胆胰外科领域文献阅读汇编

Nanoliposomal irinotecan (nal-IRI) has become an established therapy for advanced pancreatic ductal adenocarcinoma (PDAC), both in the post-gemcitabine setting and, more recently, in the first-line NALIRIFOX regimen. Concerns remain regarding cross-resistance in patients previously exposed to conventional irinotecan. We performed a systematic review and meta-analysis to evaluate the impact of prior irinotecan exposure on outcomes with nal-IRI. We conducted a systematic literature search of PubMed, Embase, and the Cochrane Library through July 2025 following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Eligible studies included patients with advanced PDAC treated with nal-IRI-containing regimens and reported outcomes stratified by prior irinotecan exposure. Data extraction and risk of bias assessments were performed independently by two reviewers. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled using random-effects models. Sensitivity and publication bias analyses were conducted. Thirteen retrospective studies comprising 2271 patients were included. One-third (33.1%) had received conventional irinotecan before nal-IRI. Prior irinotecan exposure was associated with inferior outcomes: pooled unadjusted and adjusted HRs for OS were 1.48 [95% confidence interval (CI) 1.24-1.76, P = 0.001] and 1.42 (95% CI 1.03-1.96, P = 0.030), respectively. For PFS, pooled unadjusted and adjusted HRs were 1.45 (95% CI 1.28-1.64, P < 0.001) and 1.72 (95% CI 1.16-2.54, P = 0.007), respectively. Patient-level subgroup analyses indicated that patients discontinuing prior irinotecan due to progression had significantly worse OS compared with those discontinuing for other reasons (HR 1.97, 95% CI 1.10-3.52). Most studies were high quality, and sensitivity analyses confirmed the robustness of the findings. Prior exposure to conventional irinotecan, particularly discontinuation for progression, reduced clinical benefit from subsequent nal-IRI therapy in advanced PDAC in observational cohorts. These findings support caution when considering nal-IRI soon after irinotecan progression and highlight the need for prospective sequencing studies.

Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions over a decade-plus, offering a window for interception in high-risk individuals, but current surveillance detects a minority of precursors. Mutant KRAS (mKRAS) is present in most PDACs and their precursors, making it an appealing target for immune-based interception. We conducted a phase I, first-in-human study of a peptide vaccine targeting six common KRAS mutations (mKRAS-VAX) in 20 individuals with hereditary PDAC predisposition and a radiographic pancreatic abnormality (NCT05013216) to assess safety, immunogenicity, and T cell persistence. Adverse events were grade 1-2. Vaccination elicited a significant mKRAS-specific T cell response in 18/20 participants (90%). Longitudinal TCR sequencing demonstrated persistence of vaccine-induced mKRAS-specific clonotypes for up to 2 years. Over a median follow-up of 16.5 months, no participants developed PDAC. These findings demonstrate that mKRAS-VAX is safe and generates durable T cell responses, which support the advancement of mKRAS-targeted vaccination for PDAC interception.

