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Background: A new circulating biomarker superior to carbohydrate antigen 19-9 (CA19-9) is needed for diagnosing pancreatobiliary cancer (PBca). The aim of this study was to identify serum microRNA (miRNA) signatures comprising reproducible and disease-related miRNAs., Methods: This multicenter study involved patients with treatment-naïve PBca and healthy participants. The optimized serum processing conditions were evaluated using t-distributed stochastic neighbor embedding (t-SNE) visualization. Serum miRNA candidates for disease association were selected using weighted gene coexpression network analysis (WGCNA). A miRNA signature combining multiple serum miRNAs was tested in exploratory, validation, and independent validation sets. The synthesis and secretion of diagnostic miRNAs were evaluated using human pancreatic cancer cells., Results: In total, 284 (150 healthy and 134 PBca) of 827 serum samples were processed within 2 h of blood collection before freezing, distributed in the same area as that in the t-SNE map, and assigned to an exploratory set. The 193 optimized samples were assigned to either the validation (50 healthy, 47 PBca) or independent validation (50 healthy, 46 PBca) set. Index-1, a combination of five serum miRNAs (hsa-miR-1343-5p, hsa-miR-4632-5p, hsa-miR-4665-5p, hsa-miR-665, and hsa-miR-6803-5p) with disease association in WGCNA, showed a sensitivity and specificity of > 80% and an AUC outperforming that of CA19-9 in the exploratory, validation, and independent validation sets. The AUC of Index-1 was superior to that of CA19-9 (0.856 vs. 0.649, p = 0.038) for detecting T1 tumors. miR-665, a component of Index-1, was expressed in human pancreatic cancer cells, and its transfection inhibited cell growth., Conclusions: The serum miRNA signature Index-1 is useful for detecting PBca and could facilitate the early diagnosis of PBca. These findings can help improve clinical PBca detection by providing an optimized biomarker that overcomes the limitations of the current standard., Competing Interests: Declarations. Ethics approval and consent to participate: This prospective observational study was approved by the ethics review committee of the National Cancer Center Hospital East and National Cancer Center Hospital (approval no. 2016–049, 2020–449) and the institutional review boards of collaborating institutions. The study for time-course effects was approved by the Human Tissue Samples Ethics Committee for R&D of Toray Industries, Inc. (HC2017-10, HC2021-3, and HC2021-18). All the studies complied with the principles of the Declaration of Helsinki and the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects. Written informed consent was obtained from all participants. Consent for publication: Not applicable. Competing interests: S.M. received honoraria and grants from Toray Industries, Inc., and grants from the Japan Agency for Medical Research and Development (AMED) under Grant Numbers 15ck0106027h0002 and 16ck106027h0003 during the submitted work, as well as research funding from Ajinomoto Co., Inc., PFDeNA Co., Ltd., and Mitsui Chemicals Inc. outside the submitted work. M.I. received research funding from Astellas Pharma Inc., Nihon Servier Co., Ltd., and Novartis Pharma K.K. and received honoraria from Guardant Health Japan Corp., Nihon Servier Co., Ltd., Taiho Pharmaceutical Co., Ltd., M.S.D. K.K., NIPPON KAYAKU Co., Ltd., Yakult Honsha Co., Ltd., Boehringer Ingelheim GmbH, D.F.P. (Delta Fly Pharma) Inc., Merus N.V., Invitae Corp., and Novartis Pharma K.K. outside the submitted work. M.U. received grants from Toray Industries, Inc., during the submitted work, as well as research funding from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., M.S.D. K.K., Nihon Servier Co., Ltd., Ono Pharmaceutical Co., Ltd., Incyte Biosciences Japan G.K., Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim GmbH, Eisai Co., Ltd., Novartis Pharma K.K., Astellas Pharma Inc., J-pharma Co., Ltd., DFP (Delta Fly Pharma) Inc., Novocure GmbH, and Chiome Bioscience Inc. and honoraria from Taiho Pharmaceutical Co., Ltd., AstraZeneca K.K., Yakult Honsha Co., Ltd., M.S.D. K.K., Nihon Servier Co., Ltd., Ono Pharmaceutical Co., Ltd., Incyte Biosciences Japan G.K., Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim GmbH, J-pharma Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Novartis Pharma K.K. outside the submitted work. K.H2. received honoraria and research funding from Toray Industries, Inc., during the submitted work. K.T. received research funding from Toray Industries, Inc., during the submitted work, received research funding from Hitachi High-Tech Corporation and H.U. Group Research Institute G.K., and holds a patent with H.U. Group Research Institute G.K. outside the submitted work. M.T., I.M., T.K., H.Y., H.I1, H.I2, E.H., K.N., M.N., and A.O. received research funding from Toray Industries, Inc., during the submitted work. H.S. is an employee of Toray Industries, Inc., and received grants from AMED under grant numbers 15ck0106027h0002 and 16ck106027h0003 during the submitted work. S.T. is an employee of Toray Industries, Inc., and received grants from AMED under grant numbers 15ck0106027h0002 and 16ck106027h0003 during the submitted work. The other authors declare that they have no competing interests., (© 2025. The Author(s).)

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multiomics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% have participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% CI, 13.4-16.3) for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83). Significance: Our nationwide molecular profiling initiative played pivotal roles in facilitating the enrollment of patients with advanced solid tumors into matched clinical trials and highlighted the substantial survival benefits of patients treated with matched therapy. We aim to facilitate an industry-academia data-sharing infrastructure ecosystem, fostering new drug discovery paradigms and precision medicine., (©2024 The Authors; Published by the American Association for Cancer Research.)

