Publications by authors named "Hideki Nishimura"

96 Publications

Prospective cohort study of febrile neutropenia in breast cancer patients administered with neoadjuvant and adjuvant chemotherapies: CSPOR-BC FN study.

Breast 2021 Apr 16;56:70-77. Epub 2021 Feb 16.

Division of Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan.

Background: As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G).

Patients And Methods: Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians' discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors.

Results: Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant.

Conclusions: FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC.
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http://dx.doi.org/10.1016/j.breast.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907535PMC
April 2021

Establishment of -tagged lines of Koshihikari, an elite variety of rice in Japan.

Breed Sci 2019 Dec 14;69(4):696-701. Epub 2019 Nov 14.

Institute of Plant Science and Resources, Okayama University, Kurashiki, Okayama 710-0046, Japan.

To utilize a transposon-tagged mutant as a breeding material in rice, an endogenous DNA transposon, , was introduced into Koshihikari by successive backcrossing together with , an active autonomous element. The founder line for -tagged lines of Koshihikari carried on chromosome 9 and transposed on chromosomes 1 and 8 and on chromosome 11. In -tagged lines, there were the most abnormal phenotypic mutants and many aberrant chlorophyll mutants at seedling stage. At mature stage, many semi-sterile mutants were observed. Dwarf, reduced culm number and lesion mimic mutants were also found. In total, 43.2% of the lines segregated some phenotypic mutants. Thus, the -tagged lines of Koshihikari are expected to be potentially useful for screening stress-tolerant mutants under abiotic or biotic stress conditions.
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http://dx.doi.org/10.1270/jsbbs.19049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977457PMC
December 2019

[Bronchogenic Cyst with Rapid Increase and Emergency Operation;Report of a Case].

Kyobu Geka 2019 Nov;72(12):1034-1037

Department of Chest Surgery, Nagano Municipal Hospital, Nagano, Japan.

A 21-year-old man was admitted with fever and back pain. Chest computed tomography(CT) showed a cystic mass of 7×6 cm in the right middle mediastinum. After 3 days, symptoms worsen, and chest X-ray revealed the enlargement of the cyst, and an emergent operation was performed. Since the tumor was severely adhered to the superior vena cava and the azygous vein, the cystic mass was partially resected. The pathological diagnosis was bronchogenic cyst.
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November 2019

A prospective multicentre feasibility study of stereotactic body radiotherapy in Japanese patients with spinal metastases.

Jpn J Clin Oncol 2019 Dec;49(11):999-1003

Division of Radiation Oncology, Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Objective: Stereotactic body radiotherapy has emerged as an attractive alternative to conventional radiotherapy for spinal metastases. However, it has limitations, including the need for advanced techniques and specific adverse effects. The present trial aimed to validate the feasibility and safety of stereotactic body radiotherapy in Japanese patients with spinal metastases.

Methods: Patients with one or two spinal metastases received stereotactic body radiotherapy of 24 Gy in two fractions. The primary endpoint was the proportion of severe adverse effects (≥ grade 3) in patients within 6 months after spine stereotactic body radiotherapy. Adverse effects were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. The treatment protocol was considered feasible and tolerable if the proportion of severe adverse effects was 10% or less.

Results: Overall, 20 spinal segments in 20 patients who registered between March 2014 and October 2015 were included. Minor and major deviations were observed in the planning of 2 and 0 cases, respectively. The treatment completion rate was 100%. The median follow-up after registration was 24.5 (range: 1-61) months. Although four patients experienced acute grade 2 adverse effects, no grade 3 or higher adverse effects were observed within 6 months after spine stereotactic body radiotherapy. Vertebral compression fractures were observed in two patients (14 and 16 months after stereotactic body radiotherapy). The local control and pain response rates at 6 months were 100 and 83%, respectively.

Conclusion: This study demonstrated the feasibility and safety of spine stereotactic body radiotherapy in Japanese patients with spinal metastases.
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http://dx.doi.org/10.1093/jjco/hyz130DOI Listing
December 2019

Transgenerational activation of an autonomous DNA transposon, Dart1-24, by 5-azaC treatment in rice.

Theor Appl Genet 2019 Dec 3;132(12):3347-3355. Epub 2019 Oct 3.

Institute of Plant Science and Resources, Okayama University, Kurashiki, 710-0046, Japan.

Key Message: Dart1-24, one of the 37 autonomous DNA transposon Dart1s, was heritably activated by the demethylation of the 5' region following 5-azaC treatment of rice seeds. Transposons are controlled by epigenetic regulations. To obtain newly activated autonomous elements of Dart1, a DNA transposon, in rice, seeds of a stable pale yellow leaf (pyl-stb) mutant caused by the insertion of nDart1-0, a nonautonomous element in OsClpP5, were treated with 5-azaC, a demethylating agent. In the 5-azaC-treated M1 plants, 60-70% of the plants displayed variegated pale yellow leaf (pyl-v) phenotype, depending on the concentration of 5-azaC used, suggesting that inactivated Dart1 might become highly activated by 5-azaC treatment and nDart1-0 was excised from OsClpP5 by the activated Dart1s. Although the M2 plants derived from most of these pyl-v plants showed stable pyl phenotypes, some variegated M1 plants generated pyl-v M2 progeny. These results indicated that most M1 pyl-v phenotypes at M1 were not heritable. Dart1-24, 1-27 and 1-28 were expressed in the M2 pyl-v plants, and mapping analysis confirmed that Dart1-24 was newly activated. Further, the transgenerational activation of Dart1-24 was demonstrated to be caused by the demethylation of nucleotides in its 5' region.
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http://dx.doi.org/10.1007/s00122-019-03429-7DOI Listing
December 2019

[Osimertinib Was Effective for Liver Metastasis after Surgery for Lung Cancer with Simultaneous Expression of EGFR L858Ra nd T790M Mutations-A Case Report].

