Clinical outcomes and reintervention after endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis in absence of cholangitis.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) may help detect cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC), but it may be associated with complications. This study was aimed at determining the prognostic impact of ERCP on patients with PSC without cholangitis. METHODS: Patients with PSC without cholangitis were divided into two groups: those who underwent ERCP within three years after diagnosis (ERCP-performed group) and those who did not (non-ERCP group). These groups were compared in terms of clinical outcomes (liver-related death or liver transplantation, endoscopic treatment requirement and repeated cholangitis) and the composite outcome. RESULTS: Of 99 patients with PSC with detailed medical history, 49 were included in the ERCP-performed group and 21 in the non-ERCP group. In Kaplan-Meier analysis, the non-ERCP group was less likely to achieve the three outcomes and the composite outcome, showing statistical significance (endoscopic treatment requirement; p = 0.017 and composite outcome; p = 0.014). A Cox proportional hazards model indicated that ERCP in the asymptomatic state was a significant predictor of endoscopic treatment requirement (hazard ratio [HR]: 4.37, 95% confidence interval [CI]: 1.03-18.59) and the composite outcome (HR: 4.54, 95% CI: 1.07-19.28). CONCLUSION: ERCP in patients with PSC without cholangitis is likely to require further endoscopic treatment and may be associated with poor prognosis.

Cytokine release syndrome following durvalumab and tremelimumab in advanced hepatocellular carcinoma: A case report with cytokine and damage-associated molecular pattern analysis.

Cytokine release syndrome (CRS) is a systemic inflammatory syndrome that causes fatal circulatory failure due to hypercytokinemia, and subsequent immune cell hyperactivation caused by therapeutic agents, pathogens, cancers, and autoimmune diseases. In recent years, CRS has emerged as a rare, but significant, immune-related adverse event linked to immune checkpoint inhibitor therapy. Furthermore, several previous studies suggested that damage-associated molecular patterns (DAMPs) could be involved in malignancy-related CRS. In this study, we present a case of severe CRS following combination therapy with durvalumab and tremelimumab for advanced hepatocellular carcinoma, which recurred during treatment, as well as an analysis of cytokine and DAMPs trends. A 35-year-old woman diagnosed with hepatocellular carcinoma underwent a partial hepatectomy. Due to cancer recurrence, she started a combination of durvalumab and tremelimumab. Then, 29 days post-administration, she developed fever and headache, initially suspected as sepsis. Despite antibiotics, her condition worsened, leading to disseminated intravascular coagulation and hemophagocytic syndrome. The clinical course and elevated serum interleukin-6 levels led to a CRS diagnosis. Steroid pulse therapy was administered, resulting in temporary improvement. However, she relapsed with increased interleukin-6, prompting tocilizumab treatment. Her condition improved, and she was discharged on day 22. Measurements of inflammatory cytokines interferon-γ, tumor necrosis factor-α, and DAMPs, along with interleukin-6, using preserved serum samples, confirmed marked elevation at CRS onset. CRS can occur after the administration of any immune checkpoint inhibitor, with the most likely trigger being the release of DAMPs associated with tumor collapse.

Stent Deployment Without Tract Dilation in Endoscopic Ultrasound-Guided Hepaticogastrostomy Using a Novel Partially Covered Metal Stent With a Super-Slim Stent Delivery System: A Case Report.

Endoscopic ultrasound-guided hepaticogastrostomy is performed when transpapillary biliary drainage using endoscopic retrograde cholangiopancreatography is difficult due to surgically altered anatomy, an inaccessible papilla, or difficult biliary cannulation. This procedure consists of puncturing the intrahepatic bile duct from the stomach, inserting a guidewire into the bile duct, dilating the puncture tract, and placing a stent. Recently, a novel partially covered self-expandable metal stent with a super-slim stent delivery system of 5.9 Fr has become available. With this stent, endoscopic ultrasound-guided hepaticogastrostomy can be performed without using a dilator to expand the puncture tract. Herein, we describe a technique for dilator-free stent deployment for endoscopic ultrasound-guided hepaticogastrostomy using this novel stent. We performed an endoscopic ultrasound-guided hepaticogastrostomy with this stent in a 65-year-old patient with obstructive jaundice due to pancreatic head cancer without adverse events and with satisfactory improvement in jaundice. This procedure is expected to reduce bile leakage into the abdominal cavity and shorten the procedure time.

