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Tomoharu Miyashita, Koichi Miwa,
Masafumi Inokuchi,
Hisatoshi Nakagawara,
Hidehiro Tajima,
Hiroyuki Takamura,
Itasu Ninomiya,
Hirohisa Kitagawa,
Sachio Fushida,
Takashi Fujimura,
Takanori Hattori,
Tetsuo Ohta
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ABSTRACT: Residual mucosa in the gastric stump after pylorus-preserving gastrectomy (PPG) is considered a risk factor for the development of gastric stump carcinoma (GSC). Duodenogastric reflux (DGR) and Helicobacter pylori (H. pylori) infection are suspected to contribute to the development of GSC. The aim of this study was to investigate the prevalence of H. pylori in the residual stomach after PPG for gastric cancer and to assess factors associated with the presence of H. pylori. We investigated 72 patients who had undergone PPG at least 1 year prior to the study and were confirmed to be positive for H. pylori infection on presurgical endoscopic biopsy. The extent of DGR, the prevalence of H. pylori infection based on H. pylori stool antigen (HpSA) tests and the severity of gastritis were analyzed in these post-PPG patients. None of the patients had DGR, as shown by 99mTc-PMT. Of the 72 post-PPG patients, 33 (46%) were positive for HpSA. The prevalence of H. pylori infection was significantly lower after surgery than before surgery. The endoscopic severity of remnant gastritis, as well as histological inflammation and activity, were higher in H. pylori-positive patients than in H. pylori-negative patients. In conclusion, some patients who undergo PPG and are negative for DGR experience spontaneous clearance of H. pylori infection.
Oncology Reports 05/2013; · 1.84 Impact Factor
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Tomoharu Miyashita,
Furhawn A Shah, Koichi Miwa,
Shozo Sasaki,
Koji Nishijima,
Katsunobu Oyama,
Itasu Ninomiya,
Sachio Fushida,
Takashi Fujimura,
Takanori Hattori,
John W Harmon,
Tetsuo Ohta
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ABSTRACT: The incidence of esophageal cancer continues to rise in the Western world. Prior studies have suggested that gastroduodenal content reflux from gastroesophageal reflux disease induces the inflammation-mediated progression from hyperplasia to metaplasia, and to adenocarcinoma. We further investigated the sequential development of esophageal adenocarcinoma (EADC) with the use of an established surgical rat model. The present paper will describe the impact of the inflammation-metaplasia-adenocarcinoma sequence and chemoprevention in surgical rat models. A clinically relevant rat reflux model was used to investigate the cause of carcinogenesis, the sequential development of adenocarcinoma and chemoprevention with the use of a proton pump inhibitor. We found that duodenal reflux plays an important role in the inflammation-induced transformation of esophageal mucosa to adenocarcinoma. We were able to inhibit this transformation with rabeprazole, a proton pump inhibitor. Duodenal reflux promotes inflammation in the esophagus. The inflammation-metaplasia-adenocarcinoma sequence is important in the progression and development of EADC. Carcinogenesis can be prevented with chemoprevention agents such as rabeprazole. These results will need to be validated in clinical trials.
Digestion 01/2013; 87(1):6-11. · 2.05 Impact Factor
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ABSTRACT: The mechanism through which each histological type of carcinoma arises from the esophageal mucosa remains unknown. This study was designed to investigate whether there is an association between the severity of duodeno-esophageal reflux and the histological type of esophageal cancer. A series of 120 male Fischer rats, weighing ∼180 g, were randomized to receive one of the following procedures: duodeno-forestomach reflux (DFR) with reduced exposure to duodenal contents, duodeno-esophageal reflux (DER) with increased exposure to duodenal contents and three control operations (DFR, DER control and sham). The reflux of bile was estimated with (99m) Tc-PMT scintigraphy. All animals were fed a standard diet without carcinogen. The esophageal mucosa was assessed 50 weeks after surgery for carcinoma. The median scanned fraction rate of duodeno-esophageal reflux was significantly lower for the rodents in the DFR group than those in the DER group. Five of 28 rodents in the DFR group and 17 of the 22 rodents in the DER group developed esophageal carcinoma. None of the controls developed carcinoma. The five rodents in the DFR group developed SCC. Of 22 esophageal carcinomas for the DER group, nine were SCC, 12 ADC and one was adenosquamous carcinoma. The fraction of esophageal SCC for the DFR group was significantly higher than that for the DER group, while the fraction of esophageal ADC for the DFR group was significantly lower than that for the DER group. These observations suggest that the severity of duodeno-esophageal reflux in rodents is related to the development of different histological types of esophageal carcinoma.
