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Biomedical subjects

M Bellet

Publications and source records attributed to M Bellet.

At least 19 recordsLinked to original sources
PubMed2026

Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Currently, three cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are approved in combination with endocrine therapy (ET) as first-line treatment of patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). The impact of homologous recombination repair (HRR) pathogenic variants (PV) on outcomes with first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC remains uncertain. PATIENTS AND METHODS: We conducted a multicenter, real-world, case-control study including 233 patients with HR-positive/HER2-negative MBC treated with first-line CDK4/6i and ET. Among them, 116 presented HRR PVs and 117 were matched controls with negative germline testing. The primary objective was to compare progression-free survival (PFS) and overall survival among germline-BRCA2 PV carriers, other HRR PV carriers, and controls. To minimize baseline differences in prognostic factors between PV carriers and controls, inverse probability of treatment weighting was applied. Molecular analyses in pre-CDK4/6i samples among patients with BRCA2 PV were carried out, including RAD51-foci, PAM50 intrinsic subtype, and RB1 loss of heterozygosity (LOH). RESULTS: Among the included 233 patients, median age at diagnosis was 45 years (interquartile range 39-56) and 33% had de novo metastatic disease. Primary resistance to adjuvant ET was present in 10% and secondary resistance in 27%. After a median follow-up of 44 months, patients with germline-BRCA2 PVs (n = 67) had significantly shorter PFS [11 versus 27 months; adjusted hazard ratio (aHR) 2.73, 95% confidence interval (CI) 1.65-4.51, P < 0.001] compared with controls. Among patients with endocrine-sensitive disease, germline BRCA2 PV carriers had markedly shorter PFS (median PFS 12 versus 39 months; aHR 4.04; 95% CI 1.82-8.98, P < 0.001). Exploratory analyses revealed RB1 LOH before CDK4/6i-treatment in most evaluable BRCA2 tumors. CONCLUSIONS: BRCA2 PVs were independently associated with poorer outcomes to first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC compared with controls, especially relevant among patients with endocrine-sensitive disease. These findings suggest that patients with a germline PV in BRCA2 may require alternative first-line strategies.

Humans↗
PubMed1998

Effects of chronic noradrenaline on the nitric oxide pathway in human endothelial cells.

Altered endothelium-dependent vasodilation has been observed in congestive heart failure (CHF), a disease characterized by a sustained adrenergic activation. The purpose of our study was to test the hypothesis that chronically elevated catecholamines influence the nitric oxide (NO) pathway in the human endothelium. Human umbilical vein endothelial cells (HUVEC) were exposed for 7 days to a concentration of noradrenaline (NA, 1 ng/mL) similar to that found in the blood of patients with CHF. Kinetics of endothelial constitutive NO synthase (ecNOS) and inducible NO synthase (iNOS) activity, measured by [3H]L-arginine to [3H]L-citrulline conversion, and protein expression of ecNOS and iNOS, assessed by Western blot analysis, were unaffected by chronic NA treatment. Furthermore, no changes in subcellular fraction-associated ecNOS were found; this indirectly shows that chronic NA did not cause phosphorylation of the enzyme. Moreover, [3H]L-arginine transport through the plasma membrane was conserved in chronically NA-treated cells. The data demonstrate that prolonged in vitro exposure to pathologic CHF-like NA does not affect the L-arginine: NO pathway in human endothelial cells.

Arginine↗
PubMed1995

[High-dosage chemotherapy and the autologous transplantation of peripheral hematopoietic progenitor cells in breast cancer: the initial results, analysis of toxicity and the necessary support means].

