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At least 1,063 records · Page 59Linked to original sources
PubMed2003

A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer.

Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 mug m(-2). In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44-68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1-29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole-blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.

Adult↗
PubMed2004

Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer.

In this phase II, multicentre trial, patients with metastatic breast cancer (MBC) were treated with a combination of gemcitabine, epirubicin and paclitaxel (GET). The primary objective of this study was to determine the tolerability and activity in terms of complete responce (CR) and overall response rate of the GET combination in this patient population. Patients with no prior treatment for MBC, and at least one bidimensionally measurable lesion received gemcitabine 1000 mg m(-2) intravenously (i.v.) over 30 min on days 1 and 4, followed by epirubicin i.v. at 90 mg m(-2) on day 1, and paclitaxel 175 mg m(-2) over 3 h on day 1, every 21 days, up to eight courses. From May 1999 to June 2000, 48 patients were enrolled from seven Italian institutions. A total of 297 chemotherapy courses were administered with a median of six cycles patient(-1) (range 1-8). Seven patients (15%) obtained CR and 27 patients (56%) had partial responce, for an overall response rate of 71% (95% CI: 58.3-83.7). After a median follow-up of 23.7 months (range 7.0-34.4), median progression-free survival was 10.5 months (95% CI: 9.2-11.7), and median overall survival 25.9 months. The main haematological toxicity consisted of grade 3 or 4 neutropenia that occurred in 62% of cycles (22% grade 4 and 40% grade 3). The GET combination is active and well tolerated as first-line chemotherapy for MBC.

Adult↗
PubMed2004

Prostate cancer and body size at different ages: an Italian multicentre case-control study.

We investigated the influence of anthropometric measures at diagnosis and at different ages on prostate cancer risk using an Italian multicentre case-control study conducted between 1991 and 2002 of 1294 histologically confirmed cases and 1451 controls admitted to the same network of hospitals for acute non-neoplastic conditions. Height, weight, body mass index (BMI), waist-to-hip ratio, lean body mass 1 year before diagnosis/interview were not significantly associated with risk. However, a positive association with high BMI at age 30 years was found (odds ratio=1.2 for BMI> or =24.7 vs <22.7) and: for less differentiated prostate cancer, with BMI 1 year before diagnosis/interview. This study supports possible relationships between high body mass in young adulthood, and a tendency to high weight throughout adult life, and the risk of prostate cancer.

Age Factors↗
PubMed2004

Lack of relationship between EGFR-1 immunohistochemical expression and prognosis in a multicentre clinical trial of 93 patients with advanced primary ovarian epithelial cancer (GINECO group).

Epidermal growth factor receptor 1 (EGFR-1) overexpression is usually described as linked with a worse prognosis in a variety of tumours of epithelial origin. However, its role in ovarian cancer is still controversial. The aim of the present study was to analyse the prognostic impact of EGFR-1 in a retrospective series of 93 stage III-IV primary ovarian epithelial tumours. All patients, enrolled in a multicentre GINECO prospective clinical trial, were treated with the same platinum-based combination chemotherapy, and were followed up with a median of 69 months. Epidermal growth factor receptor 1 plasma membrane expression, assessed by immunohistochemistry on paraffin-embedded tissues, was correlated with clinical parameters as well as immunohistochemical expression results of HER-2 (c-erbB-2), BAX, BCL-2, p53 and anti-Ki-67, previously studied in the same series of patients. Positive immunostaining for EGFR-1 was seen in 31 of the 93 analysed cases (33%). No correlation was found between EGFR-1 expression and clinical parameters. No correlation was found between EGFR-1 expression and other biological markers, except for HER-2, which was limit for significance. Indeed, among the EGFR-1-negative cases, 10.3% expressed HER-2, whereas the HER-2-expressing tumours accounted for 27.6% of EGFR-1-positive cases (P=0.06). Epidermal growth factor receptor 1 overexpression had no prognostic impact on both overall and progression-free survival through univariate and multivariate analyses. The potential effect of EGFR-1 and HER-2 co-expression on targeted therapy against EGFR-1 and/or HER-2 molecules has to be further analysed.

