BACKGROUND:Intratumoral microbiota have been implicated in several cancers, including pancreatic cancer, but data on pancreatic neuroendocrine tumors (PNETs) remain limited. METHODS:We analyzed two complementary cohorts: a retrospective formalin-fixed paraffin-embedded cohort comprising 53 primary PNETs, 26 paired adjacent non-tumor tissues (ANTs), and 5 liver metastases assessed by fluorescence in situ hybridization (FISH); and a prospective subset of 25 paired fresh tumor-center and ANT samples analyzed by 16S rRNA gene sequencing. Taxonomic composition, alpha and beta diversity, differential abundance, predicted microbial functions, and associations with clinicopathological features and fasting serum lipids were evaluated. RESULTS:PNETs showed a higher frequency of detectable bacterial signals and greater microbial richness and diversity than ANTs. LEfSe identified 38 nominally differentially abundant taxa (P < 0.05; LDA > 2.5), including enrichment of Blautia, Rothia, and Ferrovibrio in tumors. Their combined abundance differentiated PNETs from ANTs with an area under the curve of 0.843. Exploratory functional inference suggested enrichment of 15 pathways in PNETs, including fatty acid and short-chain fatty acid biosynthesis pathways. Serum high-density lipoprotein levels were inversely associated with intratumoral microbial richness (Ace index: r = -0.497, P = 0.049). CONCLUSIONS:PNETs exhibited greater bacterial burden, microbial richness, and diversity than ANTs, with distinct taxonomic patterns and lipid-related associations. These exploratory findings warrant external validation in larger cohorts with rigorous low-biomass contamination control.

Solid pseudopapillary neoplasm (SPN) of the Pancreas is a low-grade malignant pancreatic tumor characterized by low incidence and a predilection for young female patients. It exhibits unique histological and biological features, and its diagnosis and management differ significantly from those of more common pancreatic ductal adenocarcinoma and pancreatic cystic neoplasms, or the less common pancreatic neuroendocrine neoplasms. Surgical resection yields favorable outcomes for SPN; however, a minority of patients experience recurrence and metastasis. High-risk factors for recurrence and metastasis are increasingly being identified. To incorporate recent advances in the diagnosis and management of SPN and to advance the field, this review summarizes the highest level of evidence within the discipline, incorporating clinical expert experience. The goal is to summarize diagnostic and therapeutic strategies for SPN, thereby enhancing overall clinical outcomes.

High-density lipoprotein (HDL) is a highly heterogeneous lipoprotein with multiple physiological functions. However, observational studies present conflicting evidence regarding its association with various diseases. This review systematically summarizes evidence from Mendelian randomization (MR) studies to investigate the causal relationships between HDL-related biomarkers and a wide spectrum of disease outcomes. We systematically searched multiple databases up to November 2024. The causal relationship between HDL and 158 diseases was studied. Findings reveal that the role of HDL is highly disease-specific. Genetically predicted higher HDL levels are protective against most circulatory and digestive system diseases. Conversely, however, they are associated with an increased risk of certain conditions, including breast cancer, intracerebral hemorrhage, and age-related macular degeneration. The MR analyses revealed inconsistent and sometimes conflicting findings for several disease outcomes, notably Alzheimer's disease. This review underscores the context-dependent nature of HDL's effects, which may be driven by factors like HDL particle heterogeneity and functional transformation into a pro-inflammatory state. Future research should move beyond concentration-based metrics to focus on HDL functionality and precise subtyping to fully understand its role in disease etiology.

Background High-grade pancreatic neuroendocrine neoplasms (panNENs) are rare but aggressive tumors with poor clinical outcomes. Metabolic alterations are frequently observed in panNENs and may reflect their metabolic reprogramming. Significant intra-pancreatic fat deposition (IPFD), defined as excessive pancreatic fat accumulation, has been linked to various pancreatic diseases and identified as a prognostic factor in pancreatic cancer. Objective This retrospective multicenter study aimed to evaluate the prognostic value of metabolic alterations, particularly significant IPFD, in patients with high-grade panNENs. Methods Between 2013 and 2024, 87 patients with high-grade panNENs from three centers were included. Significant IPFD was assessed on unenhanced computed tomography images, with a pancreas-to-spleen attenuation ratio <0.70. Other metabolic data were retrospectively obtained from previous clinical assessments and medical records. Results Among 87 patients, 24 (27.6%) showed significant IPFD. Patients with significant IPFD were associated with tumors located in the pancreatic head (75.0% vs 49.2%, P = 0.030) and a higher prevalence of metabolic dysfunction-associated steatotic liver disease (20.8% vs 3.2%, P = 0.023). After adjustment for tumor differentiation and clinical stage, significant IPFD independently predicted worse overall survival (hazard ratio [HR] 2.134; 95% confidence interval [CI] 1.159-3.929, P = 0.015) and disease-specific survival (HR 2.167; 95% CI 1.137-4.133, P = 0.019). In contrast, other metabolic alterations, including obesity and metabolic syndrome, were not independently associated with survival. Conclusions Significant IPFD is an independent adverse prognostic factor for overall and disease-specific survival in patients with high-grade panNENs, highlighting its potential role in risk stratification and clinical decision-making.

