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Abstract Aims Although platinum-based combination chemotherapies are commonly used for unfavourable subsets of cancer of unknown primary (CUP), the prognosis remains poor. Several studies have suggested that gene expression profiling or immunohistochemistry was useful for the prediction of primary sites in CUP, and site-specific therapy based on predicted primary sites might improve overall outcomes. In Japan, to identify primary sites, immunohistochemical tests were commonly used for CUP in clinical practice. However, it is unclear whether site-specific therapy based on predicted primary sites by pathological examination contributes survival benefit for unfavourable CUP subsets. Patients and methods In this study, 122 patients with unfavourable subsets of CUP were retrospectively reviewed. Ninety patients assigned to cohort A after July 2012 had received chemotherapy according to predicted primary sites; 32 patients assigned to cohort B before June 2012 had received platinum-based empiric chemotherapy. Results In cohort A, 56 patients (62.2%) with predicted primary sites by pathological examination received site-specific therapy; 34 patients (37.8%) with unpredictable primary sites received platinum-based empiric chemotherapy, the same as cohort B. The median overall survival was 20.3 months in patients with predictable primary sites in cohort A and 10.7 months in those of cohort B, with a significant difference between these cohorts (P = 0.03, adjusted hazard ratio = 0.57, 95% confidence interval 0.34–0.94). Conclusion Site-specific therapy based on predicted primary sites by pathological examination could improve prognosis in patients with an unfavourable subset of CUP. Highlights • Limited data exist concerning site-specific therapy for carcinoma of unknown primary. • We evaluated prediction rate of primary sites by immunohistochemistry panel. • Site-specific therapy showed survival benefit compared with platinum empirical therapy in carcinoma of unknown primary. [ABSTRACT FROM AUTHOR] more...

Background: Microsatellite instability (MSI)-high tumors represent a distinct, small-fraction subtype in esophagogastric junction cancer or gastric cancer (GC), yet their clinical significance remains poorly understood. This study aimed to investigate the prevalence and clinicopathological features of chemotherapy-naïve metastatic or recurrent MSI-high GC as a prescreening study for a phase II trial of nivolumab plus ipilimumab., Methods: Key inclusion criteria included metastatic or recurrent adenocarcinoma of GC, ECOG performance status of 0 or 1, and no prior systemic therapy for metastatic or recurrent disease. MSI status was tested using multiplex PCR fragment analysis (MSI Testing Kit, FALCO). The primary endpoint was the prevalence of MSI-high GC., Results: Between October 2020 and October 2022, 930 eligible patients from 75 centers in Japan were analyzed. The prevalence of MSI-high GC was 5.6% (95% CI 4.2-7.3). MSI-high GC was more frequently observed in females than males (9.6% vs 3.8%, p < 0.001), patients aged ≥ 70 years compared to those < 70 years (8.0% vs 2.8%, p < 0.001), in the lower stomach than other locations (10.5% vs 3.2%, p < 0.001), HER2-negative tumors than HER2-positive tumors (6.5% vs 1.8%, p = 0.02), and in patients without liver metastasis than those with liver metastasis (6.9% vs 2.2%, p = 0.004)., Conclusions: The prevalence of MSI-high tumors among chemotherapy-naïve patients with unresectable GC was 5.6%. These tumors were associated with female sex, older age, lower stomach, HER2-negative, and absence of liver metastasis. These findings would help assuming MSI-high tumors and may have significant implications for clinical practice and studies targeting this GC subtype., Competing Interests: Declarations. Conflict of interests: Azusa Komori: None to disclose. Shuichi Hironaka: Honoraria for lectures: Bristol Myers Squibb, Ono. Shigenori Kadowaki: Grants or contracts from any entity: Ono Pharmaceutical, Taiho Pharmaceutical, MSD, Nobel Pharmaceutical, Janssen Pharmaceutical, Bayer, Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Abbvie, AstraZeneca; Honoraria for lectures: Ono Pharmaceutical, Taiho Pharmaceutical, MSD, Daiichi Sankyo, Merck KgaA, Bristol-Myers Squibb, Eli Lilly, Chugai Pharmaceutical, Bayer, Eisai, Novartis. Seiichiro Mitani: Honoraria for lectures: Taiho Pharmaceutical Co. Ltd, ONO Pharmaceutical Co. Ltd, MSD; Payment for expert testimony: Chugai Pharmaceutical Co. Ltd. Mitsuhiro Furuta: None to disclose. Takeshi Kawakami: Honoraria for lectures: Bristol-Myers Squibb Co. Ltd, Astellas Pharma, Eli Lilly Japan K.K, Yakult Honsha, Ono Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd. Akitaka Makiyama: Honoraria for lectures: Eli Lilly Japan, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical. Naoki Takegawa: None to disclose. Keiji Sugiyama: None to disclose. Hidekazu Hirano: Grants to the institution: PPD, Daiichi-Sankyo, Nippon Boehringer Ingelheim, ALX Oncology, BeiGene, Novartis, Amgen, Bristol-Myers Squibb, Taiho Pharmaceutical; Honoraria for lectures: FUJIFILM Toyama Chemical, Taiho Pharmaceutical, TEIJIN PHARMA, Novartis, Chugai Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical. Takayuki Ando: Honoraria for lectures: Bristol-Myers Squibb Co. Ltd, Eli Lilly Japan K.K, Daiichi Sankyo Co. Ltd, MSD K.K, Taiho Pharmaceutical Co. Ltd, Astellas Pharma Inc. Tomohiro Matsushima: None to disclose. Akihiko Chida: None to disclose. Tomomi Kashiwada: Honoraria for lectures: Bristol-Myers Squibb Co. Ltd, Takeda Pharmaceutical Co. Ltd, Eli Lilly Japan K.K, Taiho Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Astellas Pharma Inc. Masato Komoda: Honoraria for lectures: Ono Pharmaceutical Co. Ltd, MSD K.K, Bristol-Myers Squibb Co. Ltd, Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan K.K, Taiho Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Astellas Pharma Inc. Toshihiko Matsumoto: Honoraria for lectures: Sanofi Co, Ltd, Ono Pharmaceutical Co, Ltd, Bayer Co, Ltd, Bristol-Myers Squibb Co, Ltd, Chugai Pharmaceutical Co, Ltd, Daiichi Sankyo Co, Ltd, Merck Bio Pharma Co, Ltd, Eli Lilly Japan Co, Ltd, MSD Co, Ltd, Taiho Pharmaceutical Co, Ltd, Takeda Co, Ltd. Hisanobu Oda: Honoraria for lectures: Bristol Myers Squibb, Astellas Pharma. Hiroshi Yabusaki: None to disclose. Hisato Kawakami: Grants or contracts from any entity: Eisai Co. Ltd, Bristol-Myers Squibb Co. Ltd, Kobayashi Pharmaceutical. Co., Ltd; Royalties: MEDICAL & BIOLOGICAL LABORATORIES CO., LTD; Consulting fees: Daiichi-Sankyo Co. Ltd, Astellas Pharma Inc, Abbvie GK; Honoraria for lectures: Bristol-Myers Squibb Co. Ltd, Bayer Yakuhin Ltd, Eli Lilly Japan K.K, MSD K.K, Ono Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Merck Biopharma Co., Ltd, Takeda Pharmaceutical Co. Ltd, Yakult Pharmaceutical Industry, Teijin Pharma Ltd, Taiho Pharmaceutical Co. Ltd, Otsuka Pharmaceutical Co., Ltd, Nippon Kayaku Co. Ltd, GlaxoSmithKline K.K, Amgen, Novartis International AG. Kentaro Yamazaki: Honoraria for lectures: Chugai, Takeda, Yakult, Taiho, Daiichi Sankyo, Merk Biopharm, Lily, MSD, Bristol. Narikazu Boku: Honoraria for lectures: Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Eli Lilly, Taiho Pharmaceutical. Ichinosuke Hyodo: Participation on a Data Safety Monitoring Board or Advisory Board: Taiho Pharmaceutical Co.Ltd, Chugai Pharmaceutical Co.Ltd, Ono Pharmaceutical Co.Ltd, Eisai Pharmaceutical Co.Ltd, Daiichi Sankyo Pharmaceutical Co.Ltd, Asahi-Kasei Pharmaceutical Co.Ltd. Kenichi Yoshimura: None to disclose. Kei Muro: Research funding to the institution: Amgen, ONO PHARMACEUTICAL, Astellas, Sanofi, Taiho, PRA Health Sciences, PAREXEL International, Novartis, Chugai, MSD; Consulting fees: Amgen, AstraZeneca, ONO PHARMACEUTICAL, Astellas, Chugai; Honoraria for lectures: ONO PHARMACEUTICAL, Taiho, Bristol-Myers Squibb, Eli Lilly, MSD, Takeda, Daiichi Sankyo; Advisory Board: Astellas, Amgen, AstraZeneca, Takeda. Ethical approval: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients for inclusion in the study., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.) more...

