Technical review of endoscopic ultrasound-guided drainage/anastomosis and trans-endosonographically created route procedures for the treatment of pancreatic diseases.

Endoscopic ultrasound (EUS)-guided pancreatic duct drainage includes two procedures: EUS-guided drainage/anastomosis (EUS-D/A) and trans-papillary drainage with EUS-assisted pancreatic rendezvous. EUS-guided pancreatogastrostomy is the most common EUS-D/A procedure and is recommended as a salvage procedure in cases in which endoscopic retrograde cholangiopancreatography fails or is difficult. However, initial EUS-D/A is performed in patients with surgically altered anatomy at our institution. It is one of the most difficult interventional EUS procedures and has a high incidence of adverse events. The technical difficulties differ according to etiology, and the incidence of adverse events varies between initial EUS-D/A and subsequent trans-endosonographically/EUS-guided created route procedures. Hence, it is important to meticulously prepare a procedure based on the patient's condition and the available devices. The technical difficulties in EUS-D/A include: (1) determination of the puncture point, (2) selection of a puncture needle and guidewire, (3) guidewire manipulation, and (4) dilation of the puncture route and stenting. Proper technical procedures are important to increase the success rate and reduce the incidence and severity of adverse events. The complexity of EUS-D/A is also contingent on the severity of pancreatic fibrosis and stricture. In post-pancreatectomy cases, determination of the puncture site is important for success because of the remnant pancreas. Trans-endosonographically/EUS-guided created route procedures following initial EUS-D/A are also important for achieving the treatment goal. This article focuses on effective strategies for initial EUS-D/A, based on the etiology and condition of the pancreas. We mainly discuss EUS-D/A, including its indications, techniques, and success-enhancing strategies.

Diagnostic accuracy of endoscopic ultrasonographic shear wave elastography for assessing early chronic pancreatitis using the Japanese diagnostic criteria 2019.

Background and Aim: Endoscopic ultrasound shear wave elastography (EUS-SWE) can facilitate an objective evaluation of pancreatic fibrosis. Although it is primarily applied in evaluating chronic pancreatitis, its efficacy in assessing early chronic pancreatitis (ECP) remains underinvestigated. This study evaluated the diagnostic accuracy of EUS-SWE for assessing ECP diagnosed using the Japanese diagnostic criteria 2019. Methods: In total, 657 patients underwent EUS-SWE. Propensity score matching was used, and the participants were classified into the ECP and normal groups. ECP was diagnosed using the Japanese diagnostic criteria 2019. Pancreatic stiffness was assessed based on velocity (Vs) on EUS-SWE, and the optimal Vs cutoff value for ECP diagnosis was determined. A practical shear wave Vs value of ≥50% was considered significant. Results: Each group included 22 patients. The ECP group had higher pancreatic stiffness than the normal group (2.31 ± 0.67 m/s vs. 1.59 ± 0.40 m/s, p < 0.001). The Vs cutoff value for the diagnostic accuracy of ECP, as determined using the receiver operating characteristic curve, was 2.24m/s, with an area under the curve of 0.82 (95% confidence interval: 0.69-0.94). A high Vs was strongly correlated with the number of EUS findings (rs = 0.626, p < 0.001). Multiple regression analysis revealed that a history of acute pancreatitis and ≥2 EUS findings were independent predictors of a high Vs. Conclusions: There is a strong correlation between EUS-SWE findings and the Japanese diagnostic criteria 2019 for ECP. Hence, EUS-SWE can be an objective and invaluable diagnostic tool for ECP diagnosis.

Updated techniques and evidence for endoscopic ultrasound-guided tissue acquisition from solid pancreatic lesions.