The extraction of data that contribute to regulatory approval from real-world data (RWD) is difficult because of the lack of a standardized data format and extraction methodology. Additionally, when real-world evidence (RWE) is used as an external control group, the similarity between internal and external control data is not evaluated. To investigate the data extraction methodology for the external control data of rare molecular subtypes, we have initiated the "REALISE" study. In this study, we aim to elucidate the "relevance" and "reliability" of RWD/RWE necessary for regulatory approval. As most databases are not designed for regulatory use in the creation phase, we will investigate retrospective methodologies to ensure RWD/RWE reliability. This study will compare the "relevance" and "reliability" of the ARCAD global database, SCRUM-Japan Registry, SCRUM-Japan observational study, and Flatiron Health RWD, and statistically analyze the differences and similarities among the four databases. We will also examine the methodology for extracting sufficiently relevant data from the SCRUM-Japan observational study. Additionally, if the reliability of the RWD/RWE does not reach the required level for regulatory approval, we will examine the methodologies to ensure the "reliability" of the SCRUM-Japan observational study for regulatory approval. The obtained results will be submitted to the "Consultation for Development of Registry" in the Pharmaceuticals and Medical Devices Agency, and we will discuss the standard methodology. The procedures and findings identified in the REALISE study will be organized from the perspectives of "database construction," "data analysis," and "outcome evaluation" and will be issued as "the draft guidelines.", Competing Interests: Disclosure Hideaki Bando reports research funding from Ono Pharmaceutical and honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly in Japan. Yasutoshi Sakamoto reports no conflict of interests. Toshihiro Misumi reports honoraria from Chugai, AstraZeneca, and Miyarisan. Yuriko Takeda reports no conflict of interests. Yoshiaki Nakamura reports honoraria from Chugai Pharmaceutical, Merck Biopharma, and Guardant Health AMEA and research grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Guardant Health, Genomedia, Daiichi Sankyo, Seagen, and Roche Diagnostics. Kazuya Mizuguchi and Yoshihiro Aoyagi reports no conflict of interests. Takayuki Yoshino reports honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD and research funding from Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, Amgen, Parexel International, MSD, Daiichi Sankyo, Pfizer, Genomedia, Sysmex, Nihon Boehringer Ingelheim, and Sanofi. Atsushi Ohtsu reports research funding from BMS and honoraria from Chugai and Ono Pharmaceutical., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aims: Endoscopic self-expandable metal stent (SEMS) placement is currently the standard technique for treating unresectable malignant distal biliary obstructions (MDBO). Therefore, covered SEMS with longer stent patency and fewer migrations are required. This study aimed to assess the clinical performance of a novel, fully covered SEMS for unresectable MDBO., Methods: This was a multicenter single-arm prospective study. The primary outcome was a non-obstruction rate at 6 months. The secondary outcomes were overall survival (OS), recurrent biliary obstruction (RBO), time to RBO (TRBO), technical and clinical success, and adverse events., Results: A total of 73 patients were enrolled in this study. The non-obstruction rate at 6 months was 61%. The median OS and TRBO were 233 and 216 days, respectively. The technical and clinical success rates were 100% and 97%, respectively. Furthermore, the rate of occurrence of RBO and adverse events was 49% and 21%, respectively. The length of bile duct stenosis (<2.2 cm) was the only significant risk factor for stent migration., Conclusions: The non-obstruction rate of a novel fully covered SEMS for MDBO is comparable to that reported earlier but shorter than expected. Short bile duct stenosis is a significant risk factor for stent migration.

Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Although phase III trials have reported improved overall survival in patients with advanced esophageal squamous cell carcinoma following treatment with nivolumab, as compared with chemotherapy (paclitaxel or docetaxel), the treatment was effective only in a limited number of patients. Therefore, the aim of this study is to determine whether there is a correlation between nutritional status (Glasgow prognostic score, prognostic nutritional index, and neutrophil-to-lymphocyte ratio) and prognosis of advanced esophageal cancer in patients treated with taxane or nivolumab therapy. The medical records of 35 patients who received taxane monotherapy (paclitaxel or docetaxel), for advanced esophageal cancer between October 2016 and November 2018 (taxane cohort) were reviewed. The clinical data of 37 patients who received nivolumab therapy between March 2020 and September 2021 (nivolumab cohort) were collected. The median overall survival was 9.1 months for the taxane cohort and 12.5 months for the nivolumab cohort. In the nivolumab cohort, patients with good nutritional status had significantly better median overall survival than those with poor nutritional status (18.1 vs. 7.6 months, respectively, p = 0.009, classified by prognostic nutritional index, 15.5 vs. 4.3 months, respectively, p = 0.012, classified by Glasgow prognostic score), whereas the prognosis of the patients treated with taxane therapy was less affected by the nutritional status. This suggests that the pretreatment nutritional status of patients with advanced esophageal cancer is a key factor for successful outcomes, especially for treatment with nivolumab., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Takegawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Utilizing real-world data (RWD) for effective clinical implementation is becoming more and more appealing as the cost of drug development rises, especially for patients with rare diseases and rare molecular subtypes for whom conducting randomized controlled trials is challenging. If a regulatory approval methodology based on RWD as an external control group can be established, drug development for rarer fractions can be accelerated by lowering costs and time, as well as reducing physical and emotional burdens on both patients and healthcare professionals. Since 2017, we have been prospectively collecting the clinical data of standard therapies in patients with rare molecular fractions under the SCRUM-Japan Registry platform, which is a qualified registry utilized as external control data for regulatory submission. Based on the results of the phase II TRIUMPH study (UMIN000027887) and the extracted data from the SCRUM-Japan Registry, the pharmaceutical company submitted an application for pertuzumab and trastuzumab in patients with HER2-positive metastatic colorectal cancer in April 2021. Pertuzumab and trastuzumab were approved as expanded indications on March 28, 2022, as 6 cases out of 14 extracted from the SCRUM-Japan Registry were classified and utilized as "evaluation material" under the review process of the Pharmaceuticals and Medical Devices Agency (PMDA). Through the TRIUMPH study and the SCRUM-Japan Registry, we have paved the way for regulatory approval of RWD in Japan. In future, we must define the steps for constructing regulatory-grade registries and the method/process for utilizing RWD by accumulating case experiences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery., Patients and Methods: Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results., Results: A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies., Conclusion: Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.

