Treatment and Prognosis for Pancreatic Duct Disruption Associated With Pancreatic Cancer: A Case Series of 15 Patients.

Background Pancreatic duct (PD) disruption can occasionally be attributed to pancreatic cancer. Therapeutic interventions for PD disruption due to pancreatic cancer and their influence on pancreatic cancer prognosis remain unclear. This study investigated the therapeutic modalities and prognostic implications of PD disruption in pancreatic cancer. Methods This retrospective study included 15 patients with PD disruption concomitant with pancreatic cancer between April 2011 and March 2023. As an endoscopic intervention for PD disruption, endoscopic pancreatic stenting (EPS) or endoscopic ultrasonography-guided pancreatic fluid collection drainage (EUS-PFD) was performed. Technical success was defined as stent placement and clinical success was defined as an improvement in PD disruption. Results Of the 15 cases of PD disruption, two involved only pancreatic juice leakage without symptoms, four involved pancreatic pseudocyst (PPC) without infection, and nine involved PPC with infection. Four patients underwent EPS, nine underwent EUS-PFD, and two underwent lumen-apposing metal stent placement. All patients achieved both technical and clinical success without complications. The clinical stage of pancreatic cancer ranged from carcinoma in situ to the metastatic phase. For the treatment of pancreatic cancer, five patients underwent surgical resection, and eight underwent chemotherapy. There was no obvious recurrence of peritoneal sowing. The median overall survival from the diagnosis of pancreatic cancer in the resected and non-resected cases was 74 and 9.6 months, respectively. Conclusion Endoscopic intervention was effective in all cases of PD disruption due to pancreatic cancer. Furthermore, even in cases of pancreatic cancer after PD disruption, survival rates were similar to those in cases without PD disruption and were achieved through surgical resection or chemotherapy.

Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma.

Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer.

Association of pancreatic atrophy patterns with intraductal extension of early pancreatic ductal adenocarcinoma: a multicenter retrospective study.

BACKGROUND: Focal pancreatic parenchymal atrophy (FPPA) and upstream pancreatic atrophy (UPA) may indicate the presence of early pancreatic cancer. In early pancreatic cancer, the tumor occasionally spreads laterally along the main pancreatic duct, presenting challenges in determining the extent of surgical resection. This study aimed to investigate the association of pancreatic atrophy pattern and intraductal cancer extension. METHODS: Thirty-two patients with early-stage pancreatic cancer who underwent surgery at five participating centers were enrolled. Pancreatic atrophy was defined as the narrowing of parenchyma compared to the surrounding parenchyma and was classified as either FPPA (partial atrophy surrounding the pancreatic duct stenosis) or UPA (global atrophy caudal to the site of duct stenosis). Intraductal cancer extension was defined as an extension exceeding 10 mm. RESULTS: Preoperative computed tomography revealed FPPA, UPA, and no parenchymal atrophy in 13, 13, and 6 patients. Cases with FPPA or UPA showed significantly longer cancer extensions than those without atrophy (P = 0.005 and P = 0.03, respectively). Intraductal cancer extension was present in all but one case of FPPA. 69% (9/13) of the cases with UPA showed intraductal cancer extension, whereas cases without atrophy showed no intraductal cancer extension. Importantly, two patients with FPPA or UPA showed positive resection margins during surgery and three patients with FPPA or UPA showed recurrence in the remnant pancreas. CONCLUSIONS: The presence of FPPA and UPA indicates lateral cancer extension in early-stage pancreatic cancer. Preoperative assessment of the pancreatic parenchyma may provide valuable insights for determining the extent of surgical resection.

Predictive factors for refractory anastomotic stricture after cervical triangular anastomosis with gastric conduit reconstruction through the posterior mediastinum in minimally invasive esophagectomy.

