Current prognostic factors of advanced gastric cancer patients treated with chemotherapy: real world data from a Japanese 12 institutions.

BACKGROUND: Understanding the prognostic factors of advanced gastric cancer before starting chemotherapy is important to determine personalized treatment strategies. However, the details of chemotherapy and the prognosis of advanced gastric cancer patients have changed with the time and environment. The aim of this study was to understand the current reality of chemotherapy and to estimate the prognostic factors of advanced gastric cancer patients before starting chemotherapy at multiple centers. This includes specialized cancer hospitals and community hospitals, with the latest data under the Japanese insurance system. METHODS: We evaluated the clinical parameters and treatment details of 1025 patients who received systemic chemotherapy for unresectable advanced gastric cancer from 2012 to 2018 at 12 institutions in Japan. Prognostic factors were analyzed using the Cox proportional hazards regression model. RESULTS: As of April 2021, 953 (93%) patients had died, while 72 (7%) patients survived. The median overall survival and progression-free survival of first-line chemotherapy was 11.8 months (95% confidence interval, 10.8-12.3 months) and 6.3 months (95% confidence interval, 5.9-6.9 months), respectively. Multivariate analysis revealed eight prognostic factors: age < 40 years, performance status ≥2, no gastrectomy, diffuse histological type, albumin <3.6, alkaline phosphatase ≥300, creatinine ≥1.0 and neutrophil-to-lymphocyte ratio > 3.0. Patients using trastuzumab showed better survival than patients without (16.1 months vs. 11.1 months; P = 0.0005). CONCLUSIONS: We identified eight prognostic factors for patients with advanced gastric cancer undergoing Japanese standard chemotherapy. Our results will help clinicians develop treatment strategies for every patient.

Nonrecurrence Rate of Underwater EMR for ≤20-mm Nonampullary Duodenal Adenomas: A Multicenter Prospective Study (D-UEMR Study).

BACKGROUND AND AIMS: Endoscopic resection of nonampullary duodenal adenoma is often challenging, and its technique has not yet been standardized. To overcome the practical difficulty of conventional endoscopic mucosal resection, underwater endoscopic mucosal resection (UEMR) was recently developed; therefore, we investigated the effectiveness and safety of UEMR for nonampullary duodenal adenoma. METHODS: A multicenter, prospective cohort study was conducted at 21 institutions in Japan. We enrolled patients with no more than 2 nonampullary duodenal adenomas ≤20 mm in size, who were planned to undergo UEMR. After UEMR, follow-up endoscopies were scheduled at 2 and 12 months after the procedure, and biopsy specimens were taken from the post-UEMR scars. The primary endpoint was the proportion of patients with histologically proven nonrecurrence at follow-up endoscopy and biopsy. RESULTS: A total of 155 patients with 166 lesions underwent UEMR. One patient with a non-neoplastic lesion in the resected specimen and 10 patients with 10 lesions who were lost to follow-up were excluded. Finally, 144 patients with 155 lesions who received all follow-up endoscopies were analyzed for the primary endpoint. The proportion of patients with proven nonrecurrence was 97.2% (n = 140 of 144; 95% confidence interval, 92.8%-99.1%) which exceeded the predefined threshold value (92%). Two cases of delayed bleeding (1.2%) occurred and they were successfully managed by clips. All recurrences were successfully treated by additional endoscopic treatment. CONCLUSIONS: This multicenter, prospective cohort study demonstrated effectiveness and safety of UEMR for nonampullary duodenal adenomas ≤20 mm in size. (University Hospital Medical Network Clinical Trials Registry, Number: UMIN000030414).

Prospective analysis of the expression status of FGFR2 and HER2 in colorectal and gastric cancer populations: DS-Screen Study.