High-density lipoprotein nHDL) is a highly heterogeneous lipoprotein with multiple physiological functions. However, observational studies present conflicting evidence regarding its association with various diseases. This study systematically summarizes evidence from Mendelian randomization (MR) studies to investigate the causal relationships between HDL-related biomarkers and a wide spectrum of disease outcomes. We systematically searched multiple databases up to November 2024. The causal relationship between HDL and 158 diseases was studied. Findings reveal that the role of HDL is highly disease-specific. Genetically predicted higher HDL levels are protective against the majority of circulatory and digestive system diseases. Conversely, they are associated with an increased risk of certain conditions, including breast cancer, intracerebral hemorrhage, and age-related macular degeneration. MR analyses revealed inconsistent and sometimes conflicting findings for several disease outcomes, notably including Alzheimer's disease. This review underscores the context-dependent nature of HDL's effects, which may be driven by factors like HDL particle heterogeneity and functional transformation into a pro-inflammatory state. Future research should move beyond concentration-based metrics to focus on HDL functionality and precise subtyping to fully understand its role in disease etiology.

OBJECTIVES:The correlation between fatty pancreas (FP) and metabolic-associated steatotic liver disease (MASLD), diabetes and other metabolic diseases is still controversial, and it is crucial to recognize the risk factors of FP to prevent its clinical complications. METHODS:Retrospective collection of clinical, pathologic, and imaging data of people with obesity attending Qilu Hospital of Shandong University from January 1, 2020 to October 1, 2022. FP was diagnosed by non-enhanced computed tomography with the ratio of pancreas/spleen <0.7. Using binary logistics regression analysis to construct an FP prediction nomogram model, bootstrap repeated sampling internal validation and temporal external validation were used to test the predictive performance of the model. RESULTS:In this cohort, the average age of the participants was 32.2 years, and the average BMI was 41.3 Kg/m2. The prevalence of FP 23.3% (144/617). People with obesity with or without comorbid FP have partial differences in blood glucose, lipid. Independent factors for FP were body mass index (BMI) (OR = 1.97, 95% CI 1.29-3.01; P = 0.002), diastolic blood pressure (DBP) (OR = 1.55, 95% CI 1.03-2.33; P = 0.035), high-density lipoprotein (HDL) (OR = 1.67, 95% CI 1.11-2.52; P = 0.014), HbA1C (OR = 1.99, 95% CI 1.19-3.34; P = 0.009). This study constructed a nomogram containing these four indicators for FP, and receiver operating characteristic curve analysis indicated that the nomogram has moderate predictive performance. CONCLUSIONS:This study identified key risk factors and developed a validated prediction nomogram for FP in adults with obesity. This model may facilitate early identification of FP and the prevention of related metabolic disorders.

Pancreatic surgery is a highly challenging abdominal procedure with high morbidity, where nontechnical skills (NTS)—situational awareness, decision-making, communication, leadership—are critical to reducing adverse outcomes. However, traditional NTS training like didactic lectures and apprenticeships has limitations like high simulation costs and subjective assessments. This review synthesizes artificial intelligence (AI)’s role in transforming pancreatic surgical NTS training: it enhances situational awareness via real-time feedback and 3D reconstruction, improves decision-making through anatomical guidance and immersive simulations, optimizes communication by decoding team mental models, and fosters adaptive leadership. It emphasizes aligning AI with socio-technical system perspective to avoid cognitive dependence, aiming to boost surgeons’ NTS and elevate patient care.