BACKGROUND: In the last years high dose chemotherapy (HDC) schedules have been developed with autologous bone marrow transplantation (ABMT) which are very effective in breast cancer. Expectation has been raised concerning the cure of a subgroup of patients with metastatic breast cancer and the improvement of prognosis in high risk stages II and III. METHODS: CTCb (cyclophosphamide 6 g/m2, thiotepa 500 mg/m2 and carboplatin 800 mg/m2) was administered with autologous peripheral hematopoietic progenitor cells transplantation (TACPHP) and granulocytic colony stimulating factor (G-CSF) 5 micrograms/kg/day to 27 patients with breast cancer: 9 in stage IV in complete remission, 12 in stage II with > or = 10 affected lymph nodes and 6 in stage III. RESULTS: No toxic deaths were reported. The median time to achieve > or = 0.5 x 10(9) neutrophils/l was 8 days, to > or = 20 x 10(9) platelets/l 9 days and to > or = 50 x 10(9) platelets/l 12 days. Fever was observed in 85% of the patients although its median duration was of only one day. Extrahematologic toxicity was moderate with grade III nausea/vomiting in 48% of patients, grade III mucositis in 22%, grade III hepatitis in 19%, and grade III diarrhea in 4%. No grade IV toxicity was observed. The median follow-up is still short (10 months, range: 2-25). All the patients maintain normal hematologic peripheral blood counts and only 4 (in stage IV) have relapsed. CONCLUSIONS: The slight extrahematologic toxicity observed in the high dose chemotherapy with cyclophosphamide, thiotepa and carboplatin, and the rapid hematologic recovery provided by the TACPHP and G-CSF allow the above schedule to be administered with moderate toxicity and no mortality. This low toxic profile leads to the possibility of future trials with this chemotherapy schedule in other subgroups of patients with breast cancer.

Adult↗
PubMed1995

[Malignant pleural mesothelioma: clinical characteristics, prognostic factors and treatment].

Malignant pleural mesothelioma soon leads to death no matter what type of treatment is provided. We discuss the clinical signs, prognostic factors and treatment given in 41 cases managed over the past 13 years in our oncology department. 32% had been exposed to asbestos, 61% were 60 years old or younger, 71% had a Karnofsky's index > or = 80% and 63% were stage I (Butchart). The first symptom leading to diagnosis was pain in 66% and mean time between first symptom and diagnosis was 3 months. Thirty patients never experienced full remission of disease: 15 were treated with palliative chemotherapy (CHT), 1 with palliative radiotherapy (RT), 5 with partial pleurectomy (PP) plus RT and/or CHT. Nine were given symptomatic treatment only. Only 11 (27%) patients experienced full remission after treatment: 7 had had extrapleural pneumonectomy, 2 had been given CHT and RT series and 4 had undergone PP with or without RT and/or CHT follow-up. Only 3 of these patients were still alive with no relapse more than 1 year later. Mean survival was 8 months. Univariate analysis revealed that the prognostic factors influencing survival were age and Karnofsky's index. Patients initially treated with surgery had a higher rate of survival. In conclusion, only Karnofsky's index and age were prognostic factors in our series. The better survival of patients initially treated surgically is probably related to prior screening.

Adolescent↗
PubMed1995

Breast cancer in the elderly.

Breast cancer in the elderly has attracted considerable interest in recent years for three main reasons. Firstly, information concerning the profile (clinical and biological) of the disease in the geriatric population is scarce; secondly, the number of patients is increasing, and thirdly there are conflicting data regarding the actual effectiveness of the different treatments. The present review attempts to outline the specific characteristics of this malignancy in the elderly in terms of histological pattern, stage at diagnosis, and outcome. The feasibility of standard therapies (mastectomy/lumpectomy, axillary clearance, and radio-therapy) in the elderly is carefully analysed, and compared to the efficacy of less aggressive procedures. The use of tamoxifen as a primary treatment, instead of surgery, is critically reconsidered, as well as its use as an adjuvant therapy. Finally, the effectiveness of systemic therapy in advanced disease is also discussed.

Aged↗
PubMed1994

[High-dose chemotherapy and autologous bone marrow transplantation in high-grade metastatic sarcomas].