Gan To Kagaku Ryoho 2019 Aug;46(8):1291-1293

Dept. of Chest Surgery, Nagano Municipal Hospital.

A 63-year-old woman underwent right lower lobectomy and mediastinal dissection for lung cancer. At 5 years and 5 months after surgery, chest computed tomography revealed multiple liver metastasis. EGFR gene mutations of L858R and T790M were detected in both the primary lung cancer lesion and the liver metastasis specimen. Gefitinib was initiated as the first-line treatment, but the tumors increased in size. Osimertinib, as second-line treatment, was remarkably effective against the liver metastatic lesions and it maintained a partial response for approximately 1 year. Thus, osimertinib was effective for liver metastasis of lung cancer with EGFR mutations of L858R and T790M.
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August 2019

Retrospective assessment of a single fiducial marker tracking regimen with robotic stereotactic body radiation therapy for liver tumours.

Rep Pract Oncol Radiother 2019 Jul-Aug;24(4):383-391. Epub 2019 Jun 21.

Division of Radiation Oncology, Kobe University Graduate School of Medicine, 7-5-2 Kusunokicho, Chuou-ku, Kobe City, Hyogo 650-0017, Japan.

Aim: To investigate tumour motion tracking uncertainties in the CyberKnife Synchrony system with single fiducial marker in liver tumours.

Background: In the fiducial-based CyberKnife real-time tumour motion tracking system, multiple fiducial markers are generally used to enable translation and rotation corrections during tracking. However, sometimes a single fiducial marker is employed when rotation corrections are not estimated during treatment.

Materials And Methods: Data were analysed for 32 patients with liver tumours where one fiducial marker was implanted. Four-dimensional computed tomography (CT) scans were performed to determine the internal target volume (ITV). Before the first treatment fraction, the CT scans were repeated and the marker migration was determined. Log files generated by the Synchrony system were obtained after each treatment and the correlation model errors were calculated. Intra-fractional spine rotations were examined on the spine alignment images before and after each treatment.

Results: The mean (standard deviation) ITV margin was 4.1 (2.3) mm, which correlated weakly with the distance between the fiducial marker and the tumour. The mean migration distance of the marker was 1.5 (0.7) mm. The overall mean correlation model error was 1.03 (0.37) mm in the radial direction. The overall mean spine rotations were 0.27° (0.31), 0.25° (0.22), and 0.23° (0.26) for roll, pitch, and yaw, respectively. The treatment time was moderately associated with the correlation model errors and weakly related to spine rotation in the roll and yaw planes.

Conclusions: More caution and an additional safety margins are required when tracking a single fiducial marker.
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http://dx.doi.org/10.1016/j.rpor.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595081PMC
June 2019

Pattern of recurrence after CyberKnife stereotactic body radiotherapy for peripheral early non-small cell lung cancer.

J Thorac Dis 2019 Jan;11(1):214-221

Department of Radiation Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Hyogo, Japan.

Background: The treatment efficacy after CyberKnife stereotactic body radiotherapy (SBRT) have not been adequately addressed. The purpose of this study was to investigate pattern of recurrence according to irradiation field after CyberKnife SBRT for early-stage non-small cell lung cancer (NSCLC).

Methods: This retrospective study included patients with peripheral cT1/2N0M0 NSCLC that was treated with SBRT using a CyberKnife between May 2013 and March 2016 at single institute and followed up by more than two imaging examinations. Both operable and inoperable patients were included. Overall survival (OS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method with 95% confidence intervals (CI). Cumulative incidence curves of recurrence were calculated and compared using the Gray's test.

Results: Total 71 patients were included and analyzed in this study. The median follow-up period for surviving patients was 34 months (range, 7-64 months). The 2-year OS and PFS rate were 93% (95% CI: 83-97%) and 77% (95% CI: 65-86%), respectively. The 2-year cumulative incidence rate of infield recurrence and out-of-field recurrence were 6% (95% CI: 2-14%) and 17% (95% CI: 9-27%), respectively. Gross tumor volume (GTV) ≥9 mL and diagnosis-to-treatment interval (DTI) ≥90 days were significantly associated with infield recurrence (P<0.001 and P=0.007), and epidermal growth factor receptor (EGFR) mutation was significantly associated with out-of-field recurrence (P=0.014).

Conclusions: Treatment efficacy after CyberKnife SBRT for peripheral early-stage NSCLC was identical to previous conventional linac-based SBRT reports. With short follow-up period, it was found that GTV and DTI were the significant predictive factor of infield recurrence, and EGFR mutation was the significant predictive factor of out-of-field recurrence.
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http://dx.doi.org/10.21037/jtd.2018.12.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384354PMC
January 2019

Chloroquine Enhances Rapamycin-induced Apoptosis in MG63 Cells.

Anticancer Res 2019 Feb;39(2):649-654

Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan.

Background/aim: We previously showed that the use of autophagy inhibitors in combination with chemotherapy can enhance anticancer effects in sarcoma cell lines. In this study, we investigated the combined effect of the autophagy inhibitor chloroquine and the mTOR inhibitor rapamycin on MG63 osteosarcoma cells.

Materials And Methods: Effects of chloroquine and/or rapamycin on cell proliferation were assessed by WST-1 assays. Effects of chloroquine and/or rapamycin on the mTOR pathway components, autophagy, and apoptosis were investigated by western blot, flow cytometry, and fluorescence microscopy using immunocytochemical staining of LC3 and Annexin V-FITC/propidium iodide.

Results: Rapamycin suppressed cell growth and inhibited the mTOR pathway. Rapamycin promoted autophagy by blocking the mTOR pathway, and chloroquine enhanced apoptosis by blocking autophagy.

