Survival benefit of adjuvant treatment for ampullary cancer with lymph nodal involvement: A systematic review and meta-analysis.

BACKGROUND: The efficacy of adjuvant treatment (AT) in ampullary cancer (AmC) remains controversial. This systematic review and meta-analysis aimed to evaluate the role of AT for AmC. DATA SOURCES: A comprehensive systematic search was performed in PubMed, EMBASE, Cochrane Library, and Web of Science databases. Studies comparing overall survival (OS) and recurrence-free survival (RFS) of patients who underwent AT or not following AmC resection were included. RESULTS: A total of 3971 patients in 21 studies were analyzed. Overall pooled data showed no significant difference in effect on the OS by AT [hazard ratio (HR) = 0.998, 95% confidence interval (CI): 0.768-1.297]. No significant difference in recurrence between the AT and non-AT (nAT) groups was noted (HR = 1.158, 95% CI: 0.764-1.755). In subgroup analysis, patients who received AT showed favorable outcomes in the OS compared with those who received nAT in nodal-positive AmC (HR = 0.627, 95% CI: 0.451-0.870). Neither AT consisted of adjuvant chemotherapy with radiotherapy (HR = 0.804, 95% CI: 0.563-1.149) nor AT with adjuvant chemotherapy (HR = 0.883, 95% CI: 0.642-1.214) showed any significant effect on the OS. CONCLUSIONS: The effect of AT in AmC on survival and recurrence did not show a significant benefit. Furthermore, effectiveness according to AT strategies did not show enhancement in survival. AT had an advantage in survival compared with nAT strategy in nodal-positive AmC. In cases of AmC with positive lymph nodal involvement, AT may be warranted regardless of detailed strategies.

Aggressive hydration with lactated Ringer's solution versus plasma solution for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (ALPS study): protocol for a multicentre, double-blind, randomised controlled trial.

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) plays an indispensable role in treating pancreato-biliary diseases but carries a risk of post-ERCP pancreatitis (PEP). Despite advances in the prevention strategies, prevention of PEP remains imperfect, necessitating more refined hydration methods. This study investigates the effectiveness of lactated Ringer's solution versus plasma solution in preventing PEP. METHOD AND ANALYSIS: This multicentre, double-blind, randomised controlled trial, will be initiated by the investigator-sponsor, and conducted in three tertiary centres in South Korea. The aim of this study is to assess the effectiveness of hydration in preventing PEP in patients with naïve papillae. It will target patients with naïve papillae, focusing on those at medium to high risk of PEP. Patients aged ≤18 years and those with serious comorbidities, acute/chronic pancreatitis and various other medical conditions will be excluded. Eligible participants will be randomly assigned into two arms in equal numbers: (1) PEP prevention using lactated Ringer's solution and (2) PEP prevention using plasma solution. The primary outcome of this study will be the occurrence of PEP, and secondary outcomes will be additional risk factors and potential adverse events related to ERCP. With a total enrolment of 844 patients, the study will be able to detect significant differences between the intervention arms. ETHICS AND DISSEMINATION: Ethical approval is obtained from each institution (Asan Medical Centre, 2023-0382; Seoul National University Hospital, H-2302-05-1404; Samsung Medical Centre, SMC 2023-02-001-009). All participants provided informed consent following clear explanation of the study procedures. The results of the study will be disseminated in peer-reviewed journals and research conferences. TRIAL REGISTRATION NUMBER: NCT05832047. PROTOCOL VERSION: Ver 4.1 (2023).

Optimal timing of surgery after neoadjuvant treatment in borderline resectable pancreatic cancer.

BACKGROUND: Neoadjuvant treatment (NAT) is standard for borderline resectable pancreatic cancer (BRPC). However, consensus is lacking on the optimal surgical timing for patients with BRPC undergoing NAT. The aim of this study was to investigate the long-term outcomes of patients undergoing NAT for BRPC and suggest optimal resection timing. METHODS: Prospectively collected data for 282 patients with BRPC between January 2007 and December 2019 were retrospectively reviewed. There were 164 patients who underwent NAT followed by surgery, 45 for chemotherapy only, and 73 for upfront surgery. Among them, 150 patients who underwent R0 or R1 resection following NAT were investigated to identify prognostic factors. RESULTS: Patients receiving NAT followed by surgery showed the best survival (median overall survival [OS]; NAT followed by surgery vs. upfront surgery vs. chemotherapy only; 35 vs. 23 vs. 16 months). In the NAT group, 54 (36.0%) patients received less than 3 months of NAT, 68 (45.3%) received ≥3, <6 months, and 28 (18.7%) received longer than 6 months. Patients receiving ≥3 months of NAT showed an improved OS compared to <3 months (median; not reached vs. 27 months). In the FOLFIRINOX group, patients who received more than eight FOLFIRINOX cycles showed a good prognosis (<6 vs. 6-7 vs. ≥8 cycles; median survival, 26 vs. 41 months vs. not-reached). However, >12 cycles did not carry a survival benefit compared to 8-11 cycles. CONCLUSION: The optimal resection timing following NAT is once a patient undergoes at least 3 months of neoadjuvant chemotherapy or at least eight FOLFIRINOX cycles.

