Search Results (519)

Background/Objectives: Early detection of pancreatic cancer (PC) remains challenging due to the lack of effective screening tools. We aimed to develop a clinically applicable model to identify individuals at high risk of PC using routine health check-up data. Methods: In a 1:4 matched case–control study (111 cases and 439 controls) using data collected between 2010 and 2018, PC cases were defined as individuals diagnosed with PC within 2 years of a health check-up. A model was developed using conditional logistic regression and validated in an independent cohort of 52,043 individuals (40 PC cases; 2019–2021). Results: Five risk factors were identified: carbohydrate antigen 19-9 ≥ 39 U/mL, hemoglobin A1c ≥ 6.5%, alkaline phosphatase > 110 IU/L, weight loss ≥ 5%, and dyspepsia. A 12-point risk scoring system was constructed, with an area under the curve of 0.784 in the development and 0.841 in the validation cohort. At a threshold of ≥5, the high-risk group had a significantly higher 2-year incidence of PC than the low-risk group (2.56% vs. 0.047%; p < 0.001), a 54.76-fold risk enrichment, with a negative predictive value of 99.95% and a number-needed-to-follow of 39. Conclusions: This simple, validated model effectively stratifies short-term PC risk using routine data, potentially facilitating targeted surveillance in the general population. Full article

Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated remarkable efficacy in tumors carrying BRCA1/2 pathogenic variants (PVs) through the mechanism of synthetic lethality. PVs in other homologous recombination (HR) genes may also impair homologous recombination repair and confer sensitivity to PARPis; however, their predictive value remains uncertain and appears to vary according to the affected gene and tumor type. We review and critically discuss the current evidence regarding the predictive value of non-BRCA HR gene pathogenic variants as biomarkers of PARPi sensitivity across ovarian, breast, prostate, and pancreatic cancers. A narrative review was conducted between October 2023 and December 2025, first identifying pivotal clinical trials of PARP inhibitors across ovarian, breast, prostate, and pancreatic cancers, followed by a targeted search of PubMed, Embase, Web of Science, and Google Scholar for relevant preclinical and clinical studies. Seventeen clinical studies and multiple preclinical reports were analyzed regarding genomic frequency, HRD association, and treatment response. Preclinical studies consistently demonstrated increased PARPi sensitivity in models with alterations in several non-BRCA HR genes. Clinical evidence, however, was heterogeneous. PALB2 demonstrated the strongest and most consistent association with PARPi benefit across tumor types, while RAD51C and RAD51D also showed clinically meaningful activity, particularly in ovarian cancer. In contrast, evidence supporting PARPi sensitivity in tumors harboring ATM, CHEK2, CDK12, and several other HR gene alterations remained limited or inconsistent. Differences in gene function, biallelic inactivation, variant type, and current limitations of HRD companion diagnostic assays likely contribute to the observed variability in clinical response. Non-BRCA HR gene alterations represent promising predictive biomarkers for PARPi therapy but should not be considered a homogeneous group. Future biomarker-driven studies integrating comprehensive genomic profiling and functional assessment of homologous recombination deficiency are needed to refine patient selection and optimize the clinical application of PARPis beyond BRCA1/2-associated cancers. Full article

Background: The molecular changes associated with the progression of intraductal papillary mucinous neoplasm (IPMN) to pancreatic ductal adenocarcinoma (PDAC) and distant metastasis remain incompletely understood. Case Presentation: A man in his late 70s underwent pancreaticoduodenectomy and partial hepatectomy for a pancreatic head tumor with synchronous liver metastasis. Histology showed a 4.5 cm moderately differentiated PDAC arising in an IPMN with high-grade dysplasia (pT3N1M1). Genomic analysis of the IPMN, PDAC, and liver metastasis identified KRAS p.G12D, CDKN2A deletion, and GNAS p.R201H in the IPMN; additional SMAD4 p.R361C in the PDAC; and KRAS p.G12D, CDKN2A deletion, SMAD4 p.R361C, and APC p.R1450Ter in the liver metastasis. The APC alteration was confirmed by targeted sequencing and was accompanied by loss of heterozygosity at the APC locus. β-Catenin showed membranous expression in the IPMN and PDAC, but nuclear accumulation in the liver metastasis. Discussion: The shared KRAS, CDKN2A, and SMAD4 alterations support a common clonal origin of the PDAC and metastatic tumors. The absence of a detectable GNAS alteration in the liver metastasis and the presence of a metastasis-specific APC alteration are compatible with, but do not prove, branching evolution and selection of a metastatic subclone. Conclusions: This case shows a metastasis-specific heterozygous APC truncating alteration with loss of heterozygosity, accompanied by nuclear β-catenin accumulation, in an IPMN-associated PDAC. Full article