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer-associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy, and multiple CAF subtypes have been defined. However, defining the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior is required to better characterize the role of CAFs in PDAC. In this study, we used multiomic analyses to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs promoted epithelial-mesenchymal transition and a switch in tumor cell classification from classical to basal subtype. Furthermore, CAF-specific interleukin 8 functioned as a modulator of tumor cell subtype. Finally, neighborhood relationships between tumor cells and T cell subsets were defined, demonstrating a distinct spatial coordination among CAF and tumor cell subtypes. Overall, this study provides data supporting CAF signaling as a regulator of the cellular and behavioral heterogeneity in the PDAC TME. These findings can be used to explore rational approaches to improve therapies for this difficult-to-treat disease. Multidimensional analyses highlight the diverse role of cancer-associated fibroblasts in influencing cells in the tumor microenvironment and provide a platform for evaluating emerging therapeutic approaches and studying mechanisms dictating tumor behavior.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to its aggressive biology and therapeutic resistance. Lysine-specific demethylase 1 (LSD1), an epigenetic regulator, is overexpressed in PDAC and linked to poor prognosis, yet its context-dependent roles in metabolic subtypes and chemoresistance remain undefined. Here, we show that LSD1 knockdown has opposing, subtype-specific effects on chemotherapeutic responses: it sensitized RSK-subtype cells (L3.6pl, PANC-1) to chemotherapy but induced resistance in KRAS-subtype cells (BxPC-3, TBO368). Integrated analyses revealed mitochondrial dysfunction and defective mitophagy as hallmarks distinguishing KRAS- from RSK-subtype PDAC. Critically, mitochondrial targeting through respiratory modulation or mitophagy manipulation overrides LSD1-mediated subtype-specific chemoresistance, establishing mitochondrial fitness as the mechanistic determinant. Mechanistically, LSD1 transcriptionally regulates GLS2 to drive glutamine metabolic reprogramming, promoting reductive carboxylation in KRAS-subtype cells and oxidative metabolism in RSK-subtype cells. Our work establishes the LSD1-GLS2 axis as a metabolic switch controlling PDAC chemosensitivity and provides a framework for subtype-specific therapeutic strategies.

Ultrasound-induced luminescence offers a light-free imaging modality with deep tissue penetration and spatiotemporal controllability; however, its broader application is hindered by weak luminescent signals that limit imaging depth and signal-to-noise ratios. Here, we report an organic-inorganic heterojunction sonosensitizer, TA@TiO2, formed by coupling a trianthracene derivative (TA) with titanium oxide (TiO2). Under ultrasound irradiation, the nanoscale charge-transfer interface promotes interfacial charge transfer, significantly enhancing reactive oxygen species (ROS) generation. This increased ROS triggers amplified chemical energy conversion, resulting in a markedly enhanced ultrasound-induced luminescence signal for deep-tissue optical imaging. Compared to TA nanoparticles, TA@TiO2 exhibits superior signal transmission in scattering media and maintains high luminescence at lower power densities. In vivo studies demonstrate that TA@TiO2 enables high-contrast imaging of deep-seated tumors, such as pancreatic cancer and glioma, while providing enhanced sonodynamic therapy efficacy. The positive correlation between ultrasound-induced luminescence intensity and ROS generation allows for dynamic, imaging-guided tumor therapy. These results establish heterojunction engineering as a potent strategy for advancing ultrasound-activated theranostics.

Pancreatic cancer (PC) remains a highly lethal malignancy presenting formidable therapeutic challenges, primarily attributable to the substantial barriers posed by its dense desmoplastic stroma, profoundly immunosuppressive microenvironment, and poor drug bioavailability. Nanotechnology offers an effective strategy to enhance therapeutic efficacy through improved targeting, optimized pharmacokinetics, enhanced tissue penetration, increased biosafety, and high clinical translational potential. Consequently, this nanotechnology-based platform has been extensively investigated over the past decade for treating PC. This review examines a comprehensive overview of nanoparticle-mediated delivery systems for targeted PC therapy, critically evaluating recent developments and ongoing hurdles along the bench-to-bedside pathway. We discuss applications across chemotherapy, immunotherapy, gene therapy, and other modalities employed as monotherapies or combination regimens.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that frequently presents with disseminated disease. The PDA metastatic microenvironment imposes distinct metabolic stressors, potentially generating context-dependent vulnerabilities. Therefore, we employed CRISPR-based genetic screening in a model of PDA liver metastasis to identify novel and possibly targetable liabilities. Remarkably, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency - loss of FTH1 suppressed tumor growth specifically in the liver microenvironment. FTH1 deletion and subsequent disruption of iron handling triggers mitochondrial dysfunction and ionic imbalance, including cytosolic calcium overload. These perturbations result in the activation of a transcriptional program that triggers anti-tumor immunity mediated by immunostimulatory cytokine IL36G. Mechanistically, FTH1 deletion and subsequent ionic imbalance causes decreased protein levels of the tumor suppressor Stk11 (LKB1) which we propose to be mediated by an RNA G-quadruplex located in the 5'-UTR of LKB1. The loss of LKB1 protein levels alters signaling cascades resulting in reduced SIK signaling and inhibition of nonsense mediated decay, ultimately leading to Il36g mRNA stabilization. Taken together, this work elucidates novel ionic disruptions that regulate the translation of LKB1 through a previously undescribed quadruplex in the 5'UTR, altering signaling axes that can be targeted to generate an anti-tumor immune response in PDA.