BACKGROUND: After esophagectomy, anastomotic strictures disturb food passage and increase the incidence of aspiration pneumonia. Multiple endoscopic balloon dilatations are required for stricture treatment. Therefore, long-term quality of life and nutritional status may be adversely affected. This study aimed to identify risk factors for strictures after cervical triangular anastomosis using a gastric conduit among patients who underwent minimally invasive esophagectomy (MIE). METHODS: A total of 188 patients who underwent MIE for esophageal cancer between 2010 and 2020 at Kobe University Hospital were retrospectively examined. The incidence of strictures, number of dilatations for stricture, and time to stricture diagnosis were evaluated. Next, the potential independent risk factor for refractory strictures requiring more than 5 endoscopic balloon dilatations was clarified. RESULTS: The study included 188 patients who satisfied the inclusion criteria. Anastomotic strictures were observed in 44 patients (23%). Neoadjuvant chemotherapy was significantly more common in patients with stricture than in patients without stricture (75% vs 58%, respectively; P = .041). The median number of endoscopic balloon dilatations was 5 (IQR, 1-31). Of note, 30 patients (68%) underwent their first dilatation within 3 months after MIE. In univariate and multivariate analyses, < 69 days from surgery to first endoscopic balloon dilatation was an independent risk factor for stricture requiring more than 5 endoscopic balloon dilatations after cervical triangular anastomosis in MIE (hazard ratio, 9.483; 95% CI, 2.220-54.274; P = .002). CONCLUSION: Early postoperative anastomotic stricture might become refractory, and an appropriate treatment plan should be developed.

Risk-scoring system predicting need for hospital-specific interventional care after peroral endoscopic myotomy.

OBJECTIVES: Early identification of patients needing hospital-specific interventional care (HIC) following endoscopic treatment is valuable for optimizing postoperative hospital stays. We aimed to develop and validate a risk-scoring system for predicting HIC in patients who underwent peroral endoscopic myotomy (POEM). METHODS: This study included patients with esophageal motility disorders who underwent POEM at our hospital between April 2015 and March 2023. HIC was defined as any of the following situations: fasting for gastrointestinal rest to manage adverse events (AEs); intravenous administration of medications such as antibiotics and blood transfusion; endoscopic, radiologic, and surgical interventions; intensive care unit management; or other life-threatening events. A risk-scoring system for predicting HIC after postoperative day (POD) 1 was developed using multivariable logistic regression and was internally validated using bootstrapping and decision curve analysis. RESULTS: Of the 589 patients, 50 (8.5%) experienced HIC after POD1. Risk scores were assigned for four factors as follows: age (0 points for <70 years, 1 point for 70-79 years, 2 points for ≥80 years), preoperative prognostic nutritional index (0 points for >45, 1 point for 40-45, 4 points for <40), postoperative surgical site AEs on second-look endoscopy (7 points), and postoperative pneumonia on chest radiography (6 points). The discriminative ability (concordance statistics, 0.85; 95% confidence interval, 0.78-0.91) and calibration (slope 1.00; 0.74-1.28) were satisfactory. The decision curve analysis demonstrated its clinical usefulness. CONCLUSION: This risk-scoring system can predict the HIC after POD1 and provide useful information for determining discharge.

Near-infrared photoimmunotherapy as a complementary modality to in situ vaccine in a preclinical pancreatic cancer model.

Pancreatic cancer is one of the most refractory malignancies. In situ vaccines (ISV), in which intratumorally injected immunostimulatory adjuvants activate innate immunity at the tumor site, utilize tumor-derived patient-specific antigens, thereby allowing for the development of vaccines in patients themselves. Near-infrared photoimmunotherapy (NIR-PIT) is a novel therapy that selectively kills cancer cells exclusively in the NIR-irradiated region. Extending our previous research showing that ISV using the unique nanoparticulate Toll-like receptor 9 (TLR9) ligand K3-SPG induced effective antitumor immunity, here we incorporated NIR-PIT into K3-SPG-ISV so that local tumor destruction by NIR-PIT augments the antitumor effect of ISV. In the mouse model of pancreatic cancer, the combination of K3-SPG-ISV and CD44-targeting NIR-PIT showed synergistic systemic antitumor effects and enhanced anti-programmed cell death-1 (PD-1) blockade. Mechanistically, strong intratumoral upregulation of interferon-related genes and dependency on CD8+ T cells were observed, suggesting the possible role of interferon and cytotoxic T cell responses in the induction of antitumor immunity. Importantly, this combination induced immunological memory in therapeutic and neoadjuvant settings. This study represents the first attempt to integrate NIR-PIT with ISV, offering a promising new direction for cancer immunotherapy, particularly for pancreatic cancer.

