Discovery of ONO-8590580: A novel, potent and selective GABAA α5 negative allosteric modulator for the treatment of cognitive disorders.

The identification and SAR development of a series of negative allosteric modulators of the GABAA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABAA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.

Laparoscopic gastrectomy for gastric cancer: experience with more than 600 cases.

BACKGROUND: Among the less invasive operations noted in recent years, laparoscopic gastrectomy for gastric cancer has become popular because of advances in surgical techniques. The authors performed laparoscopic gastrectomy with regional lymph node dissection for 612 cases of gastric malignancies between March 1998 and August 2006. The technique and results of laparoscopic gastrectomy for gastric cancer are presented. METHODS: Of the 612 gastric malignancy cases, distal gastrectomy was performed in 485 cases, proximal gastrectomy in 42 cases, and total gastrectomy in 85 cases. In all the cases, D1 or D2 lymph node dissection was performed according to the general rule of the Japanese Gastric Cancer Association. RESULTS: Quicker recovery was observed in the laparoscopic gastrectomy cases than in the open cases. The postoperative complications with this technique were within a permissible range. No statistical difference was seen in the survival curve after surgery between the laparoscopic group of advanced cases preoperatively diagnosed as surgical T2N1 or lower and the open group. CONCLUSION: The laparoscopic technique is not only less invasive, but also similarly safe and curative compared with open gastrectomy.

Triangulating stapling technique for reconstruction after colectomy.

BACKGROUND/AIMS: To retrospectively compare the triangulating stapling technique for colocolonic anastomosis with hand-sewn anastomosis and functional end-to-end anastomosis. METHODOLOGY: Data from 646 patients who underwent colectomy for cancer from 1993 to 2004 were extracted by chart review. Patients were divided into three groups based on the type of anastomosis: handsewn (n=233), functional end-to-end (n=71), and the triangulating stapling method (n=346). Demographic data and clinical characteristics of the three groups were similar. RESULTS: Anastomotic leakage was significantly more common in the hand-sewn group than the triangular stapling group (hand-sewn; 3.0%, functional end-to-end; 2.8%, triangulating, 0.6%) (P < 0.05). No patient developed bleeding or stenosis at the anastomosis, and the incidence of wound infection was equivalent among the three groups. One death due to anastomotic failure occurred in each of the functional end-to-end and triangulating stapling groups. The cost of triangulating stapling was approximately Yen 36,000 lower than the cost of the functional end-to-end anastomosis. CONCLUSIONS: The triangulating stapling technique is an attractive alternative to other methods for creating a colocolonic anastomosis.

Detection of p53 gene mutations in human esophageal squamous cell carcinomas using a p53 yeast functional assay: possible difference in esophageal carcinogenesis between the young and the elderly group.

A p53 yeast functional assay, which cannot only detect p53 gene mutations but also can assess p53 gene function, was used to screen for p53 gene dysfunction in human esophageal squamous cell carcinomas. Surgically resected frozen tissues of esophageal squamous cell carcinomas from 57 patients were examined for p53 gene mutation. Because the mean age of the patients diagnosed with esophageal squamous cell carcinoma was 64 years, we classified those who were <65 years of age as the Young Group and classified the others as the Elderly Group. The incidence of p53 gene mutations was 43 of 57 (75%). The incidence of p53 gene mutations observed in the Young Group was significantly higher than in the Elderly Group (P = 0.0007). Alcohol and smoking status did not relate to p53 gene mutation expression. Survival rate after surgery was not significantly associated with the presence of p53 gene mutation. However, in the Young Group with p53 gene mutation, those who had null mutations had a significantly shorter survival than those without null mutations (P = 0.0455). No other clinicopathological factors were associated with p53 gene mutations. Possibly, there may be a difference in esophageal carcinogenesis between the Young and the Elderly groups, because the incidence of p53 gene mutations is different between the two groups. In the Young Group, p53 gene mutation may cause esophageal carcinogenesis, and null mutation for p53 gene is a significant prognostic factor.

Laparoscopic distal gastrectomy with regional lymph node dissection for gastric cancer.

BACKGROUND: Recent advances in surgical techniques have led to widespread acceptance of laparoscopic gastrectomy for gastric cancer. We performed distal gastrectomy with regional lymph node dissection in 235 patients with gastric cancer located in the middle and lower third of the stomach. METHODS: In 171 cases, reconstruction was done using the Billroth I method intracorporeally and the aid of laparoscopic linear stapling devices. The Billroth II and Roux-en-Y methods were used in the remaining 56 and eight patients, respectively, RESULTS: Patients who underwent laparoscopic distal gastrectomy had a more rapid postoperative recovery than those treated via the open approach. Postoperative complications with this technique were within a permissible range. In terms of the survival curve, there was no statistical difference between the laparoscopic group diagnosed as clinical T2N0 (c T2N0) Preoperatively and the open group. CONCLUSION: The laparoscopic technique is not only less invasive, but is also similarly safe and curative compared to open gastrectomy.

