Yasuhisa Shimazaki

Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers

Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor suppressor and tumor‐related genes. To determine the clinicopathological significance of gene promoter methylation in non‐small cell lung cancer (NSCLC), we examined the promoter methylation status of the APC, DAP‐kinase, E‐cadherin, GSTP1, hMLH1, p16, RASSF1A and RUNX3 genes in 75 NSCLCs and corresponding non‐neoplastic lung tissues by methylation‐specific PCR (MSP). The frequencies of methylation in NSCLCs and corresponding non‐neoplastic lung tissues were: 37% (28 of 75) and 48% (36 of 75) for APC, 28% (21 of 75) and 13% (10 of 75) for DAP‐kinase, 29% (22 of 75) and 15% (11 of 75) for E‐cadherin, 1% (1 of 75) and 0% (0 of 75) for GSTP1, 7% (5 of 75) and 0% (0 of 75) for hMLH1, 31% (23 of 75) and 0% (0 of 75) for p16, 43% (32 of 75) and 4% (3 of 75) for RASSF1A, and 20% (15 of 75) and 3% (2 of 75) for RUNX3, respectively. Methylation of p16 was more frequent in squamous cell carcinomas than in adenocarcinomas (P<0.05), and was associated with tobacco smoking (P<0.05). On the contrary, methylation of APC and RUNX3 was more frequent in adenocarcinomas than in squamous cell carcinomas (P<0.05). Thus, a different set of genes is thought to undergo promoter methylation, which leads to the development of different histologies. In addition, methylation of p16, RASSF1A and RUNX3 was mostly cancer‐specific (P<0.05), and may be utilized as a molecular diagnostic marker of NSCLCs.

Frequent epigenetic silencing of the p16 gene in non-small cell lung cancers of tobacco smokers.

Epidemiological studies have demonstrated a causal link between tobacco smoking and lung cancer. We investigated the association between inactivation of the p16 gene and tobacco smoking in 51 non‐small cell lung cancers (NSCLCs). Aberrations of the p16 gene were studied by PCR single‐strand conformation polymorphism analysis, followed by direct sequencing, microsatellite analysis, methylation‐specific PCR, and immunohistochemistry. Mutations were detected in 3.9% (2/51) of the tumors; the tumors carrying mutations were from smokers. The incidences of loss of heterozygosity, homozygous deletion, and promoter methylation in 37 smokers vs. 14 non‐smokers were; 45.9% vs. 28.6%, 16.2% vs. 7.1%, and 35.1% vs. 7.1%, respectively. Among these, only the association between promoter methylation and tobacco smoking was statistically significant (P<0.05). Therefore, epigenetic aberration is considered to be a major causative event in p16 silencing by tobacco smoking. Loss of p16 protein expression was apparent in 49% (25/51) of the tumors, and was associated with tobacco smoking (P<0.05) and with histological type (P<0.05). These findings suggest that tobacco smoking leads to inactivation of the p16 gene mainly through the epigenetic mechanism, ultimately increasing the risk of NSCLC, especially the squamous cell histological type.

Optimal blood flow for cooled brain at 20°C

Abstract Background . Optimal conditions for deep hypothermic perfusion and protective brain blood flow remain unclear. Methods . Dogs (n = 52) underwent 120 minutes of cardiopulmonary bypass at 20°C with perfusion flow rates of 2.5, 5, 10, 20, 40, and 100 mL · kg −1 · min −1 . We examined the effect of the various flow rates and different perfusion pressures on brain blood flow, metabolism, and intracellular pH. Results . The brain was ischemic and acidotic when the perfusion flow rate was less than 5 mL · kg −1 · min −1 and pressure was less than 10 mm Hg. When perfusion pressure was higher than 10 mm Hg, cerebral cortex blood flow was more than 9 mL · 100 g −1 · min −1 and intracellular pH, higher than 6.95. The cerebral metabolic rate for oxygen decreased at a flow rate of 2.5 mL · kg −1 · min −1 . The cerebral metabolic ratio of glucose to oxygen and the cerebral vascular resistance were lowest when perfusion pressure was 10 to 30 mm Hg. Full-flow (100 mL · kg −1 · min −1 ) perfusion caused paradoxical brain acidosis; a flow of 40 mL · kg −1 · min −1 provided the best results. Conclusions . Both extremely low-flow perfusion and excessive perfusion cause brain acidosis. Low-flow perfusion at a pressure of 20 mm Hg provides cerebral vasorelaxation and aerobic metabolism during operations at 20°C.

Heterotopic Pancreas of the Esophagus Associated With a Rare Type of Esophageal Atresia

An infant with a rare type of esophageal/tracheal anomaly associated with heterotopic pancreas of the esophagus is herein reported. The upper pouch containing heterotopic pancreas reached 1.5 cm below the tracheal carina, and the distal esophagus connected to the trachea 2 cm above the tracheal carina and thus formed a partial duplication of the esophagus. Heterotopic pancreas of the esophagus is extremely rare, with only 7 cases previously reported. Here we report the combination of heterotopic pancreas and esophageal atresia with tracheoesophageal fistula.

Minimized mortality and neurological complications in surgery for chronic arch aneurysm: axillary artery cannulation, selective cerebral perfusion, and replacement of the ascending and total arch aorta.

