Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial.

BACKGROUND: Docetaxel is a widely accepted second-line treatment in advanced non-small-cell lung cancer (NSCLC) with a risk of myelotoxicity. This study evaluated the efficacy and toxicity profile of two docetaxel regimens in NSCLC patients who had failed first-line non-docetaxel-based chemotherapy. PATIENTS AND METHODS: A total of 259 patients from 33 Spanish centers were randomized to receive either docetaxel 75 mg/m(2) administered every 3 weeks (3W arm) or docetaxel 36 mg/m(2) given weekly (1W arm) for 6 weeks followed by 2 weeks of rest. The primary end point was 1-year survival; secondary end points were median survival, time to progression, response and toxicity. RESULTS: One-year survival was 27% in the 3W and 22% in the 1W arm. Median time to progression was also similar in the two arms. Median survival was 6.6 months in the 3W arm versus 5.4 months in the 1W arm (P = 0.075). Response rates were 9.3% in the 3W arm and 4.8% in the 1W arm. More patients in the 1W arm experienced mucositis [1W, nine patients (7.2%); 3W, two patients (1.6%); P = 0.032], while febrile neutropenia was significantly higher in the 3W arm [3W, 10 patients (7.8%); 1W, one patient (0.8%); P = 0.010]. CONCLUSIONS: Both weekly and 3-weekly docetaxel were effective and well-tolerated, with different toxicity profiles. In general, there was no indication to recommend the weekly schedule. However, the significant lower rate of febrile neutropenia observed in the weekly schedule makes it a good alternative for patients at risk of severe neutropenia.     

Whipple's disease with isolated central nervous system symptomatology diagnosed by molecular identification of Tropheryma whippelii in peripheral blood

We report a new case of Whipple's disease (WD) confined to the central nervous system. The patient presented with ataxia, ophthalmoplegia, hypersomnia, hemiparesis and generalized myorhythmia. The diagnosis was confirmed by identification of specific sequences of the causal agent of WD, the actinobacteria Tropheryma whippelii (TW), by PCR of DNA extracted from peripheral blood. An epidemiological survey of TW in patients with dementia suggests that WD is an uncommon cause of dementia in our population. Molecular methods may allow rapid identification of TW in peripheral fluids, and non-invasive diagnosis of this disorder.     

Serum levels of coenzyme Q10 in patients with amyotrophic lateral sclerosis

Summary. To elucidate whether serum coenzyme Q₁₀ levels are related with the risk for amyotrophic lateral sclerosis (ALS), we compared serum levels of coenzyme Q₁₀ and the coenzyme Q₁₀/cholesterol ratio, in 30 patients with ALS and 42 matched controls using a high performance liquid chromatography technique. The mean serum coenzyme Q₁₀ levels and the coenzyme Q₁₀/cholesterol ratio did not differ significantly between the 2 study groups. These values were not influenced by the clinical form (spinal vs. bulbar) of ALS, and they did not correlate with age, age at onset, and duration of the disease. These results suggest that serum coenzyme Q₁₀ concentrations are unrelated with the risk for ALS. Received September 1, 1999; accepted January 4, 2000     

Experimental discordant hepatic xenotransplantation in the recipient with liver failure: implications for clinical bridging trials