Background: Telemedicine, or online medical care, has gained considerable attention worldwide. However, it has not been widely adopted in Japan, and the detailed status of received and provided online medical care and the reasons for its lack of popularity remain unknown., Objective: This study aims to investigate the current status of online medical care in Japan and the factors limiting its adoption from the perspective of both patients receiving and medical professionals providing online medical care., Methods: In total, 2 nationwide questionnaire surveys were conducted. The first survey, targeting both patients and healthy individuals, screened approximately 40,000 participants among 13 million people. The participants were selected to match the age distribution of the Japanese population based on government data, and their online medical care experience and medical visit status were recorded. To further investigate online medical care use and satisfaction, a web-based survey was conducted with 15% (6000/40,000) of the screened participants. The second survey, targeting medical professionals, was administered to a physician, a nurse, and a member of the administrative staff in each of 4900 randomly selected medical facilities to inquire about their online medical care practices and impressions. In addition, both surveys investigated the factors limiting online medical care expansion in Japan., Results: The response rates among patients and healthy individuals targeted for the screening and main surveys were 92.5% (36,998/40,000) and ˃80% (1312/1478, 88.77%; 1281/1522, 84.17%; 404/478, 84.5%; and 2226/2522, 88.26% in 4 survey groups), respectively. The survey of medical professionals yielded 1552 responses (n=618, 39.82% physicians; n=428, 27.58% nurses; n=506, 32.6% administrative staff). Although the facility-level response rate was low (794/4900, 16.2%), some facility categories had relatively high response rates. Only 5.29% (1956/36,998) of the patients and healthy individuals had online medical care experience. When there were more hospitals nearby and they felt it was more work to see a physician in person, they were more likely to use online medical care (more nearby hospitals: adjusted odds ratio [aOR] 1.33, 95% CI 1.18-1.50; more work: aOR 1.48, 95% CI 1.35-1.63 per survey response point in the patient group). Similarly, these factors were substantially associated with satisfaction (more nearby hospitals: aOR 1.40, 95% CI 1.14-1.73; more work: aOR 1.50, 95% CI 1.27-1.76 per survey response point in the patient group). In both surveys, the most frequently selected factor preventing the widespread use of online medical care was patients' need to switch to face-to-face medical care for mandatory tests and procedures. Inadequate awareness of and education on online medical care were also frequently selected., Conclusions: Our nationwide surveys provided insights into the current status of online medical care in Japan and simultaneously identified several problems and issues related to it, which will be useful in promoting its wider adoption., (©Yuka Sugawara, Yosuke Hirakawa, Masao Iwagami, Haruo Kuroki, Shuhei Mitani, Ataru Inagaki, Hiroki Ohashi, Mitsuru Kubota, Soichi Koike, Rie Wakimizu, Masaomi Nangaku. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 01.11.2024.) more...

