Hiromichi Kimura

Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer.

Survivin is a member of the inhibitor of apoptosis protein (IAP) family containing a single baculovirus IAP repeat domain. It is expressed during fetal development but becomes undetectable in terminally differentiated normal adult tissues. We previously reported that survivin and its splicing variant survivin-2B was expressed abundantly in various types of tumor tissues as well as tumor cell lines and was suitable as a target antigen for active-specific anti-cancer immunization. Subsequently, we identified an HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL) recognized by CD8+ cytotoxic T lymphocytes (CTLs). We, therefore, started a phase I clinical study assessing the efficacy of survivin-2B peptide vaccination in patients with advanced or recurrent colorectal cancer expressing survivin. Vaccinations with survivin-2B peptide were given subcutaneously six times at 14-day intervals. Of 15 patients who finished receiving the vaccination schedule, three suffered slight toxicities, including anemia (grade 2), general malaise (grade 1), and fever (grade 1). No severe adverse events were observed in any patient. In 6 patients, tumor marker levels (CEA and CA19-9) decreased transiently during the period of vaccination. Slight reduction of the tumor volume was observed in one patient, which was considered a minor responder. No changes were noted in three patients while the remaining eleven patients experienced tumor progression. Analysis of peripheral blood lymphocytes of one patient using HLA-A24/peptide tetramers revealed an increase in peptide-specific CTL frequency from 0.09% to 0.35% of CD8+ T cells after 4 vaccinations. This phase I clinical study indicates that survivin-2B peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in HLA-A24-expression patients with colorectal cancer.

Bacterial lipopolysaccharide reduced intestinal barrier function and altered localization of 7H6 antigen in IEC-6 rat intestinal crypt cells.

The intestinal epithelial barrier restricts the passage of potentially toxic substances into the systemic circulation and is considered to be mostly mediated by tight junctions, though the mechanisms involved in the regulation of intestinal tight junctions are not yet fully understood. In the present study, we examined whether bacterial lipopolysaccharide (LPS) altered the barrier function of tight junction and localization of tight junctional proteins, ZO‐1 and 7H6 antigen, in IEC‐6 intestinal cells. Administration of LPS to the basolateral surface of IEC‐6 cells disrupted the barrier function and caused the disappearance of 7H6 antigen from the cell border, whereas LPS administered to the apical surface altered neither the barrier function nor the localization of 7H6 antigen in IEC‐6 cells. On the other hand, the localization of ZO‐1 was not influenced by these treatments of LPS. These results suggest that the interaction of LPS with the basolateral surface of intestinal epithelial cells disrupts the barrier function and 7H6 antigen take part in the maintenance of the barrier function in IEC‐6 cells. J. Cell. Physiol. 171:284–290, 1997.

Changes in portal hemodynamics and hepatic function after partial splenic embolization (PSE) and percutaneous transhepatic obliteration (PTO)

Since April 1985, we have performed a multidisciplinary therapy consisting of partial splenic embolization (PSE), percutaneous transhepatic obliteration (PTO) or transileocolic vein obliteration (TIO), and endoscopic injection sclerotherapy (EIS) for patients with severe gastroesophageal varices and those with a portacaval shunt associated with portal hypertension. In this study, PSE and percutaneous transhepatic portography (PTP) were performed at the same time in seven liver cirrhosis patients with hypersplenism, gastroesophageal varices, or hepatocellular carcinoma. The changes in portal blood flow/pressure and hemodynamics were examined by a thermodilution method. The effects of PSE on blood biochemical parameters such as the platelet count, ICG R15, redox tolerance index (RTI), and oral glucose tolerance test (75 g OGTT) were also evaluated. PSE induced a decrease in the blood flow of the splenic artery and in the splenic vein pressure without decreasing the portal blood flow. The platelet count in the peripheral blood and the RTI increased significantly. These results suggest the possibility that PSE may reduce the potential perioperative risk in hepatocellular carcinoma complicated with liver cirrhosis.

Hepatocyte Nuclear Factor (HNF)-4α Induces Expression of Endothelial Fas Ligand (FasL) to Prevent Cancer Cell Transmigration: A Novel Defense Mechanism of Endothelium against Cancer Metastasis

Endothelial Fas ligand (FasL) contributes to the “immune privilege” of tissues such as testis and eye, in which apoptosis is induced in infiltrating Fas‐positive activated T cells and results in the inhibition of leukocyte extravasation. In this study, we examined the role of endothelial FasL in controlling cancer cell transmigration using rat lung endothelial (RLE) cell line bearing a doxycycline‐inducible hepatocyte nuclear factor (HNF)‐4α expression system. We showed that a detectable level of FasL was expressed in RLE cells and that this expression was markedly up‐regulated and well correlated to the degree of HNF–4α expression in a time‐dependent manner. When various cancer cells were overlaid on an RLE monolayer sheet, we examined the ability of endothelial FasL to induce massive apoptosis in Fas‐expressing cancer cells and found a causal link to inhibition of the transmigration. Finally, we showed that FasL was expressed in capillaries of the rat brain by immunohistochemical staining, suggesting that FasL serves its functions not only in vitro, but also in vivo. These results raise the possibility that HNF–4α is involved in regulating cancer cell transmigration by modulating the Fas‐FasL system.

