Takashi Irinoda

Evaluation of the ratio of lymph node metastasis as a prognostic factor in patients with gastric cancer

Background. Lymph node metastasis in patients with gastric cancer is one of the important prognostic factors. However, there is no consensus concerning the best classification for lymph node metastasis as a prognostic factor. So, to evaluate the ratio of the number of metastatic lymph nodes to the total number of dissected lymph nodes (the ratio of LN meta) as a prognostic factor, we compared the ratio of LN meta with lymph node status according to the Japan Classification of Gastric Carcinoma and the total number of metastatic lymph nodes with multivariate analysis. Methods. Between 1991 and 1997, a total of 360 patients with primary gastric cancer who underwent gastrectomy with D2 or more extended lymph node dissection were included in this study. Ten kinds of prognostic factors and three types of different classifications for lymph node metastasis were analyzed by multivariate analysis using the Cox regression. Results. The average number of dissected lymph nodes and metastatic lymph nodes were 55.0 (range, 11–184) and 2.6 (range, 0–86), respectively. There were significant differences of the 5-year cumulative survival rates among each group of the ratio of LN meta (0%, 1%–9%, 10%–24%, and more than 25%). Age, tumor size, curability, and the ratio of LN meta were selected as independent prognostic factors by forward stepwise selection. The ratio of LN meta showed the highest hazard ratio by Cox regression. Conclusion. The ratio of LN meta appears to be an important prognostic factor and the best classification factor for lymph node metastasis.

Quantitative Measurement of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase mRNA Level in Gastric Cancer by Real-time RT-PCR

We used real‐time reverse‐transcription polymerase chain reaction (RT‐PCR) to assay expression of the mRNA of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in gastric cancer tissue with the objective of establishing a system to measure TS and DPD in ultra‐low‐volume samples. Nude mouse xenografts of 5 human gastric cancer cell lines and 85 clinical samples were used as the specimens in this study. Sensitivity to 5‐fluorouracil (5‐FU) was determined on the basis of the relative tumor proliferation rate in mice and the results of ATP assay using serum‐free cultures of the clinical samples. mRNA expression was measured in tumor tissue by real‐tune RT‐ PCR using the ABI PRISM 7700 system. The values for expression of the mRNA for TS and DPD were corrected according to the level of glyceraldehyde‐3‐phosphate dehydrogenase mRNA expression. The xenografts yielded correlations between TS and DPD mRNA expression and the activity of the enzymes (TS: rs=0.700, DPD: rs=0.900), and an inverse correlation was noted between the mRNA levels and sensitivity to 5‐FU (TS: rs=‐0.900, DPD: rs=‐0.800). The clinical samples showed an inverse correlation between 5‐FU sensitivity and mRNA expression (TS: rs=‐0.518, DPD: rs=‐0.564). Sensitivity to 5‐FU was noted only in cases in which TS mRNA expression and DPD mRNA expression were both low. Real‐time RT‐PCR can provide a highly sensitive assessment of TS and DPD mRNA expression in gastric cancer, and it was useful for predicting 5‐FU sensitivity.

Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity

To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.

Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer

BackgroundThis study was designed to investigate the role of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in tumor progression and sensitivity to 5-fluorouracil (5-FU).MethodsA total of 275 tumor samples from 275 patients with gastric cancer were utilized in this study. TS activity was determined in 130 samples by 5-fluorodeoxyuridine monophosphate binding assay. DPD activity was measured in 140 samples by radioenzymatic assay, and TP protein level was determined in 157 samples by an enzyme-linked immunosorbent assay (ELISA) system. These parameters were compared with several clinicopathologic factors and sensitivity to 5-FU determined by in-vitro ATP assay. The antitumor activities of 5-FU, uracil plus tegafur (UFT), and 1 M tegafur — 0.4 M 5-chloro-2,4-dihydroxypyridine — 1 M potassium oxonate (S-1 [TS-1®]) were also compared, using three human gastric cancer xenografts in nude mice.ResultsThere was no correlation between either TS or TP and sensitivity to 5-FU. However, a weak inverse correlation was found between DPD activity and sensitivity to 5-FU. High DPD activity in tumor resulted in poor prognosis, especially in patients who received 5-FU-based adjuvant chemotherapy. Although TP was significantly correlated with depth of tumor invasion and with lymphatic and venous invasions, TP alone had no impact on survival. On the other hand, TS, as well as peritoneal, hepatic, and lymph node metastases, was selected as an independent prognostic factor in gastric cancer. In the animal model, there was no significant difference in antitumor activities among the drugs in a tumor with low DPD activity. However, S-1 showed superior antitumor activity to 5-FU or UFT in tumors with high DPD activity.ConclusionDPD is considered to be a most important predictive factor of 5-FU sensitivity. The use of DPD inhibitory fluoropyrimidines is strongly recommended for tumors with high DPD activity.

Pneumoperitoneum without Perforation of the Gastrointestinal Tract

Pneumoperitoneum (PP) is usually the result of perforation of the gastrointestinal (GI) tract with associated peritonitis. However, other rare causes, including spontaneous PP incidental to intrathoracic, intra-abdominal, gynecologic, and miscellaneous other origins not associated with a perforated GI tract have been described in the literature. Six cases of PP without any perforated GI tract are reported. Three patients with generalized peritonitis underwent exploratory laparotomy or laparoscopy when clinical examinations suggested an acute abdomen. At surgical procedure, perforated pyometra, perforated liver abscess and a ruptured necrotic lesion of a liver metastasis were documented in these patients, respectively. We also saw 3 PP patients not associated with peritonitis. Two patients with PP caused by pneumatosis cystoides intestinalis were encountered, 1 was managed conservatively and the other received diagnostic laparoscopy. A patient in whom pneumomediastinum and pneumoretroperitoneum were accompanied by PP caused by an alveolar rupture based on decreased pulmonary compliance due to malnutrition was managed conservatively. The history of the patient and knowledge of the less frequent causes of PP can possibly contribute towards refraining from exploratory laparotomy in the absence of peritonitis.

