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Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a rare tumor derived from mesenchymal tissue. Although standard chemotherapy for SHT/HPC has not been established, temozolomide plus bevacizumab (TMZ+Bev) therapy for SFT/HPC has been reported. The effectiveness and safety of TMZ+Bev (temozolomide 150 mg/m 2 orally on days 1-7 and days 15-21 and bevacizumab 5 mg/kg intravenously on day 8 and day 22 on a 28-day cycle), which was administered from December 2013 until April 2019 to four patients with SFT/HPC, were retrospectively analyzed. Four patients with SFT/HPC received TMZ+Bev. The age of the patients ranged from 41 to 75 years. Two were male, and the primary tumor sites were the meninges in three patients and the pleura in one. One achieved partial response; the others, stable disease (SD). The progression-free survival time ranged from 9.4 to 29.6 months according to RECIST v1.1. One patient died 59 months after using TMZ+Bev, and the others survived for 17 to 64 months. All patients experienced Grade 3 or higher lymphopenia, and three had Grade 3 or higher leukopenia and neutropenia. One patient subsequently received doxorubicin; another, pazopanib. TMZ+Bev therapy for SFT/HPC is safe and effective for maintaining long-term SD., Competing Interests: Yuichi Ando received research funding from Chugai Pharmaceutical Co., Ltd., outside the submitted work. The other authors have no conflicts of interest to disclose.

Purpose: Systemic chemotherapy (SC) before surgery is a potential treatment to improve survival in patients with advanced rectal cancer. However, the impact of SC on lateral lymph nodes (LLNs) remains unclear., Methods: A total of 78 patients with stage II/III low rectal cancer, who received 3-month oxaliplatin-based SC followed by LLN dissection (LLND) in principle, were analysed retrospectively. "Total lateral lymph node metastases (tLLNMs)" was defined as having either pathological LLNMs (pLLNMs) or lateral local recurrences (LLRs). Patients with the maximum short-axis size of LLNs ≥ 7 mm were classified into the swollen group (n = 21)., Results: In the total cohort, tLLNMs included 6 pLLNMs (7.7%) and 2 LLRs (2.6%). In the non-swollen group, no patients had pLLNMs, but one had LLR (1.8%). In the swollen group, pLLNMs and LLRs were detected in 6 (28.6%) and 1 (4.8%), respectively. The swollen group was an independent risk factor for tLLNMs (P < 0.001), leading to the significantly worse 5-year relapse-free survival (RFS) of 52.4% than the others., Conclusion: For patients without swollen LLNs, SC could allow for omission both of lateral irradiation and LLND. For patients with swollen LLNs, the lateral local control was favourable after SC and LLND without chemoradiotherapy (CRT); however, oxaliplatin-based SC might be insufficient to improve survival, requiring more intensive chemotherapy. CRT should be indicated according to the other risk factors of central local recurrence, although the swollen LLNs should be removed.

The standard chemotherapy regimen for unresectable or recurrent biliary tract cancer is gemcitabine combined with cisplatin (GC). To evaluate the effectiveness and safety of chemotherapy in patients with unresectable or recurrent biliary tract cancer in the real world, we retrospectively analyzed the clinical courses of patients who underwent chemotherapy with GC from January 2015 to November 2019. Forty-eight patients underwent the GC regimen. One patient (2.1%) achieved a complete response, seven patients (14.6%) achieved a partial response, 26 patients (54.2) achieved stable disease, 11 patients (22.9%) achieved progressive disease, and 3 patients (6.3%) were not evaluable. The overall response rate was 16.7%. The median overall survival was 14.2 months (95% CI: 13.8-14.6), and the median progression-free survival was 7.7 months (95% CI: 4.2-11.2). Thirty-nine patients (81.3%) experienced grade 3 or higher severe adverse events as follows: 54.2% experienced neutropenia, 20.8% experienced anemia, 12.5% experienced thrombocytopenia and 20.8% experienced biliary tract infection. As a second-line chemotherapy, S-1 was used in seventeen patients, and stable disease was achieved in three patients (17.6%). The GC regimen for biliary tract cancer is effective and safe for unresectable or recurrent biliary tract cancer in routine clinical practice., Competing Interests: Osamu Maeda has received research funding from Eli Lilly Japan K.K. Yuichi Ando has received research funding from Yakult Honsya Co., Ltd.; Mochida Pharmaceutical Co., Ltd.; Taiho Pharmaceutical Co., Ltd.; Eli Lilly Japan K.K.; and Nippon Kayaku Co., Ltd.

Background: Long-term follow-up reports of low-grade endometrial stromal sarcoma (LGESS) including its clinical course and pathological data are rare. We previously reported the case of a Japanese woman diagnosed with LGESS, who was treated with multidisciplinary therapy. She had been suffering from uterine cervical tumor diagnosed as cervical polyps, or fibroid in statu nascendi, since 24 years old. The patient had survived for 25 years with the disease. This report presents her progress and pathological change since the previous report., Case Presentation: At age 45, the patient experienced a relapse of the remnant LGESS tumor between the right diaphragm and liver. Although chemotherapy was not effective, the tumor was eliminated by proton therapy. At age 46 years, the remnant tumors outside the irradiated field were resected. The disease was originally diagnosed as "neuroendocrine carcinoma (NEC)" using the surgical specimen. Therefore, cisplatin and irinotecan combination chemotherapy were administered to treat the remnant dissemination. After 4 cycles of chemotherapy, the liver metastases had enlarged and were resected surgically. Consequently, no remnant tumor was visible in the abdominal cavity at the end of the surgery. To determine the origin of NEC, we examined the previously resected specimens obtained from her ileum at age 40 years. A boundary between the LGESS and neuroendocrine tumor grade 2 (NET G2)-like lesion was found in the tumor, indicating that the origin of these tumors was LGESS. After less than 2 years of chemotherapy and undergoing surgery, a relapse of the tumor in the liver induced biliary duct obstruction with jaundice, which was treated with endoscopic retrograde biliary drainage. Although pazopanib prolonged her life for 10 months, she died from sepsis at age 49 years, which was caused by the infection that spread to the liver metastatic tumor via the stented biliary ducts. Autopsy revealed adenocarcinoma-like differentiation of the tumor., Conclusion: This LGESS patient has survived for a long time owing to multidisciplinary treatment including proton therapy. The LGESS tumor differentiated to NET G2-like tissue and then further to adenocarcinoma-like tissue during the long-term follow-up.

Bone modifying agents (BMAs) have become a standard treatment to prevent skeletal-related events (SREs) in bone metastases (BMs). The aim of our study is to determine the clinical value of serum bone resorption markers for predicting clinical outcomes after using BMAs in patients with BM. Patients were enrolled between May 2013 and October 2017 at the Nagoya University Hospital, Japan. We prospectively observed changes in pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase 5b (TRACP-5b) during treatment with BMAs. The relationship between serum markers before and after treatment and clinical outcomes such as progression of bone disease (BD), SREs and overall survival (OS) were evaluated. Pearson chi-square test and Kaplan-Meier product limit methods were used for analysis. Sixty-seven patients were analyzed. The primary tumor sites were 21 lung, 16 breast and 30 others. Forty and 27 patients were treated with Denosumab and Zoledronic acid, respectively. Progression of BDs, SREs and death were observed in 10, 16 and 31 cases, respectively. The median follow-up period after using BMAs was 12.3 (range 0.3-66.3) months. ICTP at 3-4 weeks was significantly correlated with increasing BD progression, SREs and death after treatment in both the whole and lung cancer cohorts. Base line ICTP and TRACP-5b were also associated with increasing BD progression in the whole cohort. Our study showed that early posttreatment ICTP is useful for predicting BD progression, SREs and OS after use of BMAs in patients with BM and even in patients with lung cancer BM., (© 2019 UICC.)

