Details of a Researcher - Nakamura, Rieko

Papers - Nakamura, Rieko

Division display >> ／ All the affair displays 1 - 75 of about 75

Optimal minimally invasive surgical procedure for gastric submucosal tumors

Shoji Yoshiaki, Takeuchi Hiroya, Goto Osamu, Tokizawa Kazunori, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Yahagi Naohisa, Kitagawa Yuko

Gastric Cancer 1 - 8 2017.07

ISSN 1436-3291

Background: Laparoscopic wedge resection (LWR) is widely performed for managing gastric submucosal tumors (SMTs). Despite the development of novel procedures such as laparoscopy–endoscopy cooperative surgery (LECS) and nonexposed endoscopic wall-inversion surgery (NEWS), the most appropriate surgical intervention for gastric SMTs remains unclear. Methods: We retrospectively reviewed patient characteristics, surgical outcomes, postoperative courses, results of histopathological examinations, and surgical costs of 71 consecutive patients who underwent LWR, LECS, or NEWS for gastric SMTs from January 2010 to June 2016 in our institute. Results: LWR, LECS, and NEWS were performed in 31, 14, and 26 cases, respectively. Patient backgrounds were comparable between groups. LWR was not performed for esophagogastric (E–G) junction tumors to avoid postoperative stricture, and LECS was not performed for ulcerated tumors to prevent tumor dissemination. NEWS was considered for tumors smaller than 3 cm for transoral extraction. Resected specimen area of the LWR group was significantly larger than that of the other groups. Further, the LWR group had a significantly higher complication rate. Compared to the LECS group, postoperative serum C-reactive protein level was significantly lower and postoperative hospitalization was significantly shorter in the NEWS group. Also, operation costs were significantly lower in the NEWS group. Conclusions: The surgical procedure for gastric SMTs must be carefully chosen according to tumor size, location, and presence or absence of ulceration. For selected patients, NEWS is suggested to be an appropriate option for the treatment of gastric SMTs.

Access to Document (DOI)

Prognostic Impact of Change in the Fibrinogen and Albumin Score During Preoperative Treatment in Esophageal Cancer Patients

Matsuda Satoru, Takeuchi Hiroya, Kawakubo Hirofumi, Fukuda Kazumasa, Nakamura Rieko, Suda Koichi, Wada Norihito, Kitagawa Yuko

World Journal of Surgery 1 - 8 2017.06

ISSN 0364-2313

Background: For resectable advanced esophageal cancer, a transthoracic esophagectomy following preoperative treatment is recognized as one of the standard treatments. Therefore, predictive markers which can be identified before surgery need to be established to identify patients with a poor prognosis. Methods: We retrospectively reviewed 102 consecutive patients who underwent curative transthoracic esophagectomy following preoperative treatment in our institution between 2004 and 2013. Based on plasma fibrinogen and serum albumin levels, the pretreatment and preoperative fibrinogen and albumin score (FA score) were investigated and the prognostic significance of the FA score change was compared with RECIST. Results: The patients were classified according to whether the FA score had remained unchanged or decreased (n = 77) or the FA score increased (n = 25). When the correlation between the response rate and change in the FA score was investigated, the response rate was significantly lower in the group with the increased FA score. In the survival analysis, patients in the increased FA score group exhibited a significantly worse recurrence-free survival (RFS) (P = 0.038). A multivariate analysis using the clinical stage and the change in the FA score as covariates revealed that a change in the FA score (HR 1.802; P = 0.047; 95% CI 1.008–3.221) was shown to be a significant independent predictive factor for RFS. Conclusions: A change in the FA score was shown to be an independent prognostic factor for postoperative recurrence in esophageal cancer patients who have undergone transthoracic esophagectomy following preoperative treatment.

Access to Document (DOI)

The alpha-lipoic acid derivative DHLHZn

Shoji Yoshiaki, Takeuchi Hiroya, Fukuda Kazumasa, Fukunaga Koichi, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Miyasho Taku, Hiratsuka Takahiro, Inomata Masafumi, Betsuyaku Tomoko, Kitagawa Yuko

Inflammation Research 1 - 9 2017.06

ISSN 1023-3830

Objective and design: An animal experiment was performed to demonstrate the anti-inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action. Material: Rats were randomly divided into three experimental groups: control group (n = 17), DHLHZn(−) group (n = 11, ALI model rats), and DHLHZn(+) group (n = 12, ALI model rats treated by DHLHZn). Treatment: Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(−) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration. Methods: Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann–Whitney U test. Results: Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p < 0.05). ALI pathology scores were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p < 0.001). Conclusions: Anti-inflammatory effects of DHLHZn for ALI were demonstrated by BALF and histopathological findings. The mechanism of action of DHLHZn was considered to be via inhibition of the NF-kB signaling pathway. DHLHZn is thus suggested to be a new prophylactic agent for ALI.

Access to Document (DOI)

Laparoscopy-assisted distal gastrectomy in a case of gastric cancer with situs inversus totalis

Kigasawa Yu, Takeuchi Hiroya, Kawakubo Hirofumi, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kitagawa Yuko

Asian journal of endoscopic surgery 10 ( 1 ) 47 - 50 2017.02

ISSN 1758-5902

Situs inversus totalis (SIT) is a rare congenital condition in which abdominal and thoracic organs are transposed from normal positions. Laparoscopy-assisted distal gastrectomy for situs inversus totalis is technically difficult and has rarely been reported. Here, we report the case of man in his 40s with situs inversus totalis and a preoperative diagnosis of stage IA gastric cancer (cT1b, cN0, cM0). We successfully performed laparoscopy-assisted distal gastrectomy with D1+ lymph node dissection and Billroth I reconstruction. To ensure a safe procedure, we evaluated the vessels preoperatively with 3-D CT angiography. Furthermore, we performed the surgery by reversing our surgical positions, using a two-monitor method, and then reconstructing under direct vision through the incision. The surgery was performed with minimal blood loss, and no severe postoperative complications were observed. Histopathological examination revealed poorly to moderately differentiated stage IA (pT1b, pN0, pM0) adenocarcinoma. No recurrence has been observed as of 2 years postoperatively.

Access to Document (DOI)

Evaluation of pharyngo-oesophageal involvement in pemphigus vulgaris and its correlation with disease activity

Okamura A., Nakamura R., Yamagami J., Ishii K., Kawakubo H., Omori T., Takeuchi H., Amagai M., Kitagawa Y.

British Journal of Dermatology 176 ( 1 ) 224 - 226 2017.01

ISSN 0007-0963

Access to Document (DOI)

Soft palatal melanosis, a simple predictor for neoplasia in the upper aerodigestive tract in Japanese alcoholic men

Hirata Kenro, Yokoyama Akira, Nakamura Rieko, Omori Tai, Kawakubo Hirofumi, Mizukami Takeshi, Maruyama Katsuya, Kanai Takanori, Yokoyama Tetsuji

Cancer Science 2017

ISSN 1347-9032

Soft palatal melanosis can be detected by visual inspection during routine physical examination or even personally in a mirror. The aim of this study was to evaluate the association between squamous cell neoplasia in the upper aerodigestive tract (UAT) and soft palatal melanosis. We reviewed digitized records of high-quality endoscopic images of the soft palate of 1786 Japanese alcoholic men who underwent endoscopic screening. Soft palatal melanosis was observed in 381 (21.3%) of the subjects (distinct, 6.3%). Older age, an inactive heterozygous aldehyde dehydrogenase-2 genotype, smoking, and a high mean corpuscular volume were positively associated with the presence of soft palatal melanosis. The age-adjusted odds ratio (95% confidence interval) for UAT neoplasia was 1.92 (1.40-2.64) in the group with melanosis and 2.51 (1.55-4.06) in the group with distinct melanosis, compared with the melanosis-free group. A multivariate analysis showed that the presence of soft palatal melanosis was independently associated with a high risk of UAT neoplasia. We calculated the individual number of risk factors out of four easily identifiable and significant factors: age ≥55 years, current/former alcohol flushing, mean corpuscular volume ≥106 fL, and distinct soft palatal melanosis. Compared with the risk-factor-free condition, the odds ratio (95% confidence interval) values of UAT neoplasia for one, two, three, and four risk factors were 1.49 (0.97-2.30), 3.14 (2.02-4.88), 4.80 (2.71-8.51), and 7.80 (2.17-28.1), respectively. The presence of soft palatal melanosis provides a simple new strategy for identifying heavy drinkers with a high risk for UAT neoplasia.

Access to Document (DOI)

Endoscopic findings of laryngopharyngeal and esophageal involvement in autoimmune bullous disease

Nakamura Rieko, Omori Tai, Suda Koichi, Wada Norihito, Kawakubo Hirofumi, Takeuchi Hiroya, Yamagami Jun, Amagai Masayuki, Kitagawa Yuko

Digestive Endoscopy 2017

ISSN 0915-5635

Background and Aim: Autoimmune bullous disease (ABD) is induced by autoantibodies against cell adhesion molecules, and blistering may occur on the mucous membranes of the eyes, nose, mouth, oral cavity, laryngopharynx, and esophagus. Endoscopic prevalence and features of ABD-associated esophageal lesions are not well known. We conducted the present study to assess the endoscopic prevalence of ABD-associated mucosal lesions. Methods: Endoscopic prevalence of mucosal lesions, particularly laryngopharyngeal and esophageal lesions, was used as the primary endpoint to assess the significance of upper gastrointestinal endoscopy, and clinical and endoscopic features were secondary endpoints. Results: Of 123 ABD patients, 50.4% had apparent oral or laryngopharyngeal lesions and 30.8% had laryngopharyngeal lesions. Esophageal lesions were detected through normal observation in 16.8% of affected patients, whereas 40.6% exhibited epidermolysis or blood blisters by mechanical inducement, regardless of esophageal mucosal lesion detection by normal observation. Additionally, 56.0% exhibited the Nikolsky sign with mechanical inducement. Of the 123 patients, 29.2% did not have exposed skin lesions. Of these patients, 77.7% had oral cavity or laryngopharyngeal lesions, 36.1% had esophageal lesions, and 58.3% exhibited the Nikolsky sign on esophageal mucosa. Conclusion: It is important to determine the endoscopic characteristics and findings of ABD. ABD can be suspected from endoscopic findings.

Access to Document (DOI)

Downregulation of cytochrome c oxidase 1 induced radioresistance in esophageal squamous cell carcinoma

Takesue Tomoko, Kawakubo Hirofumi, Hayashida Tetsu, Tsutsui Mai, Miyao Kazuhiro, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Takeuchi Hiroya, Kitagawa Yuko

Oncology Letters 14 ( 4 ) 4220 - 4224 2017

ISSN 1792-1074

Comprehensive gene screening with transposons is a novel procedure for the systematic identification of resistant genes. The present study aimed to use this technique to identify candidate radioresistant genes in esophageal squamous cell carcinoma. A transposon is a base sequence that can translocate to another location in the genome at random. By inserting the cytomegalovirus promotor as a transcriptional activator in the transposon, the following gene in the new location becomes overexpressed and the gene located at the transposon insertion site is downregulated. Consequently, various transposon-tagged cells, which have differentially overexpressed or downregulated genes using the transposon method can be obtained. Following the irradiation of transposon-tagged cells, candidate radioresistant genes can be selected in order to detect the location of the transposon in the cells that have survived. A total of 11 genes were detected as candidate radioresistant genes. Cytochrome c oxidase 1 (MT-CO1), an enzyme involved in apoptosis through the activation of the caspase cascade, was one of the candidate genes identified. The relative expression level of MT-CO1 was 0.12 in MT-CO1-downregulated cells which was significantly lower compared with the expression level in parent TE4 cells (P<0.001). The survival rate was 28.7% in MT-CO1-downregulated cells and 10.5% in parent TE4 cells 9 days following 5-Gy irradiation. The activity of cytochrome c and caspase-3 following irradiation was significantly lower in the MT-CO1-downregulated radioresistant cells compared with in TE4 cells. In conclusion, the novel gene screening technique demonstrated to be useful for detecting candidate radioresistant genes in esophageal squamous cell carcinoma. The results of the present study revealed that the downregulation of MT-CO1 induced radioresistance occurs by inhibiting the activation of the caspase cascade in radioresistant esophageal cancer cells.