Conclusion: Chloroquine enhances the effects of rapamycin in inducing apoptosis via autophagy inhibition in MG63 cells. Thus, the combined therapy of chloroquine and rapamycin may be a potent treatment for osteosarcoma.
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http://dx.doi.org/10.21873/anticanres.13159DOI Listing
February 2019

Assessing Functionality and Benefits of Comprehensive Dose Volume Prescriptions: An International, Multi-Institutional, Treatment Planning Study in Spine Stereotactic Body Radiation Therapy.

Pract Radiat Oncol 2019 Jan 15;9(1):9-15. Epub 2018 Nov 15.

Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Purpose: This study aimed to assess the effectiveness of multiple dose-volume specifications in minimizing interinstitutional, target-prescribed, dose variations for spine stereotactic body radiation therapy (SBRT).

Methods And Materials: Seven institutions with a total of 10 treatment apparatuses participated in this study. SBRT plans for 3 representative spinal metastases were generated using 2 different protocols (Protocols 1 and 2) for target dose. While using just 2 target dose objectives (doses delivered to 95% and maximum point dose) in Protocol 1, 3 target dose constraints (doses delivered to 95% and 50% and maximum point dose) were defined in Protocol 2 with the intent to decrease target dose variation. A dose-volume histogram analysis was performed for the evaluated planning target volume (PTV) and critical neural structures such as the spinal cord and cauda equina.

Results: Doses to the organs at risk were all maintained at the maximal tolerance in both protocols; however, the interinstitutional variation of the PTV dose-volume histograms was significantly decreased with Protocol 2. Furthermore, the mean PTV covered by the prescription dose was increased from 73.0% in Protocol 1 to 85.8% in Protocol 2. There were no differences in the mean values of the nearly maximum dose of the critical neural structures between 2 protocols.

Conclusions: In spine SBRT with the emphasis on preservation of critical neural structures, the target prescribed dose should be defined by using multiple dose-volume objectives to minimize user and apparatus-dependent dose variabilities for the spinal metastases that are adjacent to the critical neural structures.
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http://dx.doi.org/10.1016/j.prro.2018.05.006DOI Listing
January 2019

Functional screening of salt tolerance genes from a halophyte Sporobolus virginicus and transcriptomic and metabolomic analysis of salt tolerant plants expressing glycine-rich RNA-binding protein.

Plant Sci 2019 Jan 29;278:54-63. Epub 2018 Oct 29.

School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakura, Hachioji, Tokyo, 192-0982, Japan.

Sporobolus virginicus is a halophytic C grass found worldwide, from tropical to warm temperate regions. One Japanese genotype showed a salinity tolerance up to 1.5 M NaCl, a three-fold higher concentration than the salinity of sea water. To identify the key genes involved in the regulation of salt tolerance in S. virginicus, we produced 3500 independent transgenic Arabidopsis lines expressing random cDNA from S. virginicus and screened 10 lines which showed enhanced salt tolerance compared with the wild type in a medium containing 150 mM NaCl. Among the selected lines, two contained cDNA coding glycine-rich RNA-binding proteins (SvGRP1 and SvGRP2). This is the first reports on the function of GRPs from halophytes in salt tolerance though reports have shown GRPs are involved in diverse biological and biochemical processes including salt tolerance in Arabidopsis and some other glycophytes. Transcriptomic analysis and GO enrichment analysis of SvGRP1-expressing Arabidopsis under salt stress revealed upregulation of polyol and downregulation of glucosinolate and indole acetic acid biosynthesis/metabolic pathways. Metabolomic analysis of the SvGRP1-transformant suggested that the increase in 3-aminoppropanoic acid, citramalic acid, and isocitric acid content was associated with enhanced salt tolerance. These findings could provide novel insight into the roles of GRPs in plant salt tolerance.
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http://dx.doi.org/10.1016/j.plantsci.2018.10.019DOI Listing
January 2019

[Late-onset Chylothorax after Right Upper Lobectomy;Report of a Case].

Kyobu Geka 2018 11;71(12):1052-1055

Department of Chest Surgery, Nagano Municipal Hospital, Nagano, Japan.

Chylothorax after pulmonary resection is diagnosed usually within a few days after surgery, hence late-onset chylothorax is relatively rare complication. A 79-year-old woman underwent right upper lobectomy and mediastinal dissection for lung cancer. A chest tube was removed on postoperative day (POD)3, and she was discharged on POD 8. Fifty days after an operation, the patient developed a dyspnea on effort, and chest radiography revealed a right-sided pleural effusion, which we diagnosed as chylothorax. Because the treatments of a fat-free diet and subcutaneous octreotide acetate administration were ineffective, thoracic duct ligation was finally performed. The post-reoperative course was uneventful.
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November 2018

SNX-2112 Induces Apoptosis and Autophagy of Nara-H Cells.

Anticancer Res 2018 Sep;38(9):5177-5181

Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, Kagawa, Japan.

Background/aim: Selective heat shock protein 90 (Hsp90) inhibitor SNX-2112 exhibits antitumor activity in multiple cancer cell types. Here, the antitumor activity of SNX-2112 in Nara-H cells was analyzed.

Materials And Methods: Antitumor activity of SNX-2112 was assessed using a cell proliferation assay. We also examined the signalling pathways involved in SNX-2112-mediated autophagy and apoptosis of Nara-H cells by western blot and morphological analyses.

Results: Cell proliferation assays demonstrated that SNX-2112 inhibited Nara-H cell growth. Western blotting revealed that SNX-2112 induced apoptosis and autophagy, inhibited mammalian target of rapamycin (mTOR) phosphorylation, and suppressed the mitogen-activated protein kinase (MAPK) signalling pathway. Morphological analysis confirmed that SNX-2112 induced autophagy and apoptosis.