This study delves into the impact of Information Technology (IT) on nursing practice in Japan, focusing on patient safety within the 2021-2022 Japanese Medical Accident Report Data. The research aims to understand how IT factors contribute to nursing-related medical incidents in a healthcare landscape rapidly integrating IT. The study identifies IT-related incidents through a retrospective analysis of medical incident reports, primarily in nursing, by analyzing categorized data and free-text descriptions for IT-related keywords. The findings indicate significant IT-related issues, with 'Other EHR Related' problems (36%) and 'EHR Reporting' errors (25%) being the most prevalent. These incidents often involve challenges in patient identification and medication management. The study suggests improvements like enhanced verification processes and automated systems to mitigate these risks. Conclusively, it underscores the dual nature of IT in nursing: while it holds the potential to enhance patient care, it also introduces challenges that necessitate specialized informatics expertise to ensure its beneficial integration into nursing practices. more...

Molecular testing to determine optimal therapies is essential for managing patients with colorectal cancer (CRC). In October 2022, the Japanese Society of Medical Oncology published the 5th edition of the Molecular Testing Guideline for Colorectal Cancer Treatment. In this guideline, in patients with unresectable CRC, RAS/BRAF V600E mutational and mismatch repair tests are strongly recommended prior to first-line chemotherapy to select optimal first- and second-line therapies. In addition, HER2 testing is strongly recommended because the pertuzumab plus trastuzumab combination is insured after fluoropyrimidine, oxaliplatin, and irinotecan in Japan. Circulating tumor DNA (ctDNA)-based RAS testing is also strongly recommended to assess the indications for the readministration of anti-EGFR antibodies. Both tissue- and ctDNA-based comprehensive genomic profiling tests are strongly recommended to assess the indications for targeted molecular drugs, although they are currently insured in patients with disease progression after receiving standard chemotherapy (or in whom disease progression is expected in the near future). Mutational and mismatch repair testing is strongly recommended for patients with resectable CRC, and RAS/BRAF V600E mutation testing is recommended to estimate the risk of recurrence. Mutational and mismatch repair and BRAF testing are also strongly recommended for screening for Lynch syndrome. Circulating tumor DNA-based minimal residual disease (MRD) testing is strongly recommended for estimating the risk of recurrence based on clinical evidence, although MRD testing was not approved in Japan at the time of the publication of this guideline., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.) more...

Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. In preclinical models, MMP9 inhibitors have been shown to enhance the cytotoxic effects of chemotherapeutic agents and to suppress distant metastasis. In this phase Ib, multicenter study, the safety and efficacy of ADX combined with S-1 plus cisplatin (SP) or S-1 plus oxaliplatin (SOX) as a first-line treatment were evaluated in Japanese patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. ADX was administrated at a dose of 800 mg every 2 weeks for the SP cohort and 1200 mg every three weeks for the SOX cohort. As of December 2019, 16 patients were enrolled (six patients in the SP cohort and 10 patients in the SOX cohort). Peripheral sensory neuropathy (69%), anorexia (63%), nausea (56%), and decreased neutrophil counts (44%) were the most common adverse events (AEs). The grade 3 or higher AEs attributed to ADX were stomatitis and abnormal hepatic function (each one patient) in the SP cohort and decreased neutrophil counts (two patients) in the SOX cohort. The objective response rate in 11 patients with measurable target lesions was 73% (8/11), based on the investigator's evaluation. Median progression-free survival was11.9 months (90% confidence interval, 5.6-16.6), and median overall survival was not reached. In conclusion, ADX combined with S-1 plus platinum demonstrated a manageable safety profile and promising clinical activity in the first-line treatment of patients with advanced gastric or GEJ adenocarcinoma.Clinical Trial Registration information: ClinicalTrials.gov Identifier: NCT02862535 (11/08/2016) and protocol ID: GS-US-296-1884., (© 2022. The Author(s).) more...

Background: Matrix metalloproteinase 9 (MMP9) is implicated in protumorigenic processes. Targeting either stromal or epithelial MMP9 reduces the incidence of metastasis. Andecaliximab is a monoclonal antibody that targets MMP9 with high affinity and selectivity. However, no study has examined whether the inhibition of T-cell programmed death 1 (PD-1) in the presence of andecaliximab increases activated lymphocyte infiltration into the tumor, thereby increasing antitumor activity more than that in anti-PD-1 monotherapy. In this study, we assessed the safety, pharmacokinetics (PK), exploratory biomarkers, and preliminary efficacy of andecaliximab as monotherapy and in combination with nivolumab in Japanese patients with advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma., Methods: This phase 1b study comprised four cohorts enrolling Japanese patients with gastric or GEJ adenocarcinoma. This paper concerns cohorts 1 and 4; cohorts 2 and 3 will be reported subsequently. Cohort 1 enrolled patients with human epidermal growth factor receptor 2 (HER2)-negative tumors (n=8) who received andecaliximab monotherapy (800 mg by intravenous infusion every 2 weeks (Q2W)), and cohort 4 enrolled patients irrespective of their HER2 status (n=10) who received 800 mg of andecaliximab in combination with nivolumab Q2W. Safety, dose-limiting toxicities (DLTs), PK, pharmacodynamics, and biomarkers were assessed in both cohorts., Results: PK of andecaliximab in Japanese patients with gastric or GEJ adenocarcinoma was similar to that reported in non-Japanese patients with advanced solid tumors. Andecaliximab monotherapy and in combination with nivolumab demonstrated no DLTs in cohort 1 and 4, respectively. Toxicities were manageable and well tolerated in both cohorts. The median progression-free survival was 1.4 months (90% CI, 0.5 to 5.4) and 4.6 months (90% CI, 0.9 to not reached) in cohorts 1 and 4, respectively. The objective response rate was 50% (90% CI, 22% to 78%) in cohort 4, and in some patients, the combination therapy was effective regardless of the biomarker status., Conclusions: The andecaliximab-nivolumab combination demonstrated a manageable safety profile and promising clinical activity in patients with advanced gastric adenocarcinoma.NCT02862535., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.) more...