Access to Document (DOI)

Two atypical cases of esophagogastric junctional bronchogenic cyst

Kigasawa Yu, Takeuchi Hiroya, Kamiya Satoshi, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Tsujikawa Hanako, Kameyama Kaori, Kitagawa Yuko

Esophagus 1 - 4 2016.12

ISSN 1612-9059

Bronchogenic cysts are congenital lesions that are derived from the lung bud and are often found in the thoracic cavity, and intra-abdominal bronchogenic cysts are really rare. They are associated with respiratory symptoms and typically require surgical resection. Herein, we describe two cases with esophagogastric junctional bronchogenic cysts. Our first case was a man in his 30s who had a submucosal tumor at esophagogastric junction, which required laparoscopic enucleation. The second case was a woman in her 50s who underwent laparoscopy-assisted proximal gastrectomy. The resected tumor was diagnosed as a bronchogenic cyst, with squamous cell carcinoma at the mucosal surface. Bronchogenic cysts are occasionally associated with complications and malignancies, and thus, preventive and diagnostic resection is recommended.

Access to Document (DOI)

CXCL12 expression promotes esophageal squamous cell carcinoma proliferation and worsens the prognosis

Uchi Yusuke, Takeuchi Hiroya, Matsuda Sachiko, Saikawa Yoshiro, Kawakubo Hirofumi, Wada Norihito, Takahashi Tsunehiro, Nakamura Rieko, Fukuda Kazumasa, Omori Tai, Kitagawa Yuko

BMC Cancer 16 ( 1 ) 2016.07

ISSN 1471-2407

Background: The chemokine CXCL12 and its corresponding receptor CXCR4 are key players in the development of several cancers. Therefore, we hypothesized that there is a functional causality between CXCL12 expression and tumor progression in patients with esophageal squamous cell carcinoma (ESCC). Methods: We performed an immunohistochemical analysis in 79 consecutive patients with ESCC. We performed in vitro and in vivo cell proliferation assays using ESCC cell lines and a newly established transfectant stably overexpressing CXCL12. Results: Immunohistochemistry revealed positive CXCR4 and CXCL12 expression in 48 (61 %) and 62 (78 %) patients, respectively. Additionally, the expression levels did not significantly correlate with any clinicopathological factors. The MIB-1 proliferation index was markedly higher in ESCC with a positive expression of CXCR4 or CXCL12. Positive CXCL12 expression was significantly correlated with lower recurrence-free survival (RFS, p = 0.02). Cox's hazard models revealed CXCL12 expression as an independent predictive factor for recurrence. In vitro, CXCL12 exposure or overexpression enhanced ESCC proliferation; and AMD3100, a specific inhibitor of CXCR4, equally decreased proliferation irrespective of CXCL12 exposure or overexpression. In the mouse model, AMD3100 significantly decreased ESCC tumor size (p = 0.03). Conclusions: CXCL12 stimulates ESCC proliferation, and its expression levels are related to lower RFS in patients with ESCC. Our findings indicate that positive CXCL12 expression may be a useful marker for predicting the outcome in patients with ESCC and is a potentially new therapeutic target for ESCC.

Access to Document (DOI)

Pylorus-Preserving Surgery Based on the Sentinel Node Concept in Early Gastric Cancer

Shimada Ayako, Takeuchi Hiroya, Ono Taiki, Kamiya Satoshi, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Nakahara Tadaki, Jinzaki Masahiro, Murakami Koji, Kitagawa Yuko

Annals of Surgical Oncology 1 - 6 2016.06

ISSN 1068-9265

Background: In patients with early stage gastric cancer in the middle third of the stomach, pylorus-preserving gastrectomy (PPG) can be an option as function-preserving surgery, although its oncologic safety is not definitively defined. This issues may be overcome using the sentinel node (SN) concept. The aim of this study was to investigate the effectiveness of the SN concept in early gastric cancer patients who are candidates for PPG. Methods: One hundred fifty-six patients with middle-third location of cT1N0 gastric cancer (single lesion,

Access to Document (DOI)

Clinical outcome of transthoracic esophagectomy with thoracic duct resection Number of dissected lymph node and distribution of lymph node metastasis around the thoracic duct

Matsuda Satoru, Takeuchi Hiroya, Kawakubo Hirofumi, Shimada Ayako, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kameyama Kaori, Kitagawa Yuko

Medicine (United States) 95 ( 24 ) 2016.06

ISSN 0025-7974

The number of dissected lymph nodes (LNs), surgical outcomes, and postoperative recurrence-free survival (RFS) were compared between thoracic duct (TD)-preserved and TD-resected groups. The distribution of metastasis in LNs around TD (TDLN) was reviewed. Transthoracic esophagectomy (TTE) with TD resection for esophageal cancer patients has been one of the standard procedures. Because the adipose tissue surrounding the TD contains LNs, TD resection might be necessary for radical LN dissection. However, few studies have investigated the oncological outcome of TTE with TD resection. Two hundred fifty-six consecutive patients who underwent TTE between 2004 and 2015 were retrospectively reviewed and classified into TD-preserved or TD-resected groups. The number of dissected LNs for each LN station and surgical outcomes were compared. RFS was analyzed in 155 patients who underwent TTE before December 2012. Since 2013, the TDLN number was prospectively examined, independent of the regional LNs (n=72). Of these, the TDLN number for each location (TDLN-Ut/Mt/Lt) was investigated and the correlation between TDLN metastasis and clinicopathological factors was analyzed. The TD was preserved in 89 patients and resected in 167 patients. Patients with TD resection showed significant advanced stage. There was no significant difference in the incidence of postoperative complications, including pneumonia, anastomotic leakage, and chylothorax. The number of dissected mediastinal LNs was significantly increased in the TD-resected group. The 5-year RFS rate of cStage I patients was 67.3% in the TD-preserved group against 90.3% in the TD-resected group, showing a tendency towards RFS extension that did not quite reach statistical significance (P=0.055). The mean TDLN-Ut/Mt/Lt numbers were 0.89/0.56/0.44, respectively. Eight of 72 (11%) patients displayed TDLN metastasis. Metastatic TDLNs were observed on the same or cranial level of the primary lesion in 7 of 8 patients. Transthoracic esophagectomy with TD resection could increase the number of dissected mediastinal LNs without increase of postoperative complication. TDLN metastasis was observed in patients with advanced disease. A prospective trial, investigating the survival between TD-preserved and TD-resected groups, should be conducted to clarify if TD should be resected in TTE.

Access to Document (DOI)

Salvage endoscopic resection as a treatment for locoregional failure or recurrence following chemoradiotherapy or radiotherapy for esophageal cancer

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

Oncology Letters 11 ( 6 ) 3631 - 3636 2016.06

ISSN 1792-1074

Radiotherapy (RT) or chemoradiotherapy (CRT) is a potentially curative, non-surgical treatment option for esophageal cancer, although the rate of local failure within the esophagus remains relatively high. Salvage esophagectomy is not regarded as a common treatment for esophageal cancer, since it is a high-risk surgery with a relatively high surgical mortality rate. Salvage endoscopic resection (ER) for local failure is used for treatment when esophageal cancer is localized and superficial. To evaluate to usefulness of salvage ER, the present study reviewed the clinicopathological records and follow-up data of 37 patients that underwent salvage ER for esophageal cancer, following initial treatment with RT or CRT. Salvage ER was conducted on a total of 78 lesions observed in the 37 patients. Since a thick epithelium and lack of normal vessels on the surface of the mucosa are characteristics of esophageal mucosa following RT or CRT, almost all the lesions were detected using iodine dyeing, and not by narrow band imaging. The growth rate of the detected lesions was relatively high, and early treatment was required. No particular complications occurred during the endoscopic treatment. A total of 11 patients survived for >5 years subsequent to initial endoscopic treatment. Only 4 patients succumbed to esophageal cancer. In conclusion, the present study demonstrated that salvage ER following CRT or RT for esophageal cancer is a minimally invasive, safe, adaptive and curative method for superficial lesions without distant metastases in patients with esophageal cancer with local failure following CRT or RT.

Access to Document (DOI)

Xanthogranulomatous gastritis of the remnant stomach mimicking a malignant tumor

Okamura Akihiko, Takahashi Tsunehiro, Saikawa Yoshiro, Nakadai Jumpei, Ono Taiki, Nakamura Rieko, Wada Norihito, Kawakubo Hirofumi, Takeuchi Hiroya, Emoto Katsura, Sasaki Aya, Kameyama Kaori, Kitagawa Yuko

Oncology Letters 11 ( 2 ) 1453 - 1456 2016.02

ISSN 1792-1074

Xanthogranulomas are known to develop in the gallbladder and kidney. Xanthogranuloma of the stomach is a rare disease, and to the best of our knowledge, only a few cases have been reported to date. The present patient was a 64-year-old man who underwent a wide resection of the stomach following a Billroth-I reconstruction for a gastric ulcer ~40 years prior to the current presentation. Due to tarry stools, a gastrointestinal endoscopy was performed, leading to identification of an ulcerated gastric lesion located at the previous suture line at the lesser curvature of the remnant stomach. This lesion was elevated, appearing to indicate a submucosal tumor. Positron emission tomography revealed uptake of fluorodeoxyglucose radiotracer by the tumor. Although not indicated by the biopsy specimens, a malignant tumor of the remnant stomach was suspected, in the form of a malignant gastrointestinal tumor or remnant gastric cancer. Curative resection of the tumor was successfully performed. Histological examination of the resected specimens revealed xanthogranulomatous inflammation consisting of foamy histiocytes and plasma cells, however, no cancer cells were observed. The tumor was diagnosed as xanthogranulomatous gastritis that mimicked a malignant tumor of the remnant stomach. The present study therefore indicates that inflammatory tumors should be considered in the differential diagnosis of malignant tumors.

