A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer.

BACKGROUND: Capecitabine (Xeloda) is a novel, oral, selectively tumor-activated fluoropyrimidine with proven activity in the treatment of advanced colorectal cancer. This trial was conducted to evaluate the efficacy, safety and feasibility of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer, with a view to replacing 5-fluorouracil (5-FU) in such patients. PATIENTS AND METHODS: Forty-four patients received capecitabine 1250 mg/m2 twice daily (2500 mg/m2/day) for 14 days followed by 7 days of rest, for up to six cycles. RESULTS: Capecitabine produced an objective response rate of 34% (all partial responses) and stable disease in 14 patients (30%). The median time to disease progression (TTP) was 3.2 months [95% confidence interval (CI) 2.7-6.4 months] and median overall survival was 9.5 months (95% CI 6.9-13.2 months). Hand-foot syndrome (HFS), nausea, anorexia, diarrhea and vomiting were the most common adverse events. While HFS was the most frequent grade 3/4 toxicity (National Cancer Institute Common Toxicity Criteria), only 9% of patients experienced grade 3 HFS. Severe myelosuppression was not reported during the study. CONCLUSIONS: Capecitabine monotherapy is active and well tolerated as first-line therapy in patients with advanced/metastatic gastric cancer. Larger comparative trials investigating capecitabine-based combination regimens in patients with advanced gastric cancer are warranted.     

Neuronal apoptosis after CNS injury: the roles of glutamate and calcium

While a role has been well established for excitotoxic necrosis in the pathogenesis of traumatic or ischemic damage to the CNS, accumulating evidence now suggests that apoptosis may also be a prominent contributor. In this review we focus on the role of glutamate and attendant intracellular calcium influx in triggering or modifying excitotoxic necrosis and apoptosis, raising the possibility that calcium influx may affect these two death pathways in opposite directions. Incorporating consideration of both pathways will probably be needed to develop the most effective neuroprotective treatments for CNS injury.     

High glucose inhibits glucose uptake in renal proximal tubule cells by oxidative stress and protein kinase C

BACKGROUND: High glucose has been considered to play an important role in alteration of renal proximal tubule transporter's activity. This study examined the mechanism by which high glucose modulates alpha-methyl-D-glucopyranoside (alpha-MG) uptake in primary cultured rabbit renal proximal tubule cells (PTCs). METHODS: PTCs were incubated with 25 mmol/L glucose alone or combined with taurine, ascorbic acid, catalase, staurosporine, and bisindolylmaleimide I. Then alpha-MG uptake and lipid peroxide (LPO) formation were examined. RESULTS: Twenty-five mmol/L glucose from four hours, but not 25 mmol/L mannitol, inhibited alpha-MG uptake by 23% compared with 5 mmol/L glucose (control). In the study to examine the relationship of oxidative stress in the high-glucose-induced inhibition of alpha-MG uptake, 25 mmol/L glucose significantly increased LPO by 27% compared with control. However, 10 mmol/L glucose did not affect alpha-MG uptake and LPO formation. Taurine (2 mmol/L), ascorbic acid (1 mmol/L), endogenous antioxidants, or catalase (600 U/mL) significantly blocked 25 mmol/L glucose-induced increase of LPO formation and inhibition of alpha-MG uptake. In the experiment to examine the effects of protein kinase C on LPO formation, 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 ng/mL) increased LPO formation, and staurosporine (10(-7) mol/L) and bisindolylmaleimide I (10(-6) mol/L) totally blocked 25 mmol/L glucose-induced increase of LPO formation and inhibition of alpha-MG uptake. In addition, taurine reduced TPA-induced increase of LPO formation and inhibition of alpha-MG uptake. CONCLUSION: High glucose induces, in part, the inhibition of alpha-MG uptake through LPO formation, and activation of protein kinase C may play a role in high-glucose-induced LPO formation in the primary cultured rabbit renal PTCs.     

Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors

In a retrospective study, the prognostic value of monitoring the decay of alpha-fetoprotein (AFP) was assessed. Serum AFP was determined serially in 18 children with malignant germ-cell or hepatic tumors: 7 endodermal sinus tumor, 3 embryonal carcinoma, 5 malignant teratoma, 2 hepatoblastomas, and 1 hepatocellular carcinoma. The actual half-life (AHL) of AFP was computed after surgical resection of the tumor. In group 1, which had complete resection and no recurrence during follow-up (n = 13), the AHL of AFP was 4.0 ± 0.9 days. In group 2, which had incomplete resection or recurrence during follow-up (n = 5), the AHL of AFP was 24.8 ± 20 days, significantly longer than that of group 1 (P = 0.0026). The increased AHL of AFP indicated residual active tumor after surgical resection. The AHL of AFP may be more sensitive than serial monitoring of AFP in detecting preclinical recurrence after surgical resection of AFP-secreting tumors. Treatment strategies can be based on AFP clearance, and prospective clinical trials are warranted.     

Radiation Therapy Results for Patients Undergoing Inappropriate Surgery in the Presence of Invasive Cervical Carcinoma

Total vaginal or abdominal hysterectomy was considered an inadequate treatment method for invasive uterine cervix cancer. Usually the procedure was inadvertently performed on patients who were thought preoperatively to have benign or premalignant conditions. Between 1985 and 1993, 64 patients undergoing hysterectomy in the presence of invasive cervical cancer were treated with external radiation therapy and/or intracavitary radiotherapy. Preoperative diagnoses were carcinomain situ(36), severe dysplasia (2), and early invasive cancer (14), and others were benign disease. Overall 5-year survival and relapse-free survival rates were 75.8 and 77.5%, respectively. For patients in retrospective stage IA, IB, and IIB (gross residual after surgery), overall 5-year survival rates were 90.9, 88.8, and 27.9%, respectively. Thirteen patients developed treatment failure; most of them (10/13) were patients with gross residual disease. Patients with early invasive cervical cancer (stage IA) had no treatment-related failure. Prognostic factors affecting survival by univariate analysis were retrospective stage (P= 0.0000) and preoperative diagnosis (P= 0.0021). Tumor histology was marginally significant factor (P= 0.0938). By multivariate analysis, only retrospective stage was significant prognostic factor (P= 0.0001). Adjuvant radiotherapy appears to be an effective treatment method for patients with presumed stage IA and IB after inadvertent hysterectomy. Survival for patients with gross disease remaining after inappropriate hysterectomy is poor. So, early cancer detection and proper management with precise pretreatment staging is necessary to avoid inadherent hysterectomy, especially in cases of gross residual disease.