Background: Liver injury induced by immune checkpoint inhibitors (ICIs) is an immune-related adverse event (irAE) whose incidence has increased with the broader use of ICIs in clinical practice. However, the incidental risk factors of immune-related liver injury are unknown. We investigated the clinical characteristics of immune-related liver injury., Methods: A total of 546 patients treated with ICIs for advanced malignancies between September 2014 and February 2019 were included retrospectively. Factors associated with immune-related liver injury were determined., Results: Immune-related liver injury (≥ Grade 3) occurred in 29 (5.3%) patients (Grade 3, n = 20; Grade 4, n = 8; Grade 5, n = 1) during the follow-up period (median 153 days). The patterns of liver injuries were hepatocellular, n = 6 (20.7%); cholestatic, n = 17 (58.6%); and mixed, n = 6 (20.7%). The median period between the initial administration of ICIs and the incidence of irAEs was 52 days. Of 29 patients with immune-related liver injury (≥ Grade 3), four showed immune-related cholangitis with non-obstructive dilation of the bile ducts. Factors that were significantly associated with the incidence of immune-related liver injury in multivariate analysis were use of ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) agent [hazard ratio [HR] 4.22, 95% confidence interval (CI) 1.65-10.80, P = 0.003], and fever over 38 °C within 24 h of initial ICI administration (HR 6.21, 95% CI 2.68-14.40, P < 0.001)., Conclusions: We found that the use of ipilimumab and the presence of fever within 24 h of initial ICI administration were predictive factors for immune-related liver injury.

Background: Spectrin αII contributes to cisplatin and carboplatin resistance in ovarian serous carcinoma cells, and its expression in surgical specimens is a valid predictor of prognosis. We sought to identify effective drugs for spectrin αII-mediated cisplatin-resistant cells., Materials and Methods: We employed SKOV3 cells with small interfering RNA-mediated spectrin αII downregulation, serous carcinoma cells (NOS2), cisplatin-resistant cells (NOS2CR2), and oxaliplatin-resistant cells (NOS2OXR)., Results: In the drug-sensitivity test, oxaliplatin was not affected by the inhibition of spectrin αII expression and was effective for cisplatin-resistant NOS2CR2 cells. NOS2OXR cells did not express higher levels of spectrin αII compared to NOS2 in western blot analysis. Six non-platinum anticancer drugs were not affected by the inhibition and was effective for resistant NOS2CR2 and NOS2OXR cells. Doxorubicin exhibited potent cytotoxicity at 2 μM against both resistant cell lines., Conclusion: Pegylated liposomal doxorubicin/oxaliplatin regimen may be effective for cisplatin-resistant ovarian carcinoma with spectrin αII-overexpression., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Nonexposed wall-inversion surgery was invented for the treatment of node-negative gastrointestinal tumors that are difficult to be resected using the endoluminal approach alone. The advantages of this surgery include 1. full-thickness resection procedure of gastrointestinal wall with minimum necessary tumor-negative margins and 2. less risk of bacterial contamination and tumor seeding into the abdominal cavity. We conducted a PubMed search to select relevant articles published until the end of October 2019 for pooled case analyses using the keyword "nonexposed wall-inversion surgery," Based on our search, we enrolled the data of 88 gastric lesions and 1 duodenal lesion retrieved from 7 case report articles and 4 original articles of clinical cases. The gastric lesions consisted of 59 gastrointestinal stromal tumors, 7 ectopic pancreases, 5 leiomyomas, 3 early gastric cancers, and 14 others, with a mean maximal tumor diameter of 25.0 mm. In 5 lesions (5.7%), intraoperative perforation was performed, and 2 lesions (2.3%) were retrieved by the transabdominal route. All 4 major postoperative complications (4.5%) were managed without resurgical interventions. The duodenal case, neuroendocrine tumor, measuring 13 mm in size, was curatively resected without complications. Nonexposed wall-inversion surgery appears to be an acceptable treatment for node-negative gastric and duodenal tumors; however, further accumulation of cases is necessary to confirm the feasibility., Competing Interests: Nothing to declare.

Background: The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we published provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors. Recently, efficacy of tropomyosin receptor kinase inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors have been established as the second tumor-agnostic treatment, making it necessary to develop the guideline prioritized for these patients., Methods: Clinical questions regarding medical care were formulated for patients with NTRK-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO) and Japanese Society of Medical Oncology (JSMO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and Japanese Society of Pediatric Hematology/Oncology, and the public comments among all Societies' members was done., Results: The current guideline describes 3 clinical questions and 15 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors., Conclusion: In the NTRK guideline, the committee proposed 15 recommendations for performing NTRK testing properly to select patients who are likely to benefit from tropomyosin receptor kinase inhibitors.

Background: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines., Methods: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors., Results: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely., Conclusion: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.

Introduction: Bacterial translocation, in which intestinal bacteria pass through the intestinal wall, enter the blood circulation, and spread to other sites of the body, is thought to cause bacteremia and sometimes febrile neutropenia (FN) in patients who receive cancer chemotherapy., Materials and Methods: We collected blood samples from 39 patients with various cancers at baseline and after chemotherapy began (during chemotherapy) and explored how frequently bacteria could be detected in the blood using a highly-sensitive, bacterial rRNA-targeted reverse transcription quantitative polymerase chain reaction (PCR) assay., Results: Bacterial traces, typically Escherichia coli and Enterobacter spp., were detected in 10 patients (25.6%) at baseline and 11 patients (28.2%) during chemotherapy. The bacterial traces were positive either at baseline or during chemotherapy in 3 (60%) of 5 patients who had FN, and 6 (46%) of 13 patients aged 65 years or older., Conclusion: These findings support the notion that bacterial translocation occurs in patients with cancer regardless of whether they receive chemotherapy and can lead to the development of FN and other treatment-related infections.

Key cytotoxic drugs of chemotherapy for gastroesophageal cancer include fluoropyrimidine, platinum, taxanes and irinotecan. Concurrent chemoradiotherapy is one of the main treatment strategies, especially for esophageal cancer. As molecular target agents, the anti-HER2 antibody trastuzumab for HER2-positive gastric cancer and the anti-angiogenesis agent ramucirumab combined with paclitaxel have been proven to improve the survival of gastric cancer patients. Recently, anti-PD-1 antibodies have become available as second- or later-line chemotherapy. Microsatellite instability is also useful as a biomarker to select patients suitable for immunotherapy. Furthermore, genome-wide analysis has improved our understanding of the biological features and molecular mechanisms of gastroesophageal cancer and will provide optimized treatment selection., Competing Interests: Conflict-of-interest statement: No potential conflict of interest.

Resistance to anticancer drugs is a critical issue in cancer treatment. Alterations in gene expression and DNA methylation profiles that accompany the acquisition of drug resistance are associated with resistance mechanisms. To analyze chemotherapy-associated alterations in gene expression and DNA methylation in gastric cancer cells obtained from ascites, ascitic fluids were collected from a patient with gastric cancer before chemotherapy with capecitabine and oxaliplatin (CapeOX), and after the disease had progressed. The fluids were cultured for 10 days, passaged into new flasks, and cultured for an additional 2 weeks. Normal cells, including white blood cells and mesothelial cells, were removed. The expression and DNA methylation profiles of 18,185 genes were analyzed using microarray, and compared between cells in ascitic fluids collected before and after the chemotherapy with CapeOX. In addition, fluorouracil- and oxaliplatin-resistant AGS cells were established and analyzed. Pathways having genes with expression profiles altered by CapeOX included those associated with 'signaling by G-protein-coupled receptor' and the 'immune system'. Genes that were commonly expressed at higher levels in CapeOX-resistant ascitic cells, fluorouracil-resistant AGS cells. and oxaliplatin-resistant AGS cells compared with those in untreated cells included telomerase reverse transcriptase (TERT), apolipoprotein C1 (APOC1) and serine/threonine/tyrosine kinase 1 (STYK1), whereas genes commonly expressed at lower levels in the three drug-resistant cell types compared with the untreated cells included defensin β4A (DEFB4A). A comparatively large number of genes exhibited altered methylation levels in drug-resistant AGS cells compared with the CapeOX-resistant cells. In addition, among the genes expressed at higher levels in decitabine-treated AGS cells, the majority were expressed at higher levels in fluorouracil-resistant AGS cells, and exhibited lower methylation levels. Taken together, the present study has demonstrated that comparing the expression profiles of gastric cancer cells obtained from ascitic fluids before and after chemotherapy with the expression profiles of drug-resistant cultured cells is a useful method for analyzing the molecular mechanisms underlying chemotherapy resistance.