Endoscopic ultrasound-guided tissue acquisition (EUS-TA), including fine-needle aspiration (EUS-FNA) and fine-needle biopsy (EUS-FNB), has revolutionized specimen collection from intra-abdominal organs, especially the pancreas. Advances in personalized medicine and more precise treatment have increased demands to collect specimens with higher cell counts, while preserving tissue structure, leading to the development of EUS-FNB needles. EUS-FNB has generally replaced EUS-FNA as the procedure of choice for EUS-TA of pancreatic cancer. Various techniques have been tested for their ability to enhance the diagnostic performance of EUS-TA, including multiple methods of sampling at the time of puncture, on-site specimen evaluation, and specimen processing. In addition, advances in next-generation sequencing have made comprehensive genomic profiling of EUS-TA samples feasible in routine clinical practice. The present review describes updates in EUS-TA sampling techniques of pancreatic lesions, as well as methods for their evaluation.

A deep learning-based cascade algorithm for pancreatic tumor segmentation.

Pancreatic tumors are small in size, diverse in shape, and have low contrast and high texture similarity with surrounding tissue. As a result, the segmentation model is easily confused by complex and changeable background information, leading to inaccurate positioning of small targets and false positives and false negatives. Therefore, we design a cascaded pancreatic tumor segmentation algorithm. In the first stage, we use a general multi-scale U-Net to segment the pancreas, and we exploit a multi-scale segmentation network based on non-local localization and focusing modules to segment pancreatic tumors in the second stage. The non-local localization module learns channel and spatial position information, searches for the approximate area where the pancreatic tumor is located from a global perspective, and obtains the initial segmentation results. The focusing module conducts context exploration based on foreground features (or background features), detects and removes false positive (or false negative) interference, and obtains more accurate segmentation results based on the initial segmentation. In addition, we design a new loss function to alleviate the insensitivity to small targets. Experimental results show that the proposed algorithm can more accurately locate pancreatic tumors of different sizes, and the Dice coefficient outperforms the existing state-of-the-art segmentation model. The code will be available at https://github.com/HeyJGJu/Pancreatic-Tumor-SEG.

Analysis of thromboembolism and prognosis in metastatic pancreatic cancer from the Tokushukai REAl­world data project.

Cancer-associated thromboembolism (CAT), including venous thromboembolism (VTE) and arterial thromboembolism (ATE), is a frequent complication of advanced pancreatic cancer. However, reports on its incidence and clinical outcomes, especially on ATE, are limited. The present study aimed to investigate the incidence of CAT and its effects on overall survival in patients with metastatic pancreatic cancer. As part of the Tokushukai REAl-world data project in Japan, 846 eligible patients with metastatic pancreatic cancer treated with first-line chemotherapy were identified between April 2010 and March 2020. Using diagnosis procedure combination data from these patients, the present study investigated the incidence of VTE, ATE and cerebral and gastrointestinal bleeding requiring hospitalization. Blood laboratory data were collected within 14 days of the start of first-line treatment, and Khorana scores were calculated. The associations between CAT complications and comorbidities, concomitant medications and prognosis were examined. Among the 846 patients, 21 (2.5) and 70 (8.3%) had VTE and ATE, respectively (including five with overlapping VTE and ATE). CAT-positive patients had a significantly higher rate of gastrointestinal bleeding events compared with CAT-negative patients [13 of 86 (15.2%) vs. 46 of 760 (6.1%); P=0.01]. CAT-positive patients had a poorer prognosis [hazard ratio (HR), 1.28; 95% confidence interval (CI), 1.01-1.62] compared with CAT-negative patients, even after adjusting for background factors (HR, 1.20; 95% CI, 0.95-1.52). Cox regression analyses showed that higher Khorana scores were associated with significantly worse prognosis. This real-world data demonstrated that the incidence rate of CAT in patients with metastatic pancreatic cancer was 10.2%, and no statistically significant differences were observed, although there was a trend toward an adverse prognosis. The Khorana score may also be useful for predicting prognosis, even in the absence of CAT. This study was registered in the UMIN Clinical Trial Registry (http://www.umin.ac.jp/ctr/index.htm; clinical trial no. UMIN000050590).

Discovery of an 8-oxoguanine regulator PCBP1 inhibitor by virtual screening and its synergistic effects with ROS-modulating agents in pancreatic cancer.