Aim: We evaluated the safety and potential clinical impact of shortened ramucirumab infusion in Japanese patients from clinical studies., Methods: Multivariate logistic regression analysis was used to assess any association between infusion rate and increased risk of an immediate infusion-related reaction(IRR). Population pharmacokinetic modeling was used to simulate concentration-time profiles and exposure parameters following a 30- or 60-minute infusion with ramucirumab., Results: From 8 pooled ramucirumab clinical studies, 55 of 559(9.8%)Japanese patients experienced at least one immediate IRR(any grade). When grouped according to infusion rate quartile, the incidence of immediate any-grade IRR was similar across quartiles. Infusion rate was not significantly associated with an increased risk of an immediate IRR; odds ratio per 1 mg/min increase was 0.912, 95% confidence interval 0.724 to 1.149, p=0.436. Patients aged ≥65 years may have a reduced risk of an immediate IRR compared with those aged <65 years, and premedication use was also associated with a reduced risk. Ramucirumab pharmacokinetic profiles were comparable following a 30- or 60-minute infusion., Conclusions: A shortened infusion duration of ramucirumab is unlikely to affect the efficacy or safety profile in Japanese patients and may be clinically beneficial for patients and health care providers., Clinical Trial Registration: RAINBOW-NCT01170663, RAISE- NCT01183780, REACH-NCT01140347, REACH-2-NCT02435433, RAINFALL-NCT02314117, RANGE-NCT02426125, RELAY-NCT02411448, I4T-MC-JVCG-NCT01703091. more...

Background: The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab., Methods: The subjects of this study were mCRC patients who experienced disease progression < 100 days from commencement of first-line chemotherapy containing BEV initiated between Apr 2007 and Dec 2016. Second-line chemotherapy regimens were classified into two groups with and without BEV/other anti-angiogenic agents (BBP and non-BBP) and efficacy and safety were compared using univariate and multivariate analysis., Results: Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0-1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46-1.34], p = 0.373, adjusted HR: 0.87 [0.41-1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38-1.12], p = 0.125, adjusted HR 0.53 [0.27-1.07], p = 0.078)., Conclusion: In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents., (© 2021. The Author(s).) more...

Purpose: We previously reported on the pilot study assessing the feasibility of using the Japanese translation of the Comprehensive Score for Financial Toxicity (COST) tool to measure financial toxicity (FT) among Japanese patients with cancer. In this study, we report the results of the prospective survey assessing FT in Japanese patients with cancer using the same tool., Patients and Methods: Eligible patients were receiving chemotherapy for a solid tumor for at least 2 months. In addition to the COST survey, socioeconomic characteristics were collected by using a questionnaire and medical records., Results: Of the 191 patients approached, 156 (82%) responded to the questionnaire. Primary tumor sites were colorectal (n = 77; 49%), gastric (n = 39; 25%), esophageal (n = 16; 10%), thyroid (n = 9; 6%), head and neck (n = 4; 3%), and other (n = 11; 7%). Median COST score was 21 (range, 0 to 41; mean ± standard deviation, 12.1 ± 8.45), with lower COST scores indicating more severe FT. On multivariable analyses using linear regression, older age (β, 0.15 per year; 95% CI, 0.02 to 0.28; P = .02) and higher household savings (β, 8.24 per ¥15 million; 95% CI, 4.06 to 12.42; P < .001) were positively associated with COST score; nonregular employment (β, -5.37; 95% CI, -10.16 to -0.57; P = .03), retirement because of cancer (β, -5.42; 95% CI, -8.62 to -1.37; P = .009), and use of strategies to cope with the cost of cancer care (β, -5.09; 95% CI, -7.87 to -2.30; P < .001) were negatively associated with COST score., Conclusion: Using the Japanese version of the COST tool, we identified various factors associated with FT in Japanese patients with cancer. These findings will have important implications for cancer policy planning in Japan. more...

Objective: Anti-epithelial growth factor receptor (EGFR) antibodies cetuximab (Cmab) and panitumumab (Pmab) have shown survival benefit for metastatic colorectal cancer (mCRC) patients. This study aimed to compare Pmab and Cmab according to the interval between bevacizumab discontinuation and anti-EGFR antibody initiation (bevacizumab-free interval; BFI)., Methods: We retrospectively evaluated mCRC patients who received Cmab or Pmab in combination with irinotecan at two institutions. Inclusion criteria were histologically confirmed mCRC, with KRAS exon 2 wild-type tumor, refractory or intolerant to fluoropyrimidines, oxali platin, and irinotecan., Results: One-hundred-seventy-eight patients fulfilled the eligibility criteria. Among them, there was no significant difference in overall survival (OS) and progression-free survival (PFS) between the Pmab (n = 44) and Cmab groups (n = 134). Of 132 patients with BFI < 6 months, the median OS was 13.3 and 11.5 months in the Pmab (n = 39) and Cmab (n = 93) groups, respectively (p = 0.043). The median PFS was 5.8 and 4.9 months in the Pmab and Cmab groups, respectively (p = 0.055). Multivariate analysis for OS confirmed the superiority of Pmab., Conclusion: Pmab showed more favorable outcomes in patients treated with bevacizumab within the last 6 months. The interval between prior bevacizumab and subsequent anti-EGFR therapy may be useful for determining the optimal anti-EGFR therapy., (© 2018 S. Karger AG, Basel.) more...