Access to Document (DOI)

Auxiliary diagnosis of lymph node metastasis in early gastric cancer using quantitative evaluation of sentinel node radioactivity

Kamiya Satoshi, Takeuchi Hiroya, Nakahara Tadaki, Niihara Masahiro, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Murakami Koji, Kitagawa Yuko

Gastric Cancer 1 - 8 2015.11

ISSN 1436-3291

Background: Sentinel node (SN) mapping using dye and radioisotope (RI) tracer has been reported to be feasible in cases of early gastric cancer. Because accurate diagnosis of micrometastasis is sometimes difficult in the limited time available during surgery, a faster and simpler method of improving the intraoperative diagnostic precision of lymph node metastasis is needed. The amount of tracer deposited in an SN can be determined from its radioactivity; however, the significance of the RI count has not been fully discussed. We investigated the clinical impact of the RI count when used as an adjunct to conventional lymph node dissection when diagnosing lymphatic metastasis in cases of early gastric cancer. Methods: From 2008 to 2009, patients with clinically diagnosed T1N0M0 gastric cancers who underwent gastrectomy and SN mapping were enrolled. SNs were examined by intraoperative and postoperative pathology. The RI count was measured for each SN with a handheld gamma probe; the correlation between nodal metastasis and the RI count was assessed. Results: A total of 308 SNs were harvested from 72 patients. Patients with SN metastasis had significantly higher total RI counts than those without SN metastasis (p = 0.007). Among cases with SN metastasis, RI counts were also significantly elevated in metastasis-positive nodes, stations, and basins. In these cases, the most of SNs having the highest RI count in each case had metastasis including isolated tumor cells. Conclusion: In early gastric cancer patients, a high RI count from an SN was correlated with lymph node metastasis. Therefore, RI counting may aid efficient pathological diagnosis and focused lymph node dissection.

Access to Document (DOI)

Clinical significance of the anterosuperior lymph nodes along the common hepatic artery identified by sentinel node mapping in patients with gastric cancer

Shimada Ayako, Takeuchi Hiroya, Kamiya Satoshi, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Nakahara Tadaki, Jinzaki Masahiro, Murakami Koji, Kitagawa Yuko

Gastric Cancer 2015.11

ISSN 1436-3291

Background: The sentinel node (SN) concept is safely applied and validated in early gastric cancer. Gastric lymph nodes are divided into five basins with the main gastric arteries, and the anterosuperior lymph nodes with the common hepatic artery (No. 8a) are classified in the right gastric artery (r-GA) basin. Although No. 8a are considered to have lymphatic flow from the r-GA basin, there might be additional multiple lymphatic flows into No. 8a. The aim of this study is to analyze the lymphatic flows to No. 8a and to investigate the clinical significance of No. 8a as a sentinel node (SN No. 8a). Methods: Four hundred and twenty-nine patients with cT1N0 or cT2N0 gastric cancer underwent SN mapping. We used technetium-99 tin colloid solution and blue dye as a tracer. Results: We detected SN No. 8a in 35 (8.2 %) patients. In these patients, we detected SN No. 8a with SNs that belonged to the left gastric artery (l-GA) basin (66 %), right gastroepiploic artery (r-GEA) basin (54 %), and right gastric artery (r-GA) basin (46 %). In addition, celiac artery lymph nodes were detected as SNs significantly more frequently. Function-preserving surgery was performed significantly less often in patients with SN No. 8a (p =0.018). Conclusions: We found that SN No. 8a seemed to have lymphatic flow not only from the r-GA basin, but also from the l-GA basin or r-GEA basin. When SN No. 8a are detected, we should be careful to perform function-preserving surgery, even in SN-negative cases.

Access to Document (DOI)

Comprehensive screening of genes resistant to an anticancer drug in esophageal squamous cell carcinoma

Tsutsui Mai, Kawakubo Hirofumi, Hayashida Testsu, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Omori Tai, Takeuchi Hiroya, Kitagawa Yuko

International Journal of Oncology 47 ( 3 ) 867 - 874 2015.09

ISSN 1019-6439

Drug resistance to chemotherapy is a major issue in esophageal cancer management. Drug resistance may be mediated by genetic changes in the tumor; therefore, the identification of gene mutations may lead to better therapeutic outcomes. We used a novel method involving transposons to screen and identify drug-resistant genes. Transposons are DNA sequences that move from one location on the gene to another. A modified piggyBac transposon was designed as an insertion mutagen, and a cytomegalovirus (CMV) promoter sequence was added to induce strong transcription. When the transposon is inserted to the upstream of a certain gene, the gene will be overexpressed while when intserted down or intragenically, it will be downregulated. After establishing a transposon-tagged cell library, we treated cell lines derived from esophageal squamous cell carcinomas (ESCC) [Tohoku esophagus (TE)] with cisplatin (CDDP). We performed splinkerette PCR and TOPO cloning on the resistant colonies. Bacterial colonies were sequenced, and next-generation sequencing was used to identify the overexpressed/downregulated sequences as candidate genes for CDDP resistance. We established 4 cell lines of transposon-tagged cells, TE4, 5, 9 and 15. We treated the two relatively viable cell lines, TE4 and TE15, with CDDP. We identified 37 candidate genes from 8 resistant colonies. Eight genes were overexpressed whilst 29 were downregulated. Among these genes was Janus kinase 2 (JAK2) that is implicated in the progression of myeloproliferative neoplasms. We identified 37 candidate genes responsible for CDDP resistance in the two cell lines derived from ESCC cells. The method is inexpensive, relatively simple, and capable of introducing activating and de-activating mutations in the genome, allowing for drug-resistant genes to be identified.

Access to Document (DOI)

Clinical Significance of Sentinel Node Positivity in Patients with Superficial Esophageal Cancer

Takeuchi Hiroya, Kawakubo Hirofumi, Nakamura Rieko, Fukuda Kazumasa, Takahashi Tsunehiro, Wada Norihito, Kitagawa Yuko

World Journal of Surgery 2015.08

ISSN 0364-2313

Background: Sentinel node (SN) mapping in esophageal cancer has been reported to be technically feasible with an acceptable detection rate and accuracy. However, the clinical significance and survival analysis findings associated with the metastatic status of SNs in patients with early-stage esophageal cancer have not been clarified. In this study, we investigated the clinical significance and survival impact of SN mapping in early-stage esophageal cancer. Methods: Among patients who were diagnosed preoperatively with clinical T1N0M0 or T2N0M0 esophageal cancer and who underwent SN mapping, 70 consecutive patients who were diagnosed with pathological T1 primary thoracic esophageal cancer were enrolled in this study. Sixty-four (91 %) patients were diagnosed with squamous cell carcinoma while 5 (7 %) patients were with adenocarcinoma. Endoscopic injection of technetium-99m tin colloid was performed before surgery, and radioactive SNs were identified by preoperative lymphoscintigraphy and intraoperative gamma probing. Standard esophagectomy with lymphadenectomy was performed in all patients, and all resected nodes were evaluated by routine pathological examination. Results: SNs were successfully detected in 65 (92.9 %) of 70 patients with pT1 esophageal cancer. The sensitivity to predict lymph node metastasis was 91.7 %, and the diagnostic accuracy based on SN status was 96.9 %. Although there was a wide distribution of SNs from cervical to abdominal areas, 84.5 % of the patients had no lymph node metastasis or had lymph node metastasis only in SN. The disease-specific survival of the patients with metastatic non-SNs was significantly worse relative to that of the patients with no lymph node metastasis or lymph node metastasis only in SN. Conclusions: This study demonstrated that radio-guided SN mapping is useful not only as an accurate diagnostic tool for detecting lymph node metastasis but also as a tool for prognostic stratification in patients with cN0 early esophageal cancer.

Access to Document (DOI)

The impact of postoperative complications on survivals after esophagectomy for esophageal cancer

Booka Eisuke, Takeuchi Hiroya, Nishi Tomohiko, Matsuda Satoru, Kaburagi Takuji, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Omori Tai, Kitagawa Yuko

Medicine (United States) 94 ( 33 ) e1369 2015.08

ISSN 0025-7974

The aim of this study was to assess the impact of postoperative complications after esophagectomy on long-term outcome. The treatment of esophageal cancer has recently been improved; however, esophagectomy with thoracotomy and laparotomy carries considerable postoperative morbidity and mortality. The real impact of postoperative complications on overall survival is still under evaluation. A retrospective analysis was performed on patients with esophageal cancer who underwent esophagectomy with thoracotomy and laparotomy, with R0 or R1 resection between January 1997 and December 2012. Of 402 patients, we analyzed the following parameters 284 patients who could be followed up for over 5 years: stage of disease, neoadjuvant therapies, surgical approaches, surgical complications, postoperative medical complications, and overall and relapse-free survivals using medical records. Of the 284 patients, 64 (22.5%) had pneumonia, 55 (19.4%) had anastomotic leakage, and 45 (15.8%) had recurrent laryngeal nerve paralysis (RLNP). Pneumonia had a significant negative impact on overall survival (P=0.035); however, anastomotic leakage and RLNP did not affect overall survival. Multivariate analysis revealed that the presence of pneumonia was predictive of poorer overall survival; the multivariate hazard ratio was 1.456 (95% confidence interval 1.020-2.079, P=0.039). Pneumonia has a negative impact on overall survival after esophagectomy. Strategies to prevent pneumonia after esophagectomy should improve outcomes in this operation.

Access to Document (DOI)

CXCR2 expression and postoperative complications affect long-term survival in patients with esophageal cancer

Nishi Tomohiko, Takeuchi Hiroya, Matsuda Sachiko, Ogura Masaharu, Kawakubo Hirofumi, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Omori Tai, Kitagawa Yuko

World Journal of Surgical Oncology 13 ( 1 ) 2015.08

Background: Esophagectomy is one of the most invasive surgical treatments for digestive tract cancer, and the blood levels of inflammatory cytokines such as interleukin-1, interleukin-6, and interleukin-8 are increased for several hours after surgery or in patients experiencing postoperative complications. CXCR2, an interleukin-8 receptor, is reportedly expressed in several carcinomas, and interleukin-8 signaling promotes cancer cell proliferation. The impact of postoperative complications following esophagectomy on long-term survival is controversial. In this study, we demonstrate the significance of CXCR2 expression and validate the effects of CXCR2 expression and postoperative complications on long-term prognosis of esophageal squamous cell carcinoma using resected specimens. Methods: Eighty-two specimens were sectioned from archived, paraffin-embedded tumor tissues obtained from patients with esophageal squamous cell carcinoma who underwent esophagectomy and extended lymphadenectomy for complete resection of cancer in our institute between 1997 and 2002. Immunohistochemistry was performed using a polyclonal antibody to CXCR2, and the correlation of stainability with clinicopathological factors and long-term survival was examined. Results: CXCR2 was expressed in 33 of 82 (40.2%) specimens. In the CXCR2-positive group, the recurrence-free survival and overall survival rates of patients who developed postoperative complications were both significantly lower than those for patients who did not develop any complications. In contrast, in the CXCR2-negative group, there was no significant difference in long-term prognosis between patients with and without complications. CXCR2 positivity combined with postoperative complications was an independent risk factor for subsequent tumor recurrence, showing the highest hazard ratio. Conclusions: Our results suggest that the patients with CXCR2-positive esophageal cancer who develop postoperative complications have a poor prognosis and should be carefully followed. Trial registration: This study was approved by Keio University School of Medicine Ethics Committee with a trial registration number of 2011-241.

Access to Document (DOI)

Superior mesenteric artery syndrome caused by massive lumbar osteophytes

Booka Eisuke, Kawakubo Hirofumi, Ishii Ken, Hikata Tomohiro, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Ishii Yoshiyuki, Takeuchi Hiroya, Kitagawa Yuko

Spine 40 ( 15 ) E909 - E912 2015.08

ISSN 0362-2436

Study Design. Case report. Objective. To present a rare case of superior mesenteric artery (SMA) syndrome caused by massive lumbar osteophytes. Summary of Background Data. SMA syndrome is a relatively rare condition thought to be secondary to functional obstruction. Although several risk factors for SMA syndrome have been reported, no other previous reports have suggested that lumbar osteophytes caused SMA syndrome. Methods. A rare case of SMA syndrome caused by massive lumbar osteophytes was treated by resecting the osteophytes. Results. An 82-year-old man, with a history of polysurgery, presented with frequent vomiting. He was diagnosed with SMA syndrome after endoscopic and several radiological examinations, and was successfully treated by the resection of the osteophytes. Conclusion. To the best of our knowledge, a case of SMA syndrome secondary to lumbar osteophytes has not been reported in the literature. The possibility of SMA syndrome caused by massive lumbar osteophytes should be taken into consideration when the cause of SMA syndrome is unknown. In addition, the resection of osteophytes could be a less invasive treatment in such cases.

