346 results on '"Sachio, Fushida"'
Search Results
2. Verification of Resectability Status for Pancreatic Cancer
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Isamu, Makino, Hidehiro, Tajima, Hirohisa, Kitagawa, Ryosuke, Gabata, Mitsuyoshi, Okazaki, Hiroyuki, Shinbashi, Yoshinao, Ohbatake, Shinichi, Nakanuma, Hiroto, Saito, Takahisa, Yamaguchi, Shiro, Terai, Koichi, Okamoto, Seisho, Sakai, Jun, Kinoshita, Keishi, Nakamura, Itasu, Ninomiya, Sachio, Fushida, and Tetsuo, Ohta
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Pancreatic Neoplasms ,Endocrinology ,Hepatology ,Mesenteric Artery, Superior ,Endocrinology, Diabetes and Metabolism ,Disease Progression ,Internal Medicine ,Humans ,Tomography, X-Ray Computed ,Pancreaticoduodenectomy - Abstract
Resectability status is considered an important indicator for progression of pancreatic cancer. We verified the superior mesenteric artery (SMA) factors of resectability status by radiological and pathological analysis in patients who underwent pancreatoduodenectomy with combined resection of the SMA.We enrolled 22 patients who underwent pancreatoduodenectomy with combined resection of the SMA. Patients were divided into 3 groups according to the contact angle between the tumor and the SMA in preoperative computed tomography images (no contact, R-sma; contact within 180 degrees, BR-sma; contact more than 180 degrees, UR-sma). We pathologically evaluated cancer progression toward the SMA.There were 3 patients with R-sma, 12 with BR-sma, and 7 with UR-sma. The median distance (mm) between the cancer and the SMA was 7.0 with R-sma, 1.0 with BR-sma, and 0 with UR-sma (P = 0.0003). Invasion to the superior mesenteric nerve plexus was positive in none with R-sma, 11 with BR-sma, and 7 with UR-sma (P0.0001). Invasion to the SMA was positive in none with R-sma and BR-sma, and 7 with UR-sma (P0.0001).Superior mesenteric artery factors of resectability status are reliable indicator for cancer progression toward the SMA.
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- 2022
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3. Life prognosis of sentinel node navigation surgery for early-stage gastric cancer: Outcome of lymphatic basin dissection
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Shinichi Kinami, Naohiko Nakamura, Tomoharu Miyashita, Hidekazu Kitakata, Sachio Fushida, Takashi Fujimura, Yasuo Iida, Noriyuki Inaki, Toru Ito, and Hiroyuki Takamura
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Early gastric cancer ,Sentinel node biopsy ,Sentinel Lymph Node Biopsy ,Dissection ,Function preserving surgery ,Gastroenterology ,General Medicine ,Lymph node dissection ,Prognosis ,Gastrectomy ,Stomach Neoplasms ,Retrospective Cohort Study ,Humans ,Lymph Node Excision ,Neoplasm Recurrence, Local ,Lymphatic basin dissection ,Retrospective Studies - Abstract
BACKGROUND Lymphatic basin dissection is a sentinel node biopsy method that is specific for gastric cancer. In this method, the dyed lymphatic system is dissected en bloc, and sentinel nodes are identified at the back table (ex vivo). Even with lymphatic basin dissection, blood flow to the residual stomach can be preserved, and function-preserving curative gastrectomy can be performed. The oncological safety of function-preserving curative gastrectomy combined with lymphatic basin dissection has not yet been fully investigated. We hypothesized that the oncological safety of sentinel node navigation surgery (SNNS) is not inferior to that of the guidelines. AIM To investigate the life prognosis of SNNS for gastric cancer in comparison with guidelines surgery. METHODS This was a retrospective cohort study. Patients were selected from gastric cancer patients who underwent sentinel node biopsy from April 1999 to March 2016. Patients from April 1999 to August 2008 were from the Department of Surgery II, Kanazawa University Hospital, and patients from August 2009 to March 2016 were from the Department of Surgical Oncology, Kanazawa Medical University Hospital. Patients who were diagnosed with gastric cancer, which was preoperatively diagnosed as superficial type (type 0), 5 cm or less in length, clinical T1-2 and node negative, and underwent various gastrectomies guided by sentinel node navigation were retrospectively collected. The overall survival (OS) and relapse-free survival (RFS) of these patients (SNNS group) were investigated. Patients with gastric cancer of the same stage and who underwent guidelines gastrectomy with standard nodal dissection were also selected as the control group. RESULTS A total of 239 patients in the SNNS group and 423 patients in the control group were included. Pathological nodal metastasis was observed in 10.5% and 10.4% of the SNNS and control groups, respectively. The diagnostic abilities of sentinel node biopsy were 84% and 98.6% for sensitivity and accuracy, respectively. In the SNNS group, 81.6% of patients underwent modified gastrectomy or function-preserving curative gastrectomy with lymphatic basin dissection, in which the extent of nodal dissection was further reduced compared to the guidelines. The OS rate in the SNNS group was 96.8% at 5 years and was significantly better than 91.3% in the control group (P = 0.0014). The RFS rates were equal in both groups. After propensity score matching, there were 231 patients in both groups, and the cumulative recurrence rate was 0.43% at 5 years in the SNNS group and 1.30% in the control group, which was not statistically different. CONCLUSION The oncological safety of patients who undergo gastrectomy guided by sentinel node navigation is not inferior to that of the guidelines surgery.
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- 2021
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4. Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis
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Shintaro Yagi, Satoshi Takada, Ryohei Takei, Itasu Ninomiya, Tetsuo Ohta, Hiroyuki Takamura, Hidehiro Tajima, Ai Harashima, Sachio Fushida, Noriyuki Inaki, Seiichi Munesue, Tomoharu Miyashita, and Yasuhiko Yamamoto
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Cancer Research ,Esophageal Neoplasms ,Carcinogenesis ,Immunology ,Adenocarcinoma ,medicine.disease_cause ,Barrett Esophagus ,Immune system ,Tumor Microenvironment ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Neoplastic transformation ,Reflux esophagitis ,Tumor microenvironment ,business.industry ,Chronic Esophagitis ,Esophageal cancer ,medicine.disease ,Metformin ,Rats ,Oncology ,Cancer research ,business - Abstract
Chronic inflammation contributes to tumor development by creating a local microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Esophageal cancer (EC) is an inflammation-associated malignancy with a poor prognosis. The nature of the switch between chronic inflammation of the esophagus and EC-related immunological changes remains unclear. Here, we examined the dynamic alterations of immune cells at different stages of chronic esophagitis, Barrett’s esophagus (BE) and EC using an esophageal spontaneous carcinogenesis rat model. We also investigated the anticancer effects of metformin. To stimulate EC carcinogenesis, chronic gastroduodenal reflux esophagitis via esophagojejunostomy was induced in 120 rats in metformin-treated and non-treated (control) groups. After 40 weeks, BE and EC developed in 96.7% and 63.3% of the control group, and in 66.7% and 23.3% of the metformin-treated group, respectively. Flow cytometric analysis demonstrated that the balance of M1/M2-polarized or phospho-Stat3-positive macrophages, regulatory T, cytotoxic T, natural killer (NK), NK T cells, and Th17 T cells was dynamically changed at each stage of the disease and were resolved by metformin treatment. These findings clarify the immunity in esophageal carcinogenesis and suggest that metformin could suppress this disease by improving the immunosuppressive tumor microenvironment and immune evasion.
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- 2021
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5. ASO Visual Abstract: Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake
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Tatsuya Aoki, Jun Kinoshita, Seiichi Munesue, Toshihide Hamabe-Horiike, Takahisa Yamaguchi, Yusuke Nakamura, Koichi Okamoto, Hideki Moriyama, Keishi Nakamura, Shinichi Harada, Yasuhiko Yamamoto, Noriyuki Inaki, and Sachio Fushida
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Oncology ,Surgery - Published
- 2023
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6. Current status of conversion surgery for stage IV gastric cancer
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Sachio Fushida, Jun Kinoshita, Hideki Moriyama, and Takahisa Yamaguchi
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medicine.medical_specialty ,medicine.medical_treatment ,Stage iv disease ,Antineoplastic Agents ,Resection ,03 medical and health sciences ,0302 clinical medicine ,Gastrectomy ,Stomach Neoplasms ,Surgical oncology ,medicine ,Humans ,Neoplasm Staging ,R0 resection ,Chemotherapy ,business.industry ,Palliative Care ,Margins of Excision ,Cancer ,Induction chemotherapy ,Induction Chemotherapy ,General Medicine ,medicine.disease ,Combined Modality Therapy ,Surgery ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,Stage iv ,business - Abstract
Palliative chemotherapy with best supportive care is a mainstay for patients with gastric cancer (GC) and distant metastasis. However, with advances in GC chemotherapy, multimodal treatment, including perioperative chemotherapy plus conversion surgery, has attracted attention as a new strategy to improve the outcome of patients with stage IV disease. Conversion surgery is defined as surgical treatment aimed at R0 resection after a good response to induction chemotherapy for tumors originally considered unresectable or marginally resectable for technical and/or oncological reasons. Various biological characteristics differ, depending on each metastatic condition in stage IV GC. The main metastatic pathways of GC can be divided into three categories: lymphatic, hematogenous, and peritoneal. In each category, considerable historical data on conversion surgery have demonstrated the benefits of individualized approaches. However, owing to the diversity of these conditions, a common definition, including the choice of induction chemotherapy, optimal timing of resection, and eligibility for conversion surgery, has not been established among surgical oncologists. Thus, we explore the current and future treatment options by reviewing the literature on this controversial topic comprehensively.
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- 2021
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7. Prognostic value of tumor-infiltrating CD163+macrophage in patients with metastatic gastric cancer undergoing multidisciplinary treatment
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Shiro Terai, Mari Shimada, Sachio Fushida, Keishi Nakamura, Hiroto Saito, Takahisa Yamaguchi, Shintaro Yagi, Itasu Ninomiya, Hideki Moriyama, Jun Kinoshita, Noriyuki Inaki, and Koichi Okamoto
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Oncology ,medicine.medical_specialty ,Cancer Research ,business.industry ,Metastatic gastric cancer ,Internal medicine ,medicine ,Genetics ,Macrophage ,In patient ,business ,CD163 ,Value (mathematics) - Abstract
Background The multidisciplinary treatment including induction chemotherapy plus conversion surgery (CS) has attracted attention as a new strategy to improve the outcome of metastatic gastric cancer (MGC). However, it is unclear which patients achieve a good response to chemotherapy and successful CS. Tumor-infiltrating immune cells (TIICs) have been reported to be both prognostic and predictive biomarkers not only in immunotherapy but also in chemotherapy in many cancer types. However, there have been no reports on the usefulness of TIICs as biomarkers in conversion surgery for MGC. The aim of the present study was to evaluate the association between the TIICs and treatment outcome for the multidisciplinary treatment in MGC. Methods We retrospectively analyzed 68 MGC patients who received docetaxel plus cisplatin plus S-1 (DCS) therapy between April 2006 and March 2019 in our institute. The number of tumor-infiltrating CD4+, CD8+, Foxp3+lymphocytes, CD68+, CD163+macrophages in pre-treatment endoscopic biopsy samples were evaluated to investigate their predictive value for multidisciplinary treatment. Results Fifty patients underwent CS following DCS therapy (CS group), whereas 18 patients underwent DCS therapy alone (non-CS group). The median survival time (MST) of CS group was 33.3 months, which was significantly longer than the MST of 9.0 months in non-CS group (p +macrophages was extracted as an independent prognostic factor for overall survival in all patients. There were more cases of high infiltration of CD163+macrophages in non-CS group than in CS group. Furthermore, in CS group, pathological responders to DCS therapy showed low infiltration of CD163+ macrophages, and high infiltration of CD8+lymphocyte. CD163 low group showed a significant prolonged survival compared with CD163 high group in patients who underwent CS (p = 0.02). Conclusions The pre-treatment CD163+macrophages infiltration would be a pivotal biomarker for predicting prognosis and pathological response to multidisciplinary treatment among TIICs in MGC. Thus, for patients with low CD163+macrophage infiltration in pre-treatment biopsy sample, diagnostic imaging should be performed frequently during chemotherapy to avoid missing the optimal timing for CS, and CS should be aggressively considered as a treatment option if curative resection is deemed feasible.
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- 2022
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8. Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake
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Tatsuya Aoki, Jun Kinoshita, Seiichi Munesue, Toshihide Hamabe-Horiike, Takahisa Yamaguchi, Yusuke Nakamura, Koichi Okamoto, Hideki Moriyama, Keishi Nakamura, Shinichi Harada, Yasuhiko Yamamoto, Noriyuki Inaki, and Sachio Fushida
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Oncology ,Surgery - Abstract
Background The lipid scavenger receptor cluster of differentiation 36 (CD36) has been shown to have a pro-metastatic function in several cancers. Adipose tissue, a favorable site for peritoneal metastasis (PM) from gastric cancer (GC), promotes this process by providing free fatty acids (FFAs); however, the role of CD36 in PM progression from GC remains to be elucidated. Materials and Methods We evaluated CD36 expression in the GC cells under various conditions. CD36 overexpressing (CD36OE) MKN45 cells were prepared and their migration and invasive properties were assessed. A PM mouse model was used to investigate the biological effects of palmitic acid (PA) and CD36. Furthermore, we examined the clinical role of CD36 expression in 82 human PM samples by immunohistochemical staining. Results Hypoxia markedly increased CD36 expression in GC cells. In normoxia, only CD36OE MKN45 cells treated with PA showed an increase in migration and invasion abilities. An increased expression of active Rac1 and Cdc42 was observed, which decreased following etomoxir treatment. Conversely, hypoxia increased those capacities of both vector and CD36OE MKN45 cells. In a mouse model transplanted with CD36OE MKN45 cells, more peritoneal tumors were observed in the high-fat diet group than those in the normal diet group. In clinical samples, 80% of PM lesions expressed CD36, consistent with hypoxic regions, indicating a significant association with prognosis. Conclusion Our findings indicate that a hypoxia in the peritoneal cavity induces CD36 expression in GC cells, which contributes to PM through the uptake of FFAs.