Intensive triamcinolone acetonide injection regimen can highly prevent stricture after extensive esophageal endoscopic submucosal dissection.

BACKGROUND: This study aimed to investigate the utility of intensive triamcinolone acetonide (TA) injections after extensive esophageal endoscopic submucosal dissection (ESD). METHODS: This retrospective study included 27 lesions in 27 consecutive patients who underwent ESD (ulcers encompassing ≥3/4 of the esophageal circumference) and received TA injections without oral steroid administration. Groups A and B included patients undergoing ESD with and without complete circumferential resection, respectively. All patients received TA injections (100 mg/session) immediately after ESD. In Group A, weekly based TA injections were performed until near-complete ulcer epithelialization. In Group B, patients did not receive additional injections or received weekly or biweekly TA injections. The primary outcome was stricture rate, and the secondary outcomes were the proportion of patients requiring endoscopic balloon dilation (EBD) and the number of TA injections. RESULTS: Group A included 7 lesions, and Group B included 20 lesions. The median (range) tumor lengths were 40 (30-90) and 45 (30-110) mm in Groups A and B, respectively. In Group A, the median circumferential resection diameter was 40 (20-80) mm. The stricture rate and the proportion of patients requiring EBD were 0 (0%) in Group A and 1 (5.0%) in Group B. The number of TA injection sessions was significantly higher in Group A than in Group B (8 [5-25] vs 1.5 [1-3]; p < 0.001). CONCLUSIONS: Intensive weekly or biweekly based TA injections might aid in preventing post-ESD stricture and the need for EBD in patients undergoing extensive resection involving the entire esophageal circumference.

Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Efficacy and safety of biosimilar infliximab in bio-naïve patients with Crohn's disease.

BACKGROUND AND STUDY AIMS: The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease. PATIENTS AND METHODS: This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration. RESULTS: The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups. CONCLUSION: The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease.

Relationship between hand-foot skin reaction and external force on patients with hepatocellular carcinoma: A cohort study.

PURPOSE: Hand-foot skin reaction (HFSR), a side effect of tyrosine kinase inhibitor (TKI) treatment, makes it difficult to walk and perform daily activities because of pain in the limbs. HFSR occurs predominantly in the sites where external forces (pressure and shear stress) are applied. This study aimed to determine whether pressure or shear stress induces the occurrence of HFSR. METHODS: This cohort study was conducted in patients who received TKI treatment for hepatocellular carcinoma. The external forces applied to the sole of the patients' foot while walking was measured, and its association with the occurrence of HFSR was examined. The degree of HFSR was assessed by the patient's response during the examination and by photographs of their feet. The patients' feet were divided into low (grade <2) or high (grade ≥2) HFSR foot group, and the differences in external forces between the groups were analyzed using t-test and Cox hazard analysis. RESULTS: Analysis of the feet of 55 study participants (n = 110) showed no significant difference between the groups on t-test (p ≥ 0.05), however, Cox hazard analysis showed an increased risk of HFSR with higher peak shear stress values at the fifth metatarsal head (hazard ratio = 1.01, p = 0.047; 95% confidence interval = 1.00-1.02). CONCLUSION: Shear stress is possibly related to HFSR occurrence. Nurses should assess whether patients' shoes fit their feet before initiating TKI treatment. They should instruct patients to wear shoes that are fit of both diameter and width for their feet.

Genomic Analysis of Undifferentiated Carcinoma of the Pancreas with Squamous Differentiation: A Case Report.