Metastasis and recurrence are the primary obstacles to long-term survival in colorectal cancer (CRC) patients. In this study, we employed single-cell RNA sequencing (scRNA-seq) to comprehensively delineate the transcriptomic landscape of primary and liver metastatic CRCs, and revealed novel cellular crosstalk between cancer cell subpopulation and myofibroblastic CAFs (myCAFs) at single-cell resolution. We identified a cancer cell subpopulation termed stem/transient amplifying-like (stem/TA-like) cells, which expressed genes associated with stem cell-like characteristics and metastatic potential. MyCAFs in their microenvironment showed the potential to remodel the extracellular matrix (ECM), regulate angiogenesis, and support a pro-metastatic microenvironment through paracrine signaling involving FN1, BGN, and other ECM components. Notably, we found that they may communicate through the ligand-receptor pairs FN1-CD44 and GDF15-TGFBR2, which may be linked to the liver metastatic process. Additionally, our findings suggest that both stem/TA-like cells and myCAFs could be involved in CRC recurrence following chemotherapy. A unique gene signature generated using the gene expression characteristics of stem/TA-like cells and myCAFs (SM signature) can be used to assess recurrence risk in CRC patients. Collectively, these findings highlight the intratumor heterogeneity and the potential roles of cancer stem cells and myCAFs in CRC liver metastasis and recurrence, providing new targets and insights for the prognostic assessment of CRC patients and the improved selection of effective treatment options.

Objective:Metabolic syndrome (MetS) and fatty pancreas are 2 prevalent health conditions that are strongly associated with an elevated risk of developing type 2 diabetes, cardiovascular disease, and pancreatic cancer. Understanding the causal relationship between these conditions is important for developing effective prevention and treatment strategies. In this study, we performed a bidirectional Mendelian randomization analysis to investigate the potential causal relationship between MetS and fatty pancreas.Methods:This study undertook bidirectional Mendelian randomization. Genetic instruments for obesity, glycemic, lipid, and blood pressure were identified as instrumental variables for MetS traits in order to evaluate their causal role in pancreatic fat etiology. Summary-level data for pancreas fat (PF) were obtained from a genome-wide association study conducted in the UK Biobank.Results:There was no causal relationship between MetS as a binary trait and PF. In addition, a causal association of increasing waist-to-hip ratio (WHR) with pancreatic fat risk was found (odds ratio [OR] = 1.173, 95% confidence interval [CI]: 1.067-1.288, P = 9 x 10-4]. Notably, there is no evidence of a causal relationship between PF and glycemic, lipid, and blood pressure. Sensitivity analyses did not indicate that pleiotropy was an important source of bias.Conclusion:MetS had no causal relationship with pancreatic fat. Of the components of the MetS, only abdominal obesity and pancreatic fat were observed to be causally related.

Previous studies have found that dyslipidemia is a risk factor for pancreatic cancer (PC), and that lipid-lowering drugs may reduce the risk of PC. However, it is not clear whether dyslipidemia causes PC. The Mendelian randomization (MR) study aimed to investigate the causal role of lipid traits in pancreatic cancer and to assess the potential impact of lipid-lowering drug targets on pancreatic cancer. Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for PC were obtained from an independent GWAS datasets. Colocalization analyses were performed to validate the robustness of the results. No significant effect of lipid-lowering drug targets on PC risk was found. Genetic mimicry of lipoprotein lipase (LPL) was potentially associated with PC risks. Significant MR associations were observed in the discovery dataset (OR 1.64 [95% CI 1.24–2.16], p = 4.48*10–4) with PC in one dataset. However, the finding was not verified in the replication dataset. Our findings do not support dyslipidemia as a causal factor for PC. Among lipid-lowering drug targets, LPL is the potential drug target in PC.

With the development of high-resolution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), various modifications resulting from the reactivity of acyl-CoA intermediates with protein residues have been identified. Acylation modifications, a diverse type of post-translational modifications (PTMs), play pivotal roles in regulating protein functions and are critically involved in tumor metabolic reprogramming. These modifications exhibit significant regulatory effects in various cancers, and their dysregulation is closely associated with malignant tumor progression. In this review, we summarize existing evidence and describe how different types of acylation modifications, including succinylation, crotonylation, lactylation, palmitoylation, and β-hydroxybutyrylation, regulate protein functions and signaling pathways, thereby influencing tumor metabolism reprogramming. Future research into the regulatory functions of acylation modifications and their roles in tumor metabolism will help elucidate the molecular mechanisms of metabolic reprogramming and provide potential targets for developing novel diagnostic and therapeutic strategies for cancer.