Access to Document (DOI)

A Prospective Randomized Trial of Enteral Nutrition After Thoracoscopic Esophagectomy for Esophageal Cancer

Takesue Tomoko, Takeuchi Hiroya, Ogura Masaharu, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Kitagawa Yuko

Annals of Surgical Oncology 2015.07

ISSN 1068-9265

Background: Several studies have reported that postoperative enteral nutrition (EN) reduced complications and decreased weight loss and hospital stay periods; however, the majority of patients analyzed in these studies underwent open thoracic surgery. No studies have been conducted regarding EN in patients after thoracoscopic esophagectomy as a less invasive surgery. The aim of this study was to investigate the efficacy of EN after thoracoscopic esophagectomy. Methods: Fifty patients who underwent thoracoscopic esophagectomy for esophageal cancer were divided into two groups: parenteral nutrition (PN; n = 25) and EN (n = 25). The rate of weight loss at postoperative day (POD) 14, levels of prealbumin at POD 10, postoperative complications until POD 14, and other perioperative data were collected for each group. Results: This study analyzed data for 47 patients. The rate of weight loss at POD 14 was significantly lower in the EN group (3.0 ± 3.2 %) than in the PN group (4.0 ± 3.6 %; p = 0.020). Prealbumin levels were 21.0 ± 7.5 mg/dL in the PN group and 18.4 ± 5.8 mg/dL in the EN group at POD 10, with no significant differences between the groups. However, the incidence of postoperative pneumonia was higher in the PN group (30.4 %) than in the EN group (12.5 %). Conclusions: EN could suppress weight loss and reduce the incidence of pneumonia after thoracoscopic esophagectomy.

Access to Document (DOI)

Surgical Resection of Remnant Gastric Cancer Following Distal Gastrectomy

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

Annals of Surgical Oncology 2015.06

ISSN 1068-9265

Background: Remnant gastric cancer (RGC) is one of the less prevalent gastric cancers. The purpose of this study was to explore the clinicopathological characteristics and results of the operation of RGC following distal gastrectomy. In particular, we examined factors related to prognosis. Methods: Between January 1970 and December 2012, 122 patients with RGC following distal gastrectomy underwent further surgery and were analyzed retrospectively. Results: Initial gastric diseases included benign (49 patients, 40.2 %) and malignant diseases (73 patients, 59.8 %). Reconstructions by initial surgery included Billroth I (80 patients, 65.6 %) and Billroth II (42 patients, 34.4 %). Tumors were located at anastomotic (44 patients, 36.1 %) and nonanastomotic sites (78 patients, 63.9 %). There were 59 patients (48.4 %) classified with pathological (p) stage I, 19 as p stage II (15.6 %), 22 as p stage III (18.0 %), and 22 (18.0 %) as p stage IV. A total of 100 patients (82.0 %) underwent curative resection, and 22 underwent noncurative resection. The number of cases of postoperative morbidity, 90-day mortality, and adjuvant chemotherapy were 23 (18.9 %), 3 (2.5 %), and 20 (16.4 %), respectively. Univariate and multivariate analyses were performed to identify the prognostic factors of RGC. Multivariate analysis revealed historical periods, pathological venous invasion, curative resection, and postoperative morbidity to be independent prognostic factors. Conclusions: The prognosis of patients with RGC can be improved by aggressively performing curative resection without causing complications.

Access to Document (DOI)

Attenuation of lipopolysaccharide-induced acute lung injury after (pro)renin receptor blockade

Ishii Kenjiro, Takeuchi Hiroya, Fukunaga Koichi, Hirano Yuki, Suda Koichi, Hagiwara Tomoko, Miyasho Taku, Yamada Shingo, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Betsuyaku Tomoko, Ichihara Atsuhiro, Kitagawa Yuko

Experimental Lung Research 41 ( 4 ) 199 - 207 2015.05

ISSN 0190-2148

Purpose/Aim: We performed a randomized, prospective animal study to investigate whether inhibiting the renin-angiotensin system with a (pro)renin receptor blocker (PRRB) prevents acute lung injury (ALI) in a rodent model. Materials: We used Thirty-six male Sprague-Dawley rats. We administered lipopolysaccharide (LPS; 2 mg/kg) intratracheally with or without PRRB pretreatment (1 mg/kg/d). Methods: We performed bronchoalveolar lavage (BAL) and lung removal at 4 h after LPS administration and measured levels of inflammatory cytokines, high mobility group box 1 (HMGB-1) protein, and total protein in bronchoalveolar lavage fluid (BALF). Myeloperoxidase (MPO) activity was detected in lung tissue homogenates using a sensitive ELISA. We performed hematoxylin and eosin staining and immunohistochemical staining for nonproteolytically activated prorenin in the left lung. Results: The PRRB decreased leukocyte counts and total protein, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-6, and IL-10 levels in the BALF and MPO activity in lung tissue. The PRRB reduced interstitial edema, hemorrhage, and the neutrophil count in the lung tissues. Consistent with the reduction in lung tissue damage, immunohistochemical staining showed that the PRRB decreased the amount of nonproteolytically activated prorenin. Conclusions: The PRRB blocked LPS-induced inflammatory response in the lung and protected against ALI. Therefore, it is a potential therapeutic agent for preventing ALI.

Access to Document (DOI)

Correlation Between Intense Postoperative Inflammatory Response and Survival of Esophageal Cancer Patients Who Underwent Transthoracic Esophagectomy

Matsuda Satoru, Takeuchi Hiroya, Kawakubo Hirofumi, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Kitagawa Yuko

Annals of Surgical Oncology 2015.04

ISSN 1068-9265

Background: The correlation between postoperative systemic inflammation and cancer survival needs to be elucidated. This study evaluated postoperative inflammation using the peak concentration of postoperative serum C-reactive protein (CRP) levels and duration of CRP elevation, then investigated its correlation with prognosis. Methods: The study retrospectively reviewed 216 consecutive patients who underwent curative transthoracic esophagectomy at the authors’ institution between 2004 and 2012. The postoperative serum CRP levels in 215 patients were analyzed during 14 days after esophagectomy. The patients’ characteristics, surgical procedures, postoperative complications, and survival were investigated. To evaluate postoperative inflammatory status objectively using CRP, patients with a delayed CRP level peak and persistent CRP elevation were classified as having an intense postoperative inflammatory response (IIR). Results: The distributions of postoperative pathologic stages 0, 1, 2, 3, and 4 were respectively 5, 70, 58, 66, and 16. Regarding postoperative complications, pneumonia was diagnosed in 42 patients (20 %), anastomotic leakage in 32 patients (15 %), and superficial surgical-site infection in 21 patients (10 %). A delayed CRP level peak was observed in 88 patients (41 %) and persistent CRP elevation in 49 patients (23 %). Overall, 31 patients (14 %) were classified as having IIR. In the survival analysis, the patients with IIR showed a significantly shorter overall survival. In the multivariate analysis, using histology, neoadjuvant treatment, field of lymph node dissection, pathologic stage, and IIR as covariates, IIR was seen as a significantly independent predictive factor for overall survival (hazard ratio 2.019; P = 0.019). Conclusions: In this study, IIR was significantly correlated with postoperative survival. Therefore, the oncologic benefit of reducing postoperative inflammation in esophageal cancer needs to be investigated.

Access to Document (DOI)

Gastric tube cancer after radical esophagectomy

Booka Eisuke, Takeuchi Hiroya, Okamoto Nobuhiko, Uchi Yusuke, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Ozawa Soji, Omori Tai, Kitagawa Yuko

Esophagus 2015.03

ISSN 1612-9059

Background: Recent improvements in the survival of patients after esophagectomy have led to an increasing occurrence of gastric cancer in the reconstructed gastric tube (GTC). The aim of this study was to assess generational changes in the clinicopathological characteristics and treatment of GTCs in a single center.Methods: Thirteen GTC lesions in ten patients were diagnosed and treated at Keio University Hospital between 2006 and 2014. In our previous study, we reported eight cases of GTC [1]. We compared clinicopathological characteristics and treatment of GTC, as well as overall survival achieved in this study with those in our previous study [1].Results: In this study, median patient age at the time of GTC detection was 74 years (range 62–81 years) and the median interval between esophagectomy and GTC detection was 95 months (range 21–159 months). Nine (69 %) of 13 lesions satisfied the criteria for endoscopic resection. On comparing this study with our previous study, there were no significant differences in patient age at the time of GTC detection, the interval between esophagectomy and GTC detection, or pathological stage [1]. Compared with our previous study, the use of less invasive treatments, such as endoscopic submucosal dissection and partial gastric tube resection with sentinel lymph node dissection, generationally increased and a significant difference was observed in the type of GTC treatment [1]. However, there was no significant difference in overall survival between the studies.Conclusion: Long-term periodic endoscopy permits less invasive treatments and combinations of various treatments for effective GTC therapy.

Access to Document (DOI)

Characteristics and diagnosis of esophageal basaloid squamous cell carcinoma

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

Esophagus 2015.03

ISSN 1612-9059

Background: Basaloid squamous cell carcinoma (BSCC) is a relatively rare, malignant disease of the esophagus. The prognosis of patients with BSCC is thought to be poorer than that of typical squamous cell carcinoma (SCC), but the treatment strategy for BSCC is generally the same as that for typical SCC. This study examined the diagnosis, the clinical and pathological characteristics, and the results of therapy in patients with BSCC.Methods: The medical records for 13 patients with pathologically confirmed esophageal BSCC were extracted. The pretreatment endoscopic diagnosis and the pathological diagnosis after resection were reviewed for each patient, and the histological features and patient outcome were examined. We especially focus on histological difference and endoscopic findings of the 13 patients with BSCC.Results: Macroscopically, BSCC was mainly visualized as an elevated lesion with normal epithelium on the surface layer which indicated the tumor growth into submucosa. Further pathological examination allowed the 13 BSCC patients to be grouped into 2 groups according to differences in the microscopic appearances of the BSCC cancer cells: a typical BSCC pattern and a pattern similar to that of poorly differentiated SCC. Six of the patients who received an esophagectomy as the primary treatment died, and only 1 patient survived. Two patients who received chemoradiotherapy before an esophagectomy did not develop recurrences. Almost all the patients who died as a result of the recurrence of esophageal cancer had a lymph node recurrence. Prognoses of BSCCs with a pattern similar to that of poorly differentiated SCC without preoperative chemotherapy were poorer than BSCCs with a typical BSCC pattern, while BSCC with a pattern similar to poorly differentiated SCC with preoperative chemotherapy showed good prognoses than BSCC without preoperative chemotherapy.Conclusions: BSCC esophageal cancer mainly appears as an elevated lesion with submucosal growth, which can be diagnosed preoperatively by understanding of macroscopic characteristics of esophageal BSCC. The outcome of the BSCC patients in the present study was relatively poor, while pretreatment diagnosis of BSCC influences the strategy of treatment and pathological diagnosis including histological difference of BSCC may lead to appropriate treatment and better prognosis of esophageal BSCC.