Metastatic sarcomas have a poor prognosis with current therapeutic regimens. High dose chemotherapy (HDC) has proved to be efficient in a selected group of solid tumors. Nine patients with high grade metastatic sarcomas were treated with HDC followed by autologous bone marrow transplantation. Four patients received HDC as a consolidation of the complete response (CR) obtained with chemotherapy (CT) and two of them were free from disease at 27 and 41 months, respectively. Other four patients had a disease total or partially refractory to conventional CT, and in one case the sensitivity to the chemotherapeutical agents was unknown. In these five cases a partial response was observed in two of the three who had measurable response parameters, but all of them died because of disease progression in a short period of time. These results suggest that there are active HDC schedules on metastatic sarcomas, but its possible benefit would be limited to the consolidation of a CR obtained with previous CT. HDC is a therapeutical alternative under investigation in patients with metastatic sarcomas with an indication that could be extended to cover localized sarcomas with poor prognosis.

Adolescent↗
PubMed1994

[Retroperitoneal lymphocele: a rarely reported complication of abdominal aortic surgery. Apropos of a case].

The authors present a case of a retroperitoneal lymphocele following prosthetic reconstruction of the abdominal aorta followed by a discussion about the principal differential diagnosis of a retroperitoneal collection following surgery on abdominal aorta. To date, only ten cases have been reported in this post-operative; it is probably a more frequent complication; the radiologist must play a major role both in the detection and the treatment of such collections.

Aortic Aneurysm, Abdominal↗
PubMed1993

Calcium antagonists-ACE inhibitors combination therapy: objectives and methodology of clinical development.

The practical objectives of a combination therapy are to obtain a better control of blood pressure (BP), and/or to improve tolerability through the use of lower doses of existing component. The prescription, in a single pill, of an angiotensin-converting enzyme (ACE) inhibitor and a calcium blocker has the theoretical and practical advantages of improving compliance by reducing the number of pills that have to be taken daily and the number of boxes the patient must carry. It also has a pharmacologic rationale mainly based on the buffering by ACE inhibitors of the calcium-blocker-induced stimulations of the renin-angiotensin system and the sympathetic nervous system, and on the reinforcement of the ACE inhibitors antihypertensive effect by the calcium-blocker-induced negative sodium balance. As an argument for such combinations, the neutralization of some dihydropyridines side effects, such as palpitations and edemas, must be addressed. The choice of each component dose is to provide a safe first-line indication and effective and flexible stepped-care treatment. It can only be the result of a complex development program, where BP effect measured at peak and at trough is investigated by the coherent utilization of parallel-group, cross-over, and factorial study designs. Safety studies in high-risk patients enrolled in special controlled trials are necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Unmasking of the hypotensive effect of nifedipine in normotensives by addition of the angiotensin converting enzyme inhibitor benazepril.

OBJECTIVE: To study the pharmacological interaction between a dihydropyridine derivative (nifedipine slow release 20 mg) and inhibition of the renin-angiotensin system (benazepril 10 mg). DESIGN: Single application at intervals of 2 weeks in an open-label three-way cross-over design. SETTING: Institutional pharmacological unit. PARTICIPANTS: Nine healthy male volunteers. MAIN OUTCOME MEASURES(S): Blood pressure and heart rate were recorded in the supine position for 24 h as well as plasma drug levels, plasma angiotensin converting enzyme activity and active plasma renin concentration. RESULTS: Nifedipine increased active plasma renin two-fold and benazepril increased it five-fold. The combination of the two drugs accelerated the increase of active renin during the first 2 h after drug intake. Whereas no hypertensive effect could be detected after nifedipine or benazepril alone, a significant fall in systolic and diastolic blood pressure was observed for up to 9 to 12 h after the combination. The increase in heart rate induced by nifedipine was minimized by the addition of benazepril. There was no interaction between the pharmacokinetics of benazeprilate and nifedipine which would explain these pharmacodynamic effects. CONCLUSION: These results demonstrate that, in normotensive volunteers, the renin-angiotensin system contributes to mask the hypotensive effect of a single oral dose of dihydropiridine. The concomitant administration of a converting enzyme inhibitor discloses the hypotensive effect and limits the baroreflex-mediated increase in heart rate secondary to vasodilation.