Objectives: To investigate metabolite alterations in the plasma of SLE patients to identify novel biomarkers and provide insight into SLE pathogenesis., Methods: Patients with SLE (n = 41, discovery cohort and n = 37, replication cohort), healthy controls (n = 30 and n = 29) and patients with RA (n = 19, disease control) were recruited. Metabolic profiles of the plasma samples were analysed using liquid chromatography-time-of-flight mass spectrometry and capillary electrophoresis-time-of-flight mass spectrometry. Transcriptome data was analysed using RNA-sequencing for 18 immune cell subsets. The importance of histidine (His) in plasmablast differentiation was investigated by using mouse splenic B cells., Results: We demonstrate that a specific amino acid combination including His can effectively distinguish between SLE patients and healthy controls. Random forest and partial least squares-discriminant analysis identified His as an effective classifier for SLE patients. A decrease in His plasma levels correlated with damage accrual independent of prednisolone dosage and type I IFN signature. The oxidative phosphorylation signature in plasmablasts negatively correlated with His levels. We also showed that plasmablast differentiation induced by innate immune signals was dependent on His., Conclusions: Plasma His levels are a potential biomarker for SLE patients and are associated with damage accrual. Our data suggest the importance of His as a pathogenic metabolite in SLE pathogenesis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Chemoradiotherapy (CRT) or radiotherapy (RT) alone is often the treatment of choice for elderly patients with esophageal cancer with the expectation of organ preservation. However, salvage treatment remains a problem when endoscopic resection is not indicated for local failure after CRT/RT. Photodynamic therapy (PDT) is indicated for local failure after CRT/RT, but there are few reports on its efficacy and safety in elderly patients. This study aimed to assess the outcome of PDT for local failure after CRT/RT for esophageal cancer in elderly patients., Methods: This retrospective single-center study included 42 patients who first underwent PDT between April 2013 and June 2021. Patients aged ≥80 and <80 years were classified into the elderly and nonelderly groups, respectively. Local complete response rate, overall survival, progression-free survival, and incidence of adverse events related to PDT were compared retrospectively between the groups., Results: The local complete response rate was 93.3% in the elderly group and 85.7 in the non-elderly group. The 2-year overall survival rate was 68.6% and 72.5%, and the 2-year progression-free survival rate was 49.5% and 70.0% in the elderly and nonelderly groups, respectively. There was no significant difference in any of these outcomes between the groups. In terms of adverse events, pneumonia and delirium tended to occur more frequently in the elderly group, but there were no serious adverse events in either group., Conclusion: The outcome of salvage PDT in the local control was comparable between the elderly and nonelderly patients for local failure after CRT/RT for esophageal cancer., Competing Interests: None., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: A congenital intrahepatic portosystemic shunt (IPSVS) is a rare vascular abnormality that is characterized by an anomalous intrahepatic venous tract that connects the intrahepatic portal vein with the hepatic venous system. Hepatic encephalopathy is an indication for IPSVS embolization, which is technically challenging because rapid blood flow through shunts can induce the migration of embolization material to systemic veins. This case report discusses the efficacy of percutaneous balloon-occluded retrograde transvenous obliteration for treating patients with IPSVSs., Case Summary: A 75-year-old woman presented with a six-month history of repeated hepatic encephalopathy due to an IPSVS without liver cirrhosis. We successfully embolized the IPSVS using percutaneous balloon-occluded retrograde transvenous obliteration with interlocking detachable coils. After the procedure, the patient exhibited no symptoms of hepatic encephalopathy for 14 mo., Conclusion: Balloon-occluded retrograde transvenous obliteration with detachable coils can be effective for the endovascular treatment of an IPSVS., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: To evaluate outcomes of endovascular treatment (EVT) using a combination of multiple endovascular techniques for acute lower limb ischemia (ALLI) and to compare outcomes based on vessel type and artery location., Methods: A total of 95 consecutive patients with ALLI (mean age, 72.0 years; 65 males; 104 lower limbs) who received emergency EVT using a combination of multiple endovascular techniques including thrombolysis, aspiration thrombectomy, stenting, and balloon angioplasty with or without surgical thromboembolectomy, between January 2005 and December 2017 were included. Vessel type was classified into native artery occlusion (native occlusion) and bypass graft occlusion (graft occlusion), including prosthetic and vein graft. Additionally, native arteries were categorized into below-knee occlusion and non-below-knee occlusion. Technical success, perioperative death (POD), ALLI-related death, amputation, amputation-free survival (AFS), and complications were compared according to vessel type (native occlusion vs. graft occlusion) and artery location (below-knee occlusion vs. non-below-knee occlusion)., Results: Of all patients with ALLI, 16.8% underwent a single endovascular technique, whereas 83.2% underwent a combination of multiple endovascular techniques. The technicalsuccess, POD, and ALLI-related death rates in the total number of patients were 94.7%, 11.6%, and 4.2%, respectively. A total of 67 patients (75 limbs) and 28 patients (29 limbs) were classified as having native occlusion and graft occlusion (prosthetic, 24 limbs; vein, 5 limbs), respectively. No significant differences in technical success (native occlusion: 92.5% vs. graft occlusion: 100%), POD (14.9% vs. 3.6%), and ALLI-related death (6.0% vs. 0%) were noted between native occlusion and graft occlusion. However, the 30-day AFS rate of native occlusion was significantly lower than that of graft occlusion (75.2% vs. 96.3%, P=0.01). The amputation rate (P=0.03) and AFS rate (P=0.03) of below-knee occlusion were significantly worse for below-knee occlusion patients than for non-below-knee occlusion patients., Conclusions: EVT using multiple endovascular techniques for ALLI is effective and safe. A combination of multiple endovascular techniques is crucial for successful treatment. However, native occlusion may have a lower AFS rate than graft occlusion, and below-knee occlusion may have a higher risk of amputation than non-below-knee occlusion., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In Japan, South Korea, and Taiwan, nivolumab might provide overall survival benefits for patients with advanced gastric cancer. However, it is effective only in a limited number of patients. The Glasgow prognostic score is an indicator of the systematic inflammatory response and nutritional status. This study aimed to investigate the ability of the Glasgow prognostic score and other markers to predict the outcomes of patients treated with nivolumab. We reviewed the medical records of patients treated for advanced gastric cancer and who received nivolumab between February 2015 and June 2019 at Hyogo Cancer Center. The patients were categorized into two groups according to their Glasgow prognostic scores. Overall, 53.3% and 46.7% of the patients were assigned to groups with Glasgow prognostic scores of 0 and 1/2, respectively. The median durations of progression-free and overall survival of the participants were 2.3 and 5.7 months, respectively. The patients with a Glasgow prognostic score of 0 had significantly higher median overall survival than those with scores of 1 or 2 (16.4 vs. 4.2 months; p = 0.0006). This observation suggests that a pretreatment Glasgow prognostic score of 0 is associated with better outcomes, and this scoring system may be used as a predictor of outcomes in patients with advanced gastric cancer treated with nivolumab., Competing Interests: The authors have declared that no competing interests exist.