Access to Document (DOI)

Factors Affecting Cytokine Change After Esophagectomy for Esophageal Cancer

Okamura Akihiko, Takeuchi Hiroya, Matsuda Satoru, Ogura Masaharu, Miyasho Taku, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Kitagawa Yuko

Annals of Surgical Oncology 2015.01

ISSN 1068-9265

Background: Esophagectomy for esophageal cancer is one of the most invasive operative procedures. Surgical stress induces the release of proinflammatory cytokines, and overproduction induces a systemic inflammatory response syndrome, which may lead to acute lung injury and multiple organ dysfunction syndrome. In addition, surgical stress may cause immunosuppression, which may affect not only perioperative mortality but also long-term survival.Methods: Between 2006 and 2013, levels of perioperative serum cytokines were evaluated in 90 patients who underwent esophagectomy for esophageal carcinoma. The serum interleukin (IL)-6, IL-8, and IL-10 levels were measured by enzyme-linked immunosorbent assays. We reviewed and assessed medical records, including cytokine profiles, and determined the factors affecting postoperative serum cytokine levels.Results: These cytokine levels peaked on postoperative day 1 and decreased gradually. Of the clinicopathologic factors, a thoracoscopic approach was a significant factor in attenuating IL-6 and IL-8 levels on postoperative day 1 in multivariate analysis, and a longer operative time was a significant factor in increasing these levels. During postoperative days 3–7, the thoracoscopic approach and early enteral nutrition were significant factors in attenuating serum cytokine changes in multivariate analysis, and postoperative infectious complications were significant factors in increasing these levels.Conclusions: The thoracoscopic approach and early enteral nutrition could attenuate the cytokine change after esophagectomy, and a longer operative time and postoperative infectious complication could increase it. We should undertake strategies to minimize the surgical stress to reduce potential short-term and long-term consequences for patients.

Access to Document (DOI)

Postoperative Hyperbilirubinemia Suggests the Occurrence of Complications After Esophagectomy for Esophageal Cancer

Takesue Tomoko, Takeuchi Hiroya, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Kitagawa Yuko

Presentations from the 9th Annual Electric Utilities Environmental Conference 2015.01

ISSN 0364-2313

Background: Serum bilirubin levels frequently increase after esophagectomy for esophageal cancer. Several studies have reported hyperbilirubinemia in patients with postoperative complications. We aimed to perform a detailed large-scale analysis to clarify this association.Methods: We compared postoperative serum bilirubin levels of 200 patients with esophageal cancer who underwent esophagectomy, with and without postoperative complications, from January 2008 to July 2013 at Keio University Hospital, Tokyo, Japan. We also analyzed other risk factors for postoperative hyperbilirubinemia by univariate and multivariate analyses in an attempt to determine the mechanism of postoperative hyperbilirubinemia.Results: Hyperbilirubinemia (total bilirubin >2.0 mg/dL) occurred in 71 patients (35.5 %). The mean total bilirubin peak level was 1.5 mg/dL in patients without complications, 2.0 mg/dL in those with at least one complication, 2.1 mg/dL in those with pneumonia, and 2.3 mg/dL in those with anastomotic leakage. Bilirubin levels were significantly higher in each complication group than in the non-complication group (p < 0.05 for all). Risk factors of postoperative hyperbilirubinemia by univariate analysis were the preoperative bilirubin level, video-assisted thoracoscopic surgery, three-field lymph node dissection, thoracic duct resection, prolonged surgical duration, severe complications (Clavien–Dindo grade ≥3), and severe anastomotic leakage (Clavien–Dindo grade ≥3). In contrast, the pT factor and postoperative enteral nutrition were negatively associated with postoperative hyperbilirubinemia. Risk factors by multivariate analysis were the preoperative bilirubin level, prolonged surgical duration, severe complications, and postoperative enteral nutrition.Conclusions: Although various factors impact postoperative hyperbilirubinemia, postoperative complications were most significantly associated with postoperative hyperbilirubinemia. Patients with postoperative hyperbilirubinemia after esophagectomy must be managed more carefully because unnoticed complications may be associated with hyperbilirubinemia.

Access to Document (DOI)

Phase i study of s-1 plus fractional cisplatin as adjuvant chemotherapy for advanced gastric cancer in an outpatient setting (KOGC-03)

Takahashi Tsunehiro, Saikawa Yoshiro, Fukuda Kazumasa, Nakamura Rieko, Wada Norihito, Kawakubo Hirofumi, Takeuchi Hiroya, Takaishi Hiromasa, Kitagawa Yuko

Anticancer Research 35 ( 1 ) 467 - 472 2015.01

ISSN 0250-7005

Aim: The aim of this phase I study was to adjust the dose of cisplatin as adjuvant combination chemotherapy with S-1 in an outpatient setting for gastric cancer.Patients and Methods: The first course was initiated with S-1 monotherapy on days 1-28. From the second to the sixth course, S-1 was administered on days 1-28 and cisplatin was added on days 1, 15, and 29. The dose level of cisplatin was escalated as follows: 20 mg/m² (level 1); 25 mg/m² (level 2); 30 mg/m2 (level 3). Dose-limiting toxicity was a delay factor of the start of the next course due to incomplete recovery.Results: The maximum tolerated and recommended doses were confirmed as level 3 and level 2, respectively.Conclusion: Although further clinical trials are recommended to evaluate efficacy, this combination of S-1 plus cisplatin regimen is expected to become a standard adjuvant treatment for gastric cancer in the outpatient setting.

Prognostic significance of circulating tumor cells in patients with advanced esophageal cancer

Tanaka Motomu, Takeuchi Hiroya, Osaki Yoshiki, Hiraiwa Kunihiko, Nakamura Rieko, Oyama Takashi, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Kitagawa Yuko

Esophagus 2014.12

ISSN 1612-9059

Introduction: The purpose of this study was to establish the clinicopathological significance of circulating tumor cells (CTCs) in patients with advanced or recurrent esophageal cancer who received either chemotherapy or chemoradiotherapy.Methods: CTCs from 38 patients with advanced or recurrent esophageal cancer were quantified using the CellSearch system before and approximately 3–5 weeks after the initiation of a new line of chemotherapy or chemoradiotherapy. The correlation between CTC counts and clinicopathological variables was examined.Results: Of the 38 patients, 15 (39 %) had recurrent esophageal cancer, and 23 patients (61 %) had primary advanced esophageal cancer. The mean age was 63 years (range 43–87 years). One patient (2.6 %) had a complete response to treatment, 16 (42.1 %) had a partial response, 12 (31.6 %) showed stable disease, and nine (23.7 %) showed signs of progressive disease. The overall survival of patients with ≥2 CTCs was significantly shorter than that of patients with <2 CTCs both at baseline and at first follow-up (p = 0.047 and p = 0.011, respectively). Significant correlation was found between the change in CTC counts and the response to treatment (p = 0.036). The overall survival in patients with ≥2 CTCs both at baseline and at first follow-up was significantly shorter than patients with <2 CTCs both at baseline and at first follow-up (p = 0.002). Patients with a reduction rate in the CTC value <80 % experienced significantly shorter survival than patients with a reduction rate of ≥80 % (p = 0.035). The CTC counts at first follow-up served as an independent prognostic factor (p = 0.011).Conclusions: Our results suggest that measuring the number of CTCs in patients with advanced or recurrent esophageal cancer can be useful for predicting the survival of patients and for monitoring the response to cancer treatments.

Access to Document (DOI)

Surveillance using trimodal imaging endoscopy after endoscopic submucosal dissection for superficial gastric neoplasia

Imaeda Hiroyuki, Hosoe Naoki, Kashiwagi Kazuhiro, Ida Yosuke, Nakamura Rieko, Suzuki Hidekazu, Saito Yoshimasa, Yahagi Naohisa, Iwao Yasushi, Kitagawa Yuko, Hibi Toshifumi, Ogata Haruhiko, Kanai Takanori

World Journal of Gastroenterology 20 ( 43 ) 16311 - 16317 2014.11

ISSN 1007-9327

AIM: To evaluate the effectiveness of trimodal imaging endoscopy (TME) to detect another lesion after endoscopic submucosal dissection (ESD) for superficial gastric neoplasia (SGN).METHODS: Surveillance esophagogastroduodenoscopy (EGD) using a TME was conducted in 182 patients that had undergone ESD for SGN. Autofluorescence imaging (AFI) was conducted after white-light imaging (WLI). When SGN was suspicious, magnifying endoscopy with narrow-band imaging (ME-NBI) was conducted. Final diagnoses were made by histopathologic findings of biopsy specimens. The detection rates of lesions in WLI, AFI, and NBI, and the characteristics of lesions detected by WLI and ones missed by WLI but detected by AFI were examined. The sensitivity, specificity, and accuracy of endoscopic diagnosis using WLI, AFI and ME-NBI were evaluated.RESULTS: In 242 surveillance EGDs, 27 lesions were determined pathologically to be neoplasias. Sixteen early gastric cancers and 6 gastric adenomas could be detected by WLI. Sixteen lesions were reddish and 6 were whitish. Five gastric neoplasias were missed by WLI but were detected by AFI, and all were whitish and protruded gastric adenomas. There was a significant difference in color and pathology between the two groups (P = 0.006). Sensitivity, specificity and accuracy in MENBI were higher than those in both WLI and AFI. Specificity and accuracy in AFI were lower than those in WLI.CONCLUSION: Surveillance using trimodal imaging endoscopy might be useful for detecting another lesion after endoscopic submucosal dissection for superficial gastric neoplasia.

Access to Document (DOI)

A case of late lymph node metastasis after three endoscopic mucosal resections of intramucosal gastric cancers

Booka Eisuke, Takahashi Tsunehiro, Tokizawa Kazunori, Uchi Yusuke, Okamura Akihiko, Fukuda Kazumasa, Nakamura Rieko, Wada Norihito, Kawakubo Hirofumi, Saikawa Yoshiro, Omori Tai, Takeuchi Hiroya, Sasaki Aya, Mikami Shuji, Kumai Koichiro, Kameyama Kaori, Kitagawa Yuko

World Journal of Surgical Oncology 339 2014.11

We describe a patient with solitary lymph node (LN) metastasis after three endoscopic mucosal resections (EMRs) in which a gastrointestinal stromal tumor was difficult to differentiate from the carcinoid and lymphoma tumors. A 77-year-old man underwent three EMRs at 62, 72, and 75 years of age, and all resections were determined to be curative. However, 2 years after the last EMR, screening abdominal ultrasonography detected a 20-mm solitary tumor at the lesser curvature of the upper stomach. Laparoscopic tumor resection confirmed the pathological diagnosis. Intraoperative pathological diagnosis showed that the adenocarcinoma was compatible with recurrence of gastric cancer; thus, total gastrectomy with D1 lymphadenectomy was performed. Metastasis was not recognized by pathological examination but was detected by preoperative radiological examinations of the LN. We report a rare recurrence case after several EMRs of intramucosal gastric cancers.