International Journal of Cancer 09/2012; · 5.44 Impact Factor
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Gan to kagaku ryoho. Cancer & chemotherapy 09/2012; 39(9):1345-9.
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ABSTRACT: BackgroundSentinel lymph node (SLN) biopsy is a promising method for the diagnosis of the axillary nodal status. We examined the availability
of the SLN biopsy using two mapping procedures: the dye- and gamma probe-guided method, and preoperative lymphoscintigraphy
by gamma camera imaging.
MethodsWe enrolled 48 patients with breast cancer. Technetium-99m-labeled human serum albumin was injected into the subdermal tissue
above the primary tumor or biopsy cavity, and preoperative gamma camera imaging was performed. After induction of general
anesthesia, patent blue dye was injected into the peritumoral area prior to the surgical procedure. A handheld gamma-detection
probe was used to assist in SLN detection. Careful dissection was performed to identify blue-stained afferent lymphatic vessels
and nodes. An SLN was defined as any blue and/or radioactive node, and was excised. After SLN biopsy, axillary lymph node
dissection of level I, II, and III was completed, in order to confirm the diagnostic ability of the SLN biopsy.
ResultsIntraoperative SLN identification of axillary lesions was successful in 43 of 48 patients (90%). The dye- and gamma probe-guided
method was successful in 25 patients (52%), the dye-guided method alone succeeded in 11 patients (23%), and the gamma probe-guided
method alone succeeded in 7 patients (15%). Preoperative lymphoscintigraphy revealed axillary focal accumulations in 29 of
48 patients (60%). All patients who underwent successful preoperative SLN identification by lymphoscintigraphy had successful
intraoperative SLN identification. A diagnostic accuracy of 95%, a sensitivity of 89%, and a specificity of 100% were achieved
in the diagnosis of axillary metastasis. Internal mammary SLNs were identified in four patients intraoperatively, but we could
not detect cancer metastasis in the internal mammary SLNs.
ConclusionsThe dye-guided and gamma probe-guided methods were complementary. Preoperative lymphoscintigraphy was useful to predict intraoperative
SLN identification. Further study is necessary to assess the role of SLN biopsy of the internal mammary lymph nodes.
Breast Cancer 04/2012; 7(1):87-94. · 1.36 Impact Factor
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Ryan A. Macke,
Katie S. Nason,
Ken-ichi Mukaisho,
Takanori Hattori,
Takashi Fujimura,
Shozo Sasaki,
Katsunobu Oyama,
Tomoharu Miyashita,
Tetsuo Ohta, Koichi Miwa,
Michael K. Gibson,
Ali Zaidi,
Usha Malhotra,
Ajlan Atasoy,
Tyler Foxwell,
Blair Jobe
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ABSTRACT: The following on Barrett's esophagus (BE) and animal models contains commentaries on the factors of BE carcinogenesis; a duodenoesophageal reflux model; translation of targeted therapies for esophageal adenocarcinoma; and novel target regimens selected through a proteomics screen.
