Prognostic factors in patients with hepatocellular carcinoma treated by transcatheter arterial embolization

BACKGROUND: Transcatheter arterial embolization induces marked antitumor response in patients with hepatocellular carcinoma, but the survival benefit of transcatheter arterial embolization remains to be determined. This study investigated prognostic factors in patients with advanced hepatocellular carcinoma treated by transcatheter arterial embolization. METHODS: A total of 128 consecutive patients with non-resectable hepatocellular carcinoma, who had undergone transcatheter arterial embolization between May 1990 and August 1998, were analyzed to investigate prognostic factors. RESULTS: Median survival time and survival proportions at 1, 3 and 5 years were 3.3 years, 92.0, 54.6 and 23.4%, respectively. By multivariate analysis using the accelerated failure time model, age <60 years, hepatitis C virus antibody positivity, serum albumin >3.5 g/dl, absence of portal vein invasion and serum alpha-fetoprotein level <400 ng/ml were significantly associated with favorable survival. For clinical application, we also propose a prognostic equation with combination of specific prognostic factors, by which survival curves of each patient could be predicted directly. CONCLUSION: The findings of the current study may be helpful in predicting the life expectancy of hepatocellular carcinoma patients treated by transcatheter arterial embolization and in designing future clinical trials of transcatheter arterial embolization for hepatocellular carcinoma.     

A new regimen for TS-1 therapy designed to minimize adverse reactions by introducing a one-week interval after each two-week dosing session

It has been reported that the response rate to TS-1 of advanced recurrent gastric cancer was the highest rate (46.5%) of effectiveness among anti-cancer agents, but the incidence of adverse reactions to this drug has been found to be as high as 83.2%, with grade 3 or severer reactions occurring in 20.3% of patients. Taking into consideration the post-marketing survey finding that adverse reactions to the drug first appear 2-3 weeks after the start of oral TS-1 therapy, we attempted a new dosing regimen for this drug, wherein each session of therapy lasted for 2 weeks, with a one-week interval between two consecutive sessions (herein-after called "the 2-week regimen"). This regimen was employed based on the expectation that the adverse reactions to the drug would be minimized and that the consecutive dosing period could be prolonged, while keeping the anti-cancer potency at a level similar to that expected with the 4-week dosing regimen with a 2-week interval between sessions (the 4-week regimen). The subjects were 38 patients with advanced or recurrent stomach cancer who were treated with TS-1 at our center between September 1999 and November 2001. Twenty-four patients treated using the 4-week method until January 2001 were taken as a historical control, and compared with 14 patients treated using the 2-week method from February 2001 and afterwards. The incidence of adverse reactions was 71% in the 2-week regimen group against 92% in the 4-week regimen group. The incidence of grade 3 or severe adverse reactions was 8% in the 2-week group and 21% in the 4-week group. Thus, the incidence of adverse reactions was lower in the 2-week group. The percentage of patients who complied with the dosing instructions completely during a 6-month period, as evaluated by the Kaplan-Meier method, was 86% in the 2-week group and 58% in the 4-week group. The response rate, as calculated in patients whose lesions could be evaluated, was 25% in the 2-week group and 19% in the 4-week group. These results suggest that the 2-week regimen may allow safer outpatient drug therapy using TS-1 and merits a trial when considering the QOL of patients. We propose conducting a phase-II multi-center clinical study of this regimen in the near future.     

A case of recurrent rectal cancer responding to weekly low-dose CPT-11/isovorin/5-fluorouracil

We report the case of 66-year-old male with recurrent rectal cancer which responded to chemotherapy using CPT-11, Isovorin, and 5-fluorouracil (5-FU). CPT-11 was administered at 40 mg (90 min i.v.) x 3 day/week, and Isovorin and 5-FU were administered at 25 mg (bolus) and 250 mg (continuous) x 5 day/week by intraarterial infusion. Three cycles of this weekly regimen resulted in regression of tumors in the iliac region with remission of the lameness caused by iliac pain. The serum CEA level decreased from 13.1 ng/ml to 0.5 ng/ml. The patient has undergone 13 cycles of the regimen modified for outpatients (CPT-11 at 40 mg x 3 day/week plus Isovorin at 25 mg and 5-FU at 250 mg 1 day/week) with inhibitions of tumor regrowth and improved serum CEA level for more than 12 months. The current case suggests that weekly low-dose CPT-11/Isovorin/5-FU may have a potent therapeutic effect against recurrent rectal cancer.     