PURPOSE: Fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) proteins are both molecular targets for cancer therapy. The objective of this study was to evaluate the expression status of FGFR2 and HER2 in patients with gastric cancer (GC) or colorectal cancer (CRC). METHODS: Archived tumor tissue samples from patients with histologically-confirmed GC or CRC suitable for chemotherapy were analyzed for FGFR2 and HER2 expression using immunohistochemistry and fluorescence in situ hybridization (HER2 in CRC only). RESULTS: A total of 176 GC patients and 389 CRC patients were enrolled. Among patients with GC, 25.6% were FGFR2-positive and 26.1% were HER2-positive. Among patients with CRC, 2.9% were FGFR2-positive and 16.2% were HER2-positive. No clear relationship was found between FGFR2 and HER2 status in either GC or CRC. In GC, FGFR2 and HER2 statuses did not differ between different primary cancer locations, whereas there were some differences between histological types. Based on FGFR2- and/or HER2-positive status, 117 patients were identified as potentially suitable for inclusion in clinical trials of therapeutic agents targeting the relevant protein (GC = 45, CRC = 72; FGFR = 56, HER2 = 62), of whom 7 were eventually enrolled into such clinical trials. CONCLUSIONS: This study indicated the prevalence of FGFR2 and HER2 in GC and CRC in the Japanese population. The screening performed in this study could be useful for identifying eligible patients for future clinical trials of agents targeting these proteins. TRIAL REGISTRATION: Clinical trial registration Japic CTI No.: JapicCTI-163380.  https://www. CLINICALTRIALS: jp/cti-user/trial/ShowDirect.jsp?directLink=RNlzx1PPCuT.PrVNPxPRwA .

[Screening for Dehydration in Outpatient Cancer Chemotherapy-Use of Serum Osmolality and Hidden Dehydration Check Sheet].

Weight loss during cancer chemotherapy affects the continuation of treatment; therefore, it is important to maintain and improve nutritional status. Additionally, appropriate fluid and electrolyte replacement is essential for maintaining life. This study included 100 patients who underwent outpatient chemotherapy in April 2021. The degree of dehydration was assessed based on serum osmolality, and the possibility of screening was examined by a hidden dehydration check sheet. Hidden dehydration was noted in 38 patients and dehydration in 6 patients. The incidence of pancreatic cancer was significantly lower than that of lung cancer. In the hidden dehydration check sheet, 51 patients were found to present with high possibility of hidden dehydration and required consultation to a medical professional. The serum osmolality of the results was not significantly different. During outpatient cancer chemotherapy, a certain percentage of patients present with hidden dehydration. To detect dehydration at an early stage, serum osmolality should be actively measured and continuous diet counseling, including confirmation of food and fluid intake, is required.

A phase II study of FOLFOXIRI plus bevacizumab as initial chemotherapy for patients with untreated metastatic colorectal cancer: TRICC1414 (BeTRI).

PURPOSE: FOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes. METHODS: Twelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR). RESULTS: Of the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8-77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively. CONCLUSIONS: FOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia.

The clinicopathological differences of sporadic non-ampullary duodenal epithelial neoplasm depending on tumor location.

BACKGROUND AND AIM: Although sporadic non-ampullary duodenal adenoma is speculated to be precancerous lesion, the relationship between adenoma and carcinoma remains unclear due to their rarity. Previous studies on sporadic non-ampullary duodenal epithelial neoplasm (SNADEN) have mainly targeted superficial tumors, like adenoma and early carcinoma. The clinicopathological features, including those of advanced carcinoma, remain poorly investigated. We assessed the clinicopathological features of SNADEN, including advanced carcinoma, focusing on tumor location. METHODS: We retrospectively collected the data of 410 patients who had been clinically and pathologically diagnosed with SNADEN at 11 institutions in Japan between June 2002 and March 2014. RESULTS: The SNADEN was mucosal neoplasia and invasive carcinoma in 321 (78.3%) and 89 (21.7%) patients, respectively. The proportion of invasive carcinomas in SNADEN was significantly higher on the oral side of the papilla of Vater (oral-Vater) than on the anal side (anal-Vater) (27.9% vs 14.4%, P < 0.001). Undifferentiated-type carcinoma was significantly more frequent with oral-Vater than anal-Vater (38.7% vs 14.8%, P = 0.026). The recurrence rate of surgically R0 resected locally advanced carcinomas was significantly higher with oral-Vater than anal-Vater (46.4% vs 8.3%, P = 0.021). Furthermore, the relapse-free survival with oral-Vater was significantly shorter than with anal-Vater (hazard ratio: 2.35; 95% confidence interval: 1.09-5.50; P = 0.028). CONCLUSIONS: The clinicopathological features of SNADEN on oral-Vater were different from those on anal-Vater. SNADEN on oral-Vater was more likely to be invasive carcinomas and might behave more aggressively due to biologically higher malignancy than that on anal-Vater.