Effect of adrenoceptor agonists on striated muscle strips of the canine oesophagus.

1. Acute psychological stress, which could be related to the release of a large amount of catecholamines, may cause oesophageal motility disorders. Therefore, the aim of our study was to elucidate the influence of adrenoceptor agonists on the striated muscle portion of the oesophagus by use of isolated strips from dogs. 2. Contractions were evoked in isolated striated muscle strips by electrical field stimulation (1 pulse min-1, 1 ms/pulse, submaximal voltage). The effects induced by administration of adrenoceptor agonists alone or in the presence of antagonists were tested to determine the nature of the adrenoceptors on this muscle preparation. 3. The administration of both the natural adrenoceptor agonists, adrenaline and noradrenaline, and the synthetic beta-adrenoceptor agonists, isoprenaline (beta 1 + beta 2), dobutamine (beta 1) or ritodrine (beta 2), enhanced the amplitude of the contractions induced by electrical stimulation in a concentration-dependent manner. The maximum responses were 82.6 (adrenaline), 66.2 (noradrenaline), 86.2 (isoprenaline), 34.6 (dobutamine) and 80.8% (ritodrine). The EC20 values obtained were respectively 2 nM, 0.2 microM, 0.91 nM, 3 microM and 80 nM. The administration of the alpha 1-adrenoceptor agonist, phenylephrine, also enhanced the contractile response in a concentration-dependent manner (EC20 value = 0.3 microM) and the maximum response was 64.6%, but the administration of the alpha 2-adrenoceptor agonist, clonidine, did not influence the contractile response. These data suggest the involvement of beta 2- and possibly alpha 1-adrenoceptors in the responses of these adrenoceptor agonists. 4 The selective P2-adrenoceptor antagonist ICI 118551 (3-100nM) shifted the concentration-effect curves for noradrenaline, phenylephrine and ritodrine to the right in a concentration-dependent manner.ICI 118551 (3 nM) also shifted the concentration-effect curves for adrenaline and isoprenaline to the right, but increasing the concentration of ICI 118551 did not cause any further antagonist activity until a concentration of 100 nM, when a further rightward shift was obtained.5. The selective alpha 1-adrenoceptor antagonist, prazosin (30-300 nM), did not affect the increased contractile responses induced by adrenaline, noradrenaline, phenylephrine, isoprenaline or ritodrine.6. In conclusion, it appears that beta2-adrenoceptors are present in the striated muscle portion of the canine oesophagus, where they mediate an enhancement of contractile responses evoked by electrical stimulation. The alpha l-agonist, phenylephrine, appears to interact with beta2-adrenoceptors on this preparation.beta 3-Adrenoceptors have already been demonstrated in smooth muscle from various parts of the gastrointestinal tract, and our study does not exclude the possibility that there is an additional population of beta 3-receptors in the canine striated muscle part of the oesophagus.

Expression of immunoreactive human hepatocyte growth factor in human esophageal squamous cell carcinomas.

Hepatocyte growth factor (HGF) is a potent mitogen for epithelial cells that promotes cell motility and invasiveness. In this study, we report that the human esophageal squamous cell carcinoma (SCC) shows a significant elevation of HGF concentration (600 +/- 416 ng/100 mg protein), compared to normal mucosa (80 +/- 183 ng/100 mg protein) (P < 0.01). An association could be established between levels of HGF and decreasing differentiation of 37 SCCs. The 2-year crude survival rates were 51.1% and 68.4% at high and low HGF concentrations, respectively. The results indicate that HGF is significantly increased in human esophageal SCCs, especially of poorly differentiated type. HGF might thus be useful as a biological biomarker for characterization of human esophageal SCCs.

Trizygotic pregnancy consisting of two fetuses and a complete hydatidiform mole with dispermic androgenesis.

A triplet pregnancy in a 23-year-old woman was terminated at 15 weeks of gestation because of her severe hypertension, lung edema, and secondary hyperthyroidism. The pregnancy consisted of a hydatidiform mole with a 46,XY karyotype and two fetuses each with 46,XX and a 46,XY karyotype. To determine the zygosity and genetic origin of the mole and fetuses, PCR- and computer-assisted genotyping were performed at 27 CA-repeat marker loci that were distributed evenly over the genome. As a result, genotypes of the three pregnancy products were distinct from each other, indicating that the triplets were trizygotic. The mole lacked any maternal alleles but inherited both of the paternal alleles and/or one paternal allele in duplicate. This, along with the XY sex chromosome constitution, indicated that the mole resulted from dispermic androgenesis. The mother developed a persistent trophoblastic tumor thereafter.

