Takanori Kyokane

Carbon monoxide overproduced by heme oxygenase-1 causes a reduction of vascular resistance in perfused rat liver

This study aimed to examine whether livers overexpressing heme oxygenase (HO)-1 could alter the vascular resistance through the vasorelaxing action of carbon monoxide (CO). The relationship among HO-1 expression, CO generation, and the vascular resistance was assessed in perfused rat livers pretreated with hemin, an inducer of HO-1. At 18 h after the hemin treatment, livers displayed marked increases in HO-1 expression in hepatocytes and venous CO flux and a reduction of the basal resistance. The reduction of the resistance in hemin-treated livers was canceled by administration of oxyhemoglobin, a reagent trapping both CO and nitric oxide (NO), but not by methemoglobin, which captures NO but not CO. Liposome-encapsulated oxyhemoglobin, which cannot access the space of Disse, did not cause vasoconstriction. Furthermore, these livers became less sensitive to endothelin-1, a vasoconstrictive peptide, than the untreated controls through mechanisms involving CO. On the other hand, at 12 or 24 h after the treatment when the HO-1 induction was not accompanied by CO overproduction, neither a decrease in the basal resistance nor vascular hyporeactivity to endothelin-1 was observed. These results suggest that CO overproduced in the extrasinusoidal compartment is a determinant of the HO-1-mediated vasorelaxation in the liver.This study aimed to examine whether livers overexpressing heme oxygenase (HO)-1 could alter the vascular resistance through the vasorelaxing action of carbon monoxide (CO). The relationship among HO-1 expression, CO generation, and the vascular resistance was assessed in perfused rat livers pretreated with hemin, an inducer of HO-1. At 18 h after the hemin treatment, livers displayed marked increases in HO-1 expression in hepatocytes and venous CO flux and a reduction of the basal resistance. The reduction of the resistance in hemin-treated livers was canceled by administration of oxyhemoglobin, a reagent trapping both CO and nitric oxide (NO), but not by methemoglobin, which captures NO but not CO. Liposome-encapsulated oxyhemoglobin, which cannot access the space of Disse, did not cause vasoconstriction. Furthermore, these livers became less sensitive to endothelin-1, a vasoconstrictive peptide, than the untreated controls through mechanisms involving CO. On the other hand, at 12 or 24 h after the treatment when the HO-1 induction was not accompanied by CO overproduction, neither a decrease in the basal resistance nor vascular hyporeactivity to endothelin-1 was observed. These results suggest that CO overproduced in the extrasinusoidal compartment is a determinant of the HO-1-mediated vasorelaxation in the liver.

Angiodysplasia of the appendix.

Angiodysplasia of the gastrointestinal tract is thought to be one of the most common causes of lower gastrointestinal bleeding in the elderly, and, in the majority of cases, lesions are located in the cecum or ascending colon. The authors report an extremely rare case of appendicular angiodysplasia. A 76-yr-old woman was hospitalized with massive recurrent red anal bleeding. Selective superior mesenteric arteriography revealed an extravasation of contrast material from the appendicular artery, and this finding proved to be bleeding from an angiodysplasia of the appendix. An appendectomy was performed, and anal bleeding did not recur postoperatively. A review of the literature revealed this to be an extremely rare case of angiodysplasia.

Simultaneous segmental obstruction of bile duct and portal vein markedly changes a population of biliary and hepatic cells in human liver

Background and aimsNo studies have investigated histologic changes caused by simultaneous segmental obstruction of the bile duct and portal vein in human liver.Patients/MethodsLiver tissues with simultaneous obstruction of the segmental bile duct and portal vein (O+/+ liver), with segmental bile duct obstruction alone (O+/− liver), and without obstruction (O−/− liver) were obtained from patients who underwent hepatectomy, and studied morphologically and immunohistochemically.ResultsIn O+/+ liver, the proportional area consisting of hepatocytes was significantly less (31.0±25.8%) than in O+/− liver (78.4±18.9%) or O−/− liver (86.5±9.2%). In contrast, the proportional area consisting of biliary epithelial cells was significantly higher in O+/+ liver (9.1±6.1%) than in O+/− liver (1.6±1.5%) or O−/− liver (0.7±0.6%). The proportional area consisting of fibrous tissue also was significantly higher in O+/+ liver than in the other two groups. In O+/+ liver, some cells located at the periphery of hepatocyte areas were immunoreactive for both hepatocyte and biliary epithelial cell markers.ConclusionSimultaneous segmental obstruction of the bile duct and portal vein induces a marked ductular increase, periportal fibrosis, and a reduction in the number of hepatocytes in human liver tissue.

Optimal schedule of adjuvant chemotherapy with S-1 for stage III colon cancer: study protocol for a randomized controlled trial

BackgroundAlthough, in Western countries, oxaliplatin-based regimens have been established as a gold standard treatment for patients with stage III or high risk stage II colon cancer after curative resection, in Japan fluorouracil-based regimens have been widely accepted and recommended in the guidelines for adjuvant settings in patients with stage III colon cancer. S-1, an oral preparation evolved from uracil and tegafur, has equivalent efficacy to uracil and tegafur/leucovorin for treating patients with advanced colorectal cancer and might be a suitable regimen in an adjuvant setting. However, the completion rate of the standard six-week cycle of the S-1 regimen is poor and the establishment of an optimal treatment schedule is critical. Therefore, we will conduct a multicenter randomized phase II trial to compare six-week and three-week cycles to establish the optimal schedule of S-1 adjuvant therapy for patients with stage III colon cancer after curative resection.Methods/DesignThe study is an open-label, multicenter randomized phase II trial. The primary endpoint of this study is three-year disease-free survival rate. Secondary endpoints are the completion rate of the treatment, relative dose intensity, overall survival, disease-free survival, and incidence of adverse events. The sample size was 200, determined with a significance level of 0.20, power of 0.80, and non-inferiority margin of a 10% absolute difference in the primary endpoint.DiscussionAlthough S-1 has not been approved yet as a standard treatment of colon cancer in an adjuvant setting, it is a promising option. Moreover, in Japan S-1 is a standard treatment for patients with stage II/III gastric cancer after curative resection and a promising option for patients with colorectal liver metastases in an adjuvant setting. However, a six-week cycle of treatment is not considered to be the best schedule, and some clinicians use a modified schedule, such as a three-week cycle to keep a sufficient dose intensity with few adverse events. Therefore, it will be useful to determine whether a three-week cycle has an equal or greater efficacy and tolerance to side-effects compared with the standard six-week cycle schedule, and thus may be the most suitable treatment schedule for S-1 treatment.Trial registrationThe University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000006750.

A Case of Pinch-off Syndrome caused by Clavicular Fracture

症例は73歳の男性で, 進行大腸癌に対し中心静脈ポートを用いた外来化学療法を施行中であった. 転倒により右鎖骨骨折を来したが, 胸部X線検査上, カテーテルの損傷はなく薬液注入も問題なかったため, 以降化学療法を3クール施行した. しかし, 次クール目を開始したところ皮下腫脹を来したため胸部X線を撮影すると, 断裂したカテーテルを左肺動脈内に認めた. 緊急で経大腿静脈的に断裂したカテーテルを摘出した. 今後CVポートを留置して外来化学療法を行うケースが増加してくると思われ, 鎖骨骨折を来しポートを抜去するか否かの選択に迫られるケースに遭遇する可能性が十分に考えられる. その際は, 透視検査を行うなど詳細な評価を行い, ポート抜去の判断をすべきであると考える.