Background: Vitamin D deficiency is common in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Whether vitamin D status influences tumor aggressiveness and clinical outcomes remains uncertain. This review examines current evidence on the prevalence, determinants, clinical associations, and clinical relevance of vitamin D deficiency in GEP-NENs. Methods: A narrative and critical review of the literature was conducted using the PubMed/MEDLINE, Scopus, and Web of Science databases. Clinical studies, observational cohorts, translational research, selected mechanistic studies, and current clinical guidelines addressing vitamin D metabolism and neuroendocrine neoplasms were evaluated. Results: Vitamin D deficiency has been reported in approximately 60–80% of patients with GEP-NENs. Low serum 25-hydroxyvitamin D concentrations likely reflect multiple disease-related factors, including malabsorption, pancreatic exocrine insufficiency, chronic diarrhea, previous gastrointestinal surgery, and nutritional impairment. Several observational studies have linked lower vitamin D status with markers of more aggressive disease, including higher Ki-67 proliferation index values and shorter progression-free survival. Nevertheless, the available data are heterogeneous, predominantly observational, and do not support a causal relationship between vitamin D deficiency and tumor progression. At present, the main clinical rationale for assessing vitamin D status is to support metabolic care, preserve bone health, and prevent osteoporosis. Conclusions: Vitamin D deficiency is a frequent and clinically relevant comorbidity in patients with GEP-NENs. Although lower vitamin D status has been associated with markers of more aggressive disease, current findings do not support vitamin D supplementation as an anticancer treatment strategy. Prospective clinical and translational studies are needed to clarify the biological and clinical significance of vitamin D signaling in GEP-NENs. Full article

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is among the most clinically relevant and conceptually intricate precancerous lesions encountered in modern gastroenterology. First identified in the early 1980s as a “mucin-producing tumor,” IPMN has since undergone a profound redefinition: from an obscure and poorly classified entity to a well-established precursor of pancreatic ductal adenocarcinoma (PDAC), shaped by characteristic molecular alterations such as KRAS, GNAS, and RNF43 mutations. Over the past two decades, the reported incidence of IPMN has risen sharply, a trend largely attributable to the widespread use of high-resolution cross-sectional imaging rather than a genuine increase in disease prevalence. IPMNs are categorized anatomically into main-duct (MD-IPMN), branch-duct (BD-IPMN), and mixed-type forms and histologically into gastric, intestinal, pancreatobiliary, and oncocytic subtypes, each associated with distinct malignant potential and prognostic implications. International consensus guidelines (Sendai 2006; Fukuoka 2012; Fukuoka revision 2017; Kyoto 2024) have progressively refined strategies for risk stratification and surgical decision-making. Nevertheless, significant debate persists regarding optimal surveillance intervals, thresholds for resection, and the management of low-risk branch-duct lesions. This review offers a comprehensive and critically evaluated synthesis about IPMN, spanning its historical recognition, molecular pathogenesis, epidemiology, clinical manifestations, diagnostic evaluation, pathological features, differential diagnosis, surveillance paradigms, long-term complications, associated conditions, therapeutic options, and future directions. Particular attention is given to longstanding “myths” that have influenced clinical practice and to emerging “realities” grounded in contemporary molecular and clinical evidence. Our aim is to provide physicians with a clear and updated framework for navigating the complexities of IPMN management in current practice. Full article