Introduction: Drugs that target reactive oxygen species (ROS) metabolism have progressed the treatment of pancreatic cancer treatment, yet their efficacy remains poor because of the adaptation of cancer cells to high concentration of ROS. Cells cope with ROS by recognizing 8-oxoguanine residues and processing severely oxidized RNA, which make it feasible to improve the efficacy of ROS-modulating drugs in pancreatic cancer by targeting 8-oxoguanine regulators. Methods: Poly(rC)-binding protein 1 (PCBP1) was identified as a potential oncogene in pancreatic cancer through datasets of The Cancer Genome Atlas (TCGA) project and Gene Expression Omnibus (GEO). High-throughput virtual screening was used to screen out potential inhibitors for PCBP1. Computational molecular dynamics simulations was used to verify the stable interaction between the two compounds and PCBP1 and their structure-activity relationships. In vitro experiments were performed for functional validation of silychristin. Results: In this study, we identified PCBP1 as a potential oncogene in pancreatic cancer. By applying high-throughput virtual screening, we identified Compound 102 and Compound 934 (silychristin) as potential PCBP1 inhibitors. Computational molecular dynamics simulations and virtual alanine mutagenesis verified the structure-activity correlation between PCBP1 and the two identified compounds. These two compounds interfere with the PCBP1-RNA interaction and impair the ability of PCBP1 to process RNA, leading to intracellular R loop accumulation. Compound 934 synergized with ROS agent hydrogen peroxide to strongly improve induced cell death in pancreatic cancer cells. Discussion: Our results provide valuable insights into the development of drugs that target PCBP1 and identified promising synergistic agents for ROS-modulating drugs in pancreatic cancer.

Prognostic Impact of a Decrease in Serum Carbohydrate Antigen 19-9 Levels After Preoperative Therapy for 4 Months or More for Borderline Resectable Pancreatic Cancer Abutting Major Arteries.

Background: This study aimed to identify the prognostic factors after pancreatectomy for borderline resectable pancreatic cancer abutting major arteries (BR-A).Methods: We retrospectively investigated relationship between preoperative and intraoperative variables and overall survival (OS) through univariate and multivariate analyses. The cut-off points of preoperative therapy duration and response rates of serum carbohydrate antigen 19-9 (CA19-9) levels after preoperative therapy were determined through a minimum P-value approach using the log-rank test for OS. Overall survival was compared among patients stratified according to the independent prognostic factors and the presence or absence of pancreatectomy.Results: After pretreatment, 17 patients underwent pancreatectomy and four patients continued chemotherapy without surgery. Multivariate analysis in 17 resected BR-A patients demonstrated decreased serum CA19-9 levels and preoperative therapy duration of ≥4 months were the independent prognostic factors [hazard ratio (HR) 0.01; P = 0.002, HR 0.13; P = 0.02]. Patients who underwent surgery with decreased serum CA19-9 levels after preoperative therapy of ≥4 months had a significantly better prognosis than those without one or both of independent prognostic factors and those who did not undergo surgery (median survival time: not estimated, 23.3 months, 10.5 months, and 10.8 months; P = 0.02, P = 0.004, and P = 0.001, respectively). Furthermore, the prognosis did not significantly differ between the patients who underwent surgery without meeting either one or both criteria and those without surgery.Conclusions: Preoperative therapy duration of ≥4 months and decreased serum CA19-9 levels are independent prognostic factors among BR-A patients.

Cellular and molecular mechanisms of gastrointestinal cancer liver metastases and drug resistance.

