PURPOSE: The aim of this multicenter prospective study was to evaluate the role of intratumoral parameters related to fluorouracil (FU) sensitivity in 103 metastatic colorectal cancer patients receiving FU-folinic acid. PATIENTS AND METHODS: Liver metastatic biopsy specimens were obtained for all patients and primary tumor biopsy specimens for 54 patients. Thymidylate synthase (TS), folylpolyglutamate synthetase, and dihydropyrimidine dehydrogenase were measured by radioenzymatic assays; TS promoter polymorphism (2R/2R v 2R/3R v 3R/3R) was determined by polymerase chain reaction; and p53 protein and mutations were analyzed by immunoluminometric assay and denaturing gradient gel electrophoresis, respectively. RESULTS: p53 mutations were observed in 56.7% of metastases. TS activity was significantly higher in 2R/3R tumors as compared with 2R/2R or 3R/3R. TS activity in metastasis was the only parameter linked to clinical responsiveness (responders exhibited the lower TS, P =.047). Univariate Cox analyses demonstrated that TS activity in primary tumor (the greater the TS, the poorer the survival; P =.040), TS promoter polymorphism in primary tumor (risk of death of 2R/3R v 2R/2R, 2.68; P =.035), and p53 stop mutation in metastasis (risk of death of stop mutations v wild type, 3.14; P =.018) were the only significant biologic predictors of specific survival. Stepwise analysis did not discriminate between TS activity and TS polymorphism. CONCLUSION: Present results confirm the value of tumoral TS activity for predicting FU responsiveness, point out the importance of detailed p53 mutation analysis for predicting survival, and suggest that TS genotype in primary tumor carries a prognostic value similar to that of TS activity. 相似文献
PURPOSE: To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy. RESULTS: Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033). CONCLUSION: Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease. 相似文献
Purpose. We have studied the antinociceptive activity and blood andbrain delivery of nasal morphine with or without Biovectornanoparticles in mice.
Methods. A tail flick assay was used to evaluate theantinociceptive activity. The kinetics of morphine were evaluated in blood andbrain, using tritiated morphine as tracer.
Results. These nanoparticles were shown to increase the durationof the antinociceptive activity of morphine after nasal administration.This effect was not due to an increase of morphine in the blood; andthe analgesic activity of morphine in association with nanoparticleswas reversed by naloxone. The ED50 value was 33.6 ±15.6 mg/kg for morphine alone and 14.4 ± 7.6 mg/kg in presenceof nanoparticles. They were only effective at low doses (1.5 to 2.5 g),a higher or a lower dose had no effect. No interaction was found betweennanoparticles and morphine. NaDOC, a permeation enhancer, was unable toimprove nasal morphine activity.
Conclusions. These results show the presence of nanoparticles onlyat a very specific dose increases the antinociceptive activity of nasalmorphine in mice. The occurrence of a direct transport of morphinefrom the nasal mucosa to the brain is discussed. 相似文献
Objective: Given the possibility of a male contraceptive pill in the near future, understanding men’s attitudes towards this contraceptive method is crucial, especially in high-risk populations with limited access to education. This research was conducted to identify the determinants of Mozambican men’s willingness to use a contraceptive pill when it is made available.
Methods: A sample of 412 Mozambican men was presented with 36 vignettes comprising four within-subject factors (cost of pills, pill efficacy, side effects and context). Each vignette presented a scenario in which a man is asked by his partner to use the contraceptive pill, and participants indicated their own willingness to use the pill under each circumstance.
Results: Cluster analysis revealed that participants took one of four different positions regarding their willingness to use a contraceptive pill: never (11%); depends on side effects alone (25%); depends on side effects and costs (11%); depends on side effects and context (46%). These positions were associated with participants’ sociodemographic characteristics.
Conclusion: Among the Mozambican men in this study, a minority appeared to believe that the responsibility for contraception should be shared between sexual partners. Men’s willingness to use a contraceptive pill was, however, more pronounced in the case of serious medical risk to their partner. Overall, only about one-fifth of participants were either reluctant or unwilling to consider using a male contraceptive pill. 相似文献
From 29 June to July 1998, four cases of legionnaires disease in British citizens were reported to the Reseau National de Sante Publique (RNSP) by the statutory notification system (declaration obligatoire (DO)) and by theEuropean Surveillance Scheme for 相似文献
Oral daily and weekly bisphosphonates represent the current mainstay of treatment for postmenopausal osteoporosis (PMO). However, the inconvenience of frequent dosing is known to negatively affect adherence to therapy in the long term. This has prompted the development of convenient oral bisphosphonate regimens that feature simple, less frequent dosing schedules. Such regimens require high potency agents, which can be given at low effective doses and that also have good tolerability. Ibandronate is a potent, nitrogen-containing bisphosphonate with proven efficacy when given intermittently to estrogen-depleted beagle dogs, rats and cynomolgus monkeys. Clinically, a pivotal prospective study has established that oral ibandronate has significant vertebral fracture efficacy in PMO, whether given daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months; extended between-dose interval >2 months). Both oral regimens were well tolerated, which is noteworthy as patients with a history of gastrointestinal (GI) disturbance were not specifically excluded. As a result of these findings, a large, multinational, randomized, double-blind study (Monthly Oral iBandronate In LadiEs: MOBILE) is currently exploring the non-inferiority of once-monthly oral ibandronate (100 or 150 mg) to the oral daily ibandronate (2.5 mg) regimen with proven anti-fracture efficacy, in terms of lumbar spine bone mineral density (BMD) change. As with the trials investigating the weekly administration of other bisphosphonates, vertebral fracture efficacy will be inferred if the study demonstrates the non-inferiority of once-monthly ibandronate to the proven oral daily regimen in terms of spinal BMD change. The availability of this once-monthly ibandronate regimen is expected to offer benefits in terms of convenience (by having to follow dosing recommendations once a month vs. once daily or weekly) and potentially tolerability (by reducing the potential for upper GI irritation that can result from frequent, repeated exposure). Greater convenience and tolerability may enhance the therapy adherence and, hence, improve long-term therapeutic outcomes in PMO. 相似文献
The permeability transition pore (PTPC), a polyprotein complex, participates in the mitochondrial homeostasis as well as in the mitochondrial phase of the intrinsic pathway of apoptosis. It integrates multiple death signals including alterations of the intracellular milieu, translocation of pro-apoptotic members of the Bax/Bcl-2 family, p53, and viral proteins. As a consequence, PTPC can act as a coordinator of the pro-apoptotic mitochondrial membrane permeabilization process and the release of pro-apoptotic intermembrane space proteins into the cytosol. Moreover, the deregulation of PTPC has been involved in several major human pathologies such as cancer, neurodegeneration, ischemia/reperfusion, aging, as well as hepatotoxicity. Therefore, PTPC has emerged as a promising potential therapeutic target. Here, we will review the current knowledge concerning the two opposite functions of the PTPC and its implication in various pathologies. We will discuss the possibility to target this complex with peptides to modulate apoptosis in an innovative therapeutic perspective. 相似文献
Necrotizing pneumonia caused by Staphylococcus aureus strains carrying the Panton-Valentin leukocidin gene is a newly described disease entity. We report a new fatal case of necrotizing pneumonia. An S. aureus strain with an agr1 allele and of a new sequence type 377 was recovered, representing a new, emerging, community-acquired methicillin-resistant clone. 相似文献