Abstract  Objective: Cerebral complication is still a major concern in surgery for arteriosclerotic aortic arch disease. For preventing this complication, axillary artery cannulation, selective cerebral perfusion, and replacement of the ascending and arch aorta were applied to thoracic aortic aneurysm involving aortic arch. Method: From May 1999 to July 2002, consecutive 39 patients with true aneurysm (29 patients) or chronic aortic dissection (10 patients) involving aortic arch underwent replacement of the ascending and arch aorta with an elephant trunk under hypothermic cardiopulmonary bypass through the axillary artery cannulation and selective cerebral perfusion. The brain was continuously perfused without any intermission through the axillary artery. Concomitant operation included coronary artery bypass grafting (CABG) in two patients, aortic valve replacement (AVR) in one, Bentall operation in two, mitral valve replacement (MVR) in one, and aortic valve sparing operation in one. Patient age at operation was 40–84 (72 + 9) years and 24 of them were older than 70 years of age. Results: There was one operative death (2.5%) due to bleeding from the left lung, and one hospital death due to respiratory failure. Postoperative permanent neurological dysfunction was found in one patient (2.5%). Two patients presented temporary neurological dysfunction (5%). Thirty‐six of the 39 patients were discharged from hospital on foot. Conclusion: Continuous perfusion through the axillary artery with selective cerebral perfusion and replacement of the ascending and arch aorta may minimize cerebral complication leading to satisfactory results in patients with chronic aortic aneurysm involving aortic arch.

Intravenous Leiomyomatosis with Cardiac Extension

Intravenous leiomyomatosis with cardiac extension is an extremely rare uterine tumor. We report here a case of a patient with a uterine leiomyoma which extended into the right atrium through the left ovarian vein, progressing into the left renal vein along the inferior vena cava. Complete one-stage removal of the tumor was performed using cardiopulmonary bypass, and the patient has shown a favorable outcome. Successful therapy for intravenous leiomyomatosis is dependent on total surgical excision of the tumor, cessation of ovarian function and avoidance of postoperative estrogen replacement therapy.

Removal of cartilage rings of the graft and omentopexy for extended tracheal autotransplantation

BACKGROUND One of the serious problems in longer-size tracheal transplantation is infection or severe stenosis of the graft, probably caused by an inadequate blood supply even with omentopexy. For obtaining an appropriate blood supply, we experimentally developed a new technique that included removal of some cartilage rings of the graft and omentopexy. METHODS Twenty-one adult mongrel dogs were used. In group A (n = 11), a nine-cartilage ring length of the trachea in which six of nine rings were removed, leaving one cartilage ring at each end of the graft and another in the center, was autotransplanted with omentopexy. Two artificial tracheal rings outside the graft were used for maintaining the lumen. In group B (n = 10), a nine-cartilage ring length of the trachea was autotransplanted with omentopexy. RESULTS In group A, all dogs survived until being sacrificed, whereas 5 group B dogs died of graft infection and mediastinitis (p<0.05 versus group A). Mucosal blood flow of the graft in group A was normal and higher than in group B (p<0.05). Grade of the graft stenosis at death or sacrifice was 14%+/-1% in group A and 58%+/-25% in group B (p<0.05). CONCLUSIONS Removal of some cartilage rings improved blood supply to the graft and resulted in satisfactory survival and nonsignificant tracheal stenosis in extended tracheal autotransplantation.

Choledochal cyst and duodenal atresia: a rare combination of malformations

Abstract. A rare case of congenital duodenal atresia (DA) associated with a choledochal cyst (CC) is reported. At 38 weeks of gestation, a 1,610-g girl was born by cesarean section with a prenatal diagnosis of congenital DA. After the disease was confirmed by radiographs, she underwent a duodenoduodenostomy for complete separation of the duodenum with an annular pancreas. Thirty-two months after the initial operation, she developed upper abdominal pain and acholic stools. Abdominal ultrasonography demonstrated a CC and dilated intrahepatic bile ducts. Magnetic resonane cholangiopancreatography showed an anomalous arrangement of the choledochus and the main pancreatic duct. A diffusely dilated extrahepatic bile duct was resected, and a hepaticoduodenostomy was performed after a cholecystectomy. The patient was discharged without complications. We could not find a similar case report in the English literature. Although it is not reported that there is a close relation of DA and CC in embryologic development, the presence of this combination should be considered.

Choledochal cyst and duodenal atresia: a rare combination

Abstract A rare case of congenital duodenal atresia (DA) associated with a choledochal cyst (CC) is reported.At 38 weeks of gestation, a 1,610-g girl was born by cesarean section with a prenatal diagnosis of DA. After the disorder was confirmed by X-ray, she underwent a duodenoduodenostomy for a complete separation of the duodenum with an annular pancreas. Thirty-two months after the initial operation, she developed upper abdominal pain and acholic stools. Abdominal ultrasonography demonstrated a CC and dilatated intrahepatic bile ducts. Magnetic resonance cholangiopancreatography showed an anomalous arrangement of the choledochus and main pancreatic duct. A diffusely dilatated extrahepatic bile duct was resected, and a hepaticoduodenostomy was performed after cholecystectomy. The patient was discharged without complications. We could not find a similar case report in the English literature. Although it is not reported that there is a close relationship in embryologic development of DA and CC, one should be aware of the possibility of this combination.

Retrograde cerebral perfusion: experimental approach to brain oedema.

Retrograde cerebral perfusion is used during aortic surgery as an adjunct to profoundly hypothermic circulatory arrest.1–3 Although it may protect the brain and extend the safe period of circulatory arrest, brain oedema is a possible side-effect. However, whether retrograde cerebral perfusion causes brain oedema or not has not been shown. Also, it is not known what causes brain oedema after retrograde cerebral perfusion, if it does: brain ischaemia, intracranial hypertension, or both during retrograde cerebral perfusion? To investigate these questions, we designed the present study, using a developed experimental model with simultaneous sagittal sinus and superior vena caval perfusion.4