Pancreatic acinar cell carcinoma (PACC) is a rare exocrine pancreatic malignancy accounting for approximately 1–2% of adult pancreatic neoplasms. Although historically grouped with pancreatic ductal adenocarcinoma (PDAC), accumulating evidence demonstrates that PACC represents a biologically distinct entity with unique clinical, pathologic, and molecular characteristics. Compared with PDAC, PACC more commonly presents as a large pancreatic mass, is less frequently associated with obstructive jaundice, and exhibits lower rates of KRAS mutations. Recent genomic studies have identified recurrent alterations involving DNA damage repair pathways, WNT/β-catenin signaling, and actionable kinase fusions, including BRAF and RAF1 rearrangements. In advanced disease, fluoropyrimidine- and platinum-based regimens appear to demonstrate greater activity than traditional gemcitabine-based approaches, although prospective comparative data are lacking. This review summarizes the current understanding of the epidemiology, clinical presentation, pathology, molecular landscape, treatment approaches, and prognostic factors associated with PACC. We highlight emerging opportunities for precision oncology and discuss ongoing challenges in the management of this uncommon pancreatic malignancy. Full article

Background and Objectives: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is an emerging minimally invasive therapeutic option for pancreatic and selected extra-pancreatic lesions. However, its clinical adoption is limited by heterogeneous indications, non-standardized techniques, and variable quality of evidence. This systematic review assessed the published literature on EUS-RFA and classified available evidence according to the Oxford Centre for Evidence-Based Medicine levels of evidence. Materials and Methods: A systematic search was performed to identify peer-reviewed studies reporting clinical or translational data on EUS-RFA. Studies were grouped by indication, including pancreatic insulinoma, non-functioning pancreatic neuroendocrine neoplasms, branch-duct intraductal papillary mucinous neoplasms and other pancreatic cystic neoplasms, pancreatic ductal adenocarcinoma, pancreatic metastases, adrenal adenoma, and miscellaneous indications. Each study was categorized according to Oxford level of evidence based on study design. Results: Thirty-seven records were included in the final evidence map, comprising 36 clinical studies classifiable according to Oxford levels of evidence and one translational record not classifiable as clinical therapeutic evidence. Among the 36 clinically classifiable studies, one provided Level 1b evidence, consisting of a randomized trial evaluating EUS-guided celiac ganglion RFA for pancreatic cancer-related pain palliation, and three provided Level 2b evidence, including non-randomized comparative cohorts in pancreatic insulinoma and unresectable pancreatic ductal adenocarcinoma. Most clinically classifiable studies were Level 4 evidence (32/36), mainly uncontrolled prospective or retrospective cohorts and case series. One preclinical/translational study was not classifiable within clinical therapeutic evidence levels. Pancreatic insulinoma was the most evidence-supported tumor-ablation indication, with comparative data suggesting efficacy comparable to surgery and a more favorable safety profile. For non-functioning pancreatic neuroendocrine neoplasms, branch-duct IPMN, renal cell carcinoma pancreatic metastases, and adrenal adenomas, available data suggest feasibility and encouraging short-term outcomes but remain predominantly non-comparative. In pancreatic ductal adenocarcinoma, EUS-RFA remains investigational as an adjunct to systemic therapy. Conclusions: EUS-RFA is a promising therapeutic platform, but evidence remains highly indication-dependent and dominated by low-level observational studies. Standardized protocols, indication-specific outcomes, prospective registries, and comparative trials are needed. Full article