Annals of the New York Academy of Sciences 09/2011; 1232(1):392 - 400. · 3.15 Impact Factor
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ABSTRACT: Segmental resection of the stomach was first described at the end of the 19th century by Mikulicz, who devised it to preserve the pylorus when performing gastric ulcer surgery. Although this technique was abandoned because of delayed gastric emptying, in 1967 Maki et al. developed a new improved concept of segmental gastrectomy: pylorus-preserving gastrectomy (PPG). The dramatic decrease in the occurrence of gastric ulcers limited the opportunity to perform these operations; however, PPG was then used for treating early gastric cancer, the incidence of which has increased remarkably over the last two decades. From the viewpoint of surgical oncology, a rationale to justify reducing the range of lymphadenectomy is required for preserving the curability. Therefore, we devised a new technique of transectional gastrectomy using sentinel node navigation for early gastric cancer located in the middle third of the stomach. The results of a questionnaire about postoperative symptoms and endoscopic assessment indicated the superiority of transectional gastrectomy over conventional distal gastrectomy. Future confirmation of the sentinel node concept through a multi-institutional validation study conducted by the Japanese Society of Sentinel Node Navigation Surgery would lead to widespread adoption of transectional gastrectomy.
Surgery Today 05/2010; 40(5):398-403. · 1.22 Impact Factor
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ABSTRACT: Duodenal reflux causes inflammation-related squamous cell carcinogenesis in the forestomach of rats without any carcinogens. The aim of this study was to investigate the efficacy of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, in preventing this carcinogenesis.
A series of 188 rats underwent a surgical duodenogastric reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing meloxicam (0.3 mg/kg body weight/day) (meloxicam group). The animals were sequentially sacrificed at Weeks 20, 30, 40, 50, and 60 after surgery. The forestomach was examined for the presence of carcinoma, the incidence of reflux-related morphological changes, COX-2 expression, and its activity.
At Week 60, squamous cell carcinoma developed in 8 of 21 animals (38%) in the control group, but none of 20 (0%) in the meloxicam group (P<.05). In addition, basal cell dysplasia developed in 19 of 21 (90%) animals in the control group, but only 4 of 20 (20%) in the meloxicam group (P<.01). COX-2 immunoreactivity was predominantly detected in macrophages in the epithelial stroma. Compared with nonsurgical rats, RNA expression of COX-2 in the epithelium was up-regulated, reaching peak at an early stage of Week 20 in both groups (P<.005). The expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE2 production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (P<.005).
Meloxicam was effective in preventing reflux-induced squamous cell carcinogenesis via an inflamed squamous epithelium.
Cancer 12/2008; 115(2):454-64. · 4.77 Impact Factor
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ABSTRACT: Lymphocytic mastopathy is a benign breast disease characterized by dense fibrosis, lobular atrophy, and aggregates of lymphocytes in a periductal and perivascular distribution. The condition affects young to middle-aged women and frequently shows an association with diabetes mellitus or autoimmune disorders. Here, we report a case of the disease clinically and radiologically mimicking primary breast neoplasms. The patient was a 50-year-old woman without diabetes who presented with two firm lumps in her right breast. Breast imaging findings from mammography, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI), respectively, revealed an abnormal appearance suspicious of malignancy. A core-needle biopsy specimen showed atypical accumulation of lymphoid cells, which was not easy to differentiate from primary breast lymphomas. Moreover, (18)fluorodeoxyglucose positron emission tomography (FDG-PET) examination detected abnormal uptake in the same lesions. Histological examination of a surgically obtained specimen showed characteristic appearance of lymphocytic mastopathy, which predominantly consisted of B-lymphocytes. In our case, it was difficult to distinguish this entity from breast cancer or low-grade B-cell lymphoma without surgical biopsy.