Distant metastases and drug resistance account for poor survival of patients with gastrointestinal (GI) malignancies such as gastric cancer, pancreatic cancer, and colorectal cancer. GI cancers most commonly metastasize to the liver, which provides a unique immunosuppressive tumour microenvironment to support the development of a premetastatic niche for tumor cell colonization and metastatic outgrowth. Metastatic tumors often exhibit greater resistance to drugs than primary tumors, posing extra challenges in treatment. The liver metastases and drug resistance of GI cancers are regulated by complex, intertwined, and tumor-dependent cellular and molecular mechanisms that influence tumor cell behavior (e.g. epithelial-to-mesenchymal transition, or EMT), tumor microenvironment (TME) (e.g. the extracellular matrix, cancer-associated fibroblasts, and tumor-infiltrating immune cells), tumor cell-TME interactions (e.g. through cytokines and exosomes), liver microenvironment (e.g. hepatic stellate cells and macrophages), and the route and mechanism of tumor cell dissemination (e.g. circulating tumor cells). This review provides an overview of recent advances in the research on cellular and molecular mechanisms that regulate liver metastases and drug resistance of GI cancers. We also discuss recent advances in the development of mechanism-based therapy for these GI cancers. Targeting these cellular and molecular mechanisms, either alone or in combination, may potentially provide novel approaches to treat metastatic GI malignancies.

The interplay of extracellular vesicles in the pathogenesis of metabolic impairment and type 2 diabetes.

The pathogenesis of type 2 diabetes (T2D) involves dysfunction in multiple organs, including the liver, muscle, adipose tissue, and pancreas, leading to insulin resistance and ß cell failure. Recent studies highlight the significant role of extracellular vesicles (EVs) in mediating inter-organ communication in T2D. This review investigates the role of EVs, focusing on their presence and biological significance in human plasma and tissues affected by T2D. We explore specific EV cargo, such as miRNAs and proteins, which affect insulin signaling and glucose metabolism, emphasizing their potential as biomarkers. By highlighting the diagnostic and therapeutic potential of EVs, we aim to provide new insights into their role in early detection, disease monitoring, and innovative treatment strategies for T2D.

Construction and anti-pancreatic cancer activity of selenium nanoparticles stabilized by Prunella vulgaris polysaccharide.

Selenium nanoparticles (SeNPs), as a potential cancer therapeutic agent, have attracted extensive attention due to their high anticancer activity and low toxicity. Polysaccharides could be the modifiers and stabilizers to improve the stability and dispersibility of SeNPs in aqueous solution. This study aimed to investigate the physicochemical characterization, stability, and anti-pancreatic cancer cell activities of SeNPs stabilized by a heteroxylan PVP3-1 extracted from the clusters of Prunella vulgaris Linn. Our results showed that PVP3-1 with Mw of 154 kDa was composed of →4)-ß-D-Xylp(1→, →2, 4)-ß-D-Xylp(1→, t-α-L-Araf(1→ and 4-MeO-α-D-GlcpA(1→. Red, zero-valent, and uniform spherical SeNPs with an average diameter of about 60 nm and high stability in aqueous solution were constructed successfully by polysaccharide PVP3-1. Anti-pancreatic cancer cell activity assays showed that PVP3-1-SeNPs could inhibit the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, PVP3-1-SeNPs induced apoptosis and autophagy of pancreatic cancer cells through inhibiting mTOR signaling pathway. In conclusion, these results indicated that PVP3-1-SeNPs could be potential anti-tumor nanoparticles for treating pancreatic cancer.

Cell fate simulation reveals cancer cell features in the tumor microenvironment.

To elucidate the dynamic evolution of cancer cell characteristics within the tumor microenvironment (TME), we developed an integrative approach combining single-cell tracking, cell fate simulation, and three-dimensional (3D) TME modeling. We began our investigation by analyzing the spatiotemporal behavior of individual cancer cells in cultured pancreatic (MiaPaCa2) and cervical (HeLa) cancer cell lines, with a focus on the α2-6 sialic acid (α2-6Sia) modification on glycans, which is associated with cell stemness. Our findings revealed that MiaPaCa2 cells exhibited significantly higher levels of α2-6Sia modification, correlating with enhanced reproductive capabilities, whereas HeLa cells showed less prevalence of this modification. To accommodate the in vivo variability of α2-6Sia levels, we employed a cell fate simulation algorithm that digitally generates cell populations based on our observed data while varying the level of sialylation, thereby simulating cell growth patterns. Subsequently, we performed a 3D TME simulation with these deduced cell populations, considering the microenvironment that could impact cancer cell growth. Immune cell landscape information derived from 193 cervical and 172 pancreatic cancer cases was used to estimate the degree of the positive or negative impact. Our analysis suggests that the deduced cells generated based on the characteristics of MiaPaCa2 cells are less influenced by the immune cell landscape within the TME compared to those of HeLa cells, highlighting that the fate of cancer cells is shaped by both the surrounding immune landscape and the intrinsic characteristics of the cancer cells.