GM2 gangliosidosis variant 0 (Sandhoff disease, SD) is a fatal, progressive neurodegenerative lysosomal storage disease caused by mutations of the HEXB gene. In canine SD, a pathogenic mutation (c.283delG) of the canine HEXB gene has been identified in toy poodles. In the present study, a TaqMan probe-based real-time PCR genotyping assay was developed and evaluated for rapid and large-scale genotyping and screening for this mutation. Furthermore, a genotyping survey was carried out in a population of toy poodles in Japan to determine the current mutant allele frequency. The real-time PCR assay clearly showed all genotypes of canine SD. The assay was suitable for large-scale survey as well as diagnosis, because of its high throughput and rapidity. The genotyping survey demonstrated a carrier frequency of 0.2%, suggesting that the current mutant allele frequency is low in Japan. However, there may be population stratification in different places, because of the founder effect by some carriers. Therefore, this new assay will be useful for the prevention and control of SD in toy poodles. more...

Introduction: The March 11, 2011 disaster was unparalleled in the disaster history of Japan. There is still enormous effort required in order for Japan to recover from the damage, not only financially, but psychosocially. This paper is a review of the studies that have been undertaken since this disaster, from after the March 11th disaster in 2011 to the end of 2012, and will provide an overview of the disaster-health research literature published during this period., Methods: The Japanese database Ichushi Ver. 5 was used to review the literature. This database is the most frequently used database in Japanese health-sciences research. The keywords used in the search were "Higashi Nihon Dai-shinsai" (The Great East Japan Earthquake)., Results: A total of 5,889 articles were found. Within this selection, 163 articles were categorized as original research (gencho ronbun). The articles were then sorted and the top four key categories were as follows: medicine (n = 98), mental health (n = 18), nursing (n = 13), and disaster management (n = 10). Additional categories were: nutrition (n = 4), public health (n = 3), radiology, preparedness, and pharmacology (n = 2 for each category). Nine articles appeared with only one category label and were grouped as "others.", Conclusion: This review provides the current status of disaster-health research following the Great East Japan Earthquake. The research focus over the selected period was greatly directed towards medical considerations, especially vascular conditions and renal dialysis. Considering the compounding factors of the cold temperatures at the time of the disaster, the geography, the extensive dislocation of the population, and the demographics of an aging community, it is noteworthy that the immediate and acute impact of the March 11th disaster was substantial compared with other events and their studies on the impact of disaster on chronic and long-term illness. The complexity of damage caused by the earthquake event and the associated nuclear power plant event, which possibly affected people more psychologically than physically, might also need to be investigated with respect to long term objectives for improving disaster preparedness and management. more...

Background: It has already been more than 50 years since the Pavlik harness was introduced in Japan, and today the Pavlik harness is widely recognized as the standard initial treatment modality for developmental dysplasia of the hip. We performed a multicenter nationwide questionnaire study concerning the results of Pavlik harness treatment twice in 1994 and 2008., Methods: In 1994 and in 2008, we sent questionnaires to 12 institutes in Japan specializing mainly in pediatric orthopedics. We compare the results of these two studies and discuss differences in reduction rates, incidence of avascular necrosis in the femoral epiphysis and the percentage of joints with acceptable morphology (Severin grade I + II/total) at skeletal maturity. We statistically assessed these results to see whether there were changes in the treatment outcomes over this 14-year period., Results: Reduction of the dislocated hips was obtained by the Pavlik harness in 80.2% (1990/2481 hips; 1994) and 81.9% (1248/1523 hips; 2008). The incidences of avascular necrosis of the proximal femoral epiphysis in the dysplastic hips were 14.3% (119/835 hips; 1994) and 11.5% (76/663 hips; 2008). The type of avascular necrosis in hips from the 2008 study was determined according to the classification of Kalamchi and MacEwen: 24/69 hips (34.8%) were classified as group I; 20/69 hips (29.0%) as group II; 11/69 hips (15.9%) as group Ill; 14/69 hips (20.3%) as group IV. The percentages of hips with acceptable outcomes at skeletal maturity discerned from Severin X-ray changes (grade I + II/total) were 72.3% (604/835 hips; 1994) and 77.7% (488/628 hips; 2008)., Conclusion: Reduction rates and the incidence of avascular necrosis in 2008 were statistically similar to the results in 1994. The rate of acceptable outcome (Severin grade I + II/total) in 2008 was statistically higher than that of 1994. more...

Neuronal ceroid lipofuscinosis (NCL) is a neurodegenerative disease caused by a number of different genes. A mutational analysis of the feline CLN3 gene was performed in a cat with NCL that had vacuolated lymphocytes, which is a feature of human NCL caused by defects of the CLN3 gene. To determine the candidate gene(s) responsible for this case, NCL-specific ultrastructures of storage materials were analysed. A sequence analysis indicated that the CLN3 gene was not likely to be responsible for this case of feline NCL because no deleterious mutation was detected. An ultrastructural analysis did not reveal any candidate gene because of inconsistency with any pattern found in human NCL. These findings suggest that the diagnostic criteria for human NCL are not directly applicable to feline NCL., (Copyright © 2012 Elsevier Ltd. All rights reserved.) more...

Polymerase chain reaction (PCR)-based assays combined with microchip electrophoresis were developed and evaluated for diagnosis and genotyping of GM2 gangliosidosis variant 0 (Sandhoff-like disease) in Japanese domestic cats. A preliminary genotyping survey was carried out in the population of Japanese domestic cats (1,015 cats in total) in southern Japan. Three kinds of assays including PCR primer-induced restriction analysis (PIRA) and mutagenically separated (MS)-PCR were carried out using blood-stained Flinders Technology Associates filter papers (FTA cards) as templates. The PCR products were analyzed by both agarose gel and microchip electrophoreses. All assays were sufficient to determine the genotypes of this disease, but MS-PCR offered the most rapid and simplest test, as it does not need the restriction enzyme step required in PCR-PIRA. The use of microchip electrophoresis in combination with FTA cards for sampling could shorten the time required for genotyping and simplify the procedure as well. The genotyping survey in the current study did not find any cats that possessed the mutant allele, suggesting that the prevalence of this allele is low (<0.1%) in southern Japan. more...