Adult↗
PubMed2004

Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX.

This multicentre phase II study was designed to evaluate the antitumour activity and toxicity of bifractionated camptothecin (CPT-11) and 5-fluorouracil/ leucovorin (5-FU/LV) in the treatment of patients with metastatic colorectal cancer (MCC) who had been pretreated with 5-FU/LV-oxaliplatin (FOLFOX regimen). In all, 35 patients were enrolled in a two-stage trial. Treatment consisted of two daily doses of CPT-11, 90 mg m2 administered over 90 min, followed by LV, 200 mg m2 administered over 2 h plus 5-FU 400 mg m2 as a bolus and 600 mg m2 as a 22-h continuous infusion administered with disposable pumps as outpatient therapy. Toxicity was closely monitored. Response was evaluated by computed tomography scans every 8 weeks. All 35 patients were assessable for toxicity and response to treatment. Seven patients had a partial response, giving an overall response rate of 20%; 11 patients had stable disease (31.4%) and 17 progressed (48.5%). The median progression-free survival was 7.1 months and median survival was 14 months. A total of 10 patients (30%) experienced grade 3-4 toxicity, including nausea (15%), diarrhoea (12%) and neutropenia (15%), while seven patients (21%) had grade 2 alopecia. The bifractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed substantial antitumour activity and was well tolerated in this group of patients with a poor prognosis, pretreated with the FOLFOX regimen.

Adult↗
PubMed2005

Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF.

The purpose of the study was to establish the optimal dose of capecitabine (X) to be used within a multicentre, randomised study evaluating the potential roles of oxaliplatin (O) and X in chemonaive patients (pts) with advanced oesophagogastric cancer. Two by two design was used, and pts were randomised to one of four regimens and stratified for extent of disease, performance status (PS) and centre. The treatment regimens are epirubicin, cisplatin, 5-fluorouracil (ECF), EOF, ECX or EOX. Doses: E 50 mg m(-2), C 60 mg m(-2) and O 130 mg m(-2) i.v. 3 weekly; F 200 mg m(-2) day(-1) i.v. and X 500 mg m(-2) b.i.d.(-1) (escalated to 625 mg m(-2) b.i.d.(-1) after results of first interim analysis) p.o., continuously. First interim analysis was performed when 80 pts had been randomised. Dose-limiting fluoropyrimidine toxicities were stomatitis, palmar plantar erythema (PPE) and diarrhoea; 5.1% of X-treated pts experienced grade 3/4 toxicity. Protocol planned dose escalation of X to 625 mg m(-2) b.i.d.(-1) was instituted and a second interim analysis has been performed; results are presented in this paper. A total of 204 pts were randomised at the time of the protocol planned 2nd interim analysis. Grade 3/4 fluoropyrimidine-related toxicity was seen in 13.7% pts receiving F, 8.4% pts receiving X 500 mg m(-2) b.i.d.(-1) and 14.7% pts receiving X 625 mg m(-2) b.i.d.(-1). Combined complete and partial response rates were ECF 31% (95% CI 18.7-46.3), EOF 39% (95% CI 25.9-53.1), ECX 35% (95% CI 21.4-50.3), EOX 48% (95% CI 33.3-62.8). Grade 3/4 fluoropyrimidine toxicity affected 14.7% of pts treated with X 625 mg m(-2) b.i.d.(-1), which is similar to that observed with F, confirming this to be the optimal dose. The replacement of C by O and F by X does not appear to impair efficacy. The trial continues to total accrual of 1000 pts.

Administration, Oral↗
PubMed2005

Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study.