Conclusion: SNX-2112 induced autophagy and apoptosis of Nara-H cells by inhibiting mTOR and MAPK pathways. Our results support developing SNX-2112 to treat human soft tissue sarcomas.
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http://dx.doi.org/10.21873/anticanres.12840DOI Listing
September 2018

[Micronodular Thymoma with Lymphoid Stroma;Report of a Case].

Kyobu Geka 2018 Mar;71(3):232-235

Department of Thoracic Surgery, Nagano Municipal Hospital, Nagano, Japan.

We report a surgical case of micronodular thymoma with lymphoid stroma (MNT), which is a rare type of thymoma. A 66-year-old man was referred to our hospital for further examination and treatment of a nodule in the mediastinum. Computed tomography(CT) showed a 20-mm nodule in the anterior mediastinum, and positron emission tomography-CT showed slight uptake in the same region. Thymoma was suspected and videoassisted thymectomy was performed. Histopathological findings showed spindleshaped tumor cells forming storiform, with the background of lymphoid stroma, and the tumor was diagnosed as MNT. The long-term outcome after resection of MNT currently remains unclear, and accumulation of further cases is required.
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March 2018

Additional chemotherapy improved local control and overall survival after stereotactic body radiation therapy for patients with oligo-recurrence.

Radiat Oncol 2018 Apr 23;13(1):75. Epub 2018 Apr 23.

Department of Radiation Oncology, Kobe Minimally invasive Cancer Center, 8-5-1, Minatojima Nakamachi, Chuo-ku, Kobe, Hyogo, 650-0046, Japan.

Background: Oligo-recurrence has been considered to confer improved prognosis than other oligometastatic conditions, and stereotactic body radiation therapy (SBRT) is considered as an option of local therapy for lung or liver metastases. The purpose of this study was to investigate the efficacy and safety of SBRT for lung and liver oligo-recurrent lesions and evaluate predictive factors for local control and prognosis.

Methods: This retrospective study included patients who presented with 1-3 matachronous lung or liver metastases, and treated with SBRT between May 2013 and March 2016 at a single institution. All patients harbored a controlled primary lesion. Patients with < 6 months of follow-up were excluded. Local control, progression free survival, and overall survival rates were analyzed according to the Kaplan-Meier product limit method. Univariable log-rank and multivariable Cox regression analyses were performed to clarify predictive factors for local control and prognosis. Toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 4.0.

Results: Seventy-six patients with a total of 70 and 44 lung and liver lesions were included. The median follow-up period was 21 (range, 7-43) months. The 1-year local control, progression-free survival and overall survival rates were 89, 38 and 96%, respectively. Smaller gross tumor volume and additional chemotherapy after SBRT were significant predictive factors for better local control (p = 0.005 and p = 0.047), and the presence of a single metastatic lesion was a significant factor of good progression free survival (p = 0.008). Additional chemotherapy after SBRT was not a significant predictive factor but conferred to better overall survival (p = 0.078). Among colorectal cancer patients, post SBRT chemotherapy was significantly associated with better OS (p = 0.025). Over grade 3 adverse event was seen in only one patient.

Conclusion: SBRT is a safe and effective treatment for patients with lung and liver oligo-recurrence. Additional chemotherapy after SBRT improved local control, and single metastatic lesion was a significant predictive factor of better PFS in this study. Among colorectal cancer patients, additional chemotherapy after SBRT significantly associated better OS.
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http://dx.doi.org/10.1186/s13014-018-1031-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914071PMC
April 2018

Effects of linagliptin versus voglibose on treatment-related quality of life in patients with type 2 diabetes: sub-analysis of the L-STEP study.

Endocr J 2018 Jun 10;65(6):657-668. Epub 2018 Apr 10.

Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Treatment-related quality of life (QOL) is an important aspect of diabetes management. However, no studies have compared the influence of dipeptidyl peptidase-4 inhibitors versus alpha-glucosidase inhibitors on treatment-related QOL. This prespecified sub-analysis of the Linagliptin Study of Effects on Postprandial blood glucose (L-STEP) compared the effects of linagliptin (5 mg once daily) and voglibose (0.2 mg/meal thrice daily) on treatment-related QOL in Japanese patients with type 2 diabetes (T2DM) inadequately controlled with diet and exercise therapy. Among 366 subjects in the original study, 182 in the linagliptin group and 173 in the voglibose group were included in this analysis. The outcome of this study was change in QOL as assessed by the Diabetes Therapy-Related Quality of Life 17 (DTR-QOL17) questionnaire from baseline to week 12. Compared with baseline data, total DTR-QOL17 scores were significantly higher after 12 weeks of linagliptin and voglibose treatment. The change in the total DTR-QOL17 score and the score of one domain, burden on social activities and daily activities, was significantly greater in the linagliptin group than in the voglibose group. In addition, only linagliptin treatment was identified as a factor associated with an increased total DTR-QOL17 score. Linagliptin is superior to voglibose in terms of improving treatment-related QOL in Japanese patients with T2DM.
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http://dx.doi.org/10.1507/endocrj.EJ18-0088DOI Listing
June 2018

Correlation between global methylation level of peripheral blood leukocytes and serum C reactive protein level modified by MTHFR polymorphism: a cross-sectional study.

BMC Cancer 2018 02 13;18(1):184. Epub 2018 Feb 13.

Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: Chronic inflammatory conditions are associated with higher tumor incidence through epigenetic and genetic alterations. Here, we focused on an association between an inflammation marker, C-reactive-protein (CRP), and global DNA methylation levels of peripheral blood leukocytes.

Methods: The subjects were 384 healthy Japanese women enrolled as the control group of a case-control study for breast cancer conducted from 2001 to 2005. Global DNA methylation was quantified by Luminometric Methylation Assay (LUMA).