The efficacy of nab-paclitaxel combined with gemcitabine (GnP) and of chemoradiotherapy (CRT) for unresectable locally advanced pancreatic ductal adenocarcinoma (UR-LA PDAC) is still unclear. We previously conducted a phase I study of CRT using GnP and determined the recommended dose and have now designed a phase II trial to evaluate the efficacy of CRT incorporating GnP for UR-LA PDAC. Eligibility criteria are chemotherapy-naïve patients with UR-LA PDAC as defined by the NCCN guidelines version 2. 2016. Study patients will receive 100 mg/m 2 nab-paclitaxel and 800 mg/m 2 gemcitabine on Days 1, 8, and 15 per 4-week cycle with concurrent radiation therapy (total dose of 50.4 Gy in 28 fractions of 1.8 Gy per day, 5 days per week). Treatment will be continued until disease progression or surgery, which is to be performed only for patients in whom the disease is well-controlled at 8 months from beginning the protocol treatment. Primary endpoint is 2-year overall survival rate and co-primary endpoint is resection rate. Secondary endpoints are overall survival, progression free survival, time to treatment failure, response rate, disease control rate, early tumor shrinkage, depth of response, reduction of SUV-max on PET-CT, serum tumor markers, relative dose intensity, safety, and Quality of life. This study will show the efficacy and safety of chemoradiotherapy combined with GnP.

We herein report a case of lung metastases with unusual radiological appearances that mimicked those of chronic airway infection, causing diagnostic difficulty. A 60-year-old woman who underwent liver transplantation from a living donor was incidentally diagnosed with bile duct adenocarcinoma after a histopathological analysis of her explanted liver. Six months later, chest computed tomography (CT) revealed bilateral bronchogenic dissemination that had gradually worsened, suggesting chronic airway infection. A biopsy with bronchoscopy from a mass lesion beyond a segmental bronchus revealed adenocarcinoma identical to that of her bile duct adenocarcinoma, leading to the diagnosis of multiple lung metastases from bile duct adenocarcinoma.

Purpose: For unresectable locally advanced (UR-LA) pancreatic cancer, chemoradiotherapy has been recommended by the NCCN guidelines. We designed a chemoradiotherapy protocol using nab-paclitaxel combined with gemcitabine (GnP) for patients with UR-LA pancreatic cancer. The purpose of this phase I study was to determine a recommended dose (RD) for this novel regimen., Methods: Patients with UR-LA pancreatic cancer were eligible. The frequency of dose-limiting toxicities (DLTs) was evaluated, and the RD was determined. Patients were classified according to the designated dose levels of chemoradiotherapy using the GnP regimen. After additional 6 cycles of the GnP regimen were administered, surgery was considered if the patients had stable disease and tumor marker levels had normalized., Results: DLT (grade 4 thrombocytopenia) was observed only in 1 of 12 patients, and the RD was set at level 3. Grade 3-4 leukopenia was observed in 9 (75.0%) patients, and neutropenia in 7 (58.3%). The response rate was 41.7%, and the disease control rate was 100%. Conversion surgery was performed in 6 (50%) patients, and curative resection (R0) was performed in all 6 patients (100%). Stratification according to the Evans classification system demonstrated one patient with grade 1b, one with grade 2, two with grade 3, and two with grade 4 disease., Conclusion: The RD for weekly administration was 800 mg/m 2 for gemcitabine and 100 mg/m 2 for nab-paclitaxel with a 50.4 Gy radiation. The GnP regimen at this dosage was promising with 6 of 12 patients proceeding to conversion surgery, and should be evaluated further in a phase II trial.

Background: Dose-dense chemotherapy consisting of a combination of epirubicin and cyclophosphamide (EC) improves the survival of patients with breast cancer. Although pegfilgrastim was used at a subcutaneous dose of 6.0 mg in a pivotal study of dose-dense EC treatment, pegfilgrastim at a dose of 3.6 mg has been approved in Japan. We have assessed the feasibility of dose-dense EC treatment supported with a 3.6 mg dose of pegfilgrastim by evaluating the relative dose intensity (RDI) and safety of the treatment, together with measuring the pegfilgrastim concentrations remaining on the day of starting the next cycle of chemotherapy., Methods: Patients with primary breast cancer received a total of 4 cycles of dose-dense EC treatment every 2 weeks, together with a subcutaneous injection of 3.6 mg pegfilgrastim on the day after chemotherapy. The serum granulocyte colony-stimulating factor (G-CSF) concentrations were measured on the 15th day of every chemotherapy cycle., Results: From March 2015 through to July 2016, a total of 51 patients (median age 51 years; range 33-73 years) were studied. The mean RDI was 95.2% (range 60.0-100%). Although most adverse events were consistent with those reported in previous studies, pneumocystis pneumonia developed in two patients during the following course of docetaxel treatment. The median serum G-CSF concentration was 92.5 (range 30.4-440) pg/ml., Conclusions: With support provided by pegfilgrastim injection at a dose of 3.6 mg, dose-dense EC is feasible and associated with maintenance of a high RDI. There was no clinically significant accumulation of serum G-CSF concentrations associated with the use of a 3.6 mg dose of pegfilgrastim at 2-week intervals.

Domestication is the process by which plants or animals evolved to fit a human-managed environment, and it is marked by innovations in plant morphology and anatomy that are in turn correlated with new human behaviours and technologies for harvesting, storage and field preparation. Archaeobotanical evidence has revealed that domestication was a protracted process taking thousands of plant generations. Within this protracted process there were changes in the selection pressures for domestication traits as well as variation across a geographic mosaic of wild and cultivated populations. Quantitative data allow us to estimate the changing selection coefficients for the evolution of non-shattering (domestic-type seed dispersal) in Asian rice ( Oryza sativa L.), barley ( Hordeum vulgare L.), emmer wheat ( Triticum dicoccon (Shrank) Schübl.) and einkorn wheat ( Triticum monococcum L.). These data indicate that selection coefficients tended to be low, but also that there were inflection points at which selection increased considerably. For rice, selection coefficients of the order of 0.001 prior to 5500 BC shifted to greater than 0.003 between 5000 and 4500 BC, before falling again as the domestication process ended 4000-3500 BC. In barley and the two wheats selection was strongest between 8500 and 7500 BC. The slow start of domestication may indicate that initial selection began in the Pleistocene glacial era.This article is part of the themed issue 'Process and pattern in innovations from cells to societies'., (© 2017 The Author(s).)

Aim: To evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients., Methods: We performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage IV gastric cancer. In particular, 30 or 40 mg/m 2 of docetaxel on day 1, 60 mg/m 2 of cisplatin on day 1, and 2000 mg/m 2 of capecitabine for 2 wk were administered every three weeks., Results: Three patients were treated with modified DCX (mDCX) with 30 mg/m 2 docetaxel, and five patients were treated with this regimen with 40 mg/m 2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes., Conclusion: mDCX was well tolerated by Japanese patients with stage IV gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery., Competing Interests: Conflict-of-interest statement: Kodera Y has received research funding from Chugai Pharmaceutical Co., Ltd., Sanofi, Yakult Honsha Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., and Bristol-Myers Squib. Goto H has received research funding from Bristol-Myers Squibb, and Takeda Pharmaceutical Co., Ltd. Ando Y has received research funding from Sanofi, Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Honsya Co., Ltd., and Mochida Pharmaceutical Co., Ltd.