The combination of intravenous (i.v.) vinorelbine and epirubicin is highly active in the treatment of metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated a regimen alternating i.v. and oral vinorelbine in combination with epirubicin as first-line chemotherapy of patients with MBC. In all, 49 patients with MBC received, as first-line treatment, a combination regimen consisting of i.v. vinorelbine 25 mg m(-2) plus epirubicin 90 mg m(-2) given on day 1, and oral vinorelbine 60 mg m(-2) on day 8 (or day 15 if neutrophils <1500 mm(-3)) every 3 weeks, in an open-label, multicentre phase II study. Treatment was to be repeated for a maximum of six cycles. The study population had a median age of 55 years, half of the patients had received prior adjuvant chemotherapy and 86% presented a visceral involvement. In all, 25 responses were documented and validated by an independent panel review, yielding response rates of 51% (95% CI: 36-66) in the 49 enrolled patients and 54.5% (95% CI: 39-70) in the 44 evaluable patients. Median durations of progression-free survival and survival were 8 and 20 months, respectively. Neutropenia was the main dose-limiting toxicity, but complications were uncommon, four patients having experienced febrile neutropenia and six having developed neutropenic infection. Other frequently reported adverse events included stomatitis, nausea and vomiting, which were rarely severe. No toxic death was reported. Among patients who received six cycles, global score of quality of life remained stable. This regimen alternating oral and i.v. vinorelbine in combination with epirubicin is effective and safe. Oral vinorelbine on day 8 offers greater convenience to the patient, and decreases the need for i.v. injection and reduces time spent in hospital. Therefore, oral vinorelbine is a convenient alternative to the i.v. form in combination regimens commonly used to treat MBC.

Administration, Oral↗
PubMed2005

Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study.

The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2x2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95% confidence intervals (CI): 0.73-1.09) for patients receiving FA and 0.99 (95% CI 0.80-1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95% CI: 0.80-1.30) and 0.94 (95% CI 0.73-1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients.

Adult↗
PubMed2006

Epoetin alfa in platinum-treated ovarian cancer patients: results of a multinational, multicentre, randomised trial.

This multicentre, open-label, controlled clinical trial assessed the effects of epoetin alfa treatment on haematologic and quality of life (QOL) parameters in 182 anaemic (Hb< or = 12 g dl(-1)) ovarian cancer patients receiving platinum chemotherapy. Patients were randomised 2 : 1 to receive epoetin alfa 10,000-20 000 IU three times weekly plus best standard treatment (BST) or BST only. Main study end points were changes from baseline in haemoglobin (Hb) level, transfusion requirements, and QOL. For the epoetin alfa group, mean Hb increased by 1.8 g dl(-1) by weeks 4-6 and was significantly increased from baseline through study end (P<0.001). The mean change in Hb from baseline was significantly (P<0.001) greater for epoetin alfa than BST patients at all post-baseline evaluations. Significantly fewer epoetin alfa than BST patients required transfusion(s) after the first 4 weeks of treatment (7.9 vs 30.5%; P<0.001). Also, significant (P< or = 0.04) differences favouring the epoetin alfa group over the BST group were found for all three median CLAS scores (Energy Level, Ability to Do Daily Activities, Overall QOL) and the median average CLAS score during chemotherapy. These findings support use of epoetin alfa to increase Hb levels, reduce transfusion use, and improve QOL in anaemic ovarian cancer patients receiving platinum chemotherapy.

Adult↗
PubMed2006

Factors influencing p53 expression in ovarian cancer as a biomarker of clinical outcome in multicentre studies.

The prognostic impact of p53 immunostaining in a large series of tumours from epithelial ovarian cancer patients in a two-centre study was analysed. The study population (n=476) comprised of a retrospective series of 188 patients (Dutch cohort) and a prospective series of 288 patients (Scottish cohort) enrolled in clinical trials. P53 expression was determined by immunohistochemistry on tissue microarrays. Association with progression-free survival (PFS) and overall survival (OS) was analysed by univariate and multivariate Cox regression analysis. Aberrant p53 overexpression was significantly associated with PFS in the Dutch and Scottish cohorts (P=0.001 and 0.038, respectively), but not with OS in univariate analysis. In multivariate analysis, when the two groups were combined and account taken of clinical factors and country of origin of the cohort, p53 expression was not an independent prognostic predictor of PFS or OS. In this well-powered study with minimal methodological variability, p53 immunostaining is not an independent prognostic marker of clinical outcome in epithelial ovarian cancer. The data demonstrate the importance of methodological standardisation, particularly defining patient characteristics and survival end-point data, if biomarker data from multicentre studies are to be combined.

