Hiroto Ishikawa

Prolongation of canine liver allograft survival by a novel immunosuppressant, FTY720. Effect of monotherapy and combined treatment with conventional drugs

BACKGROUND The immunosuppressive effect and other properties of a novel immunosuppressant, FTY720, have been studied mostly in the experimental transplantation of various extrahepatic organs. In this experiment, we evaluated the antirejection potency and adverse effects of this agent on liver grafts using a canine liver transplantation model. METHODS Forty-eight orthotopic liver transplantations were performed by the standard technique under a veno-venous bypass. Liver recipients were divided into two studies: a single-dose study with FTY720 at various doses and a combined dose study with conventional immunosuppressants (cyclosporine or tacrolimus) alone and combined with FTY720. Survival, biochemical and hematological tests, blood levels of immunosuppressants, and postmortem histology were determined. RESULTS The median survival of untreated control animals was 9 days, whereas treatment with FTY720 at a dose of 0.1 mg/kg/day prolonged graft survival to 49.5 days. FTY720 at 1 mg/kg/day showed a slight but insignificant prolongation to 16 days, but when the dose was increased to 5 mg/kg/day, the graft was rejected at 10 days. The combination of FTY720, 0.1 mg/kg/day, with a subtherapeutic dose of cyclosporine, 5 mg/kg/ day, prolonged median animal survival from 40 days with cyclosporine alone to 74 days. A combination of FTY720 (0.1 mg/kg/day) with tacrolimus (0.5 mg/kg/ day) compromised animal survival, reducing survival from 83.5 days with tacrolimus alone to 30.5 days due to infectious complication and emaciation by overimmunosuppression. No evident drug-induced side effects were observed. CONCLUSIONS FTY720 has a potent immunosuppressive effect when used alone at 0.1 mg/kg/day in canine liver transplantation. FTY720 is a promising candidate for future clinical application in orthotopic liver transplantation.

Protective effect of angiotensin II type I receptor antagonist, CV-11974, on ischemia and reperfusion injury of the liver

BACKGROUND Microcirculatory disturbance has been shown to play a critical role in hepatic ischemia and reperfusion (I/R) injury. Angiotensin II (AngII) is one of the most potent endogenous vasoconstrictors. Angiotensin II type I (AT1) receptor antagonist has been reported to have protective effects on I/R injury of the heart and kidney. However, effect on hepatic I/R injury has not been determined. In this study, we investigate our hypothesis that AT1 receptor antagonist, CV-11974, attenuates hepatic I/R injury. METHODS Twelve beagle dogs underwent a 2-hr total hepatic vascular exclusion with veno-venous bypass. CV-11974 was given to animals at a dose of 0.002 mg/ kg/min for 5 min followed by 0.001 mg/kg/min for 25 min via portal vein before ischemia (group II, n=6). Nontreated animals were used as the control (group I, n=6). Animal survival, hemodynamics, hepatic tissue blood flow (HTBF), liver function, platelet count, renin activity, and AngII concentration of hepatic vein, energy metabolism, and histopathology were analyzed. RESULTS Two-week survival was 33% in group I, in contrast, 100% in group II. Mean arterial blood pressure during early reperfusion was maintained, and HTBF after reperfusion was significantly higher in group II. Treatment attenuated liver enzyme release and decrease of platelet count, increased renin and AngII, suppressed ATP degradation during ischemia and enhanced ATP resynthesis after reperfusion. Neutrophil infiltration and histopathological damages were lessened in group II. CONCLUSIONS Our data demonstrated that the local renin-angiotensin system might play a role in hepatic microcirculation. AT1 receptor blockade with CV-11974 attenuated hepatic microcirculatory disturbance and ameliorated I/R injury.

Attenuation of ischemia and reperfusion injury of canine livers by inhibition of type II phospholipase A2 with LY329722.