Repeat endoscopic submucosal dissection close to the initial endoscopic submucosal dissection scar for superficial esophageal squamous cell carcinoma.

BACKGROUND: Repeat endoscopic submucosal dissection for metachronous recurrence of esophageal squamous cell carcinoma close to previous endoscopic submucosal dissection scars is challenging. Therefore, this study evaluated the efficacy and safety of repeat endoscopic submucosal dissection for recurrent esophageal squamous cell carcinoma. METHODS: The study included 1680 patients. After propensity score matching, esophageal endoscopic submucosal dissection-related outcomes were compared between the post-endoscopic submucosal dissection scar group (n = 91) and first endoscopic submucosal dissection group (n = 910). The Kaplan-Meier method and log-rank tests were used to compare both groups' survival and local recurrence curves. RESULTS: After propensity score matching, the two groups showed no significant difference in en bloc resection rate (97.80% vs. 99.56%, p = 0.096), treatment time (64.75 min vs 61.33 min, p = 0.448), recurrence rate (3.30% vs. 2.20%, p = 0.458), and stricture rate (7.69% vs. 4.07%, p = 0.110). However, the perforation rate was higher in the post-endoscopic submucosal dissection scar group than in the first endoscopic submucosal dissection group (4.40% vs. 1.10%, p = 0.031). The 5-year overall survival rates in the post-endoscopic submucosal dissection scar and first endoscopic submucosal dissection groups were 88.6% and 89.0%, respectively. CONCLUSIONS: Repeated esophageal endoscopic submucosal dissection for recurrent esophageal squamous cell carcinoma yielded satisfactory clinical outcomes and survival rates. Therefore, repeat endoscopic submucosal dissection may effectively treat esophageal squamous cell carcinoma recurrence close to the initial endoscopic submucosal dissection scars.

Impaired Consciousness Due to Hyperammonemia During S-1 Administration for Unresectable Pancreatic Cancer.

A 71-year-old woman diagnosed with unresectable locally advanced pancreatic cancer was initially treated with gemcitabine and nab-paclitaxel as first-line therapy. The tumor exhibited no significant progression; however, after 12 cycles, the patient developed drug-induced interstitial pneumonia, leading to the discontinuation of gemcitabine and nab-paclitaxel therapy. Following recovery from pneumonia, S-1 therapy was initiated as second-line treatment. During S-1 treatment, she was hospitalized because of impaired consciousness and was subsequently diagnosed with hyperammonemia induced by S-1. Although rarely reported, S-1-induced hyperammonemia is potentially a significant adverse effect. Here, we herein report the case of a patient with pancreatic cancer.

Efficacy and safety of same-day preparation with sodium picosulfate plus magnesium citrate on the day of colonoscopy for bowel preparation: Multicenter, single-arm, open-label study.

BACKGROUND AND AIM: Sodium picosulfate plus magnesium citrate (SP + MC) is a well-tolerated bowel preparation agent. However, Japan currently approves only two methods of taking SP + MC: the day-before and split-dose preparation, without approval of same-day preparations. This study aimed to evaluate the efficacy and safety of same-day SP + MC preparations. METHODS: This was a multicenter, single-arm, nonrandomized, open-label study. We enrolled 145 Japanese patients between June and December 2023. The patients received two sachets of SP + MC dissolved in 300 ml of water and 1200 mL or more of clear liquid on the day of colonoscopy. Bowel cleansing efficacy, adverse events (AEs), and patient satisfaction were evaluated. RESULTS: Of the enrolled patients, 137 underwent colonoscopy according to our protocol. Bowel preparation was adequate in 133 patients (97.1%). The mean total Boston Bowel Preparation Score was 8.3 ± 1.2. Five patients experienced AEs (3.6%): two (1.5%), abdominal pain; one (0.73%), ischemic enteritis; one (0.73%), vomiting or nausea; and one (0.73%), headache. All AEs were treated conservatively. None of the patients exhibited abnormal blood test results or clinical symptoms after receiving SP + MC. Regarding patient satisfaction, all patients were able to take SP + MC as directed; 136 (99.2%) expressed a preference for this bowel preparation for future colonoscopies. CONCLUSION: The same-day SP + MC preparation showed high bowel-cleansing efficacy and satisfaction in Japanese patients without serious AEs.