Background: Bevacizumab (BEV), a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, enhances the antitumor effectiveness of paclitaxel (PTX)-based chemotherapy in many metastatic cancers. A recent study in mice showed that VEGF receptor inhibitors can interfere with the neuroprotective effects of endogenous VEGF, potentially triggering the exacerbation of PTX-induced neuropathy. In clinical trials, exacerbation of neuropathy in patients who received PTX combined with BEV (PTX+BEV) has generally been explained by increased exposure to PTX owing to the extended duration of chemotherapy. We investigated whether the concurrent use of BEV is associated with the exacerbation of PTX-induced neuropathy., Methods: Female patients with breast cancer who had received weekly PTX or PTX+BEV from September 2011 through May 2016 were studied retrospectively. PTX-induced neuropathy was evaluated at the same time points (at the 6th and 12th courses of chemotherapy) in both cohorts. A multivariate Cox proportional-hazards model was used to assess the independent effect of BEV on the time to the onset of neuropathy., Results: A total of 107 patients (median age, 55 years; range, 32-83) were studied. Sixty-one patients received PTX as adjuvant chemotherapy, 23 received PTX for metastatic disease, and 23 received PTX+BEV for metastatic disease. Peripheral sensory neuropathy was worse in patients who received PTX+BEV than in those who received PTX alone: at the 6th course, Grade 0/1/2/3 = 4/13/4/0 vs. 25/42/6/0 (P = 0.095); at the 12th course, 2/3/11/3 vs. 7/30/23/2 (P = 0.016). At the 12th course, the incidence of Grade 2 or higher neuropathy was significantly higher in patients treated with PTX+BEV than in those treated with PTX alone (74% vs. 40%; P = 0.017). In multivariate analysis, BEV was significantly associated with an increased risk of neuropathy (HR 2.32, 95% CI 1.21-4.44, P = 0.012)., Conclusions: The concurrent use of BEV could worsen PTX-induced neuropathy in patients with breast cancer., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests. Hidemi Goto received honoraria and research funding from Bristol-Myers Squibb. Yuichi Ando received research funding from Mochida Pharmaceutical Co., Ltd and Nippon Kayaku Co.,Ltd. Yuichi Ando received honoraria from Pfizer Japan Inc. Yuichi Ando received honoraria and research funding from Chugai Pharmaceutical Co., Ltd. Yuichi Ando is a current reviewer in the PLOS ONE journal. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials since there were no restrictions on the sharing of data or materials in this study.

Chemotherapy-induced peripheral neurotoxicity (CIPN) seriously impairs patients' quality of life cumulatively and dose-dependently. Because assessment of CIPN usually depends on patients' subjective evaluation of symptoms, objective and quantitative measures are needed. We evaluated a point-of-care nerve conduction device (POCD), previously validated for the assessment of diabetic peripheral neuropathy. Sensory nerve action potential (SNAP) amplitude and sensory nerve conduction velocity (SNCV) of the sural nerve were measured using a portable, automated POCD (DPNCheck; NeuroMetrix Inc., Waltham, MA, USA) in patients with a clinical diagnosis of CIPN of grade 1 or higher. We compared SNAP and SNCV among patients with different grades of CIPN according to the Common Terminology Criteria for Adverse Events. A total of 50 patients (22 men, 28 women; median age, 64 years; grade 1/2/3, 21/18/11) were evaluated. Anticancer drugs responsible for CIPN were cisplatin in five patients, oxaliplatin in 15, carboplatin in 5, paclitaxel in 16, docetaxel in 14, nab-paclitaxel in 7, vincristine in 6, and bortezomib in 3. Unadjusted SNAP was 8.45 ± 3.67 μV (mean ± SD) in patients with grade 1 CIPN, 5.42 ± 2.68 μV with grade 2, and 2.45 ± 1.52 μV with grade 3. Unadjusted SNCV was 49.71 ± 4.77 m/s in patients with grade 1 CIPN, 48.78 ± 6.33 m/s with grade 2, and 44.14 ± 7.31 m/s with grade 3. The adjusted SNAP after controlling for age significantly differed between each CTCAE grade (P < 0.001, ancova). The adjusted SNCV after controlling for age and height also differed significantly (P = 0.027). Differences in the severity of CIPN could be detected objectively and quantitatively using this POCD., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Anticancer drug sensitivity affects prognosis in ovarian carcinoma. Previously, we purified spectrin αII and βII tetramers from cisplatin-resistant ovarian serous adenocarcinoma cells and demonstrated that they contribute to platinum anticancer drug resistance. In this clinical study, we focused on the role of spectrin αII expression. It is our objective to demonstrate the potential of spectrin αII expression as a useful predictor of anticancer drug resistance and postoperative prognosis in epithelial ovarian carcinoma. Spectrin αII expression in the ovarian adenocarcinoma surgical specimens of 193 patients was examined by immunohistochemical staining. Staining strength was scored 3+, regarded as positive expression, and 2+, 1+, and 0, regarded as non-positive expression. Prognoses obtained from clinical records were evaluated by statistical analysis. In the 193 cases studied, positive spectrin αII expression was associated with worse overall survival when compared with non-positive expression (P < 0.001 by log-rank test), and spectrin αII expression was identified as an independent predictive factor of overall survival (hazard ratio[HR]: 3.77, 95% confidence interval[CI]: 1.77-8.00; P < 0.001 by multivariate Cox's proportional hazards model). In the study about progression-free survival, spectrin αII expression was not associated with prognoses. However, similar results as overall survival were obtained for survival after recurrence of the 92 recurrent cases (P = 0.0051 by log-rank test, HR: 4.49, 95% CI: 2.06-9.79; P < 0.001 by multivariate Cox's proportional hazards model). In a detailed overall survival study of 66 serous adenocarcinoma patients and 127 nonserous adenocarcinoma patients, similar results were also obtained. Spectrin αII expression is a useful predictor of anticancer drug resistance and postoperative prognosis in epithelial ovarian carcinoma.., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Low skeletal muscle density (SMD) and low skeletal muscle index (SMI) are associated with poor overall survival (OS) in patients with various types of cancer. We retrospectively studied SMD and SMI using computed tomographic (CT) scans in patients with gastric cancer receiving chemotherapy to evaluate its prognostic significance. SMD and SMI were obtained from CT-based analysis using Slice-O-Matic® medical imaging software in patients who received S-1 plus cisplatin chemotherapy for metastatic gastric cancer. The CT images taken within 1 month before starting chemotherapy were used. The cut-off values for determining low SMD [<33 Hounsfield units (HU) in obese and <41 HU in non-obese patients] and low SMI (<41 cm2/m2 in females, <43 cm2/m2 in non-obese males and <53 cm2/m2 in obese males) were referenced from a large population based study. The CT images of 53 patients were reviewed. The median SMD was 36.8 HU (range, 19.5-59.3 HU), and the median SMI was 39.8 cm2/m2 (range, 23.7-60.0 cm2/m2). Patients with low SMD had significantly shorter OS compared with patients having normal SMD (8.9 vs. 12.8 months, P=0.03). However, OS did not differ significantly between patients with low and normal SMI (11.1 and 14.3 months, P=0.18). Multivariate analyses confirmed that low SMD was an independent predictor of poor outcomes (P<0.01). SMD is an important prognosticator of survival in patients with metastatic gastric cancer receiving chemotherapy.