Pancreatic cystic lesions (PCLs) represent a highly heterogeneous category of pancreatic abnormalities with an increasing prevalence due to advances in imaging modalities and an aging population. While the majority of PCLs are benign, a subset harbors a variable risk of malignant transformation. Current guidelines rely primarily on imaging features for risk stratification, but limitations in diagnostic accuracy have led to many unnecessary surgical procedures and conversely, missed opportunities for timely resection in cases that progress to malignancy.Recent advances in biomarker discovery hold great promise for improving the management of PCL. In this review, we focus on comparing the diagnostic efficacy of classical tumor markers, highlighting the controversies and challenges associated with each. In addition, we explore the heterogeneous expression of mucins in different subtypes of intraductal papillary mucinous neoplasms (IPMNs) and review the role of common genetic mutations and next-generation sequencing (NGS) in the genomic assessment of PCLs. Importantly, we summarize the results of several novel gene panels and evaluate their diagnostic performance and clinical potential. Although accurate diagnosis and risk stratification of PCLs remain challenging, advances in biomarkers and molecular techniques continue to reveal their potential in precision medicine, with promising implications for clinical translation.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, which is mostly solitary in the pancreas. Surgery-based comprehensive treatment with adjuvant chemotherapy is the currently advanced treatment modality, neoadjuvant chemotherapy has achieved satisfactory results, however, due to the high heterogeneity of PDAC, its sensitivity to chemotherapy is also different. A 66-year-old man presented with discomfort in the upper abdomen and computed tomography (CT) scans revealed 2 tumor lesions in the head and tail of the pancreas, respectively. Endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) was performed to clarify the pathology and the patient was recommended to undergo neoadjuvant therapy. Through 5 courses of neoadjuvant chemotherapy, the 2 tumors showed different treatment effects, and after evaluation, total pancreatectomy and splenectomy were provided to patients. We report a case of 1 patient presenting with 2 pancreatic cancer lesions, who demonstrated different therapeutic responses after receiving neoadjuvant chemotherapy due to the heterogeneity of PDAC.

Pancreatic cancer (PC) is a highly malignant and lethal tumor in gastrointestinal tract. Lactate accumulation is a classical feature of metabolic reprogramming in cancers. Lactate-derived lysine lactylation (Kla) is identified as a new type of post-translational modifications (PTMs), which is confirmed to be involved in multiple biological processes. However, the cancer-specific regulation of protein Kla in PC requires further elucidation. Here, we report a range of dysregulated Kla sites specifically related to RNA splicing in human pancreatic cancer, leading to the observation that the Kla at lysine 176 of heterogeneous nuclear ribonucleoprotein C (HNRNPC K176la) is significantly elevated in PC. Blocking HNRNPC K176la dramatically inhibits pancreatic cancer growth and metastasis. Mechanistically, K176la strengthened the binding of HNRNPC with poly-U motifs in p21-activated kinase 6 (PAK6) pre-mRNA, facilitating the expression of the oncogenic isoform PAK6S. Therefore, our study identifies a number of cancer-specific Kla sites spanned on alternative splicing (AS)-related proteins and unravels the significance of HNRNPC K176la in RNA splicing and PC development.

Objective To examine the historical development of robotic pancreaticoduodenectomy (RPD) and evaluate its clinical applicability and future directions. Methods This review article synthesizes the evolution of robotic pancreaticoduodenectomy by reviewing key clinical studies and advancements in robotic technology, with a focus on the da Vinci system. Results Robotic pancreaticoduodenectomy has demonstrated clear advantages in precision, lymph node dissection, and postoperative recovery, although it remains associated with longer operative time and higher costs compared to open pancreaticoduodenectomy. Discussion The rapid technological advances in robotic surgery have transformed the landscape of pancreatic surgery, but challenges such as high costs, longer operation time, and the lack of haptic feedback remain significant. Emerging trends like AI integration and single-port surgery hold promise for future developments. Conclusion While RPD provides immediate clinical benefits in terms of recovery and complication rates, further studies on long-term oncologic outcomes and cost-effectiveness are necessary for a comprehensive understanding of its role in pancreatic surgery.

Pancreatic cancer is an aggressive malignancy with poor therapeutic responses to conventional treatments, partly due to its unique proliferation and drug resistance. This review focuses on the lipid metabolism in pancreatic cancer cells, emphasizing the crosstalk between mitochondria and other organelles. It highlights the importance of cellular membranes, endoplasmic reticulum, lipid droplets, and mitochondria in lipid transportation and metabolism, which are crucial for energy supplementation and cell structure to resist chemotherapy in pancreatic cancer. The review also discusses how these organelles interact to support the malignancy and suggests that lipid metabolism-regulating drugs targeting different organelles could overcome the resistance of treatments like gemcitabine. Moreover, it points out the role of mitochondrial and other organelles in the PD-L1 regulation of pancreatic cancer, indicating potential for novel therapeutic strategies.