Results: With adjustment for lifestyle-related factors, including folate intake, the global DNA methylation level of peripheral blood leukocytes was significantly but weakly increased by 0.43% per quartile category for CRP (P for trend = 0.010). Estimated methylation levels stratified by CRP quartile were 70.0%, 70.8%, 71.4%, and 71.3%, respectively. In addition, interaction between polymorphism of MTHFR (rs1801133, known as C677T) and CRP was significant (P for interaction = 0.046); the global methylation level was significantly increased by 0.61% per quartile category for CRP in the CT/TT group (those with the minor allele T, P for trend = 0.001), whereas no association was observed in the CC group (wild type).

Conclusions: Our study suggests that CRP concentration is weakly associated with global DNA methylation level. However, this association was observed more clearly in individuals with the minor allele of the MTHFR missense SNP rs1801133. By elucidating the complex mechanism of the regulation of DNA methylation by both acquired and genetic factors, our results may be important for cancer prevention.
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http://dx.doi.org/10.1186/s12885-018-4089-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812223PMC
February 2018

Clinical log data analysis for assessing the accuracy of the CyberKnife fiducial-free lung tumor tracking system.

Pract Radiat Oncol 2018 Mar - Apr;8(2):e63-e70. Epub 2017 Nov 4.

Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe, City, Hyogo, Japan.

Purpose: The CyberKnife Xsight Lung Tracking (XLT) and 1-View tracking systems can synchronize beam targeting to a visible lung tumor with respiratory motion during irradiation without requiring internal fiducial markers. The systems use a correlation model that relates external marker positions to tumor positions as well as a prediction model that predicts the target's future position. In this study, the correlation and prediction model uncertainties related to the CyberKnife fiducial-free tumor tracking system were evaluated using clinical log data.

Methods And Materials: Data from 211 fractions in 42 patients with lung tumors were analyzed. Log files produced by the CyberKnife Synchrony system were acquired after each treatment; the mean correlation and prediction errors for each patient were calculated. Additionally, we examined the tracking tumor-related parameters and analyzed the relationships between the model errors and tracking tumor-related parameters.

Results: The overall means ± standard deviations (SDs) of the correlation errors were 0.70 ± 0.43 mm, 0.36 ± 0.16 mm, 0.44 ± 0.22 mm, and 0.95 ± 0.43 mm for the superoinferior (SI), left-right (LR), anteroposterior (AP), and radial directions, respectively. The overall means ± SDs of the prediction errors were 0.13 ± 0.11 mm, 0.03 ± 0.02 mm, 0.03 ± 0.02 mm, and 0.14 ± 0.11 mm for the SI, LR, AP, and radial directions, respectively. There were no significant differences in these errors between the XLT and 1-View tracking methods. The tumor motion amplitude was moderately associated with the correlation error and strongly related to the prediction error in the SI and radial directions.

Conclusions: Clinical log data analysis can be used to determine the necessary margin sizes in treatment plans to compensate for correlation and prediction errors in the CyberKnife fiducial-free lung tumor tracking system. The tumor motion amplitude may facilitate margin determination.
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http://dx.doi.org/10.1016/j.prro.2017.10.014DOI Listing
September 2018

Investigation of the efficacy and safety of CyberKnife hypofractionated stereotactic radiotherapy for brainstem metastases using a new evaluation criterion: 'symptomatic control'.

J Radiat Res 2017 Nov;58(6):834-839

Division of Radiation Oncology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan.

The treatment of brainstem metastases remains a challenge as the brainstem itself is considered a neurological organ at risk. We aimed to investigate the efficacy and safety of CyberKnife hypofractionated stereotactic radiotherapy (HFSRT) for brainstem metastases, and to examine the balance between efficacy and safety for the management of neurological symptoms. A total of 26 lesions [pons (n = 18), medulla (n = 4) and midbrain (n = 4)] in 20 patients treated with CyberKnife hypofractionated stereotactic radiotherapy were retrospectively analyzed. The total radiation doses (18-30 Gy) were delivered in 3 or 5 equal fractions. The median follow-up was 6.5 (range, 0.5-38.0) months. The 6- and 12-month local control rates were 100% and 90%, respectively. Symptomatic failures, defined as the worsening and appearance of neurological symptoms due to the brainstem lesion after CyberKnife HFSRT, were observed in 6 patients [local failure (n = 1) and adverse events (n = 5). The symptomatic control and overall survival rates were 90% and 72% (after 6 months), respectively, and 76% and 53% (after 12 months), respectively. Longer symptomatic control was associated with site of lesion origin, and longer overall survival was associated with a graded prognostic assessment score of >2. To our knowledge, this is the second study to investigate the efficacy and safety of CyberKnife HFSRT for brainstem metastases. The local control rate was comparable with that of prior stereotactic radiosurgery studies. We propose a new evaluation criterion-'symptomatic control'-to evaluate the efficacy and safety of brainstem radiotherapy.
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http://dx.doi.org/10.1093/jrr/rrx042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710515PMC
November 2017

Identification of the suitable leaf margin for liver stereotactic body radiotherapy with flattening filter-free beams.

Med Dosim 2017 Winter;42(4):268-272. Epub 2017 Jul 12.

Division of Medical Technology Support, Kobe Minimally Invasive Cancer Center, 8-5-1, Minatojima-nakamachi, Chuo-ku, Kobe, Japan.

