Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Cytochrome P450 (CYP) 2A6 and CYP2E1 are enzymes with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogens. The polymorphic CYP2A6 and CYP2E1 have been implicated in increased susceptibility to certain malignancies. In our study, 120 Japanese patients with gastric adenocarcinoma and 158 healthy controls were compared for frequencies of CYP2A6 and CYP2E1 genotypes. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion allele, which causes lack of the enzyme activity, was significantly higher in the gastric cancer patients than in the healthy control subjects (OR = 3.14, 95% confidence interval (95% CI) = 1.05-9.41). Subdividing gastric adenocarcinoma according to tumor differentiation, patients with the well-differentiated type were 4.9-fold more likely to have the CYP2A6 homozygote deletion genotype (OR = 4.91, 95% CI 1.17-20.52). Stratifying by smoking status, we did not find the risk of CYP2A6 gene deletion allele in gastric adenocarcinoma. The CYP2E1 polymorphism detected by RsaI was not significantly different between gastric adenocarcinoma patients (40.8%) and the control population (44.3%). No statistically significant changes were observed when the CYP2E1 genotype was examined relative to tumor differentiation and smoking status. These results suggest that the CTY2A6 deletion is associated with gastric adenocarcinoma among Japanese populations.     

Locoregional adoptive immunotherapy resulted in regression in distant metastases of a recurrent esophageal cancer

 Esophageal cancer is one of the most common malignant diseases. However, postoperative recurrences are still resistant to currently available radiochemotherapy. We recently reported a study on the initial clinical efficacy of locoregional adoptive immunotherapy for advanced esophageal cancer. We report here our clinical experience of remarked responses in distant metastatic lesions in a patient with recurrent cancer after receiving this immunotherapy. A male patient underwent curative surgery, and presented with multiple recurrent metastases in the supraclavicular lymph nodes (LNs), liver, and abdominal aortic LNs. Autologous tumor-activated lymphocytes (AuTLs) generated ex vivo were regionally injected into supraclavicular LNs every 2 weeks 13 times. Mean numbers of the administrated cells were 0.8 × 10⁹ cells/injection. AuTLs established from peripheral blood lymphocytes stimulated by autologous tumor cells with interleukin-2 were tested for their cytotoxicity before every treatment. During immunotherapy, Grade 2 diarrhea and fever were observed. The clinical partial responses were obtained in all lesions and were sustained for 11 months. Because clinical toxicity was tolerable, this immunotherapy might be useful for patients with far-advanced esophageal cancers. Received: June 19, 2002 / Accepted: September 26, 2002 Correspondence to:U. Toh     

Intraarterial cellular immunotherapy for patients with inoperable liver metastases of esophageal cancer

PURPOSE: We report 2 patients with refractory liver metastatic tumor after esophagectomy for advanced esophageal cancer, who responded markedly to locoregional cellular immunotherapy by repeated intraarterial infusions of autologous tumor cell-activated T lymphocytes (AuTL), even after they failed the standard chemotherapy of cisplatin (CDDP) and 5-fluorouracil (5-FU). METHODS: AuTL administrations were made through the hepatic artery via a subcutaneous reservoir located at the right upper leg. Six injections were administered to both patients, repeated at 2-week intervals. The total number of administered T cells reached 2.4 x 10(9) and 3.1 x 10(9), respectively. RESULTS: A 39% and 51% regression in each infused field, compared with the size of liver tumor before treatment, was observed by computed tomography (CT) scan in patient 1 and 2, respectively. The responses continued up to the 10th and 11th month after the intraarterial infusion, confirmed by follow-up CT scan. The adverse effects of intraarterial immunotherapy were tolerable, with grade 1-2 fever and nausea in each patient. CONCLUSIONS: Clinical regression of liver metastases of esophageal cancer was observed in both patients who received this intraarterial cellular immunotherapy. Liver metastases of esophageal cancer may be controlled effectively and safely by repeating the intraarterial AuTL infusion as a locoregional immunotherapy over a long period.     