FMS-like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co-altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co-alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non-FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.

Background: Balloon-assisted transcatheter arterial embolization (TAE) using n-butyl cyanoacrylate (NBCA) and lipiodol (Lp) mixture is a new endovascular treatment technique for iatrogenic arterial bleeding by groin puncture. It is less invasive compared to surgical repair, and NBCA migration into the circulation can be prevented by temporary balloon occlusion of the parent artery without ultrasound-guidance. This study aimed to report on the technical aspects and evaluate the efficacy and safety of fluoroscopically guided balloon-assisted transcatheter arterial embolization using NBCA for iatrogenic arterial bleeding by groin puncture., Materials and Methods: The study included five patients (mean age 54.6 years; 3 male and 2 female) with iatrogenic arterial bleeding by groin puncture. We performed transcatheter arterial embolization using NBCA while occluding the responsible artery with a balloon catheter during the embolization to prevent NBCA migration. Two sheaths were inserted into the common femoral artery. A microcatheter was advanced into the pseudoaneurysm or extravasation via the contralateral sheath. A balloon catheter was advanced into the responsible artery until the balloon portion covered the leakage site via another sheath. After balloon inflation, the NBCA and Lip mixture was slowly injected until the pseudoaneurysm, or the extravasation was filled without touching the balloon. The microcatheter was removed immediately after the filling. We assessed technical success, overall success, and complications., Results: The injured arteries were the external iliac artery (n = 1), the common femoral artery (n = 2), and the proximal portion of the superficial femoral artery (n = 2). NBCA was injected once in four cases and twice in one case where complete hemostasis could not be achieved with one injection. The technical and overall success rate was 100% with no complications, including distal embolization of NBCA., Conclusions: Balloon-assisted TAE using NBCA is a feasible, effective, and safe treatment for iatrogenic arterial bleeding by groin puncture. It may also be applicable in other arterial bleeding situations where the potential risk of distal embolization can be decreased by applying the balloon-assisted technique.

The patient was a 70-year-old man with idiopathic orbital inflammation (IOI) that appeared on the severely affected side of preceding myasthenia gravis (MG). The patient was diagnosed with MG 5 years prior to the onset of IOI. When IOI was diagnosed, an edrophonium test was negative. IOI was considered because he complained of left orbital pain, eyelid swelling, and cerebral MRI exhibited the enhanced lesions along the left orbital periosteum. A biopsy specimen revealed pathological findings compatible with IOI. The administration of corticosteroids was effective for improving the ocular symptoms. IOI should be considered when ocular symptoms deteriorated with soft tissue swelling/pain in MG patients.