A clear consensus does not exist about whether the initial dose of gemcitabine, an essential anticancer antimetabolite, should be reduced in patients with liver dysfunction. Adult patients with biliary tract or pancreatic cancer were divided into three groups according to whether they had mild, moderate, or severe liver dysfunction, evaluated on the basis of serum bilirubin and liver transaminase levels at baseline. As anticancer treatment, gemcitabine at a dose of 800 or 1000 mg/m(2) was given as an i.v. infusion once weekly for 3 weeks of a 4-week cycle. The patients were prospectively evaluated for adverse events during the first cycle, and the pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine, were studied to determine the optimal initial dose of gemcitabine as monotherapy according to the severity of liver dysfunction. A total of 15 patients were studied. Liver dysfunction was mild in one patient, moderate in six, and severe in eight. All 15 patients had been undergoing biliary drainage for obstructive jaundice when they received gemcitabine. Grade 3 cholangitis developed in one patient with moderate liver dysfunction who received gemcitabine at the dose level of 1000 mg/m(2). No other patients had severe treatment-related adverse events resulting in the omission or discontinuation of gemcitabine treatment. The plasma concentrations of gemcitabine and difluorodeoxyuridine were similar among the groups. An initial dose reduction of gemcitabine as monotherapy for the treatment of biliary tract or pancreatic cancers is not necessary for patients with hyperbilirubinemia, provided that obstructive jaundice is well managed. (Clinical trial registration no. UMIN000005363.), (© 2015 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A 79-year-old man with lymph node recurrence of malignant melanoma received nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody. He had pre-existing ocular myasthenia gravis (MG) and a continued small amount of corticosteroid. Grade 3 creatine phosphokinase elevation appeared after two doses of nivolumab, and the treatment was postponed until it improved to grade 1. After three doses of nivolumab, he experienced diplopia and facial muscle weakness which were consistent with an acute exacerbation of MG, and the symptoms relieved without additional treatment for MG. He achieved shrinkage of metastasis after ten doses of nivolumab. Although a case who died due to MG after administration of nivolumab was reported recently, pre-existing MG is considered not to be always a contraindication of nivolumab.

Background: Antiemetics are being used both for the treatment and prophylaxis of opioid-induced nausea and vomiting (OINV) in clinical practice, despite the lack of evidence for the prophylactic benefit. Data regarding the actual status of prophylactic antiemetic use for OINV remain to be elucidated., Objective: The objective of this study was to evaluate the practice among Japanese physicians of the prophylactic use of antiemetics when starting opioids prescription for the prevention of opioid-induced nausea and vomiting., Methods: This questionnaire survey was targeted among physicians experienced in cancer pain treatment at two institutions of Japan (Nagoya University Hospital and Ichinomiya City Municipal Hospital). The questionnaire assessed the physicians' practice and beliefs regarding the prophylactic antiemetics prescription when they start opioids in patients with cancer pain., Results: Questionnaires were filled in and received from 112 physicians from two institutions. Eighty-two percent of physicians prescribed prophylactic antiemetics at the beginning of opioid prescription, and the most commonly prescribed drug for this purpose was prochlorperazine (88%)., Conclusion: Despite the lack of evidence, Japanese physicians commonly prescribe prophylactic antiemetics, most commonly prochlorperazine, for OINV. Prospective clinical trials are necessary to evaluate the efficacy of this practice.

Introduction: Low-grade endometrial stromal sarcoma is very rare and difficult to diagnose in the early stage. A standard treatment has not been established. In this case report of a patient with long-term survival, we describe an effective treatment for advanced low-grade endometrial stromal sarcoma., Case Presentation: A 24-year-old Japanese woman who presented with prolonged menstruation was diagnosed with leiomyoma on the basis of a specimen resected transvaginally. She underwent ten resections in 10 years without a malignancy diagnosis. During this period, she gave birth. At age 34 years, she visited our hospital, complaining of lower abdominal pain. A 10cm tumor was detected behind her uterus. The disease was diagnosed as an advanced malignant ovarian tumor before surgery. A laparotomy was performed, with many remnants left in the abdominal cavity. The final diagnosis was advanced low-grade endometrial stromal sarcoma. After 12 cycles of gemcitabine and docetaxel combination chemotherapy, the tumor disappeared completely. A retrospective pathological review of the specimens resected transvaginally showed that the tumors included low-grade endometrial stromal sarcoma elements. When the patient was age 42 years, the sarcoma recurred. It was detected around the right diaphragm and liver. Despite administration of gemcitabine and docetaxel, ascites and pleural effusion accumulated. Administration of medroxyprogesterone acetate, leuprorelin acetate, and anastrozole gradually reduced the ascites and pleural effusion. In addition to the three hormone drugs, 18 cycles of paclitaxel and carboplatin were administered. The patient recovered from her critically ill state and is currently alive with reduced tumor at age 45 years., Conclusions: Our patient with low-grade endometrial stromal sarcoma whose disease began in her youth gave birth and experienced long-term survival with surgery, chemotherapy, and hormone therapy.

FOLFIRINOX is a standard chemotherapeutic regimen for patients with advanced pancreatic cancer who have a good performance status. In this study, we present the case of a 64-year-old male who developed dysarthria following FOLFIRINOX treatment, and review all four cases of dysarthria encountered among the nine patients who received this treatment in our hospital. In all cases, dysarthria occurred during the infusion of irinotecan in the first course of treatment, persisted for several hours, and then resolved rapidly without any sequelae. Physical and neurological examinations at the onset of dysarthria revealed no other abnormalities. Imaging studies revealed no abnormal findings. Atropine was prophylactically administered in the second and subsequent courses of treatment and effectively prevented or alleviated dysarthria. This acute neurological symptom is surprising and uncommon in traditional cancer chemotherapy, and medical oncologists may initially suspect the onset of stroke or cerebrovascular disease. However, consistent with our experience, all reported cases resolved completely, with no need for dose reduction or treatment interruption.

Aim: To evaluate the clinical value of the newly modified Simple Endoscopic Score for Crohn's disease (mSES-CD)., Methods: Seventy-six Crohn's disease (CD) patients who underwent transanal double balloon endoscopy (DBE) in our hospital between 2003 and 2012 were retrospectively reviewed. DBE is defined as small intestinal endoscopy using two attached balloons. We included patients with stenosis which hampered passage of the scope and those who underwent DBE with observation for at least 80 cm from the ileocecal valve. Our new mSES-CD assesses the endoscopic activity of two consecutive small intestinal segments located 0-40 cm and 40-80 cm from the ileocecal valve by DBE, in addition to the activity of four colorectal segments. To compare the usefulness of mSES-CD with SES-CD, we similarly divided the patients into two groups according to total mSES-CD score (low disease activity group, < 4; high disease activity group, ≥ 4). The clinical value of mSES-CD in predicting clinical outcome in patients with CD was evaluated using the occurrence of surgery after DBE as an endpoint., Results: Median age of the 76 CD patients was 36 years (range, 16-71). Thirty-nine patients had stenosis which hampered passage of the DBE to 80 cm on the proximal side from the ileocecal valve. Median evaluable length of small intestine by DBE was 80 cm (range, 3-200). A total of 74 patients had one or more small intestinal lesions detected by DBE, of which 62 (83.8%) were within 80 cm of the ileocecal valve on the proximal side. Only two patients (2.7%) with proximal-side lesions more than 80 cm from the ileocecal valve did not have lesions within 80 cm. Patients with high mSES-CD scores showed significantly shorter surgery-free survival than those with low scores (P < 0.05). In contrast, surgery-free survival did not significantly differ between the low and high SES-CD groups (P > 0.05). Multivariate analysis by a Cox proportional hazards model identified mSES-CD as an independent factor for surgery-free survival., Conclusion: mSES-CD is useful in evaluating the risk of surgery-free survival in patients with CD.

