Risk assessment of metachronous gastric cancer after endoscopic submucosal dissection based on endoscopic intestinal metaplasia.

Background and Aim: The incidence of metachronous gastric cancer (MGC) after endoscopic treatment for early gastric cancer (EGC) is high, but a method of risk assessment for MGC based on endoscopic findings has not been established. In this study, we focused on endoscopic intestinal metaplasia (IM) and investigated the risk for MGC after endoscopic submucosal dissection (ESD) for EGC. Methods: This retrospective observational study involved patients who underwent curative ESD for EGC from April 2015 to January 2021. We assessed endoscopic IM using the pretreatment endoscopic examination images. The severity of endoscopic IM was classified into four levels: 0 (none), 1 (mild), 2 (moderate), and 3 (severe). Four different gastric areas were evaluated. We divided the patients into a low-score group and a high-score group, and compared the cumulative incidence of MGC. Results: In total, 156 patients who met the inclusion criteria were followed up for at least 12 months after ESD, and MGC developed in 14 patients during a mean period oof 41.5 months. The endoscopic IM scores in the lesser curvature of the antrum, lesser curvature of the corpus, and greater curvature of the corpus were higher in patients with MGC than in those without MGC. In the corpus, the 5-year cumulative incidence of MGC was significantly higher in the high-score group than in the low-score group (29.8% vs 10.0%, P = 0.004). Conclusion: The severity of endoscopic corpus IM was associated with MGC. Thus, patients with severe corpus IM at the time of ESD require careful examination and intensive follow-up.

Hemoperitoneum due to a ruptured right gastroepiploic artery following non-interventional endoscopic ultrasonography: a case report.

Endoscopic ultrasonography has become a routine procedure in clinical practice and is widely accepted as a safe procedure. Previous studies have reported that severe bleeding rarely occurs even when performing fine-needle aspiration biopsy. Severe hemorrhage following non-interventional endoscopic ultrasonography has never been reported. We herein report a case of hemorrhagic shock due to hemoperitoneum caused by a ruptured right gastroepiploic artery consequent to a diagnostic endoscopic ultrasonography. The patient was administered two antithrombotic agents. An extensive diagnostic workup contributed to the correct diagnosis, which led to a successful treatment by transcatheter arterial embolization. Endoscopists should be aware of this rare, but potentially fatal, adverse event of endoscopic ultrasonography.

Biliary stent removal through a transgastric fistula created with endoscopic ultrasound-guided hepaticogastrostomy.

Therapeutic endoscopic ultrasound has become widespread as an effective procedure for biliary drainage; however, it is rarely used to remove foreign bodies such as a biliary stent. A 57-year-old man was referred to our hospital for a benign biliary stricture in the left hepatic duct after hepatectomy. Initially, a 7-Fr plastic stent was placed in the left hepatic duct with the distal end set above the papilla, and it was replaced with an 8.5-Fr stent as the stricture remained after 3 months. Endoscopic retrograde cholangiopancreatography was performed to retrieve the plastic stent 3 months later; however, the stent could not be moved because the proximal flap was caught in the stricture. Attempts using various devices failed to retrieve the stent; thus, endoscopic ultrasound-guided hepaticogastrostomy was performed to create a route for stent retrieval. Eventually, the plastic stent was successfully retrieved with biopsy forceps through a fully covered self-expandable metallic stent located in a transgastric fistula. We propose our new method involving endoscopic ultrasound-guided hepaticogastrostomy for endoscopic stent retrieval that fails via the transpapillary route.

Clinical outcome of a highly flexible duodenal stent for gastric outlet obstruction: A multicenter prospective study.

BACKGROUND AND AIM: Endoscopic duodenal stenting for patients with malignant gastric outlet obstruction (GOO) has been widespread; however, clinical trials evaluating the structures of duodenal stents are lacking. Thus, we aimed to investigate the clinical outcomes of a highly flexible duodenal stent for GOO patients. METHODS: A prospective study of duodenal stenting for GOO patients from five hospitals between August 2017 and August 2018 was performed. WallFlex Duodenal Soft were used in all procedures. The primary endpoint was clinical success, defined as an improvement in the GOO scoring system. RESULTS: The study enrolled 31 patients (12 women, 19 men) with GOO, with a median age of 70 (range 52-90) years. Primary diseases were pancreatic cancer, gastric cancer, biliary tract cancer, and others in 14, 10, 3, and 4 patients, respectively. The technical success rate was 97%, and the clinical success rate was 87%. Simultaneous biliary drainage was performed in 19% of patients. Adverse events occurred in three patients. Chemotherapy was given in 41% of clinically successful cases, and the median overall survival time after stent placement was 82 days (range, 30-341 days), and. Stent dysfunction occurred in 30% of clinically successful cases (stent ingrowth in seven and stent overgrowth in one patient). The median time to stent dysfunction was 157 days (range, 11-183 days). Six patients were treated with additional stent placement after dysfunction. CONCLUSION: Placement of a highly flexible duodenal stent is an effective and safe treatment for patients with GOO (UMIN-CTR 000028783).

Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy.

According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct-DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue- and ct-DNA samples. The 21 patients were subjected to quantitative ct-DNA monitoring at 4 to 8-week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation-negative cases, next-generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct-DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%-31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%-0.2%]). In the ct-DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression-free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50 days, P < .001). Therefore, ct-DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy.

Differential diagnosis of gallbladder polypoid lesions using contrast-enhanced ultrasound.

PURPOSE: The purpose of the study is to evaluate the utility of contrast-enhanced ultrasound (CEUS) for the differential diagnosis of gallbladder polypoid lesions (GPLs). METHODS: Thirty-six patients with GPLs (17 with gallbladder cancer, 19 with benign polyps) who underwent CEUS were enrolled in the study. The mean age of patients was 65.7 ± 12.6 years. Perflubutane-based contrast agent and high-mechanical index mode, which can eliminate the background B-mode and provide precise visualization of tumor vessels, were used for CEUS, and two blinded readers evaluated the images, retrospectively. RESULTS: Patient age and size of malignant GPLs (72.4 ± 9.4 years and 23.4 ± 7.5 mm) were significantly greater than those for benign lesions (59.6 ± 12.3 years and 12.4 ± 2.9 mm) (P < 0.01, respectively), and the receiver operating characteristic analysis showed the cut-off value as over 65 years and 16 mm. Univariate analysis showed that heterogeneity in B-mode (80% [12/15]), sessile shape (76% [13/17]), dilated vessel (71% [12/17]), irregular vessel (82% [14/17]), and heterogeneous enhancement (59% [10/17]) on CEUS were significantly correlated with malignant GPLs (P < 0.01, respectively). On CEUS, the diagnostic criterion for malignant GPLs was defined as having one or more of the above four features because of the highest accuracy. Sensitivity, specificity, and accuracy for malignant GBLs were 88%, 68%, and 78% for patient age; 76%, 89%, and 83% for size of GPLs; 80%, 68%, and 74% for B-mode; and 94%, 89%, and 92% for CEUS, respectively. CONCLUSIONS: CEUS is useful for the differential diagnosis of malignant and benign GPLs.

Phase II study of fixed dose-rate gemcitabine plus S-1 as a second-line treatment for advanced biliary tract cancer.

PURPOSE: Gemcitabine plus platinum is considered standard first-line chemotherapy for patients with advanced biliary tract cancer. However, no standard second-line therapy has been established for this disease. According to reports, S-1 exerts anti-tumor effects on advanced biliary tract cancer and gemcitabine is more effective via fixed dose-rate administration. We evaluated the efficacy and safety of a combination of fixed dose-rate gemcitabine and S-1 after failure of gemcitabine or gemcitabine plus cisplatin therapy. METHODS: This single-arm phase II study (clinical trial number: UMIN000005918) set the response rate as the primary endpoint and used a MiniMax two-stage design with a null hypothesis < 7% and alternative hypothesis ≥ 25%. Thirty-five patients were needed to yield a power of 90% and α value of 0.05. Patients received gemcitabine (1000 mg/m2, div, 100-min period, day 1) and S-1 (40 mg/m2 twice daily, oral, days 1-7), every 2 weeks until disease progression or intolerable adverse events were observed. RESULTS: Forty-one patients were enrolled, and 3 of 23 first-stage patients responded. The overall response rate was 9.8% [95% confidence interval (CI): 2.7-19.2%]. The median overall and progression-free survival were 7.0 [95% CI: 5.3-8.6] and 2.6 months (95% CI: 1.6-3.5), respectively. The most common grade 3-4 adverse events were leukopenia (19.5%), neutropenia (19.5%), anemia (14.6%), thrombocytopenia (7.3%), and anorexia (4.8%). CONCLUSION: Second-line fixed dose-rate gemcitabine plus S-1 was not sufficiently effective and tolerable in patients with advanced biliary tract cancer refractory to gemcitabine or gemcitabine plus cisplatin.

Switch to miriplatin for multinodular hepatocellular carcinoma unresponsive to transarterial chemoembolization with epirubicin: a prospective study.