Pancreatic cancer is an intractable malignancy associated with a dismal prognosis. Undifferentiated carcinoma, a rare subtype, poses a clinical challenge owing to a limited understanding of its molecular characteristics. In this study, we conducted genomic analysis specifically on a case of undifferentiated carcinoma of the pancreas exhibiting squamous differentiation. An 80-year-old male, previously treated for colorectal cancer, presented with a mass with central cystic degeneration in the pancreatic tail. The mass was diagnosed pathologically as undifferentiated carcinoma of the pancreas with squamous differentiation. Despite surgical resection and chemotherapy, the patient faced early postoperative recurrence, emphasizing the aggressive nature of this malignancy. Genomic analysis of distinct histologic components revealed some common mutations between undifferentiated and squamous components, including Kirsten rat sarcoma virus (KRAS) and TP53. Notably, the squamous component harbored some specific mutations in SMARCA4 and SMARCB1 genes that code for members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. The common mutations in the undifferentiated and squamous cell carcinoma components from this analysis suggest that they originate from a common origin. The discussion also underscores the scarcity of genomic analyses on undifferentiated carcinoma of the pancreas, with existing literature pointing to SWI/SNF complex-related gene mutations. However, our case introduces chromatin remodeling factor mutations as relevant in squamous differentiation. In conclusion, this study provides valuable insights into the genomic landscape of undifferentiated pancreatic carcinoma with squamous differentiation. These findings suggest the importance of further research and targeted therapies to improve the management of undifferentiated carcinoma of the pancreas and enhance patient outcomes.

Clinical risk factors for portal hypertension-related complications in systemic therapy for hepatocellular carcinoma.

BACKGROUND: During systemic therapy, the management of portal hypertension (PH)-related complications is vital. This study aimed to clarify factors associated with the incidence and exacerbation of PH-related complications, including the usefulness of contrast-enhanced computed tomography (CECT) in the management of PH-related complications during systemic therapy. METHODS: A total of 669 patients who received systemic therapy as first-line treatment (443 patients for sorafenib, 131 for lenvatinib, and 90 for atezolizumab/bevacizumab [ATZ/BEV]) were enrolled in this retrospective study. Additionally, the lower esophageal intramural vessel diameters (EIV) on CECT and endoscopic findings in 358 patients were compared. RESULTS: The cutoff values of the EIV diameter on CECT were 3.1 mm for small, 5.1 mm for medium, and 7.6 mm for large varices, demonstrating high concordance with the endoscopic findings. esophageal varices (EV) bleeding predictors include EIV ≥ 3.1 mm and portal vein tumor thrombosis (PVTT). In patients without EV before systemic therapy, factors associated with EV exacerbation after 3 months were EIV ≥ 1.9 mm and ATZ/BEV use. Predictors of hepatic encephalopathy (HE) include the ammonia level or portosystemic shunt diameter ≥ 6.8 mm. The incidence of HE within 2 weeks was significantly higher (18%) in patients with an ammonia level ≥ 73 µmol/L and a portosystemic shunt ≥ 6.8 mm. The exacerbating factors for ascites after 3 months were PVTT and low albumin levels. CONCLUSIONS: Careful management is warranted for patients with risk factors for exacerbation of PH-related complications; moreover, the effective use of CECT is clinically important.

Characteristics of factors contributing to follow-up for suspect delayed bleeding after colorectal endoscopic submucosal dissection.

BACKGROUND AND AIMS: Delayed bleeding (DB) is a major adverse event associated with colorectal endoscopic submucosal dissection (ESD) that sometimes causes difficulties in making decisions regarding endoscopic hemostasis. This study identified the factors that contribute to follow-up without endoscopic hemostasis when DB is suspected after colorectal ESD. METHODS: In total, 583 patients (603 tumors) who underwent ESD or hybrid ESD for colorectal tumors at Chiba University Hospital between June 2009 and January 2022 were retrospectively registered. Of these, 141 cases (141 tumors) with DB; with hematochezia or hemoglobin decrease ≥2 g/dL after colorectal ESD were analyzed. The DB group was divided into the Hemostasis group (H group; endoscopic hemostasis performed) and no-Hemostasis group (no-H group; no endoscopy performed, or endoscopy performed but no hemostasis performed after hematochezia or hemoglobin decrease). Univariate and multivariate logistic regression analyses were performed to assess the factors contributing to follow-up. RESULTS: Thirty-one patients with 31 tumors were categorized into the H group, while 110 patients with 110 tumors were in the no-H group. Multivariate regression analysis revealed that date from ESD to first hematochezia ≤Day 3 (odds ratio [OR] 4.55, 95% confidence interval [CI] 1.44-14.33; p = 0.010) and bleeding duration ≤1 day (OR 3.35, 95% CI 1.35-8.34; p = 0.009) contributed to follow-up. CONCLUSIONS: In cases of DB after colorectal ESD, a bleeding duration ≤1 day or date from ESD to first hematochezia ≤Day 3 may contribute to follow-up observation without endoscopic hemostasis.