Current Status of Conversion Hepatectomy After Sorafenib and Lenvatinib Treatment for Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: Sorafenib and lenvatinib have long been used as a first-line treatment for advanced hepatocellular carcinoma (HCC). Along with the development of systemic chemotherapy for HCC, the concept of conversion hepatectomy has recently become widespread. The present study aimed to assess the clinical outcomes of sorafenib and lenvatinib for HCC regarding the possibility of conversion hepatectomy in clinical practice. PATIENTS AND METHODS: A total of 295 patients with advanced HCC receiving sorafenib and lenvatinib, accounting for 306 treatments (sorafenib, n=157; lenvatinib, n=149, 11 patients received lenvatinib after sorafenib treatment) at five different institutions were enrolled. Patients were assessed for their clinical characteristics and therapeutic response using both Response Evaluation Criteria in Solid Tumors criteria (RECIST) and modified RECIST (mRECIST) criteria. Additionally, an indication of surgery after tyrosine kinase inhibitor administration was determined based on the tumor status of patients. RESULTS: The median survival times of patients treated with sorafenib and lenvatinib were 12.8 and 16.4 months, respectively, without significant difference (p=0.1645). The objective response rates (ORR) of sorafenib based on mRECIST and RECIST were 10.1% and 5.9%, respectively, and those of lenvatinib were 38.1% and 19.0%, respectively. Among the 306 treatments, two cases (sorafenib and lenvatinib, one each) underwent hepatectomy after systemic chemotherapy. CONCLUSION: Few cases with unresectable HCC were amenable to conversion hepatectomy after sorafenib and lenvatinib treatments due to the limited ORR by RECIST. Cautious approach must be taken when administering neoadjuvant chemotherapy aimed at conversion hepatectomy.

Diagnostic guide for immune checkpoint inhibitor-induced liver injury.

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI-induced liver injury) as an immune-related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R-value is useful in deciding treatment strategies for ICI-induced liver injury. Histologically, the most representative feature is an acute hepatitis-like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8-positive T lymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non-obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI-induced cholangitis are classified as non-hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI-induced liver injury.

Successful cannulation of a difficult pancreatic duct using the uneven method.

Video 1Pancreatic cannulation via the uneven method.

Risk Factors for Immune Checkpoint Inhibitor-Induced Liver Injury and the Significance of Liver Biopsy.

Immune checkpoint inhibitor (ICI)-induced liver injury (LI) is a common adverse event, but the clinical characteristics based on the classification of hepatocellular injury and cholestatic types are not fully evaluated. This study aims to analyze risk factors and histological findings in relation to the classification of ICI-induced LI. In total, 254 ICI-induced LI patients among 1086 treated with ICIs between September 2014 and March 2022 were classified according to the diagnostic criteria for drug-induced LI (DILI), and their risk factors and outcomes were evaluated. Kaplan-Meier analyses showed that overall survival in patients with hepatocellular-injury-type LI was significantly longer than others (p < 0.05). Regarding pre-treatment factors, the lymphocyte count was significantly higher in patients with ICI-induced LI, especially in hepatocellular-injury-type LI. Gamma glutamyl transferase (γGTP) and alkaline phosphatase (ALP) were also significantly lower in patients with ICI-induced LI (p < 0.05). Multivariate analyses revealed that malignant melanoma, high lymphocyte count, and low ALP levels were extracted as factors contributing to hepatocellular-injury-type LI. The histological findings among 37 patients diagnosed as ICI-induced LI via liver biopsy also revealed that the spotty/focal necrosis was significantly frequent in hepatocellular-injury-type LI, whereas ductular reactions were frequently observed in cholestatic-type LI. It is suggested that the histological inflammation pattern in patients with LI is closely correlated with the type of DILI.

Current Roles of Ramucirumab in the Sequential Treatment of Unresectable Hepatocellular Carcinoma.