Serum cytokine level during continuous venovenous hemofiltration in toxic shock-like syndrome due to group G beta Streptococcus bacteremia in a patient with idiopathic thrombocytopenic purpura

We report a case of toxic shock-like syndrome due to a rare infection of group G Streptococcus bacteremia in a patient with idiopathic thrombocytopenic purpura and its successful treatment with continuous venovenous hemofiltration (CVVH). As the result of sepsis treatment with CVVH, in addition to administration of vasopressors and antibiotics, serum levels of interleukin-1beta, interleukin-10 and tumor necrosis factor-a fell and shock was controlled.     

Effects of alcohol and oxidative stress on liver pathology: the role of the mitochondrion

This article represents the proceedings of a symposium at the 2001 Research Society on Alcoholism meeting in Montreal, Canada. The chairs were Alan Cahill and Carol C. Cunningham. The presentations were (1) Mitochondrial regulation of ethanol-induced hepatocyte apoptosis: possible involvement of proapoptotic Bcl-2 family protein Bax, by Masayuki Adachi and Hiromasa Ishii; (2) Effects of ethanol on mitochondrial reactive oxygen species production and oxidative protein modification, by Shannon M. Bailey; (3) Acute ethanol binges elicit widespread oxidative mitochondrial DNA damage and depletion: protective effects of antioxidants and inhibitors of ethanol metabolism, by Bernard Fromenty; and (4) Effects of chronic ethanol consumption upon hepatic mtDNA oxidative modification and depletion, by Alan Cahill and Adrian Davies.     

Relationships between surface-detected EMG signals and motor unit activation

INTRODUCTION: Surface-detected electromyographic (S-EMG) signals are used in exercise science to assess the extent of muscle activation, muscle fatigue, and neural activity during muscle contraction. However, the relationship has not been studied between S-EMG signal amplitude and motor unit activation at different muscle force levels. METHODS: S-EMG signals were measured from 76 healthy subjects during target force levels of 5, 10, 20, 30, and 50% of maximal voluntary contraction (MVC) of the knee extensors over 20-30 s. Mean absolute S-EMG amplitude, surface-detected motor unit action potential amplitude (S-MUAP), motor unit mean firing rate (mFR), and motor unit mean voltage, which is the product of S-MUAP amplitude and mFR, were assessed in the vastus medialis by using EMG signal-decomposition and spike-triggered averaging techniques. RESULTS: Motor unit mean voltage increased to the same degree as mean absolute S-EMG amplitude with increasing force, implying that motor unit size and firing rate explain the increase in mean absolute S-EMG amplitude with increasing force generation. In addition, mean absolute S-EMG amplitude increased linearly during the course of each 20-30 s contraction, with the slope being greater at higher force levels. A small change was observed in the shape of needle-detected motor unit action potentials during the contraction, but this change was not sufficient to explain the large change in mean absolute S-EMG amplitude during the contraction. CONCLUSION: Mean absolute S-EMG amplitude at different force levels and its changes during the course of a submaximal contraction are dependent on the number of motor units active, their size, and firing rates.     

HLA-A2-restricted cytotoxic T lymphocyte activity during interferon beta therapy in patients with chronic hepatitis C

BACKGROUND AND AIMS: Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) may contribute to viral clearance and liver cell injury in patients with chronic hepatitis C. In the present study, we attempted to determine the serial HCV-specific CTL activity during interferon-beta (IFN-beta) therapy in patients with chronic hepatitis C and whether there is any relationship between the CTL response and clinical response to IFN-beta therapy. METHODS: Eight HLA-A2-positive patients with chronic hepatitis C were treated initially with 6 million U/ml of IFN-beta every day for 8 weeks and then 3 times weekly for the subsequent 16 weeks. Peripheral blood mononuclear cells (PBMC) were collected before the start, 4 weeks after the start, and after the end of IFN treatment and were stimulated with 2 peptides corresponding to core sequences, which were previously reported to have an HLA-A2 restricted-CTL epitopes. Cytolytic activity was determined by a standard 51Cr-release assay using allogenic HLA-matched EBV-transformed B lymphoblastoid cell lines (B-LCL). RESULTS: HCV-specific CTL responses were detected in 2 of the 8 patients before treatment with IFN-beta. One of 2 patients was not observed HCV-specific CTL responses after 4 weeks of IFN-beta treatment, however these two patients showed CTL responses at the end of IFN-beta treatment, and finally HCV-RNA was negative. In addition, HCV-specific CTL responses were observed in 4 patients after 4 weeks of IFN-beta treatment. Three of these 4 patients showed CTL responses only at 4 weeks after IFN-beta treatment. However, there were no differences between clinical parameters or between IFN efficacy in HCV specific CTL response-positive (n = 4) and -negative (n = 4) patients at 4 weeks after the start of IFN-beta treatment. CONCLUSIONS: These findings suggest that there are few relations between peripheral HCV-specific CTL response and clinical response to IFN therapy in patients with chronic hepatitis C, although IFN enhances the host immune response against HCV synergistically with antiviral activities.     