From pre-clinical efficacy to promising clinical trials that delay Type 1 diabetes.

Recent advancements in immunology and islet biology have unveiled remarkable prospects for the postponement of Type 1 diabetes (T1D) through the strategic modulation of the immune system. In this Perspective, we discuss the pharmaceutical strides achieved, traversing from pre-clinical validation to the execution of impactful clinical trials. We begin with the initial investigations involving cyclosporine and glucocorticoids in rodent models, such as the non-obese diabetic (NOD) mouse, which guided early clinical trials. We then discuss the pre-clinical studies using suitable mouse models that eventually led to contemporary clinical trials targeting immune cell functionality and cytokine signaling pathways. Collectively, these discoveries promote the exciting paradigm of immune system modulation to mitigate autoimmunity, which continues to broaden. Notably, the use of baricitinib, a potent JAK1/2 inhibitor, and teplizumab, an anti-CD3 monoclonal antibody, represent discrete methodologies converging upon a singular outcome: the preservation of islet beta-cell functionality. The latter interventional strategies build on the original idea that tempering specific facets of the immune system will generate therapeutic benefit. Enthusiasm from these discoveries stems from efficacy with reduced side effects when compared with past approaches. The success of therapeutic intervention(s) in pre-clinical studies, combined with knowledge about stages of progression to clinical T1D, have ultimately encouraged the design of more successful clinical trials targeting highly specific populations at risk. Collectively, these findings instill a profound sense of optimism, suggesting that the prevention and even reversal of T1D may soon be within reach.

Can cereal-based oral contrast agents-assisted ultrasound become an alternative to non-contrast magnetic resonance imaging (MRI) in radiological follow-up for pancreatic cystic lesions?

Background: Pancreatic cystic lesions (PCLs) are recommended to be examined by magnetic resonance imaging (MRI), yet MRI still has limitations, such as high costs, the risk of triggering claustrophobia, and relatively low availability compared with ultrasound. Oral contrast agents-assisted ultrasound has been used to examine the gallbladder and stomach, but whether oral contrast agents could improve the accuracy of transabdominal ultrasound (TAUS) for PCLs and could be a potential alternative to non-contrast MRI for PCL follow-up has not been studied. This study aimed to explore the value of cereal-based oral contrast agents in improving the accuracy of PCLs during TAUS. Methods: This is a prospective cohort study. Patients with PCL who were admitted to our center between January 2023 and January 2024 were enrolled, and TAUS was performed before and after taking cereal-based oral contrast agents. The imaging quality of the PCL was measured by structural visualization scores. The structural visualization scores of oral contrast agent-assisted ultrasound and non-contrast MRI were also compared. Results: A total of 27 patients with PCLs were enrolled, and 30 PCLs were detected. The sonolucency of the PCL improved after oral contrast agent administration. Before taking the agent, only 30% of patients had satisfactory sonolucency; after taking the oral contrast agent, the corresponding proportion reached 80% (P=0.002). The structural visualization score of the PCL determined by oral contrast agent-assisted TAUS was higher than that determined without the aid of an agent [1 (0-6) vs. 1 (0-3), P=0.001], which was mainly reflected in the increase in the number of visible septa after taking the agent. No significant difference was detected between the structural visualization score of the PCL examined by oral contrast agent-assisted TAUS and that examined by non-contrast MRI and the correlation between the 2 types of scores were satisfactory [1 (0-6) vs. 2 (0-7), P=0.070, Spearman correlation factor r=0.880]. Conclusions: This study used a structured scoring system to confirm that cereal-based oral contrast agents could improve the ultrasound quality of PCLs, and the correlation between the quality of oral contrast agent-assisted ultrasound and non-contrast MRI findings on PCLs was satisfactory. Further research to improve visualization of PCLs on TAUS using oral contrast agents could result in TAUS being a potential alternative to MRI in the follow-up of PCLs in resource-limited situations.