The purpose of this study is to identify the suitable leaf margin for liver stereotactic body radiotherapy (SBRT) with flattening filter-free (FFF) beams, as compared with that with flattening filter (FF) beams. SBRT treatment planning for 10 patients with liver cancer was performed using 10-MV FFF and FF beams obtained from a Varian TrueBeam (Varian Medical Systems, Palo Alto, CA) linear accelerator. Each plan was generated with the leaf margin to the planning target volume (PTV) ranging from -3 to 5 mm. The prescription dose at D95 (dose covering 95% of the volume) was 48 Gy in 4 fractions to the PTV. The following dosimetric parameters were evaluated quantitatively: homogeneity index (HI), conformity index (CI), gradient index (GI), the normal liver receiving a dose greater than or equal to 20 Gy (V20), and the mean normal liver dose. The HI for FFF and FF beams increased as the leaf margin decreased. The leaf margins that achieved the best CI and GI were 0.1 and -0.3 mm for FFF beams, and 0.1 and -0.9 mm for FF beams. The liver V20 and the mean liver dose reached their minimum values at leaf margins of -0.8 and 0.0 mm for FFF beams, and -0.8 and 0.0 mm for FF beams. The suitable leaf margin for SBRT planning did not differ significantly for FFF and FF beams. Our data showed that, for both FFF and FF beams, a leaf margin of 0 or -1 mm was optimal for liver SBRT planning in terms of both target coverage and normal tissue sparing.
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http://dx.doi.org/10.1016/j.meddos.2017.06.002DOI Listing
August 2018

A rare case of acute osteomyelitis due to Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus in a young healthy adult.

Int J Surg Case Rep 2017 17;33:4-7. Epub 2017 Feb 17.

Department of Orthopedic Surgery, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan. Electronic address:

Introduction: Most community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections affect skin or soft tissues, while invasive and life-threatening illnesses including osteomyelitis are less common. CA-MRSA infections occur especially in the pediatric age group, while the occurrence of CA-MRSA osteomyelitis in adults is uncommonly reported.

Presentation Of Cases: A rare case of acute osteomyelitis of the femur caused by Panton-Valentine leukocidin (PVL)-positive CA-MRSA in a 37-year-old man in good health is presented. A pure bone biopsy revealed extensive inflammation, suggestive of acute osteomyelitis, with no evidence of neoplasm, and PVL-positive MRSA was isolated from the culture. Antibiotic treatment, with 6 weeks of intravenous vancomycin and 4 weeks of clindamycin, followed by 2 weeks of oral linezolid, was given, and 2 years after treatment completion, there has been no relapse of infection.

Conclusion: This case strongly suggests that we need to be aware of CA-MRSA osteomyelitis, which requires a high level of suspicion, prompt diagnosis, and appropriate antibiotic treatment.
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http://dx.doi.org/10.1016/j.ijscr.2017.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334497PMC
February 2017

Dosimetric factors predicting radiation pneumonitis after CyberKnife stereotactic body radiotherapy for peripheral lung cancer.

Br J Radiol 2016 Dec 2;89(1068):20160560. Epub 2016 Nov 2.

2 Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.

Objective: The aims of this study were to investigate the frequency of symptomatic radiation pneumonitis (RP) after CyberKnife lung stereotactic body radiotherapy (SBRT) and to evaluate predictive factors of symptomatic RP.

Methods: 56 patients with peripheral non-small-cell lung cancer were treated using the CyberKnife VSI System (Accuracy Inc., Sunnyvale, CA) between May 2013 and September 2015. Total radiation doses ranged from 48 to 56 Gy, as delivered in four equal fractions. Symptomatic RP was defined as a grade of ≥2. Predictive factors for symptomatic RP were evaluated using univariate and multivariate analyses.

Results: With a median follow-up duration of 12.5 months (range, 3-27 months), symptomatic RP was observed in 6 (10.7%) of the 56 patients. In the univariate analysis, percent vital capacity (p < 0.05), maximum tumour diameter (p < 0.05), gross tumour volume (p < 0.05), planning target volume (p < 0.01), mean lung dose (p < 0.01) and a normal lung volume receiving 5-50 Gy of radiation (V) (p < 0.01) were identified as significant predictive factors for symptomatic RP. In the multivariate analysis, only a V >3.4% (p = 0.011) was identified as a significant predictive factor of symptomatic RP.

Conclusion: The incidence of symptomatic RP after CyberKnife SBRT was almost identical to the incidences reported in the linear accelerator-based SBRT. A significant association was observed between a V >3.4% and the risk of developing symptomatic RP. Advances in knowledge: This is the first report that has investigated prognostic factors for symptomatic RP after CyberKnife SBRT for lung cancer. The newly developed scoring system may help to predict symptomatic RP.
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http://dx.doi.org/10.1259/bjr.20160560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604921PMC
December 2016

Modulation of circulating endothelial progenitor cells by erythropoiesis-stimulating agents in patients with chronic kidney disease stage G5 and 5D
.

Clin Nephrol 2016 Nov;86 (2016)(11):242-252

Aims: Circulating endothelial progenitor cells (EPCs) play a pivotal role in vasculogenesis and promote angiogenesis by secreting growth factors. Recent studies have suggested that erythropoietin (EPO) may accelerate not only angiogenesis but also vasculogenesis, beyond erythropoiesis. The aim of this study was to investigate whether two erythropoiesis-stimulating agents (ESAs) modulate vascular-related factors and EPC mobilization in patients with chronic kidney disease stage G5 and dialysis (CKD G5 and 5D).

Materials And Methods: We conducted a 12-week prospective study in 63 patients; 21 patients received recombinant human erythropoietin (rhEPO) (EPO group, 4,565.5 ± 1,994.4 IU/week), 21 patients received darbepoetin (DA) (DA group, 40.1 ± 13.8 µg/week), and 21 patients received no ESAs (no-ESA group). Vascular mediators, including EPCs, vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), high-sensitivity C-reactive protein, and asymmetric dimethyl arginine, were measured at 0 and 12 weeks. EPCs were measured by flow cytometry as CD45lowCD34+CD133+ cells. We also performed a subanalysis of dialysis (5D) patients (n = 32) in the three groups.