Breast Cancer 10/2008; 16(2):141-6. · 1.36 Impact Factor
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ABSTRACT: Duodenogastric reflux (DGR) causes glandular stomach carcinogenesis in rats without carcinogens. We aimed to investigate how this carcinogenesis might be prevented by a selective COX-2 inhibitor, meloxicam. A series of 188 Fisher 344 rats underwent a surgical DGR procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other an experimental chow containing meloxicam [0.3 mg/kg bw/day] (meloxicam group). The animals were sequentially sacrificed at weeks 20, 30, 40, 50 and 60 after surgery. The stomachs were removed and examined for the presence of carcinoma, incidence of reflux-induced morphologic changes, COX-2 expression and its activity. Adenocarcinoma in the glandular stomach developed in 7 of 21 animals (33%) in the control group at week 60, but none of 20 (0%) in the meloxicam group (p < 0.01). Moreover, reflux-induced gastritis was definitely alleviated in the meloxicam group compared with the control group. COX-2 immunoreactivity was predominantly detected in stromal cells such as macrophages and fibroblasts. Compared with nonsurgical rats, RNA expression of COX-2 in the mucosa increased, reaching peak at an early phase of week 20 in both groups (p < 0.005). Expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE(2) production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (p < 0.01). Gastric carcinogenesis via duodenal reflux was mediated by the COX-2 pathway in rats. Administration of meloxicam prevented this carcinogenesis by suppressing the inflammatory process.
International Journal of Cancer 10/2008; 123(7):1491-8. · 5.44 Impact Factor
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ABSTRACT: We studied the prognosis of 185 stage IV gastric cancer cases. The univariate analysis and multivariate analysis suggested that liver metastases (H) and peritoneal disseminations (P) were prognostic factors, the number of factors may be it, and lymph nodes metastases (N) and invasion to the other organs (T) were not it. Based on these findings, we proposed a subclassification of stage IV: IVa [T1-3N3-or T4N2] and IVb [the others]. The survival rates for IVa significantly exceeded those of IVb and did not differ from those of 25 stage IIIb gastric cancer cases.
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 04/2008; 105(3):361-6.
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ABSTRACT: A 69-year-old man complaining of enlarged cervical mass, appetite loss and lower abdominal pain was found to have abdominal tumors in heaps forming a large mass around the retroperitoneum. The biopsy specimen in the cervical mass showed undifferentiated carcinoma with neuroendocrine feature. This malignancy followed a poorly aggressive course and caused death in only 24 hospital days. The disease was diagnosed as undifferentiated neuroblastoma arising in the retroperitoneum by autopsy with appropriate immunohistochemical studies. Adult neuroblastoma in the peritoneum is rare and our case showed a aggressive behavior and unfortunate outcome.
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 01/2008; 104(12):1745-51.
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ABSTRACT: Duodenogastroesophageal reflux causes esophageal adenocarcinoma in rats without the use of a carcinogen. This etiology is unclear, but may be associated with endogenous nitrosation in the gastrointestinal tract. Thioproline (TPRO) is an effective nitrite-trapping agent and blocks endogenous nitrosation. We investigated how ingested TPRO affected esophageal adenocarcinogenesis in rats with duodenogastroesophageal reflux (DGER) or gastroesophageal reflux (GER). A series of 200 male Fischer 344 rats received surgery to induce reflux of duodenogastric contents or gastric contents alone into the esophagus. The rats were separated into two divisions according to the surgical procedure employed (DGER or GER), and each division was further subdivided into two groups: one group was fed a special diet (CRF-1 containing 0.5% of TPRO); the other group was fed a standard diet (CRF-1). The rats were given no carcinogen and sacrificed at ten-week intervals from the 25th to the 45th week after surgery. Pathological examination was carried out using hematoxylin-eosin or immunohistochemical staining. Erosion, regenerative thickening, basal cell hyperplasia and columnar-lined epithelium (CLE) were found in both groups of the DGER rats. Adenocarcinoma (AC) appeared only in the DGER rats sacrificed at 35 and 45 weeks following surgery. The incidence of AC at the 45th week was significantly lower in the group of rats fed the diet containing TPRO, as compared to those fed the standard diet, whereas the incidences of CLE were the same for both groups. iNOS protein and nitrotyrosine protein were identified in the CLE and macrophages of the DGER group using immunohistochemical staining. There were no remarkable pathological changes in the esophagi of the rats which underwent the GER procedure. In conclustion, TPRO has an inhibitory effect on esophageal reflux-induced adenocarcinogenesis in rats in that it prevents the progression from CLE to AC.
