Glutathione administration against cisplatin-induced nephrotoxicity does not modify its cytotoxic activity.

Glutathione (GSH) is an intracellular thiol compound which has been shown to protect against cisplatin-induced nephrotoxicity, in animal models and clinical trials. In order to determine whether GSH interferes with cisplatin activity, the lymphoma L5178Y was implanted in 50 DBA/2 mice, and then they were treated with cisplatin with or without previous GSH. Two similar experiments were carried out with three different groups: Group 1: Control group without cisplatin; Group 2: Treatment with cisplatin without GSH, and Group 3: GSH administration prior to cisplatin. Tumor area and survival have been considered as parameters to measure the activity of cisplatin. The average Values of tumor areas in the mice pretreated with GSH were not significantly different from those corresponding to the group treated with cisplatin alone. Sixty days survival was 55% and 73% in the groups pretreated with GSH and with cisplatin alone respectively, the difference was not statistically significant. In conclusion, GSH administration prior to cisplatin does not modify its cytotoxic activity.

Association of K-ras codon 12 transversions with short survival in non-small cell lung cancer.

K-ras activating point mutations appear to have a role in human lung cancer, however, the prognostic significance of these abnormalities remains unclear. The aim of our work was to clarify the role of K-ras mutations as prognostic indicators in patients affected by non-small cell lung cancer (NSCLC). We studied 94 resected primary NSCLCs for K-ras mutations by the PCR-RFLP technique, followed by sequencing. K-ras activating mutations were present in 34% of tumors, a higher incidence being detected in adenocarcinomas. Comparing the impact of K-ras mutation types, we found that K-ras transversions were associated with a shorter survival in NSCLC.

Emetic control in breast cancer patients receiving iv CMF.

Two consecutive antiemetic studies were performed in a homogeneous population of female breast cancer patients receiving i.v. CMF chemotherapy for six courses. Survival analyses (failure-free survival and emesis-free survival) were used as method of assessment of efficacy in these studies. The first of the two studies was a randomized, single-blind, placebo-controlled trial comparing three different dose levels of i.v. methylprednisolone (80 mg i.v., 250 mg i.v. and 500 mg i.v.) and placebo. 104 consecutive female breast cancer patients entered the study. There were no statistically significant differences in failure-free survival or emesis-free survival among the three methylprednisolone dose levels. Both failure-free survival and emesis-free survival were significantly superior in the three methylprednisolone arms than in the placebo group (p<0.05 to p<0.01). Since the results obtained with methylprednisolone alone in the first study were not completely satisfactory, the second study analyzed the interest of adding oral thyethylperazine (6 mg p.o. every 8 h) to i.v. methylprednisolone (80 mg) in 31 consecutive female patients scheduled to receive 6 courses of i.v. CMF. Sixty-eight percent of patients were free of emesis during the 6 courses of i.v. CMF chemotherapy with i.v. methylprednisolone plus oral thyethylperazine. This figure was significantly better than the emesis-free survival observed in methylprednisnolone-treated patients in the first study (p<0.05). Patients who did not achieve a complete response with methylprednisolone plus thyethylperazine in study 2 were treated with methyl-prednisolone (80 mg i.v.) and ondansetron (8 mg i.v. before chemotherapy and 8 mg per os every 8 h for 3 days) in subsequent courses of chemotherapy. Nearly 3/4 of such patient were rendered emesis-free with subsequent ondansetron treatment. Overall, 90% of patients obtained an excellent control of emesis with first-line methylprednisolone plus thyethylperazine or methylprednisolone-ondansetron rescue. The cost per patient of this antiemetic approach compares favorably with that of ondansetron as primary antiemetic therapy.

Experimental study of the protective effect of glutathione against cisplatin-induced nephrotoxicity.

Glutathione (GSH) is the most important intracellular thiol-compound which participates in the detoxification mechanisms of the cell. Its high affinity to react with platinum complexes would give rise to lower or non-toxic metabolites and prevent cisplatin nephrotoxicity. In order to determine if GSH can protect against cisplatin-induced renal toxicity, 120 female Wistar rats received LD-100 or LD-50 of cisplatin with or without GSH, at two different dose levels and by two different routes. Biochemical and histological changes as survival was observed in each group. The administration of GSH did not modify cisplatin LD-100. When cisplatin LD-50 was used, a significant improvement in the survival rate was observed in the group which received GSH as chemoprotector (100% vs 40%). The average values of urea and creatinine were significantly lower in the group treated with GSH (115 vs 370 mg/dl and 1.07 vs 4.02 mg/dl respectively). The degree of the tissue injury was also lower in the GSH group. The administration of GSH prior to cisplatin reduces its nephrotoxicity in this animal model. Further clinical trials are necessary to verify this protective effect when cisplatin is used as a cyclic administration and at different dose levels.

Prevalence of p53 overexpression or mutations, but not k-ras mutations, in recurrent patients affected by colorectal-carcinoma.

In order to establish prognostic indicators of poor clinical evolution in colorectal cancer, we have studied p53 abnormalities and K-ras mutations in 65 patients affected by colorectal carcinoma who had undergone radical surgery. A single event of p53 protein overexpression or p53 mutation, but not K-ras mutation, was significantly prevalent in recurrent tumors. A double event of K-ras mutation and p53 protein overexpression was prevalent in patients showing Dukes' stage C, but showed a lack of prevalence in patients who recurred. The presence of p53 protein overexpression does not assure an underlying mutation in colorectal carcinoma.

Aztreonam in association with piperacillin as an empirical antibiotic-treatment in febrile granulocytopenic patients with solid tumors.

Forty-one patients with a total of 46 febrile episodes during granulocytopenia were included in a study to evaluate the efficacy of the association of aztreonam (2 g/6 hours iv) and piperacillin (4 g/6 hours iv) as an empirical antibiotic treatment. Forty-four episodes were evaluable for efficacy and toxicity. In 24 episodes (54.5%) response to treatment (disappearance of fever and improvement in the clinical signs of infection in the first 72 hours) was observed. In the subgroup of the microbiologically documented infections, 4 out of 12 episodes (33.3%) showed response to treatment. Gram-positive microorganisms were present in 7 of these 12 episodes (58.3%). Vancomycin rescue treatment obtained a response in the majority of episodes which initially had failed. Overall survival of the treated group was 93.2%. Toxicity of the antibiotic treatment was minimal. In 5 cases there was an increase in the prothrombin time (not clinically significant). Three cases showed cutaneous rash. Two cases presented diarrhoea due to dysbacteriosis and one case presented with raised blood bilirubin levels and renal impairment. Some of these manifestations coincided with modifications in the initial treatment regimen. The association of aztreonam and piperacillin may be a useful alternative to classical empirical antibiotic treatment in patients with granulocytopenia and fever. Initial addition of vancomycin is recommended especially in centres with a high incidence of infections due to Gram-positive micro-organisms or in patients with venous catheters.

Neutropenic enteritis - a 2-case report and literature-review.

In the last decade, clinical management of neutropenic enteritis has been most controversial due to the large variability in the clinical manifestations and evolution. In this work, two-case report are presented showing the broad spectrum of symptoms and prognosis. Intestinal perforation, abscess, obstruction and pneumatosis are factors associated with poor prognosis referred in the literature, and all of which indicate an early surgical intervention. In its absence, a close medical control with hematological support and broad spectrum antibiotic therapy could be indicated. In this case, surgery should be the approach for patients with a rapidly progressive evolution or massive or continuous intestinal bleeding, in spite of the conservative therapy.