Background: Most diseases are thought to arise from interactions between environmental factors and the host genotype. To detect gene-environment interactions in the development of lifestyle-related diseases, and especially cancer, the Japan Multi-institutional Collaborative Cohort (J-MICC) Study was launched in 2005., Methods: We initiated a cross-sectional study to examine associations of genotypes with lifestyle and clinical factors, as assessed by questionnaires and medical examinations. The 4519 subjects were selected from among participants in the J-MICC Study in 10 areas throughout Japan. In total, 108 polymorphisms were chosen and genotyped using the Invader assay., Results: The study group comprised 2124 men and 2395 women with a mean age of 55.8 ± 8.9 years (range, 35-69 years) at baseline. Among the 108 polymorphisms examined, 4 were not polymorphic in our study population. Among the remaining 104 polymorphisms, most variations were common (minor allele frequency ≥0.05 for 96 polymorphisms). The allele frequencies in this population were comparable with those in the HapMap-JPT data set for 45 Japanese from Tokyo. Only 5 of 88 polymorphisms showed allele-frequency differences greater than 0.1. Of the 108 polymorphisms, 32 showed a highly significant difference in minor allele frequency among the study areas (P < 0.001)., Conclusions: This comprehensive data collection on lifestyle and clinical factors will be useful for elucidating gene-environment interactions. In addition, it is likely to be an informative reference tool, as free access to genotype data for a large Japanese population is not readily available. more...

Poorly differentiated type synovial sarcoma (PDSS) is a variant of synovial sarcoma characterized by predominantly round or short-spindled cell morphology. Although accumulating evidence from clinicopathologic studies suggests a strong association between this variant of synovial sarcoma and poor prognosis, little has been reported on the molecular basis of PDSS. To gain insights into the mechanism(s) that underlie the emergence of PDSS, we analyzed the gene expression profiles of 34 synovial sarcoma clinical samples, including 5 cases of PDSS, using an oligonucleotide microarray. In an unsupervised analysis, the 34 samples fell into 3 groups that correlate closely with histologic subtypes: monophasic, biphasic, and poorly differentiated types. PDSS was characterized by down-regulation of genes associated with neuronal and skeletal development and cell adhesion. Moreover, upregulation of genes on a specific chromosomal locus, 8q21.11, was identified. This locus-specific transcriptional activation in PDSS was confirmed by reverse transcriptase-PCR analysis of 9 additional synovial sarcoma samples. Our results indicate that PDSS tumors constitute a distinct group based on expression profiles. more...

Background: Hip fractures following falls by the elderly, which increase with age, are increasing in number annually. The incidence of refracture (second hip fractures) has been reported to be 5%-10% in Japan and is expected to increase with the aging of the population in the future. Therefore, through a retrospective cohort study, we attempted to clarify the risk factors associated with second hip fractures., Methods: A total of 400 patients were consecutively treated for hip fracture at a single orthopedic hospital between January 2001 and December 2007. We excluded 16 subjects: 11 patients who died within a year after a hip fracture and 5 who were <50 years of age. The remaining 384 patients, consisting of 64 men and 320 women, were chosen as the study subjects. The mean age of the subjects at the time of the initial fracture was 83.1 +/- 9.0 years (range 51-102 years). Age, sex, interval between the two fractures, body mass index (BMI), length of bed-rest periods and of rehabilitation periods, living place after an initial fracture, and complicating diseases were determined from medical records. Furthermore, effectors of second hip fractures were extracted using the Cox proportional hazard model., Results: In all, 384 patients were observed for 1140.0 person-years (mean: 3.0 +/- 1.4 years per patient) following the initial hip fracture. During the observation period, 49 second hip fractures were identified, giving an overall incidence of 0.043 per person-year. The second fracture occurred within 3 years in 85.7% (42 patients). Dementia and respiratory disease were recognized as being significantly related to refracture. Using a Cox proportional hazard model, dementia showed a significant influence, with the hazard ratio (HR) 1.87 [95% confidence interval (CI) 1.02-3.41; P = 0.042]. Respiratory diseases also were associated with second hip fracture (HR 4.41, 95% CI 2.33-8.34; P < 0.001)., Conclusions: In this study, 85.7% of refractures occurred within 3 years of the first fracture, with dementia and respiratory disease being the complicating factors that influenced refracture. more...

Background: Hyperhomocysteinemia is correlated with diseases and lifestyle habits. However, there is no epidemiological evidence concerning the distribution and prevalence of hyperhomocysteinemia in a local community., Objective: The purpose of this study was to clarify the distribution and prevalence of hyperhomocysteinemia and the existence or nonexistence of familial clustering., Methods: The subjects were participants in the Basic Health Check Service 1999. We administered a questionnaire and obtained blood samples from 865 subjects (306 men, 559 women) who agreed to participate in our study., Results: Hyperhomocysteinemia was present in 52 men (17.0%) and 25 women (4.5%). Ten subjects who had hyperhomosysteinemia ha a family member who also had hyperhomocysteinemia. The odds ratio for hyperhomocysteinemia adjusted for age and sex was 4.77 (p < 0.01, 95% CI = 1.95-11.65)., Conclusion: Hyperhomocysteinemia shows familial clustering. Men and elderly persons were more likely to have hyperhomocysteinemia., (Copyright 2009 S. Karger AG, Basel.) more...