Aim: To evaluate long-term prognosis following cyclosporine treatment by examining the rate of surgery avoidance among cyclosporine responders., Methods: We retrospectively reviewed clinical records for 29 patients diagnosed with severe steroid-refractory ulcerative colitis in our hospital from August 1997 to August 2008 and treated with cyclosporine by continuous intravenous infusion. All patients were treated with intravenous corticosteroids for more than 5 d prior to cyclosporine therapy. Administration was continued for up to 21 d under serum monitoring to maintain cyclosporine levels between 400 and 600 ng/mL. Clinical activity was assessed before and after cyclosporine therapy using the clinical activity index score, with a reduction of ≥ 5 considered to indicate a response. Among responders, we defined cases not requiring surgery for more than 5 years as exhibiting long-term efficacy of cyclosporine. Factors considered to be possibly predictive of long-term efficacy of cyclosporine were sex, age, disease duration, clinical activity index score, C-reactive protein level, hemoglobin level, disease extent, endoscopic findings, and clinical course., Results: Cyclosporine was not discontinued due to side effects in any patient. Nineteen (65.5%) of 29 patients were considered responders. A statistically significant (P = 0.004) inverse association was observed between an endoscopic finding of "mucosal bleeding" and responsive cases. Fifteen (9 males, 6 females) of these 19 patients were followed for 5 years or more, of whom 9 (60%) exhibited long-term efficacy of cyclosporine. Of the 10 non-responders, 9 (90%) underwent surgery within 6 mo of cyclosporine therapy. None of the following factors had a significant impact on the long-term efficacy of cyclosporine: sex, age, duration of disease, clinical activity index score, C-reactive protein level, hemoglobin level, extent of disease, endoscopic findings, or clinical course. In contrast, a significant association was observed for maintenance therapy with azathioprine after cyclosporine therapy (P = 0.0014)., Conclusion: Maintenance therapy with azathioprine might improve the long-term efficacy of continuously infused cyclosporine for severe steroid-refractory ulcerative colitis patients.

Background and Aim: Secondary stomach cancer in lesions of the remnant stomach occurs relatively soon after distal gastrectomy using the Billroth I reconstruction procedure. Prophylactic eradication of Helicobacter pylori after endoscopic resection of early gastric cancer should be used to prevent the development of metachronous gastric carcinoma. However, the effect of H. pylori eradication on the gastric remnant has not been clearly determined., Methods: Eight patients who were H. pylori-positive after distal gastrectomy for primary gastric cancer underwent eradication therapy and were followed by endoscopy for 9 years. Upper gastroenteroscopy series were done before and at 1, 3, 5, 7 and 9 years after eradication, and biopsy specimens were taken from the lesser and greater curvatures, respectively. Histological changes, including chronic inflammation, activity, atrophy, and intestinal metaplasia, were evaluated using the updated Sydney system., Results: Successful eradication was confirmed using the urea breath test in all eight patients. Chronic inflammation scores were improved after eradication at both the lesser (mean scores ± SD: before eradication, 2.9±0.5; 1 year after, 2.3±0.4; 3 years, 1.8±0.3; 5 years, 1.5±0.3; 7 years, 1.3±0.3; and 9 years, 1.0±0.3) and greater curvatures (before, 2.9±0.4; 1 year after, 1.9±0.3; 3 years, 1.4±0.4; 5 years, 1.3±0.3; 7 years, 1.1±0.2; and 9 years, 0.6±0.3). Atrophy scores improved more quickly after eradication than chronic inflammation scores at both the lesser (before, 2.4±0.5; 1 year after, 1.8±0.4; 3 years, 0.8±0.3; 5 years, 0.3±0.1; 7 years, 0.0; and 9 years, 0.0) and greater curvatures (before, 2.2±0.4; 1 year after, 1.3±0.3; 3 years, 0.5±0.3; 5 years, 0.0; 7 years, 0.0; and 9 years, 0.0). No secondary stomach cancers were found on endoscopy., Conclusions: Undergoing H. pylori eradication improved possible precancerous lesions of the gastric remnant among patients who had undergone distal gastrectomy. Prophylactic H. pylori eradication in the gastric remnant may be useful in preventing the development of metachronous gastric carcinoma., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Malignant ascites due to peritoneal metastasis is one of the major problems caused by advanced gastrointestinal cancer. Although drainage of a large amount of ascitic fluid improves symptoms such as abdominal fullness, it may lead to protein loss and renal dysfunction. Cell-free and concentrated ascites reinfusion therapy (CART) may help avoid such complications due to paracentesis. The purpose of this study was to evaluate the safety of CART. We performed a total of 51 sessions of CART in 5 patients, 4 of whom had gastric cancer and 1 appendiceal cancer. We retrospectively evaluated laboratory data immediately prior to CART, on the following day, 1 week later and 2 weeks later. We also measured the amount of total protein and albumin in collected and concentrated ascites. The mean amount of collected ascites was 4,007 ml. All the patients exhibited improvement of symptoms such as abdominal fullness. Four patients developed fever (>38°C) immediately after reinfusion of the concentrated ascites and 3 of these patients required corticosteroid administration. The mean total protein and albumin in the collected ascites were 122 and 64 g, respectively, and those in the concentrated ascites 75 and 39 g, respectively. The serum levels of total protein, albumin and creatinine after CART were almost identical to those prior to CART. Blood hemoglobin concentration was significantly decreased 1 day after CART and returned to baseline levels in 1-2 weeks. CART does not cause renal dysfunction and does not decrease serum albumin; therefore, repeated CART is safe and may be used to improve the symptoms of malignant ascites from gastrointestinal cancer.

Background: Magnetic anchor-guided endoscopic submucosal dissection (MAG-ESD) was developed to reduce adverse events such as bleeding and perforation and to facilitate ESD. However, the external electromagnet required miniaturization to make it suitable for daily clinical practice., Objective: To evaluate the feasibility of simplified MAG-ESD using permanent magnets., Design: Case series., Setting: Nagoya University Hospital., Subjects: Beagle dogs., Interventions: The simplified MAG-ESD was performed on 10 representative areas of the stomachs of beagle dogs. The magnetic anchor consisted of an internal magnet attached to a hemoclip. The external and internal magnets were made from the rare earth neodymium., Main Outcome Measurements: The feasibility of countertraction with good visualization using simplified MAG-ESD. The rate of perforation, the time required for preparation, and attaching the magnetic anchor were also evaluated., Results: All lesions were successfully resected without perforation. The magnetic anchor could be controlled easily, and direct visualization was maintained by adequate counter traction. Preparing the magnetic anchor and grasping the mucosal edge using the hemoclip was easy and required a median of only 4 minutes (range, 2-7 minutes)., Limitations: Animal experiment, low number and lesion size., Conclusions: This simplified MAG-ESD is feasible and allowed excellent visualization in the dog stomach. The feasibility of this system should be assessed in humans., (Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

A 75-year-old woman was diagnosed with esophageal cancer with difficulty in swallowing. She had a past history of rheumatoid arthritis, scleroderma, interstitial pneumonia, angina pectoris (with coronary artery bypass surgery) and arrhythmia (with pacemaker implantation). She refused surgery, and chemotherapy and radiotherapy were not performed because of the high risk accompanied with multiple comorbidities. She received proton therapy at another hospital and the primary lesion shrank. Bone metastasis in the thoracic vertebrae was diagnosed 10 months after diagnosis of esophageal cancer. Non-steroidal anti-inflammatory drugs and zoledronic acid were administered for back pain. Oxycodone was also administered but discontinued due to nausea. After strontium-89 ((89)Sr) chloride administration, her back pain was relieved. (89)Sr was administered five times every 3 months, and the pain did not worsen until her death due to pneumonia 2 years after diagnosis of esophageal cancer. (89)Sr was effective for pain from bone metastasis of esophageal cancer, and its repeated administration was safe.