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- 2022
9. Correction to: Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis
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Tetsuo Ohta, Sachio Fushida, Ryohei Takei, Seiichi Munesue, Noriyuki Inaki, Satoshi Takada, Ai Harashima, Shintaro Yagi, Itasu Ninomiya, Hiroyuki Takamura, Yasuhiko Yamamoto, Tomoharu Miyashita, and Hidehiro Tajima
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Cancer Research ,Oncology ,business.industry ,Immunity ,Immunology ,Cancer research ,Immunology and Allergy ,Medicine ,business ,Esophageal carcinogenesis ,Metformin ,medicine.drug - Published
- 2021
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10. A multicenter non-randomized phase III study of sentinel node navigation surgery for early gastric cancer
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Yuko Kitagawa, Sachio Fushida, Kazumasa Fukuda, Shinichi Kadoya, Hironori Tsujimoto, Norio Mitsumori, Yasunori Sato, Satoshi Kamiya, Hirofumi Kawakubo, Tomoyuki Irino, Satoru Matsuda, Junichi Sakamoto, Naoto Takahashi, Hiroya Takeuchi, Hideki Hayashi, Shoji Natsugoe, Masaki Ohi, Masanori Terashima, Shinichi Kinami, Shuhei Mayanagi, and Kazuhito Nabeshima
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Male ,Cancer Research ,medicine.medical_specialty ,Endpoint Determination ,medicine.medical_treatment ,Sentinel lymph node ,Stomach Neoplasms ,Clinical endpoint ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Prospective Studies ,Lymph node ,Sentinel Lymph Node Biopsy ,business.industry ,Cancer ,General Medicine ,Sentinel node ,medicine.disease ,Early Gastric Cancer ,Surgery ,Dissection ,medicine.anatomical_structure ,Oncology ,Quality of Life ,Lymph Node Excision ,Female ,Gastrectomy ,Neoplasm Recurrence, Local ,Sentinel Lymph Node ,business ,Follow-Up Studies - Abstract
This prospective multicenter non-randomized phase III study aims to evaluate the long-term outcome of sentinel node navigation surgery for early gastric cancer compared with conventional distal or total gastrectomy. Clinically diagnosed primary T1N0M0 gastric cancer patients with a single lesion (≤40 mm) and without previous endoscopic treatment will be enrolled in this study. Sentinel nodes are identified by dye and radioisotope tracers and are subjected to intraoperative rapid pathology. For patients with negative sentinel node metastasis, individualized surgery consisting of limited stomach resection and sentinel node basin dissection is performed, while standard gastrectomy with D2 lymph node dissection is employed for the positive sentinel node patients. A total of 225 patients will be accrued from 13 hospitals that have experience in sentinel node mapping. The primary endpoint is 5-year relapse-free survival. The secondary endpoints are overall survival, sentinel node detection rate, diagnostic accuracy for sentinel node, distribution of sentinel nodes and metastatic sentinel node/non-sentinel node, and postoperative quality of life.
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- 2020
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11. Interactions Between Neutrophils and Platelets in the Progression of Acute Pancreatitis
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Seisho Sakai, Tomoharu Miyashita, Shinichi Harada, Jun Kinoshita, Hidehiro Tajima, Keishi Nakamura, Sachio Fushida, Isamu Makino, Shinichi Nakanuma, Tetsuo Ohta, Tomokazu Tokoro, Itasu Ninomiya, and Koichi Okamoto
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Blood Platelets ,Male ,Taurocholic Acid ,Pathology ,medicine.medical_specialty ,Neutrophils ,Endocrinology, Diabetes and Metabolism ,Connective tissue ,Inflammation ,Cell Communication ,Pathogenesis ,Leukocyte Count ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Internal Medicine ,medicine ,Animals ,Platelet ,HMGB1 Protein ,Rats, Wistar ,Pancreas ,Peroxidase ,Hepatology ,biology ,Platelet Count ,business.industry ,medicine.disease ,Thromboxane B2 ,medicine.anatomical_structure ,Pancreatitis ,chemistry ,030220 oncology & carcinogenesis ,Myeloperoxidase ,Plasminogen activator inhibitor-1 ,Acute Disease ,Disease Progression ,biology.protein ,Acute pancreatitis ,030211 gastroenterology & hepatology ,medicine.symptom ,business - Abstract
Objective Severe acute pancreatitis is a serious disease, but its detailed mechanism has not yet been elucidated. We aimed to clarify the interaction between neutrophils and platelets in the pathogenesis of acute pancreatitis. Methods We induced acute pancreatitis in rats by injection of sodium taurocholate into the biliopancreatic duct and killed them over time. We observed the histological changes in pancreatic tissue with special attention to the dynamics of neutrophils and platelets. We also measured the concentrations of neutrophil- and platelet-derived factors in pancreatic tissue and blood samples. Results Neutrophils and platelets in the pancreatic tissue showed a similar pattern of migration. They initially spread in the interlobular connective tissue and finally into the lobules. The concentration of myeloperoxidase gradually increased in the inflamed pancreas until 24 hours and the concentration of thromboxane B2, plasminogen activator inhibitor 1, and CD41 also increased with time. Finally, the concentration of serum myeloperoxidase, citrullinated histone H3, and high-mobility group box 1 increased over time. Conclusions The interaction between neutrophils and platelets in pancreatic tissue plays an important role in the mechanism of advancing severity in acute pancreatitis. Circulating damage-associated molecular patterns induced by excessive local inflammation may lead to other organ injuries.
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- 2020
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12. Extravasated platelet aggregation contributes to tumor progression via the accumulation of myeloid‑derived suppressor cells in gastric cancer with peritoneal metastasis
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Sachio Fushida, Tomoharu Miyashita, Shiro Terai, Yoshinao Ohbatake, Itasu Ninomiya, Koichi Okamoto, Isamu Makino, Mitsuyoshi Okazaki, Jun Kinoshita, Hidehiro Tajima, Takahisa Yamaguchi, Shinichi Nakanuma, Hiroyuki Takamura, Keishi Nakamura, Satoko Ishikawa, and Tetsuo Ohta
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0301 basic medicine ,Cancer Research ,epithelial-mesenchymal transition ,myeloid-derived suppressor cell ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Epithelial–mesenchymal transition ,extravasated platelet aggregation ,Tumor microenvironment ,Oncogene ,business.industry ,gastric cancer ,FOXP3 ,Cancer ,Articles ,medicine.disease ,Molecular medicine ,030104 developmental biology ,Oncology ,Tumor progression ,peritoneal metastasis ,030220 oncology & carcinogenesis ,Cancer research ,Myeloid-derived Suppressor Cell ,business - Abstract
Extravasated platelet aggregation (EPA) serves an important role in the cancer microenvironment during cancer progression, and has been demonstrated to interact with tumor cells in several types of cancer. EPA induces epithelial-mesenchymal transition (EMT) via transforming growth factor-β, and also recruits immunosuppressive cells, including regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). However, the role of EPA in gastric cancer with peritoneal metastasis remains unknown. The present study analyzed the association between EPA and prognosis in patients with gastric cancer with peritoneal metastasis. The present study evaluated 62 patients diagnosed with advanced gastric cancer with peritoneal metastasis between 2001 and 2016. EPA, EMT, Treg cells and MDSCs in peritoneal metastatic lesions were detected by immunohistochemical evaluation of CD42b, SNAIL, FOXP3 and CD33, respectively. CD42b expression was observed in 56.5% (35/62) of peritoneal metastatic lesions. CD42b expression in peritoneal metastatic lesions was associated with poor overall survival compared with lower frequencies (hazard ratio, 2.03; 95% confidence interval, 1.12–3.69; P=0.018). SNAIL, FOXP3 and CD33 expression were not associated with overall survival, but CD33 expression was markedly higher in CD42b-positive patients (P=0.022). These results indicated that EPA affects immunosuppression by recruiting MDSCs in the tumor microenvironment via the secretion of soluble factors, resulting in tumor progression. EPA may be a novel therapeutic target for gastric cancer with peritoneal metastasis.
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- 2020
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13. Interleukin-17A derived from mast cells contributes to fibrosis in gastric cancer with peritoneal dissemination
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Hiroto Saito, Daisuke Fujimori, Shinichi Harada, Jun Kinoshita, Hidehiro Tajima, Sachio Fushida, Katsuya Gunjigake, Tetsuo Ohta, Takahisa Yamaguchi, Itasu Ninomiya, and Toshihide Horiike
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Adult ,Male ,Cancer Research ,medicine.medical_treatment ,Mice, Nude ,Mast cell ,Mice ,Stomach Neoplasms ,Fibrosis ,Cell Line, Tumor ,IL-17A ,medicine ,Animals ,Humans ,Mast Cells ,Peritoneal Neoplasms ,Aged ,Aged, 80 and over ,Mice, Inbred BALB C ,business.industry ,Interleukin-17 ,Gastroenterology ,Degranulation ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Coculture Techniques ,Transplantation ,Cytokine ,medicine.anatomical_structure ,Oncology ,Tumor progression ,Cancer research ,Original Article ,Female ,Interleukin 17 ,Peritoneum ,Gastric cancer ,business ,Peritoneal dissemination - Abstract
Objectives Interleukin-17A (IL-17A) is pro-inflammatory cytokine and acts as profibrotic factor in the fibrosis of various organs. Fibrosis tumor-like peritoneal dissemination of gastric cancer interferes with drug delivery and immune cell infiltration because of its high internal pressure. In this study, we examined the relationship between IL-17A and tissue fibrosis in peritoneal dissemination and elucidated the mechanism of fibrosis induced by IL-17A using human peritoneal mesothelial cells (HPMCs) and a mouse xenograft model. Methods Seventy gastric cancer patients with peritoneal dissemination were evaluated. The correlation between IL-17A and fibrosis was examined by immunofluorescence and immunohistochemistry. A fibrosis tumor model was developed based on subcutaneous transplantation of co-cultured cells (HPMCs and human gastric cancer cell line MKN-45) into the dorsal side of nude mice. Mice were subsequently treated with or without IL-17A. We also examined the effect of IL-17A on HPMCs in vitro. Results There was a significant correlation between IL-17A expression, the number of mast cell tryptase (MCT)-positive cells, and the degree of fibrosis (r = 0.417, P Conclusions IL-17A derived from mast cells contributes to tumor fibrosis in peritoneal dissemination of gastric cancer. Inhibiting degranulation of mast cells might be a promising treatment strategy to control organ fibrosis.
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- 2020
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14. Peripheral Blood Platelet–Lymphocyte Ratio Is Good Predictor of Chemosensitivity and Prognosis in Gastric Cancer Patients
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Yuka Ohe, Keishi Nakamura, Takahisa Yamaguchi, Jun Kinoshita, Itasu Ninomiya, Koichi Okamoto, Tetsuo Ohta, Hiroto Saito, Sachio Fushida, and Hidehiro Tajima
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0301 basic medicine ,medicine.medical_specialty ,Lymphocyte ,medicine.medical_treatment ,Inflammation ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Blood test ,Univariate analysis ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Cancer ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Docetaxel ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,medicine.symptom ,business ,medicine.drug - Abstract
Introduction Platelets are one factor promoting tumor development. Conversely, lymphocytes are one factor for immune protection. The peripheral blood platelets-lymphocyte ratio (PLR) is useful as an inflammation/immune indicator to predict postoperative recurrence and prognosis of a variety of malignancies. The peripheral blood neutrophil-lymphocyte ratio (NLR) has also been reported as a useful inflammation/immune indicator. However, there are few studies evaluating the relationship between these peripheral blood indicators and the effectiveness of chemotherapy. Thus, we examined these relationships in gastric cancer patients. Patients and Methods Between 2005 and 2018, 41 gastric cancer patients treated with preoperative DCS therapy (docetaxel, cisplatin, and S-1) therapy followed by gastrectomy were evaluated. Data for peripheral blood tests prior to the initiation of chemotherapy were used. The effectiveness of chemotherapy was determined using Response Evaluation Criteria in Solid Tumors (RECIST) and the pathological response of primary lesions (Ef grade). The relationship between the blood test results and the effectiveness of chemotherapy was evaluated. Results Each optimal cut-off value of peripheral inflammation/immune indicators was calculated through ROC curves. Although the pathological responder (Ef grade 2 or 3) revealed significantly better prognosis than the non-responder (Ef grade 0-1b), no relationship was found between responder according to RECIST and prognosis (P=0.014, P=0.992). In univariate analysis, a low PLR (
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- 2020
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15. Prophylactic Effect of Recombinant Human Soluble Thrombomodulin for Hepatic Sinusoidal Obstruction Syndrome Model Mice
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Tomoharu Miyashita, Tetsuo Ohta, Sachio Fushida, Isamu Makino, Satoshi Takada, Shunsuke Kanou, Hidehiro Tajima, Mitsuyoshi Okazaki, Yasuhiko Yamamoto, Yoshinao Ohbatake, Hiroyuki Takamura, Shinichi Nakanuma, and Makoto Nakura
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Cancer Research ,Biopsy ,Thrombomodulin ,Hepatic Veno-Occlusive Disease ,Pharmacology ,Placebo ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,Mice ,03 medical and health sciences ,0302 clinical medicine ,law ,Enos ,Animals ,Humans ,Medicine ,Platelet activation ,biology ,business.industry ,biology.organism_classification ,Immunohistochemistry ,Recombinant Proteins ,Blood Cell Count ,Staining ,Disease Models, Animal ,Treatment Outcome ,Liver ,030220 oncology & carcinogenesis ,Recombinant DNA ,biology.protein ,Pre-Exposure Prophylaxis ,Antibody ,business ,Plasminogen activator ,Biomarkers ,Immunostaining ,Research Article - Abstract
Aim The present study aimed to examine the effects of prophylactic administration of recombinant human soluble thrombomodulin (rTM) for the prevention of sinusoidal obstruction syndrome (SOS). Materials and methods Crl:CD1 mice were allocated to the rTM, placebo, and control groups. The rTM group received an intraperitoneal administration of rTM, with intraperitoneal administration of monocrotaline (MCT) 1 h later. The placebo group received PBS instead of rTM, and the control group received PBS instead of rTM and MCT. Mice were sacrificed 48 h after MCT administration, and blood and liver tissues were evaluated. Immunostaining was performed using anti-CD42b and anti-SE-1 antibodies, and AZAN staining. Levels of plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS) in whole liver tissues were estimated using RT-PCR. Results Hematoxylin-eosin staining showed that SOS-related findings were markedly attenuated in the rTM group compared to the placebo group. CD42b immunostaining showed the presence of extravasated platelet activation (EPA) in the Disse space in the placebo group, but this was less noticeable in the rTM group. PAI-1 levels were significantly lower in the rTM group than in the placebo group in RT-PCR. However, eNOS levels were significantly higher in the rTM group than in the placebo group. Conclusion Administration of rTM may prevent SOS by protecting sinusoidal endothelial cells.
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- 2020
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16. Adipocytes contribute to tumor progression and invasion of peritoneal metastasis by interacting with gastric cancer cells as cancer associated fibroblasts
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Toshihide Hamabe‐Horiike, Shin‐ichi Harada, Kyoko Yoshida, Jun Kinoshita, Takahisa Yamaguchi, and Sachio Fushida
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Cancer Research ,Oncology - Abstract
Peritoneal metastasis (PM) is one of the most common causes of noncurative surgery and the most frequent recurrence pattern in gastric cancer (GC). During the process of PM, GC cells detached from primary tumor interact with human peritoneal mesothelial cells (HPMC) overlapped with adipose tissues such as the omentum or mesentery. Although the interaction with HPMC promotes the malignancy of GC, the role of adipose tissues remains unclear.We aimed to clarify how adipose tissue are affected by adjacent primary tumors during the expression of adipokines and to elucidate whether GC cells transform adipocytes into CAFs in vitro. In addition, we investigated whether GC cells are affected by adipocytes in their ability to infiltrate.We investigated the phenotypic conversion of adipocytes during the malignant process of GC cells in vivo and in vitro. We evaluated the expression levels of adiponectin in the omental adipose tissue of gastric cancer patients by western blotting. Following adipocytes/gastric cancer cells coculture, adipocyte markers, adiponectin receptors, and inflammatory cytokine markers were detected by real-time PCR and/or western blotting in the single-cultured and co-cultured adipocytes; cancer-associated fibroblast (CAF) markers were detected by immunofluorescence and western blotting in the single-cultured and co-cultured adipocytes; invasion assays were performed in single cultured and co-cultured MKN45 and OCUM.In omental adipose tissues that are situated close to the primary tumors, the expression of adiponectin tended to decrease in patients with subserosal or serosal invasion. By co-culturing with GC cells, adipocytes were dedifferentiated and the expression levels of CAF marker FSP1 and inflammatory cytokines, PAI-1 and IL-6, significantly increased (p 0.05). Furthermore, GC cells co-cultured with adipocytes showed enhanced invasion ability.Our findings suggest that the phenotypic conversion of adipocytes may promote the malignancy of GC in the construction of the cancer microenvironment of PM.
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- 2021
17. A case of primary malignant melanoma of the esophagogastric junction with abscopal effect after nivolumab administration
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Takahisa Yamaguchi, Sachio Fushida, Jun Kinoshita, Hiroto Saito, Mari Shimada, Shiro Terai, Hideki Moriyama, Koichi Okamoto, Keishi Nakamura, Itasu Ninomiya, and Noriyuki Inaki
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Esophagogastric junction ,RD1-811 ,Surgery ,Case Report ,Abscopal effect ,Melanoma - Abstract
Background The abscopal effect is a rare phenomenon in which local irradiation causes tumor regression outside the irradiated area. There have been no reports of abscopal effect in patients with gastrointestinal melanoma with metastasis. Here, we report a case of primary malignant melanoma of the esophagogastric junction with abscopal effect after long-term treatment with nivolumab. Case presentation A 75-year-old woman was referred to our hospital with a gastroesophageal lesion. Upper gastrointestinal endoscopy revealed a raised lesion on the posterior wall of the greater curvature of the cardia and tenderness in the lower esophagus. Immunostaining of the tumor biopsy showed positive staining for Melan-A, human melanoma black-45 (HMB45), and S-100, indicating malignant melanoma of the esophagogastric junction. Contrast-enhanced computed tomography (CT) of the abdomen showed a mildly stained lesion protruding into the cardiac part of stomach and enlarged surrounding lymph nodes. The patient was diagnosed with malignant melanoma of the esophagogastric junction and proximal gastrectomy with lower esophagus resection was performed. Histological examination showed large, round tumor cells with nuclear atypia. Immunostaining was positive for Melan A, HMB45, S-100 protein, and SRY-box transcription factor 10, and the final diagnosis was malignant melanoma of the esophagogastric junction, with regional lymph node metastases. Three months after surgery, follow-up CT indicated left pleural metastasis; therefore, the patient was administered nivolumab, an immune checkpoint inhibitor (ICI). Following three courses of nivolumab, the patient exhibited grade 3 renal dysfunction (Common Terminology Criteria for Adverse Events version 5.0). After that, we have not administered nivolumab treatment. Five months after the development of renal dysfunction, a CT scan demonstrated an unstained nodule within the pancreatic, and the patient was diagnosed with pancreatic metastasis; intensity-modulated radiotherapy was performed. Six months later, CT revealed pancreatic nodule and pleural metastasis was shrunk; after an additional 2 months, pleural metastasis and effusion had disappeared. The patient is alive with no additional lesions. Conclusions We report a case of primary malignant melanoma of the esophagogastric junction with an abscopal effect following nivolumab treatment. The findings of this case report suggest that ICIs in combination with radiotherapy may be effective for treating metastatic or recurrent malignant melanoma of the gastrointestinal tract.
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- 2021
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18. Crosstalk between cancer-associated fibroblasts and immune cells in peritoneal metastasis: inhibition in the migration of M2 macrophages and mast cells by Tranilast
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Yusuke Nakamura, Jun Kinoshita, Takahisa Yamaguchi, Tatsuya Aoki, Hiroto Saito, Toshihide Hamabe-Horiike, Shinichi Harada, Sachiyo Nomura, Noriyuki Inaki, and Sachio Fushida
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Cancer Research ,Macrophages ,Gastroenterology ,General Medicine ,Fibroblasts ,Fibrosis ,Mice, Inbred C57BL ,Mice ,Oncology ,Cancer-Associated Fibroblasts ,Stomach Neoplasms ,Cell Line, Tumor ,Tumor Microenvironment ,Animals ,Humans ,ortho-Aminobenzoates ,Mast Cells ,Peritoneal Neoplasms ,Cell Proliferation - Abstract
Background The role of tumor–stroma interactions in tumor immune microenvironment (TME) is attracting attention. We have previously reported that cancer-associated fibroblasts (CAFs) contribute to the progression of peritoneal metastasis (PM) in gastric cancer (GC), and M2 macrophages and mast cells also contribute to TME of PM. To elucidate the role of CAFs in TME, we established an immunocompetent mouse PM model with fibrosis, which reflects clinical features of TME. However, the involvement of CAFs in the immunosuppressive microenvironment remains unclear. In this study, we investigated the efficacy of Tranilast at modifying this immune tolerance by suppressing CAFs. Methods The interaction between mouse myofibroblast cell line LmcMF and mouse GC cell line YTN16 on M2 macrophage migration was investigated, and the inhibitory effect of Tranilast was examined in vitro. Using C57BL/6J mouse PM model established using YTN16 with co-inoculation of LmcMF, TME of resected PM treated with or without Tranilast was analyzed by immunohistochemistry. Results The addition of YTN16 cell-conditioned medium to LmcMF cells enhanced CXCL12 expression and stimulated M2 macrophage migration, whereas Tranilast inhibited the migration ability of M2 macrophages by suppressing CXCL12 secretion from LmcMF. In PM model, Tranilast inhibited tumor growth and fibrosis, M2 macrophage, and mast cell infiltration and significantly promoted CD8 + lymphocyte infiltration into the tumor, leading to apoptosis of cancer cells by an immune response. Conclusion Tranilast improved the immunosuppressive microenvironment by inhibiting CAF function in a mouse PM model. Tranilast is thus a promising candidate for the treatment of PM.
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- 2021
19. Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid‐induced cancer development
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Hiroyuki Sugihara, Itasu Ninomiya, Jun Kinoshita, Masayoshi Munemoto, Ken-ichi Mukaisho, Koichi Okamoto, Tomoharu Miyashita, Takashi Fujimura, Sachio Fushida, Yusuke Haba, Katsunobu Oyama, and Naoko Taniura
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Male ,0301 basic medicine ,Cancer Research ,Esophageal Neoplasms ,Carcinogenesis ,Cell ,medicine.disease_cause ,chemistry.chemical_compound ,0302 clinical medicine ,Bile acid ,NF-kappa B ,General Medicine ,Esophageal cancer ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Original Article ,metabolomics analyses ,Esophageal Squamous Cell Carcinoma ,Signal Transduction ,medicine.drug_class ,pentose phosphate pathway ,Adenocarcinoma ,Glucosephosphate Dehydrogenase ,Pentose phosphate pathway ,Acetylglucosamine ,Bile Acids and Salts ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Rats, Wistar ,bile acids ,Lysine ,NF‐κB ,Cancer ,Hexosamines ,Original Articles ,medicine.disease ,Taurocholic acid ,digestive system diseases ,Biosynthetic Pathways ,Rats ,Glucose ,030104 developmental biology ,chemistry ,Cell culture ,Cancer research ,hexosamine biosynthesis pathway - Abstract
Esophageal squamous cell carcinomas (ESCCs) as well as adenocarcinomas (EACs) were developed in rat duodenal contents reflux models (reflux model). The present study aimed to shed light on the mechanism by which bile acid stimulation causes cancer onset and progression. Metabolomics analyses were performed on samples of neoplastic and nonneoplastic tissues from reflux models, and K14D, cultivated from a nonmetastatic, primary ESCC, and ESCC‐DR, established from a metastatic thoracic lesion. ESCC‐DRtca2M was prepared by treating ESCC‐DR cells with taurocholic acid (TCA) to accelerate cancer progression. The lines were subjected to comprehensive genomic analyses. In addition, protein expression levels of glucose‐6‐phosphate dehydrogenase (G6PD), nuclear factor kappa B (NF‐κB) (p65) and O‐linked N‐Acetylglucosamine (O‐GlcNAc) were compared among lines. Cancers developed in the reflux models exhibited greater hexosamine biosynthesis pathway (HBP) activation compared with the nonneoplastic tissues. Expression of O‐GlcNAc transferase (OGT) increased considerably in both ESCC and EAC compared with nonneoplastic squamous epithelium. Conversely, cell line‐based experiments revealed the greater activation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. G6PD overexpression in response to TCA exposure was observed. Both NF‐κB (p65) and O‐GlcNAc were expressed more highly in ESCC‐DRtca2M than in the other cell lines. Moreover, ESCC‐DRtca2M cells had additional chromosomal abnormalities in excess of ESCC‐DR cells. Overall, glucose metabolism was upregulated in both esophageal cancer tissue and cell lines. While bile acids are not mutagenic, chronic exposure seems to trigger NF‐κB(p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression. Glucose metabolism was upregulated in both esophageal cancer tissue and cell lines, and the HBP was activated in the former. The cell line‐based experiments demonstrated upregulation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF‐κB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.
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- 2019
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20. Use of esophageal stent for the treatment of postoperative gastrointestinal–airway fistula after esophagectomy
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Ichitaro Mochizuki, Koichi Okamoto, Itasu Ninomiya, Jun Kinoshita, Tatsuya Aoki, Takahisa Yamaguchi, Hidehiro Tajima, Hiroyuki Takamura, Isamu Makino, Sachio Fushida, Tomoharu Miyashita, Tetsuo Ohta, Shinichi Nakanuma, Shiro Terai, Keishi Nakamura, and Yuta Fujiwara
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Gastric Fistula ,Lung Diseases ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Fistula ,Self Expandable Metallic Stents ,behavioral disciplines and activities ,03 medical and health sciences ,0302 clinical medicine ,Esophageal stent ,mental disorders ,medicine ,Humans ,Esophageal Fistula ,Aged ,Tracheal Diseases ,business.industry ,Gastroenterology ,Postoperative complication ,Stent ,Middle Aged ,Esophageal cancer ,medicine.disease ,Surgery ,Esophagectomy ,Cardiothoracic surgery ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Respiratory Tract Fistula ,business - Abstract
A gastrointestinal-airway fistula (GAF) after esophagectomy is a very serious postoperative complication that can cause severe respiratory complications due to digestive juice inflow. Generally, GAF is managed by invasive surgical treatment; less-invasive treatment has yet to be established. We performed esophageal stent placement (ESP) in three cases of GAF after esophagectomy. We assessed the usefulness of ESP through our clinical experience. All GAFs were successfully managed by ESP procedures. After the procedure, the stent positioning and expansion were appropriately evaluated by radiological assessments over time. The stent was removed after endoscopic confirmation of fistula closure on days 8, 23, and 71. Only one patient with a long-term indwelling stent developed a manageable secondary gastrobronchial fistula as a procedure-related complication. In conclusion, ESP was shown to be a less-invasive and effective therapeutic modality for the treatment of GAF.
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- 2019
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21. The Embryonic Stem Cell-Specific Transcription Factor ZFP57 Promotes Liver Metastasis of Colorectal Cancer
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Hiroyuki Takamura, Hiroshi Koide, Itasu Ninomiya, Yuhki Tada, Sachio Fushida, Yasuhiro Shoji, Takashi Yokota, and Tetsuo Ohta
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Male ,Homeobox protein NANOG ,Colon ,Colorectal cancer ,Mice, Nude ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,Medicine ,Survival rate ,Transcription factor ,Aged ,business.industry ,Liver Neoplasms ,Rectum ,Nanog Homeobox Protein ,Middle Aged ,HCT116 Cells ,medicine.disease ,Xenograft Model Antitumor Assays ,Embryonic stem cell ,Progression-Free Survival ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,Liver ,Cell culture ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Female ,030211 gastroenterology & hepatology ,Surgery ,Colorectal Neoplasms ,business ,HT29 Cells - Abstract
Background The embryonic stem cell-specific transcription factor, ZFP57, has been shown to play an important role in tumor formation. In this study, we examined if ZFP57 is involved in colorectal cancer metastasis. Materials and methods First, we used colorectal cancer cell lines to perform in vivo metastatic experiments with nude mice. Next, we carried out immunohistochemical analysis of clinical specimens of colorectal cancers. Results In liver metastatic experiments using human colorectal cancer HT29 and HCT116 cells, liver polymetastases occurred at high frequency in ZFP57-overexpressing HT29 and HCT116 cells, whereas both control cells only resulted in oligometastases. Next, we analyzed ZFP57 expression using clinical specimens. Liver metastasis-positive cases were more frequently associated with ZFP57 overexpression than negative cases in primary lesions of colorectal cancer, and the overexpression was particularly remarkable in tumor invasive lesions. Furthermore, ZFP57 overexpression was significantly correlated not only with liver metastasis but also with lymph node metastasis. In addition, the expression level of ZFP57 was significantly correlated with that of the metastasis-related gene NANOG. We also found that ZFP57 overexpression reduced the progression-free survival rate of patients with colorectal cancer. Conclusions This study demonstrated that ZFP57 plays an important role in the hematogenous metastasis of colorectal cancer, suggesting that it could be used as a novel treatment target.
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- 2019
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22. Infectious Complications in Adult ABO-Incompatible Liver Transplantation: Our Preliminary Experience
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Hironori Hayashi, Shinichi Nakanuma, Tomoharu Miyashita, Hiroyuki Takamura, Takashi Tani, Yoshinao Ohbatake, Itasu Ninomiya, Tetsuo Ohta, Sachio Fushida, and Hidehiro Tajima
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Splenectomy ,030232 urology & nephrology ,Immunosuppression ,030230 surgery ,Liver transplantation ,Living donor ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,ABO blood group system ,Internal medicine ,Antibody mediated rejection ,medicine ,Surgery ,Rituximab ,ABO-incompatible transplantation ,business ,medicine.drug - Abstract
The number of ABO-incompatible living donor liver transplantations (ABO-I LDLT) has increased owing to the use of preoperative rituximab for immunosuppression. However, controversy remains regarding adequate immunosuppression owing to rejection and infection. Here, we present 5 cases of our ABO-I LDLT experience, emphasizing rejection and infectious complications, retrospectively. The treatment protocol included prophylactic rituximab followed by plasma exchange prior to transplantation, splenectomy, and immunosuppressive and prophylactic antibiotic regimens after transplantation. Four of the 5 patients also received local infusion therapy via the portal vein. Neither hyperacute nor antibody-mediated rejection occurred. All grafts were functioning well at discharge. Rehospitalization was required for 2 patients due to severe infection within 6 months of transplantation. Invasive aspergillosis was successfully treated in 1 patient, but the other patient died from severe sepsis with overwhelming postsplenectomy infection syndrome. Our results confirm that, although improved immunosuppressive therapy markedly reduces rejection in ABO-I LDLT, it is also associated with an increased risk of various life-threatening infections.
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- 2019
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23. Citrullinated Histone H3: Early Biomarker of Neutrophil Extracellular Traps in Septic Liver Damage
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Ai Harashima, Tomoharu Miyashita, Hideo Takayama, Yasuhiko Yamamoto, Tetsuo Ohta, Sachio Fushida, Kozo Nomura, and Seiichi Munesue
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Lipopolysaccharides ,Male ,Lipopolysaccharide ,Extracellular Traps ,Flow cytometry ,Histones ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,Histone H3 ,0302 clinical medicine ,Animals ,Medicine ,Mice, Inbred BALB C ,biology ,medicine.diagnostic_test ,business.industry ,Liver Diseases ,Citrullination ,Neutrophil extracellular traps ,medicine.disease ,Cilostazol ,chemistry ,030220 oncology & carcinogenesis ,Neutrophil elastase ,Myeloperoxidase ,biology.protein ,Cancer research ,030211 gastroenterology & hepatology ,Surgery ,business ,Biomarkers - Abstract
Background Neutrophil extracellular traps (NETs) play a crucial role in host defense, but excess and prolonged interaction of NETs with platelets can cause severe inflammation and host organ damage. Modification of histone H3 by citrullination is involved in in vitro NET formation. The phosphodiesterase III inhibitor, cilostazol (Ciz), which has a protective effect on liver sinusoidal endothelial cells and inhibits platelet aggregation, may prevent organ damage caused by excess NETosis. In this study, we investigated whether citrullinated histone H3 (H3Cit) could serve as a biomarker for the detection of critical liver damage in sepsis and the efficacy of phosphodiesterase-III inhibition for preventing the liver dysfunction induced by NETosis. Materials and methods Mice injected with lipopolysaccharide (LPS; 1 mg/kg) were used as a sepsis model with or without treatment with Ciz (200 mg/kg). H3Cit, myeloperoxidase, and neutrophil elastase levels were measured by immunohistochemistry. We evaluated H3Cit-positive neutrophils in the peripheral blood by flow cytometry. Results Immunohistochemistry revealed that H3Cit-, neutrophil elastase-, and myeloperoxidase-positive cell numbers in the livers peaked at 12 h after LPS administration. However, flow cytometry showed a significant increase in H3Cit-positive neutrophils in the peripheral blood only 4 h after LPS injection. Treatment with Ciz significantly ameliorated all parameters. Conclusions H3Cit is a useful biomarker for early detection of NETosis or liver dysfunction, and Ciz may be an effective treatment for septic liver damage.
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- 2019
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24. Oral cryotherapy for prophylaxis of oral mucositis caused by docetaxel, cisplatin, and fluorouracil chemotherapy for esophageal cancer
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Shinichi Nakanuma, Koichi Okamoto, Itasu Ninomiya, Tetsuo Ohta, Hidehiro Tajima, Keishi Nakamura, Takahisa Yamaguchi, Hiroyuki Takamura, Shiro Terai, Jun Kinoshita, Sachio Fushida, Tomoharu Miyashita, and Isamu Makino
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Male ,medicine.medical_specialty ,Esophageal Neoplasms ,medicine.medical_treatment ,Administration, Oral ,Cryotherapy ,Docetaxel ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Mucositis ,Humans ,Infusions, Intravenous ,Adverse effect ,Aged ,Retrospective Studies ,Cisplatin ,Stomatitis ,Chemotherapy ,business.industry ,Ice ,Middle Aged ,Esophageal cancer ,medicine.disease ,Treatment Outcome ,Fluorouracil ,030220 oncology & carcinogenesis ,Quality of Life ,Female ,030211 gastroenterology & hepatology ,business ,medicine.drug - Abstract
Chemotherapy, including preoperative chemotherapy, plays an important role in the treatment of esophageal cancer. However, although docetaxel, cisplatin, and fluorouracil (DCF) therapy has a powerful antitumor effect, the associated adverse events make it difficult to maintain the patient’s general condition. Oral mucositis is an important adverse effect of chemotherapy, and its severity, frequency, and impact on patient quality of life should not be underestimated. This study evaluated the role of oral cryotherapy for prophylaxis of oral mucositis caused by DCF therapy. We retrospectively examined the incidence and severity of adverse events, including mucositis, in 72 patients with esophageal cancer treated with DCF. Fifty-eight patients received cryotherapy during docetaxel administration and 14 received no cryotherapy. The incidence of mucositis of all grades and grade 3 was significantly lower in the cryotherapy group compared with the no-cryotherapy group (24.1% vs. 71.4%, P
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- 2019
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25. A Case of Pancreatic Insulinoma in which the Tumor was Difficult to Localize Preoperatively
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Yuto Kitano, Tomoharu Miyashita, Isamu Makino, Yuya Sugimoto, Hidehiro Tajima, Testuo Ohta, and Sachio Fushida
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Pancreatic Insulinoma ,Pathology ,medicine.medical_specialty ,business.industry ,Medicine ,business - Published
- 2019
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26. O1-6 REVIVE study: An observational study in chemotherapy (CTx) after nivolumab (NIVO) for advanced gastric cancer (AGC)
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Yasuhiro Sakamoto, Yukiya Narita, Toshihiro Misumi, Hiroshi Matsuoka, Hiroaki Tanioka, Takeshi Kawakami, Tomohiro Matsushima, Hiroto Miwa, Hirokazu Shoji, Atsushi Ishiguro, Sachio Fushida, Kou Miura, Takanobu Yamada, Katsunori Shinozaki, Takuro Mizukami, Tomohiro Nishina, Toshikazu Moriwaki, Seiichiro Mitani, Michio Nakamura, and Kei Muro
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Oncology ,Hematology - Published
- 2022
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27. nPTD classification: an updated classification of gastric cancer location for function preserving gastrectomy based on physiological lymphatic flow
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Hidekazu Kitakata, Takashi Fujimura, Shinichi Kinami, Naohiko Nakamura, Hiroyuki Takamura, Sachio Fushida, Tomoharu Miyashita, and Tohru Itoh
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Dissection (medical) ,Curvature ,Surgical oncology ,Gastrectomy ,Stomach Neoplasms ,Biopsy ,Medical Illustration ,Genetics ,medicine ,Humans ,Neoplasm Invasiveness ,Coloring Agents ,RC254-282 ,Aged ,Lymphatic Vessels ,Retrospective Studies ,Aged, 80 and over ,Sentinel node biopsy ,medicine.diagnostic_test ,business.industry ,Sentinel Lymph Node Biopsy ,Stomach ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Sentinel node ,Middle Aged ,medicine.disease ,Curvatures of the stomach ,Function preserving gastrectomy ,Oncology ,Lymphatic flow ,Lymphatic Metastasis ,Lymph Node Excision ,Female ,Radiology ,Lymph ,business ,Gastric cancer ,Organ Sparing Treatments ,Research Article - Abstract
Background The correlation between tumor location and lymphatic flow distribution in gastric cancer has been previously reported, and PTD (Proximal – Transitional – Distal) classification was proposed. Our group updated and developed the nPTD classification. Method We retrospectively studied gastric cancer patients who underwent the dye method sentinel node biopsy from 1993 to 2020. The inclusion criteria were a single lesion type 0 cancer of ≤5 cm in the long axis, clinically node-negative, and invasion within the proper muscle layer pathologically. In this study, the distribution of dyed lymphatic flow was evaluated for each occupied area of the tumor. Results We included 416 patients in this study. The tumors located in the watershed of the right and left gastroepiploic arteries near greater curvature had extensive lymphatic flow; therefore, a newly circular region with a diameter of 5 cm is set on the watershed of the greater curvature between P and T zone as the ‘n’ zone. In addition, for cancers located in the lesser P curvature, lymphatic flow to the greater curvature was not observed. Therefore, the P zone was divided into two: the lesser curvature side (PL) and the greater curvature side (PG). Conclusions The advantage of the nPTD classification is that it provides not only proper nodal dissection but also adequate function-preserving gastrectomy. If the tumor is localized within the PL, the proximal gastrectomy resection area can be further reduced. In contrast, for cancers located in the ‘n’ zone, near-total gastrectomy is required because of the extensive lymphatic flow.
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- 2021
28. [A Case of an Asymptomatic Coagulopathy after Peritoneovenous Shunt Placement for Malignant Ascites of Gastric Cancer]
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Tetsuya, Asakawa, Hiroto, Saito, Mari, Shimada, Takahisa, Yamaguchi, Shiro, Terai, Koichi, Okamoto, Jun, Kinoshita, Keishi, Nakamura, Itasu, Ninomiya, and Sachio, Fushida
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Male ,Peritoneovenous Shunt ,Stomach Neoplasms ,Ascites ,Humans ,Middle Aged ,Neoplasm Recurrence, Local ,Peritoneal Neoplasms - Abstract
The patient was a 61‒year‒old man who had an advanced gastric cancer with peritoneal dissemination. After chemotherapy, intraoperative findings during a total gastrectomy revealed the disappearance of the dissemination nodules. Although adjuvant chemotherapy was performed, the presence of massive ascites led to the recurrence of the peritoneal dissemination 5 months after the surgery. While the chemotherapy regimen was altered, we observed no reduction in malignant ascites. The patient complained of abdominal distention and was admitted to our hospital for symptom management. We performed a cell‒free and concentrated ascites reinfusion therapy(CART)several times. However, symptom management proved difficult; therefore, the patient underwent a peritoneovenous shunt(Denver shunt)placement. After the shunting, we observed no organ injury and improved abdominal distention; however, an asymptomatic coagulopathy was present in the course. Additionally, blood examinations showed increased FDP‒DD and thrombin‒antithrombin complex(TAT). However, 6 months after the shunting, coagulopathy improved and the patient reported the absence of abdominal distention. This report describes a patient with an asymptomatic coagulopathy after Denver shunt placement and evaluated the clinical course by using TAT values.
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- 2021
29. [Four Cases of Surgical Treatment for Radiation Enteritis]
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Satoru, Hashimoto, Jun, Kinoshita, Shiro, Terai, Keishi, Nakamura, Hiroto, Saito, Koichi, Okamoto, Shinichi, Nakanuma, Isamu, Makino, Hidehiro, Tajima, Itasu, Ninomiya, Sachio, Fushida, and Tetsuo, Ohta
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Humans ,Intestinal Mucosa ,Radiation Injuries ,Enteritis ,Intestinal Obstruction ,Pelvic Neoplasms - Abstract
Although radiation therapy for pelvic cancer leads to improved outcomes, it may cause radiation enteritis. Radiation enteritis is classified as early and late reaction. Late reaction indicate progressive and irreversible changes caused by ischemic changes of the intestinal mucosa. Severe cases require a surgical treatment, which is challenging because of severe adhesions and a high risk of suture failure. In addition, the postoperative course may be unfavorable in some cases. We performed surgery for 4 radiation enteritis cases; however, the postoperative course was unfavorable in 2 cases because of impaired absorption and ileus of the remaining short bowel. These patients could not eat adequately after discharge; therefore, we needed to explain and make them understand the benefits and disadvantages of radiation therapy.
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- 2021
30. [Laparoscopy Assisted Subtotal Gastrectomy(BillrothⅠ Reconstruction)for Gastric Cancer in the Upper Stomach-A Report of Three Cases]
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Takahisa, Yamaguchi, Jun, Kinoshita, Tomoya, Tsukada, Makoto, Nakura, Atsushi, Hirose, Toshifumi, Watanabe, Hironori, Hayashi, Koji, Amaya, Kiichi, Maeda, Koichi, Shimizu, Sachio, Fushida, and Masahide, Kaji
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Male ,Postoperative Complications ,Gastrectomy ,Stomach Neoplasms ,Humans ,Female ,Laparoscopy ,Gastroenterostomy ,Retrospective Studies - Abstract
We experienced 3 cases of upper gastric cancer who underwent BillrothⅠ reconstruction in laparoscopy assisted subtotal gastrectomy. Two cases were female and 1 was male. The postoperative course was uneventful in all cases without heartburn, and the surgical margin was negative. The body weight loss rate was 5.8-12.6%, and the short-term results were relatively acceptable. Although the number of cases in this study was small, reconstruction with BillrothⅠ/delta-shaped anastomosis after laparoscopy assisted subtotal gastrectomy were considered to be useful.
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- 2021
31. Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer
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Sachiyo Nomura, Yusuke Nakamura, Koichi Sato, Takahisa Yamaguchi, Sachio Fushida, Jun Kinoshita, Masami Yamamoto, Katsuya Gunjigake, Daisuke Fujimori, Tetsuya Tsukamoto, Takashi Ohama, and Tetsuo Ohta
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Adult ,Male ,0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,CD8-Positive T-Lymphocytes ,lcsh:RC254-282 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Stomach Neoplasms ,Fibrosis ,Cell Line, Tumor ,Genetics ,Animals ,Humans ,Medicine ,Myofibroblasts ,Peritoneal Neoplasms ,Aged ,Aged, 80 and over ,Tumor microenvironment ,business.industry ,Macrophages ,Immunocompetent mouse model ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Actins ,Coculture Techniques ,Mice, Inbred C57BL ,030104 developmental biology ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Peritoneal metastasis ,Cancer cell ,Immunohistochemistry ,Female ,Gastric cancer ,business ,Immunocompetence ,CD163 ,Neoplasm Transplantation ,Research Article - Abstract
BackgroundPeritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients.MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6 J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with α-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+cells was significantly lower in PM lesions than in primary lesions (P +cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P = 0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P P = 0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P P ConclusionsThis model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.
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- 2020
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32. Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer
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Daisuke Fujimori, Jun Kinoshita, Takahisa Yamaguchi, Yusuke Nakamura, Katsuya Gunjigake, Takashi Ohama, Koichi Sato, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Tetsuo Ohta, and Sachio Fushida
- Abstract
Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (PP=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (PPConclusionsThis model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.
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- 2020
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33. Comparison of prognostic impact of anatomic location of the pancreas on postoperative pancreatic fistula in laparoscopic and open gastrectomy
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Hiroto Saito, Sachio Fushida, Isamu Makino, Mari Shimada, Hideki Moriyama, Shiro Terai, Keishi Nakamura, Takahisa Yamaguchi, Itasu Ninomiya, Hidehiro Tajima, Shinichi Nakanuma, Koichi Okamoto, and Jun Kinoshita
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medicine.medical_specialty ,Left gastric artery ,medicine.medical_treatment ,Gastroenterology ,Pancreatic Fistula ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Gastrectomy ,Stomach Neoplasms ,medicine.artery ,Internal medicine ,Laparoscopic gastrectomy (LG) ,medicine ,Humans ,lcsh:RC799-869 ,Pancreas ,Retrospective Studies ,Postoperative pancreatic fistula (POPF) ,Open gastrectomy (OG) ,business.industry ,General Medicine ,Odds ratio ,Hepatology ,Prognosis ,medicine.disease ,Confidence interval ,medicine.anatomical_structure ,Pancreatic fistula ,030220 oncology & carcinogenesis ,Laparoscopy ,lcsh:Diseases of the digestive system. Gastroenterology ,030211 gastroenterology & hepatology ,Complication ,business ,Amylase level in the drained fluid (D-Amy) ,Research Article - Abstract
Background Postoperative pancreatic fistula (POPF) is a serious complication after gastric cancer surgery. The current study aimed to investigate the significance of the anatomic location of the pancreas as a predictor for POPF in both laparoscopic gastrectomy (LG) and open gastrectomy (OG). Methods In total, 233 patients with gastric cancer were assessed retrospectively. We measured the maximum vertical (P-L height; PLH) and horizontal length (P-L depth; PLD) between the upper border of pancreas and the root of left gastric artery on a preoperative CT in the sagittal direction. The maximum length of the vertical line between the surface of the pancreas and the aorta (P-A length), previously reported as prognostic factor of POPF, was also measured. We investigated the correlations between these parameters and the incidence of POPF in LG and OG groups. Results Among the patients in this study, 118 underwent OG and 115 underwent LG. In LG, the median PLH and P-A length in patients with POPF were significantly longer compared with those without POPF (p = 0.026, 0.034, respectively), but not in OG. There was no significant difference in the median PLD between the patients with or without POPF in both LG and OG. The multivariate analysis demonstrated that PLH (odds ratio [OR] 4.19, 95% confidence interval [CI] 1.57–11.3, P = 0.004) and P-A length (OR 4.06, 95%CI 1.05–15.7, P = 0.042] were independent factors for predicting POPF in LG. However, intraoperative blood loss (OR 2.55, 95%CI 1.05–6.18, P = 0.038) was extracted as an independent factor in OG. The median amylase level in the drained fluid (D-Amy) were significantly higher in patients with high PLH(≥12.4 mm) or high P-A length (≥45 mm) compared with those with low PLH or low P-A length in LG. However, there were no differences in the D-Amy levels by PLH or P-A length in OG patients. Conclusions The anatomic location of the pancreas is a specific and independent predictor of POPF in LG but not in OG. PLH is a simple parameter that can evaluate the anatomic position of the pancreas, and it may be useful for preventing POPF after LG.
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- 2020
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34. Surgically resected primary esophageal choriocarcinoma accompanied with Barrett’s adenocarcinoma: a case report
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Itasu Ninomiya, Tetsuo Ohta, Yuta Fujiwara, Isamu Makino, Jun Kinoshita, Hiroko Ikeda, Koichi Okamoto, Keishi Nakamura, Sachio Fushida, Shiro Terai, Hiroto Saito, and Takahisa Yamaguchi
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medicine.medical_specialty ,medicine.medical_treatment ,lcsh:Surgery ,Case Report ,Lesion ,Esophagus ,Biopsy ,medicine ,Choriocarcinoma ,Lung ,medicine.diagnostic_test ,business.industry ,Nodule (medicine) ,lcsh:RD1-811 ,Barrett’s adenocarcinoma ,medicine.disease ,Esophagectomy ,medicine.anatomical_structure ,embryonic structures ,Adenocarcinoma ,Radiology ,medicine.symptom ,business - Abstract
Background Choriocarcinomas are usually classified as either gestational or non-gestational. Primary choriocarcinomas in the gastrointestinal tract, especially primary choriocarcinomas in the esophagus, are extremely rare. We report a case of a rare primary esophageal choriocarcinoma mixed with squamous cell carcinoma-like components in association with Barrett’s adenocarcinoma. Case presentation A 58-year-old man visited the hospital, complaining of hematemesis and tarry stools. In emergency upper gastrointestinal endoscopy, a bleeding esophageal tumor was observed. Additionally, a contrast computed tomography (CT) scan showed a large hypervascular tumor 4.8 cm in diameter in the left kidney. He came to our institution for further examination and treatment of the esophageal tumor and kidney lesion. The patient had an easy bleeding elevated tumor 2 cm in diameter at the left wall of the middle thoracic esophagus and a left renal carcinoma. Histopathological diagnosis of the biopsy specimen of the esophageal tumor was a poorly differentiated carcinoma. However, a precise histological type diagnosis could not be obtained. In June 2016, mediastinoscopic transhiatal esophagectomy and posterior mediastinal gastric tube reconstruction were performed to treat his esophageal tumor. Histopathologically, most of the tumor comprised hCG-positive syncytiotrophoblasts. Therefore, we confirmed it as a primary esophageal choriocarcinoma. Furthermore, the tumor contained a poorly differentiated squamous cell carcinoma-like component that was also diagnosed as a choriocarcinoma using immunohistochemical staining and there was a small Barrett’s esophageal adenocarcinoma lesion in the Barrett's epithelium near the tumor. Three months after surgery, a CT scan demonstrated multiple lung metastatic nodules and multiple intrahepatic masses. Needle biopsy from the lung nodule showed a choriocarcinoma. Despite chemotherapy, the metastatic choriocarcinoma regrew rapidly and multiple bone metastases appeared. He died because of his esophageal choriocarcinoma 13 months after primary resection. Conclusions We encountered an extremely rare case of esophageal choriocarcinoma combined with squamous cell carcinoma-like components in association with a simultaneous Barrett’s adenocarcinoma that we followed for the entire course of his disease, from resection to end of life. Esophageal choriocarcinomas are rare with peculiar characteristics and very poor prognoses. Additional cases are needed to establish an appropriate future treatment.
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- 2020
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35. Optimization of robot-assisted thoracoscopic esophagectomy in the lateral decubitus position
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Koichi Okamoto, Shiro Terai, Hideki Moriyama, Itasu Ninomiya, Hiroto Saito, Takahisa Yamaguchi, Sachio Fushida, and Jun Kinoshita
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medicine.medical_specialty ,Esophageal Neoplasms ,business.industry ,medicine.medical_treatment ,Thoracoscopy ,Gastroenterology ,Robotics ,Surgery ,Surgical morbidity ,Esophagectomy ,03 medical and health sciences ,Dissection ,0302 clinical medicine ,Blood loss ,Robotic Surgical Procedures ,Cardiothoracic surgery ,030220 oncology & carcinogenesis ,Lateral Decubitus Position ,medicine ,Thoracoscopic esophagectomy ,Humans ,030211 gastroenterology & hepatology ,Robotic surgery ,business - Abstract
On the introduction of robot-assisted thoracoscopic esophagectomy (RATE), we refined the robotic system application to enhance our surgical experience obtained through thoracoscopic esophagectomy (TE) in the lateral decubitus position (LDP). Herein, we evaluate our methods introduced to optimize RATE in the LDP. We performed RATE in the LDP with camera rotation and manual hand control assignment to reproduce the surgical view and manipulation of open esophagectomy. Forty patients underwent RATE between July 2018 and August 2020. After the initial 30 cases (initial RATE group), we optimized the port arrangement and robot settings in the most recent ten cases (recent RATE group). The surgical results of RATE were compared with those of 30 patients underwent TE between April 2014 and May 2019 selected by propensity score-matched analysis based on cStage (TE group). Operative duration was significantly longer in the initial RATE group than the TE group and the recent RATE group. Thoracic blood loss was significantly less in the initial RATE group than the TE group. Console time was significantly shorter in the recent RATE group than the initial RATE group. There was no surgical mortality in RATE and the surgical morbidity rate was similar in the three groups. Camera rotation and manual hand control assignment during RATE in the LDP reproduced the surgical view and manipulation of open esophagectomy and TE in the LDP. The robotic platform enabled meticulous dissection and reduced blood loss, but was initially time-consuming. Optimization of the port arrangement minimized operative duration.
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- 2020
36. Pretreatment with a Phosphodiesterase-3 Inhibitor, Milrinone, Reduces Hepatic Ischemia-Reperfusion Injury, Minimizing Pericentral Zone-Based Liver and Small Intestinal Injury in Rats
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Hironori Hayashi, Hiroyuki Takamura, Yoshinao Ohbatake, Tomoharu Miyashita, Hiroyuki Shinbashi, Isamu Makino, Hidehiro Tajima, Shinichi Nakanuma, Tetsuo Ohta, Mitsuyoshi Okazaki, Sachio Fushida, Ryosuke Gabata, and Seisho Sakai
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,Phosphodiesterase 3 ,Liver transplantation ,Phosphodiesterase 3 Inhibitors ,03 medical and health sciences ,0302 clinical medicine ,Ischemia ,Internal medicine ,Intestine, Small ,medicine ,Animals ,Rats, Wistar ,Ischemic Preconditioning ,Survival rate ,Liver injury ,Transplantation ,Original Paper ,business.industry ,General Medicine ,medicine.disease ,Rats ,Endocrinology ,Liver ,Apoptosis ,030220 oncology & carcinogenesis ,Reperfusion Injury ,Milrinone ,Immunohistochemistry ,030211 gastroenterology & hepatology ,business ,Reperfusion injury ,medicine.drug - Abstract
BACKGROUND Severe pericentral zone (zone 3)-based liver injury (LI) may become intractable, with allograft dysfunction after liver transplantation. The phosphodiesterase-3 inhibitor, milrinone, has been reported to attenuate hepatic ischemia-reperfusion injury (IRI). This study clarified how hepatic IRI involved zone 3-based LI, in which zone milrinone was effective, and whether milrinone could improve small intestinal injury (SII) with hepatic IRI. MATERIAL AND METHODS Rats were divided into sham, ischemia-reperfusion (IR), or IR+milrinone groups (n=13 per group). Milrinone was administered intraportally via intrasplenic injection, and whole hepatic ischemia was induced for 30 min. Five hours after reperfusion, serum chemistry and histopathological findings were compared. Expression of CD34 for the detection of altered sinusoidal endothelium as sinusoidal capillarization and cleaved caspase-3 as an apoptosis marker were analyzed via immunohistochemistry. Survival rates were examined after 45 min of whole hepatic ischemia. RESULTS Serum aspartate aminotransferase and direct bilirubin levels were significantly decreased in the IR+milrinone group compared with those of the IR group. The degree of LI, sinusoidal capillarization and apoptosis at zone 3 in the IR group was significantly increased compared with those at the periportal zone (zone 1). These findings at zone 3 in the IR group were improved in the IR+milrinone group. SII with villus congestion and apoptosis in the IR group was significantly attenuated in the IR+milrinone group. The 7-day survival rate was significantly elevated in the IR+milrinone group as compared with that of the IR group. CONCLUSIONS A hepatic IRI model caused zone 3-based LI and SII, which were attenuated by intraportal administration of milrinone.
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- 2020
37. Established fibrous peritoneal metastasis in an immunocompetent mouse model accurately reflects the real clinical immune microenvironment of gastric cancer
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Jun Kinoshita, Takashi Ohama, Masami Yamamoto, Koichi Sato, Sachiyo Nomura, Takahisa Yamaguchi, Daisuke Fujimori, Tetsuya Tsukamoto, Sachio Fushida, Yusuke Nakamura, Katsuya Gunjigake, and Tetsuo Ohta
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Peritoneal metastasis ,business.industry ,Immune microenvironment ,Cancer research ,Medicine ,Cancer ,business ,medicine.disease ,Immunocompetent mouse - Abstract
Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (PP=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (PPConclusionsThis model is the first immunocompetent mouse model to accurately reflect the TME of human clinical PM. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.
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- 2020
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38. A phase I study of preoperative (neoadjuvant) chemotherapy with gemcitabine plus
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Hidehiro, Tajima, Isamu, Makino, Ryosuke, Gabata, Mitsuyoshi, Okazaki, Yoshinao, Ohbatake, Hiroyuki, Shimbashi, Shinich, Nakanuma, Hiroto, Saitoh, Mari, Shimada, Takahisa, Yamaguchi, Koichi, Okamoto, Hideki, Moriyama, Jun, Kinoshita, Keishi, Nakamura, Tomoharu, Miyashita, Itasu, Ninomiya, Sachio, Fushida, Hiroko, Ikeda, and Tetsuo, Ohta
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Articles - Abstract
Neoadjuvant chemotherapy (NAC) has become a standard treatment for borderline resectable pancreatic ductal adenocarcinoma (PDAC). The present study examined the maximum tolerated dose of NAC with gemcitabine plus nab-paclitaxel (GnP) in patients with resectable PDAC. Between 2015 and 2019, 39 patients with resectable PDAC were enrolled in the present study. GnP was administered for two 28-day cycles on days 1, 8 and 15. The planned doses for levels 1, 2 and 3 were 75, 100 and 125 mg/m(2), respectively, for nab-paclitaxel and 600, 800 and 1,000 mg/m(2), respectively, for gemcitabine. Dose-limiting toxicity (neutropenia, anemia, thrombocytopenia and/or liver injury) was observed in 44.4% of patients treated at dose level 1 (21 patients) and 60.0% of those treated at dose level 2 (18 patients). Therefore, the maximum tolerated dose was set as level 1. Six patients withdrew from protocol treatment because of non-hematologic adverse events (skin rash, pancreatitis and biliary tract infection). Among the 31 patients with pathologically confirmed PDAC, partial response, stable disease and disease progression were recorded in 4 (12.9%), 24 (77.4%) and 3 (9.7%) patients, respectively. NAC significantly reduced tumor size according to computed tomography, and CA19-9 levels and the (18)F-fluorodeoxyglucose maximum standardized uptake value were decreased in positron emission tomography. No postoperative complications attributable to NAC were recognized. Among the 27 patients with PDAC who underwent resection, the pathological treatment effect was judged as grades Ia, Ib and II in 21 (77.8%), 4 (14.8%) and 2 (7.4%) patients, respectively. R0 resection was performed in 24 out of 27 patients (88.9%). Adjuvant chemotherapy with oral S-1 was administered to 21 out of 27 patients (77.8%). In conclusion, NAC with GnP was safe and feasible for resectable PDAC at dose level 1. In the future, verification of the long-term results of the present study will be necessary, and a phase II clinical trial is anticipated.
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- 2020
39. Effects of Cytoreductive Surgery Combined with Perioperative Chemotherapy on Long-Term Survivals of Colorectal Cancer Patients with Peritoneal Metastasis, with Special Reference to the Involved Peritoneal Sectors and Organs
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Yutaka, Yonemura, Aruna, Prabhu, Shouzou, Sako, Haruaki, Ishibashi, Masamitsu, Hirano, Akiyoshi, Mizumoto, Nobuyuki, Takao, Masumi, Ichinose, Shunsuke, Motoi, Yang, Liu, Kazuo, Nishihara, and Sachio, Fushida
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Survival Rate ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Cytoreduction Surgical Procedures ,Hyperthermia, Induced ,Peritoneum ,Colorectal Neoplasms ,Combined Modality Therapy ,Peritoneal Neoplasms - Abstract
Peritoneal Surface Oncology Group International(PSOGI)proposed a novel treatment, named comprehensive treatment for peritoneal metastasis(PM)from colorectal cancer(CRC). The present study demonstrated the efficacies of the treatment regarding the peritoneal sectors and organs involved with PM from CRC.Among 365 patients received laparotomy, 278 CRC patients with PM underwent complete cytoreductive surgery(CC-0).After CC-0 resection Grade 3, Grade 4, and Grade 5 postoperative complication were found in 20(7.2%), 26(9.3%), and 6(2.2%). Five- and 10-year survival rate(YSR)of CC-0 resection were 24.5%, and 11.6% with median survival time(MST)of 42.0 months. Regarding the peritoneal cancer index(PCI)of small bowel(SB-PCI), all patients of PCI B3 died of the disease. In contrast, 10-YSR of patients with SB-PCI of 0, 1, and 2 were 26.1%, 19.5%, and 6.2%, respectively. Ten-YSR of patients with the number of involved peritoneal sectors C9 ranged from 6.9% to 29.8%. MST of patients with PM in each peritoneal sector(sector 0 to sector 8)ranged from 26.4 months to 49.2 months, and 10-YSR ranged from 4.2%to 17.2%. Ten-YSR of patients with involvement of rectum, stomach, liver capsule, seminal vesicle, ureter, uterus, or ovary ranged from 0% to 16.9%.From the present data, PM should be removed aggressively to achieve complete cytoreduction, when the patients with PCIC26, involved peritoneal sectorsC9 and SB-PCIC2 are supposed to receive complete cytoreduction of PM.
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- 2020
40. Platelet adherence to cancer cells promotes escape from innate immune surveillance in cancer metastasis
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Sachio Fushida, Hidehiro Tajima, Takahisa Yamaguchi, Mitsuyoshi Okazaki, and Tetsuo Ohta
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Blood Platelets ,Male ,Cancer Research ,Epithelial-Mesenchymal Transition ,Biology ,Metastasis ,Mice ,Platelet Adhesiveness ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Platelet activation ,Neoplasm Metastasis ,Tumor microenvironment ,Mice, Inbred BALB C ,Innate immune system ,CD44 ,Cancer ,medicine.disease ,Immunity, Innate ,Pancreatic Neoplasms ,Disease Models, Animal ,Hyaluronan Receptors ,Oncology ,Cancer cell ,Cancer research ,biology.protein ,Tumor Escape - Abstract
The impacts of post‑operative abdominal infectious complications increase hematogenous distant metastasis and result in poor long‑term survival after curative resection. Even if curative resection can be performed, the presence of circulating tumor cells is affected. The liver, the most common site of metastases, is an important organ in innate immune surveillance. However, the molecular mechanisms of distant hematogenous metastasis are not yet fully known. Platelets are crucial components in the tumor microenvironment that function to promote tumor progression and metastasis. The purpose of this study was to identify the effect of platelets on escape from innate immune surveillance in post‑operative abdominal infectious complications. Platelet adherence was assessed by co‑culturing human pancreatic cancer cells including transforming growth factor (TGF‑β)‑treated BxPC‑3. CD44 isoform, transcription factors and epithelial‑mesenchymal transition markers were examined using western blotting. We also assessed whether cancer cells surrounded by activated platelets could escape from innate immune surveillance, using infectious and non‑infectious mouse models injected intraperitoneally with LPS. Platelets were found to preferentially adhere to mesenchymal cells rather than epithelial cells. BxPC‑3 epithelial cells showed upregulation of CD44‑variant and epithelial splicing regulatory protein 1 (ESRP‑1) expression. However, Panc‑1 mesenchymal cells and TGF‑β‑treated BxPC‑3 cells showed upregulation of CD44‑standard and zinc finger E‑box‑binding homeobox 1 (ZEB‑1) expression and a reduction in ESRP‑1. In the non‑infectious model, cancer cells were not found in the liver. In the infectious model, although epithelial cells without platelet adhesion were in an apoptotic state, mesenchymal cells showed many viable cancer cells surrounded by activated platelets. Cancer cells were suggested to have phenotypic plasticity through the switching of CD44 isoforms. Mesenchymal cells, which express CD44‑standard, could escape from immune surveillance by becoming surrounded by adhered activated platelets. Therefore, it may be necessary to administer antiplatelet agents to prevent distant hematogenous metastasis when post‑operative abdominal infectious complications occur.
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- 2020
41. Mechanisms of Peritoneal Metastasis Formation
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Yoshio Endou, Syouzou Sako, Masahiro Miura, Sachio Fushida, Keizou Taniguchi, Masumi Ichinose, Nobuyuki Takao, Haruaki Ishibashi, Akiyoshi Mizumoto, Satoshi Wakama, Yutaka Yonemura, Kazuo Nishihara, Shun-ichi Motoi, and Yang Liu
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Pathology ,medicine.medical_specialty ,Chemistry ,Adhesion (medicine) ,Pelvic cavity ,medicine.disease ,Metastasis ,medicine.anatomical_structure ,Lymphatic system ,Peritoneum ,Cancer cell ,medicine ,Pseudomyxoma peritonei ,Pouch - Abstract
Mechanisms of peritoneal metastasis (PM) formation remain unclear. It has long been considered that the establishment of PM is a multi-step process. Here are the recent new concepts of the formation of PM, in terms of three patterns of PM: trans-mesothelial, trans-lymphatic, and superficial growing metastasis. Trans-mesothelial metastasis is established through detachment of cancer cells, adhesion on distant peritoneal surface, invasion into submesothelial tissue, and proliferation. Trans-lymphatic metastasis develops by the migration of peritoneal free cancer cells (PFCCs) into omental milky spots and/or initial lymphatic vessels. Superficial growing metastasis is established by growing of PFCCs on the peritoneal surface after trapping or adhesion to pocket-like structure or pouch in pelvic cavity or in peritoneum absorbed by negative pressure generated omental milky spots or initial lymphatic vessels.
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- 2020
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42. TCRT-19-0200_revised_Supplemental_table_and_figures - Clinical features and diagnostic imaging of cholangiolocellular carcinoma compared with other primary liver cancers: a surgical perspective
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Takamura, Hiroyuki, Gabata, Ryousuke, Yoshinao Obatake, Nakanuma, Shinichi, Hayashi, Hironori, Kozaka, Kazuto, Sasaki, Motoko, Okazaki, Mitsuyoshi, Yamaguchi, Takahisa, Shimbashi, Hiroyuki, Terai, Shiro, Okamoto, Koichi, Makino, Isamu, Kinoshita, Jun, Nakamura, Keishi, Tomoharu Miyashita, Hidehiro Tajima, Itasu Ninomiya, Sachio Fushida, Kitao, Azusa, Kitahara, Masaaki, Arai, Kuniaki, Yamashita, Taro, Yamashita, Tatsuya, Ikeda, Hiroko, Satoh, Yasunori, Harada, Kenichi, Syuichi Kaneko, Toshihumi Gabata, Kosaka, Tateo, and Ohta, Tetsuo
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110320 Radiology and Organ Imaging ,FOS: Clinical medicine ,Biochemistry ,111299 Oncology and Carcinogenesis not elsewhere classified - Abstract
TCRT-19-0200_revised_Supplemental_table_and_figures for Clinical features and diagnostic imaging of cholangiolocellular carcinoma compared with other primary liver cancers: a surgical perspective by Hiroyuki Takamura, Ryousuke Gabata, Yoshinao Obatake, Shinichi Nakanuma, Hironori Hayashi, Kazuto Kozaka, Motoko Sasaki, Mitsuyoshi Okazaki, Takahisa Yamaguchi, Hiroyuki Shimbashi, Shiro Terai, Koichi Okamoto, Isamu Makino, Jun Kinoshita, Keishi Nakamura, Tomoharu Miyashita, Hidehiro Tajima, Itasu Ninomiya, Sachio Fushida, Azusa Kitao, Masaaki Kitahara, Kuniaki Arai, Taro Yamashita, Tatsuya Yamashita, Hiroko Ikeda, Yasunori Satoh, Kenichi Harada, Syuichi Kaneko, Toshihumi Gabata, Tateo Kosaka and Tetsuo Ohta in Technology in Cancer Research & Treatment
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- 2020
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43. REVIVE study: A prospective observational study in chemotherapy (CTx) after nivolumab (NIVO) therapy for advanced gastric cancer (AGC)
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Tomohiro Matsushima, Yukiya Narita, Toshihiro Misumi, Yasuhiro Sakamoto, Hiroshi Matsuoka, Hiroaki Tanioka, Takeshi Kawakami, Hiroto Miwa, Hirokazu Shoji, Atsushi Ishiguro, Takanobu Yamada, Sachio Fushida, Kou Miura, Katsunori Shinozaki, Takuro Mizukami, Tomohiro Nishina, Toshikazu Moriwaki, Seiichiro Mitani, Michio Nakamura, and Kei Muro
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Cancer Research ,Oncology - Abstract
257 Background: NIVO therapy is a standard care treatment for heavily pretreated patients with AGC. Improvement in objective response rate (ORR) to CTx after NIVO therapy for various cancer types has been reported. However, the efficacy and safety of CTx for AGC after progression on NIVO remains unclear. Methods: The REVIVE trial was a prospective, multicenter, observational study that evaluated the efficacy and safety of CTx in NIVO-refractory or NIVO-intolerant patients (pts) with AGC (UMIN000032182). The primary endpoint was overall survival (OS) of CTx following NIVO therapy. The median threshold and expected survival times were set as 4.0 and 7.0 months (M). The secondary endpoints are ORR, disease control rate (DCR), progression-free survival (PFS), and incidence of adverse events (AEs), including immune-related adverse events (irAEs). CTx consisted of irinotecan alone (IRI), trifluridine/tipiracil alone (FT), and oxaliplatin-containing regimens (OX). Results: Of 395 pts treated with NIVO who met the eligibility at formal registration from Jun 2018 to Sep 2020, 199 pts who received CTx after NIVO were evaluated. Pt characteristics were as follows: median age, 69 years; male, 70%; ECOG PS 0/1/2, 38/51/12%; histology (diffuse/intestinal), 39/59%; metastatic lesions (peritoneum/liver/lung), 38/34/15%; number of metastatic organ sites (0–1/≥2), 40/60%; measurable lesions, 83%; and CTx regimens (IRI/FT/OX), 64/31/5%. Median OS and PFS were 7.5 M (95%CI, 6.7–9.7) at 145 events for OS and 2.9 M (95%CI, 2.2–3.5) at 184 events for PFS. The ORR and DCR were 17.0% (95%CI, 11.6–23.6) and 46.7% (95%CI, 38.9–54.6). Median OS, median PFS, ORR, and DCR according to CTx regimens (IRI/FT/OX) were 8.1/7.1/6.2 M, 3.3/2.8/2.4 M, 18.9/10.9/25.0%, and 47.8/43.5/50.0%, respectively. At the start of CTx, 42 pts had irAEs due to prior NIVO therapy. The most common any-grade and grade ≥3 AEs during CTx included decreased appetite (46% and 7.5%), fatigue (26% and 2.5%), nausea (24% and 1.5%), constipation (16% and 0%), and diarrhea (28% and 4.0%). No treatment-related deaths were observed. Conclusions: Prior NIVO therapy may lead to improved prognosis after CTx without unexpected AEs in pts with AGC, warranting further investigations after NIVO is approved as first-line treatment.[Table: see text]
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- 2022
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44. A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2)
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Taroh Satoh, Kenji Kunieda, Li-Tzong Chen, Naotoshi Sugimoto, Ken Kato, Sachio Fushida, Takako Eguchi Nakajima, Keisho Chin, Tomohiro Nishina, Kensei Yamaguchi, Masahiro Goto, Takaki Yoshikawa, Kei Muro, Masahiro Tsuda, Narikazu Boku, Keisei Taku, Kazuhiro Yoshida, Yoshito Komatsu, Keiko Minashi, Yasuo Iwamoto, Soh Saitoh, Takao Tamura, Taito Esaki, Hirofumi Fujii, Mizutomo Azuma, Eiji Oki, Yasushi Omuro, Yoon-Koo Kang, Yasuo Hamamoto, Nozomu Machida, and Akihito Tsuji
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Population ,Placebo ,Gastroenterology ,Ramucirumab ,Young Adult ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Asian People ,Double-Blind Method ,Japan ,Stomach Neoplasms ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Adverse effect ,education ,Aged ,Aged, 80 and over ,Salvage Therapy ,education.field_of_study ,business.industry ,Hazard ratio ,General Medicine ,Middle Aged ,Progression-Free Survival ,Clinical trial ,Nivolumab ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,Original Article ,Gastro-esophageal junction cancer ,030211 gastroenterology & hepatology ,Esophagogastric Junction ,Gastric cancer ,business - Abstract
Background Nivolumab, an anti-programmed death-1 agent, showed survival benefits in Asian patients, including Japanese, with gastric/gastro-esophageal junction (G/GEJ) cancer. We report the analysis of the Japanese subpopulation from ATTRACTION-2 that evaluated nivolumab versus placebo in unresectable advanced or recurrent G/GEJ cancer after ≥ 2 chemotherapy regimens. Methods Data from the Japanese subpopulation in the randomized, double-blind, placebo-controlled, phase 3 trial were analyzed (data cutoff, February 25, 2017). Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Results Among the overall study population of 493 patients, 226 (nivolumab 152; placebo 74) were enrolled from 28 sites in Japan. In the Japanese subset, median OS was longer with nivolumab versus placebo (5.4 months, 95% CI 4.6–7.4 versus 3.6 months, 95% CI 2.8–5.0). The risk of death was lower in the nivolumab versus placebo group (hazard ratio 0.58, 95% CI 0.42–0.78; p = 0.0002). Incidences of serious adverse events were 23% (35/152) and 25% (18/72) in the nivolumab and placebo groups, respectively. In the Japanese ITT population, 22% of nivolumab-treated and 28% of placebo-treated patients received prior ramucirumab treatment. Overall, clinical activity of nivolumab was observed regardless of prior ramucirumab use. In the nivolumab group, ORR and PFS were numerically higher in patients with prior ramucirumab use than in those without. Conclusions In the Japanese subpopulation, patients receiving nivolumab had longer OS, similar to the overall population, with a manageable safety profile. The interaction between nivolumab and ramucirumab will be clarified in ongoing clinical trials. Electronic supplementary material The online version of this article (10.1007/s10120-018-0899-6) contains supplementary material, which is available to authorized users.
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- 2018
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45. Multidisciplinary therapy for scirrhous gastric cancer: a retrospective analysis and proposal of new treatment strategy
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Sachio Fushida, Tomoya Tsukada, Tetsuo Ohta, Itasu Ninomiya, Takashi Fujimura, Jun Kinoshita, Takahisa Yamaguchi, and Katsunobu Oyama
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0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,intraperitoneal chemotherapy ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Original Research ,Univariate analysis ,Chemotherapy ,Taxane ,business.industry ,Cancer ,medicine.disease ,taxanes ,030104 developmental biology ,Oncology ,Docetaxel ,Cancer Management and Research ,Fluorouracil ,peritoneal metastasis ,030220 oncology & carcinogenesis ,Gastrectomy ,Lymphadenectomy ,business ,medicine.drug - Abstract
Sachio Fushida,1 Jun Kinoshita,1 Katsunobu Oyama,1 Takashi Fujimura,2 Tomoya Tsukada,3 Takahisa Yamaguchi,1 Itasu Ninomiya,1 Tetsuo Ohta1 1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan; 2Department of Surgery, Toyama City Hospital, Toyama, Japan; 3Department of Surgery, Toyama Prefectural Central Hospital, Toyama, Japan Background: Scirrhous gastric cancer (SGC) is highly invasive and metastatic because of its interactions with stromal cells, such as fibroblasts and macrophages, and extracellular matrix, leading to a higher incidence of peritoneal metastasis (PM) than other gastric cancers (GCs). Taxane-based intraperitoneal chemotherapy (IPC) is a promising therapy for PM. We retrospectively analyzed outcomes of multidisciplinary therapies that included IPC for SGC. Patients and therapy: Of 1,679 GC patients treated between 1990 and 2012, we analyzed 119 patients who underwent multidisciplinary therapy for SGC. Patients without PM received gastrectomy with lymphadenectomy and resection of involved adjacent organs followed by intraoperative IPC using cisplatin. Patients with PM received chemotherapy using fluorouracil, with or without methotrexate plus IPC using cisplatin before 2000, and S-1 plus IPC using paclitaxel or docetaxel since 2000. Results: Of the 119 patients, 73 (61%) had PM and 63 (53%) had positive peritoneal lavage cytology. Of the 89 gastrectomy patients, 30 (34%) had macroscopic residual tumors (R2). Of the patients treated since 2000, 66 (100%) received S-1 plus taxanes and 44 patients (67%) received taxane-based IPC. Median survival time was significantly longer in the post-2000 group (22.8 months) than in the pre-2000 group (9.5 months). In univariate analysis, lavage cytology, PM, taxane-based IPC, gastrectomy, and R2 resection were significant prognostic factors. However, only R2 resection was an independent prognostic factor in multivariate analysis (hazard ratio: 5.53, 95% CI: 2.05–14.93). Conclusion: As use of taxane-based IPC is not an independent prognostic factor, new multidisciplinary therapies are necessary to avoid R2 resections. Keywords: peritoneal metastasis, intraperitoneal chemotherapy, taxanes
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- 2018
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46. Survival benefit of multimodal local therapy for repeat recurrence of thoracic esophageal squamous cell carcinoma after esophagectomy
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Isamu Makino, Hiroyuki Takamura, Tomoharu Miyashita, Tetsuo Ohta, Itasu Ninomiya, Hidehiro Tajima, Jun Kinoshita, Koichi Okamoto, and Sachio Fushida
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Male ,Esophageal Neoplasm ,medicine.medical_specialty ,Multivariate analysis ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Surgical oncology ,medicine ,Humans ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Gastroenterology ,Middle Aged ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Surgery ,Esophagectomy ,Radiation therapy ,Treatment Outcome ,Survival benefit ,Cardiothoracic surgery ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Esophageal Squamous Cell Carcinoma ,Neoplasm Recurrence, Local ,business - Abstract
This study was performed to clarify the optimal therapeutic strategy for recurrent disease after esophagectomy. We investigated the prognosis of 37 patients who developed recurrence among 128 patients who underwent curative thoracoscopic esophagectomy (TE) at Kanazawa University Hospital. The prognostic factors after recurrence were examined by univariate and multivariate analyses. Of these 37 recurrences, 29 patients underwent local therapy (surgery, 10 patients; surgery followed by radiation, 2 patients; radiation, 17 patients). Radiation includes intensity-modulated radiation therapy, chemoradiation, and simple radiation therapy. Seventeen patients (58.6%) were considered to have undergone successful therapy by disappearance or diminishment of the targeted region without regrowth. Eleven of 17 patients (64.7%) showed repeat recurrence at another site. Multiple local therapy was performed for repeat recurrence or uncontrollable first therapy. Finally, 57 local therapies were performed. Using multimodal local therapy, 37 (64.9%) of 57 recurrences were successfully managed. The 12 patients treated by surgery as the initial therapy showed the most favorable survival. Seventeen patients who underwent successful initial therapy showed better survival than others. Multiple or miscellaneous organ metastasis, abdominal lymphatic recurrence and best supportive care at recurrence were statistically significant negative variables for survival after recurrence. Performance of surgery and successful therapy as the initial recurrence were statistically significant positive variables for survival after recurrence. Multivariate analysis showed that successful therapy at the initial recurrence was the only independent variable for survival after recurrence. Multimodal local therapy for repeat recurrence after TE contributes to the improvement of survival after recurrence.
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- 2018
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47. Postoperative changes in neutrophil-to-lymphocyte ratio and platelet count: A simple prognostic predictor for adult-to-adult living donor liver transplantation
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Hironori Hayashi, Yoshinao Ohbatake, Hidehiro Tajima, Hiroyuki Takamura, Shinichi Nakanuma, Ichiro Onishi, Sachio Fushida, Koichi Shimizu, Takashi Tani, and Tetsuo Ohta
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Adult ,Blood Platelets ,Male ,medicine.medical_specialty ,Optimal cutoff ,Low platelet count ,Neutrophils ,lcsh:Surgery ,Neutropenia ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Outcome Assessment, Health Care ,Living Donors ,medicine ,Humans ,Platelet ,Lymphocyte Count ,Lymphocytes ,Postoperative Period ,Neutrophil to lymphocyte ratio ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,Platelet Count ,business.industry ,fungi ,Clinical course ,Complete blood count ,lcsh:RD1-811 ,Middle Aged ,Prognosis ,medicine.disease ,Liver Transplantation ,Surgery ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,business ,Living donor liver transplantation ,Biomarkers - Abstract
Summary: Background/Objective: The neutrophil-to-lymphocyte ratio (NLR) is a simple index that represents systemic inflammatory change. The number of platelets is also known to reflect both post-transplant graft regeneration and dysfunction. Thus, we aimed to investigate the usefulness of NLR and platelet number in predicting the clinical course after adult-to-adult living donor liver transplantation (AA-LDLT) in the acute postoperative period in recipients. Methods: Between January 1999 and December 2013, 61 patients underwent their first AA-LDLT at our institute. We retrospectively analyzed their clinical data, including NLR and number of platelets, until postoperative day 14, and evaluated their ability to predict prognosis after AA-LDLT. Results: The optimal cutoff values of postoperative maximum NLR and maximum platelets to predict prognosis were 50 and 80 × 103/μL, respectively. The 1- and 5-year survival rates were 87.5% and 79.1% in the normal maximum NLR group, respectively, and 46.2% for both in the high maximum NLR group (p = 0.0033). The 1- and 5-year survival rates, respectively, were 90.9% and 84.1% in the high maximum platelets group and 47.1% and 41.2% in the low maximum platelets group (p
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- 2018
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48. Preventive effect of oral hangeshashinto (TJ-14) on the development of reflux-induced esophageal cancer
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Itasu Ninomiya, Tomoharu Miyashita, John W. Harmon, Sachio Fushida, Keishi Nakamura, Koichi Okamoto, Ken-ichi Mukaisho, Tetsuo Ohta, Daichi Sadatomi, Shinichi Nakanuma, Katsunobu Oyama, Daisuke Matsui, Yuki Yamazaki, Hidehiro Tajima, Toru Kono, Naoki Fujitsuka, Isamu Makino, Hiroyuki Takamura, and Jun Kinoshita
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medicine.medical_specialty ,Bile acid ,business.industry ,medicine.drug_class ,Hyperplasia ,Esophageal cancer ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Chenodeoxycholic acid ,Internal medicine ,Metaplasia ,medicine ,Mucositis ,030211 gastroenterology & hepatology ,Surgery ,Prostaglandin E2 ,medicine.symptom ,business ,CD163 ,medicine.drug - Abstract
Background Prostaglandin E2 is one of the potential products that promotes development of tumors and also is a strong inducer of M2 phenotype macrophages, which contribute to tumor development in the immunosuppressed microenvironment. Hangeshashinto (TJ-14), a Japanese traditional medicine (Kampo medicine), has been reported to be effective in preventing chemotherapy-induced oral mucositis through the reduction of prostaglandin E2. We previously developed a surgical rat reflux model of esophageal cancer and used this well-established animal model to investigate the action of TJ-14 in preventing esophageal cancer. We also assessed the effect of TJ-14 on the downregulation of prostaglandin E2 production, utilizing esophageal squamous cell carcinoma cell line exposed to bile acid. Methods An end-to-side esophagojejunostomy was performed for the reflux model. A daily oral diet was subsequently administered, consisting of either diet-incorporated TJ-14 or standard diet as a control group. The rats were killed at 40 weeks after surgery. The incidence of esophageal cancer, Barrett's metaplasia, and proliferative hyperplasia were assessed histologically. CD163, a M2 phenotype macrophage marker, was assessed with immunohistochemistry. Prostaglandin E2 enzyme immunoassay and lactate dehydrogenase assay were performed on chenodeoxycholic acid or gastroesophageal reflux contents exposed to esophageal squamous cell carcinoma cell line. Results Sixty-seven percent of the controls (n = 12) developed esophageal cancer, but animals that received TJ-14 (n = 10) had a cancer incidence of 10% (P = .007). Barrett's metaplasia was found in 83% of the rats in the control group and 50% of the rats in the TJ-14 indicating a protective tendency of TJ-14 (P = .095). All of the rats developed proliferative hyperplasia. The number of M2 phenotype macrophage were significantly decreased in the TJ-14 group compared to the control group in both Barrett's metaplasia and esophageal cancer lesions. TJ-14 inhibited chenodeoxycholic acid or gastroesophageal reflux content–induced prostaglandin E2 production in esophageal squamous cell carcinoma cell. Conclusion TJ-14 reduced the incidence of reflux-induced esophageal cancer and the infiltration of M2 macrophages in a surgical rat model or suppressed prostaglandin E2 production in esophageal squamous cell carcinoma cell. Further investigation is required regarding the potential clinical use of TJ-14 as an esophageal cancer chemopreventive agent.
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- 2018
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49. The effect of HIF-1α and PKM1 expression on acquisition of chemoresistance
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Katsunobu Oyama, Tetsuo Ohta, Mitsuyoshi Okazaki, Itasu Ninomiya, Jun Kinoshita, Shinichi Harada, Sachio Fushida, Tomoya Tsukada, and Tomoharu Miyashita
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0301 basic medicine ,HIF-1α ,PKM2 ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Original Research ,gastric cancer ,chemoresistance ,Cancer ,medicine.disease ,Vascular endothelial growth factor ,030104 developmental biology ,Oncology ,chemistry ,Paclitaxel ,Cancer Management and Research ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Growth inhibition ,PKM1 - Abstract
Mitsuyoshi Okazaki,1 Sachio Fushida,1 Tomoya Tsukada,1 Jun Kinoshita,1 Katsunobu Oyama,1 Tomoharu Miyashita,1 Itasu Ninomiya,1 Shinichi Harada,2 Tetsuo Ohta1 1Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan; 2Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Ishikawa, Japan Background: In patients with gastric cancer, one of the greatest obstacles to effective chemotherapy is the development of chemoresistance. It has been previously reported that hypoxia-inducible factor-1 alpha (HIF-1α) is associated with acquisition of chemoresistance, and more recent studies have also noted an association of pyruvate kinase muscle 1 (PKM1) and chemoresistance. The purpose of this study was to identify the effect of HIF-1α and PKM1 expression on the development of acquired chemoresistance using a paclitaxel (PTX)-resistant gastric cancer cell line.Materials and methods: A cancer cell line resistant to PTX was established from MKN45 cells by stepwise exposure to drug (rMKN45-PTX). The expressions of HIF-1α, apoptosis, vascular endothelial growth factor (VEGF), multidrug transporters and glycolytic enzyme were examined by Western blotting, enzyme-linked immunosorbent assay and immunohistochemistry. We also assessed the tumor proliferation by subcutaneous tumor and peritoneal dissemination of mouse xenograft model.Results: The resistance index was 6.1 by determining as the ratio of the 50% growth inhibition (IC50) of rMKN45-PTX/IC50 of MKN45. Expression of nuclear factor kappa B and HIF-1α was increased in rMKN45-PTX cells compared with the parent cells. Expression of Bax and caspase-3 was significantly downregulated, whereas expression of Bcl-xL, P-glycoprotein, multidrug resistance-associated protein and VEGF was increased in rMKN45-PTX. The expression level of PKM1 was upregulated in rMKN45-PTX, leading to an increase in the PKM1/PKM2 ratio. Using xenograft models, we demonstrated that mouse subcutaneous tumors derived from rMKN45-PTX were significantly larger than those derived from MKN45 cells.Conclusion: Under the stress of chemotherapeutic agent exposure, high expression of HIF-1α affects various downstream genes. Although the underlying mechanism is unknown, our data suggest that PKM1 is also a molecular target for gastric cancer treatment. Keywords: HIF-1α, PKM1, chemoresistance, gastric cancer
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- 2018
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50. Phosphodiesterase III inhibitor attenuates rat sinusoidal obstruction syndrome through inhibition of platelet aggregation in Disse's space
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Tomoharu Miyashita, Sachio Fushida, Takashi Miyata, Hiroyuki Takamura, Tomohiko Wakayama, Katsunobu Oyama, Hironori Hayashi, Tetsuo Ohta, Shinichi Harada, Miki Hirata, Isamu Makino, Itasu Ninomiya, Hidehiro Tajima, Shinichi Nakanuma, and Shoichi Iseki
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Liver injury ,medicine.medical_specialty ,Hepatology ,business.industry ,Gastroenterology ,medicine.disease ,Pathophysiology ,Transaminase ,Cilostazol ,Endothelial stem cell ,03 medical and health sciences ,0302 clinical medicine ,Coagulative necrosis ,Endocrinology ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,030211 gastroenterology & hepatology ,Platelet ,business ,Plasminogen activator ,medicine.drug - Abstract
Background and aim Sinusoidal obstruction syndrome (SOS) is a serious drug-induced liver injury. However, the pathophysiology of the disease remains unclear. This study investigated the effects of cilostazol (CZ), a phosphodiesterase III inhibitor, in a monocrotaline (MCT)-induced rat model of SOS. Methods Male Wistar rats were administrated MCT to induce SOS. Rats were divided into control, MCT, and MCT + CZ groups. In the MCT + CZ group, CZ was administered at 48 h, 24 h, and 30 min prior to and 8 h and 24 h after MCT administration. The MCT group was treated with water instead of CZ. At 48 h after MCT administration, blood and liver samples were collected to assess biochemistry and liver histology. Expression of rat endothelial cell antigen, CD34, CD41, P-selectin, and caspase-3 in the liver were analyzed. Plasminogen activator inhibitor-1 (PAI-1) in hepatocytes was analyzed using western blotting and polymerase chain reaction. Results In the MCT group, macroscopic findings showed a dark-red liver surface. Histological findings showed sinusoidal dilatation, coagulative necrosis of hepatocytes, and endothelial damage of the central vein. These changes were attenuated in the MCT + CZ group. Elevated serum transaminase and decreased platelet counts were observed in the MCT + CZ group compared with those in the MCT group. Treatment with CZ reduced MCT-induced damage to the liver sinusoidal endothelial cells, inhibited extravasated platelet aggregation, and suppressed hepatocyte apoptosis around the central vein. CZ attenuated hepatic PAI-1 protein and mRNA levels. Conclusions Cilostazol attenuated MCT-induced SOS by preventing damage to liver sinusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI-1 levels were suppressed with CZ treatment.
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- 2018
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