Pancreatic ductal adenocarcinoma (PDAC) is largely refractory to immune checkpoint blockade, owing to its immunosuppressive tumour microenvironment. Neutrophil extracellular traps (NETs) accumulate in PDAC and correlate with disease progression, yet whether NETs reprogram cancer-associated fibroblast (CAF) heterogeneity and the upstream tumour-intrinsic signals that sustain pathological NETosis remain undefined. To delineate how NETs instruct CAF subtype specification and immunosuppression in PDAC, identify upstream NETosis drivers and evaluate combinatorial therapeutic strategies targeting this axis. Quantitative spatial analysis of human PDAC specimens, NETs-pancreatic stellate cell and patient-derived CAF cocultures, biotinylated DNA pull-down with liquid chromatography-tandem mass spectrometry, live-cell integrin-blocking assays, Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing, orthotopic and hepatic colonisation models, CD8+ T-cell functional assays and single-cell RNA sequencing of an eight-arm therapeutic study were employed. NETs-DNA directly engaged integrin α5β1 (ITGA5) on fibroblasts via its N-terminal domain, initiating a FAK (focal adhesion kinase)/SRC (Src family tyrosine kinase)-YAP (Yes-associated protein)-IL-6 (interleukin-6)-JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3) autocrine cascade specifying inflammatory CAF (iCAF) differentiation. Tumour-derived neutrophil gelatinase-associated lipocalin (NGAL), induced by IL-17, drove extracellular signal-regulated kinase (ERK)-reactive oxygen species-mediated NETosis. NETs-reprogrammed iCAFs accelerated tumour growth, hepatic colonisation and CD8+ T-cell exhaustion, with exhausted T cells spatially enriched in iCAF-rich regions. A composite NETs/ITGA5 signature stratified overall survival in patients with PDAC. Single-cell transcriptomics demonstrated that triple therapy (anti-IL-17+AV3+anti-PD-1) shifted fibroblasts from iCAF towards myofibroblastic CAF dominance, restored CD8+ T-cell effector programmes and achieved the greatest tumour suppression and survival benefit. We define an IL-17/NGAL/NETs/ITGA5 axis linking neutrophil-derived extracellular DNA to iCAF specification and immunosuppression in PDAC. Cotargeting IL-17 and ITGA5 synergises with PD-1 blockade, providing a rationale for combinatorial immunotherapy.

For decades, we have viewed pancreatic fibrosis as a passive scar-the end-stage wreckage of chronic inflammation or a late accomplice of growing tumors. A recent study by He Ren and colleagues sheds critical light on the origins of the phenomenon tracing it to an unexpected cellular culprit: a rare subset of pancreatic epithelial cells that express FOXP3-a transcription factor predominantly associated with regulatory T cells. These epithelial FOXP3 (E-FOXP3) positive cells do not need oncogenic Kras or overt inflammation to ignite fibrosis. On their own, they orchestrate a glycosylation-dependent IL-6 switch that turns quiescent pancreatic stellate cells into a self-amplifying fibrotic machine. In discovering a proto-fibrogenic "trigger cell" that acts silently, long before any symptom or radiological sign, the work redefines the cellular hierarchy of pancreatic fibrocarcinogenesis. Further, the paper identifies a post-translational "sugar code" as a therapeutic foothold, and opens a long-sought preemptive window for intercepting pancreatic cancer at its most curable stage-before the desmoplastic fortress is ever built.

