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.

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

BACKGROUND: The technique and results of laparoscopic gastrectomy in 110 patients with gastric cancer located in the upper third of the stomach are presented. METHODS: Proximal gastrectomy was performed for lesions in the upper third of the stomach, and total gastrectomy for those that spread over both the upper and middle third. D1 and D2 lymph node dissection was undertaken in patients with T1 or T2 lesions. Anastomosis of the oesophagus was performed intracorporeally using a conventional circular stapling device or a laparoscopic linear stapler. RESULTS: Median operating time was 247 min for proximal gastrectomy and 285 min for total gastrectomy; median blood loss was 207 and 334 ml respectively. A median of 23 lymph nodes was harvested from patients in the proximal gastrectomy group and 34 from those having a total gastrectomy. There was minimal morbidity and fast recovery after surgery. Postoperative recurrence occurred in only one patient, giving a recurrence rate of 0.9 per cent. CONCLUSION: Laparoscopic gastrectomy for upper gastric cancer appears to be a safe and curative procedure.

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.

A novel laparoscopic technique for stapled colon and rectal anastomosis.

BACKGROUND: We present new techniques of stapling anastomosis at laparoscopic colorectal surgery with retrospective review of data. METHODS: A triangulating stapling technique (T method) was performed in 101 laparoscopic colectomies. Adouble stapling technique (DST) with rectal division by a conventional linear stapler (Abd method) was used in 5 cases of upper/middle rectal cancers and subsequent eversion of the distal rectum from the anus (Ev method) was used for 4 low rectal cancers. Four hundred ninety-six colectomies and 280 rectal surgeries were reviewed. RESULTS: Leakage was lower in the T group (0.5%, n=196) than in the hand-sewn group (3.0%, n=233). Leakage of the DST using a laparoscopic linear stapler (12.1%, n=91) was significantly higher than with conventional DST (2.1%, n=189). There was no leakage with either Abd method or Ev method. The T-method is acceptable after laparoscopic colectomy. CONCLUSION: New methods of rectal division using conventional devices are expected to yield reliable anastomosis at laparoscopic rectal surgery.

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.

Immunologic effects of allogeneic versus autologous blood transfusion in patients undergoing radical oesophagectomy.

Blood transfusion is often required in patients undergoing radical oesophagectomy, and is associated with immunosuppression that may worsen postoperative and long-term outcomes. However, the immunologic effects of allogeneic versus autologous transfusion have not been studied in this group of patients. We analyzed 103 patients who underwent radical oesophagectomy for oesophageal cancer, including 45 patients who received allogeneic transfusions (Allo), 16 patients who donated autologous blood but were not transfused (Auto-1) and 42 patients who received autologous transfusions (Auto-2). Peripheral blood lymphocyte subsets and natural killer (NK) cell activity were analyzed for 2 weeks postoperatively. Furthermore, the rate of infectious complications such as pneumonia and wound infection was compared. Patients receiving blood transfusion had decreased CD4+ lymphocyte counts and NK cell activity postoperatively, compared to Auto-1 patients. However, these abnormalities were corrected by day 14 in the Auto-2 group, but not in the Allo group. CD8+ lymphocyte counts were decreased in all groups postoperatively, returning to normal by 14 days in the Auto-1 group only. The rate of infectious complications was significantly higher in the Allo than in the Auto group. Blood transfusion is associated with adverse immunologic effects in patients undergoing radical oesophagectomy. However, autologous blood transfusion is favourable compared to allogeneic transfusion. Autologous transfusion programs should be employed when possible in this group of patients.

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.

A comparison of video-assisted thoracoscopic oesophagectomy and radical lymph node dissection for squamous cell cancer of the oesophagus with open operation.