Objectives: There have been epidemiological studies of adverse events (AEs) among general patients but those of patients cared by cardiologist are not well scrutinized. We investigated the occurrence of AEs and medical errors (MEs) among adult patients with cardiology in Japan., Methods: We conducted a cross-sectional study of adult outpatients at a Japanese teaching hospital from February through November 2006. We measured AE and ME incidents from patient report, which were verified by medical records, laboratory data, incident reports, and prescription queries. Two independent physicians reviewed the incidents to determine whether they were AEs or MEs and to assess severity and symptoms., Results: We identified 144 AEs and 30 MEs (16.3 and 3.9 per 100 patients, respectively). Of the 144 AEs, 99 were solely adverse drug events (ADEs), 20 were solely non-ADEs, and the remaining 25 were both causes. The most frequent symptoms of ADEs were skin and allergic reactions due to medication. The most frequent symptoms of non-ADEs were bleeding due to therapeutic interventions. Among AEs, 12% was life threatening. Life-threatening AEs were 25% of non-ADEs and 5% of ADEs (P = 0.0003). Among the 30 MEs, 21MEs (70%) were associated with drugs., Conclusions: Adverse events were common among cardiology patients. Adverse drug events were the most frequent AEs, and non-ADEs were more critical than ADEs. Such data should be recognized among practicing physicians to improve the patients' outcomes.

Purpose: To report an unusual case of an abdominal aortic aneurysm (AAA) rupture caused by migration of a Zenith stent-graft main body years after its separation from the suprarenal stent., Case Report: A 72-year-old man underwent endovascular aneurysm repair with a Zenith stent-graft for an infrarenal AAA in year 2000. At that time, a femorofemoral bypass was performed because the left external iliac and common femoral arteries were dissected during treatment. In 2013, follow-up computed tomography (CT) showed disconnection of the uncovered proximal stent, which led to a type Ia endoleak. An additional Zenith main body and Large Palmaz XL balloon-expandable stent were deployed; the endoleak disappeared. In 2016, the patient had abdominal pain, and emergency CT showed AAA rupture caused by migration of the first main body deployed in 2000 under the distal edge of the contralateral (left) leg of the additional main body from 2013, which led to a type IIIa endoleak between the 2 main bodies. A converter and iliac legs were deployed to successfully seal the type IIIa endoleak. The patient remains well 18 months after the second repair; CT scans document stable stent-grafts and no endoleak., Conclusion: Physicians should be aware of the potential risk for AAA rupture caused by late main body migration after treatment for suprarenal stent separation from a Zenith stent-graft.

Background: To confirm the feasibility and explore the clinical applicability of amplicon sequencing by next generation sequencing (NGS) of biopsy samples from patients with advanced solid tumors, we conducted a prospective study., Methods: Patients with unresectable, advanced, or recurrent solid tumors were included. Key eligibility criteria were as follows: 20 years or older, any planned systemic therapy, adequate lesion for biopsy, and written informed consent. Samples were fixed in 10% buffered formalin and embedded in paraffin. Cancer-derived DNA was extracted, and amplicon sequencing was performed using Ion AmpliseqTM Cancer Hotspot Panel version 1.0 or version 2.0 by central vendor. We evaluated the success rate of sequencing, and the proportion of the patients with actionable mutations. We organized an expert panel to share the results of targeted sequence, make annotations and reports, and discuss concomitant ethical/legal/social issues., Results: A total of 232 patients were included, and 208 were successfully analyzed (success rate of 89.7%). The biopsy procedures were safe, with only one case of Grade 3 vasovagal reaction. The proportion of actionable/druggable mutations was 38.9% (81/208), which was not significantly different between the cancer panel version 1.0 and version 2.0 (P = 0.476). Expert panel could discuss the findings and make sufficient reports., Conclusions: We confirmed the feasibility of NGS-based amplicon sequencing using biopsy samples, making the basis for nationwide genome screening for cancer patients using biopsy samples. Our results suggest that focused panel may be sufficient to detect major mutations.

Aim: To evaluate the relationship between the location of hepatocellular carcinoma (HCC) and the efficacy of transarterial chemoembolization (TACE)., Methods: We evaluated 115 patients (127 nodules), excluding recurrent nodules, treated with TACE between January 2011 and June 2014. TACE efficacy was evaluated according to mRECIST. The HCC location coefficient was calculated as the distance from the central portal portion to the HCC center (mm)/liver diameter (mm) on multiplanar reconstruction images rendered (MPR) to visualize bifurcation of the right and left branches of the portal vein and HCC center. The HCC location coefficient was compared between complete response (CR) and non-CR groups in Child-Pugh grade A and B patients., Results: The median location coefficient of HCC among all nodules, the right lobe, and the medial segment was significantly higher in the CR group than in the non-CR group in the Child-Pugh grade A patients (0.82 vs 0.62, P < 0.001; 0.71 vs 0.59, P < 0.01; 0.81 vs 0.49, P < 0.05, respectively). However, there was no significant difference in the median location coefficient of the HCC in the lateral segment between in the CR and in the non-CR groups (0.67 vs 0.65, P > 0.05). On the other hand, in the Child-Pugh grade B patients, the HCC median location coefficient in each lobe and segment was not significantly different between in the CR and in the non-CR groups., Conclusion: Improved TACE efficacy may be obtained for HCC in the peripheral zone of the right lobe and the medial segment in Child-Pugh grade A patients., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to declare.