Impact of Body Mass Index of Japanese Gallbladder Cancer Patients on their Postoperative Outcomes.

　We investigated the relationship between body mass index (BMI) and postoperative outcomes in 450 gallbladder cancer patients in Japan. We collected patient information, including sex, age, underlying disease, BMI, stage, surgery method, postoperative time to discharge, and postoperative Medicare fees, from the Japanese administrative database associated with the Diagnosis Procedure Combination system. We classified patient BMIs as underweight (BMI<18.5 kg/m2), normal (BMI≥18.5 kg/m2 and <25 kg/m2) or overweight/obese (BMI≥25 kg/m2), then investigated the relationship between these categories and two postoperative outcomes: time to discharge and postoperative Medicare fees. The median postoperative time to discharge was 12 days in all patients, and 12 days in each of the three weight groups (p=0.62, n.s.). The median postoperative Medicare fees from surgery until discharge were (USD): all patients, $5,002; underweight, $5,875; normal weight, $4,797; and overweight/obese, $5,179 (p=0.146, n.s.). A multivariate analysis with adjustment for competing risk factors revealed that BMI was not associated with increased risk of longer postoperative time to discharge (normal weight: HR 1.17, p=0.29; overweight/obese: HR 1.17, p=0.37) or higher postoperative Medicare fees (OR 0.99, p=0.86, n.s.). Thus, high BMI was not found to be a factor for poor postoperative outcomes in Japanese patients with gallbladder cancer.

Impact of Body Mass Index on Survival of Pancreatic Cancer Patients in Japan.

The impact of body mass index (BMI) on postoperative survival in Japanese patients with pancreatic cancer is unclear. We examined the relationship between preoperative BMI and the prognosis of Japanese patients who underwent surgery for pancreatic cancer to determine whether BMI affects these patients' prognosis. Of the patients who underwent pancreatectomy between January 2004 and August 2015 at our institution, 246 were pathologically diagnosed with pancreatic tubular adenocarcinoma; the cancer was located in the pancreatic head (n=161) and in the body and tail (n=85). We classified the patients by BMI: underweight (n=22), normal weight (n=190), and overweight/obese (n=34) groups. We retrospectively analyzed medical records for patient characteristics, lesion location, disease stage, postoperative complications, chemotherapy, and prognosis. Lesion location, disease stage, postoperative complications, and chemotherapy were not significantly different among the BMI groups. The median survival times were as follows (days): all patients, 686; underweight, 485; normal weight, 694; and overweight/obese, 839. In a multivariate analysis, after adjusting for competing risk factors, low BMI was associated with an increased risk of death (normal weight: HR 0.58, p=0.038; overweight/obese: HR 0.54, p=0.059). High BMI was not found to be a postoperative factor for poor prognosis in Japanese pancreatic cancer patients.

The characteristics and outcomes of small bowel adenocarcinoma: a multicentre retrospective observational study.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1-2% of gastrointestinal tumours. We investigated the clinical characteristics, outcomes, and prognostic factors of primary SBA. METHODS: We retrospectively analysed the characteristics and clinical courses of 205 SBA patients from 11 institutions in Japan between June 2002 and August 2013. RESULTS: The primary tumour was in the duodenum and jejunum/ileum in 149 (72.7%) and 56 (27.3%) patients, respectively. Sixty-four patients (43.0%) with duodenal adenocarcinoma were asymptomatic and most cases were detected by oesophagogastroduodenoscopy (EGD), which was not specifically performed for the detection or surveillance of duodenal tumours. In contrast, 47 patients (83.9%) with jejunoileal carcinoma were symptomatic. The 3-year survival rate for stage 0/I, II, III, and IV cancers was 93.4%, 73.1%, 50.9%, and 15.1%, respectively. Multivariate analysis revealed performance status 3-4, high carcinoembryonic antigen, high lactate dehydrogenase (LDH), low albumin, symptomatic at diagnosis, and stage III/IV disease were independent factors for overall survival (OS). Ten patients (18.5%) with stage IV disease were treated with a combination of resection of primary tumour, local treatment of metastasis, and chemotherapy; this group had a median OS of 36.9 months. CONCLUSIONS: Although most SBA patients were diagnosed with symptomatic, advanced stage disease, some patients with duodenal carcinoma were detected in early stage by EGD. High LDH and symptomatic at diagnosis were identified as novel independent prognostic factors for OS. The prognosis of advanced SBA was poor, but combined modality therapy with local treatment of metastasis might prolong patient survival.