OBJECTIVE: The aim of this prospective study was to evaluate the efficacy of transarterial chemoembolization using miriplatin, a platinum-based anticancer drug, as a retreatment regimen for hepatocellular carcinoma (HCC) unresponsive to chemoembolization using epirubicin. METHODS: Between April 2013 and December 2014, we enrolled 57 consecutive chamoembolization-naïve patients with unresectable HCC, and performed chemoembolization with epirubicin. Treatment effect, necrotizing rate of the target nodules, was evaluated at 1-3 months after treatment using contrast-enhanced CT or MRI. We subsequently included retreatment chemoembolization with miriplatin for patients whose treatment effect was <50% after chemoembolization with epirubicin. The treatment effect after chemoembolization with miriplatin and the liver function before and after chemoembolization were evaluated. RESULTS: Eighteen patients of the 57 showed a treatment effect <50% after chemoembolization with epirubicin, and were switched to chemoembolization with miriplatin. The treatment effect after chemoembolization with miriplatin was ≥50% in four (22%) patients. Four of the remaining 14 (78%) patients who had <50% necrosis exhibited deterioration of the liver function after chemoembolization with miriplatin. Univariate analysis indicated that an alpha-fetprotein-L3 level <10% and a serum albumin level ≥3.6 g/dl were predictive factors of therapeutic response after chemoembolization with miriplatin (P < 0.05). However, there was no predictive factor regarding the deterioration of liver function after chemoembolization with miriplatin. CONCLUSIONS: In unresectable HCC patients who were unresponsive to chemoembolization with epirubicin, switching the chemotherapeutic regimen to a platinum-based anticancer drug in retreatment chemoembolization should be considered as a treatment option. Trial registration: UMIN 000015887.

Short-term efficacy of transarterial chemoembolization with epirubicin-loaded superabsorbent polymer microspheres for hepatocellular carcinoma: comparison with conventional transarterial chemoembolization.

PURPOSE: This study aimed to compare the short-term efficacy of transarterial chemoembolization (TACE) with epirubicin-loaded superabsorbent polymer embolics (SAP) and conventional TACE in TACE-naïve patients with unresectable hepatocellular carcinoma (HCC). METHODS: Fifty consecutive patients (mean age, 72.8 years; hepatitis C, 46%; BCLC-A or B, 52% or 48%) treated with TACE with SAP during 2013-2015 and 55 consecutive patients (mean age, 71.8 years; hepatitis C, 40%; BCLC-A or B, 51% or 49%) treated with conventional TACE during 2011-2013 were evaluated. Safety evaluations were based on CTCAE ver. 4.0. Short-term efficacies, i.e., at 1 month after TACE, were assessed using the European Association for the Study of the Liver criteria. Overall survival rates were calculated using the Kaplan-Meier method. Short-term response markers were analyzed by univariate and multivariate analyses. RESULTS: There was no significant difference in the incidence of any grade of adverse events. The objective response rates were 50% and 62% in patients treated with TACE with SAP and with conventional TACE, respectively (P = 0.358). The overall survival rates were not significantly different (P = 0.810); the 1-year survival rates and the median survival time of the patients treated with TACE with SAP and with conventional TACE were 76% and 74%, and 18 months and 21 months, respectively. Overall survival was related to the short-term response. An alpha-fetoprotein level <1,000 ng/mL was a significant short-term response marker on multivariate analysis. CONCLUSIONS: For TACE-naïve patients, TACE with SAP and conventional TACE had comparable safety and short-term efficacies.

Duodenal stenting followed by systemic chemotherapy for patients with pancreatic cancer and gastric outlet obstruction.

OBJECTIVES: Endoscopic duodenal stenting has recently been proposed as a substitute for surgical gastrojejunostomy for the treatment of gastric outlet obstruction. We aimed to evaluate the efficacy and safety of duodenal stenting followed by systemic chemotherapy for patients with advanced pancreatic cancer with gastric outlet obstruction. METHODS: This was a single-center, retrospective cohort study, conducted at an academic medical center, of 71 patients with advanced pancreatic cancer and gastric outlet obstruction (mean age: 67.6 years; range: 31-92 years) who underwent duodenal stenting with or without subsequent chemotherapy. Overall survival, duration of oral intake of foods, the rate of introduction of chemotherapy, progression-free survival, and adverse events were evaluated. RESULTS: Stent placement was technically successful in 69 (97%) patients. Thirty-six (51%) patients were treated with chemotherapy: 17 with gemcitabine alone, 15 with S-1 alone, 3 with FOLFIRINOX, and 1 with paclitaxel. Median progression-free survival and overall survival after chemotherapy were 2.6 months (95% confidence interval: 1.3-3.9 months) and 4.7 months (95% confidence interval: 2.6-6.8 months), respectively. Cases of grade 3 anemia were frequently observed during chemotherapies following duodenal stenting (32%). Tumor stage, performance status, neutrophil-to-lymphocyte ratio, and introduction of chemotherapy were independent prognostic factors for survival (hazard ratios of 3.73, 2.21, 2.69, and 1.85 with p-values of <0.001, 0.010, <0.001, and 0.045, respectively). CONCLUSIONS: The findings of this study suggest that endoscopic duodenal stenting is an advantageous treatment in advanced pancreatic cancer patients with gastric outlet obstruction regarding its safety and smooth conduction of subsequent chemotherapies.

Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer.

OBJECTIVE: In this subanalysis of a phase III trial using three categorized doses of S-1, the influence of the actual doses on safety and efficacy was evaluated. METHODS: We compared the efficacy and safety of the S-1 or gemcitabine plus S-1 combination (GS) arm between the top 10% group and the bottom 10% group according to the initial doses of S-1: ≥77.6 versus ≤65.9 mg/m2/day (n = 28 vs. 28) in the S-1 arm, and ≥65.1 versus ≤53.8 mg/m2/day (n = 27 vs. 28) in the GS arm. RESULTS: Overall and progression-free survival were not significantly different between these two groups: hazard ratios of 0.818 and 0.761 with p values of 0.498 and 0.330 in the S-1 arm, and hazard ratios of 0.836 and 0.759 with p values of 0.557 and 0.323 in the GS arm, respectively. Incidences of grade 3-4 hematological toxicities were significantly higher in the top 10% group than in the bottom 10% group: 42.9 versus 14.3 and 85.2 versus 57.1%, with p values of 0.037 and 0.037 in the S-1 and the GS combination arm, respectively. CONCLUSIONS: Higher actual doses of S-1 were associated with a higher incidence of hematological toxicity even in the same dose setting.

Potential prognostic significance of a new proteomic profile in patients with advanced pancreatic adenocarcinoma.

OBJECTIVES: Seven-signal proteomic approach has recently been developed as a new proteomic profile measured by matrix-assisted laser desorption/ionization mass spectrometry. The aim of this study was to evaluate prognostic significance of this proteomic value in patients with pancreatic adenocarcinoma. METHODS: Blood samples from the patients with pancreatic adenocarcinoma were prospectively collected before treatments including surgical resection and systemic chemotherapies. The seven-signal proteomic profiles of the samples were measured, and the prognostic significance of the proteomic value was evaluated through comparison with other existing prognostic markers. RESULTS: Cut-off value of the proteomic profiles at 52 stratified overall prognosis of the patients (6.5 months vs. 10.9 months with the values ≥52 vs. <52, p = 0.020). In subgroup analyses of inoperable cases with carcinoembryonic antigen level of <5 ng/ml or performance status of 0-1, the proteomic value at 52 stratified their prognosis (p = 0.002 and p = 0.006, respectively). CONCLUSIONS: The new seven-signal proteomics showed useful prognostic significance for patients with pancreatic adenocarcinoma. Further studies with a large sample size would be required to evaluate whether this proteomic approach possibly complements the existing parameters, such as carcinoembryonic antigen and performance status.

Renal toxicity associated with weekly cisplatin and gemcitabine combination therapy for treatment of advanced biliary tract cancer.

OBJECTIVE: A combination of weekly cisplatin plus gemcitabine is a new standard regimen for patients with advanced biliary tract cancer (BTC). This regimen does not require prolonged hydration schedules; however, the long-time safety profile has not been evaluated so far. In particular, the aim of this study was to evaluate the renal function during this regimen. METHODS: We reviewed 79 consecutive patients with BTC who received the weekly cisplatin plus gemcitabine regimen. The incidence of adverse events was evaluated by CTCAE v4.0. RESULTS: A total of 402 courses were administered. The median cumulative dose of cisplatin was 250 mg (range: 25-825). The renal function was exacerbated gradually throughout the treatment course. The incidence of a decreased glomerular filtration rate (GFR) at <50 ml/min was significantly related to a pretreatment GFR at <80 ml/min and a total dose of cisplatin>400 mg [p=0.011, odds ratio (OR) 58.2, 95% confidence interval (CI): 2.5-1334.0 and p=0.021, OR 18.3, 95% CI: 1.6-215.5]. CONCLUSIONS: The combination of weekly cisplatin and gemcitabine for advanced BTC gradually affected the renal function, and it was highly recommended to focus on both the change of GFR and total dose of cisplatin during this regimen.