Adult↗
PubMed1999

Prognostic value of uPA and p53 accumulation measured by quantitative biochemical assays in 1245 primary breast cancer patients: a multicentre study.

The purpose of this retrospective multicentre study was to assess the prognostic value of urokinase plasminogen activator (uPA) and p53 levels in a large series of primary breast cancer, using an automatic quantitative luminometric method. Samples of 1245 operable breast tumours were collected from seven French institutions and patients were followed for a median of 75 months. The median uPA and p53 levels assayed in cytosols by means of the immunoluminometric technique (LIA) were 0.31 and 0.20 ng mg(-1) of protein respectively. In univariate analysis, high levels of uPA and p53 were associated with shorter disease-specific survival, disease-free interval, and distant recurrence-free interval. The 5-year survival rates were 95.5% among patients with uPA values below the 20th percentile, and 77.5% in those with values above the 80th percentile. The 5-year survival rates were 91.0% in patients with p53 values below the 20th percentile, and 77.6% in those with values above the 80th percentile. In multivariate analysis, the risk of disease-related death increased with uPA levels after adjustment for tumour size, histological grade, lymph node involvement, and estrogen receptor status. A high level of uPA was also related to a shorter disease-free interval and distant recurrence-free interval. In node-negative patients, a high level of uPA remained strongly related to the three outcomes. When adjusted for other prognostic factors, p53 was no longer significantly related to the outcomes. Given its rapidity and simple application to routinely prepared cytosols, this LIA may be useful for evaluating the prognostic impact of uPA in primary breast cancer, particularly in node-negative patients. According to our results, the prognostic value of p53 accumulation is limited when uPA is included in multivariate analysis.

Adult↗
PubMed1998

Allogeneic bone marrow transplantation vs filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: first results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation.

In a multicentre trial involving 20 transplant centres from 10 countries haematopoietic stem cells were obtained either from the bone marrow of 33 sibling donors or from the peripheral blood of 33 such donors after administration of filgrastim (10 microg/kg/day). The haematopoietic stem cells were infused into their HLA-identical recipients suffering from acute leukaemias in remission or chronic myeloid leukaemia in chronic phase. PBPC donors tolerated filgrastim administration and leukapheresis well with the most frequent side-effects being musculoskeletal pain, headache, and mild increases of LDH, AP, Gamma-GT or SGPT. Pain and haematoma at the harvest site and mild anaemia were the most frequent complaints of BM donors. Severe or life-threatening complications were not seen with any type of harvest procedure. Time to platelet recovery greater than 20 x 10(9)/l was 15 days (95% confidence interval (CI) 13-16 days) in the PBPCT group and 19 days (CI 16-25) in the BMT group. Time to neutrophil recovery greater than 0.5 x 10(9)/l was 14 days (CI 12-15 days) in the PBPCT group as compared to 15 days (CI 15-16 days) in the BMT group. The numbers of platelet transfusions administered to PBPCT and BMT patients were 12 (range: 1-28) and 10 (range: 3-39), respectively. Sixteen patients (48%) transplanted with bone marrow and 18 patients (54%) transplanted with PBPC developed acute GVHD of grades II-IV; acute GVHD of grades III or IV developed in six (18%) and seven (21%) patients, respectively. Kaplan-Meier plots for transplant-related mortality until day 100 and leukaemia-free survival at a median of 400 days after BMT or PBPCT showed no significant differences. Administration of filgrastim and leukapheresis in normal donors were feasible and well tolerated. The number of days with restricted activity and of nights spent in hospital was lower in donors of PBPC. Transplantation of PBPC to HLA-identical siblings with early leukaemia resulted in earlier platelet engraftment. The incidence of moderate to severe acute GVHD, transplant-related mortality, and leukaemia-free survival did not show striking differences. Further investigation of allogeneic PBPCT as a substitute for allogeneic BMT is warranted.