Magnified endoscopic features of duodenal follicular lymphoma and other whitish lesions.

The sensitivity and specificity of magnified endoscopic features for differentiating follicular lymphoma from other diseases with duodenal whitish lesions have never been investigated. Here we compared the magnified endoscopic features of duodenal follicular lymphoma with those of other whitish lesions. We retrospectively reviewed the cases of patients with follicular lymphoma (n＝9), lymphangiectasia (n＝7), adenoma (n＝10), duodenitis (n＝4), erosion (n＝1), lymphangioma (n＝1), and hyperplastic polyp (n＝1). The magnified features of the nine follicular lymphomas included enlarged villi (n＝8), dilated microvessels (n＝5), and opaque white spots of various sizes (n＝9). The lymphangiectasias showed enlarged villi, dilated microvessels, and white spots, but the sizes of the white spots were relatively homogeneous and their margin was clear. Observation of the adenoma and duodenitis revealed only whitish villi. Although the lymphangioma was indistinguishable from the follicular lymphomas by magnified features, it was easily diagnosed based on the macroscopic morphology. In conclusion, magnified endoscopic features, in combination with macroscopic features, are useful for differentiating follicular lymphomas from other duodenal diseases presenting whitish lesions.

Prompt resolution of hypoglycemia by hepatic transarterial embolization for malignant insulinoma with multiple liver metastases.

A 45-year-old female who presented with loss of consciousness and a cold sweat was found to have a pancreatic tumor and multiple liver metastases. Laboratory studies showed marked hypoglycemia and inappropriately elevated serum insulin, C-peptide, and serum tumor markers. Fine needle aspiration revealed Grade 3 small-cell type primary pancreatic neuroendocrine carcinoma. Consequently, the diagnosis of malignant insulinoma was made. Transarterial embolization (TAE) for hepatic metastases resulted in the reduction of tumor volume and prompt resolution of hypoglycemic attacks, whereas diazoxide and systemic chemotherapy had been ineffective for controlling blood glucose levels, and octreotide was unavailable due to the allergic effect. This case report highlights the potential usefulness of TAE for malignant insulinomas in the management of hypoglycemia.

Endoscopic submucosal dissection of esophageal cancer using the Mucosectom2 device: a feasibility study.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is being increasingly used for superficial esophageal cancers. However, esophageal ESD is technically difficult, time consuming, and less safe compared with endoscopic mucosal resection (EMR). To perform ESD safely and more efficiently, various types of knives have been developed. This study compared the efficacy of our newly developed device, Mucosectom2, with that of conventional devices for esophageal ESD. PATIENTS AND METHODS: Between May 2007 and February 2011, ESD was performed for 172 esophageal lesions. Of these, 120 lesions were treated by conventional devices only, whereas 52 lesions were treated by conventional devices and the Mucosectom2. Procedure time, en bloc and R0 resection rates, and adverse events were retrospectively compared between the conventional and Mucosectom2 groups. RESULTS: The median procedure time was 48.0 minutes in the conventional group and 21.5 minutes in the Mucosectom2 group; the procedure time was significantly shorter in the Mucosectom2 group than in the conventional group (P < 0.0001). The en bloc and R0 resection rates were lower in the conventional group than those in the Mucosectom2 group, although these differences were not significant. The rate of exposure of the muscle layer in the Mucosectom2 group was significantly lower than in the conventional group (P = 0.04). The rates of perforation and postoperative bleeding were not significantly different between the two groups. CONCLUSIONS: This feasibility study suggests that, compared with conventional ESD devices, the Mucosectom2 may decrease the time required for esophageal ESD. Although our groups appeared comparable, they were studied at different times. Endoscopic expertise and endoscope quality may have differed during these periods, thereby affecting the results of our study. A prospective trial is therefore required to confirm our results.