Purpose: To evaluate the usefulness and safety of endovascular treatments for acute upper limb ischemia (AULI) by using multiple techniques, and to compare catheter-directed thrombolysis (CDT) and percutaneous aspiration thromboembolectomy (PAT) as initial procedures., Materials and Methods: The study included 18 patients (4 men and 14 women) with AULI, who underwent a total of 20 sessions of endovascular treatment using various endovascular techniques between January 2005 and April 2016. The patients were initially treated with CDT [n = 9, CDT-based group (C-G)], PAT [n = 6, PAT-based group (P-G)], or angioplasty (n = 3). In case of residual emboli, we performed additional endovascular techniques. We assessed technical success, clinical success, and complications. Additionally, we compared the urokinase dosage between the groups., Results: The mean patient age was 74.4 years. Technical and clinical success was obtained in all patients. Among the 18 patients, 1 underwent CDT only, 2 underwent PAT only, 1 underwent angioplasty only, and 14 underwent multiple techniques. Two patients from the C-G experienced major complications (cerebellar hemorrhage 1; pseudo-aneurysm in a branch of the ulnar artery 1). The mean urokinase dosage was lower in the P-G than in the C-G (40,000 vs. 246,667 IU; Mann-Whitney U test, P = 0.004)., Conclusion: Endovascular treatment is effective and safe for AULI. A combination of multiple endovascular techniques is important for successful treatment. PAT is suggested as an initial procedure among endovascular techniques, in terms of a lower dosage of urokinase and a lower complication rate., Level of Evidence: IV, Case-control studies.

Objectives: To investigate haemodynamic changes in hepatocellular carcinoma (HCC) and liver under hepatic artery occlusion., Methods: Thirty-eight HCC nodules in 25 patients were included. Computed tomography (CT) during hepatic arteriography (CTHA) with and without balloon occlusion of the hepatic artery was performed. CT attenuation and enhancement volume of HCC and liver with and without balloon occlusion were measured on CTHA. Influence of balloon position (segmental or subsegmental branch) was evaluated based on differences in HCC-to-liver attenuation ratio (H/L ratio) and enhancement volume of HCC and liver., Results: In the segmental group (n = 20), H/L ratio and enhancement volume of HCC and liver were significantly lower with balloon occlusion than without balloon occlusion. However, in the subsegmental group (n = 18), H/L ratio was significantly higher and liver enhancement volume was significantly lower with balloon occlusion; HCC enhancement volume was similar with and without balloon occlusion. Rate of change in H/L ratio and enhancement volume of HCC and liver were lower in the segmental group than in the subsegmental group. There were significantly more perfusion defects in HCC in the segmental group., Conclusions: Hepatic artery occlusion causes haemodynamic changes in HCC and liver, especially with segmental occlusion., Key Points: • Hepatic artery occlusion causes haemodynamic changes in hepatocellular carcinoma and liver. • Segmental occlusion decreased rate of change in hepatocellular carcinoma-to-liver attenuation ratio. • Subsegmental occlusion increased rate of change in hepatocellular carcinoma-to-liver attenuation ratio. • Hepatic artery occlusion decreased enhancement volume of hepatocellular carcinoma and liver. • Hepatic artery occlusion causes perfusion defects in hepatocellular carcinoma.

Background: Delayed perforation is a rare but severe complication of endoscopic submucosal dissection (ESD) for early gastric neoplasm (EGN). The aim of this study was to clarify clinical factors related to delayed perforation after ESD., Methods: A total of 1158 consecutive patients with 1199 EGNs underwent ESD at our hospital between January 2000 and December 2015. Univariate analysis was used to identify clinicopathological factors related to delayed perforation. Moreover, duration of cautery needed for hemostasis was measured by comparison between perforated and nonperforated points in patients with delayed perforation., Results: Delayed perforation occurred in 5 of 1158 consecutive patients with 1199 EGNs who underwent ESD (0.42%). All cases were diagnosed within 24 h after ESD and recovered with conservative management. On univariate analysis, location in the upper stomach was the factor most significantly associated with delayed perforation ( P < 0.01). Duration of cautery needed for hemostasis was significantly longer at perforated points (9 s) than at nonperforated points (3.5 s) in five patients., Conclusions: Location in the upper stomach was the risk factor most prominently associated with delayed perforation after ESD for EGNs. In addition, delayed perforation appears associated with excessive electrocautery for hemostasis.

We report the case of a man in his 70s who suffered from intestinal infarction caused by acute portal vein and mesenteric vein thrombosis (PVMVT). Combination therapy with percutaneous transcatheter thrombectomy and surgical bowel resection was successfully performed, and a satisfactory outcome was achieved. Intestinal infarction caused by PVMVT can be fatal and has a high mortality rate even if surgical resection is performed. The combination therapy of interventional radiology and surgery might be a safe and effective method for patients with this life-threatening condition.