The National BioResource Project (NBRP) is a Japanese project that aims to establish a system for collecting, preserving and providing bioresources for use as experimental materials for life science research. It is promoted by 27 core resource facilities, each concerned with a particular group of organisms, and by one information center. The NBRP database is a product of this project. Thirty databases and an integrated database-retrieval system (BioResource World: BRW) have been created and made available through the NBRP home page (http://www.nbrp.jp). The 30 independent databases have individual features which directly reflect the data maintained by each resource facility. The BRW is designed for users who need to search across several resources without moving from one database to another. BRW provides access to a collection of 4.5-million records on bioresources including wild species, inbred lines, mutants, genetically engineered lines, DNA clones and so on. BRW supports summary browsing, keyword searching, and searching by DNA sequences or gene ontology. The results of searches provide links to online requests for distribution of research materials. A circulation system allows users to submit details of papers published on research conducted using NBRP resources. more...

Introduction: Competencies is an important concept used for assessing health professionals' capability to perform their role. By means of a literature review of Japanese professional journals this paper will investigate the competencies concept, particularly with relation to disaster nursing., Methods: The literature research was conducted using the database ichu-shi (ver. 4). All literature is written and published in Japanese and was published between 2001 and 2008. Due to an unfamiliarity of the term 'competencies' in Japanese, the key words were sought while deconstructing the meaning and concepts of 'competencies' into terms more recognisable in the Japanese context. Twelve key words: disaster, capability, education, practice, licensure, ability, function, prevention, response, planning, emergency, and disaster nursing were chosen as being most likely to find literature relevant to the English Language concept of competencies. The searched articles were then written into the disaster nursing competencies review worksheet for analysis., Result: One hundred and twenty articles were found by searching a combination of these key words. Of these articles, those that were not in the context of disaster nursing were eliminated. As a result, 43 articles were chosen as being suitable for analysis of the context. These articles are classified into four themes., Conclusion: These theme groups indicated a foundation for competencies in disaster nursing. The definition of competencies in Japanese nursing journals was quite varied and cannot be easily defined as common disaster nursing competencies. Given the variety of areas and the distinct phases in disaster nursing, as well as the 'what for' and 'who governs', disaster nursing competencies will need its own discussion in order to establish the common competencies internationally. more...

The nematode C. elegans is a small and simple animal, which is easy to culture and store. Many detailed descriptions, biological resources, and methods for genetical and biochemical analyses have accumulated due to past research activities, and C. elegans is readily useful for molecular analyses with transgenic, RNAi, and mutants. Thus, C. elegans is an ideal model organism for detailed molecular analyses and functional genomics. more...

Introduction: The Impact of Event Scale Revised (IES-R) has been used in various epidemiological studies to assess the prevalence of post-traumatic stress disorder (PTSD). Previous studies using the IES-R Japanese version to assess the mental health of firefighters were based on the premise that firefighters had experienced a traumatic event(s) as a matter of course. However, use of the IES-R-J does not indicate whether or not a traumatic event was experienced. The purpose of this study is to clarify the differences between: (1) IES-R-J high and low score groups; and (2) those who report symptoms similar to those of PTSD with and without having been being exposed to a traumatic event., Methods: Questionnaire packets distributed to all 157 workers in a Japanese fire station included the IES-R, the Japan Brief Job Stress Questionnaire, a questionnaire regarding traumatic event experiences, and demographic questions. Participants who scored > or = 25 points on the IES-R-J scale were defined as the PTSD high risk (HR) group; those with scores < 25 points as the PTSD low risk (LR) group., Results: One hundred thirty-one of the 157 subjects (83.4%) responded to the questionnaire; three were excluded from the analysis because of missing data. The mean total IES-R-J score was 14.9 +/- 15.2. Twenty-eight subjects scored in the PTSD HR group (> or = 25); 100 scored in the LR group (< 25). A total of 54 (42.2%) participants had experienced a traumatic event; 57.8% had not. In the HR group, 14 subjects had experienced a traumatic event and 14 had not. Participants who had experienced a traumatic event reported a higher incidence of intrusion/re-experience symptoms than did those who had not experienced a traumatic event. The level of social support significantly affected the risk for PTSD. Firefighters who scored > or = 25 on the IES-R-J and, thus, considered to be at high risk for the development of PTSD, were less confident about their health, experienced more job stressors and had less social support than did those whose IES-R-J scores were < 25. Having experienced a traumatic event was reported by only 42% of all the participants and by only 50% of those in the high risk PTSD group., Conclusions: Although the IES-R is an easily-administered tool useful in epidemiological studies evaluating psychological stress, it is recommended that the questionnaire be amended to include a question regarding the existence of a threatened experience or event and to analyze the data using positive and negative predictive value methodology. more...

Previous psychophysical studies have shown that the perceptual distinction between voiceless fricatives and affricates in consonant-vowel syllables depends primarily on frication duration, whereas amplitude rise slope was suggested as the cue in automatic classification experiments. The effects of both cues on the manner of articulation between /integral of/ and /t integral of/ were investigated. Subjects performed a forced-choice task (/integral of/ or /t integral of) in response to edited waveforms of Japanese fricatives /integral of i/, /integral of u/, and /integral of a/. We found that frication duration, onset slope, and the interaction between duration and onset slope influenced the perceptual distinction. That is, the percent of /integral of/ responses increased with an increase in frication duration (experiments 1-3). The percent of /integral of/ responses also increased with a decrease in slope steepness (experiment 3), and the relative importance between slope portions was not even but weighted at onset (experiments 1 and 2). There was an interaction between the two cues of frication duration and steepness. The relative importance of the slope cue was maximum at a frication duration of 150 ms (experiment 3). It is concluded that the frication duration and amplitude rise slope at frication onset are acoustic cues that discriminate between /integral of/ and /t integral of/, and that the two cues interact with each other. more...