Adolescent↗
PubMed2002

A randomised, crossover, multicentre study to compare the performance of 0.1% (w/v) sodium hyaluronate with 1.4% (w/v) polyvinyl alcohol in the alleviation of symptoms associated with dry eye syndrome.

AIMS: To assess the safety and performance of a 0.1% (w/v) solution of sodium hyaluronate (HA, Fermavisc, in the alleviation of symptoms of severe dry eye in comparison with a 1.4% (w/v) solution of polyvinyl alcohol. METHODS: A randomised, crossover, multicentre study carried out at eight centres in the UK. Eligible patients giving written informed consent were randomised to the order in which they would receive the two study products. Each treatment period lasted for 4 weeks, then the patient crossed over to the other study product. Symptoms of burning and grittiness were assessed by visual analogue scale (VAS) at each study visit and other objective clinical assessments of ocular structure and function were carried out at baseline and the end of each treatment period. RESULTS: Thirty-nine patients were entered into the study and 32 completed both treatment periods and were included in the statistical analyses. A significant improvement in the patients' VAS assessment of burning was seen after treatment with HA (P = 0.03, 95% Confidence Interval: -23.5 to -1.1). This treatment also resulted in a significantly lower rose bengal staining score (P = 0.04, 95% Confidence Interval: -1.62 to -0.05 for the right eye). CONCLUSION: The results show a significant clinical benefit in terms of relief of the symptom of burning when HA is applied topically to the eye three or four times per day or as required. HA also appears to have a protective effect on the corneal epithelium, as shown by a reduction in the level of staining of corneal epithelial cells by rose bengal. This study confirms that Fermavisc is a safe and effective product for use in the alleviation of symptoms of severe dry eye syndrome.

Adult↗
PubMed2001

The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study.

OBJECTIVE: Assessment of the effects of orlistat 120 mg three times daily vs placebo on weight loss and serum lipids in obese hypercholesterolemic patients. DESIGN: A 24 week multicentre, double-blind, randomized, placebo-controlled trial. After a 2-week single-blind run-in period (placebo+diet (-600 kcal/day; < or =30% of calories as fat)), 294 patients were submitted to the hypocaloric diet and randomly assigned to either orlistat 120 mg or placebo three times daily. Patients who completed the double-blind study (n=255) were eligible for participation in a subsequent 24 week open-label orlistat extension phase. SUBJECTS: Patients with body mass index (BMI) 27-40 kg/m2 and hypercholesterolemia (low-density-lipoprotein cholesterol, LDL-C, 4.1-6.7 mmol/l). MEASUREMENTS: Efficacy assessments included weight loss, lipid levels, other cardiovascular risk factors and anthropometric parameters. Safety assessments. RESULTS: Weight loss during run-in was similar in both groups. After randomization, orlistat-treated patients lost significantly more weight than placebo recipients: mean percentage weight loss from start of run-in to week 24 was-6.8% in the orlistat group and -3.8% in the placebo group (P<0.001). Moreover, more patients in the orlistat group than in the placebo group achieved clinically meaningful weight loss of > or =5% (64 vs 39%) or > or =10% (23 vs 13%) at week 24. Treatment with orlistat was associated with significantly greater changes in total cholesterol (-11.9% vs -4.0%; P<0.001) and LDL-C (-17.6 vs -7.6%; P<0.001). For any category of weight loss during the double-blind treatment period, change in LDL-C was more pronounced in orlistat-treated patients than in placebo recipients, indicating that orlistat had a direct cholesterol-lowering effect that was independent of weight reduction (P<0.001). Adjunction of orlistat during the extension phase in patients who initially received placebo induced a further decrease in weight, total cholesterol and LDL-C. Orlistat was generally well tolerated with a safety profile comparable to placebo, with the exception of a higher incidence of gastrointestinal events (> or =1 event in 64 vs 38% of patients). CONCLUSION: Orlistat as an adjunct to dietary intervention promotes weight loss and reduces LDL-C beyond the effect of weight loss in overweight or obese patients with concomitant hypercholesterolemia.