The biological significance of forkhead box A1 (FOXA1) in non-steroid-driven malignancies, such as pancreatic ductal adenocarcinoma (PDAC), has garnered increasing recognition. It assumes a pivotal role in regulating critical processes such as PDAC cell lineage, metabolism, and metastasis. However, its regulatory mechanisms remain elusive. Here, we demonstrate that histone deacetylase 5 (HDAC5) mediates the deacetylation of FOXA1 at lysine residue 270 (K270), leading to repression of FOXA1's global chromatin occupancy. In HDAC5-loss PDAC, K270 hyper-acetylated FOXA1 is reprogrammed to the transcription start sites (TSSs) of HIF1α-targeted genes, functioning as a pioneer factor of HIF1α signaling. Additionally, we show that HDAC5 antagonizes LSD1-mediated FOXA1 activation by converging on the dynamic equilibrium of acetylation-methylation transition at K270. Pharmacological inhibition of HIF1α/LSD1 suppresses the growth and progression of HDAC5-deficient PDAC in in vivo and in vitro models. Our study reveals the role of FOXA1 as a pioneer factor of HIF1α in PDAC, providing potential therapeutic strategies for HDAC5-deficient PDAC.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers due to its aggressive biology and resistance to existing therapies. Oncofetal chondroitin sulfate (ofCS) is a tumour-restricted glycosaminoglycan broadly expressed across solid cancers but largely absent from normal adult tissues. We developed C9-based chimeric antigen receptor (CAR)-T cells targeting ofCS to overcome poor antigen specificity and the immunosuppressive tumour microenvironment (TME). To optimise ofCS-targeted C9 CAR-T cell therapy for PDAC through integrated CAR design optimisation, metabolic enhancement and TME reprogramming. C9 and charge-optimised C9-66 CAR-T cells were engineered using a humanised ofCS-binding single-chain antibody fragment. Antitumour efficacy, functional durability and metabolic fitness were assessed in murine and patient-derived PDAC models. Enhancement strategies included inosine-mediated metabolic reprogramming, Nr5a2 overexpression and sequential TME remodelling using GLP-1R modulation, CSF-1R blockade and programmed cell death protein-1 inhibition. C9 CAR-T cells exhibited potent cytotoxicity, delayed tumour progression and extended survival in PDAC models. Compared with the parental construct, charge-optimised C9-66 CAR-T cells showed reduced exhaustion and more sustained activity in vivo. Inosine enhanced cytokine production, promoted central-memory differentiation and mitigated exhaustion, whereas Nr5a2 overexpression increased mitochondrial respiration and cytotoxicity. Sequential GLP-1R on-off modulation with macrophage and checkpoint blockade enhanced intratumoural CAR-T cell activity and prolonged survival. Human C9-66 CAR-T cells retained specific ofCS recognition and lysed patient-derived PDAC cells in vitro and in vivo. C9-66 CAR-T cells with metabolic optimisation and TME reprogramming represent a tumour-specific and clinically translatable immunotherapeutic strategy for PDAC and other ofCS-expressing solid tumours.