Oncology Reports 01/2008; 18(6):1443-9. · 1.84 Impact Factor
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Takeo KOSAKA,
Hisashi MATSUMOTO,
Tetsuya ISHIDA,
Shigeru TAKEGAWA,
Shigekazu OOYAMA,
Toru KAMATA,
Masahiro KANNO,
Akio YAMAGUCHI,
Yutaka YONEMURA, Koichi MIWA,
Itsuo MIYAZAKI,
Toru II
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ABSTRACT: We compared values of the DNA Index (DI) and bromodeoxyuridine (BrdUrd) labeling index (BULI) of biopsy specimens with those of resected specimens from 12 patients with colorectal cancer, to evaluate the cell cycle by flow cytometry (FCM). From each patient, 4 biopsy specimens were endoscopically removed. Also, small pieces of tissue, 0.5 cm in diameter, were taken from 4 different sites of the resected tumor. Both kinds of specimens were labeled in vitro with BrdUrd. Their DI and BULI values were evaluated from the DNA/BrdUrd bivariate scatter diagram by FCM. It was found that the coefficients of variation (CVs) for endoscopic biopsy specimens were siginificantly lower than those for resected specimens, 4.2 ± 1.3 (Mean ± S. D.) and 5.4 ± 1. 7, respectively. In 8 cases without intratumoral DI heterogeneity, there was a good correlation in the values of DI between the biopsy and resected specimens (r = 0.99, p < 0.01). A significant correlation was also found in the BULI values between the two types of specimens (r = 0.73, p < 0.01). These results suggested that 4 biopsy specimens were enough to estimate DI and BULI by FCM and that DI and BULI values determined by flow cytometry could be useful for decision-making about the therapeutic modality for preoperative patients.
Digestive Endoscopy 08/2007; 2(3):317 - 322. · 1.19 Impact Factor
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ABSTRACT: A 49-year-old woman with a complaint of severe abdominal pain and lumbargo was diagnosed with pancreatic cancer invading the superior mesenteric artery and vein. Since the lesion was unresectable by general Whipple's procedure, she was treated with gemcitabine and opiate. However, these treatments resulted in failure due to the side effects such as bone marrow suppression, severe nausea, and constipation. After the bone marrow suppression disappeared, she received augmented regional pancreatoduodenectomy, which is a pylorus preserving pancreatoduodenectomy with resection of the superior mesenteric artery and vein. Consequently, she could have a good QOL without opiates.
Gan to kagaku ryoho. Cancer & chemotherapy 12/2006; 33(12):1762-4.
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ABSTRACT: In this randomized multicenter Phase III study, patients with curatively resected Stage II/IIIA gastric cancer were assigned to postoperative adjuvant therapy with an oral fluoropyrimidine S-1 alone (2 weeks of treatment and 1 week of rest for 6 months, followed by 2 weeks of treatment and 2 weeks of rest for 6 months) or S-1 combined with an oral biological response modifier PSK (the same regimen of S-1 plus daily PSK for 12 months). The main objective was to evaluate the survival benefit and quality of life (QOL) of combined therapy. The primary end points were the time to relapse and the duration of survival after surgery, i.e. the rates of disease-free survival and overall survival at 3 and 5 years. The secondary end points were the relations of survival rates to drug compliance, QOL, adverse events, postoperative complications, relapse status, and the preoperative expression of immune or tumor markers. The sample size was 140 per treatment arm.