Adolescent↗
PubMed1999

Improved efficacy with maintained tolerability in the treatment of primary hypertension. Comparison between the felodipine-metoprolol combination tablet and monotherapy with enalapril. Swedish Multicentre Group.

In this multicentre, double-blind, parallel-group study, 120 out-patients with mild to moderate primary hypertension were randomised, after a 4-week single-blind placebo run-in period, to a combination tablet of felodipine-metoprolol 5/50 mg (Logimax, Mobloc, Astra) once daily or enalapril 10 mg once daily. If blood pressure (BP) remained suboptimally controlled after 4 weeks (supine diastolic BP >90 mm Hg 24-h post dose), the dose was doubled for a further 4 weeks. After 8 weeks felodipine-metoprolol reduced supine BP significantly more than enalapril (19.7/12.0 mmHg and 11.1/7.2 mm Hg, respectively). The mean differences in change in BP between treatments were 8.6/4.8 mm Hg in favour of felodipine-metoprolol (P = 0.001/P <0.001). A statistically significant difference to the advantage of felodipine-metoprolol was also seen in standing BP. Even though the dose was increased in a larger proportion of patients in the enalapril group (61%) than in the felodipine-metoprolol group (40%), fewer enalapril-treated patients achieved adequate BP control (41% vs 63% on felodipine-metoprolol, P <0.05). Both treatments were well tolerated. Three patients treated with felodipine-metoprolol and four with enalapril discontinued treatment due to adverse events. A similar number of patients reported adverse events in each treatment group. In conclusion, a combination tablet of felodipine-metoprolol 5/50-10/100 mg once daily reduced BP more effectively than enalapril 10-20 mg once daily 24 h post dose. The result was expected, but a more important observation was that both treatments were tolerated to a similar degree. Obviously, a considerable BP reduction may be well tolerated, as was the main purpose to demonstrate in this study.

Adrenergic beta-Antagonists↗
PubMed1997

Multicentric evaluation of the MDR phenotype in leukemia. French Network of the Drug Resistance Intergroup, and Drug Resistance Network of Assistance Publique-Hôpitaux de Paris.