Objective: Current therapeutic regimens for pancreatic neuroendocrine neoplasms (pNENs) remain limited and fail to yield notable improvements in overall survival. Therefore, the development of novel agents is of paramount importance. Bruton’s tyrosine kinase inhibitors (BTKis) have demonstrated promising therapeutic potential in solid tumors; however, ibrutinib, a classic BTKi, exhibits unsatisfactory clinical efficacy against pNENs. In this study, we synthesized a novel pyrrolopyrimidine-based BTKi, QY21, and aimed to investigate its inhibitory effects on pNEN cell proliferation both in vitro and vivo and identify the core signaling pathways mediating its suppressive effects on pNENs. Methods: CCK-8, EdU, and colony formation assays were conducted to assess the effect of QY21 on pNENs in vitro. Transcriptome sequencing, quantitative real-time PCR, Western blotting, and flow cytometry were employed to explore the mechanisms. A xenograft tumor model in nude mice was established for in vivo validation. Results: QY21 significantly suppressed pNENs proliferation in vitro. Compared with the control and ibrutinib groups, QY21 exhibited stronger tumor growth inhibition in vivo. Histopathological analysis revealed a decreased Ki-67 index in the QY21 group, with no significant organ-toxic lesions observed. Transcriptome sequencing identified ATF3 as the core mediator responsible for the anti-proliferative effect of QY21. ATF3 was poorly expressed in pNENs, while QY21 markedly upregulated ATF3 expression. Mechanistically, QY21 induced ferroptosis by elevating ATF3 levels. The knockdown of ATF3 or administration of ferrostatin-1 significantly attenuated the anti-proliferative capacity of QY21, accompanied by reduced accumulation of reactive oxygen species and lipid peroxidation. Conclusions: This study demonstrates that the novel BTKi QY21 suppresses pNENs proliferation by triggering ATF3-mediated ferroptosis, providing a potential preclinical strategy for pNENs. Full article

Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer. This study investigated the association between MRI-derived pancreatic fat fraction and IPMN. Materials and Methods: This retrospective case–control study included 60 patients with IPMN and 120 controls evaluated between 2018 and 2025. All participants underwent pancreatic MRI with proton density fat fraction (PDFF) imaging. Pancreatic fat fraction was measured in the pancreatic head, body, and tail on PDFF maps, and mean pancreatic fat fraction was calculated. Group comparisons, receiver operating characteristic analysis, and logistic regression analyses were performed to evaluate the association between pancreatic fat fraction and IPMN. Results: A total of 180 participants were included in the study, comprising 60 patients with IPMN and 120 controls without IPMN. Patients with IPMN were significantly older than controls (72.5 vs. 57.0 years, p = 0.001). The IPMN group demonstrated higher glucose and LDH levels and lower HDL cholesterol, hemoglobin, hematocrit, and platelet counts compared with controls (all p < 0.05). Pancreatic fat fraction measurements were significantly increased in patients with IPMN across all pancreatic regions. Head, body, tail, and mean pancreatic fat fractions were markedly higher in the IPMN group than in controls (all p = 0.001). In multivariable logistic regression analyses, age and pancreatic fat fraction remained independently associated with IPMN presence. ROC analysis demonstrated excellent diagnostic performance, with mean pancreatic fat fraction showing the highest discriminative ability (AUC = 0.968), followed by head (AUC = 0.934), body (AUC = 0.922), and tail fat fraction (AUC = 0.876). Conclusions: Pancreatic fat fraction was significantly higher in patients with IPMN and remained independently associated with IPMN presence after multivariable adjustment. Mean pancreatic fat fraction demonstrated excellent diagnostic performance for distinguishing IPMN from non-IPMN individuals. Quantitative MRI-based assessment of pancreatic fat may represent a useful imaging biomarker for IPMN detection. Full article

Benign biliary tumors and precursor neoplasms of the biliary tract are a heterogeneous group of uncommon neoplasms with significant clinical and diagnostic implications. Their importance lies in their variable malignant potential and morphological and molecular similarities to pancreatic neoplasms. The sixth edition of the World Health Organization Classification of Digestive System Tumours (WHO DST6), published online in 2026, introduced major revisions to the classification of these entities. According to WHO DST6, benign tumors and precursor neoplasms of the liver and intrahepatic bile ducts include bile duct adenoma, biliary adenofibroma, and mucinous cystic neoplasm, whereas those of the gallbladder and extrahepatic bile ducts include biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile ducts, intraductal tubulopapillary neoplasm of the bile ducts, intraductal oncocytic papillary neoplasm of the bile ducts, and mass-forming intracholecystic neoplasm. Despite these advances, their histological and molecular heterogeneity continues to pose significant diagnostic challenges, particularly in distinguishing them from malignant biliary tumors on limited biopsy specimens and in recognizing early invasive lesions. This review summarizes the clinicopathological and molecular features of benign biliary tumors and precursor neoplasms, emphasizing differential diagnosis and key updates introduced in WHO DST6. Full article