Case report: Sclerosing encapsulating peritonitis in a cat with disseminated pancreatic adenocarcinoma of presumed ductal origin.

A 9-year-old, neutered male, domestic short-haired cat was referred for recurrent ascites of unknown etiology over a week. Physical examination revealed abdominal distension and ultrasonography revealed a large volume of ascites throughout the abdominal cavity; this was interpreted as modified transudate. The mesentery and abdominal fat were hyperechoic and edematous. Fat tissue was assessed using fine-needle aspiration cytology, and adipocytes, fat-phagocytizing macrophages, and neutrophils were identified. Computed tomography revealed a pancreatic mass connected to the left pancreatic leg. Exploratory laparoscopy confirmed nodular masses and organ adhesions, leading to a tentative diagnosis of sclerosing encapsulating peritonitis. The cat was administered prednisolone, vitamin E, and tamoxifen but died 22 days after the initial therapy. Necropsy revealed a multi-lobulated pancreatic tumor (10 × 10 cm) tightly attached to the stomach and intestine, with a large amount of ascites. The peritoneum, stomach, intestine, and mesentery were covered with numerous disseminated nodules of various sizes (1-5 mm diameter). Microscopically, the tumor consisted of extensive adipose tissue, locally extensive inflammatory infiltrates, fibrous connective tissue, and small invasive proliferative glands. Well-defined small irregular glands composed of single-layered epithelial cells that appear to be of ductal origin were surrounded by an abundant desmoplastic stroma. Neoplastic nodules were widespread in the liver, stomach, peritoneum, mesentery, mesenteric lymph nodes, lungs, and urinary bladder. Immunohistochemistry revealed that the neoplastic glands were positive for pan-cytokeratin, confirming the pancreatic epithelial origin of the tumor. This is the first report of sclerosing encapsulating peritonitis accompanied by aggressive pancreatic adenocarcinoma of presumed ductal origin and extensive metastasis in a cat.

Metastatic Pancreatic Adenocarcinoma Downstaged to T0N0 with Chemotherapy and Targeted Therapy, Confirmed by Surgical Pathology: A Case Report.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive human tumor that is typically diagnosed at a later stage when surgery is not possible. Case Presentation: We report the case of a 62-year-old woman who presented to the emergency department with abdominal pain. Computed tomography (CT) revealed a solitary hepatic lesion and a pancreatic body lesion. The pancreatic body lesion was biopsied endoscopically, and a tissue diagnosis was obtained to confirm the diagnosis of PDAC. She was then treated with 12 cycles of FOLFIRINOX with stable disease on CT. Due to the history of a hepatic lesion, she received 11 cycles of gemcitabine/Abraxane and a combination of a MEK inhibitor, Mekinist, and a BRAF inhibitor, BRAFTOVI. Subsequently, the patient underwent a liver biopsy. The biopsy result was negative, and the tumor was deemed resectable. The patient underwent a distal pancreatectomy. Surgical pathology demonstrated a 1.1-cm low-grade papillary mucinous neoplasm with negative margins and lymph nodes, staged T0N0. Adjuvant chemotherapy was not administered. Conclusion: To our knowledge, this is the first report of a patient with metastatic pancreatic adenocarcinoma who received prolonged IV and oral chemotherapy. At the time of the operation, the pathological stage was T0N0. The patient has recently been seen 9 months after surgery with no evidence cancer recurrence. Additionally, ctDNA remains negative.

SCG2 and CPE may be novel markers for the identification of pancreatic neuroendocrine tumors and solid pseudopapillary neoplasms.