Results: In the EPO group, EPC count increased significantly from 0 to 12 weeks in a dose-dependent manner (r = 0.62, p = 0.005), and the increase was more conspicuous in the subgroup of dialysis 5D patients. In the DA group, the EPC number did not change at 12 weeks. Neither rhEPO nor DA affected the serum levels of the aforementioned biomarkers other than EPC. ;Conclusion: We speculate that the pleiotropic effects of rhEPO and DA beyond their hematopoietic effects may differ between CKD G5 and 5D patients.
.
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http://dx.doi.org/10.5414/CN108747DOI Listing
November 2016

Efficacy of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis/inferior vena cava tumor thrombosis: evaluation by comparison with conventional three-dimensional conformal radiotherapy.

J Radiat Res 2016 Sep 6;57(5):512-523. Epub 2016 Apr 6.

Division of Radiation Oncology, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-Cho, Chuou-Ku, Kobe, Hyogo 650-0017, Japan.

This study aimed to evaluate the efficacy of stereotactic body radiotherapy (SBRT) compared with three-dimensional conformal radiotherapy (3DCRT). Forty-three patients with portal vein tumor thrombosis (PVTT)/inferior vena cava tumor thrombosis (IVCTT) treated with SBRT (27 with CyberKnife (CK) and 16 with TrueBeam (TB)) from April 2013 to December 2014, and 54 treated with 3DCRT from June 2008 to March 2013 were evaluated. Dosimetric parameters, response to radiotherapy (RT) and survival outcomes were compared in total SBRT vs. 3DCRT, CK vs. 3DCRT and TB vs. 3DCRT, respectively. The median biologically effective dose 10 (BED) values in total SBRT, CK, TB and 3DCRT were 73.4 Gy, 75.0 Gy, 60.5 Gy and 58.5 Gy, respectively (P < 0.001 in total SBRT vs. 3DCRT, P < 0.001 in CK vs. 3DCRT, P = 0.004 in TB vs. 3DCRT). The tumor response rates were 67%, 70%, 62% and 46%, respectively (P = 0.04, P = 0.04, P = 0.25). The 1-year overall survival rates were 49.3%, 56.7%, 38.1% and 29.3%, respectively (P = 0.02, P = 0.02, P = 0.30), and the 1-year local progression rates were 20.4%, 21.9%, 18.8% and 43.6%, respectively (P = 0.01, P = 0.04, P = 0.10). The use of SBRT made it possible to achieve a higher BED compared with the use of 3DCRT. Improvements in local control and survival were achieved in the CK group and the total SBRT group. Our results suggest that SBRT may have the potential to be the standard RT technique for the treatment of PVTT/IVCTT.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045071PMC
http://dx.doi.org/10.1093/jrr/rrw028DOI Listing
September 2016

Radiotherapy for brainstem gliomas in children and adults: A single-institution experience and literature review.

Asia Pac J Clin Oncol 2017 Apr 3;13(2):e153-e160. Epub 2016 Mar 3.

Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe, Japan.

Aim: To evaluate the treatment results of radiotherapy (RT) in children and adults with brainstem gliomas (BSGs) and review the previous literature.

Methods: Thirty patients (14 children, 16 adults) with BSG treated using RT were retrospectively evaluated. The median ages of the children and adults were 8 years (range: 2-16 years) and 49 years (range: 19-75 years), respectively. A histological diagnosis was obtained in 11 patients. The median total radiation dose was 56 Gy (range: 50-70 Gy) with a single fraction size of 1.8-2.0 Gy. Temozolomide was administered concurrently with RT in 14 patients.

Results: Tumor progression after RT occurred in 26 patients (14 children and 12 adults). Four adults survived without tumor progression. The median survival times for children and adults were 8.5 and 39 months, respectively. The 1-, 2- and 3-year overall survival rates for children/adults were 29%/75%, 14%/68% and 0%/53%, respectively (P = 0.001), and the 1-, 2- and 3-year progression-free survival rates for children/adults were 14%/69%, 0%/49% and 0%/35%, respectively (P < 0.001). Grade 3 or higher acute and late toxicities did not occur.

Conclusion: In this study, the prognosis of children with BSGs was considerably poorer than that of adults, and our results are consistent with those of previous studies. Efforts should be made to improve the survival outcomes of patients with BSGs, especially children.
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http://dx.doi.org/10.1111/ajco.12451DOI Listing
April 2017

Amyloplast Membrane Protein SUBSTANDARD STARCH GRAIN6 Controls Starch Grain Size in Rice Endosperm.

Plant Physiol 2016 Mar 20;170(3):1445-59. Epub 2016 Jan 20.

Institute of Plant Science and Resources, Okayama University, Kurashiki 710-0046, Japan (R.M., M.M., H.K., H.N., W.S.);Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan (M.K.);RIKEN Center for Sustainable Resource Science, Yokohama, Kanagawa 230-0045, Japan (M.K.);Fukui Agricultural Experiment Station, Fukui 918-8215, Japan (K.T.); andDepartment of Biological Production, Akita Prefectural University, Akita 010-0195, Japan (N.C., N.F.).

Starch is a biologically and commercially important polymer of glucose. Starch is organized into starch grains (SGs) inside amyloplasts. The SG size differs depending on the plant species and is one of the most important factors for industrial applications of starch. There is limited information on genetic factors regulating SG sizes. In this study, we report the rice (Oryza sativa) mutant substandard starch grain6 (ssg6), which develops enlarged SGs in endosperm. Enlarged SGs are observed starting at 3 d after flowering. During endosperm development, a number of smaller SGs appear and coexist with enlarged SGs in the same cells. The ssg6 mutation also affects SG morphologies in pollen. The SSG6 gene was identified by map-based cloning and microarray analysis. SSG6 encodes a protein homologous to aminotransferase. SSG6 differs from other rice homologs in that it has a transmembrane domain. SSG6-green fluorescent protein is localized in the amyloplast membrane surrounding SGs in rice endosperm, pollen, and pericarp. The results of this study suggest that SSG6 is a novel protein that controls SG size. SSG6 will be a useful molecular tool for future starch breeding and applications.
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http://dx.doi.org/10.1104/pp.15.01811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775137PMC
March 2016

A Rare Case of Tumoral Calcium Pyrophosphate Dihydrate Crystal Deposition Disease of the Wrist Joint.