Laparoscopic distal gastrectomy with regional lymph node dissection for gastric cancer.

Recently, a minimally invasive operation for gastric malignancies has been advocated, and the laparoscopic operation is noted as a technique that increases the quality of life. We performed distal gastrectomy with regional lymph node dissection on 160 cases of gastric cancer located in the middle or lower third of the stomach. In 123 cases, Billroth I reconstruction was performed intracorporeally using the quadrilateral (square) stapling technique with a laparoscopic linear stapling device to prevent postoperative anastomotic bleeding and stenosis. In the remaining 37 cases, the Billroth II method was performed with a linear stapling device [1]. This technique is not only less invasive but also as safe as open gastrectomy, which was performed on 100 gastric cancer cases of similar staging.

Comparison of three-field esophagectomy for esophageal cancer incorporating open or thoracoscopic thoracotomy.

BACKGROUND: Thoracoscopic esophagectomy for esophageal cancer has been performed as an alternative to open surgery to reduce surgical trauma. However, its effect on pulmonary function, exercise tolerability, and quality of life is unknown. METHODS: Fifty-one patients with esophageal cancer underwent thoracic esophagectomy with radical lymphadenectomy by posterolateral thoracotomy (29 cases) or thoracoscopic surgery (22 cases). Patients performed spirometry and exercise tolerance testing and completed a quality-of-life questionnaire before and 3 months after surgery. RESULTS: Pre-to-postoperative change in vital capacity was 74.3 +/- 10.6% in the thoracotomy group and 84.9 +/- 10.4% in the thoracoscopy group (p = 0.021). Maximum oxygen uptake was similar, but dyspnea was the more common factor limiting exercise tolerance postoperatively in the thoracotomy group. Change in pre-to-postoperative performance status was 1.20 +/- 0.62 in the thoracotomy group and 0.55 +/- 0.51 in the thoracoscopy group (p = 0.0003). CONCLUSIONS: Thoracoscopic esophagectomy for esophageal cancer has better preservation of pulmonary function and quality-of-life.

Learning curve of video-assisted thoracoscopic esophagectomy and extensive lymphadenectomy for squamous cell cancer of the thoracic esophagus and results.

BACKGROUND: The efficacy of thoracoscopic radical esophagectomy for cancer of the thoracic esophagus and the learning curve required have yet to be clearly established. METHODS: Eighty treatment-naive patients with esophageal cancer without contiguous spread underwent esophageal mobilization and extensive mediastinal lymphadenectomy through a 5-cm minithoracotomy and four trocar ports. The outcomes in the first 34 patients (group 1) and the last 46 patients (group 2) were compared. RESULTS: There were no differences in background or clinicopathologic factors between the two groups. The duration of the thoracoscopic procedure and blood loss were less (p <0.0001), the incidence of postoperative pulmonary infection was less (p = 0.0127), and the number of mediastinal nodes retrieved was greater (p = 0.0076) in group 2. Multivariate analysis demonstrated that surgical experience (number of cases performed) predicted the risk of pulmonary infection (p = 0.0331). CONCLUSION: Video-assisted thoracoscopic radical esophagectomy can be performed with safety and efficacy comparable to those of open esophagectomy. Morbidity decreases with the surgeon's experience.

Usefulness of self-expandable metallic stent with an antireflux mechanism as a palliation for malignant strictures at the gastroesophageal junction.

BACKGROUND: Patients with unresectable malignant gastroesophageal strictures often are troubled with reflux esophagitis after stent placement. METHODS: A self-expandable metallic stent (SEMS) without an antireflux mechanism was placed in seven patients with unresectable malignant gastroesophageal strictures (group A), and SEMS with an antireflux mechanism was placed in five patients (group B). After we obtained monitoring systems, two patients in group A and all the patients in group B underwent measurement of bilirubin and pH in the esophagus using a 24-h bilirubin and pH monitor. RESULTS: The mean percentage of total time less than 0.14 for use of the bilirubin absorbance unit was 12.4% in group B and 64.0% in group A. The mean percentage of total time for a pH less than 4 was 2.9% in group B and 37.8% in group A. CONCLUSION: The placement of SEMS with the antireflux mechanism can be effective not only for palliation of gastroesophageal stricture, but also for prevention of reflux.

Video-assisted thoracoscopic esophagectomy and radical lymph node dissection for esophageal cancer. A series of 75 cases.