Background. Membrane phospholipid breakdown, caused by ischemia and reperfusion (I/R) of the liver, releases free fatty acids including arachidonic acids and lysophospholipids, which serve as precursors of various inflammatory lipid derivatives. Phospholipase A2 (PLA2) is a key enzyme that initiates this reaction. In this study, we tested our hypothesis that a type II PLA2 inhibitor, LY329722, could attenuate hepatic I/R injury caused by a 2-hr total hepatic vascular exclusion (THVE) in dogs. Methods. Eighteen beagle dogs, subjected to a 2-hr THVE, were divided into three groups. Group 1 (n=6) was untreated and served as a control group. LY329722 was administered to animals in group 2 (n=6) intravenously (0.2 mg·kg−1·hr−1) for 60 min before ischemia, and to animals in group 3 (n=6) for 60 min starting 15 min before reperfusion (0.2 mg·kg−1·hr−1). Animal survival, systemic and splanchnic hemodynamics, hepatic tissue blood flow, liver functions, energy metabolism, hepatic venous thromboxane B2 and endothelin-1 levels, phospholipid levels and tumor necrosis factor-&agr; mRNA expression in liver tissue, and histopathologic findings were evaluated. Results. Two-week animal survival was 33% (two of six) in group 1, and 100% (six of six) in groups 2 and 3. LY329722 improved systemic and splanchnic hemodynamics, hepatic tissue blood flow, and energy metabolism, reduced liver enzyme, thromboxane B2, and endothelin-1 release, prevented hepatic phospholipid degradation and tumor necrosis factor-&agr; mRNA expression, and lessened histopathologic damage and the number of neutrophil infiltrating into the liver tissue. Conclusion. The present study demonstrated that a type II PLA2 inhibitor, LY329722, attenuated hepatic I/R injury caused by a 2-hr THVE model in dogs.

Metastatic Pulmonary Adenocarcinoma 13 Years After Curative Resection for Pancreatic Cancer: Report of a Case and Review of Japanese Literature

CONTEXT For the majority of patients, ductal adenocarcinoma of the pancreas remains a lethal disease. Currently, surgical extirpation for localized disease offers the only chance for long-term survival. CASE REPORT We report a patient who underwent successful resection of isolated lung metastasis occurring 13 years after pancreatic cancer resection. A 59-year-old woman underwent distal pancreatectomy for pancreatic cancer 13 years previously, followed by adjuvant chemotherapy, and was followed-up at the outpatient clinic of a local hospital. From around June 2010, she noticed bloody sputum, so she visited a local hospital. Since her chest X-ray and CT revealed a 1.5 cm mass shadow in the segment 10 of her right lung and she was referred to the Respiratory Disease Center of our hospital. As a result of through examinations, she was strongly suspected of having lung metastasis of pancreatic cancer, and underwent partial pneumonectomy. Postoperative histopathological examination of the resected specimen was consistent with lung metastasis of pancreatic cancer. She is still alive and currently receives third line of chemotherapy. CONCLUSION Patients who have achieved long-term survival after pancreatic cancer resection and can tolerate surgery may benefit from resection of a lung metastasis of pancreatic cancer in terms of survival, if it controls the metastasis.

Total Esophagectomy versus Proximal Esophagectomy for Esophageal Cancer at the Cervicothoracic Junction

Abstract. To investigate the adequate extent of esophagectomy and lymphadenectomy for an esophageal cancer localized at the cervicothoracic junction, the mortality and morbidity rates, survival rates, and patterns of recurrence were retrospectively analyzed in two groups—14 patients who underwent total esophagectomy with or without laryngectomy and 15 patients who underwent proximal esophagectomy with or without laryngectomy—at Kurume University Hospital from 1981 to 1996. Proximal esophagectomy with or without laryngectomy resulted in a lower hospital mortality rate and better overall survival for patients who underwent curative esophagectomy compared with total esophagectomy with or without laryngectomy. Multivariate analysis indicated that the extent of esophagectomy (total esophagectomy versus proximal esophagectomy) was not a prognostic factor. The incidence of recurrence was not different between the two groups. Lymph node metastasis or recurrence from such esophageal cancers was localized to the neck and upper mediastinum. For an esophageal cancer localized at the cervicothoracic junction, therefore, proximal esophagectomy with or without laryngectomy and with cervical and upper mediastinal lymphadenectomy could be better indicated for preselected patients.