Silent gallbladder stone in kidney transplantation recipients: should it be treated? A retrospective cohort study.

BACKGROUND: Treatment and follow-up strategies for silent gallbladder stones in patients before kidney transplantation (KT) remain unknown. Therefore, the authors aimed to elucidate the role of pre-KT cholecystectomy in preventing biliary and surgical complications. MATERIALS AND METHODS: This study retrospectively analyzed 2295 KT recipients and 3443 patients waiting for KT at a single tertiary center from January 2005 to July 2022. The primary outcomes were the incidences of biliary and postcholecystectomy complications in KT recipients. Firth's logistic regression model was used to assess the risk factors for biliary complications. RESULTS: Overall, 543 patients awaiting KT and 230 KT recipients were found to have biliary stones. Among the KT recipients, 16 (7%) underwent cholecystectomy before KT, while others chose to observe their biliary stones. Pre-KT cholecystectomy patients did not experience any biliary complications, and 20 (9.3%) patients who chose to observe their stones experienced complications. Those who underwent cholecystectomy before KT developed fewer postcholecystectomy complications (6.3%) compared with those who underwent cholecystectomy after KT (38.8%, P =0.042), including reduced occurrences of fatal postoperative complications based on the Clavien-Dindo classification. Multiple stones [odds ratio (OR), 3.09; 95% CI: 1.07-8.90; P =0.036), thickening of the gallbladder wall (OR, 5.39; 95% CI: 1.65-17.63; P =0.005), and gallstones >1 cm in size (OR 5.12, 95% CI: 1.92-13.69, P =0.001) were independent risk factors for biliary complications. Among patients awaiting KT, 23 (4.2%) underwent cholecystectomy during the follow-up, resulting in one postcholecystectomy complication. CONCLUSION: Gallstone-related biliary complications following KT and subsequent cholecystectomy was associated with more serious complications and worse treatment outcomes. Therefore, when KT candidates had risk factor for biliary complications, pre-emptive cholecystectomy for asymptomatic cholecystolithiasis could be considered to reduce further surgical risk.

Diagnostic Performance of Endoscopic Ultrasound Elastography for Differential Diagnosis of Gallbladder Polyp.

BACKGROUND AND AIMS: It is difficult to differentiate between neoplastic and non-neoplastic gallbladder (GB) polyps before surgery. Endoscopic ultrasound-elastography (EUS-EG) is a non-invasive complementary diagnostic method. The utility of EUS-EG in the differential diagnosis of GB polyps has not been investigated. We aimed to investigate the diagnostic performance of EUS-EG for the differential diagnosis of GB polyps. METHODS: Patients with GB polyps were prospectively enrolled from June 2020 until November 2022. EUS-EG and semi-quantitative evaluation of the strain ratio (SR) were performed for differential diagnosis of GB polyps. Fifty-three eligible patients were divided into two groups based on the final diagnosis after surgery. Patient demographics, EUS characteristics, and SR values were compared. Receiver-operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff SR value that discriminates between neoplastic and non-neoplastic GB polyps. RESULTS: The median SR value for neoplastic polyps (32.93 [interquartile range: 22.37-69.02]) was significantly higher than for non-neoplastic polyps (5.40 [2.36-14.44]; p<0.001). There were significant differences in SR values between non-neoplastic, benign neoplastic (23.38 [13.62-39.04]), and malignant polyps (49.25 [27.90-82.00]). The optimal cut-off SR value to differentiate between neoplastic and non-neoplastic polyps was 18.4. In multivariable logistic regression, SR value >18.4 (odds ratio 33.604, 95% confidence interval 2.588-436.292) was an independent predictor of neoplastic polyps. CONCLUSIONS: EUS-EG and SR values can be used as a supplementary method for evaluating GB polyps.

Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib.

Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK/ERK (Ras, Ras/Raf/MEK/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug's effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF/c-MET signaling pathway, trametinib's mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer.

Comparison of long-term outcomes of endoscopic ultrasound-guided hepaticogastrostomy and choledochoduodenostomy for distal malignant biliary obstruction: a multicenter retrospective study.

Background: Endoscopic ultrasound-guided biliary drainage (EUS-BD), classified as choledochoduodenostomy (CDS) and hepaticogastrostomy (HGS), is a feasible and effective alternative for distal malignant biliary obstruction (MBO) in failed endoscopic retrograde cholangiopancreatography. However, the preferred technique for better outcomes has not yet been evaluated. Objectives: We compared the long-term outcomes between the techniques. Design: Retrospective comparative study. Methods: We reviewed consecutive patients who underwent EUS-CDS or EUS-HGS with transmural stent placement for distal MBO between 2009 and 2022. The primary outcome was the stent patency. The secondary outcomes were technical and clinical success, adverse events (AEs) of each technique, and independent risk factors for stent dysfunction. Results: In all, 115 patients were divided into EUS-CDS (n = 56) and EUS-HGS (n = 59) groups. Among them, technical success was achieved in 98.2% of EUS-CDS and 96.6% of EUS-HGS groups. Furthermore, clinical success was 96.4% in EUS-CDS and 88.1% in EUS-HGS groups, without significant difference (p = 0.200). The mean duration of stent patency for EUS-CDS was 770.3 days while that for EUS-HGS was 164.9 days (p = 0.010). In addition, the only independent risk factor for stent dysfunction was systematic treatment after EUS-BD [hazard ratio and 95% confidence interval 0.238 (0.066-0.863), p = 0.029]. The incidence of stent dysfunction of EUS-HGS was higher than EUS-CDS (35.1% versus 18.2%, 0.071), despite no significant differences even in late AEs. Conclusion: In distal MBO, EUS-CDS may be better than EUS-HGS with longer stent patency and fewer AEs. Furthermore, systematic treatment after EUS-BD is recommended for the improvement of stent patency.

Enhanced Anti-tumor Effect of Flavopiridol in Combination With Gemcitabine in Pancreatic Cancer.

BACKGROUND/AIM: The efficacy of current chemotherapies for pancreatic ductal adenocarcinoma (PDAC) is still unsatisfactory. Flavopiridol inhibits multiple cyclin-dependent kinases, causing cell cycle arrest and inducing cancer cell apoptosis. This study aimed to evaluate the anti-tumor effect of flavopiridol and gemcitabine in PDAC in vitro and in vivo. MATERIALS AND METHODS: PANC-1 and MIA PaCa-2 cell lines were treated with gemcitabine and flavopiridol alone, in combination, and sequentially, and cell proliferation, apoptosis, and the cell cycle were evaluated. Proteins related to cell cycle progression (cyclin A, CDK2, E2F-1, and p53) were quantified using western blotting. A xenograft mouse model was generated, and the effects of gemcitabine and flavopiridol, administered alone or in combination, were evaluated by measuring tumor volume and apoptosis degree using the TUNEL assay. RESULTS: Sequential administration of gemcitabine and flavopiridol suppressed PDAC cell proliferation and induced apoptosis. Flavopiridol treatment led to an increase in the number of cells in the S and a decrease in those in the G0/G1 phases. Gemcitabine increased and decreased the number of S- and G2/M-phase cells, respectively. Furthermore, flavopiridol treatment decreased cyclin A and CDK2 expression and increased E2F-1 expression. In a xenograft mouse model, the combined administration of gemcitabine and flavopiridol demonstrated the most significant reduction in tumor volume and induction of apoptosis. CONCLUSION: Flavopiridol potentiates the anti-tumor activity of gemcitabine by inducing cell cycle arrest and apoptosis. Its synergistic inhibition of PDAC cell proliferation, when combined with gemcitabine, positions flavopiridol as a promising candidate for cancer treatment.

Prognostic value of initial and longitudinal changes in body composition in metastatic pancreatic cancer.