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors that have traditionally been regarded as “immune cold” and largely refractory to PD-1/PD-L1 checkpoint blockade, with notable exceptions such as Merkel cell carcinoma (MCC). The advent of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has enabled unprecedented dissection of the NEN tumor microenvironment (TME), but a cross-subtype synthesis is lacking. This review aims to integrate single-cell and spatial transcriptomic findings across major NEN subtypes to reframe NEN immunosuppression and delineate translational implications. To this end, we performed a structured narrative review of PubMed-indexed studies up to 30 April 2026, prioritizing original human scRNA-seq, single-nucleus RNA-seq, spatial transcriptomic, and spatial proteomic studies of NENs, supplemented by mechanistic, clinical, and biomarker-focused reports providing essential context. Across these studies, synthesis spanning pancreatic, pulmonary, gastrointestinal, cutaneous, pituitary, adrenal, and other NEN subtypes highlights conserved features beyond the PD-1/PD-L1 axis, including myeloid-dominated infiltration with alternative checkpoints (VISTA, TIM-3, Galectin-9), cancer-associated fibroblast-mediated immune exclusion, lineage-state-dependent immune visibility, and direct immunomodulation by neuroendocrine secretory products such as calcitonin gene-related peptide. We propose a four-layer framework integrating these mechanisms and linking them to emerging biomarkers and therapies, including DLL3-directed bispecifics, alternative checkpoint inhibitors, stromal-targeting agents, and peptide receptor radionuclide therapy combinations. Together, these findings indicate that single-cell and spatial transcriptomic studies reframe NEN immunosuppression as a multilayered, subtype-dependent process, providing a conceptual scaffold for biomarker-guided, subtype-adapted therapeutic strategies and prospective clinical trial design in neuroendocrine oncology. Full article

Purpose: To develop and technically validate a reproducible multicentre MRI radiomics workflow for pancreatic cyst risk stratification using paired T1- and T2-weighted imaging from public datasets. Methods: Public datasets were screened and Cyst-X was selected as the primary cohort because it contained pancreatic MRI, risk labels, masks and metadata. A linked Cyst-X subset was enriched with metadata, filtered to an exact paired T1/T2 cohort, and processed through image–mask quality control, 1.0 mm isotropic resampling, intensity normalisation, PyRadiomics feature extraction, feature reduction and patient-level centre-held-out validation. The revised modelling strategy used a T2 + clinical all-patient primary analysis (n = 409) and a complete-case paired T1/T2 sensitivity analysis (n = 299). Results: The final cohort comprised 409 patients and 818 image-level rows across EMC, IU, MCF and NYU. All 818 image–mask pairs passed post-preprocessing QC. T2 radiomics were complete for all 409 patients; however, 110 T1 feature sets were missing, all from MCF. In the all-patient T2 + clinical model comparison, logistic regression achieved the highest macro-AUC (0.737). The T2 + clinical random forest comparator achieved macro-AUC 0.716 (95% CI 0.678–0.755), accuracy 0.545 (95% CI 0.496–0.592) and macro-F1 0.530 (95% CI 0.481–0.577). The paired T1/T2 complete-case random forest sensitivity model achieved macro-AUC 0.735 (95% CI 0.691–0.777), accuracy 0.575 (95% CI 0.520–0.632) and macro-F1 0.554 (95% CI 0.494–0.605). Conclusion: This study demonstrates the feasibility of constructing a reproducible public data MRI radiomics workflow for pancreatic cyst risk stratification. Model performance was modest, and independent external validation is required before clinical application. Full article