We report a rare case of polypoid leiomyosarcoma of the esophagus that was treated by endoscopic submucosal dissection (ESD). A 63-year-old man with complaints of progressive dysphagia was referred to Hyogo Cancer Center for treatment of esophageal tumor. Esophagoscopy revealed a polypoid tumor 25 mm in diameter on the left side of the upper esophagus. Despite several biopsy specimens, the diagnosis could not be confirmed. Computed tomography showed a protruded, homogeneously enhancing mass in the upper esophagus, but no lymph node enlargement or metastasis. After 1.5 months, the esophagogram showed a filling defect 47 mm in diameter in the upper esophagus. Given this rapid tumor growth, en bloc resection was done by ESD for therapeutic diagnosis. After this treatment, the tumor seemed to grow larger, showing a short stalk and occupying the esophageal lumen. Histopathologically, the tumor comprised pleomorphic spindle cells with mitosis. Tumor invasion involved the lumina propria mucosae and contact with the muscularis mucosae, but not involving the submucosa. Immunohistochemical examination showed positive staining for smooth muscle actin and HHF35, but negative for desmin, caldesmon, CD34, c-kit, DOG1, ALK, S-100 protein and cytokeratin. These histopathological findings were compatible with a diagnosis of esophageal leiomyosarcoma derived from the muscularis mucosae., (© 2015 The Authors. Digestive Endoscopy © 2015 Japan Gastroenterological Endoscopy Society.)

Esophagectomy with extended lymphadenectomy and gastric conduit reconstruction is a radical procedure for the treatment of esophageal cancer that is associated with a high morbidity rate. Gastric conduit necrosis is a fatal complication that occurs in 2% of patients. Conventionally, two-stage salvage surgery consisting of removal of the necrotic gastric conduit followed by reconstruction has been performed; however, this procedure has a high morbidity rate. We describe a 61-year-old man who underwent minimally invasive esophagectomy complicated by slowly progressive gastric conduit necrosis associated with complete neck drainage and a stable overall condition. There was a 2 cm gap in the anastomosis. Because there was no evidence of residual gastric conduit necrosis, a removable, covered self-expanding metal stent (SEMS) was inserted to bridge the anastomosis. The stent was fixed to the patient's ear with silk thread through the lasso on its proximal end to prevent migration. Eight weeks after insertion, the stent was removed easily without any associated complications. The anastomotic defect was completely bridged with granulation tissue, showing progressive epithelialization without leakage or stenosis. The patient was discharged home in good general health. This is the first report of the successful conservative management of esophago-gastric conduit anastomosis disruption with SEMS placement.

Background: Adjunctive thrombus aspiration (TA) during primary percutaneous coronary intervention (PCI) was reported to promote better coronary and myocardial reperfusion. However, long-term mortality benefit of TA remains controversial. The objective of this study is to investigate the clinical impact of TA on long-term clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI., Methods and Results: The CREDO-Kyoto AMI Registry is a large-scale cohort study of acute myocardial infarction patients undergoing coronary revascularization in 2005-2007 at 26 hospitals in Japan. Among 5429 patients enrolled in the registry, the current study population consisted of 3536 patients who arrived at the hospital within 12 hours after the symptom onset and underwent primary PCI. Clinical outcomes were compared between the 2 patient groups with or without TA. During primary PCI procedures, 2239 out of 3536 (63%) patients underwent TA (TA group). The cumulative 5-year incidence of all-cause death was significantly lower in the TA group than in the non-TA group (18.5% versus 23.9%, log-rank P<0.001). After adjusting for confounders, however, the risk for all-cause death in the TA group was not significantly lower than that in the non-TA group (hazard ratio: 0.90, 95% CI: 0.76 to 1.06, P=0.21). The adjusted risks for cardiac death, myocardial infarction, stroke, and target-lesion revascularization were also not significantly different between the 2 groups., Conclusions: Adjunctive TA during primary PCI was not associated with better 5-year mortality in STEMI patients., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objective: The reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 1997 to 2011 were reviewed to assess serious adverse events induced by the administration of antipsychotics to children., Methods: Following pre-processing of FAERS data by elimination of duplicated records as well as adjustments to standardize drug names, reports involving haloperidol, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, and aripiprazole were analyzed in children (age 0-12). Signals in the data that signified a drug-associated adverse event were detected via quantitative data mining algorithms. The algorithms applied to this study include the empirical Bayes geometric mean, the reporting odds ratio, the proportional reporting ratio, and the information component of a Bayesian confidence propagation neural network. Neuroleptic malignant syndrome (NMS), QT prolongation, leukopenia, and suicide attempt were focused on as serious adverse events., Results: In regard to NMS, the signal scores for haloperidol and aripiprazole were greater than for other antipsychotics. Significant signals of the QT prolongation adverse event were detected only for ziprasidone and risperidone. With respect to leukopenia, the association with clozapine was noteworthy. In the case of suicide attempt, signals for haloperidol, olanzapine, quetiapine, risperidone, and aripiprazole were detected., Conclusions: It was suggested that there is a level of diversity in the strength of the association between various first- and second-generation antipsychotics with associated serious adverse events, which possibly lead to fatal outcomes. We recommend that research be continued in order to gather a large variety and quantity of related information, and that both available and newly reported data be placed in the context of multiple medical viewpoints in order to lead to improved levels of care.

Background: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption., Aim: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver., Methods: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs., Results: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa., Conclusions: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.