Burnout and stress are common, related problems in service professionals, and post-traumatic stress disorder (PTSD) is a major concern among fire service workers. The purpose of this study was to evaluate the impact of PTSD and job-related stressors on burnout. A total of 243 fire service workers completed questionnaires, including the Impact of Event Scale-Revised (IES-R), Maslach Burnout Inventory (MBI), and Japan Brief Job Stress Questionnaire. Relationships were found between PTSD and burnout, and between job stressors and burnout. Social support reduced the impact on burnout. Stressors that impacted on burnout in fire service personnel were PTSD-related acute stress and general job-related chronic stress. Countermeasures, not only against job stress, but also against PTSD-related stress, are essential to prevent burnout. Social support and the development of human relationships in the work place are crucial in mitigating burnout. more...

Object: The purpose of this study was to compare the stress levels of Japanese ambulance men between on-duty and off-duty days, by using the physiological indices of heart rate variability (HRV) and cortisol in urine, measured over each 24-h period., Methods: Measurements were made during one on-duty and one off-duty day for each subject. The participants were monitored for 24 h with a Holter recording system and a parameter reflecting overall stress levels was obtained by measuring the cortisol level in urine collected over 24 h., Results: The circadian variation of cardiac autonomic nervous system activity was affected when the subjects were on duty. The low-frequency/high-frequency power ratio (=low-frequency power/high-frequency power: LF/HF), which is a useful parameter that reflects the balance of cardiac autonomic nervous activity, differed significantly between the waking and sleeping times on the off-duty day (P=0.03), while it did not differ between these two states on the on-duty day (P=0.56). Similarly, the normalized high-frequency power [=high-frequency/(high-frequency+low-frequency) power: HF/(HF+LF)] ratio, which is a useful measure of the activity of the parasympathetic nervous system, differed significantly between these two states on the off-duty day (P=0.04), while there was no significant difference in the ratio between the two states on the on-duty day (P=0.13)., Conclusion: These results show that the diurnal balance of the cardiac autonomic nervous system is affected on the on-duty day, even though it is possible for ambulance men to sleep regular hours. more...

Dysplasia of the hip, the most common cause of secondary coxarthrosis, has a relatively high prevalence in Japan. Rotational acetabular osteotomy (RAO) is an interventional strategy that seeks to reduce the abnormal amount of high stress concentration in the acetabulum and thereby to prevent the development of coxarthrosis. Long-term clinical results have been reported, but functional evaluations of the gait before and after RAO are underreported. The aim of our recently initiated long-term prospective study is to assess the effect of RAO on the gait characteristics of patients using quantitative gait analysis. Thus far 22 patients (1 male, 21 females; mean age 30 years, range 15-43 years) have been enrolled, treated, and completed the preoperative and postoperative gait analyses. Hip pain during walking decreased in all patients after the RAO. The postoperative hip extension motion angle on the treated side increased significantly and correlated positively with the improvement in the Japanese Orthopaedic Association (JOA) pain score. The current study shows that coxalgia and gait function improved after RAO. more...

The prevalence of chromosomal translocation t(14;18) was examined in 41 cases of follicular lymphoma covering all histopathological subtypes, using the polymerase chain reaction and hybridization method with non-radioactive oligonucleotide probes. DNAs were extracted from unfixed fresh-frozen and/or formalin-fixed paraffin-embedded biopsy specimens. The t(14;18) chromosomal translocation, resulting in bcl-2-JH (immunoglobulin heavy chain gene joining segment) fusion gene, was detected in 7 (36.8%) of 19 follicular small cleaved cell lymphomas and 6 (54.5%) of 11 follicular mixed, small cleaved cell and large cell lymphomas. Meanwhile, 11 cases of follicular large cell lymphoma revealed no bcl-2-JH fusion gene. There was a statistically significant difference in the frequency of bcl-2-JH rearrangement between follicular, small cleaved cell and large cell lymphoma (two-sided Fisher exact test, P = 0.049). The difference of bcl-2 rearrangement frequency between follicular, mixed and large cell lymphoma was also statistically significant (P = 0.012). more...

A seroepidemiologic study of the prevalence of Helicobacter pylori infection in Japan was performed, and the relationship between serum pepsinogen I and II levels (markers of gastritis and gastric atrophy) and H. pylori infection was investigated. Four hundred and eighteen asymptomatic children and adults were studied. The prevalence of anti-H. pylori immunoglobulin G antibody increased with age. For persons born after 1950, the frequency of H. pylori infection increased at approximately 1% per year; for those born before 1950 the prevalence was high (70%-80%) and relatively constant. Serum pepsinogen I and II levels were significantly higher in H. pylori-infected volunteers than in H. pylori-uninfected volunteers [51.6 +/- 3 vs. 42.9 +/- 2 ng/mL (P less than 0.05) for pepsinogen I; 16.0 +/- 1 vs. 7.5 +/- 0.8 ng/mL (P less than 0.001) for pepsinogen II]. The ratio of pepsinogen I to pepsinogen II was significantly lower in H. pylori-infected volunteers (3.5 +/- 0.2) than in uninfected volunteers (6.3 +/- 0.3; P less than 0.001). The apparent decrease in prevalence of H. pylori accompanying the Westernization of Japan may eventually be accompanied by a reduction in the frequency of atrophic gastritis, the precursor lesion of the epidemic form of gastric carcinoma, and ultimately result in a decrease in the incidence of gastric carcinoma in Japan. more...

Liver disorders were reviewed in 76 patients with mycoplasma pneumoniae pneumonia (MP) admitted to Kamo Hospital from 1979 to 1989. Liver dysfunction was detected in 16 patients (21%). Liver disorder were detected in 10% of MP from 1979 to 1980, but in 20% from 1984 to 1985, and in 36% from 1988 to 1989. By multiple regression analysis CRP was found to be the most significant factor among other factors such as prevalence, age, sex, history of smoking, history of drinking, and days after onset of fever. more...