BACKGROUND: The efficacy of thoracoscopic radical esophagectomy for cancer has yet to be established, mainly because previous reports have not included a sufficient number of cases. METHODS: Seventy-five treatment-naive patients with esophageal cancer without contiguous spread underwent esophageal mobilization and extensive mediastinal lymphadenectomy through a 5-cm mini-thoracotomy and four trocar ports. RESULTS: Video-assisted thoracoscopic surgery was performed without major intraoperative complications or emergency conversion to open surgery. We retrieved 34.1+/-13.0 mediastinal nodes, including 11.5+/-3.8 tracheobronchial nodes and 6.2+/-3.0 recurrent laryngeal nodes. Mean time of operation and blood loss were less in the last 39 patients than the first 36 (186.7+/-25.3 min and 165.4+/-101.8 g vs 270. 2+/-96.0 min and 421.5+/-31.2 g, respectively: p <0.0001 and p <0.001). Pulmonary morbidity was 5% in the later 39 patients. Survival was 90%, 80%, and 57% at 1, 2, and 5 years after surgery. CONCLUSION: Thoracoscopic radical esophagectomy has less morbidity and comparable survival to conventional surgery, after a moderate amount of experience. Mini-thoracotomy is essential to perform the procedure safely and effectively.

Superficial undifferentiated small cell carcinoma of the esophagus showing an interesting growing pattern in histology.

We report a case of superficial undifferentiated small cell carcinoma of the esophagus. The histology of the tumor was interesting; there was squamous cell differentiation within the epithelial layer and undifferentiated small cells growing within the submucosal layer. The tumor had a negative Grimelius reaction, suggesting no differentiation into a hormone-producing carcinoma known as an apudoma (Amine Precursor Uptake and Decarboxylation (APUD)). The serum levels of ACTH and calcitonin were within normal limits. As the patient was elderly and had a history of pleural tuberculosis causing poor pulmonary function, and owing to the fulminant nature of this carcinoma, he underwent blunt dissection of the esophagus by posterior mediastinal gastric pull-up. The patient recovered quickly and was able to be discharged with a good quality of life until the tumor recurred as a liver metastasis 6 months later.

Laparoscopy-assisted resection for jejunal carcinoma.

Laparoscopic surgery has been applied in small bowel resections for various diseases, such as obstruction including intussusception, diverticula, and tumors. We report a case of successful resection of a jejunal carcinoma that was diagnosed before surgery by using a laparoscopy-assisted technique.

Hand-assisted laparoscopic distal gastrectomy with regional lymph node dissection for gastric cancer.

Recently, a minimally invasive operation for gastric malignancies has been advocated, and the laparoscopic operation is noted as a technique that raises the quality of life. We performed distal gastrectomy with regional lymph node dissection by hand-assisted laparoscopic surgery for 60 cases of gastric cancer located in the middle or lower third of the stomach. Billroth I reconstruction was applied intracorporeally to the first 30 cases by using the double stapling method with a conventional circular stapling device, and in the final 30 cases, the quadrilateral (square) stapling technique with a laparoscopic linear stapling device was used to prevent postoperative anastomotic bleeding. This technique not only is less invasive, but also is similarly curative compared with open gastrectomy that was performed for 60 gastric cancer cases of similar staging before the beginning of this procedure.

Thoracic esophageal cancer recurred later than 2 years after esophagectomy with extended lymphadenectomy.

PURPOSE: Although the majority of recurrence was found in 2 years after esophagectomy, esophageal cancer could recur lately. To find efficient follow up, the patients were compared by periods of recurrence detected. SUBJECTS AND METHODS: Esophagectomized 227 patients were subjected. Median follow up period was 1289 days. The disease recurred in 84 patients (Group A) in 2 years after surgery and in 17 (Group B) lately. Clinicopathological factors were compared between these 2 groups. RESULTS: There was no difference in background and clinicopathological factors, except Group A was at significantly advanced stage than B. The most common pattern of recurrence was hematogeneous in Group A, whereas lymphatic in Group B, which was significantly different. In Group B, survival rate of patients detected by lymphatic recurrence, which responded to radiation, was higher than that detected by hematogeneous one. CONCLUSION: To prolong survival, the patients should be carefully followed up later than 2 years after surgery with regard for lymphatic recurrence.

Esophageal cancer complicated by acute myelofibrosis--report of an autopsy case.

An autopsy case of esophageal cancer complicated by myelofibrosis was studied. A 62-year-old Japanese patient with esophageal cancer, received surgical treatment and then splenectomy. The resected spleen was normal in appearance. Five months later he received radiation therapy for the cancer. After the therapy, his blood profile revealed thrombocytopenia and leukoerythroblastosis, and the bone marrow punctures were dry tap. He died of disseminated fungal infections at eleven months after the first operation. An autopsy of the patient revealed a striking increase in the megakaryocytes and a moderate increase in the reticulin fibers in the bone marrow. Myeloid metaplasia was noted in the lymph nodes, kidneys, and other organs and tissues, although the lymph nodes were not grossly swollen. These findings suggest esophageal cancer complicated by acute myelofibrosis. This it the first case report on esophageal cancer complicated by acute myelofibrosis.