Japanese Journal of Clinical Oncology 09/2006; 36(8):519-22. · 1.78 Impact Factor
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ABSTRACT: the present study was performed to examine the sequential process of the development of Barrett's oesophagus (BE) and oesophageal adenocarcinoma (ADC) induced by duodeno-oesophageal reflux (DER) in rats. Total gastrectomy was performed in male Wistar rats weighing approximately 250 g followed by reconstruction with oesophago-jejunostomy, which causes unavoidable DER without exposure to exogenous carcinogens. Animals were selected at random and sacrificed every 10 weeks after surgery until 50 weeks. Severe squamous oesophagitis with erosion, regenerative thickening (RT), and basal cell hyperplasia (BCH) were observed on the 10th week after surgery. On the 20th week, glandular structures that stained positively with Galactose oxidase-Schiff (foveolar metaplasia) were observed in the basal layer of the oesophageal squamous epithelium. On the 30th week, the glands developed and formed cysts that stained positively with concanavalin A (pyloric glandular metaplasia) and/or high-iron diamine and Alcian blue (intestinal metaplasia). From the 40th week after surgery, ADC cells surrounded by columnar-lined epithelium were found. Persistent stimulation with DER can alter the stem cells in the squamous epithelial basal layer leading to the formation of columnar-lined cells and subsequent ADC. Foveolar metaplasia was observed as part of the sequence of events leading to the development of columnar-lined epithelium (CLE), followed by the appearance of pyloric glandular metaplasia and intestinal metaplasia, completing the histogenesis of BE.
Oncology Reports 07/2006; 15(6):1469-75. · 1.84 Impact Factor
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ABSTRACT: Forty seven patients with early gastric cancer received a 30-minute intravenous injection of bromodeoxyuridine (BrdU), 1000 mg each 1 hour before laparotomy, to label tumor cells in the S phase. In 13 of 47 patients, specimens obtained by endoscopic biopsy were cultured in vitro at 37°C for 1 hour under three times the atmospheric pressure in a vial with 400 μM BrdU. Labeled cells were detected in the resected specimen and the cultured specimen by immunohistochemical staining procedure. The BrdU labeling index (LI, defined as the percentage of labeled cells in relation to the 1000 tumor cells) was calculated for each specimen. All patients without lymph node metastasis had an in vivo BrdU LI of less than 12%. In contrast, 31% of patients with early gastric cancer with an in vivo BrdU LI greater than 12% had lymph node metastasis. There was a correlation between the in vivo and the in vitro LI. Therefore, the in vitro BrdU LI of specimens obtained by endoscopic biopsy may be a useful indicator of lymph node status in patients with individual early gastric cancers before operations. If the in vitro BrdU LI is less than 12%, lymph node dissection may not be necessary.
Cancer 06/2006; 64(8):1665 - 1668. · 4.77 Impact Factor
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ABSTRACT: Analysis of DNA ploidy patterns was performed on 129 cases of primary gastric cancer and the results were correlated with histologic findings and in vivo bromodeoxyuridine (BrdU) labeling. Forty-nine cases were diploid (38%) and 80 cases were aneuploid (62%). There was no correlation between DNA ploidy and histologic type. In aneuploid tumors, incidence of lymphatic invasion, lymph node metastasis, and rate of advanced cases were significantly higher than those in diploid tumors. During the follow-up period of 5 to 10 years, 23 of 40 patients (55%) with aneuploid tumors died of disease within 3 to 120 months. Only 13 of 36 patients (36%) with diploid tumors died of disease. The BrdU labeling indices (BrdU LI) ranged from 2.8% to 26.7%, with a mean of 10.4%. There was no correlation between BrdU LI and histologic type or stage. The mean BrdU LI of early cancers was 8.1%. The mean BrdU LI of advanced cancers was 11.9%. The BrdU LI of cancers with lymphatic invasion or lymph node metastasis was higher than those without them. The mean BrdU LI of diploid cancers was 6.0%. The mean BrdU LI of aneuploid cancers was 11.9%. There was a good correlation between BrdU LI and DNA ploidy patterns. These results indicate that DNA ploidy patterns and BrdU LI may possibly be useful prognostic markers for gastric cancers.
Cancer 06/2006; 62(8):1497 - 1502. · 4.77 Impact Factor
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ABSTRACT: Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were developed as one of the anti-inflammatory drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However,coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP),which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum,and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors.
World Journal of Gastroenterology 04/2006; 12(9):1336-45. · 2.47 Impact Factor