Access to Document (DOI)

Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells

Sako Hiroyuki, Fukuda Kazumasa, Saikawa Yoshiro, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Kawakubo Hirohumi, Takeuchi Hiroya, Ohmori Tai, Kitagawa Yuko

PLoS One 9 ( 9 ) 2014.09

Despite the benefits of imatinib for treating gastrointestinal stromal tumors (GIST), the prognosis for high risk GIST and imatinib-resistant (IR) GIST remains poor. The mechanisms of imatinib resistance have not yet been fully clarified. The aim of the study was to establish imatinib-resistant cell lines and investigate nilotinib, a second generation tyrosine kinase inhibitor (TKI), in preclinical models of GIST and imatinib-resistant GIST. For a model of imatinib-resistant GIST, we generated resistant cells from GK1C and GK3C cell lines by exposing them to imatinib for 6 months. The parent cell lines GK1C and GK3C showed imatinib sensitivity with IC₅₀of 4.59±0.97 μM and 11.15±1.48 μM, respectively. The imatinib-resistant cell lines GK1C-IR and GK3C-IR showed imatinib resistance with IC₅₀values of 11.74±0.17 μM (P<0.001) and 41.37±1.07 μM (P<0.001), respectively. The phosphorylation status of key cell signaling pathways, receptor tyrosine kinase KIT (CD117), platelet-derived growth factor receptor alpha (PDGFRA) and downstream signaling kinases: serine-threonine kinase Akt (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) or the non-receptor tyrosine kinase: proto-oncogene tyrosine-protein kinase Src (SRC), was analyzed in established cell lines and ERK1/2 phosphorylation was found to be increased compared to the parental cells. Nilotinib demonstrated significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines. Thus, nilotinib may have clinical potential for patients with GIST or imatinib-resistant GIST.

Access to Document (DOI)

Cumulative Prognostic Scores Based on Plasma Fibrinogen and Serum Albumin Levels in Esophageal Cancer Patients Treated with Transthoracic Esophagectomy

Matsuda Satoru, Takeuchi Hiroya, Kawakubo Hirofumi, Fukuda Kazumasa, Nakamura Rieko, Takahashi Tsunehiro, Wada Norihito, Saikawa Yoshiro, Omori Tai, Kitagawa Yuko

Annals of Surgical Oncology 2014.06

ISSN 1068-9265

Purpose The purpose of this study was to establish a prognostic indicator based on preoperative plasma fibrinogen and serum albumin levels (FA score) in esophageal cancer patients and to compare the correlation with survival to that of the Glasgow prognostic score. Methods Patient characteristics, clinicopathological factors, and preoperative biochemical markers (fibrinogen, albumin, and C-reactive protein) were investigated in esophageal cancer patients who underwent transthoracic esophagectomy. Pretreatment fibrinogen and albumin levels were reviewed in patients who received neoadjuvant treatment. Patients with elevated fibrinogen and decreased albumin levels were allocated a score of 2, those with only one of these abnormalities were allocated a score of 1, and those with neither of these abnormalities were allocated a score of 0. The fibrinogen cut-off value was defined as 350 mg/dL according to our previous report, and the albumin cut-off value was defined as the lower quartile. Results Among 199 consecutive patients, the interquartile range of preoperative albumin was 3.8-4.3 g/dL and the cut-off value was 3.8 g/dL. Thus, 108 (54 %), 68 (34 %), and 23 (12 %) patients had an FA score of 0, 1, and 2. The patients with a high preoperative FA score showed considerably shorter disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that pretreatment stage and preoperative FA score were independently associated with postoperative DFS and OS. Conclusions Preoperative FA score was significantly associated with postoperative survival in esophageal cancer patients, and the prognostic value is currently being validated in a prospective multicenter cohort study.

Access to Document (DOI)

Intra-abdominal desmoid tumor mimicking gastric cancer recurrence

Okamura Akihiko, Takahashi Tsunehiro, Saikawa Yoshiro, Mayanagi Shuhei, Fukuda Kazumasa, Nakamura Rieko, Wada Norihito, Kawakubo Hirofumi, Omori Tai, Takeuchi Hiroya, Sasaki Aya, Kitagawa Yuko

World Journal of Surgical Oncology 12 ( 1 ) 2014.05

Intra-abdominal desmoid tumors are rare and most often occur in patients with a history of familial adenomatous polyposis, surgery, or pregnancy. We report a case of an intra-abdominal desmoid tumor mimicking the recurrence of gastric cancer. A 57-year-old male had undergone distal gastrectomy for advanced gastric cancer. Serum levels of carcinoembryonic antigen were found to be elevated 27 months after surgery. Computed tomography revealed a 15-mm mass in the mesentery of the transverse colon. In addition, radiotracer fluorodeoxyglucose uptake of the tumor was detected by positron emission tomography. The patient was diagnosed with gastric cancer recurrence, and chemotherapy consisting of cisplatin and S-1 was commenced. After five courses of chemotherapy, although no significant clinical response was seen, no new lesions were seen either. Thus, a curative resection of the recurrent tumor seemed possible, which was successfully performed. Histological examination of the resected specimen revealed spindle-shaped tumor cells with collagen fiber progression; no cancer cells were detected. The tumor was diagnosed as an intra-abdominal desmoid tumor. We report a rare case of an intra-abdominal desmoid tumor that mimicked a recurrent tumor arising from gastric cancer. In patients with history of surgery for intra-abdominal malignancies, it may be difficult to distinguish the recurrence of malignancy from desmoid tumors but the possibility of desmoid tumors must be considered in the differential diagnosis.

Access to Document (DOI)

CC-Chemokine receptor CCR7

Irino Tomoyuki, Takeuchi Hiroya, Matsuda Sachiko, Saikawa Yoshiro, Kawakubo Hirofumi, Wada Norihito, Takahashi Tsunehiro, Nakamura Rieko, Fukuda Kazumasa, Omori Tai, Kitagawa Yuko

BMC Cancer 14 ( 1 ) 2014.04

Background: CC-chemokine receptor 7 (CCR7), a known lymph node homing receptor for immune cells, has been reported as a key molecule in lymph node metastasis. We hypothesized a clinicopathological correlation and functional causality between CCR7 expression and lymph node metastasis in patients with esophageal squamous cell carcinoma (ESCC).Methods: We performed immunohistochemical analysis of 105 consecutive and 61 exclusive pathological T1 ESCC patients, followed by adhesion assay and in vivo experiment using a newly developed lymph node metastasis mouse model. The adhesive ability in response to CC-chemokine ligand 21/secondary lymphoid-tissue chemokine (CCL21/SLC) was assessed in the presence or absence of lymphatic endothelial cells and anti-CCR7 antibody. We established a heterotopic transplantation mouse model and analyzed lymph node metastasis by quantitative real-time RT-PCR.Results: Positive CCR7 expression in immunohistochemistory was detected in 28 (27%) of 105 consecutive patients and 17 (28%) of 61 T1 patients, which significantly correlated with lymph node metastasis (p = 0.037 and p = 0.040, respectively) and poor five-year survival (p = 0.013 and p = 0.012, respectively). Adhesion assay revealed an enhanced adhesive ability of CCR7-expressing cells in response to CCL21/SLC, in particular, in the presence of lymphatic endothelial cells (p = 0.005). In the mouse model, lymph nodes from mice transplanted with CCR7-expressing cells showed significantly higher DNA levels at 5 weeks (p = 0.019), indicating a high metastatic potential of CCR7-expressing cells.Conclusion: These results demonstrated the significant clinicopathological relationship and functional causality between CCR7 expression and lymph node metastasis in ESCC patients.

Access to Document (DOI)

Successful management of anastomotic leakage and lung fistula after esophagectomy

Wada Takeyuki, Takeuchi Hiroya, Yoshikawa Takahisa, Oyama Takashi, Nakamura Rieko, Takahashi Tsunehiro, Kawakubo Hirofumi, Wada Norihito, Saikawa Yoshiro, Omori Tai, Kitagawa Yuko

Annals of Thoracic Surgery 97 ( 3 ) 1071 - 1073 2014.03

ISSN 0003-4975

Access to Document (DOI)

Clinical utility of the Revised Cardiac Risk Index in non-cardiac surgery for elderly patients

Hirano Yuki, Takeuchi Hiroya, Suda Koichi, Oyama Takashi, Nakamura Rieko, Takahashi Tsunehiro, Kawakubo Hirofumi, Wada Norihito, Saikawa Yoshiro, Obara Hideaki, Jinno Hiromitsu, Hasegawa Hirotoshi, Tanabe Minoru, Kitagawa Yuko

Surgery Today 44 ( 2 ) 277 - 284 2014.02

ISSN 0941-1291

Purpose: We investigated the association between the Revised Cardiac Risk Index (RCRI) and postoperative outcomes in patients undergoing non-cardiac surgery. Methods: The predictive value of the RCRI for the risk of perioperative complications, length of hospital stay and hospital cost were evaluated from a prospective cohort of 119 patients aged ≥65 years undergoing elective major digestive, breast or vascular surgery. Results: Comparing three groups RCRI 0, 1 and ≥2, the morbidity rates were 0, 30 and 68 %; the median length of hospitalization was 5, 14 and 28 days; and the median cost was 665,000, 1,480,000 and 2,160,000 yen, respectively. The mortality rate was 0 % in all groups. The RCRI 0 group included only non-high-risk (breast and peripheral vascular) surgeries. In addition, comparing the two groups by excluding non-high-risk surgeries (RCRI 1 and ≥2), the median morbidity rates were 31 and 67 %, the median length of hospitalization was 15 and 28 days, and the median cost was 1,550,000 and 2,130,000 yen, respectively. The RCRI score was the only independent predictor of the perioperative complications. Conclusions: In the case of non-cardiac surgery, the RCRI can identify patients at higher risk of perioperative complications, a prolonged hospital stay and higher hospital cost.

Access to Document (DOI)

Endoscopic laryngo-pharyngeal surgery (ELPS) for superficial carcinoma of the pharynx and cervical esophagus

Kawakubo Hirofumi, Omori Tai, Nakamura Rieko, Takeuchi Hiroya, Kitagawa Yuko

Gastroenterological Endoscopy 56 ( 1 ) 64 - 70 2014.01

ISSN 0387-1207

Recent advances in endoscopic procedures, such as narrow band imaging systems and magnifying endoscopy, have enabled the precise observation of the hypopharynx and cervical esophagus. We developed endoscopic laryngo-pharyngeal surgery (ELPS) as minimally invasive surgery for superficial carcinoma of the larynx and pharynx. First, we insert the laryngoscope with endoscopic guide and place it at on the upper part of the vocal cord. We lift the larynx by the laryngoscope and fix the laryngoscope. The curved laryngoscope gives us a good visual field and working space between the hypopharynx and the cervical esophagus. After lifting the larynx using the laryngoscope, the endoscopist inserts the endoscope and the operator inserts the forceps and electric device transorally. After iodine staining, we mark the normal mucosa just 1-2 mm away from the cancer margin and inject Epinephrine-added physiological saline solution to the subepithelial layer. After the circumferential cutting, we resect the lesion with the forceps and electric device. ELPS for superficial carcinoma of the hypopharynx and cervical esophagus is a feasible and effective treatment.

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

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.