BACKGROUND: Sarcopenia or visceral adipose tissue has been reported to be related to pancreatic cancer prognosis. However, clinical relevance of the comprehensive analysis of body compositions and their longitudinal changes is lacking. This study analysed the association between body composition changes after chemotherapy and survival in patients with metastatic pancreatic cancer. METHODS: We retrospectively included 456 patients (mean age ± standard deviation, 61.2 ± 10.0 years; 272 males and 184 females) with metastatic pancreatic cancer who received palliative chemotherapy from May 2011 to December 2019. Using deep learning-based, fully automated segmentation of contrast-enhanced computed tomography (CT) at the time of diagnosis, cross-sectional areas of muscle, subcutaneous adipose tissue and visceral adipose tissue were extracted from a single axial image of the portal venous phase at L3 level. Skeletal muscle index (SMI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI) and mean skeletal muscle attenuation (MA) were calculated, and their effect on overall survival (OS) was analysed. Longitudinal changes in body composition and prognostic values were also analysed in a subgroup of patients with 2- and 6-month follow-up CT (n = 349). RESULTS: A total of 452 deaths occurred during follow-up in the entire cohort. The survival rate was 49.3% (95% confidence interval [CI], 44.9-54.2) at 1 year and 3.7% (95% CI, 2.0-6.8) at 5 years. In multivariable analysis, higher MA (≥44.4 HU in males and ≥34.8 HU in females) at initial CT was significantly associated with better OS in both males and females (adjusted hazard ratio [HR], 0.706; 95% CI, 0.538-0.925; P = 0.012 for males, and HR, 0.656; 95% CI, 0.475-0.906; P = 0.010 for females), whereas higher SATI (≥42.8 cm2/m2 in males and ≥65.8 cm2/m2 in females) was significantly associated with better OS in female patients only (adjusted HR, 0.568; 95% CI, 0.388-0.830; P = 0.003). In longitudinal analysis, SMI, VATI and SATI significantly decreased between initial and 2-month follow-up CT, whereas mean MA significantly decreased between 2- and 6-month follow-up CT. In multivariable Cox regression analysis of longitudinal changes, which was stratified by disease control state, SATI change was significantly associated with OS in male patients (adjusted HR, 0.513; 95% CI, 0.354-0.745; P < 0.001), while other body composition parameters were not. CONCLUSIONS: In patients with metastatic pancreatic cancer, body composition mostly changed during the first 2 months after starting chemotherapy, and the prognostic factors associated with OS differed between males and females. Initial and longitudinal changes of body composition are associated with OS of metastatic pancreatic cancer.

Safety and Efficacy of Neoadjuvant SABR in Pancreatic Cancer: Effect of Magnetic Resonance Imaging-Guided Respiratory-Gated Adaptive Radiation Therapy.

Purpose: We aimed to evaluate the safety and efficacy of neoadjuvant SABR using magnetic resonance imaging-guided respiratory-gated adaptive radiation therapy (MRgRg-ART) in pancreatic cancer. Methods and Materials: We performed a single-institution retrospective review in patients with pancreatic cancer who underwent neoadjuvant SABR followed by surgical resection. After neoadjuvant chemotherapy, those considered resectable by the multidisciplinary team received SABR over 5 consecutive days using MRgRg-ART. Factors associated with severe postoperative complications (Clavien-Dindo grade ≥III) and prognostic factors for overall survival were analyzed. Results: Sixty-two patients were included in the analysis, with a median follow-up of 10.3 months. The median prescribed dose to the planning target volume was 50 Gy. Fifty-two (85.3%) patients underwent R0 resection, and 11 (18.0%) experienced severe postoperative complications. No factors were associated with the incidence of severe postoperative complications. There were 3 cases of locoregional recurrence, resulting in a 12-month local control rate of 93.1%. Elevated postoperative carbohydrate antigen 19-9 was significantly associated with poor overall survival in the multivariate analysis (P = .037). Conclusions: Neoadjuvant SABR with 50 Gy using MRgRg-ART delivered to pancreatic cancer resulted in a notable survival outcome with acceptable toxicities. Further studies are warranted to investigate the long-term effects of this method.

Clinical Significance of Venous Thromboembolism in Patients with Advanced Cholangiocarcinoma.

Background/Aims: Patients with active cancer frequently develop venous thromboembolism (VTE). However, there is little data about VTE in patients with advanced cholangiocarcinoma (CCA). Therefore, we investigated the clinical significance of VTE in patients with advanced CCA. Methods: We analyzed the data of a total of 332 unresectable CCA patients diagnosed between 2010 and 2020 in this retrospective study. We investigated the incidence and risk factors for VTE, and its effect on survival in patients with advanced CCA. Results: During a median follow-up of 11.6 months, 118 patients (35.5%) developed VTE. The cumulative incidence of VTE was 22.4% (95% confidence interval [CI], 0.18 to 0.27) at 3 months and 32.8% (95% CI, 0.27 to 0.38) at 12 months. Major vessel invasion was an independent risk factor for VTE (hazard ratio, 2.88; 95% CI, 1.92 to 4.31; p<0.001). Patients who developed VTE during follow-up had shorter overall survival than patients who did not (11.50 months vs 15.83 months, p=0.005). In multivariable analysis, VTE (hazard ratio, 1.58; 95% CI, 1.23 to 2.02; p<0.001) was associated with poor overall survival. Conclusions: Major vessel invasion is related to the occurrence of VTE in advanced CCA. The development of VTE significantly decreases the overall survival and is an important unfavorable prognostic factor for survival.

Optimal Follow-up of Incidental Pancreatic Cystic Lesions without Worrisome Features: Clinical Outcome after Long-term Follow-up.

Background/Aims: : The optimal duration and interval of follow-up for cystic lesions of the pancreas (CLPs) is not well established. This study was performed to investigate the optimal duration and interval of follow-up for CLPs in clinical practice. Methods: : Patients with CLPs without worrisome features or high-risk stigmata underwent follow-up with computed tomography at 6, 12, 18, and 24 months and then every 12 months thereafter. A retrospective analysis of prospectively collected data was performed. Results: : A total of 227 patients with CLPs detected from 2000 to 2008 (mean initial diameter, 1.3±0.6 cm) underwent follow-up for a median of 120 months. Twenty-two patients (9.7%) underwent surgery after a median of 47.5 months. Malignancies developed in four patients (1.8%), one within 5 years and three within 10 years. One hundred and fourteen patients (50.2%) were followed up for more than 10 years. No malignancy developed after 10 years of follow-up. During surveillance, 37 patients (16.3%) experienced progression to surgical indication. In patients with CLPs less than 2 cm in diameter, development of surgical indications did not occur within 24 months of follow-up. Conclusions: : CLPs should be continuously monitored after 5 years because of the persistent potential for malignant transformation of CLPs. An interval of 24 months for initial follow-up might be enough for CLPs with initial size of less than 2 cm in clinical practice.

Side-by-side placement of fully covered metal stents versus conventional 7F plastic stents in malignant hilar biliary obstruction: Prospective randomized controlled trial.

OBJECTIVES: We aimed to evaluate the efficacy and safety of metal stents compared with plastic stents when bilateral side-by-side stents were deployed for malignant hilar biliary obstruction (MHBO). METHODS: Fifty patients with unresectable advanced MHBO were randomly assigned to the metal stent (MS, n = 25) or plastic stent group (PS, n = 25). Fully covered self-expandable metal stents with 6 mm diameter and plastic stents with either 7F straight or double pigtail were used for MS and PS groups, respectively. Time to recurrent biliary obstruction (TRBO) was evaluated as the primary outcome. RESULTS: Both groups had 100% technical success rates; 88% and 76% of clinical success rates were obtained in MS and PS, respectively. Although stent migrations were more frequent in MS than PS (48% vs. 16%, P = 0.02), the mean TRBO was significantly longer in MS (190 days; 95% confidence interval [CI] 121-260 days vs. 96 days; 95% CI 50-141 days, P = 0.02). The placement of plastic stents (hazard ratio 2.42; 95% CI 1.24-4.73; P = 0.01) was the only significant risk factor associated with TRBO in multivariable analysis. The rates of adverse events were similar between the two groups (difference 0%; 95% CI -25% to 25%; P > 0.99). CONCLUSIONS: During bilateral side-by-side deployment in MHBO, the use of metal stents appears to be preferable to plastic stents in terms of TRBO, despite a higher frequency of stent migration.

Antiproliferative Activity of Piceamycin by Regulating Alpha-Actinin-4 in Gemcitabine-Resistant Pancreatic Cancer Cells.