Perioperative monitoring of fluid responsiveness after esophageal surgery using stroke volume variation

Presented at:The 107th Annual Congress of Japan Surgical Society, Osaka International Convention Center, Japan, 11–13 April 2007. Objective: To assess the utility of a new arterial pressure-based cardiac output (FloTrac™) and central venous oximetry (PreSep™) monitoring system in the perioperative management of patients undergoing radical esophagectomy. Case series: From May 2006, a new analyzing device (Vigileo™ monitor; Edwards Lifesciences LLC, Tokyo, Japan), which can be used in combination with the FloTrac™ and PreSep™ sensors, has been used in nine patients who have undergone radical operations for thoracic esophageal cancer at our hospital. Stroke volume variation (SVV), calculated for each respiratory cycle and displayed on the Vigileo monitor, precisely predicted intravascular hypovolemia. The maximum SVV of patients who needed fluid resuscitation was significantly higher than that of patients who had a stable circulation. The mean value of the maximum SVV in the patient with or without fluid resuscitation was 25 ± 6.9 and 13 ± 1.4%, respectively (p < 0.04). In addition, continuous monitoring of central venous oxygen saturation enabled evaluation of oxygen supply to tissues to aid in determining the need for red blood cell transfusion. The Vigileo monitor (with Flo Trac and PreSep sensors) provided reliable information for the perioperative management of high-risk patients after highly invasive general surgery without the need for an invasive central or pulmonary catheter.

Microvessel count predicts metastasis and prognosis in patients with gastric cancer.

In order to evaluate the clinical relevance of angiogenesis in patients with gastric cancer, we investigated the microvessel count in gastric cancer tissues and compared the results with several clinicopathologic factors and prognosis.

Intussusception in Adults: A 21-Year Experience in the University-Affiliated Emergency Center and Indication for Nonoperative Reduction

Background: While intussusception is relatively common in children, it is rare in adults. Methods: We retrospectively reviewed the records of all patients older than 18 years with the diagnosis of intussusception between 1981 and 2001. Results: Eleven patients with surgically or endoscopically proven intussusception were encountered at the University-affiliated emergency center. The patients ranged in age from 19 to 88 years with a mean age of 45 years. Males predominated by a ratio of 7:4. Most patients (82%) presented with symptoms of bowel obstruction. The mean duration of symptoms was 4.5 days with a range of 4 h to 25 days. Correct pre-treatment diagnosis was made in 82% of the patients using abdominal ultrasonography and computed tomography (CT). The causes of intussusception were organic lesions in 64% of the patients, postoperative in 18% and idiopathic in 18%, respectively. 73% of patients had emergency operations, and an attempt at nonoperative reduction was performed and completed successfully in 3 patients with ileo-colic or colonic type of intussusception. There have been no cases of morbidity or mortality in our series and no recurrence has occurred up to the present time. Conclusions: Abdominal ultrasonography and CT were effective tools for the diagnosis of intussusception. Patients with ileo-colic and colonic intussusception without malignant lesions could be good candidates for nonoperative reduction prior to definitive surgery.

Pulmonary involvement in Crohn's disease report of a case and review of the literature.

Crohns disease (CD) is a granulomatous systemic disorder of unknown etiology. Obvious pulmonary involvement is exceptional in patients with CD. We report a case of a 38-year-old man who suffered from CD for more than 14 years and was treated with oral steroids for more than 10 years. Surgical excision of parts of the ileum was performed for life-threatening ileal bleeding caused by CD. After acute tapering of oral steroids, pulmonary symptoms and radiologic abnormalities were noted. Lung biopsy through thoracoscopy was performed and revealed signs of chronic inflammation with multiple subepithelial noncaseating and epithelioid granulomas on pathologic examination. Intravenous steroids were required in the initial management of life-threatening pulmonary dysfunction after diagnostic thoracoscopy and led to marked improvement. Tuberculocidal therapy was performed until all microbiological cultures were negative. Oral steroid dosage had slowly been tapered over 1 month. He was discharged with clinical and radiologic improvements. After 36 months, the patients condition is stable on continued treatment with prednisolone and mesalazine.

Laparoscopic paracecal hernia repair.

The diagnosis and treatment of internal abdominal hernia usually require laparotomy. We report a case of preoperative diagnosis and laparoscopic repair of paracecal hernia. A 90-year-old woman was referred with features of a well-established small bowel obstruction (SBO). Computed tomography and a small bowel contrast examination showed a paracecal hernia. With the patient under general anesthesia, laparoscopic surgery was carried out with the use of pneumoperitoneum, and an easy reduction of the incarcerated intestinal loop was achieved by gentle traction of the intestine. The bowel was assessed for viability and showed no evidence of nonviability. The abnormal orifice in the paracecal region was observed. The orifice was closed with 3-0 PDS II (polydiaxonone) sutures laparoscopically. A laparotomy was avoided, and the patient recovered without significant complications. We conclude that laparoscopy can play a useful role in the treatment of internal hernia causing SBO when an obstructive lesion has been detected and decompression accomplished preoperatively.