BACKGROUND: A direct comparison of open operation and video-assisted thoracoscopic surgery (VATS) for radical oesophagectomy has yet to be published. METHODS: Medical records of 149 patients with oesophageal squamous cell carcinoma who underwent oesophagectomy and three-field lymphadenectomy were reviewed. Seventy-seven patients had the thoracic procedure performed via a 5-cm minithoracotomy and four ports (VATS group); the others were operated on by conventional posterolateral thoracotomy (open group). RESULTS: The mean number of retrieved mediastinal nodes, blood loss and morbidity were similar in the VATS and open groups (33.9 versus 32.8 nodes, 284 versus 310 g, and 32 versus 38 per cent respectively). The thoracic procedure took longer in patients having VATS than in the control group (227 versus 186 min; P = 0.031). Vital capacity reduction was less with VATS than in the open group (15 versus 22 per cent; P = 0.016). The 3- and 5-year survival rates were similar: 70 and 55 per cent respectively for VATS compared with 60 and 57 per cent for the open procedure. CONCLUSION: VATS provides comparable results to open radical oesophagectomy, with less surgical trauma.

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.

Successful prenatal treatment of congenital heart block with ritodrine administered transplacentally.

Congenital heart block (CHB) is rather rare, and a poorer prognosis has been documented in fetuses with a ventricular rate <55 beats per minutes (bpm), in which therapeutic interventions during pregnancy have been warranted. We present a case of CHB associated with maternal anti-SSA/Ro antibody, diagnosed at 28 weeks' gestation. Fetal echocardiography revealed atrioventricular dissociation, with an atrial rate of 170 bpm and a ventricular rate of 54 bpm. To increase the fetal heart rate, maternal intravenous ritodrine infusion was undertaken, fetal ventricular rate was rapidly increased to 65 bpm. The pregnancy successfully continued until term, and a female infant weighing 2919 g was delivered by cesarean section with Apgar scores of 8 and 8 and 1 and 5 min. The infant is now 12 months of age and growing normally on oral terbutaline without pacing. In a case of fetal heart block, maternal administration of ritodrine may be a therapeutic intervention to improve the fetal and neonatal prognosis.

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.

Prognostic factors after oesophagectomy and extended lymphadenectomy for squamous oesophageal cancer.

BACKGROUND: The prognosis of patients without nodal metastasis of oesophageal cancer is generally good, but recurrence develops in some cases. METHODS: Data on 88 consecutive patients with squamous oesophageal cancer who underwent three-field lymph node dissection from 1986 to September 1998 and who had no evidence of nodal disease were reviewed retrospectively. Disease status was based on histological examination of the section of each node with the largest surface area, stained with haematoxylin and eosin. RESULTS: The 3- and 5-year survival rates of patients without lymph node metastasis were 85 and 81 per cent respectively, better than in patients with metastasis. Twelve patients died from recurrence. Recurrence was haematogenous in nine patients and locoregional in three. Survival was worse in men, for patients with lesions located in the upper thoracic oesophagus, and in those with lymphatic or blood vessel invasion. Only the presence of lymphatic invasion correlated with survival on multivariate analysis (P = 0.04). CONCLUSION: Although survival was generally good in patients without nodal metastasis from oesophageal cancer following three-field lymph node dissection, patients with lymphatic invasion remained at risk for haematogenous dissemination.

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.

HLA-class I antigens in patients with unexplained recurrent abortion.

In order to clarify the genetic background of recurrent spontaneous abortion, the frequency of HLA-A, -B, and -C alleles was analyzed in eighty-nine patients with a history of unexplained primary recurrent abortion. The frequency of each HLA-A, -B, and -C antigen allele was calculated in patients with recurrent abortion and their husbands, and compared with the frequencies in the general population represented by 207 individuals in the Niigata district of Japan. The incidence of individuals homozygous for the HLA-A, -B, and -C alleles was also compared between the patient group and the control group. The frequency of HLA-B35 in the patient group (5 of 89, 5.6%) was significantly lower than in the general population (40 of 207, 19.3%) (Odds Ratio, 0.25; 95% Confidence Interval, 0.09-0.65; P < 0.005; Pc, not significant). The frequencies of other HLA-A, -B, and -C alleles were not significantly different between the patient group and the general population. No significant difference in the frequency of HLA-A, -B, and -C alleles was observed between the husband group and the general population. The incidence of individuals homozygous for HLA-A, -B, or -C alleles in the patient group was not significantly different from the general population. The significantly lower frequency of HLA-B35 in patients with unexplained recurrent abortion suggests that the Th2-associated immune reactions may be lacking in such patients, as it has been reported that an enhanced Th2 response in conjunction with a decreased T Th1 response is a common immune reaction in HLA-B35-positive individuals.

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.