Background: Distinguishing pancreatic neuroendocrine tumors (pNETs) from solid pseudopapillary neoplasms (SPNs) is challenging, primarily due to their overlapping pathological characteristics. To address this, our study aims to identify and validate novel biomarkers that effectively differentiate between these two conditions. We focus on the exploration of new immunohistochemical markers to enhance this distinction. Methods: In this study, we analyzed genetic variations in pNETs and SPNs using the GSE43795 dataset from the Gene Expression Omnibus (GEO) database. Our approach was to identify genes with higher expression in pNETs compared to SPNs and normal pancreatic tissues. We conducted enrichment analyses to understand the functions of these genes. Furthermore, protein-protein interaction (PPI) network analysis was utilized to identify key genes associated with pNETs. Our sample consisted of 163 pancreatic tumor specimens, comprising 78 pNETs and 85 SPNs. We also collected clinicopathological data and used immunohistochemistry to measure the expression levels of these key genes. Results: The enrichment analysis revealed that genes overexpressed in pNETs were mainly involved in signal release, vesicle transport, and ion pathway activation, playing significant roles in endocrine processes like insulin secretion, dopamine synapses, and circadian rhythm regulation. The PPI analysis identified secretogranin II (SCG2), carboxypeptidase E (CPE), and chromogranin A (CgA, CHGA) as key markers for differentiating pNETs from SPNs. Immunohistochemical validation of these markers demonstrated high sensitivity (SCG2: 98.7%, CPE: 97.4%) and specificity (100%), indicating their superior discriminative power compared to traditional markers like CgA, ß-catenin, lymphoid enhancer-binding factor 1 (LEF1), and vimentin. Conclusions: Our study indicates that SCG2 and CPE are effective, novel immunohistochemical biomarkers for differentiating pNETs from SPNs.

Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer.

Background: Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane immunoglobulin-superfamily receptor, is expressed primarily on cells such as macrophages and dendritic cells. TREM2 has been shown to be associated with diseases such as neurodegeneration, fatty liver, obesity, and atherosclerosis. Currently, it has become one of the hotspots in oncology research. However, the role of TREM2 in pan-cancer, especially pancreatic cancer, remains unclear. Methods: We used the Tumor-immune System Interactions Database (TISIDB) to explore TREM2 expression differences, Tumor Immune Single-cell Hub 2 (TISCH2) to explore TREM2 expression distribution, Tumor IMmune Estimation Resource 2.0 (TIMER 2.0) to explore immune infiltration, cBio Cancer Genomics Portal (cBioPortal) to explore genetic variation, Genomics of Drug Sensitivity in Cancer (GDSC) to explore drug resistance, and Kaplan-Meier plotter database to explore the relationship between TREM2 and prognosis in pancreatic cancer. In addition, we used The Cancer Genome Atlas-pancreatic adenocarcinoma (TCGA-PAAD) and normal pancreas samples from the Genotype-Tissue Expression (GTEx) databases to explore the relationship between TREM2 and lymph node metastasis. We verified the protein level of TREM2 in pancreatic cancer by Human Protein Atlas (HPA) and western blotting and detected the colocalization of TREM2 with malignant cell markers by multiplex immunohistochemistry (mIHC). Finally, we identified the tumor-promoting role of TREM2 in pancreatic cancer via in vitro experiments, such as cell cycle assays, colony formation assays, and transwell migration and invasion assays. Results: Our results showed that TREM2 was differentially expressed in various tumors according to different molecular and immune subtypes of pan-cancer. It was found that TREM2 was mainly expressed in monocytes/macrophages. In addition, our study showed that TREM2 expression was closely associated with macrophages in the tumor microenvironment (TME) of pan-cancer. TREM2 was shown to be related to anti-inflammatory and immunosuppressive effects in most cancers. Furthermore, we found that amplification was the main somatic mutation of TREM2 in pan-cancer. Further correlational analysis revealed a significant negative association of TREM2 expression with sensitivity to AZD8186, which is a selective inhibitor of PI3K, but not gemcitabine and paclitaxel. Finally, through the knockdown and overexpression of TREM2, our findings verified that TREM2 on cancer cells promoted the progression of PAAD. Conclusions: In conclusion, our comprehensive analysis identified that TREM2 expression level was correlated with the TME and the immunosuppressive effects. In particular, our study indicated that TREM2 was involved in the progression of pancreatic cancer.