BACKGROUND/AIM: The treatment algorithm for systemic therapies for advanced hepatocellular carcinoma (HCC) has changed dramatically; however, the therapeutic landscape for sequential second-line or later-line treatments, including ramucirumab, remains controversial. This study aimed to investigate the role of ramucirumab for treating HCC. PATIENTS AND METHODS: We retrospectively analyzed data from 17 patients with advanced HCC who received ramucirumab, and 8 of them who received lenvatinib re-administration after ramucirumab treatment failure. RESULTS: The median overall survival of 17 patients treated with ramucirumab was 11.5 months. The median ratios of the 1-month post-treatment α-fetoprotein (AFP) levels and albumin-bilirubin (ALBI) scores to the pre-treatment AFP levels and ALBI scores following ramucirumab treatment were 0.880 and 0.965, respectively. The median ratios of the 1-month post-treatment AFP and ALBI levels to the pre-treatment levels were 1.587 and 0.970 for mALBI grade 1/2a, and 1.313 and 0.936 for mALBI grade 2b/3, respectively. Six of the eight patients who received lenvatinib rechallenge treatment exhibited a decrease in AFP levels one month post-lenvatinib treatment. Deterioration of liver function 3 months post-lenvatinib treatment was noted in five of the eight patients who received lenvatinib rechallenge treatment after ramucirumab. CONCLUSION: Ramucirumab may be equally useful in patients with unresectable HCC who have poor liver function or whose liver function is aggravated by other therapies. Rechallenge treatment with lenvatinib after ramucirumab may be a valid treatment option for HCC.

Clinical Significance and Remaining Issues of Anti-HBc Antibody and HBV Core-Related Antigen.

Currently, hepatitis B virus (HBV) core antibody (anti-HBc antibody) and HBV core-related antigen (HBcrAg) are widely used as serum markers for diagnosis based on the HBV core region. This review focused on anti-HBc antibodies and HBcrAg and aimed to summarize the clinical significance of currently used assay systems and the issues involved. While anti-HBc is very significant for clinical diagnosis, the clinical significance of quantitative assay of anti-HBc antibody has been reevaluated with improvements in diagnostic performance, including its association with clinical stage and prediction of carcinogenesis and reactivation. In addition, concerning the new HBcrAg, a high-sensitivity assay method has recently been established, and its diagnostic significance, including the prediction of reactivation, is being reevaluated. On the other hand, the quantitative level of anti-HBc antibody expressed in different units among assay systems complicates the interpretation of the results. However, it is difficult to standardize assay systems as they vary in advantages, and caution is needed in interpreting the assay results. In conclusion, with the development of highly sensitive HBcrAg and anti-HBc antibody, a rapid and sensitive detection assay system has been developed and used in clinical practice. In the future, it is hoped that a global standard will be created based on the many clinical findings.

Randomised controlled, patient-blinded, multicentre, superiority trial to evaluate the efficacy of the line-attached sheath-type traction device for endoscopic submucosal dissection in patients with superficial gastric neoplasms.

INTRODUCTION: EndoTrac is a line-attached sheath-type traction device that enables us to control the direction and the force of traction during endoscopic submucosal dissection (ESD). The efficacy of EndoTrac for gastric ESD has not been fully verified. METHODS AND ANALYSIS: The G-Trac study is a multicentre (nine general hospitals and two university hospitals in Japan) collaborative trial assessing the efficacy of EndoTrac for gastric ESDs. Patients with superficial gastric neoplasms will be enrolled and randomly assigned to undergo either conventional ESD or EndoTrac ESD. Allocation will be stratified according to tumour location, operator experience and tumour diameter at an allocation rate of 1:1. The type of endoknife used will be confirmed before randomisation. The primary outcome, procedure time, will be compared between the groups in both intention-to-treat and per-protocol analyses using the Wilcoxon rank sum test. The efficacy-related, safety-related and device-related outcomes will be assessed in the secondary analysis. The planned sample size of the 142 patients in the two groups will enable us to detect a difference with a power of 80% by using the Wilcoxon rank sum test, assuming an effect size of 0.54, asymptotic relative efficiency of 0.864 and a two-sided type 1 error rate of 5%. ETHICS AND DISSEMINATION: This trial was approved by the certified review board of Kobe University (22 December 2022). The results from this trial will be disseminated through peer-review journals, presentations at national and international conferences, and data sharing with other researchers. TRIAL REGISTRATION NUMBER: jRCT1052220166.

Anti-integrin αvß6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.