Access to Document (DOI)

Report of a case successfully treated with chemo-radiation against local recurrence after gastric cancer surgery

Igarashi Takahiro, Saikawa Yoshiro, Kumagai Koshi, Nakamura Rieko, Takahashi Tsunehiro, Takeuchi Yuya, Kitagawa Yuko

Japanese Journal of Cancer and Chemotherapy 36 ( 8 ) 1363 - 1366 2009.08

ISSN 0385-0684

A 68-year-old male was diagnosed as type 2 gastric cancer in the upper part of the stomach, then diagnosed as cT2 (MP) N0M0H0P0, cStage I B. Total gastrectomy and splenectomy with D2 lymph node dissection were performed. Final diagnosis including pathology was pT1 (SM) N1M0H0P0, pStage IB, and with his informed consent, an anti-cancer drug, UFT, was given as postoperative adjuvant therapy. Four months after the surgery, a 35-mm sized tumor recurring around the distal region of pancreas was detected by abdominal computed tomography (ACT). Then, combination chemo-radiotherapy using S-1, cisplatin and radiation (50 Gy) was performed. One year after the initial surgery, ACT showed a complete response (CR) of the recurred tumor, while outpatient chemotherapy with S-1+CPT-11 and S-1+paclitaxel was continuously performed, because of elevated CEA. Two years after initial surgery, the CEA value was elevated to 28.4 ng/mL, and so S-1 +docetaxel was applied. The patient is still alive with no sign of lesion recurrence by CT 3 years after initial surgery. Outpatient chemotherapy helped the patient maintain good quality of life. In addition, initial therapy for the recurred tumor including radiation proved to be a powerful way to control local growth of gastric cancer, even if hematogenous/lymphatic spreading of gastric cancer cells might be difficult to suppress with such chemo-radiotherapy.

Dynamic alteration of gene expression induced by anticancer-agent exposure in gastric cancer cell lines

Takahashi Tsunehiro, Saikawa Yoshiro, Nakamura Rieko, Kumagai Koshi, Takeuchi Hiroya, Kubota Tetsuro, Kitagawa Yuko

Oncology Reports 21 ( 2 ) 451 - 459 2009

ISSN 1021-335X

The prognosis for advanced gastric cancer remains very poor due to the limited effectiveness of chemotherapy agents. The range in efficacy of these chemotherapy agents is likely the result of various factors including gene expression. In addition, the emergence of drug resistance during chemotherapy can result in the undesirable outcome of patients experiencing the side effects of chemotherapy without benefiting in terms of tumor response. Gene expression profiling provides a unique opportunity to gain insight into the development of different types of gastric cancer. We applied the TaqMan low density array to investigate the expression of 96 genes in four gastric cancer cell lines (TMK-1, MKN-45, MKN-74 and CDDP-resistant MKN-74). The cell lines displayed different patterns of gene expression alteration after exposure to the chemotherapeutic drugs cisplatin and 5-fluorouracil. We also established that cisplatin-resistant MKN-74 cells do not show the same gene expression patterns as the parental MKN-74 cell line at 0, 8 and 24 h after CDDP exposure. This study reveals the underlying complexity of biological and pathological events and could, perhaps, contribute to new experimental protocols or treatments that would achieve a consistent and desirable outcome of chemotherapy.

Access to Document (DOI)

Phase II Study of Chemoradiotherapy With S-1 and Low-Dose Cisplatin for Inoperable Advanced Gastric Cancer

Saikawa Yoshiro, Kubota Tetsuro, Kumagai Koshi, Nakamura Rieko, Kumai Koichiro, Shigematsu Naoyuki, Kubo Atsushi, Kitajima Masaki, Kitagawa Yuko

International Journal of Radiation Oncology Biology Physics 71 ( 1 ) 173 - 179 2008.05

ISSN 0360-3016

Purpose: The results of a pilot study using S-1/low-dose cisplatin/radiotherapy led us to hypothesize that the initial chemoradiotherapy regimen would induce a 70% efficacy rate with a 10% pathologic complete response rate. Patients and Methods: Only patients with unresectable or incurable advanced gastric cancer were eligible. The patients received induction S-1 and cisplatin therapy with radiotherapy followed by chemotherapy alone. Results: Of the 30 patients recruited and assessed, 29 were eligible for clinical evaluation of measurable lesions. The response rate was 65.5%, with 19 with a partial response, 8 with no change, and 2 with progressive disease of 29 patients. Of the 30 patients recruited, 10 (33.3%) underwent stomach resection and D2 LN dissections. The pathologic complete response rate was 13.3% (4 patients), and the R0 resection rate was 100% (10 patients). The survival analysis showed a median survival time of 25 months. Grade 3 toxicity occurred in 66.7% for leukocytopenia, 33.3% for thrombocytopenia, 23.3% for nausea and appetite loss, and 6.7% for anemia, diarrhea, and renal dysfunction. Although all the patients had been hospitalized with a poor performance status with a giant tumor, 97% (29 of 30) could be discharged after the first cycle, resulting in an improvement in quality of life. Conclusion: Chemoradiotherapy could be a powerful regimen for controlling tumor progression in advanced gastric cancer, improving patients' quality of life with tolerable toxicity. A complete histologic response rate of >10% would be expected, even for large tumors with metastatic lesions.

Access to Document (DOI)

Development of 36 clones producing human monoclonal antibodies specific to cancer cells and their ability to inhibit cancer cell growth

Nakamura Rieko, Saikawa Yoshiro, Hosokawa Saiko, Fukuda Kazumasa, Kumai Koichiro, Kubota Tetsuro, Kitajima Masaki, Kitagawa Yuko

Anticancer Research 28 ( 3 A ) 1651 - 1657 2008.05

ISSN 0250-7005

The development of a specific antibody for cancer therapy could enable a potent strategy for overcoming cancer. As ideal immunotherapy, a human monoclonal antibody (HuMoAb) might have a useful antitumor effect without any lethal toxicities. Thirty-six unique clones producing HuMoAbs were successfully developed using tumor infiltrating lymphocytes collected from 28 patients with several malignant solid tumors. The 36 tumor-specific immunoglobins were found among 9,450 clones after 43 fusions by the conventional hybridoma method. Among these 36 HuMoAbs, 9 had a remarkable tumor-specific reaction and no reaction with normal tissues, as determined with quantum dots-streptavidin and a fluorescence microscope. The inhibition of cell proliferation by the HuMoAbs was evaluated with the MTT assay. Over 40% cell growth inhibition was confirmed with 4 of the 36 HuMoAbs. Two of the antibodies had highly-specific reactivity to carcinomatous lesions with strong growth inhibition and up to 94.3% inhibition of the control growth. In conclusion, 36 clones with HuMoAbs that have specific reactions with cancer cells were successfully established. These HuMoAbs might be utilized as either anticancer or drug delivery agents.

Clinical experience of second-line chemotherapy with S-1/CPT-11 for highly advanced gastric cancer

Kumagai Koshi, Saikawa Yoshiro, Nakamura Rieko, Takahashi Tsunehiro, Kubota Tetsuro, Kumai Koichiro, Kitagawa Yuko, Kitajima Masaki

Gan to kagaku ryoho. Cancer & chemotherapy 35 ( 2 ) 245 - 250 2008.02

ISSN 0385-0684

We have performed chemoradiation with S-1 and low-dose CDDP as an initial treatment for 27 patients with incurable or unresectable highly advanced gastric cancer since 2002. Twelve out of 27 patients received combination chemotherapy of S-1 and CPT-11 as the second-line chemotherapy. On this regimen, S-1 was administered orally at a dose of 80 mg-120 mg daily, and CPT-11 at a dose of 60 mg/m(2) once in 2 or 3 weeks for outpatients. Clinical effects after therapy showed a response rate of 30.0%. Considering the prognostic outcome of the regimen, the one-year survival rate of the therapy was 66.7%, and the median survival time was more than 1 year, suggesting second-line chemotherapy will be one of the beneficial regimens in gastric cancer patients. Although 4 patients showed grade 3 bone marrow suppression (33.3%), they were all able to continue the therapy, after recovering from toxicity by means of G-CSF and/ or cessation of chemotherapy. The incidence and level of toxicity accompanying subjective symptoms, however, were relatively low, and the regimen was useful as an outpatient treatment maintaining good quality of life and improving their prognosis. Treatment with an appropriate regimen at an appropriate time will enable these patients to have good quality of life and survival.

Retrospective analysis of treatment for advanced gastric cancer with peritoneal dissemination

Nakamura Rieko, Saikawa Yoshiro, Wada Norihito, Yoshida Masashi, Kubota Tetsuro, Kumai Koichiro, Kitajima Masaki, Kitagawa Yuko

Gan to kagaku ryoho. Cancer & chemotherapy 34 ( 11 ) 1827 - 1831 2007.11

ISSN 0385-0684

Recent development and clinical application of novel anticancer agents like S-1 have been reported to show a good outcome against gastric cancer (GC) with peritoneal dissemination (P). In our study, a retrospective analysis of the treatment for GC with P was performed. Since 1989, a chemosensitivity test with MTT assay (MTTA) using surgical specimen was performed to choose chemotherapy after surgery, resulting in good prognosis in patients who received drugs which were determined effective by the MTTA. Since 1999, S-1 was introduced as adjuvant chemotherapy, and, since 2002, initial treatment with S-1/CDDP was used for GC with P, suggesting a better prognostic outcome compared with previous results with ineffective chemotherapy or surgery alone. In conclusion, prognosis of GC with P has been improving by effective regimens with novel anticancer agents like S-1. Further research and clinical trials will be necessary to achieve a more satisfactory outcome with the treatment of GC with P.

A patient with gastric cancer and liver metastases successfully treated with combination chemotherapy including S-1

Nakamura Rieko, Saikawa Yoshiro, Kumagai Koushi, Kiyota Tsuyoshi, Ohashi Masaki, Yoshida Masashi, Kubota Tetsuro, Kumai Koichiro, Kitajima Masaki

International Journal of Clinical Oncology 12 ( 4 ) 295 - 299 2007.08

ISSN 1341-9625

We report the case of a 62-year-old man with advanced gastric cancer and multiple liver metastases who was successfully treated with combined chemotherapy including S-1. The patient was clinically diagnosed with stage IV (T3 N2 H1 P0) disease and was initially treated with 100 mg/body per day S-1 administered orally for 21 days and 10 mg/body per day cisplatin (CDDP) infused on days 1-5, 8-12, and 15-19. This chemotherapy resulted in significant reduction of the liver and gastric tumors. After receiving additional CDDP/S-1 administration as an outpatient, the patient's liver masses disappeared as shown on abdominal computed tomography (CT). With the patient's desire and informed consent, he underwent curative surgery with total gastrectomy, D1+α lymph node dissection, and partial resection of liver S4. After discharge without any surgical complication, CT revealed regrowth of the S4 liver mass, and combined docetaxel and CDDP was selected as second-line chemotherapy with local radiation therapy against the hepatic metastasis. Additionally, a third regimen with irinotecan and S-1 was given. At 2 years 7 months after the initial treatment, no sign of cancer (including liver metastasis and peritoneal dissemination) has been identified by radiological follow-up examinations.

Access to Document (DOI)

Retrospective analysis of prognosis for scirrhous-type gastric cancer

Nakamura Rieko, Saikawa Yoshiro, Wada Norihito, Yoshida Masashi, Kubota Tetsuro, Kumai Koichiro, Kitajima Masaki

International Journal of Clinical Oncology 12 ( 4 ) 291 - 294 2007.08

ISSN 1341-9625

Background. Scirrhous gastric cancer is biologically aggressive, and the prognosis is poor even with curative surgery. We compared outcomes with different therapies in order to identify prognostic factors. Methods. Records for 83 patients, who were treated between 1991 and 2004, were evaluated for survival and stage, treatment, and clinicopathological factors. Results. Cumulative 5-year overall survival was 10.2% for all 83 patients, including 27 (32.5%) patients with stage II/III disease and 56 (67.4%) with stage IV disease. The 5-year overall survival rate and median survival time for patients with stage II/III disease after curative surgery were 24.3% and 1150 days. For patients with stage IV disease, 2-year and 5-year survival rates after initial surgery were 13.7% and 0% and median survival was 250 days. In contrast, preoperative chemotherapy for advanced, unresectable disease produced 2-year and 3-year overall survival rates of 53.6% and 26.8% and medican survival was 910 days. Conclusion. Aggressive surgery alone does not seem to improve outcome, but preoperative chemotherapy might be beneficial and should be investigated further.