Multiple endocrine neoplasia (MEN) syndromes are rare hereditary disorders characterized by the development of multiple endocrine and non-endocrine tumours with variable penetrance and age-dependent expression. Although uncommon, these syndromes are highly relevant from both biological and clinical perspectives, as they exemplify the direct link between germline genetic alterations and tumorigenesis. Early tumour detection is critical in MEN syndromes because many associated neoplasms—such as medullary thyroid carcinoma (MTC), pancreatic neuroendocrine tumours (NETs), pheochromocytomas, and parathyroid disease—may remain clinically silent for prolonged periods while retaining malignant potential. Delayed diagnosis is associated with advanced disease and worse outcomes, whereas early identification enables curative or organ-preserving interventions. This clinical challenge has driven the development of integrated diagnostic strategies combining genetic testing, biochemical markers, and imaging. Among these, genetic testing plays a pivotal role, providing definitive diagnosis, enabling family screening, and guiding risk-adapted surveillance. The aim of this review is to provide a comprehensive synthesis of genetically driven diagnostics in MEN syndromes, outlining the current state of the art and future directions in precision medicine. Full article

Pancreatic cancer (PC) remains one of the malignancies with the most unfavorable prognosis and limited treatment options. The lack of biomarkers for early diagnosis and the asymptomatic nature of the disease contribute to delays in diagnosis and high mortality rates. In recent years, the role of the human microbiota in cancer biology has become increasingly significant, and the oral microbiota in particular has been found to be involved in the pathogenesis and prognosis of several neoplasms. This review summarizes the current evidence relating the salivary microbiota to PC in three key areas: screening and diagnostic potential, pathophysiology and tumor progression, as well as presenting prognostic implications and potential influence on therapy. With regard to early diagnosis, it has been reported that patients with PC have reduced levels of Neisseria elongata (N. elongata) and Streptococcus mitis (S. mitis) and elevated levels of Granulicatella adiacens. Several studies have shown that bacteria present in the saliva can migrate from the oral cavity to pancreatic tissue via hematogenous or enteric routes, where they may actively contribute to tumor development and progression. In particular, it has been shown that Porphyromonas gingivalis (P. gingivalis) and Veillonella atypica (V. atypica) translocate from the mouth to pancreatic tumors, promoting carcinogenesis by inducing a pro-inflammatory tumor microenvironment. Furthermore, some studies have identified certain species associated with prognosis and response to PC treatment. Despite the encouraging results, differences in study methodology, the lack of standardized methods and the scarcity of longitudinal data currently hinder clinical application. Large-scale, multi-omics prospective studies are needed to clarify causality and validate their clinical utility. Overall, the salivary microbiota represents a promising and non-invasive tool for improving early diagnosis, understanding prognosis and enhancing the management of PC. Full article

Background: The clinical characteristics of pancreatic acinar cell carcinoma (ACC) remain poorly defined due to its rarity. This study aimed to evaluate the morphological features and clinical outcomes of pancreatic ACC. Method: This multicenter retrospective study analyzed clinical data from seven referral hospitals. Electronic medical records were comprehensively reviewed to extract patient data. Survival outcomes were calculated from the date of pathologic confirmation of ACC. Results: Of the 37 patients, 28 (75.7%) were male. The age distribution at diagnosis ranged widely from 12 to 86 years, with a median of 62.0 years; seven patients (18.9%) were aged under 50 years. Morphologically, 24 patients (64.9%) presented with solid masses, whereas four had cystic masses and four exhibited mixed solid and cystic components. Regarding tumor resectability, 19 patients (51.4%) had resectable disease, 7 (18.9%) were locally advanced, and 11 (29.7%) were metastatic. In terms of treatment, 22 patients (59.4%) underwent surgical resection, 12 (32.4%) received palliative chemotherapy, and the remainder received best supportive care. In the surgical resection group, the median OS was not reached, demonstrating significantly prolonged survival (mean OS, 7.6 years; 5-year OS rate, 51%). In contrast, the median OS was 0.9 years in the palliative chemotherapy group and 0.1 years in the best supportive care group (p = 0.040). Conclusions: Pancreatic ACC showed a broad age distribution, with approximately 20% of patients aged <50 years, and pleomorphic morphological features, including solid, cystic, and mixed patterns. Patients who underwent surgical resection demonstrated favorable long-term survival outcomes compared to historical data for pancreatic ductal adenocarcinoma. Full article