Randomized Phase III study of 5-fluorouracil continuous infusion vs. sequential methotrexate and 5-fluorouracil therapy in far advanced gastric cancer with peritoneal metastasis (JCOG0106).

OBJECTIVE: Owing to the risks of serious and sustained toxicity, anticancer drugs such as cisplatin and irinotecan cannot be readily administered to patients with gastric cancer and severe peritoneal metastasis. Therefore, a standard chemotherapy regimen has yet to be established for these types of patients. This randomized study investigated the utility of sequential methotrexate and 5-fluorouracil therapy vs. 5-fluorouracil continuous infusion for gastric cancer with peritoneal metastasis. METHODS: Eligible patients had radiologically confirmed peritoneal metastasis with intestinal stenosis, peritoneal tumor or ascites. Treatment with 5-fluorouracil continuous infusion (800 mg/m(2)/day, ci, d1-5, q4w) or methotrexate and 5-fluorouracil therapy (methotrexate, 100 mg/m(2), bolus infusion, followed 3 h later by 5-fluorouracil, 600 mg/m(2), bolus infusion, with leucovorin rescue, q1w) was continued until disease progression or unacceptable toxicity. The projected sample size was 236, providing 80% power to detect a 40% increase in median overall survival in methotrexate and 5-fluorouracil therapy with a one-sided α of 0.05. RESULTS: All 237 randomized patients were included in the primary analysis. The methotrexate and 5-fluorouracil therapy arm was not superior to the 5-fluorouracil continuous infusion arm (median survival time, 9.4 months in the 5-fluorouracil continuous infusion arm, 10.6 months in the methotrexate and 5-fluorouracil therapy arm; hazard ratio, 0.94; 95% confidence interval, 0.72-1.22; one-sided P = 0.31). Frequencies of Grade 3 or higher neutropenia, Grade 3 or higher anorexia and treatment-related deaths were 0.9, 27.4 and 1.7%, respectively, in the 5-fluorouracil continuous infusion arm, and 31.9, 33.6 and 0.9%, respectively, in the methotrexate and 5-fluorouracil therapy arm. CONCLUSIONS: Methotrexate and 5-fluorouracil therapy is not suitable for use as standard therapy for advanced gastric cancer with peritoneal metastasis.

A prospective analysis of efficacy and long-term outcome of radiation therapy for gastric mucosa-associated lymphoid tissue lymphoma.

BACKGROUND/AIMS: Few studies exist on the efficacy and long-term outcome of radiation therapy (RT) for gastric mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: Twenty-two patients with stage I or stage II(1) disease were prospectively evaluated, including 14 patients without Helicobacter pylori(H. pylori) infection and 8 patients with persistent lymphoma after H. pylori eradication. RT dose was 30 Gy in daily fractions of 1.5 Gy. All patients underwent endoscopic and histological follow-up regularly. RESULTS: The study included 22 patients with a mean age of 63 years. The t(11;18)(q21;q21) translocation occurred in 8 of the 22 cases. All patients showed complete remission without any serious toxicity. At a median follow-up evaluation 74 months (range 27-159) after completion of RT, the overall and relapse-free survival rates after 5 years were 91 and 84%, respectively. Although no patient showed local recurrence of lymphoma, distant recurrence was detected in 3 patients, all of whom were H. pylori negative; MALT lymphoma relapsed in two patients with the t(11;18)(q21;q21) translocation, and diffuse large-cell lymphoma developed in one patient without the translocation. CONCLUSION: RT provides excellent local control of the gastric MALT lymphoma. However, continuous follow-up is mandatory as relapse may occur in other sites.