Gemcitabine remains a cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), yet the emergence of resistance constitutes a major clinical challenge with poorly understood epigenomic mechanisms. Here, we identified the pioneer transcription factor Foxa1 as a master regulator of gemcitabine resistance through multi-omics analysis. Mechanistically, Foxa1 drives widespread super-enhancer (SE) reprogramming and 3D genome remodelling in resistant cells, which coordinately activates the expression of key resistance genes, notably Rrm1 and Cdadc1. This is accompanied by increased chromatin accessibility, elevated H3K27ac enrichment at SEs, and enhanced Foxa1 binding at regulatory elements. Moreover, post-translational stabilization of Foxa1 via USP7-mediated deubiquitination sustains this epigenomic program. Genetic ablation of Foxa1 or specific SE regions near Rrm1 resensitizes resistant cells to gemcitabine. Building upon this mechanism, we demonstrate that bromodomain and extraterminal (BET) inhibitors, which disrupt SE function, potently reverse resistance. Notably, the clinical-stage BET inhibitor AZD5153, in combination with gemcitabine, achieves robust tumor suppression and overcomes resistance in cell-derived xenograft (CDX) models by dismantling the Foxa1-mediated resistant transcriptome and reinvigorating drug sensitivity. Our findings establish Foxa1-orchestrated enhancer reprogramming as a fundamental mechanism of gemcitabine resistance and unveil a promising epigenetic therapy to restore treatment efficacy in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States, driven by its aggressive biology and high metastatic incidence at diagnosis. With a 5-year survival rate of just 8%, PDAC remains one of the most lethal cancers. Mutant KRAS, present in more than 90% of cases, serves as a key driver of tumorigenesis and metabolic reprogramming. In this issue of Cancer Research, Thakur and colleagues uncover a novel metabolic adaptation that PDAC cells use to survive therapeutic stress. Their integrated metabolomic and lipidomic analyses show that ERK inhibition-targeting a key KRAS pathway effector-not only disrupts glycolysis and glutamine metabolism but also triggers a compensatory increase in fatty acid oxidation (FAO). This shift occurs through lipophagy, a lysosome-mediated lipid degradation process, rather than cytosolic lipolysis. Mechanistically, ERK inhibition promotes the nuclear translocation of TFEB, which drives the upregulation of FAO and lipophagy genes. This metabolic reprogramming enables PDAC cells to survive KRAS pathway blockade. Importantly, cotargeting FAO alongside ERK or KRAS inhibitors elicits a potent synergistic antitumor effect in vivo. This dual-target strategy holds promise for overcoming PDAC resistance to KRAS-targeted therapies, laying the groundwork for novel combination treatments. See related article by Thakur et al., p. 3519.

The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. In this study, we demonstrated that ATM-deficient tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. In genetically engineered mouse models, pancreatic stellate cell and cancer-associated fibroblast (CAF) coculture systems, single-nucleus multiomics, and human PDAC models, tumoral loss of ATM serine/threonine kinase drove CAFs toward αSMA+ myofibroblastic (myCAF) differentiation, independently of p53 status. The myCAFs, in turn, promoted cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increased reactive oxygen species and contractility signaling, enhancing TGFβ1 secretion. Pharmacologic TGFβ inhibition reversed myCAF differentiation, sensitized tumors to chemotherapy, and impaired tumor progression in both murine and human ATM-null models. These findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGFβ signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy. TGF-β-driven myofibroblastic stromal differentiation in ATM-deficient pancreatic cancer generates a genotype-specific tumor microenvironment, providing a targetable axis and highlighting the need to integrate epithelial genotype and stromal context in pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. In this study, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid (FA) oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and FA oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled FA oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacologic inhibition of FA oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that FA oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC. Treating pancreatic cancer with inhibitors that target the KRAS pathway rewires metabolism by increasing lipophagy and fatty acid oxidation, which can be targeted to sensitize tumors to KRAS signaling inhibition. See related commentary by Delgado Herrera and Ferrer, p. 3374.

The output signal of the sensor is closely correlated with its detection sensitivity, while the selection of luminescent materials and the presence of interfering substances in the detection medium can both affect the output signal. In this study, a bifunctional peptide (HWRGWVDEDKDKDKC) with antibody targeted fixation and interface anti-adsorption properties was designed by integrating recognition (HWRGWV), charge neutralization (DE), antifouling (DKDKDKDK) and anchoring (C) fragments, which endowed the constructed biosensing interface with high target capture efficiency and good antifouling ability. At the same time, AuAgTb-MOF with multiple synergistic amplification effects was developed as luminophore. Concretely, the antenna effect of 3,5-dicarboxyphenylboronic acid to Tb3+, the catalysis of Ag NPs for S2O82- and the conductivity of Au NPs significantly prompted the luminescence of AuAgTb-MOF. The design of intramolecular self-enhanced AuAgTb-MOF not only reduced energy transfer losses, but also simplified the construction of the biosensing platform. On this basic, the constructed biosensor had a wide detection range of 10-4 to 103 U/mL and a low limit of detection of 3.38 × 10-5 U/mL (IUPAC standard), realizing the sensitive and precise detection for pancreatic cancer markers, thus providing a positive reference for the clinical diagnosis of pancreatic cancer.