A 61-year-old female was admitted to our hospital for esophageal cancer treatment. Esophagectomy with 2-field lymphadenectomy was performed. Postoperative findings revealed the lesion was a poorly differentiated squamous cell carcinoma invading into the diaphragm and there were no carcinoma cells on the surgical margins. Eight months after surgery, a recurrence was suspected by the presence of tumors at the pericardia, right axillary lymph node and around the descending aorta. The patient was re-admitted for chemotherapy and administrated fluorouracil and cisplatin 4 days after admission. After 7 days, she complained of dysphagia. Esophagogastroduodenoscopy showed no abnormal lesion that could cause the symptom. Computed tomography revealed massive progression of the pericardial tumor, bilateral pleural effusion and congested liver. Echocardiography showed the diffuse pericardial tumor caused restriction of ventricular dilation and hemodynamics of constrictive pericarditis. The patient died 29 days after re-admission. Autopsy revealed squamous cell carcinoma involving the mediatinum and pericardium. The pericardium was completely full of cancer tissue but no fluid. We concluded that the direct cause of death was neoplastic constrictive pericarditis.

This study investigated the anatomical relationship between the common carotid artery and internal jugular vein during head rotation for the effective performance of percutaneous transjugular procedures. The subjects included 30 volunteers who had never undergone internal jugular vein cannulation. In the supine position, two-dimensional ultrasonographic images of the right internal jugular vein and common carotid artery were obtained, 2 and 4 cm above the clavicle, along the lateral border of the sternal head of the sternocleidomastoid muscle. Ultrasonographic images were examined for head rotation at 0°, 15°, 30°, 45°, 60°, and 75° from the midline to the left. The percentage of overlap of the common carotid artery by the internal jugular vein and the flattening of the internal jugular vein at each head rotation position were measured and evaluated. The overlap of the common carotid artery by the internal jugular vein significantly increased at ≥45° of head rotation 2 cm above the clavicle (P < 0.01) and at ≥30° of head rotation 4 cm above the clavicle (P < 0.01), compared with that observed in the neutral position. The flattening of the internal jugular vein significantly decreased at ≥45° of head rotation 2 cm above the clavicle (P < 0.01) and at ≥30° of head rotation 4 cm above the clavicle (P < 0.01). Head rotation should be kept to <45° at 2 cm above the clavicle and <30° at 4 cm above the clavicle to decrease the risk of accidental puncture of the common carotid artery during internal jugular vein puncture. Moreover, flattening of the internal jugular vein gradually decreases during head rotation to the side.

Objective: Definitive chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) is one of the standard therapies for esophageal squamous cell carcinoma (ESCC); however, inter-individual variations in clinical outcomes have yet to be investigated. In the present study, single nucleotide polymorphisms (SNPs) in SLC23A2 gene were retrospectively evaluated in 49 Japanese patients with ESCC who were treated with a definitive 5-FU/CDDP-based CRT, and the predictive values for the clinical response, severe acute toxicities, and long-term survival were assessed., Methods: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course being repeated after a 2-week interval. The SLC23A2 SNPs rs2681116, rs13037458, rs1715364, rs4987219, and rs1110277 were evaluated., Results: The rs2681116 and rs13037458 had a tendency to predict the clinical response (p=0.144 and 0.085, respectively) and long-term survival (p=0.142 and 0.056, respectively). The rs4987219 and rs1110277 correlated with severe acute leukopenia (p=0.025) and stomatitis (p=0.019), respectively., Conclusions: Further investigations with a larger number of patients or an in vitro study are needed to confirm the predictive values of genetic polymorphisms in SLC23A2.

Squamous cell carcinoma (Sqc) of the pancreas is considered to be extremely rare. We report the case of a 79-year-old male with Sqc of the pancreas complicated by massive gastric ulcer fistula and multiple lymph node metastases. After completing two courses of S-1 chemotherapy, the gastric ulcer fistula and lymph node metastases improved. Sqc of the pancreas is usually associated with a poor prognosis. Various therapeutic regimens have been used for this type of cancer, but none has been proven effective. To the best of our knowledge, this report is the first on the effective response of pancreatic Sqc treated by S-1 chemotherapy.

CYP3A and P-glycoprotein (P-gp) play important roles in drug metabolism and excretion; however, their functions in pathological conditions remain unclear. Hepatobiliary abnormalities have been described in patients with ulcerative colitis, which may affect drug metabolism and excretion in the liver and small intestine. We examined the functions of CYP3A and P-gp in the liver and small intestine of mice with dextran sodium sulfate (DSS)-induced colitis. Up to day 7, inflammatory markers were significantly increased in the livers of DSS-treated mice, accompanied by decreased CYP3A. Additionally hepatobiliary transporters and Pregnane X receptor, which regulates the transcriptional activation of CYP3A, were reduced. Both CYP3A and P-gp were significantly decreased in the upper small intestine of DSS-treated mice on day 7. This was associated with the increased expression of inducible nitric oxide synthase, but not changes in nuclear receptor expression. On day 7 of DSS treatment, the concentrations of cyclosporine A (CsA), a substrate of both CYP3A and P-gp, were significantly higher than controls. These results indicated the existence of a second inflammatory response in the liver and upper small intestine of mice with DSS-induced colitis, and bioavailability of CsA was increased by the dysfunction of CYP3A and P-gp in these organs.

Background: Genotypes of tumor necrosis factor alpha (TNF-α) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-α and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long-term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT)., Methods: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course being repeated after a 2-week interval. The TNF-α -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated., Results: The TNF-α -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher's exact test), but had no effect on long-term survival (CC(-857) vs. CT(-857) + TT(-857), P = 0.072, Fisher's exact test, P = 0.070, Log-rank test)., Conclusions: The TNF-α -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT.