Details of a Researcher - Nakamura, Rieko

Papers - Nakamura, Rieko

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Clinical features and prognostic factors of brain metastasis from esophageal carcinoma

Okamura Akihiko, Takeuchi Hiroya, Sako Hiroyuki, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Ozawa Soji, Kitagawa Yuko

Esophagus 11 ( 4 ) 217 - 222 2014

ISSN 1612-9059

Background: Brain metastasis from esophageal carcinoma is uncommon. The aims of this study were to assess the frequency of brain metastasis from esophageal carcinoma, describe treatment modalities and their outcomes, and determine predictors of survival. Methods: Between 2004 and 2012, 680 patients with esophageal carcinoma were registered at Keio University Hospital, Tokyo, Japan. Of these patients, 16 (2.3 %) were diagnosed with brain metastasis. We reviewed their medical records and performed statistical analyses. Results: The median survival after diagnosis of brain metastasis was 5.0 months (95 % CI 1.2-8.7 months). The only statistically significant baseline characteristic that predicted worse survival from brain metastasis was the onset form of brain metastasis (p = 0.01). At the onset of brain metastasis, the median survival from brain metastasis was 13.0 months (95 % CI 0.0-31.0 months) in patients without extracranial metastasis and 2.0 months (95 % CI 0.0-4.3 months) in patients with extracranial metastasis (p = 0.01). Conclusions: Approximately 2 % patients with esophageal carcinoma were diagnosed with brain metastasis. The prognosis of brain metastasis is extremely poor, but long-term survival may be expected with intensive treatment for brain metastasis when the first metastatic site is the brain.

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Suitability of sentinel node mapping as an index of metastasis in early gastric cancer following endoscopic resection

Mayanagi Shuhei, Takeuchi Hiroya, Kamiya Satoshi, Niihara Masahiro, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Nakahara Tadaki, Mukai Makio, Kitagawa Yuko

Annals of Surgical Oncology 21 ( 9 ) 2987 - 2993 2014

ISSN 1068-9265

Background. When pathological diagnosis following endoscopic resection (ER) for early gastric cancer (EGC) suggests probable lymph node metastasis, additional surgery with lymphadenectomy should be performed. The sentinel node (SN) concept has yet to be applied to tumors following ER. The aim of this study was to evaluate the feasibility of SN navigation surgery for such tumors. Methods. Forty patients diagnosed with EGC lesions <4 cm in diameter underwent gastrectomy with SN mapping following ER. A technetium-99 m tin colloid solution and a dye were injected into the submucosal layer around the post-ER scar in all four abdominal quadrants. We then compared the SN distribution and metastases among the patients who underwent ER and controls (n = 192). Results. SNs were identifiable in all patients, and the mean number of SNs per case was 4.9. The location of the SN basin was similar in the patients who underwent ER and the controls. One patient (3 %) whose primary tumor had invaded the submucosal layer had a metastatic SN. The median time from ER to surgery was 73 days. No postoperative recurrence was observed in any patient over a median follow-up of 1,023 days. Conclusions. Our findings suggest that the SN basin is not greatly affected by ER. The SN concept could be suitable for tumors following ER, but conventional gastrectomy with lymphadenectomy involving the SN basin should be used at present.

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Effectiveness of polymyxin B-direct hemoperfusion (PMX-DHP) therapy using a polymyxin B-immobilized fiber column in patients with post-esophagectomy sepsis

Takahashi Masashi, Takeuchi Hiroya, Kawakubo Hirofumi, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Omori Tai, Kitagawa Yuko

Esophagus 11 ( 3 ) 189 - 196 2014

ISSN 1612-9059

Background: Post-esophagectomy complications have an extremely poor prognosis. Recently, polymyxin B-direct hemoperfusion (PMX-DHP) therapy using a polymyxin B-immobilized fiber column was reported to be beneficial in gram-negative and/or gram-positive bacterial sepsis. The present retrospective study investigated the effectiveness and safety of PMX-DHP therapy in severe sepsis or septic shock after esophagectomy. Methods: Fifteen severe sepsis or septic shock patients were included. Seven (four, pneumonia; two, anastomotic leakage; and one, reconstructed colon necrosis) patients received 2-5 h of PMX-DHP therapy (PMX-DHP therapy group), whereas 8 (three, pneumonia; three, anastomotic leakage; and two, gastric tube necrosis) received conventional therapy (control group). Results: Length of stay in the intensive care unit (ICU) was significantly shorter in the PMX-DHP therapy group than in the conventional therapy group (P = 0.040). In the comparison of pre- and post-PMX-DHP therapy groups, the total Sequential Organ Failure Assessment (SOFA) score, respiratory system score, and P/F ratio improved (P = 0.0027, P = 0.025, and P = 0.0087, respectively) in the post-PMX-DHP therapy group. In the comparison of conventional and PMX-DHP therapy groups, the variations in the total SOFA score, respiratory system score, and P/F ratio improved (P = 0.019, P = 0.0063, and P = 0.0015, respectively) in the PMX-DHP therapy group. Moreover, the respiratory system score was lower (P = 0.0062) in the PMX-DHP therapy group at the time of discharge from the ICU. No adverse effects were observed during the course of PMX-DHP therapy. Conclusions: PMX-DHP therapy was safe and effective in improving respiratory and general conditions of patients with severe sepsis and septic shock after esophagectomy and decreased the length of stay in the ICU.

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Optimal surgical management for esophagogastric junction carcinoma.

Matsuda Tatsuo, Takeuchi Hiroya, Tsuwano Shinichi, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Kitagawa Yuko

General Thoracic and Cardiovascular Surgery 62 ( 9 ) 560 - 566 2014

Esophagogastric junction carcinoma incidence is increasing worldwide. However, surgical strategies for this cancer remain controversial. This study aimed to clarify the optimal surgical strategy for esophagogastric junction carcinoma. We retrospectively reviewed a database of 68 consecutive patients with esophagogastric junction carcinoma [Japanese classification of gastric carcinoma (Nishi's definition): adenocarcinoma, N=53; squamous cell carcinoma, N=15] who underwent curative surgical resection at Keio University Hospital between January 2000 and September 2008. In both adenocarcinoma and squamous cell carcinoma, most lymph node metastases were located in the lesser curvature area. Mediastinal lymph node metastasis was observed in 4 patients (7.5%) with adenocarcinoma and 7 patients (46.7%) with squamous cell carcinoma. No patient presented with lymph node metastases in the pyloric region. The therapeutic value of extended lymph node dissection was 0, except for lymph node station numbers 1, 2, 3, 4sa, 7, and 110. Extended lymph node dissection in the lesser curvature area showed a high therapeutic value. The para-aortic lymph node was the most frequent nodal recurrence site. All patients with tumor centers located below the esophagogastric junction (N=37) did not develop mediastinal lymph node metastasis or recurrence. Proximal gastrectomy through a transhiatal approach may be the optimal surgical strategy for esophagogastric carcinoma. Mediastinal lymph node dissection through a thoracic approach seems unnecessary, particularly when the tumor center is located below the esophagogastric junction. To confirm the necessity of para-aortic nodal dissection, further studies are required.

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EpCAM, a potential therapeutic target for esophageal squamous cell carcinoma

Matsuda Tatsuo, Takeuchi Hiroya, Matsuda Sachiko, Hiraiwa Kunihiko, Miyasho Taku, Okamoto Minoru, Kawasako Kazufumi, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Kitagawa Yuko

Annals of Surgical Oncology 21 ( SUPPL. 3 ) 2014

ISSN 1068-9265

Background. Molecular-targeted drugs are not available for esophageal squamous cell carcinoma (ESCC), which has a poor prognosis. We investigated the clinicopathological significance of epithelial cell adhesion molecule (EpCAM) expression and the utility of EpCAM as a potential therapeutic target. Methods. The relationship between EpCAM expression and clinicopathological factors was examined by immunohistochemistry in 74 patients with resectable ESCC. A total of ten ESCC cell lines were analyzed for EpCAM expression. The effects of EpCAM knockdown in TE4, TE10, and TE14 cells were examined with regard to cell proliferation and gene expression in vitro and tumor growth in vivo. The antitumor effect of catumaxomab in ESCC cell lines was examined. Results. EpCAM overexpression was associated with poor survival in ESCC patients (P = 0.026). Multivariate Cox regression analysis showed that EpCAM overexpression was a significant and independent prognostic factor for surgically treated ESCC (P = 0.004). TE4 and TE10 cells showed high EpCAM expression, in contrast to TE14. EpCAM siRNA knockdown in TE4 and TE10 cells downregulated CCND1 and CCNE2 and suppressed cell proliferation. Low EpCAM expression reduced tumorigenesis; TE4 cells initiated tumorigenesis in seven of the ten mice injected, whereas shRNA knockdown resulted in smaller tumors in two of ten mice at 6 weeks after transplantation. Concentration- and time-dependent antitumor effects of catumaxomab were observed in TE4 and TE10 cells. Conclusions. EpCAM overexpression is an independent prognostic factor for surgically treated ESCC. EpCAM contributes to cell proliferation and tumorigenesis and may be a useful therapeutic target for ESCC.

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Clinical significance of plasma fibrinogen level as a predictive marker for postoperative recurrence of esophageal squamous cell carcinoma in patients receiving neoadjuvant treatment

Matsuda S., Takeuchi H., Fukuda K., Nakamura R., Takahashi T., Wada N., Kawakubo H., Saikawa Y., Omori T., Kitagawa Y.

Diseases of the Esophagus 27 ( 7 ) 654 - 661 2014

ISSN 1120-8694

Among multidisciplinary therapies developed for advanced esophageal cancer, neoadjuvant chemotherapy and chemoradiotherapy have been established as standard treatments. To deliver cautious follow up and intense treatment for high-risk patients, a simple and instructive biomarker for the postoperative recurrence needs to be identified. Fibrinogen, a common component of hemostasis, has been suggested to not only play an important role in cancer metastasis, but also correlate with tumor recurrence. We aim to clarify the validity of plasma fibrinogen as a marker for predicting the postoperative recurrence of esophageal squamous cell carcinoma patients who received neoadjuvant treatment. We reviewed 72 consecutive patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy or chemoradiotherapy, followed by esophagectomy at the Keio University Hospital from 2001 to 2010. Of them, we retrospectively examined 68 patients who underwent plasma fibrinogen examination before and after neoadjuvant treatment and underwent transthoracic radical esophagectomy. We investigated patient characteristics, clinicopathological factors, neoadjuvant treatment effects, postoperative course, and plasma fibrinogen levels. We investigated pretreatment and preoperative (postneoadjuvant treatment) plasma fibrinogen levels, as well as changes in fibrinogen levels before and after neoadjuvant treatment. Patients with preoperative hyperfibrinogenemia (>350mg/dL) and patients with increased plasma fibrinogen levels during neoadjuvant treatment showed significantly shorter postoperative disease-free survival (DFS) (P=0.002 and P=0.037, respectively). Moreover, we classified these patients into three classes on the basis of their preoperative fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment. Patients who had both high preoperative plasma fibrinogen and increased fibrinogen levels showed significantly shorter DFS than others. In contrast, patients who had normal preoperative plasma fibrinogen and decreased fibrinogen levels showed significantly longer DFS. Based on this fibrinogen classification, we could differentiate between significantly favorable and poor prognosis patients group. Overall, this classification (hazard ratio=1.812, P=0.013) and the response to neoadjuvant treatment (hazard ratio=0.350, P=0.007) were found to be significant determining factors for postoperative DFS. With the validity of preoperative plasma fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment, the plasma fibrinogen level was found to be a possible biomarker for postoperative recurrence in advanced esophageal cancer patients who received neoadjuvant treatment. Moreover, plasma fibrinogen classification could be a simple and valuable predictive marker for postoperative follow up.

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The neutrophil elastase inhibitor sivelestat suppresses accelerated gastrointestinal tumor growth via peritonitis after cecal ligation and puncture

Kumagai Koshi, Saikawa Yoshiro, Takeuchi Hiroya, Suda Koichi, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Kawakubo Hirofumi, Wada Norihito, Miyasho Taku, Kitagawa Yuko

Anticancer Research 33 ( 9 ) 3653 - 3660 2013.09

ISSN 0250-7005

Background: We examined whether tumor growth is enhanced by cecal ligation and puncture (CLP) and suppressed by a neutrophil elastase inhibitor, sivelestat. Materials and Methods: C57BL/6 mice were divided in CLP/sivelestat, CLP alone, and control (simple laparotomy) groups. Murine CT26 colon carcinoma cells were injected subcutaneously into the back of each mouse and tumor growth and serum cytokine levels were assessed. Results: Mice subjected to CLP alone exhibited enhanced tumor growth compared to controls with subcutaneously injected CT26 cells (0.64±0.24 g vs. 0.021±0.027 g, p<0.001), while treatment with CLP/sivelestat produced smaller tumors than CLP alone (0.28±0.23 g vs. 0.64±0.24 g, p=0.006). Cytokine assays showed suppressed production of interleukin (IL)-6 and IL-10 in the CLP/sivelestat group, and increased IL-6 and IL-10 in the CLP-alone group. Conclusion: Intraabdominal inflammation induced by CLP enhances the growth of subcutaneously implanted tumors, while perioperative administration of sivelestat suppresses tumor growth by affecting systemic inflammation.

Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma

Ogura Masaharu, Takeuchi Hiroya, Kawakubo Hirofumi, Nishi Tomohiko, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Omori Tai, Miyasho Taku, Yamada Shingo, Kitagawa Yuko

Surgery (United States) 154 ( 3 ) 512 - 520 2013.09

ISSN 0039-6060

Background CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells. CXCL-8/CXCR-2 network is believed to be involved in angiogenesis, growth, and invasion of tumor cells. To date, the clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we investigated the role of CXCL- 8/CXCR-2 network in ESCC. Methods The subjects included 78 patients with primary ESCC. We examined CXCL-8 and CXCR-2 expression in surgically resected specimens using immunohistochemistry. The association between CXCL-8/CXCR-2 expression and level of preoperative serum cytokines, C-reactive protein (CRP), coagulation factors, clinicopathologic background factors, and survival of ESCC patients was assessed. Results Thirty-seven (47%) and 36 (46%) patients were positive for CXCL-8 and CXCR-2 expression, respectively. Both CXCL-8 and CXCR-2 were expressed in 26 patients (33%). We compared the results of these 26 patients [CXCL-8(+)/CXCR-2(+) group] with those of the other group (n = 52). The depth of invasion (pT factor; P <.001), lymph node metastasis (pN factor; P =.001), pathologic stage (P <.001), lymphatic invasion (P =.010), and venous invasion (P =.001) were significantly more advanced in the CXCL-8(+)/CXCR-2(+) group compared with the other group. Preoperative IL-6, IL-8, CRP, fibrin/fibrinogen degradation product, and fibrinogen levels in the CXCL-8(+)/CXCR-2(+) group were also significantly higher than those in the other group (P =.046,.009,.029,.010, and <.001, respectively). The CXCL-8(+)/CXCR-2(+) group also showed a significantly lower recurrence-free survival (RFS; P <.001) and disease-specific survival (P =.008). As per Cox's hazards model, CXCL-8/CXCR-2 expression (hazard ratio, 2.89; P =.008) was independent predictive factor for RFS. Conclusion Increased expression of both CXCL-8 and CXCR-2 correlated with tumor progression, metastasis, higher preoperative levels of proinflammatory cytokines, CRP, activation of exogenous coagulation factors, and poor prognosis in ESCC patients. These results indicate that overexpression of both CXCL-8 and CXCR-2 may be a useful marker for predicting the outcome in ESCC patients, and more important, has potential in becoming a critical diagnostic marker for selection of appropriate treatments.

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Clinical utility of preoperative evaluation of bronchial arteries by three-dimensional computed tomographic angiography for esophageal cancer surgery

Wada T., Takeuchi H., Kawakubo H., Nakamura R., Oyama T., Takahashi T., Wada N., Saikawa Y., Omori T., Jinzaki M., Kuribayashi S., Kitagawa Y.

Diseases of the Esophagus 26 ( 6 ) 616 - 622 2013.08

ISSN 1120-8694

An identification of bronchial arteries (BAs) is critical in esophageal cancer surgery to avoid tracheobronchial ischemia and unexpected massive bleeding during surgical procedure particularly in thoracoscopic video-assisted esophagectomy. We describe the efficacy of three-dimensional computed tomographic angiography (3D-CTA) of BAs for preoperative evaluation in esophageal cancer surgery. Sixty-four patients with esophageal cancer who preoperatively underwent multidetector computed tomography examination were included in this study. We evaluated the number, origin, and intraoperative preservation rate of BAs, and we compared the number of thoracic paratracheal lymph nodes harvested between two groups comprising patients who either underwent preoperative 3D-CTA of BAs (3D-CTA group) or did not (non-3D-CTA group). The right and left BAs were preoperatively identified in 62 patients (97%) and 55 patients (86%), respectively, using 3D-CTA. In 34 patients (53%), the right BA originated as a common trunk with the right intercostal artery. In 48 patients (75%), the left BA originated from the descending aorta as a single or double branch. Some anomalies such as the right BA originated from the left subclavian artery were observed. In all patients, either the right or the left BA was preserved. The number of harvested lymph nodes in left side of paratrachea was significantly increased in 3D-CTA group, than those in non-3D-CTA group. 3D-CTA clearly revealed BA anatomy, contributing to BA preservation and safe and precise lymphadenectomy in esophageal cancer surgery. 3D-CTA of BAs is useful for preoperative evaluation in esophageal cancer surgery.

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Intraoperative fluorescence lymphography using indocyanine green in a patient with chylothorax after esophagectomy

Kaburagi Takuji, Takeuchi Hiroya, Oyama Takashi, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Kamiya Satoshi, Tanaka Motomu, Wada Takeyuki, Kitagawa Yuko

Surgery Today 43 ( 2 ) 206 - 210 2013.02

ISSN 0941-1291

We report a case of chylothorax treated successfully by a new diagnostic tool: indocyanine green (ICG) fluorescence lymphography. The patient, a 65-year-old man with adenocarcinoma of the esophagogastric junction, underwent radical esophagectomy, which was followed by the development of chylothorax. On postoperative day 10, we performed transabdominal ligation of the thoracic duct. During the re-operation, we injected ICG into the mesentery of the small bowel. We then performed mass ligation of the tissue right and dorsal of the aorta, including the thoracic duct, after which a near-infrared camera system revealed a fluorescent stripe on the caudal part of the ligation. The remnant thoracic duct appeared to be dilated as a result of lymphatic stasis. The patient was discharged 35 days after his initial surgery. We report this case to demonstrate the usefulness of intraoperative ICG lymphography as a tool to identify and confirm ligation of the thoracic duct transabdominally.

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Intractable esophago-mediastinal fistula as a rare complication following thoracoabdominal aortic replacement

Wada Takeyuki, Takeuchi Hiroya, Fujimura Naoki, Nakamura Rieko, Oyama Takashi, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Shimizu Hideyuki, Yozu Ryohei, Kitagawa Yuko

Esophagus 8 ( 4 ) 277 - 281 2011.12

ISSN 1612-9059

Although occurring infrequently, esophagomediastinal fistula is potentially life-threatening.Wereport a rare case of intractable esophago-mediastinal fistula following thoracoabdominal aortic replacement. A 62-year-old male patient with aortic dissection underwent thoracoabdominal aortic replacement. He suddenly developed septic shock with esophageal perforation on the 6th postoperative day. Conservative therapy was employed, and he was discharged from the hospital. However, he suffered another attack of septic shock resulting from an esophago-mediastinal fistula. Gastrointestinal endoscopy revealed a suture thread beside an esophageal fistula. The patient consequently underwent esophagectomy. After removal of the esophagus, we found a suture thread with pledgets in the mediastinum and removed it. He recovered successfully thereafter. Esophago-mediastinal fistula associated with pledgets is a rare complication of thoracoabdominal aortic replacement. We believe that radical surgery can be an effective treatment. A review of the current literature did not reveal any similar cases. In this report, we discuss the clinical course of such a rare case.

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Laparoscopy-assisted proximal gastrectomy with sentinel node mapping for early gastric cancer

Takeuchi Hiroya, Oyama Takashi, Kamiya Satoshi, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Kitagawa Yuko

World Journal of Surgery 35 ( 11 ) 2463 - 2471 2011.11

ISSN 0364-2313

Background Laparoscopy-assisted proximal gastrectomy (LAPG) remains a relatively uncommon procedure because of certain technical issues, such as curability, safety, and retention of postoperative patients' quality of life. The aim of the present study was to evaluate the feasibility of a newly developed LAPG procedure for early-stage proximal gastric cancer. Methods We enrolled 37 consecutive patients who were preoperatively diagnosed with cT1N0M0 primary gastric cancer in the upper third of the stomach with the primary tumor diameter less than 4 cm. Laparoscopy-assisted proximal gastrectomy with sentinel node (SN) mapping and esophagogastric anastomosis with a circular stapler and transoral placement of the anvil was attempted. Results The LAPG procedure was completed in 36 patients. It was converted to laparoscopy-assisted total gastrectomy in one patient because one SN detected intraoperatively was positive for metastasis by intraoperative pathological diagnosis. There were no severe postoperative complications in any patient. Only one patient (3%) complained of mild reflux symptoms immediately after operation, which were graded endoscopically as B by the Los Angeles Classification of gastroesophageal reflux disease; however, the symptoms were controlled well by a proton-pump inhibitor. Sentinel nodes were detected successfully in 37 (100%) of our patients. The mean number of dissected lymph nodes and identified SNs per case was 29.7 and 5.8, respectively. The sensitivity of prediction of nodal metastasis (including isolated tumor cells) and diagnostic accuracy based on SN status were 100% (3/3) and 100% (37/37), respectively. All patients have been free from recurrence for a median follow-up period of 26 months. Conclusions This study reveals that our novel LAPG approach is curative and represents a feasible minimally invasive surgical procedure with minimal morbidity and postoperative reflux esophagitis in patients with upper-third early-stage gastric cancer.

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Effect of lansoprazole versus roxatidine on prevention of bleeding and promotion of ulcer healing after endoscopic submucosal dissection for superficial gastric neoplasia

Imaeda Hiroyuki, Hosoe Naoki, Suzuki Hidekazu, Saito Yoshimasa, Ida Yosuke, Nakamura Rieko, Iwao Yasushi, Ogata Haruhiko, Hibi Toshifumi

Journal of Gastroenterology 46 ( 11 ) 1267 - 1272 2011.11

ISSN 0944-1174

Proton pump inhibitors have been reported to be more useful than histamine-2 receptor antagonists for the prevention of bleeding after endoscopic submucosal dissection (ESD) for superficial gastric neoplasia. The aim of this study was to assess the effects of the proton pump inhibitor lansoprazole and the histamine-2 receptor antagonist roxatidine for the prevention of bleeding and the promotion of ulcer healing after ESD and to compare the cost-effectiveness of these two drugs. The study subjects were 129 patients who underwent ESD for superficial gastric neoplasia. The patients were randomly assigned to the lansoprazole group (L group) or the roxatidine group (R group). Either drug was administered intravenously from the morning of the ESD day to the day after the ESD, followed by oral treatment for an additional 8 weeks. A second-look endoscopy was performed on the day after the ESD, and a repeat endoscopy was performed at 8 weeks after the ESD. The incidence of bleeding and the ulcer-healing rate at 8 weeks after the ESD were analyzed, as well as the total cost of treatment with these antisecretory agents. Three patients in each group were excluded from the analysis, leaving 62 patients in L group and 61 in R group. Two of the 62 patients (3.2%) in L group and three of the 61 patients (4.9%) in R group showed bleeding after ESD ; there was no significant difference between the two groups (P = 0.68). The ulcer-healing rate was 93.5% (58/62) in L group and 93.4% (57/61) in R group (P = 1). The total cost of treatment with the antisecretory agent from the day of the ESD to day 56 after the ESD was Yen 13,212 for lansoprazole and Yen 5,841 for roxatidine. Roxatidine appears to have high cost-effectiveness in the prevention of bleeding and in the promotion of ulcer healing after ESD for superficial gastric neoplasia.

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Retrospective analysis of prognostic outcome of gastric cancer in young patients

Nakamura Rieko, Saikawa Yoshiro, Takahashi Tsunehiro, Takeuchi Hiroya, Asanuma Humiki, Yamada Yoshinori, Kitagawa Yuko

International Journal of Clinical Oncology 16 ( 4 ) 328 - 334 2011.08

ISSN 1341-9625

Background: It has been suggested that gastric cancer in young patients has a worse prognosis than in older patients, but this is controversial. This retrospective investigation was undertaken to understand the clinicopathological features and identify the prognostic factors of gastric cancer in young patients. Methods: Patients included in this study were those treated and followed up for gastric cancer from 1989 to 2005. Operative records, clinical, pathological, and follow-up data were reviewed. The critical age cut-off value for obtaining distinctive prognoses was 34 years. Results: Of 1730 gastric cancer patients whose records were reviewed, 27 were less than 34 years old (YGC group). The YGC group contained significantly higher percentages of females, stage IV, macroscopic type 4 tumors, poorly differentiated histology, peritoneal dissemination, and epigastric pain symptoms than the gastric cancer group aged 34 years or more (OGC group). Survival in the YGC group was significantly worse than in the OGC group (p = 0.0363). Ten-year survival was 68.5% in the YGC group and 81.8% in the OGC group. Survival in the YGC group was poorer for the stage IV patients, compared with OGC patients, especially for the stage IV patients with peritoneal dissemination and without liver metastases (H0P1 patients) (p = 0.049). Conclusions: Age in gastric cancer affects the prognosis, which in gastric cancer patients less than 34 years old was significantly poorer than for older patients, because of the high incidence of stage IV cancer with peritoneal dissemination in gastric cancer patients less than 34 years old.

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Endoscopic submucosal dissection using the Flex and the Dual knives

Yahagi Naohisa, Uraoka Toshio, Ida Yosuke, Hosoe Naoki, Nakamura Rieko, Kitagawa Yuko, Ogata Haruhiko, Hibi Toshifumi

Techniques in Gastrointestinal Endoscopy 13 ( 1 ) 74 - 78 2011.01

ISSN 1096-2883

Endoscopic submucosal dissection (ESD) is a novel endoscopic resection technique that enables reliable en bloc resection of large and difficult gastrointestinal lesions. We initially performed ESD using the tip of a thin-type snare to serve as a blunt-end short needle knife. However, the device had limitations; therefore, we developed a more reliable and durable device, the Flex knife. It cut well in any direction and was easy to control because of its soft and flexible nature, making it extremely useful for ESD of colorectal and esophageal lesions that required delicate maneuvering. Although the Flex knife achieved excellent treatment results, its use was still technically limited by the loop-shape tip, resulting in difficulty with knife length adjustments, frequent intraprocedure accumulation of debris on the tip, and slippage of the knife tip away from the operating field. Therefore, we designed an improved version of the Flex knife, the Dual knife. It resembles a short needle knife with a small apical disk. It has a fixed knife length: 1.5 mm for esophageal and colorectal ESD and 2 mm for gastric ESD. The small disk is useful for marking and hemostasis in a closed position and for stabilization of the knife movement against scarred or floppy tissue in an opened position, resulting in overall improved knife maneuverability and durability. In the practical Flex and Dual knife technique, sufficient submucosal injection and partial incision as well as partial submucosal dissection is key for successful ESD. Combining the endoscopist's knowledge and skill with the soft and flexible properties of the Flex and the Dual knives results in relatively safe and highly effective ESD outcomes.

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Octreotide acetate enables the administration of chemoradiotherapy, including the oral anticancer drug S-1, in gastric cancer patients with malignant gastrointestinal obstruction

Takahashi Tsunehiro, Saikawa Yoshiro, Igarashi Takahiro, Tsuwano Shinichi, Kumagai Koshi, Nakamura Rieko, Ooyama Takashi, Wada Norihito, Takeuchi Hiroya, Takaishi Hiromasa, Kitagawa Yuko

Oncology Letters 1 ( 4 ) 673 - 677 2010.07

ISSN 1792-1074

Advanced gastric cancer frequently RESULTS in the inability to ingest food or drink orally, a condition called malignant gastrointestinal obstruction (MGO). MGO is clinically defned as a gastrointestinal outlet obstruction caused by a large tumor, or malignant bowel obstruction with peritoneal dissemination. MGO impacts the quality of life by interfering with oral intake and by causing gastrointestinal symptoms, such as nausea, vomiting and abdominal pain. Octreotide acetate (OA) is an analogue of somatostatin which has been increasingly used to relieve gastrointestinal symptoms since it decreases the secretion of digestive juices and increases the absorption of water and electrolytes. In Japan, the oral anticancer drug S-1 was recently adopted as a key chemotherapeutic agent in advanced gastric cancer; however, its oral formulation precludes its utility in the MGO setting. This is a pilot study of chemoradiotherapy plus OA in gastric cancer with MGO. Patients were initially treated with OA to control gastrointestinal symptoms. Following resolution of their symptoms, the patients received chemotherapy with S-1 plus low-dose cisplatin and radiation. Irradiation was targeted at the primary tumor and surrounding lesions, including the lymph nodes. Grade 4 toxicity was observed in only 1 patient, and no treatment-related deaths were noted. After treatment, 3 patients achieved a partial response and 4 achieved stable disease. Of the 9 patients, 8 were able to tolerate solid food orally and were discharged. The outcomes of these cases suggest that OA is a useful adjunctive therapy that enables advanced gastric cancer patients with MGO to receive S-1-containing chemotherapy.

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Gastric carcinogenesis and the cancer stem cell hypothesis

Saikawa Yoshiro, Fukuda Kazumasa, Takahashi Tsunehiro, Nakamura Rieko, Takeuchi Hiroya, Kitagawa Yuko

Gastric Cancer 13 ( 1 ) 11 - 24 2010.03

ISSN 1436-3291

Normal stem cells (NSCs) are reported to exist in most tissues, including the brain, bone marrow, and probably the gastrointestinal tract. In the latter case, they are thought to possess both the self-renewal capacity and asymmetrical division capacity to generate progenitor cells which differentiate into epithelial cells. NSCs in the normal gastric mucosa are thought to be present in the proliferative zone of the neck/isthmus region, and to undergo a complex bipolar migration from the neck/isthmus region either upward or downward, becoming differentiated normal epithelial cells. NSCs in human gastric mucosa are difficult to identify due to the current lack of a useful marker. A precise definition of cancer stem cells (CSCs) is still under discussion. CSCs are generally defined as malignant cells with NSC capacity. However, many studies of CSCs have demonstrated their rapid growth and high metastatic potential, while NSCs are thought to be slow-growing and self-renewing, and to lack functional capacities such as cell migration and attachment. Recent evidence suggests the existence of CSCs in a wide variety of solid tumors. In this review, we will discuss the existence and cell biology of gastric NSCs and CSCs. We will also discuss whether gastric CSCs originate as organ-specific stem cells or as bone marrow-derived cells (BMDCs). Under certain conditions, the local microenvironment may promote the development of gastric cancer. Thus, Helicobacter pylori infection and the accompanying chronic inflammatory processes will supply critical initiators inducing cell growth and the tissue repair response, leading to carcinogenesis. This mechanism will be discussed in light of stem cell research. Progress in stem cell research in the gastric field is still limited to experimental animal models. However, recent studies should enhance our understanding of human cancer biology, and provide novel tools for the treatment of incurable gastric cancer.

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Factors influencing the long-term survival in patients with esophageal cancer who underwent esophagectomy after chemoradiotherapy

Takeuchi Hiroya, Saikawa Yoshiro, Oyama Takashi, Ozawa Soji, Suda Koichi, Wada Norihito, Takahashi Tsunehiro, Nakamura Rieko, Shigematsu Naoyuki, Ando Nobutoshi, Kitajima Masaki, Kitagawa Yuko

World Journal of Surgery 34 ( 2 ) 277 - 284 2010.02

ISSN 0364-2313

Background: Salvage esophagectomy is potentially the only treatment available that can offer a chance of long-term survival when definitive chemoradiotherapy (CRT) fails to achieve local control for patients with esophageal squamous cell carcinoma (ESCC). However, salvage esophagectomy is a highly invasive procedure with various postoperative complications compared to planned esophagectomy after neoadjuvant chemoradiotherapy (CRT). We hypothesize that severe postoperative complications may affect not only surgical mortality but also tumor recurrence and long-term survival for patients with salvage esophagectomy after definitive CRT. Methods: For the present study we reviewed the surgical procedures, postoperative complications, and the prognosis of 65 consecutive patients with thoracic ESCC who underwent the esophagectomy after neoadjuvant (neoadjuvant group: n = 40) or definitive (salvage group: n = 25) CRT. Results: Most patients underwent right-transthoracic extended esophagectomy and reconstruction using gastric conduit by way of subcutaneous route with left cervical anastomosis. The incidence of postoperative pneumonia was found to be higher in the salvage group than in the neoadjuvant group. In both groups, the survival of patients with R0 resection was significantly better than those with R1/R2 resection. Moreover, in the salvage group, the postoperative survival rate of patients with pneumonia or bacteremia/sepsis was significantly lower than that for patients who did not suffer the same complications. In the neoadjuvant group, R0 resection was selected to be the only independent prognostic factor in univariate and multivariate analysis. In contrast, in the salvage group, R0 resection and bacteremia/sepsis remained significant and were independent of the other factors in multivariate analysis. Conclusions: This study reveals that postoperative morbidity affects not only the perioperative mortality but also the long-term survival of patients with ESCC who undergo salvage esophagectomy after definitive CRT.

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Feasibility and efficacy of combination chemotherapy with S-1 and fractional cisplatin for advanced gastric cancer

Takahashi Tsunehiro, Saikawa Yoshiro, Takaishi Hiromasa, Takeuchi Hiroya, Wada Norihito, Oyama Takashi, Nakamura Rieko, Kitagawa Yuko

Anticancer Research 30 ( 9 ) 3759 - 3762 2010

ISSN 0250-7005

Background: There is a great need for effective outpatient chemotherapy for advanced gastric cancer in patients with good performance status. The present pilot study evaluated the use of combination chemotherapy with S-1 and fractional CDDP for unresectable-recurrent gastric cancer in an outpatient setting. Patients and Methods: A total of 41 patients with unresectable or recurrent gastric cancer were treated with this combination chemotherapy. S-1 was administered orally every day on days 1-28 and CDDP was infused on days 1, 15, and 29. Results: Thirty-six patients had measurable lesions and 19 patients had partial responses, resulting in an overall response rate of 52.8%. The median survival time was 494 days. There was no grade 4 haematological toxicity, no grade 3 or more non-haematological toxicity, and no treatment-related death. Conclusion: This combination chemotherapy has no serious toxicities in patients with unresectable and recurrent gastric cancer and can be used effectively in an outpatient setting.

Octreotide acetate successfully treated a bowel obstruction caused by peritoneally disseminated gastric cancer, thereby enabling the subsequent use of oral S-1 chemotherapy

Kumagai Koshi, Saikawa Yoshiro, Fukuda Kazumasa, Ito Ryo, Igarashi Takahiro, Tsuwano Shinichi, Nakamura Rieko, Takahashi Tsunehiro, Takeuchi Hiroya, Kitagawa Yuko

International Journal of Clinical Oncology 14 ( 4 ) 372 - 375 2009.08

ISSN 1341-9625

A 68-year-old woman presented with severe bowel obstruction and was subsequently diagnosed with stage IV gastric cancer with peritoneal dissemination. She was immediately stabilized in the hospital with the placement of a nasointestinal tube. Abdominal computed tomography showed multiple intraperitoneal nodules consistent with peritoneal dissemination of the gastric cancer. The patient's inability to tolerate oral intake was a contraindication to using S-1 chemotherapy, currently one of the most effective medications used for gastric cancer in Japan. Therefore, she was initially treated with octreotide acetate (OA). Her bowel obstruction was sufficiently attenuated on the seventh day after the initiation of treatment with OA to permit the initiation of oral S-1, along with low-dose cisplatin (CDDP) and radiation. S-1 was orally administered at a dose of 100 mg/day per body (80 mg/m² per day) on days 1-28, and CDDP was infused at a dose of 7.8 mg/day per body (6 mg/m² per day) on days 1-5, 8-12, and 15-19. Radiation therapy (2 Gy/day for 5 days/week) was performed with the chemotherapy. Despite no change being shown on her imaging findings with the chemotherapy, the patient's bowel obstruction resolved and she was able to tolerate both liquids and solid food orally. She was discharged 2 months after admission. Seven months after beginning the chemotherapy, she was still doing well on outpatient chemotherapy with S-1 and CDDP, and had no decline in her quality of life or progression of her disease.

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