Cancer-associated fibroblasts (CAFs) are principal determinants of pancreatic ductal adenocarcinoma (PDAC) progression. CAFs can shape tumor behavior via multiple pathways, underscoring the need for a complete understanding of the regulatory mechanisms that govern CAF function. Here, we identified N6-methyladenosine (m6A) remodeling as a hallmark of CAF activation and defined a critical role for the m6A demethylase ALKBH5 in PDAC metastasis. Activated CAFs exhibited a global reduction in m6A abundance, with ALKBH5 emerging as a key regulator of the CAF epitranscriptome. Functionally, CAF-derived ALKBH5 enhanced pancreatic cancer cell migration and invasion in vitro and promoted epithelial-mesenchymal transition-associated gene expression in tumor cells in an m6A-dependent manner. Orthotopic co-implantation models and host genetic ablation models demonstrated that ALKBH5 plays a critical role in metastatic dissemination, with minimal impact on primary tumor growth. Mechanistically, ALKBH5 enhanced the m6A-dependent translation of HSF1 in CAFs, at least in part by relieving IGF2BP3-associated translational constraints. Elevated HSF1 subsequently activated LIF transcription through distal enhancer elements, establishing an ALKBH5-HSF1-LIF signaling axis that mediated the pro-metastatic CAF-tumor cell communication. Clinically, enrichment of ALKBH5⁺HSF1⁺ CAFs independently predicted poor prognosis and was preferentially observed in metastatic PDAC. Collectively, these findings uncover a CAF-intrinsic epitranscriptomic program that drives PDAC metastasis and highlight stromal m6A regulation as a potential therapeutic vulnerability.

Intrahepatic cholangiocarcinoma (ICC) is a lethal hepatic malignancy characterized by a prominent desmoplastic stroma. Here, we demonstrated that ARID1A, a core component of the SWI/SNF protein complex, is upregulated in ICC and plays an oncogenic role. Mechanistically, ARID1A stabilized NICD1 protein by inhibiting AMPK-dependent autophagy and lysosomal degradation, thereby sustaining Notch signaling. TLL1, a metalloproteinase that promotes collagen maturation, was found to be a downstream effector of ARID1A/Notch signaling. Specifically, TLL1 derived from ICC cells activated hepatic stellate cells (HSCs) and thus promoted tumor progression. Accordingly, ablation of TLL1 attenuated cancer-associated fibroblast (CAF) infiltration, collagen accumulation, and tumor progression. Moreover, virtual screening of a bioactive compound library identified acarbose, an effective medicine for glycemic control, as a potent inhibitor for TLL1. Pharmacological inhibition of TLL1 with acarbose suppressed HSC activation, collagen deposition, and tumor development. Collectively, these results establish a tumor-promoting ARID1A/Notch/TLL1 axis in ICC and reveal acarbose as a potential precision therapy for ARID1A-high ICC patients.