Adult↗
PubMed1991

[3-dimensional reconstruction of x-ray computed tomographic views in fractures of the acetabulum].

In 21 cases of acetabulum fractures of 19 patients, the authors compare the findings given by three dimensional reconstructions of axial CT scan cuts with the plain films. The number of CT scan cuts is reasonable for each patient. Working time is about 20 to 30 minutes for the technician. In the cases of complex and displaced fractures, three dimensional imaging brings often decisive informations for the therapeutic management of these patients. Unusual views are often allowed but completely adapted to each type of fracture.

Acetabulum↗
PubMed1990

From the parallel group design to the crossover design, and from the group approach to the individual approach.

The consequences of heterogeneity in response to antihypertensive drugs for the clinical development programs of new antihypertensive drugs and for the care of the individual hypertensive patient have not previously been sufficiently recognized. They play a role in the inappropriate choice of too-high daily doses of some antihypertensive drugs at the end of extensive international development programs. They are also implicated in the insufficient control of blood pressure observed in the long-term multicenter trials in hypertension, where some patients have been treated for several years with drugs that were not the most appropriate for their disease and which did not adequately control their blood pressure. In addition to the parallel group studies, the use of double-blind two-period or multiple period crossover designs can provide valid data for the dose-finding of new antihypertensive drugs and their comparative evaluation. At the end of the trial, these designs also offer each patient the opportunity to be treated with the right dose of the drug most appropriate for his or her disease.

Antihypertensive Agents↗
PubMed1990

Treating the individual hypertensive patient: considerations on dose, sequential monotherapy and drug combinations.

For the general practitioner to be able to prescribe optimal therapy to his individual hypertensive patients, he needs accurate information on the therapeutic agents he is going to administer and practical treatment strategies. The information on drugs and drug combinations has to be applicable to the treatment of individual patients and not just patient study groups. A basic requirement is knowledge of the dose-response relationship for each compound in order to choose the optimal therapeutic dose. Contrary to general assumption, this key information is difficult to obtain and often not available to the physician for many years after marketing of a drug. As a consequence, excessive doses are often used. Furthermore, the physician needs comparative data on the various antihypertensive drugs that are applicable to the treatment of individual patients. In order to minimize potential side effects due to unnecessary combinations of compounds, the strategy of sequential monotherapy is proposed, with the goal of treating as many patients as possible with monotherapy at optimal doses. More drug trials of a crossover design and more individualized analyses of the results are badly needed to provide the physician with information that he can use in his daily practice. In this time of continuous intensive development of new antihypertensive agents, much could be gained in enhanced efficacy and reduced incidence of side effects by taking a closer look at the drugs already available and using them more appropriately in individual patients.

Antihypertensive Agents↗
PubMed1990

Use of crossover trials to obtain antihypertensive dose-response curves and to study combination therapy during the development of benazepril.

When a new drug is developed, one of the first requirements is to establish the correct dose. Unfortunately, in dose-determination studies, not enough lessons have been learned from the past. Pilot studies are often planned without sufficient statistical power, due to an insufficient number of patients and highly variable blood pressure measurements. In the development of the new angiotensin converting enzyme (ACE) inhibitor benazepril, crossover trials were used to obtain useful information. At the end of phase II of the benazepril development, a double-blind crossover study was carried out with 25 patients, and the results made it possible to redefine the 12- and 24-h effects of benazepril in comparison with placebo. Moreover, the crossover trial allowed an investigation of the biological effects of the treatment. In further work, the efficacy of 10 mg benazepril, administered once a day, was confirmed in comparison with captopril and enalapril, with a beta-risk of less than 20%. Since this crossover study yielded reliable data, and there was no carryover effect, a similar crossover design was used to study the interaction between benazepril and nifedipine. In the past, mistakes were made and many antihypertensive drugs were administered in high doses, with no further beneficial effect on blood pressure and an increased risk of side effects. Work described in this paper shows that fewer but better designed and implemented studies can improve the efficiency and value of dose-finding studies for antihypertensive drugs.

Antihypertensive Agents↗