Asymptomatic Pneumoperitoneum With a Large Amount of Gas Appeared During Endoscopic Ultrasound-Guided Biliary Drainage.

We report a case in which a large amount of intraperitoneal free gas developed during endoscopic ultrasound-guided biliary drainage with the rendezvous technique. A 62-year-old woman presented with obstructive jaundice caused by a pancreatic head tumor. Endoscopic retrograde cholangiopancreatography was attempted but failed due to difficulty cannulating the bile duct. Consequently, endoscopic ultrasound-guided hepaticogastrostomy was performed using a fully covered metal stent. Subsequently, the rendezvous technique was employed to access the biliary system and perform an endoscopic sphincterotomy. Finally, a fully covered metal stent was placed transpapillary. Fluoroscopic imaging during the procedure revealed a large amount of gas between the liver and diaphragm. Despite the pneumoperitoneum, the patient experienced no abdominal pain or fever. One week later, a computed tomography scan confirmed the disappearance of free air in the intraperitoneal cavity. The patient's subsequent clinical course remained uneventful, and she was discharged from the hospital. This case highlights the potential for pneumoperitoneum to develop during endoscopic ultrasound-guided biliary drainage, particularly when using the rendezvous technique. It is crucial to differentiate this finding from gastrointestinal perforation based on clinical presentation and imaging features.

Natural killer group 2D-major histocompatibility complex class I polypeptide-related sequence A activation enhances natural killer cell-mediated immunity against hepatocellular carcinoma: A review.

The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8+ T lymphocytes have a response rate of approximately 30%. In addition to CD8+ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%-50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta-analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome-wide association study on chronic viral hepatitis showed that a single-nucleotide polymorphism of major histocompatibility complex class I polypeptide-related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single-nucleotide polymorphism-driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane-bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell-mediated cytotoxicity.

Liquid biopsy of wash samples obtained via endoscopic ultrasound-guided fine-needle biopsy: Comparison with liquid biopsy of plasma in pancreatic cancer.

OBJECTIVES: Pancreatic cancer (PC) has a poor prognosis and limited treatment options. Liquid biopsy, which analyzes circulating tumor DNA (ctDNA) in blood, holds promise for precision medicine; however, low ctDNA detection rates pose challenges. This study aimed to investigate the utility of wash samples obtained via endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) as a liquid biopsy for PC. METHODS: A total of 166 samples (42 formalin-fixed paraffin-embedded [FFPE] tissues, 80 wash samples, and 44 plasma samples) were collected from 48 patients with PC for genomic analysis. DNA was extracted and quantified, and 60 significantly mutated genes were sequenced. The genomic profiles of FFPE tissues, wash samples, and plasma samples were compared. Finally, the ability to detect druggable mutations in 80 wash samples and 44 plasma samples was investigated. RESULTS: The amount of DNA was significantly lower in plasma samples than in wash samples. Genomic analysis revealed a higher detection rate of oncogenic mutations in FFPE tissues (98%) and wash samples (96%) than in plasma samples (18%) and a comparable detection rate in FFPE tissues and wash samples. Tumor-derived oncogenic mutations were detected more frequently in wash samples than in plasma samples. Furthermore, the oncogenic mutations detection rate remained high in wash samples at all PC stages but low in plasma samples even at advanced PC stages. Using wash samples was more sensitive than plasma samples for identifying oncogenic and druggable mutations. CONCLUSIONS: The wash sample obtained via EUS-FNB is an ideal specimen for use as a liquid biopsy for PC.

The efficacy of bile liquid biopsy in the diagnosis and treatment of biliary tract cancer.