Clinical and molecular features of early onset pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is a major health burden and may become the second cause of death by cancer in developed countries. The incidence of early-onset pancreatic cancer (EOPC, defined by an age at diagnosis <50 years old) is increasing. Here, we conducted a study of all PDAC patients followed at our institution. Patients were classified as EOPC or non-early onset (nEOPC, >50). Eight hundred and seventy eight patients were included, of which 113 EOPC, exhibiting a comparable performance status. EOPC were more often diagnosed at the metastatic stage (70.0% vs 58.3%) and liver metastases were more prevalent at diagnosis (60.2% vs. 43.9%). The median overall survival (OS) from diagnosis was 18.1 months, similar between EOPC and nEOPC. Among patients who underwent surgery, recurrence-free survival was similar between age groups. Among metastatic patients, first line progression free survival was similar but EOPC received more treatment lines (72.3% vs. 58.1% received ≥2 lines). Regarding molecular alterations, the mean tumor mutational burden (TMB) was lower in EOPC (1.42 vs. 2.95 mut/Mb). The prevalence of KRAS and BRCA1/2 mutations was similar, but EOPC displayed fewer alterations in CNKN2A/B. Fifty eight patients (18.6%) had actionable alterations (ESCAT I-III) and 31 of them received molecularly matched treatments. On the transcriptomic level, despite its clinical aggressiveness, EOPC was less likely to display a basal-like phenotype. To conclude, EOPC were diagnosed more frequently at the metastatic stage. OS and 1st line PFS were similar to nEOPC. EOPC displayed specific molecular features, such as a lower TMB and fewer alterations in CDKN2A/B.

Utility of ligamentum teres hepatis flap reinforcement to prevent postoperative pancreatic fistulas in robotic distal pancreatectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a significant contributor to morbidity and mortality after robotic distal pancreatectomy (RDP). Ligamentum teres hepatis (LTH) reinforcement of the pancreatic remnant may reduce the incidence of POPF. METHODS: Patients ≥18 years old, who underwent RDP at the University of Massachusetts Memorial Medical Center from 01/01/2018-08/31/2022. Primary endpoint was POPF incidence. Secondary outcomes included peri- and postoperative variables. RESULTS: Thirty-three patients underwent RDP, of which LTH reinforcement was used in 21 (64 â€‹%) cases. Six (18 â€‹%) patients developed a POPF. No association was identified between LTH flap reinforcement and POPF (OR 1.18, 95 â€‹% CI 0.18 to 7.85, p â€‹= â€‹0.87). There were no peri- or postoperative complications related to ligamentum teres flap creation. CONCLUSIONS: LTH reinforcement of the pancreatic remnant can be safely performed during RDP. Further studies are needed to assess the utility of this intervention to mitigate the risk of pancreatic fistula formation following RDP.

Identification of procyanidins as α-glucosidase inhibitors, pancreatic lipase inhibitors, and antioxidants from the bark of Cinnamomum cassia by multi-bioactivity-labeled molecular networking.

This study examined the suppressive effects of 16 selected plant-based foods on α-glucosidase and pancreatic lipase and their antioxidant properties. Among these, the bark of Cinnamomum cassia (Cinnamon, WLN-FM 15) showed the highest inhibitory activity against α-glucosidase and the highest antioxidant activity. Additionally, WLN-FM 15 showed promising results in the other tests. To further identify the bioactive constituents of WLN-FM 15, a multi-bioactivity-labeled molecular networking approach was used through a combination of GNPS-based molecular networking, DPPH-HPLC, and affinity-based ultrafiltration-HPLC. A total of nine procyanidins were identified as antioxidants and inhibitors of α-glucosidase and pancreatic lipase in WLN-FM 15. Subsequently, procyanidins A1, A2, B1, and C1 were isolated, and their efficacy was confirmed through functional assays. In summary, WLN-FM 15 has the potential to serve as a functional food ingredient with the procyanidins as its bioactive constituents. These results also suggest that the multi-bioactivity-labeled molecular networking approach is reliable for identifying bioactive constituents in plant-based foods.