Ryuzo Koyama

GST-π gene-transduced hematopoietic progenitor cell transplantation overcomes the bone marrow toxicity of cyclophosphamide in mice

Autologous transplantation of bone marrow cells (BMCs) transduced with the multidrug resistance 1 (MDR1) gene or dihydrofolate reductase (DHFR) gene has already been applied in clinical chemoprotection trials. However, anticancer drugs frequently used in high-dose chemotherapy (HDC), such as alkylating agents, are not relevant to MDR1 or DHFR gene products. In this context, we have previously reported that glutathione S-transferase-pi (GST-pi) gene-transduced human CD34(+) cells showed resistance in vitro against 4-hydroperoxicyclophosphamide, an active form of cyclophosphamide (CY). In the present study, a subsequent attempt was made in a murine model to evaluate the effectiveness of transplantation of GST-pi-transduced BMCs to protect bone marrow against high-dose CY. The gene transfection was carried out retrovirally, employing a recombinant fibronectin fragment. Transfection efficiency into CFU-GM was 30%. After the transplantation, recipient mice (GST-pi mice) received three sequential courses of high-dose CY. As the chemotherapy courses advanced, both shortening of recovery period from WBC nadir and shallowing of WBC nadir were observed. In contrast to the fact that three of seven control mice died, possibly due to chemotoxicity, all seven GST-pi mice were alive after the third course, at which point the vector GST-pi gene was detected in 50% of CFU-GM derived from their BMCs and peripheral blood mononuclear cells. When BMCs obtained from these seven mice were retransplanted into secondary recipient mice, 20% of CFU-GM from BMCs showed positive signals for vector GST-pi DNA after 6 months. These data indicate that the GST-pi gene can confer resistance to bone marrow against CY by being transduced into long-term repopulating cells.

Meningeal carcinomatosis from an ovarian primary with complete response to adjuvant chemotherapy after cranial irradiation.

Abstract Meningeal metastasis is rare in the clinical course of ovarian carcinoma, and its prognosis is poor. Meningeal dissemination of carcinoma is usually treated by intrathecal administration of methotrexate and total brain irradiation, although these treatments are usually ineffective. We experienced a case of meningeal relapse from ovarian carcinoma resistant to multiple antineoplastic agents in a 64-year-old woman who was treated with eight different chemotherapy regimens after her initial operation 7 years previously. Intrathecal administrations of methotrexate or cisplatin with dexamethasone were not effective. Fifty-Gy whole cranial irradiation inhibited increases in serum carbohydrate antigen (CA)125 levels and further tumor growth. Adjuvant chemotherapy was required to alleviate frequent headaches and to decrease serum CA125 level and tumor size. Intravenous administration of 45 mg paclitaxel and 35 mg cisplatin, and oral administration of 50 mg etoposide were carried out for 5 days. This treatment was repeated every 3 weeks. After four courses of treatment, meningeal carcinomatosis was not detectable on computed tomography (CT) and magnetic resonance imaging (MRI) scans. The patients serum levels of CA125 rapidly fell to beneath normal limits and remained normal. She is still alive and clinically free of recurrence 4 months after the last cycle of chemotherapy. As well as reporting our experience with this case, we also present a review of the literature on meningeal carcinomatosis from ovarian cancer.

Rheologic analysis of gastric mucosal hemodynamics in patients with cirrhosis

BACKGROUND Portal hypertensive gastropathy causes some gastric mucosal microcirculatory disorders in cirrhotic patients, but the nature of the rheologic dysfunction in the gastric microcirculation remains to be clarified. METHODS To examine the rheologic properties of the gastric microcirculation, we subjected 112 cirrhotic patients and 51 control subjects to endoscopic laser Doppler flowmetry and measured multiple variables of flow, red blood cell volume, and velocity. Furthermore, based on these results, we analyzed the shear rate which reflects the status of the microcirculatory system. To validate the laser Doppler flowmetry, we derived the relationship between red blood cell volume and cross-sectional areas of submucosal collecting venules; near-infrared endoscopy was used to evaluate this relationship. RESULTS Analysis of shear rate according to the severity of portal hypertensive gastropathy showed that the mucosa was exposed to strong hemokinetic stress in severe cases, characterized by a higher shear rate than in control subjects or in mild cases. Nitroglycerin, administered by intravenous infusion (1.0 microg/kg/min), reduced blood flow and restored shear rate to control levels in patients with severe portal hypertensive gastropathy. CONCLUSION This rheologic study of the gastric mucosa suggests that a disorder of the shear rate control mechanism in the microcirculation is associated with severe portal hypertensive gastropathy.

A Pleural Effusion Caused by Fibrous Hematopoietic Tumor Successfully Treated With Prednisolone in a Patient With Agnogenic Myeloid Metaplasia With Myelofibrosis

A 46-year-old woman suffering from agnogenic myeloid metaplasia (AMM) since 1994 was being followed as an outpatient. In November 1999, she exhibited respiratory failure caused by massive pulmonary effusion, which was speculated to have been produced by chest tumors. A biopsy specimen revealed findings compatible with fibrous hematopoietic tumor (FHT): prominent fibroblasts and fibrosis with scanty megakaryocytes. Serum concentrations of transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF) were significantly higher than those of other cases of AMM without FHT. The effusion did not respond to administrations of various chemotherapeutic agents, but after prednisolone administration, the effusion disappeared and the tumors also diminished.TGF-β and PDGF were the possible causes of FHT formation, and for such fibrotic extramedullary regions, the administration of prednisolone should be considered.