BACKGROUND: Diagnosing biliary tract cancer is difficult because endoscopic retrograde cholangiopancreatography (ERCP) is performed fluoroscopically, and the sensitivity of bile cytology is low. Liquid biopsy of bile using targeted sequencing is expected to improve diagnosis and treatment, but few studies have been conducted. In this study, we examined whether liquid biopsy of bile improves the diagnostic sensitivity of biliary strictures. METHODS: A total of 72 patients with biliary strictures who underwent ERCP at Chiba University Hospital between April 2018 and March 2021 were examined. Of these, 43 and 29 were clinically and pathologically diagnosed as having malignant and benign biliary strictures, respectively. We performed targeted sequencing of bile obtained from these patients, and the sensitivity of this method was compared with that of bile cytology. Detection of at least one oncogenic mutation was defined as having malignancy. RESULTS: The sensitivity of bile cytology was 27.9%, whereas that of genomic analysis was 46.5%. Comparing bile cytology alone with the combination of cytology and genomic analysis, the latter was more sensitive (53.5%, p < .001). Among the 43 patients with malignant biliary strictures, mutations with FDA-approved drugs were detected in 11 (26%). CONCLUSIONS: Liquid biopsy of bile can potentially diagnose malignancy and detect therapeutic targets.

Severe ulcerative colitis induced by COVID-19 vaccination.

A 37-year-old woman developed severe colitis with diffuse mucosal erythema and ulcerations throughout the entire colon after the 3rd vaccination of COVID-19. Stool culture was negative, and the pathological findings showed increased lymphoplasmacytic and neutrophilic infiltration in the colonic lamina propria, which were consistent with ulcerative colitis. After the treatment with anti-tumor necrosis factor-α agent, the ulceration markedly improved with development of severe colonic stenosis, which was successfully dilated with endoscopic balloon dilation. In case of COVID-19 vaccination, it should be noted that vaccination could be a trigger for the onset of UC.

Differences in Mucosal Permeability Among Patients With Ulcerative Colitis Classified Based on the Colonic Location and Disease Activity.

INTRODUCTION: Factors affecting mucosal permeability (MP) in ulcerative colitis (UC) are largely unknown. We aimed to investigate the difference in MP among patients with UC classified according to the colonic locations and to evaluate the correlations between local MP and endoscopic or histological activity of UC. METHODS: The transepithelial electrical resistance (TER), which is inversely proportional to permeability, of tissue samples from the mucosa of the ascending colon, descending colon, and rectum of patients with UC and healthy individuals (HIs) was measured by using the Ussing chamber. TERs were compared between patients with UC and HIs and evaluated according to colonic locations and disease activity of UC. RESULTS: Thirty-eight patients with UC and 12 HIs were included in this study. Both in HIs and patients with UC, MP tends to be higher in the anal side. TER in the ascending colon was significantly lower in patients with UC than in HIs (45.3 ± 9.0 Ω × cm 2 vs 53.5 ± 9.7 Ω × cm 2 , P = 0.01). The increased permeability in UC was observed also in the descending colon, only when the inflammation involved the location. A significant correlation between TER and endoscopic activity was found in the rectum only ( r = -0.49, P = 0.002). There were no significant correlations between TERs and UC histology. DISCUSSION: The MP in the colon differs according to the colonic location. The ascending colon among patients with UC showed disease-specific changes in MP, whereas the MP is increased in proportion to the endoscopic activity in the rectum.

Parathyroid Hormone-Related Peptide-Producing Gallbladder Cancer Presenting With Humoral Hypercalcemia of Malignancy: A Case Report.

Humoral hypercalcemia of malignancy (HHM) is often reported in cancers derived from the squamous epithelium; however, there are very few reports of HHM in patients with gallbladder cancer. We report a case of a parathyroid hormone-related protein (PTHrP)-producing gallbladder cancer presenting with HHM. A 43-year-old woman presented with appetite loss, nausea, and brown-colored urine. Blood tests revealed that she had hypercalcemia, high serum bilirubin, and high serum parathyroid hormone. Contrast-enhanced computed tomography revealed a gallbladder tumor, liver metastasis, and bile duct obstruction caused by the gallbladder tumor in the hilar region. No bone metastasis was observed. Endoscopic retrograde cholangiopancreatography revealed pancreaticobiliary maljunction. Metal biliary stents were placed, and a transpapillary biopsy of the gallbladder tumor revealed a pathological diagnosis of adenocarcinoma. The patient was diagnosed with HHM due to gallbladder cancer with liver metastasis. Although her hypercalcemia and jaundice improved, her appetite loss and nausea did not improve. Subsequently, the patient developed disseminated intravascular coagulation, and her general condition gradually deteriorated. Due to her poor general condition, chemotherapy could not be administered. The patient died six weeks after visiting our hospital. Although rare, some gallbladder cancers cause HHM due to PTHrP production.