HEMOBILIA CAUSED BY A GIANT BENIGN HEMANGIOMA OF THE LIVER : REPORT OF A CASE

We report herein the extremely unusual case of a 39-year-old woman in whom a giant cavernous hemangioma caused hemobilia. Cavernous hemangioma is the most common benign neoplasm of the liver and rarely causes any clinical symptoms or signs, while hemobilia usually occurs secondary to accidental operative or iatrogenic trauma, vascular disease, inflammatory disorders, gallstones, or tumors of the liver. Although invasive or malignant hepatic tumors often result in a communication between the biliary tract and the blood vessels, only one case of hemobilia caused by a benign cavernous hemangioma has ever been reported, but with no details about the patient. Our patient presented to a local hospital with severe melena as the initial main symptom, where ligation of the right hepatic artery was performed. This failed to relieve her symptoms, and she was subsequently referred to our department where a right hepatectomy was performed. Histopathological examination revealed no malignancy combined with the tumor; however, the hemangioma was exposed to the bile duct in segment VIII, which was presumably the cause of the hemobilia. This patient remains in good health almost 6 years after her operation. To the best of our knowledge this is the first case report of hemobilia caused by a cavernous hemangioma, and is accompanied by a detailed analysis.

Beneficial effects of administering intraportal prostaglandin E1 postoperatively to hepatectomy patients with massive intraoperative blood loss

Massive intraoperative blood loss is a major cause of complications following hepatectomy. To evaluate the efficacy of intraportal prostaglandin E1 (PGE1) for preventing liver deterioration in hepatectomy patients with an intraoperative blood loss of over 2000 ml, a retrospective analysis was conducted on 10 patients given intraportal PGE1 (portal group), 6 given intravenous PGE1 (venous group), and 10 given no treatment (control group). PGE1 was infused at 250 or 500 μg/day in the portal group and at 720 μg/day in the venous group, and continued for 3 days postoperatively. Alanine aminotransferase (ALT) and total bilirubin (T.Bil) were measured on postoperative days (PODs) 1, 3, 5, and 7. ALT was lower in the portal group than in the other two groups on each POD, and significantly lower than in the control group on POD 3 (P<0.05). T.Bil was significantly lower in the portal group than in the control group on PODs 5 and 7 (P<0.05). T.Bil on POD 7 was under 1.5 mg/dl in 1 (10.0%), 6 (60.0%), and 2 (33.3%) of the control, portal, and venous group patients, respectively, with a significant difference between the control and portal groups (P<0.05). These results confirmed that intraportal PGE1 was beneficial for improving hepatic function and preventing cholestasis in patients with a blood loss of over 2000 ml at risk of developing postoperative liver deterioration.

Partial splenic embolization in patients with liver cirrhosis and hepatocellular carcinoma: Effects on portal hemodynamics

Partial splenic embolization (PSE) was performed on patients with liver cirrhosis to control hypersplenism and gastroesophageal varices. In this study, we evaluated the effects of PSE on the portal hemodynamics and hepatic function of 17 cirrhotic patients with hepatocellular carcinoma. The mean splenic volume and the peak platelet count increased significantly and the splenic vein pressure decreased significantly after PSE. However, the portal blood flow did not change. Changes in the 15-min retention rate of indocyanine green and the arterial ketone body ratio were not significant, but the redox tolerance index increased from 0.24 ± 0.28 × 10−2 to 0.59 ± 0.35 × 10−2. These results suggest that PSE may reduce perioperative risks in cirrhotic patients with hepatocellular carcinoma who are candidates for hepatic resection.

Multifocal and microscopic chromophobe renal cell carcinomatous lesions associated with 'capsulomas' without FCLN gene abnormality

Chromophobe renal cell carcinoma (RCC) accounts for approximately 5% of renal epithelial neoplasms. Multiple and/or bilateral chromophobe RCCs in an individual are generally rare but frequently occur in patients with Birt–Hogg–Dubé syndrome (BHDS) and in patients with tuberous sclerosis complex (TSC). The responsible genes in both BHDS and TSC act as tumor suppressors. Therefore, it seems that some genetic backgrounds are required for the generation and progression of multiple chromophobe RCCs. Here, we report a case of multiple and bilateral chromophobe RCCs along with several small‐sized capsular angiomyolipomas known as ‘capsulomas’ in a 39‐year‐old woman who had neither a particular medical history nor specific gene mutation. There has been no report of sporadic multiple chromophobe RCCs and ‘capsulomas’ developing in a patient without genetic features, having potential for novel genetic variation.