As the use of robotic cholecystectomy increases, its value remains poorly defined for complex elective cholecystectomy (CEC), where complex gallbladder pathology results in increased technical difficulty. To determine whether a robotic approach is associated with improved clinical outcomes and altered total hospital cost as compared with a laparoscopic approach for patients undergoing CEC. This cohort study analyzed data from an academic hepatobiliary referral center for patients who underwent cholecystectomy from August 2018 to August 2024. CEC was defined by preoperative criteria: prior aborted or partial cholecystectomy, presence of a cholecystostomy tube, and/or history of gallbladder perforation or fistula. Robotic-assisted vs laparoscopic cholecystectomy. The primary outcome was a composite of an unplanned postoperative endoscopic retrograde cholangiopancreatography or interventional radiology procedure. Secondary outcomes included operative time, postoperative complications, and operative and total hospital costs. A total of 863 patients underwent cholecystectomy and met inclusion criteria; 525 (60.8%) were female and 338 (39.2%) were male, and their median (IQR) age was 61 (45-71) years. Among patients undergoing CEC, the laparoscopic approach was independently associated with an increased need for unplanned endoscopic or percutaneous intervention compared with the robotic group (odds ratio, 4.24; 95% CI, 1.24-14.52; P = .02). There were no significant differences in postoperative outcomes between the laparoscopic and robotic groups in patients undergoing non-CEC. Patients undergoing the laparoscopic approach had significantly reduced operating room costs when compared with patients undergoing a robotic approach in both the CEC ($7720 vs $8936, respectively) and non-CEC groups ($6368 vs $ 8351, respectively). However, there was no difference in the overall total cost of care between laparoscopic CEC and robotic CEC groups ($14 309 vs $14 476, respectively). The overall total cost of care was significantly higher for patients undergoing robotic non-CEC as compared with laparoscopic non-CEC ($11 416 vs $9925, respectively). This study found that for complex gallbladder disease, robotic cholecystectomy offers a clinical advantage, reducing complications and downstream interventions without increasing the overall costs of care. These findings suggest strategic application of the robotic platform may offer clinical advantages in high-complexity gallbladder surgery, maximizing patient benefit and resource efficiency.

Fecal microbiota transplantation (FMT) has shown promise in overcoming resistance to immune checkpoint inhibitors (ICIs) in early-phase cancer trials. We investigated the safety, feasibility and efficacy of FMT from ICI responders to patients with advanced cancers progressing on ICIs. This was a single-arm phase IIa basket trial (MITRIC; NCT05286294) including patients with ICI-refractory cancer. Long-term ICI responders were used as FMT donors. Patients received FMTs in combination with ICIs; two FMT administrations (by colonoscopy) were scheduled before the first radiological evaluation after 6 weeks, and up to three later FMTs were allowed (by enema). Co-primary endpoints were the evaluation of FMT-related adverse events and objective response rate. Feasibility, clinical benefit rate, progression-free survival (PFS), overall survival (OS), implant engraftment, immune response and biomarkers were among the secondary objectives. The study enrolled 12 patients with melanoma (n=9), head and neck squamous cell carcinoma (HNSCC; n=1), renal cell carcinoma (n=1) or microsatellite instability-high pancreatic cancer (n=1). FMT was well tolerated, whereas immune-related toxicity occurred in 6/12 patients. All patients received the first FMT; 10/12 patients also underwent the second FMT. No objective responses were observed, while 5/12 patients recorded stable disease. Clinical benefit per-protocol (stable disease >6 months) was achieved in a patient with melanoma, who had regression of some lesions and remains alive after 33 months without further systemic treatment. Mixed responses with regression of some lesions were observed in another melanoma patient, and in a patient with HNSCC. The median PFS was 1.5 months, and median OS was 10.1 months. Sequencing of fecal samples indicated engraftment after the first FMT in most patients. Mass cytometry analysis of peripheral blood cells suggested that an activated and differentiated T-cell signature was associated with improved PFS and OS, while a naïve T-cell phenotype and a myeloid-dominant environment were unfavorable. CD14+ monocytes and serum interleukin-8 increased at group level over time. FMT in combination with ICIs was safe and feasible in patients with advanced cancers, but with limited clinical activity. Further studies are required to clarify the potential benefit of FMT, identify the appropriate patient population and define criteria for donor selection. NCT05286294.