Acetate is the major short-chain fatty acid produced by commensal bacteria in the gut and is known as a nutrient source for epithelial cells of the mucosa. Acetate also suppresses interleukin (IL)-2 production in T cells by inhibiting nuclear factor of activated T cells (NFAT) nuclear translocation via tubulin-α acetylation. Using acetylation of tubulin-α as a biomarker, we have examined the influence of acetate in the large intestine. Because of high concentrations of acetate in fecal material, tubulin-α acetylation is dominant in the proximal large intestine relative to other sections of the large intestine and is induced in epithelial cells of the colonic mucosa. Flagellin stimulation induces IL-8 production in epithelial cells and acetate suppresses this IL-8 production via tubulin-α acetylation. Flagellin stimulation activates nuclear factor-κB, CREB and AP-1, but not NFAT. Of these transcription factors, acetate specifically inhibits AP-1 activation. Acetate impairs flagellin-induced activation of the Rap1-MEK-ERK-Elk-1 pathway with acetylation of tubulin-α that is bound to Rap1, resulting in reduced expression of c-Fos, a subunit of AP-1. These findings reveal a novel action of acetate via tubulin-α acetylation in epithelial cells of the colonic mucosa.

The mechanisms of drug resistance in cancer are not fully elucidated. To study the drug resistance of gastric cancer, we analyzed gene expression and DNA methylation profiles of 5-fluorouracil (5-FU)- and cisplatin (CDDP)-resistant gastric cancer cells and biopsy specimens. Drug-resistant gastric cancer cells were established with culture for >10 months in a medium containing 5-FU or CDDP. Endoscopic biopsy specimens were obtained from gastric cancer patients who underwent chemotherapy with oral fluoropyrimidine S-1 and CDDP. Gene expression and DNA methylation analyses were performed using microarray, and validated using real-time PCR and pyrosequencing, respectively. Out of 17,933 genes, 541 genes commonly increased and 569 genes decreased in both 5-FU- and CDDP-resistant AGS cells. Genes with expression changed by drugs were related to GO term 'extracellular region' and 'p53 signaling pathway' in both 5-FU- and CDDP-treated cells. Expression of 15 genes including KLK13 increased and 12 genes including ETV7 decreased, in both drug-resistant cells and biopsy specimens of two patients after chemotherapy. Out of 10,365 genes evaluated with both expression microarray and methylation microarray, 74 genes were hypermethylated and downregulated, or hypomethylated and upregulated in either 5-FU-resistant or CDDP-resistant cells. Of these genes, expression of 21 genes including FSCN1, CPT1C and NOTCH3, increased from treatment with a demethylating agent. There are alterations of gene expression and DNA methylation in drug-resistant gastric cancer; they may be related to mechanisms of drug resistance and may be useful as biomarkers of gastric cancer drug sensitivity.

OBJECTIVE. Inflammatory bowel disease (IBD) is a chronic debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor. GLP-2 released from enteroendocrine cells is inactivated by dipeptidyl peptidase-4 (DPP-4). The aim of this study was to examine whether the DPP-4 inhibitor anagliptin improves experimental murine colitis. MATERIAL AND METHODS. Male C57BL/6 mice aged 8 weeks were exposed to 1.5% dextran sulfate sodium (DSS) in drinking water for 7 days to induce experimental colitis. Anagliptin (0.1% in diet) was administrated from 2 days before the beginning of DSS to 7 days after the end of DSS. Changes in body weight and disease activity index were evaluated daily. Histological colitis severity, cellular proliferation and gene expression were determined in colonic tissues. RESULTS. Treatment with anagliptin clearly improved body weight loss and disease activity index in the recovery phase. Histological score in the DSS + anagliptin group at day 14 was significantly lower than that in the DSS alone group. Treatment with anagliptin increased the Ki67-positive rate at days 10 and 14, and tended to increase insulin-like growth factor-1 mRNA expression in the DSS + anagliptin group. CONCLUSION. In this model of experimental colitis, the DPP-4 inhibitor anagliptin facilitated the restoration of mucosal damage, thereby resulting in the acceleration of healing. These findings suggest a new and novel therapeutic approach for the treatment of IBD.

Hepatic portal venous gas is a rare condition that occurs when intraluminal gas or gas produced by intestinal bacteria enters the portal venous circulation. It has recently been recognized as a rare complication of colon procedures by endoscopy or barium enema. Given the frequency of these procedures in patients with inflammatory bowel disease, hepatic portal venous gas may occur more frequently in these patients than previously reported. Here, we report a woman with Crohn's disease who developed hepatic portal venous gas following colonoscopy who was treated with conservative therapy.

Background: Ulcerative colitis (UC) often occurs in women of childbearing age. Compared to Western countries, however, few studies have investigated the impact of UC on the progress of pregnancy in Asian populations., Methods: We retrospectively examined 91 pregnancies in 64 patients with UC experienced at our hospital and related institutions from 1991 to 2011, focusing on the relationship between the progression of UC during pregnancy, progress of the pregnancy itself, and the treatment of UC., Results: In 80 of 91 pregnancies the patient had already been diagnosed with UC at the time she became pregnant, of whom 31 (38.8%) experienced exacerbation during pregnancy. Regarding severity, moderate or severe active-stage disease during pregnancy was seen in 13.7% of those who had been in remission at the onset of pregnancy versus 58.6% of those who had been in the active stage at onset (OR 8.9: 95%CI 3.0~26.4; P<0.01). The incidence of miscarriage or abortion was 9.8% in pregnancies in which UC was in remission at onset versus 31% in those in which it was in the active stage at onset (OR 4.1: 95%CI 1.2~13.9; P=0.02). Among patients, 62.5% were receiving pharmaceutical treatment at onset of pregnancy. Exacerbation during pregnancy occurred in 26.5% of the group who continued to receive the same treatment during pregnancy versus 56.3% of those with a dose decrease or discontinuation after onset (OR 3.6: 95%CI 1.0~12.4; P=0.04)., Conclusions: UC patients wishing to conceive should do so when in remission and continue appropriate pharmaceutical treatment during pregnancy.

Background: The distal esophagus harbors a complex bacterial population. We hypothesized that a better understanding of bacterial communities in the esophagus would facilitate understanding of the role of bacteria in esophageal disease. Here, we investigated bacterial composition in the distal esophagus in subjects with a normal esophagus, reflux esophagitis, and Barrett's esophagus., Methods: Two biopsy specimens were obtained from the distal esophagus at 1 cm above the gastroesophageal junction under endoscopic examination in 18 patients (6 each with normal esophagus, reflux esophagitis, and Barrett's esophagus) and used for histological examination and DNA extraction. Fragments of 16S rDNA genes were amplified by PCR using general bacterial primers, and bacterial populations were examined. A third biopsy specimen was taken from the patients with Barrett's esophagus to histologically confirm the replacement of squamous epithelium with columnar epithelium in the distal esophagus., Results: Endoscopic diagnoses of normal esophagus, esophagitis, and Barrett's esophagus were confirmed by histological findings. The total amount of bacterial DNA detected did not significantly differ among groups (p > 0.1). On average, each of the 18 subjects yielded about 350 clones, of which 40 were randomly picked and sequenced. Analysis of 147 16S rDNA sequences from 240 clones of 6 subjects with normal esophagus yielded four phyla, Proteobacteria (49%), Firmicutes (40%), Bacteroidetes (8%), and Actinobacteria (3%). Similar analysis of 139 16S rDNA sequences from 240 clones of 6 patients with reflux esophagitis yielded 6 phyla, Proteobacteria (43%), Firmicutes (33%), Bacteroidetes (10%), Fusobacteria (10%), Actinobacteria (2%), and TM7 (2%). while that of 138 16S rDNA sequences from 240 clones of 6 cases of Barrett's esophagus yielded 5 phyla, Firmicutes (55%), Proteobacteria (20%), Bacteroidetes (14%), Fusobacteria (9%), and Actinobacteria (2%). Thus, microbial communities differed among patients with a normal esophagus, reflux esophagitis and Barrett's esophagus., Conclusions: Esophageal bacterial composition differs under conditions of normal esophagus, reflux esophagitis, and Barrett's esophagus. Diverse bacterial communities may be associated with esophageal disease.

