by limited effective therapeutic options and an unfavorable prognosis, largely attributed to the complexity of the tumor immune microenvironment. Tertiary lymphoid structures (TLSs), which are ectopic lymphoid aggregates that develop within tumors, constitute a crucial component of this microenvironment and have shown considerable prognostic significance. However, the maturation heterogeneity of TLS subtypes within the tumor immune microenvironment, as well as their associations with clinicopathological characteristics and patient outcomes, remain poorly defined. This study aimed to comprehensively characterize the spatial distribution patterns and prognostic relevance of TLS subtypes in patients with pMMR RC.MethodsWe retrospectively analysed tissue sections from 155 patients with pMMR RC who underwent radical resection. TLS maturation subtypes were identified by using hematoxylin and eosin staining and immunohistochemistry, with their spatial distribution quantified and associated with prognosis.ResultsThe number of all TLS maturation subtypes in the invasive margin was significantly higher than that in the central tumor region (invasive margin vs central tumor region, P < 0.001). Among these, primary follicle-like TLS exhibited the greatest abundance across all tumor regions. Univariate survival analysis revealed that a higher infiltration of secondary follicle-like TLS across all tumor regions was significantly associated with improved survival, whereas increased early TLS infiltration was associated with poorer outcomes. Multivariate analysis further confirmed that the overall infiltration level of secondary follicle-like TLS was an independent predictor of both overall survival and disease-free survival in patients with pMMR RC.ConclusionSecondary follicle-like TLS infiltration independently predicts survival in pMMR RC, underscoring its potential as a prognostic biomarker and immunotherapeutic target.

This study aimed to investigate the associations between parenteral energy/amino acid doses and clinical outcomes in patients who were fasting after gastroenterological cancer surgery. Patients who were fasting for ≥ 7 days after gastroenterological cancer surgery between 2011 and 2022 were identified in a Japanese medical claims database. The associations between parenteral energy/amino acid doses which are supplied to patients via the peripheral or central vein and clinical adverse events were investigated. Low- (< 0.8 g/kg/day) and high- (≥ 0.8 g/kg/day) amino acid dose groups were compared using propensity score matching (PSM). The primary outcome was clinical adverse events, and secondary outcomes were in-hospital mortality, postoperative complications, decline in activities of daily living, rehospitalization, length of hospital stay, and hospitalization costs. Of 18,294 eligible patients, no association was found between clinical adverse events and energy doses (Wald test, P = 0.065). Patients who had high-amino acid doses were significantly associated with lower clinical adverse events than patients who had low-amino acid doses (Wald test, P = 0.002). After PSM, 2,585 pairs were formed. Clinical adverse events (42.1% vs 45.1%; odds ratio, 0.88; 95% confidence interval [CI], 0.79-0.99), in-hospital mortality (4.2% vs 5.4%; odds ratio, 0.77; 95% CI, 0.59-0.99), and hospitalization costs (19,788 vs 20,606 USD; regression coefficient, -1,538; 95% CI, -2,250 to -833) were significantly lower in the high-amino acid group. There were no significant differences in other outcomes. Parenteral amino acid dosing may play an important role in improving clinical outcomes in patients after gastroenterological cancer surgery, particularly in those who are fasting for 7 days or longer.

BackgroundPrimary hyperparathyroidism (PHPT) is an uncommon but clinically significant cause of acute pancreatitis (AP). Its clinical course and prognosis remain inadequately characterized compared to common AP etiologies.MethodsA bibliometric analysis was performed to evaluate global research trends on PHPT-associated acute pancreatitis (PHPT-AP). We conducted a retrospective cohort study at Peking Union Medical College Hospital between 2000–2025. Clinical data were compared with patients with biliary and hypertriglyceridemia-induced AP. Subgroup analyses evaluated differences between PHPT with mild/moderately severe AP and severe AP (SAP), and between AP and chronic pancreatitis (CP). Statistical analyses included logistic regression and Mann–Whitney U tests.ResultsThe bibliometric results revealed limited literatures but increasing attention to PHPT-pancreatitis. Our cohort showed PHPT-AP patients exhibited worse outcomes compared to non-PHPT-AP, with higher risks of SAP (OR 3.73, 95% CI 1.28–10.86, P = 0.016), intensive care unit admission (OR 3.79, 95% CI 1.17–12.32, P = 0.027), and in-hospital mortality (OR 12.76, 95% CI 1.52–107.3, P = 0.019). Serum calcium (median 4.2 mmol/L vs. 3.5 mmol/L, P = 0.015) and parathyroid hormone (median 1514.0 pg/mL vs. 312.0 pg/mL, P = 0.007) were significantly higher in PHPT-SAP. A three-phase calcium trajectory was observed in SAP: an initial hypercalcemic phase, a plateau under therapy, and eventual normalization after surgical or extracorporeal interventions. PHPT-CP was associated with longer PHPT duration, recurrent AP, and higher diabetes prevalence.ConclusionPHPT-AP is associated with a worse prognosis and requires proactive management. Serum calcium correlates with severity and should be monitored dynamically. Early surgery or continuous veno-venous hemofiltration may be warranted in severe cases. Prolonged PHPT with recurrent AP and lifestyle risk factors may contribute to CP.