Mortality disparity in cancer between Black individuals and White individuals in the US has been declining since its peak in the early 1990s, but a comprehensive analysis of cancer type-specific contributions to this reduction is lacking. To examine cancer type-specific contributions to the reduction in the all-cancer excess mortality rate among Black individuals compared with White individuals between the peak period (1991-1995) and a contemporary period (2019-2023) in the US. A cross-sectional temporal analysis was conducted between March 2025 and October 2025. Non-Hispanic Black individuals and White individuals who died of cancer between 1991 and 2023 were included in the analysis. The data were compiled by the National Center for Health Statistics. Race as recorded on death certificates. All-cancer and cancer type-specific excess mortality rates per 100 000 for Black individuals compared with White individuals were calculated by sex. Changes in excess mortality rates were estimated by subtracting the current excess mortality rate for 2019 to 2023 from the peak excess mortality rate for 1991 to 1995. Cancer type-specific contributions to all-cancer excess mortality rate reduction were expressed as percentages. The analysis included 2 461 715 cancer deaths in 1991 to 1995 (11.8% non-Hispanic Black individuals; 47.4% were female) and 2 674 385 cancer deaths in 2019 to 2023 (13.2% non-Hispanic Black individuals; 47.2% were female). Between 1991 to 1995 and 2019 to 2023, the all-cancer excess mortality rate decreased by 98.4 (95% CI, 96.1-100.7) per 100 000 in Black males and by 21.7 (95% CI, 20.3-23.1) per 100 000 in Black females. Among males, lung (31.1% [95% CI, 29.9%-32.4%]), prostate (25.8% [95% CI, 24.7%-27.0%]), and esophageal (12.1% [95% CI, 11.7%-12.5%]) cancer accounted for the largest share of reductions in the all-cancer excess mortality rate. Among females, colorectal (18.8% [95% CI, 16.6%-20.9%]), cervical (16.9% [95% CI, 15.8%-18.0%]), and lung (15.1% [95% CI, 12.3%-17.9%]) cancer accounted for the largest share of reductions in the all-cancer excess mortality rate. Despite these gains in excess mortality rate reduction, prostate, lung, and stomach cancer remained among the top 5 cancer types with the largest contemporary excess mortality rate among males, whereas colorectal cancer increased in rank (from fifth to second) as well as liver cancer (from tenth to fifth), reflecting comparatively smaller or stalled progress. Breast cancer and uterine corpus cancer ranked highest during the contemporary period in excess mortality rate among Black females compared with White females (7.2 per 100 000 and 4.9 per 100 000, respectively), followed by myeloma, colorectal, and pancreatic cancer. In this cross-sectional temporal analysis, the marked reductions in excess mortality indicate meaningful progress achieved for several major cancer types through population-wide cancer control efforts. Persistent or worsening disparities in breast cancer and uterine corpus cancer and substantial residual disparities in prostate cancer highlight priorities for equitable interventions. These findings may guide more targeted and efficient cancer prevention and control strategies to further accelerate progress.

KRAS mutations are among the most prevalent oncogenic alterations in colorectal, lung and pancreatic cancer, yet their detection remains analytically challenging in the presence of an overwhelming wild-type (WT) background. Here, we report a photoelectrochemical (PEC) genotyping platform that integrates clamp-inhibited loop-mediated isothermal amplification (C-LAMP) with enzyme-free singlet oxygen (1O2)-driven PEC transduction for mutation-selective KRAS detection. Locked nucleic acid (LNA) clamp probes selectively suppress WT amplification during isothermal amplification, enriching mutant alleles and enabling single-nucleotide variant (SNV) discrimination with high selectivity. Amplified products are magnetically captured and transduced into photocurrent via visible-light-induced 1O2 redox cycling, eliminating enzymatic reporters and reducing background interference. The C-LAMP/PEC platform achieves a limit of detection of 35 copies μL-1 (58 aM) and a minimum detectable variant allele frequency (VAF) of 4.8% in heterogeneous mutant/WT genomic DNA mixtures. Analytical performance was validated in cancer cell lines and in patient-derived fresh frozen tissues, showing complete concordance with Nanopore sequencing and droplet digital PCR (ddPCR) within the evaluated cohort (n = 16). This work introduces a robust and modular PEC biosensing strategy that combines molecular WT suppression with enzyme-free photoelectrochemistry, offering an economically competitive and instrumentation-simplified approach for clinically relevant KRAS mutation analysis toward decentralized testing.