Potential usefulness of mucin immunohistochemical staining of preoperative pancreatic biopsy or juice cytology specimens in the determination of treatment strategies for intraductal papillary mucinous neoplasm

We classified resected intraductal papillary mucinous neoplasms (IPMNs) into four subtypes (gastric, intestinal, pancreatobiliary and oncocytic) according to their morphological features and mucin expression, determined their clinicopathological characteristics and investigated the possibility of preoperatively diagnosing these subtypes. Sixty resected tumors, 4 preoperative tumor biopsies and 10 preoperative pancreatic juice cytology specimens were analyzed. The gastric and intestinal types accounted for the majority of IPMNs. Non-gastric type IPMNs were of high-grade malignancy. Many of the pancreatobiliary-type IPMNs were in an advanced stage and were associated with a poor prognosis. The results of mucin immunohistochemical staining of preoperative biopsy and surgically resected specimens were in agreement with each other, and in close agreement with those for pancreatic juice cytology specimens obtained from 10 patients during endoscopic retrograde cholangiopancreatography (ERCP). The immunostaining of preoperative biopsy specimens and ERCP-obtained pancreatic juice cytology specimens may be useful in the differential diagnosis of gastric and intestinal types of IPMN. If such techniques enable the preoperative diagnosis of IPMN subtypes, their use in combination with conventional preoperative imaging modalities may lead to surgical treatment best suited for the biological characteristics of the four subtypes.

Perioperative challenges associated with a pancreaticoduodenectomy and distal pancreatectomy for pancreatic cancer in patients with situs inversus totalis: Report of two cases

Situs inversus totalis is a rare anatomic variant of a complete mirror-image transposition of the thoracic and abdominal viscera. The performance of a pancreaticoduodenectomy and distal pancreatectomy in patients with situs inversus totalis is both rare and challenging. We herein present two cases of pancreatic cancer with situs inversus totalis. The abdominal anatomy was preoperatively assessed by multidetectorrow computed tomography, three-dimensional reconstruction, and angiography. We herein report that a pancreaticoduodenectomy and distal pancreatectomy with standard regional lymphadenectomy are feasible in patients with situs inversus totalis. Due to the transposition of the viscera and major blood vessels in such cases, preoperative knowledge of the exact anatomy, mapping of anomalies, and meticulous forward planning are essential for performing these technically difficult and complex hepatobiliary-pancreatic surgeries.

Bowel obstruction caused by an internal hernia that developed after laparoscopic subtotal colectomy: a case report

IntroductionLaparoscopic surgery is a minimally invasive approach with good treatment outcomes and is currently the standard surgery for colorectal cancer in Japan. Mesenteric closure is considered unnecessary in laparoscopic colorectal surgery because it can damage the bowel and blood vessels. However, an internal hernia may develop if the mesentery is not repaired.Case presentationWe report a case of internal hernia in a 61-year-old male of Japanese ethnicity. The patient had advanced sigmoid colon cancer, early-stage transverse colon cancer, and multiple adenomatous polyposis, and underwent laparoscopically-assisted subtotal colectomy. Bowel obstruction developed six days postoperatively and did not improve with conservative treatment. Abdominal computed tomography detected an internal hernia, prompting emergency surgery in which the ileum protruding into the mesenteric defect and an anastomotic stricture were detected. Reanastomosis, mesentery closure, and ileostomy were performed after hernia repair.ConclusionIn this case, open surgery was necessary due to bowel obstruction after laparoscopic colectomy. This outcome indicated that mesenteric closure should have been performed. Thus, the benefits of mesenteric closure require assessment in future cases.

Late-occurring coil migration into the duodenum.

A 74-year-old man presented with hypovolemic shock due to acute arterial haemorrhage from his abdominal drainage tube, which was placed at the choledochojejunostomy, at 12 days following surgical resection of bile duct carcinoma. Postoperative abscess formation was noticed at the same region, and urgent parent artery embolisation using 0.018-inch fibred platinum microcoils was performed from the distal to proximal ends of the pseudoaneurysm arising from the gastroduodenal artery (figure 1). The …

A Patient with Advanced Gastric Cancer and Situs Inversus Totalis: Report of a Case

Situs inversus totalis (SIT) is a rare congenital anomaly in which the positions of the abdominal and thoracic cavity structures are reversed. The reported incidence of SIT is one in 10,000 to 50,000 live births. There are few reports of gastric cancer in individuals with SIT or of the potential complications of surgical intervention in such cases. We report the case of a 79-year-old woman with SIT who underwent surgical treatment for advanced gastric cancer at our hospital and review the pertinent literature. Prior to surgery, abdominal computed topography angiography with 3-dimensional reconstruction was performed to uncover any variations and to verify the exact structures and locations of vessels. Total gastrectomy with D2 lymphadenectomy and cholecystectomy were performed safely and with careful consideration of the mirror-image anatomy.