Access to Document (DOI)

Endoscopic classifications as diagnostic factors of peptic ulcer and early gastric cancer - A possible reason why Helicobacter pylori infection causes gastric ulcers along lesser curvature

Yoshida M., Saikawa Y., Hosoda S., Kumai K., Kubota T., Ishikawa H., Nakamura T., Nakamura R., Kameyama K., Takahashi S., Kurihara N., Kitajima M.

Alimentary Pharmacology and Therapeutics 24 ( SUPPL.4 ) 303 - 310 2006.12

ISSN 0269-2813

Background: Endoscopic classifications were reported to reflect the pathophysiology of gastric mucosa. However, relationship between gastric lesions and classifications has not been examined well. Aim: To investigate the relationship between endoscopic classifications and cancers or ulcers. Methods: In this study, 487 patients undergoing upper gastrointestinal endoscopy in Takahashi Clinic and 257 patients with early gastric cancer in Keio University Hospital were enrolled. Results: Incidence of reflux oesophagitis was higher in Helicobacter pylori-negative patients. K-form was better in the H. pylori-positive patients. Most cancers in the patients with the closed-type or reflux oesophagitis were of undifferentiated types. Incidences of ulcers were highest in C-2 and C-3 in which the borders of atrophy cross the medial oblique muscle bundle, the border circular muscle bundle or both, and 94% of ulcers in C-2 and C-3 stomach were located along the lesser curvature. Conclusion: The predominant existence of undifferentiated types in patients with reflux oesophagitis or closed-type stomach can be useful information for early diagnosis of cancers. The relationship between the Kimura-Takemoto classification and ulcer location may explain why H. pylori infection is related to ulcer formation along the lesser curvature.

Access to Document (DOI)

Endoscopic classifications as diagnostic factors of peptic ulcer and early gastric cancer - A possible reason why Helicobacter pylori infection causes gastric ulcers along lesser curvature

Yoshida M., Saikawa Y., Hosoda S., Kumai K., Kubota T., Ishikawa H., Nakamura T., Nakamura R., Kameyama K., Takahashi S., Kurihara N., Kitajima M.

Alimentary Pharmacology and Therapeutics Symposium Series 2 ( 1 ) 303 - 310 2006.07

ISSN 1746-6334

Access to Document (DOI)

A recent trial of chemo-radiation with S-1 against gastric cancer

Saikawa Yoshiro, Kiyota Tsuyoshi, Nakamura Rieko, Wada Norihito, Yoshida Masashi, Kubota Tetsuro, Kumai Koichiro, Shigematsu Naoyuki, Kubo Atsushi, Kitajima Masaki

Gan to kagaku ryoho. Cancer & chemotherapy. 33 Suppl 1 99 - 105 2006.06

ISSN 0385-0684

A recent development of novel anticancer agents like S-1, CPT-11 or taxanes has improved a therapeutic outcome for advanced gastric cancer, while conventional anticancer agents showed less anticancer effect against gastric cancer. The present main drug in Japan is S-1, which is easily used for outpatient with a high efficacy rate and low toxicity, also shows better effect in combination with other anticancer drugs than S-1 alone. In the present article, we demonstrated significant meaning of additional radiation therapy with anticancer drugs like S-1. With novel anticancer drugs like S-1, we will expose a clinical advantage and appropriateness for chemo-radiation therapy against gastric cancer discussed in the present references according to chemo-radiation therapy. Although chemo-radiation therapy has been recognized as one of the standard therapies for gastric cancer in Western countries, radiation therapy was selected in Japan for palliation therapy of recurrent disease or a terminal cancer to improve patients' QOL. On the other hand, we demonstrated in our trial of chemo-radiation therapy with S-1/low-dose CDDP/radiation (TSLDR), which was applied to initial treatment against highly advanced Stage IV gastric cancer and revealed the usefulness of the regimen in anticancer effect and toxicity. In addition, chemo-radiation therapy including novel anticancer agents like S-1 will be discussed based on various kinds of view points, expecting a better clinical outcome of multimodal therapies against advanced gastric cancer.

Metastatic gastric cancer from malignant fibrous histiocytoma

Akatsu Yukako, Saikawa Yoshiro, Kubota Tetsuro, Kiyota Tsuyoshi, Nakamura Rieko, Akatsu Tomotaka, Takahashi Tsunehiro, Yoshida Masashi, Otani Yoshihide, Kumai Koichiro, Kitajima Masaki

Surgery Today 36 ( 4 ) 385 - 389 2006.04

ISSN 0941-1291

Metastatic gastric cancer originating from malignant fibrous histiocytoma (MFH) is rare. To our knowledge, only nine other cases have been reported. We report the case of a 75-year-old man who underwent a distal gastrectomy for advanced gastric carcinoma, 2 years after resection of an MFH from the left side of his back. We based our preliminary diagnosis of primary advanced gastric carcinoma on the results of a preoperative biopsy specimen, which suggested either poorly differentiated adenocarcinoma or nonepithelial cell-originating malignant disease-like lymphoma. The resected stomach contained a large ulcerative tumor in the antral section, which was positive for Kp-1 and S-100 by immunohistochemical staining, confirming a pathological diagnosis of metastatic MFH of the stomach. He died of recurrence in the mediastinal space 16 months after the gastrectomy. Our analysis of this and previous cases suggests that resection may be inappropriate for patients with gastric metastasis of MFH because of the extremely high malignant potential of this tumor.

Access to Document (DOI)

Role of the MTT chemosensitivity test in the prognosis of gastric cancer patients after postoperative adjuvant chemotherapy

Nakamura Rieko, Saikawa Yoshiro, Kubota Tetsuro, Kumagai Atsushi, Kiyota Tsuyoshi, Ohashi Masaki, Yoshida Masashi, Otani Yoshihide, Kumai Koichiro, Kitajima Masaki

Anticancer Research 26 ( 2 B ) 1433 - 1437 2006.03

ISSN 0250-7005

The clinical usefulness of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) chemosensitivity test (MTT assay; MTTA) in the selection of anticancer drugs against advanced gastric cancer (AGC) was evaluated. MTTA is widely used to predict patient responses to particular drugs, allowing for the selection of appropriate chemotherapeutic drugs and the avoidance of ineffective chemotherapeutic drugs, thereby improving patient survival. Since 1989, we have accumulated MTTA efficacy data from AGC patients. In this study, the present clinical roles of MTTA and the data from 202 patients with stage III or IV gastric cancer analyzed for survival outcome following surgery, with or without postoperative chemotherapy, evaluated by MTTA, are discussed. The patients were divided into 3 groups; an adapted group found to be sensitive to chemotherapy by MTTA, a non-adapted group found to be insensitive to chemotherapy by MTTA and a group that received no chemotherapy. For stage III gastric cancer patients, the adapted group had a statistically better survival rate compared to the other groups, while for stage IV patients, there was no difference in survival rate between any of the groups. However, further classification of stage IV patients as to the presence or absence of peritoneal dissemination (P) showed that the adapted group with P showed better prognoses than the other groups with P. The analysis of data collected since 2000 revealed that the 11 patients in the taxane-adapted group, who received chemotherapeutic regimens that included taxanes and were found to be sensitive to taxanes by MTTA, demonstrated better survival than the taxane non-adapted group (n=11) (p=0.045). In conclusion, MTTA results predicted patient prognoses, based on the selection of appropriate chemotherapy.

Preoperative combination chemotherapy with TS-1 is effective in a case gastric cancer with peritoneal dissemination

Nakamura Rieko, Saikawa Yoshiro, Kubota Tetsuro, Nakamura Tetsuya, Akatsu Yukako, Takahashi Tsunehiro, Yoshida Masashi, Otani Yoshihide, Kumai Koichiro, Kitajima Masaki

Gan to kagaku ryoho. Cancer & chemotherapy 32 ( 9 ) 1323 - 1326 2005.09

ISSN 0385-0684

We report a case of peritoneal cancer dissemination with Type 4 gastric cancer, successfully treated with combination chemotherapy with TS-1. The patient was a 59-year-old female, who complained of abdominal distension with pain, weight loss, and poor appetite. She was diagnosed as unresectable Type 4 gastric cancer, T3N2MOHOP1CY1M0, Stage IV with massive ascites (cytology: Class V). After 2 courses of combined chemotherapy with TS-1 and cisplatin (CDDP), primary tumor reduction was confirmed and no cancer cells were detected from a pathological investigation with biopsied specimens by endoscopy. As additional therapy for remained ascites, intraperitoneal administration of paclitaxel and docetaxel was performed, resulting in a remarkable decrease of ascites with cytological disappearance of cancer cells. The patients underwent total gastrectomy with lymph node dissection, pathological diagnosis of primary site and lymph nodes showed grade 2 effect, and no cancer cells were detected in ascites and peritoneum, microscopically. While she died of peritoneal recurrence after the surgery, the case suggested the clinical advantage of controlling the advanced cancer-bearing state by combination chemotherapy with TS-1, instead of surgery.

Is chemoradiation effective or harmful for stage VI gastric cancer patients?

Saikawa Yoshiro, Kubota Tetsuro, Takahashi Tsunehiro, Akatsu Yukako, Nakamura Rieko, Yoshida Masashi, Shigematsu Naoyuki, Otani Yoshihide, Kumai Koichiro, Hibi Toshifumi, Kitajima Masaki

Oncology Reports 13 ( 5 ) 865 - 870 2005.05

ISSN 1021-335X

We aim to clarify beneficial effect of pre-operative radiation with chemotherapy in highly advanced gastric cancer patients, evaluating histological response, toxicity and patients' quality of life (QOL). We used pre-operative radiation with S-1 and low-dose cisplatin to treat 8 patients with highly advanced gastric cancer (clinical stage IV) in a pilot study. Clinical staging after therapy showed 5 PRs (partial response), 2 NCs (no change), and 1 PD (partial disease) following evaluation of the primary tumor and suspicious metastatic lesions in the lymph nodes, esophagus, liver, and peritoneum, for a response rate of 62.5% (5/8 cases). Of 8 patients, 6 underwent surgery, and 2 of these 6 patients had a histologically complete response (grade 3 effect) and 3 patients had a partial response (grade 2 effect), suggesting that a high histological response (5/6 cases; 83.3%) is expected by the chemoradiation. The survival analysis showed that 5 out of the 8 patients died within 10 months after initiating therapy, while 3 patients are alive without recurrence at 15, 18, and 30 months after therapy, suggesting a relatively good outcome for clinical stage IV gastric cancer. All cases showed grade 2-4 bone marrow suppression toxicity and/or grade 0-2 gastrointestinal toxicity, while 5 out of 8 patients (62.5%) showed improvement in appetite loss at the end of the therapy, indicating that the patients' quality of life (QOL) was preserved. Chemoradiation may be a powerful regimen for obtaining histological response with tolerable toxicity and improved QOL in highly advanced gastric cancer patients.

　 Previous page - Next page 　