Although gemcitabine-based regimens are widely used as an effective treatment for pancreatic cancer, acquired resistance to gemcitabine has become an increasingly common problem. Therefore, a novel therapeutic strategy to treat gemcitabine-resistant pancreatic cancer is urgently required. Piceamycin has been reported to exhibit antiproliferative activity against various cancer cells; however, its underlying molecular mechanism for anticancer activity in pancreatic cancer cells remains unexplored. Therefore, the present study evaluated the antiproliferation activity of piceamycin in a gemcitabine-resistant pancreatic cancer cell line and patient-derived pancreatic cancer organoids. Piceamycin effectively inhibited the proliferation and suppressed the expression of alpha-actinin-4, a gene that plays a pivotal role in tumorigenesis and metastasis of various cancers, in gemcitabine-resistant cells. Long-term exposure to piceamycin induced cell cycle arrest at the G0/G1 phase and caused apoptosis. Piceamycin also inhibited the invasion and migration of gemcitabine-resistant cells by modulating focal adhesion and epithelial-mesenchymal transition biomarkers. Moreover, the combination of piceamycin and gemcitabine exhibited a synergistic antiproliferative activity in gemcitabine-resistant cells. Piceamycin also effectively inhibited patient-derived pancreatic cancer organoid growth and induced apoptosis in the organoids. Taken together, these findings demonstrate that piceamycin may be an effective agent for overcoming gemcitabine resistance in pancreatic cancer.

Savolitinib: A Promising Targeting Agent for Cancer.

Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.

Genetic susceptibility to post-endoscopic retrograde cholangiopancreatography pancreatitis identified in propensity score-matched analysis.

BACKGROUND/AIMS: A previous history of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a risk factor for PEP, suggesting that there may be a genetic predisposition to PEP. However, nothing is known about this yet. The aim of this study was to identify genetic variations associated with PEP. METHODS: A cohort of high-risk PEP patients was queried from December 2016 to January 2019. For each PEP case, two propensity score-matched controls were selected. Whole exome sequencing was performed using blood samples. Genetic variants reported to be related to pancreatitis were identified. To discover genetic variants that predispose to PEP, a logistic regression analysis with clinical adjustment was performed. Gene-wise analyses were also conducted. RESULTS: Totals of 25 PEP patients and 50 matched controls were enrolled. Among the genetic variants reported to be associated with pancreatitis, only CASR rs1042636 was identified, and it showed no significant difference between the case and control groups. A total of 54,269 non-synonymous variants from 14,313 genes was identified. Logistic regression analysis of these variants showed that the IRF2BP1 rs60158447 GC genotype was significantly associated with the occurrence of PEP (odds ratio 2.248, FDR q value = 0.005). Gene-wise analyses did not show any significant results. CONCLUSION: This study found that the IRF2BP1 gene variant was significantly associated with PEP. This genetic variant is a highly targeted PEP risk factor candidate and can be used for screening high-risk PEP groups before ERCP through future validation. (ClinicalTrials.gov no. NCT02928718).

Analysis of ultrasonographic images using a deep learning-based model as ancillary diagnostic tool for diagnosing gallbladder polyps.

BACKGROUND: Accurately diagnosing gallbladder polyps (GBPs) is important to avoid misdiagnosis and overtreatment. AIMS: To evaluate the efficacy of a deep learning model and the accuracy of a computer-aided diagnosis by physicians for diagnosing GBPs. METHODS: This retrospective cohort study was conducted from January 2006 to September 2021, and 3,754 images from 263 patients were analyzed. The outcome of this study was the efficacy of the developed deep learning model in discriminating neoplastic GBPs (NGBPs) from non-NGBPs and to evaluate the accuracy of a computer-aided diagnosis with that made by physicians. RESULTS: The efficacy of discriminating NGBPs from non- NGBPs using deep learning was 0.944 (accuracy, 0.858; sensitivity, 0.856; specificity, 0.861). The accuracy of an unassisted diagnosis of GBP was 0.634, and that of a computer-aided diagnosis was 0.785 (p<0.001). There were no significant differences in the accuracy of a computer-aided diagnosis between experienced (0.835) and inexperienced (0.772) physicians (p = 0.251). A computer-aided diagnosis significantly assisted inexperienced physicians (0.772 vs. 0.614; p < 0.001) but not experienced physicians. CONCLUSIONS: Deep learning-based models discriminate NGBPs from non- NGBPs with excellent accuracy. As ancillary diagnostic tools, they may assist inexperienced physicians in improving their diagnostic accuracy.

Association between glycemic status and the risk of acute pancreatitis: a nationwide population-based study.