Correlation between hospital-onset and community-onset Clostridioides difficile infection incidence: Ward-level analysis following hospital relocation.

BACKGROUND: The development of hospital-onset Clostridioides difficile infection (HO-CDI) is affected by patient and environmental risk factors. We investigated changes in the incidence of HO-CDI after relocation to a newly built hospital with 50% private rooms and evaluated the associated factors. METHODS: A retrospective study was conducted to assess trends in CDI incidences before and after the relocation using segmented regression analysis model. The association between CDI incidence and environmental factors at the ward-level was assessed using a linear regression analyses model. RESULTS: The HO-CDI incidence decreased from 6.14 to 1.17 per 10,000 patient-days in the old and new hospital, respectively. Similarly, the community-onset CDI (CO-CDI) incidence decreased from 1.71 to 0.46 per 1000 admissions. HO-CDI incidence was positively correlated with CO-CDI incidence and inversely correlated with the private room ratio (adjusted R2 = 0.83). Almost half of the CO-CDI patients had been hospitalized within 28 days preceding the onset. DISCUSSION: Environmental improvements after relocation may have reduced the reservoir of C. difficile, resulting in a decrease in the number of asymptomatic carriers and CO-CDI patients. CONCLUSION: Relocation to a new hospital significantly reduced HO-CDI incidence, concomitantly decreasing the incidence of CO-CDI, potentially due to environmental improvements.

Clinicopathological Characteristics of Superficial Barrett's Adenocarcinoma in a Japanese Population: A Retrospective, Multicenter Study.

Objective Although Barrett's adenocarcinoma (BA) remains a minor disease in Japan, its incidence has been gradually increasing. We analyzed the characteristics of BA in Japanese populations. Methods We retrospectively reviewed medical records and analyzed the clinicopathological differences between short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE), as well as metastasis. Local recurrence and metachronous lesions were analyzed only in patients who underwent endoscopic resection (ER). Patients Consecutive patients who had pathological T1 BAs resected by ER or surgery from January 2003 to December 2017. Results A total of 168 patients were analyzed, including 139 with SSBE and 29 with LSBE. In total, 67% of the SSBE lesions and 32% of the LSBE lesions were located between 0 and 3 o'clock (p=0.0014). No patients who achieved pathological margin-free resection (pR0) and 17% of patients who did not achieve pR0 experienced local recurrence (p=0.0131). None of the patients without lymphovascular involvement, a poorly differentiated component, lesion size of >30 mm, and submucosal invasion of >500 µm experienced metastasis. The 5-year cumulative incidence rate of metachronous BA after ER was 0% in patients with SSBE and 40% in patients with LSBE (p=0.0005). Conclusion Superficial BA was likely to be detected at the right anterior wall of SSBE in the Japanese population. The risk for metachronous BA after ER was high in Japanese patients with LSBE, as in Western patients.

Usefulness and problems of endoscopic ultrasonography in prediction of the depth of tumor invasion in early gastric cancer.

The objectives of this study were to evaluate the accuracy of endoscopic ultrasonography (EUS) in local and regional staging of early gastric cancer, to analyze the factors influencing the accuracy of EUS, and to reveal the usefulness and problems of EUS in pre-treatment staging of gastric cancer. We examined 105 lesions in 104 patients with histologically confirmed gastric cancer and retrospectively evaluated them with EUS. The diagnostic accuracy, sensitivity, and specificity of EUS were determined by comparing the pre-treatment EUS with the postoperative histopathological findings. The overall diagnostic accuracy of EUS for the depth of cancer invasion was 86%. The overall sensitivity and specificity were 60% and 96%, respectively. The accuracy significantly declined in lesions located in the upper-third of the stomach (70%). Type 0-I lesions tended to be over-staged (12&), and the upper-third lesions tended to be under-staged (23%). The accuracy significantly declined in differentiated adenocarcinoma with massive submucosal invasion (56.5%). EUS is useful for evaluating the depth of gastric cancer invasion which determines the feasibility of endoscopic treatment. However, it is noteworthy that the diagnostic accuracy of the invasion depth diminished for lesions in the upper third of the stomach.

Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study.

BACKGROUND: The best chemotherapy regimen for metastatic gastric cancer is uncertain, but promising findings have been reported with irinotecan plus cisplatin and S-1 (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate). We aimed to investigate the superiority of irinotecan plus cisplatin and non-inferiority of S-1 compared with fluorouracil, with respect to overall survival, in patients with metastatic gastric cancer. METHODS: We undertook a phase 3 open label randomised trial in 34 institutions in Japan. We enrolled patients aged 20-75 years or younger, who had histologically proven gastric adenocarcinoma, and randomly assigned them by minimisation to receive either: a continuous infusion of fluorouracil (800 mg/m(2) per day, on days 1-5) every 4 weeks (n=234); intravenous irinotecan (70 mg/m(2), on days 1 and 15) and cisplatin (80 mg/m(2), on day 1) every 4 weeks (n=236); or oral S-1 (40 mg/m(2), twice a day, on days 1-28) every 6 weeks (n=234). The primary endpoint was overall survival. Analyses were done by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00142350, and with UMIN-CTR, number C000000062. FINDINGS: All randomised patients were included in the primary analysis. Median overall survival was 10.8 months (IQR 5.7-17.8) for individuals assigned fluorouracil, 12.3 months (8.1-19.5) for those allocated irinotecan plus cisplatin (hazard ratio 0.85 [95% CI 0.70-1.04]; p=0.0552), and 11.4 months (6.4-21.3) for those assigned S-1 (0.83 [0.68-1.01]; p=0.0005 for non-inferiority). Three treatment-related deaths occurred in the irinotecan plus cisplatin group and one was recorded in the S-1 group. INTERPRETATION: S-1 is non-inferior to fluorouracil and, in view of the convenience of an oral administration, could replace intravenous fluorouracil for treatment of unresectable or recurrent gastric cancer, at least in Asia. Irinotecan plus cisplatin is not superior to fluorouracil in this setting.

A rare case of immunotherapy-induced cholangitis and gastritis.

Immune checkpoint inhibitor-related liver injury usually appears as a hepatitis pattern, with a cholangitis pattern being a rare immune-related adverse event. We report a Japanese man in his fifties with immune checkpoint inhibitor-induced cholangitis and gastritis. The patient had been treated for approximately 7 months with carboplatin, pemetrexed sodium hydrate, and bevacizumab for an undifferentiated cancer of unknown primary, with metastases to the right pleura and nasolacrimal duct. The patient was then treated with immune checkpoint inhibitors, including 2 months of atezolizumab followed by 1 month of ramucirumab and docetaxel. Laboratory examinations showed elevated levels of biliary tract enzymes. He complained of generalized fatigue. Computed tomography revealed thickening of the gallbladder and external hepatic bile duct walls and the periportal collar sign. Endoscopic retrograde cholangiopancreatography was negative for bile duct obstruction but showed diffuse asymmetric irregular findings from the hilar region to the distal bile duct. Upper endoscopy showed diffuse irregular erosions and redness. Histopathological examination of specimens of bile duct and gastric mucosa revealed CD8-predominant inflammatory cell infiltrates. We diagnosed the findings as immunotherapy-induced cholangitis and gastritis. Because there are no published reports on immunotherapyinduced cholangitis combined with gastritis, we here report our patient as a rare case.

Whipple's Disease with Long-term Endoscopic Follow-up.

A 72-year-old man presented with anorexia and 15-kg weight loss over 3 years. Endoscopy revealed yellow, shaggy mucosa alternating with erythematous, eroded mucosa in the duodenum. Biopsy specimens showed massive infiltration of periodic acid-Schiff-positive macrophages in the lamina propria, consistent with Whipple's disease. The patient was treated with intravenous ceftriaxone for four weeks, followed by oral trimethoprim-sulfamethoxazole. His condition improved, and he gradually gained weight. Although the endoscopic findings improved with continuous trimethoprim-sulfamethoxazole administration, macrophage infiltration of the duodenal mucosa persisted. However, the patient has been symptom-free for eight years.