Case Rep Orthop 2015 17;2015:313291. Epub 2015 Nov 17.

Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.

Introduction. Tumoral calcium pyrophosphate dihydrate (CPPD) crystal deposition disease (CPPDCD), also known as tophaceous calcium pyrophosphate deposition disease (CPDD), is a tumorlike lesion, and it should be distinguished from usual CPDD that causes severe joint inflammation and arthralgia. A case of tumoral CPPDCD of the wrist joint that required differentiation from synovial osteochondromatosis is described. Case Presentation. The patient was a 78-year-old woman with a 5-year history of nodular lesions at the right wrist that had gradually increased in size. An excisional biopsy and a histological examination of the excised nodular lesions by hematoxylin and eosin (H&E) staining were performed, demonstrating numerous polarizable, rhabdoid, and rectangular crystals, surrounded by fibroblasts, macrophages, and foreign body-type giant cells, consistent with tumoral CPPDCD. Conclusion. Tumoral CPPDCD, especially at the wrist joint, is rare, and, to the best of our knowledge, only 2 articles have been published. This case seems to need further follow-up for recurrence, because tumoral CPPDCD may recur after complete or incomplete surgical excision.
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http://dx.doi.org/10.1155/2015/313291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691467PMC
January 2016

GSK-3 inhibitor inhibits cell proliferation and induces apoptosis in human osteosarcoma cells.

Oncol Rep 2016 Apr 15;35(4):2348-54. Epub 2016 Jan 15.

Department of Orthopaedic Surgery, Kagawa University Faculty of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that functions in numerous signaling pathways initiated by diverse stimuli. The functions of GSK-3 in cancer differ depending on cell type. In the present study, we examined the effects of a specific GSK-3 inhibitor on the regulation of osteosarcoma cell proliferation and apoptosis. Immunohistochemical analysis and real-time reverse transcription-polymerase chain reaction (RT-PCR) were performed to determine the expression pattern of GSK-3 in human osteosarcoma cells. We used the MTS assay, western blotting, measurement of single-stranded DNA and morphological analyses to study the effects of a GSK-3 inhibitor, SB216763 on osteosarcoma cell proliferation and survival. We detected an increase in mRNA expression of GSK-3 and aberrant nuclear accumulation of GSK-3 in the osteosarcoma cells. Pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of osteosarcoma cells. Inhibition of GSK-3 resulted in a decreased expression of Bcl-2 and a subsequent increase in osteosarcoma cell apoptosis via the mitochondrial pathway. The present study demonstrated that GSK-3 activity is critical for tumorigenicity and cell survival in osteosarcoma cells. Our findings suggest that GSK-3 is a potential therapeutic target for the treatment of human osteosarcoma.
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http://dx.doi.org/10.3892/or.2016.4565DOI Listing
April 2016

Apoptosis and antitumor effects induced by the combination of an mTOR inhibitor and an autophagy inhibitor in human osteosarcoma MG63 cells.

Int J Oncol 2016 Jan 3;48(1):37-44. Epub 2015 Nov 3.

Department of Orthopaedic Surgery, Kagawa University School of Medicine, Miki-cho, Kita-gun, Kagawa, Japan.

The inhibition of the mammalian target of rapamycin (mTOR) signaling pathway promotes the initiation of autophagy. Although it remains under debate whether chemotherapy-induced autophagy in tumor cells is a protective response or is invoked to promote cell death, recent studies indicate that autophagy is a self-defense mechanism of cancer cells that are subjected to antitumor agents and that blocking autophagy can trigger apoptosis. The aim of this study was to examine the effects of rapamycin, an mTOR inhibitor, on MG63 osteosarcoma cells. We further examined whether the combination of rapamycin and the small molecule inhibitor of autophagy Spautin-1 (specific and potent autophagy inhibitor-1) enhanced the rapamycin-induced apoptosis in MG63 cells. We examined the effects of rapamycin treatment on cell proliferation, phosphorylation of mTOR pathway components, and autophagy by western blot analysis. Furthermore, we examined the effects of rapamycin with or without Spautin-1 on the induction of apoptosis by western blot analysis and immunohistochemical staining. We found that rapamycin inhibited cell proliferation and decreased the phosphorylation of mTOR pathway components in MG63 cells. Rapamycin induced the apoptosis of MG63 cells, and this apoptosis was enhanced by Spautin-1. It was considered that Spautin-1 suppressed the protective mechanism induced by rapamycin in tumor cells and induced apoptosis. Therefore, the combination of an mTOR inhibitor and an autophagy inhibitor may be effective in the treatment of osteosarcoma because it effectively induces the apoptotic pathway.
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http://dx.doi.org/10.3892/ijo.2015.3227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734606PMC
January 2016

A Case of Pulmonary Squamous Cell Carcinoma Revealed Ground Glass Opacity on Computed Tomography.

J Thorac Oncol 2015 Aug;10(8):1229-30

*Department of Chest and Breast Surgery, Nagano Municipal Hospital, Nagano, Japan; †Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan; ‡Department of Pathology, Kyoto University Hospital, Kyoto, Japan; §Department of Thoracic Surgery, Shinshu University Hospital, Matsumoto, Japan; ‖Department of Respiratory Medicine, Nagano Municipal Hospital, Nagano, Japan; and ¶Department of Pathology, Nagano Municipal Hospital, Nagano, Japan.

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http://dx.doi.org/10.1097/JTO.0000000000000462DOI Listing
August 2015