Background: A close association between patterns identified by magnifying narrow-band imaging (M-NBI) and histological type has been described. M-NBI patterns were also recently reported to be related to the mucin phenotype; however, detials remain unclear., Materials and Methods: We investigated the cellular differentiation of gastric cancer lesions, along with their mucosal distribution observed by M-NBI. Ninety-seven depressed-type early gastric cancer lesions (74 differentiated and 23 undifferentiated adenocarcinomas) were visualized by M-NBI. Findings were divided into 4 patterns based on abnormal microvascular architecture: a chain loop pattern (CLP), a fine network pattern (FNP), a corkscrew pattern (CSP), and an unclassified pattern. Mucin phenotypes were judged as gastric (G-type), intestinal (I-type), mixed gastric and intestinal (M-type), and null (N-type) based on 4 markers (MAC5AC, MUC6, MUC2, and CD10). The relationship of each pattern of microvascular architecture with organoid differentiation indicated by cancer cell differentiation and its distribution in each histological type of early gastric cancer was investigated., Results: All CLP and FNP lesions were differentiated. The cancer cell distribution showed organoid differentiation in 84.2% (16/19) and 61.1% (22/36) of the two types of lesions, respectively, and there was a significant difference from the unclassified pattern with organoid differentiation (p<0.001). Almost all (94.7%; 18/19) CSP lesions were undifferentiated, and organoid differentiation was observed in 72.2% (13/18). There was a significant difference from the unclassified pattern with organoid differentiation (p<0.05)., Conclusions: Cellular differentiation and distribution are associated with microvascular architecture observed by M-NBI.

Background and Aims: The number of patients with Crohn's disease (CD) and the number of cases of intestinal cancer associated with CD have both been increasing in Japan. However, the number of reported cases is lower than for ulcerative colitis-associated cancer. The aim of this study was to identify the clinical picture of CD-associated intestinal cancer in a consecutive series of patients with CD and to stress the importance of surveillance., Methods: We enrolled 174 consecutive patients (130 men, 44 women, mean age 25 years) diagnosed with CD and investigated the development of intestinal cancer from October 1998 to July 2010. There were 104 cases of the ileocolitis type, 47 of ileitis, and 23 of colitis., Results: Intestinal cancer developed in two male patients (1.5% of the total), whose respective ages at onset of CD were 41 and 19 years, and 55 and 37 years at onset of cancer. Both cases were of ileocolitis-type CD; one cancer developed in the rectum and the other in the small bowel, and both were accompanied by severe stricture. Histopathological results revealed well and moderately differentiated adenocarcinoma, respectively., Conclusions: Intestinal cancer developed in patients with ileocolitis-type CD of more than 10 years' duration. Our findings suggest that patients with chronic, widespread CD should be under cancer surveillance., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

To overcome drug resistance in ovarian carcinoma, novel resistance mechanisms must be elucidated for clinical application. We purified 2 proteins in the 300 kDa range from cisplatin-resistant cells (NOS2CR2) by affinity chromatography with cisplatin-exposed Glutathione Sepharose 4B. The purified proteins were identified as spectrin αII and βII by peptide mass mapping analysis. Western blot analysis detected greater expression of spectrin αII and βII in NOS2CR2 than in wild-type cells (NOS2). The same result was obtained for spectrin βII expression by immunohistochemical staining. To determine whether spectrin αII and βII contribute to resistance, a drug sensitivity test was performed on SKOV3 ovarian cancer cells transfected with small interfering RNA. Sensitivity to platinum drugs was increased in the expression reduced cells. In a clinical study of five ovarian serous adenocarcinoma cases, tumor specimens taken after treatment with carboplatin stained more strongly for spectrin βII expression than untreated specimens. Fifty-two tumor specimens from 46 patients with ovarian serous adenocarcinoma were immunohistochemically stained for spectrin βII and scored. Tumors previously treated by chemotherapy scored higher than those not treated. Of 27 cases with detectable residual tumors at the time of surgery, cases scoring 4-6 had shorter progression-free survival periods after platinum-based chemotherapy than cases scoring 0-3 (p = 0.012). The cytoskeleton proteins Spectrin αII and βII contributed to drug resistance by anchoring the GS-Pt complex to the cell membrane, arresting cisplatin activity. Thus spectrin βII may be a useful predictor of platinum sensitivity in ovarian serous adenocarcinoma., (Copyright © 2011 UICC.)

Activated macrophages play a critical role in the pathogenesis of numerous diseases by producing pro-inflammatory cytokines such as interleukin (IL)-1β and IL-6. While the mechanisms of bacterial component recognition and signal transduction have been well investigated, viability regulation in activated macrophages remains unclear. We screened herbal ingredients to find an agent that reduces the viability of lipopolysaccharide (LPS)-stimulated macrophages and observed that dehydrocorydaline, a component of Corydalis yanhusuo, reduced the viability of macrophage-derived RAW264.7 cells and primary macrophages in the presence of LPS. Dehydrocorydaline inhibited the elevation of mitochondrial membrane potential and induced ATP depletion in LPS-stimulated macrophages but neither affected basal mitochondrial membrane potential nor ATP content in non-stimulated macrophages. Dehydrocorydaline also prevented increased concentrations of IL-1β and IL-6 in culture media of LPS-stimulated macrophages. Mode of dehydrocorydaline action indicates that elevated mitochondrial membrane potential may be a novel target to specifically reduce viability and suppress cytokine production in LPS-stimulated macrophages., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP-negative. The role of this classification in predicting recurrence and disease-free survival (DFS) in resected stage III CRC was evaluated., Methods: Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE-1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed., Results: Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K-means clustering analysis identified 3 discrete subgroups: CIMP1 (n = 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n = 40, 24.8%), associated with KRAS mutations; and CIMP-negative (n = 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP-negative) and a worse DFS (P = .015). Also in proximal CRC, LINE-1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P = .049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P = .008 for classification by K-means clustering analysis; P = .040 for LINE-1 methylation status)., Conclusions: DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings., (Copyright © 2010 American Cancer Society.)

Background: Real-time tissue sonoelastography (EG) is a new non-invasive technique that visualizes differences in tissue strain. We evaluated the usefulness of EG in patients with ulcerative colitis (UC) by investigating the association between EG and colonoscopic findings and disease activity., Methods: Thirty-seven UC patients undergoing EG and colonoscopy were invited to enroll. EG findings were classified as normal, homogeneous, random, or hard, and colonoscopic findings as normal, mucosal edema and erosion, punched-out ulcer, and extensive mucosal abrasion. Clinical findings were evaluated using clinical activity index (CAI) scores for each patient at colonoscopy., Results: On EG, 10 cases were classified as normal, 11 as homogeneous, 6 as random, and 10 as hard. EG findings showed a significant correlation those of colonoscopy (p < 0.001). Seven of 10 (70%) normal-type patients were in the remission phase, while all 6 random-type patients were in the active phase. Among active-phase patients, 4 of 7 (57%) homogeneous-type patients responded to steroid or leukocytapheresis therapy, while 3 of 6 (50%) random-type patients required treatment with cyclosporine. Three of 10 (30%) hard-type patients required colectomy., Conclusions: In this small series, EG findings reflected colonoscopic findings and correlated with disease activity among patients with UC.