The wide discrepancies in the frequency of 'positive' samples for multidrug resistance (MDR) phenotype within the same type of tumor observed in the literature justified the need for the definition of consensus recommendations. To define standard techniques of MDR phenotype measurement, we ran a large multicentric evaluation of the different methods available. Thirty-six French centers participated in the study, and 742 samples of 2-10 x 10(6) viable cells were sent by overnight express mail between December 1993 and February 1996. The same batches of MRK16, 4E3 and UIC2 were used. Nineteen samples of leukemia (12 AML, 1 ALL, 6 lymphoproliferative syndromes) and six leukemic cell lines with different levels of MDR expression were tested. Five meetings reached agreement concerning the guidelines for each technique, except immunocytochemistry. The 19 fresh samples were tested by each center using one to four techniques among cytofluorometry, immunocytochemistry, functional tests and RT-PCR. Five samples were diagnosed as 'negative' according to local criteria, with few discordant results (0 to 16% of 'positive' results). For all the 14 remaining samples, large discrepancies were observed from center to center, and from one technique to another. No correlations could be found between techniques. Flow cytometric analysis of cells already exposed to MRK16 or control IgG2A, fixed in paraformaldehyde and sent to centers did not reduce the discrepancies between centers in two of the four samples with moderate expression, emphasizing the role of histogram interpretation. The use of alternative monoclonal antibodies (4E3 and UIC2) did not reduce the discrepancies observed. In a second step, the K562 parental cell line, a low resistant subline (K562/HHT100, x7 resistance index to DNR) and a high resistant subline (K562/HHT300, x125 resistance index to DNR) were sent blindly three times, with an increasing level of recommendations for flow cytometry. Dramatic improvements were observed in cytometric results when the result was expressed as the ratio of arithmetic mean of fluorescence of antibody (10 microg of MRK16)/arithmetic mean of fluorescence of control (10 microg IgG2A): the proportion of expected results increased from 61 to 100% for K562, and from 37 to 85% for K562/HHT100. For uptake and drug efflux measurements, the use of 1 h uptake of 0.1 microM of rhodamine, followed by 1 h efflux +/-10 microM of verapamil, permitted an increased reproducibility of the technique from 71 to 100% for K562 and K562/HHT100. Whatever the technique used, concordant results were obtained for K562/HHT300. The immunocytochemistry, using several antibodies (MRK16, JSB1 and C219) gave many non-interpretable results (44%), due to a frequent high background and discordant results between antibodies in the same centers, and discordant conclusions between centers. The group does not recommend this technique for circulating tumoral cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Excess of allele1 for alpha3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study.

The available data from preclinical and pharmacological studies on the role of gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in brain GABAergic system activity contributes to the vulnerability to bipolar affective disorders (BPAD). Moreover, the localization of the alpha3 subunit GABA receptor GABRA3 gene on the Xq28, a region of interest in certain forms of bipolar illness, suggests that GABRA3 may be a candidate gene in BPAD. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentric case-control sample, matched for sex and ethnogeographical origin. Allele and genotype (in females) frequencies were compared in 185 BPAD patients and 370 controls. A significant increase of genotype 1-1 was observed in BPAD females compared to controls (P=0.0004). Furthermore, when considering recessivity of allele 1 (females with genotype 1-1 and males carrying allele 1), results were even more significant (P= 0.00002). Our findings suggest that the GABRA3 polymorphism may confer susceptibility to or may be in linkage disequilibrium with another gene involved in the genetic etiology of BPAD.

Alleles↗
PubMed1997

Chronic pain/dysaesthesiae in spinal cord injury patients: results of a multicentre study.

The aim of the multicentre study entitled 'Description and Documentation of Painful States in Spinal Cord Injury Patients', in addition to the description and documentation of chronic pain and stressful dysaesthesiae in SCI patients, was the search for correlations between these symptoms and medical and psychosocial variables. To this end, the sample was selected to be as representative as possible. All patients referred for in-patient or out-patient treatment at the centres taking part were enrolled in the study in order of presentation, providing they gave consent and met the inclusion criteria. Psychosocial, medical and demographic data were elicited by a standardized battery of questions and a standardized physical examination, as were any chronic pain/dysaesthesiae (P/D) present in any localization. Among 901 patients, 34% had no chronic pain or dysaesthesiae, 50% had pain only, 11% had painful dysaesthesiae and 5%, non-painful but chronic and distressing dysaesthesiae. The intensity of P/D was noted as seven or more on a 10 cm visual analogue scale by 61% of the patients affected and was experienced as rather or very distressing in 75% of cases. Most (86%) P/D were located below the spinal lesion or in the transition zone. There were significant correlations between the presence of P/D and age on questioning and at onset of the paraplegia/tetraplegia, problems with rectal paralysis, expectations of life as a paraplegic/tetraplegic, and subjective assessment of changes in working life. Highly significant correlations were found with subjective distress resulting of paraplegia/tetraplegia as such, depressed mood and psychosomatic disturbances of wellbeing. Overall, among the selected variables of our study, we found that correlations between P/D and psychosocial variables were more frequent and closer than those between P/D and medical variables.

Adolescent↗