BACKGROUND: Although diabetes is reportedly associated with the occurrence of acute pancreatitis (AP), the risk of AP according to the duration and severity of diabetes is not yet clear. We aimed to investigate the risk of AP based on glycemic status and the presence of comorbidities using a nationwide population-based study. METHODS: We enrolled 3,912,496 adults who underwent health examinations under the National Health Insurance Service in 2009. All participants were categorized by glycemic status as normoglycemic, impaired fasting glucose (IFG), or diabetes. Baseline characteristics and the presence of comorbidities at the time of health check-up were investigated, and the occurrence of AP was followed up until 31 December 2018. We estimated the adjusted hazard ratios (aHRs) for AP occurrence according to the glycemic status, duration of diabetes (new-onset, duration < 5 years, or ≥ 5 years), type and number of anti-diabetic medications, and presence of comorbidities. RESULTS: During the observation period of 32,116,716.93 person-years, 8,933 cases of AP occurred. Compared with normoglycemia, the aHRs (95% confidence interval) were 1.153 (1.097-1.212) in IFG, 1.389 (1.260-1.531) in new-onset diabetes, 1.634 (1.496-1.785) in known diabetes < 5 years, and 1.656 (1.513-1.813) in patients with known diabetes aged ≥ 5 years. The presence of comorbidities associated with diabetes severity had a synergistic effect on the relationship between diabetes and AP occurrence. CONCLUSION: As glycemic status worsens, the risk of AP increases, and there is a synergistic effect when comorbidities coexist. To reduce the risk of AP, active control of factors that can cause AP should be considered in patients with long-standing diabetes and comorbidities.

Antiproliferative Activity of Krukovine by Regulating Transmembrane Protein 139 (TMEM139) in Oxaliplatin-Resistant Pancreatic Cancer Cells.

Krukovine (KV) is an alkaloid isolated from the bark of Abuta grandifolia (Mart.) Sandw. (Menispermaceae) with anticancer potential in some cancers with KRAS mutations. In this study, we explored the anticancer efficacy and mechanism of KV in oxaliplatin-resistant pancreatic cancer cells and patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutation. After treatment with KV, mRNA and protein levels were determined by RNA-seq and Western blotting, respectively. Cell proliferation, migration, and invasion were measured by MTT, scratch wound healing assay, and transwell analysis, respectively. Patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutations were treated with KV, oxaliplatin (OXA), and a combination of KV and OXA. KV suppresses tumor progression via the downregulation of the Erk-RPS6K-TMEM139 and PI3K-Akt-mTOR pathways in oxaliplatin-resistant AsPC-1 cells. Furthermore, KV showed an antiproliferative effect in PDPCOs, and the combination of OXA and KV inhibited PDPCO growth more effectively than either drug alone.

Acute Pancreatitis and the Risk of Dementia in Diabetes: A Nationwide Cohort Study Using Korean Healthcare Claims Database.

BACKGROUND: Diabetes is a major risk factor for the development of dementia, which has been proven to be associated with systemic inflammation. Acute pancreatitis, also a local and systemic inflammatory disease, is the most common gastrointestinal disease requiring acute hospitalization. OBJECTIVE: The effect of acute pancreatitis on dementia was investigated in type 2 diabetic patients. METHODS: Data was collected from the Korean National Health Insurance Service. The study sample included type 2 diabetes patients who received general health examination from 2009 to 2012. Cox proportional hazard regression analysis was used to evaluate the association between acute pancreatitis and dementia with adjustment of confounders. Stratified subgroup analysis by age, sex, smoking, alcohol consumption, hypertension, dyslipidemia, and body mass index was conducted. RESULTS: Among the 2,328,671 participants in total, 4,463 patients had a history of acute pancreatitis before the health examination. During a median follow-up of 8.1 (IQR, 6.7-9.0) years, 194,023 participants (8.3%) developed all-cause dementia. Previous history of acute pancreatitis was a significant risk factor for dementia after adjustment of confounding variables (HR 1.39 [95% CI 1.26-1.53]). In the subgroup analysis, patient characteristics such as age under 65 years, male, current smoker, and alcohol consumption were significant risk factors for dementia in patients with a history of acute pancreatitis. CONCLUSION: The history of acute pancreatitis was associated with the development of dementia in patients with diabetes. Because the risk of dementia increases with alcohol consumption and smoking in diabetic patients with history of acute pancreatitis, abstinence from alcohol and smoking should be recommended.