BACKGROUND: Clinical xenotransplantation might start with bridge-to-bridge trials. Situations where hyperacute rejection is avoided would provide opportunities for the initiation of bridging trials. Patients with liver failure have a diminished capacity to initiate antibody and complement-induced injury of xenogeneic endothelium. Hyperacute rejection of a liver xenograft manifests as a coagulopathy. We examined the ability of a recipient with liver failure to hyperacutely reject a liver xenograft in the dog-to-pig model in the immediate postoperative period. STUDY DESIGN: Liver failure in pigs was induced with galactosamine. Canine livers were transplanted into pigs with liver failure and into healthy pigs. The postoperative course was monitored for 1 hour for histologic changes in the xenograft, changes in platelet counts, and whole blood clotting with Sonoclot analysis. In vitro assays with pig serum and canine hepatic sinusoidal endothelial cells were used to assess the effect of liver failure on serum cytotoxicity and xenoreactive antibody levels. RESULTS: All untreated pig recipients of liver xenografts died from a coagulopathy. Recipients with liver failure manifested no signs of coagulopathy, and had minimal change in platelet counts or Sonoclot (Sienco Inc., Morrison, CO) tracings. Liver xenograft biopsies from recipients with liver failure showed no evidence of the tissue injury that characterized the biopsies of control recipients. Serum from pigs was less cytotoxic to the canine hepatic sinusoidal endothelium after induction of liver failure. The xenoreactive antibody levels and repertoire were similar in the pig serum before and after liver failure was induced. CH50 (total complement) levels were diminished in pigs after the induction of liver failure. CONCLUSIONS: Liver xenotransplantation used in bridging trials in recipients with liver failure might not face the barrier of hyperacute rejection.     

Superior therapeutic profile of poly-L-glutamic acid-paclitaxel copolymer compared with taxol in xenogeneic compartmental models of human ovarian carcinoma.

Previous preclinical studies with ectopic tumor models have demonstrated remarkable improvements in the therapeutic profile of paclitaxel, formulated as a copolymer with poly-L-glutamic acid, compared with paclitaxel in the clinical formulation, Taxol. In this study, we evaluated these formulations in two human ovarian carcinoma xenograft models, NMP-1 and HEY, in nude mice. i.p. implantation in female nude mice of either cell line gave rise to progressive disease within the peritoneum, in the parenchyma of visceral organs, and eventually at extraperitoneal sites; the resultant, increasing morbidity then required host sacrifice. i.p. administration of multiple-dose Taxol at its maximum tolerated dose 1 week after tumor implantation afforded minimal or no increased survival compared with controls in either model. Consistent with the predictions of drug copolymer behavior, paclitaxel, as the poly-L-glutamic acid-paclitaxel copolymer, displayed much less toxicity than Taxol in these hosts. When evaluated for antitumor efficacy in both the Taxol-resistant NMP-1 and HEY models, significant improvement in survival, and even some cures, were observed after a single i.p. treatment with this copolymer. The observed antitumor response correlated with histopathological analysis of peritoneal and extraperitoneal tumor burden in comparing control HEY mice sacrificed near the onset of morbidity with mice receiving paclitaxel copolymer. We conclude that both the i.p. NMP-1 and HEY models have significant value in establishing the efficacy of candidate agents, which might address Taxol-resistant human ovarian carcinoma. Furthermore, the poly-L-glutamic acid-paclitaxel copolymer has a superior therapeutic profile in these Taxol-resistant compartmental models.     

Phase I clinical and pharmacokinetic study of NSC 655649, a rebeccamycin analogue, given in both single-dose and multiple-dose formats.

PURPOSE: NSC 655649 was given in both single- and multiple-dose formats, to characterize maximum tolerated dose (MTD), toxicity, and pharmacokinetic profile. Experimental Design: Patients with advanced malignancies were treated with escalating doses of NSC 655649 in either a single-dose format (step 1) or a multiple-dose format (step 2). In step 1, NSC 655649 was given as a 30-60 min infusion. In step 2, the NSC 655649 dose was divided into three consecutive daily doses. Plasma and urine were sampled to assess the pharmacokinetic and excretory characteristics of NSC 655649. A total of 12 patients were enrolled at the MTD for the purpose of gender equity. RESULTS: Forty-three patients were treated with NSC 655649 for a total of 108 cycles in step 1, and 26 patients were treated for a total of 41 cycles in step 2. The MTD for both steps 1 and 2 was determined to be 572 mg/m(2). Myelosuppression was the dose-limiting toxicity. Local venous irritation was generally grade 1-2 in severity but could only be adequately prevented by administration of study drug through central i.v. access. One patient with adenocarcinoma of unknown primary experienced a partial response on step 1. Four patients experienced stable disease of >100 days duration. CONCLUSIONS: NSC 655649 may be safely given at an MTD of 572 mg/m(2) in both single-dose and multiple-dose formats. Optimally, this drug should be administered through central i.v. access.     

Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma.

Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new agents that bypass these resistance mechanisms. We have reported that ascorbic acid (AA) enhances the activity of arsenic trioxide (As(2)0(3)) against drug-resistant MM in vitro by depleting intracellular glutathione (GSH). These data led us to open a National Cancer Institute/Cancer Therapy Evaluation Program-sponsored Phase I/II trial of As(2)0(3) + AA for relapsed/refractory MM. We now present the completed Phase I component of this trial. The primary objective of the trial's Phase I component was to assess whether the addition of AA affected the well-described toxicity profile of As(2)0(3) alone. Correlative studies were undertaken of As(2)0(3) and AA pharmacokinetics, the ability of AA to deplete intracellular GSH in vivo, and the development of arsenic resistance. Six patients with stage IIIA relapsed/refractory myeloma were studied. We found that 0.25 mg/kg/day As(2)O(3) + 1,000 mg/day AA could be given for 25 days (over a 35-day period) without dose-limiting toxicity. One episode of grade 3 hematological toxicity (leukopenia) and no grade 3 nonhematological toxicities (in particular, cardiac) were observed. The coadministration of AA did not alter the pharmacokinetics of As(2)0(3), and elevated AA levels were associated with decreased intracellular GSH. Serial in vitro studies demonstrated continued sensitivity of patient myeloma cells to As(2)0(3) + AA. Two patients (both with thalidomide-refractory disease) had partial responses; four patients had stable disease. In conclusion, we have found that As(2)0(3) + AA has acceptable toxicity and that there is promising evidence of activity in refractory/relapsed myeloma.     

Aspectos clínicos de la biología molecular del cáncer de próstata

The recombinant DNA technology has been an invaluable tool for understanding the mechanisms of carcinogenesis. For example, we have been able to know that in our own genome there are genes with the capacity to induce transformation (oncogenes) or with the capacity to block it (tumor suppresor genes). This technology has also helped to develop new strategies for the diagnosis and treatment of cancer. Unfortunately none of the genetic changes described to date for prostate cancer (CaP), has been accepted as a universal molecular marker for clinical use. On the other hand the restitution, blockade or the acquisition of certain genetic activities have been used to control local or locally advanced CaP, by means of gene therapy. The toxicity generated by the viral vectors used in the first gene therapy-clinical trials (phases I/II) has been moderate and the results encouraging. For these reasons, gene therapy could be used as an adjuvant treatment for the management of these cases in the near future.     

The torturous road to democracy--domestic crisis in Nepal

Largely unnoticed by the outside world, an armed Maoist insurgence has wrested control of areas in 45 of Nepal's 75 administrative regions and has resulted in more than 1700 deaths since 1996.(1) State figures indicate that 1000 of these people were Maoist and about 400 were police-120 of whom died in attacks on police outposts in early April and July of 2001 alone. The remainder were "class enemies" of the "People's War"-ie, members of ruling parties. As public security collapses, the consequences for the Nepalese are random imprisonment, torture, and risk of extrajudiciary execution from both sides. Torture has increased greatly as a consequence of the insurgence, but was already deeply rooted in Nepalese authority and used as a primary approach to solving crime. More than 70% of Nepalese prisoners claim to have been tortured while in custody, and at least 50% claim they signed confessions as a result. INSEC (Informal Sector Service Centre), a human rights organisation, documented 1035 cases of state perpetrated torture in the year 2000,(2) which has been suggested to be a gross underestimate of the true figure. The long-term physical, social, and psychosocial consequences for survivors are often severe. The Centre for Victims of Torture, Nepal, a non-government organisation based in Kathmandu, has been studying the effect of torture on survivors, and has implemented Nepal's only treatment programmes for those brave enough to seek help.