A case of rectal cancer with multiple liver metastases that responded dramatically to pharmacokinetic modulating chemotherapy/CPT-11 therapy

A 67-year-old male patient suffering from rectal cancer complicated by multiple hepatic metastases underwent low anterior resection, cholecystectomy and hepatic arterial cannulation. He was treated postoperatively with arterial infusion pharmacokinetic modulating chemotherapy (PMC) and venous infusion CPT-11 (modified PMC). After three courses of modified PMC, a complete response (CR) of the hepatic metastatic lesions was noted. PMC/CPT-11 therapy was managed at our outpatient clinic, and seems to be a useful treatment option.     

Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms

Nasu-Hakola disease (NHD) is an autosomal recessive disorder characterized by presenile dementia and bone cysts. Finnish patients revealed a large deletion in DAP12 gene encoding a key element for transducing activation signal. The authors examined six Japanese cases for DAP12 alleles. Five of the six had loss-of-function mutation, either a single-base deletion or a novel point mutation. The single patient without mutation normally expressed DAP12 protein. Japanese NHD has at least three genetic forms regarding DAP12.     

Immunocytochemical localization of synphilin-1, an α-synuclein-associated protein, in neurodegenerative disorders

Alpha-synuclein is a major component of Lewy bodies (LB) in Parkinson's disease (PD) and dementia with LB (DLB), as well as of glial cytoplasmic inclusions (GCI) in multiple system atrophy (MSA). Recently, a novel protein called synphilin-1 has been identified that associates with alpha-synuclein, and it has been reported that co-transfection of both alpha-synuclein and synphilin-1 in mammalian cells yielded eosinophilic cytoplasmic inclusions resembling LB. Immunocytochemical and ultrastructural investigations have now been performed on the brain of patients with various neurodegenerative disorders using anti-synphilin-1 antibodies. These antibodies immunostained the neuropil in a punctate pattern throughout the brain of control subjects. In PD, most LB observed in the brain stem were positive for synphilin-1. These LB showed intense staining in their central cores, but their peripheral portions were only weakly stained or unstained. Pale bodies and Lewy neurites, which were positive for alpha-synuclein, were synphilin-1 negative. In DLB, a small fraction of cortical LB were immunolabeled by anti-synphilin-1. In MSA, numerous GCI were positive for synphilin-1. Immunoelectron microscopy revealed that the reaction product was localized within filamentous and circular structures in LB. Various neuronal and glial inclusions in neurodegenerative disorders other than LB disease and MSA were synphilin-1 negative. These findings suggest that abnormal accumulation of synphilin-1 is specific for brain lesions in which alpha-synuclein is a major component.     

Neuronal migration disturbance and consequent cytoarchitecture in the cerebral cortex following transplacental administration of methylmercury

To understand the effects of methylmercury (MeHg) on neuronal migration in the developing cerebral cortex, we performed double administrations of MeHg and 5-bromo-2-deoxyuridine (BrdU) to pregnant rats on different embryonic days (E11, E13, E16 or E21). Histopathological examination of a proportion of the offspring on postnatal day 28 revealed no apparent cytoarchitectural abnormalities in the primary motor and primary somatosensory cortices of the cerebrum. Morphometric analysis revealed no significant differences in total neuron population in either of these areas, and no differences in subpopulations of cells in any of the cortical layers, between any of the MeHg-exposed groups and the control animals. However, BrdU immunohistochemistry revealed an abnormally widespread distribution of the labeled cells throughout cortical layers II-VI of offspring exposed to MeHg on E16 and E21, indicating disruption of the inside-out pattern of neuronal migration. We examined one aspect of cell-fate determination by applying immunohistochemistry with antibodies against calbindin, parvalbumin, calretinin, and gamma-aminobutyric acid, but found no differences in the topographic distributions of the antibody-labeled cells in the cortex between the controls and the MeHg-exposed offspring. These results suggest that it is the extrinsic circumstances - rather than the timing of neuron generation - that regulates the expression of these proteins.