Alcoholic liver diseases and hepatitis virus C in Japan]

Recently incidence of alcoholic liver disease (ALD) has been increasing in Japan associated with an increase in alcoholic beverage consumption. There have been a large number of reports about the relationship between alcohol and hepatocarcinogenesis, but it remains controversial. In the present study, we addressed the recent trend in incidence of ALD including liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in heavy drinkers in Japan. We carried out nation-wide survey by asking for the hospitals that are approved by the Japanese Society of Gastroenterology for recent aspects of in-patients with ALD. Except for HCC, percentage of ALD without viral hepatitis is more than 70%, which is increased when compared to the national survey carried out in 1992. In alcoholic LC patients, those who did not have viral hepatitis were 81%. However, the percentage of HCC without viral hepatitis was 34% of all of the heavy drinkers with HCC. Regarding the case in our university hospital, 138 cases (32%) of 432 patients with HCC were heavy drinkers. However, regarding in our general hospital, 15 cases of 23 patients with HCC (61%) were heavy drinkers. In conclusion, since the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers.     

Alveolar echinococcosis of the liver in children

Alveolar echinococcosis of the liver is uncommon in childhood. We have treated 124 patients with this disease in our hospital over the past 50 years; 7 of them were less than 15 years old (4.7%). Five were females and 2 were males. In adults, it takes more than 10 years after infestation for clinical symptoms to develop. Alveolar echinococcosis in children seems to progress more rapidly than in adults. Among the first 3 pediatric patients, 2 had hepatomegaly and the 3rd was detected due to liver dysfunction. The last 4 were detected by serologic tests and ultrasonographic examination in connection with mass screening, as the lesions were too small to produce symptoms except in 1 case. The 1st patient had an unresectable lesion and died after 3 years. Hepatectomy was performed in 6 cases: 1 lateral segmentectomy, 4 lobectomies, and 1 partial hepatectomy. The patients are all alive and doing well at 1, 5, 8, 10, 18, and 19 years, respectively, after operation. Early diagnosis and complete removal of the lesion are indispensable to a good prognosis. Alveolar echinococcosis occurs in limited areas, so that mass screening can be effectively performed.     

Intratumoral pyrimidine nucleoside phosphorylase (pynpase) activity predicts a selective effect of adjuvant 5’-deoxy-5-fluorouridine (5’ dfur) on breast cancer

BACKGROUND: Pyrimidine nucleoside phosphorylase (PyNPase) is the enzyme that converts 5'-deoxy-5-fluorouracil (5'DFUR) to 5-fluorouracil (5FU). Its activity in cancer tissue may correlate with the selective antitumor activity of 5'DFUR in breast cancer. METHODS: Two hundred and sixteen T2 breast cancer patients were treated consecutively with surgery followed by 5'DFUR (600 mg/body/day) + tamoxifen (20 mg/body/day) for 2 years. PyNPase activity in breast cancer tissue, determined by high-performance liquid chromatography, ranged from 4.2-626.0 micrograms FU/mg protein/hr (mean +/- SD, 203.5 +/- 122.4), and the examined patients were divided into two groups: group A (high PyNPase group), cases with the PyNPase activity equal to or more than the mean value of 203.5 micrograms FU/mg protein/hr, and group B (low PyNPase group), cases with activity less than the mean value. RESULTS: Although there was no difference in relapse-free survival (RFS) between groups A and B, among node-positive patients (n = 83) those in group A tended to have a longer RFS. When divided into subgroups according to estrogen receptor (ER) status, among node-positive and ER-positive tumors (n = 49), the RFS was significantly better in group A than in group B (p < 0.05). CONCLUSION: Intratumoral PyNPase activity might be of use as a predictor of the effect of adjuvant 5'DFUR on breast cancer.