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Biomedical subjects

Michel Marty

Publications and source records attributed to Michel Marty.

14 recordsLinked to original sources
PubMed2006

In vivo repopulation ability of genetically corrected bone marrow cells from Fanconi anemia patients.

Fanconi anemia (FA) is a rare inherited genomic instability syndrome representing one of the best examples of hematopoietic stem cell deficiency. Although FA might be an excellent candidate for bone marrow (BM) genetic correction ex vivo, knockout animal models are not sufficient to guide preclinical steps, and gene therapy attempts have proven disappointing so far. Contributing to these poor results is a characteristic and dramatic early BM-cells die-off when placed in culture. We show here that human primary FA BM cell survival can be ameliorated by using specific culture conditions that limit oxidative stress. When coupled with retrovirus-mediated transfer of the main complementation group FANCA-cDNA, we could achieve long-term reconstitution of the stem cell compartment both in vitro and in vivo. Gene-corrected BM cultures grew for >120 days, and after cultured cell transplantation into NOD/SCID mice, clonogenic human cells carrying the FANCA transgene could be detected 6 months after transduction. By comparison, untransduced cells died in culture by 15 days. Of necessity for ethical reasons, experiments were conducted on a very limited number of primary BM cells. By using low cytokine regimen and conditions matching regulatory requirements, a contingent of gene-corrected cells slowly emerges with an unmet potential for in vivo engraftment. Future therapeutic applications of stem cells might be expanding from these data. In addition, we provide a model of gene-corrected human primary cell growth that carries the potential to better delineate the combined role of both DNA damage and oxidative stress in the pathogenesis of FA.

Animals↗
PubMed2006

Stent-graft repair for thoracic aortic disease: results of an independent nationwide study in France from 1999 to 2001.

BACKGROUND: The purpose of this study was to assess the overall short-term outcome of stent-graft repair for thoracic aortic disease in France between June 1999 and May 2001. METHODS: This retrospective study was designed by the French National Health Insurance Fund for Salaried Workers. To ensure objectivity, data were retrieved at each center and checked by a team of medical advisors. RESULTS: Between June 1999 and May 2001, a total of 166 stent-graft repairs for thoracic aortic disease were performed in 166 patients, mainly by surgeons in the operating room (88%). Patients were classified according to the American Society of Anesthesiologists as status I or II in 24% of cases, status III in 56%, and status IV or V in 20%. The diameter of the thoracic aneurysm was less than 50 mm in 17% of cases. Seventeen patients (10%) died during the first 3 months, including 8 within the first 30 days after the procedure. A total of 49 complications were noted in 34 patients (20.5%). Endoleaks occurred in 27 patients (16.3%), including 8 that necessitated further treatment. Other stent-related complications included rupture (n = 3), aortoesophageal or tracheal fistula (n = 3), paraplegia (n = 6), stent migration (n = 2), visceral embolism (n = 5), and cerebral embolism (n = 2). There were 14 delivery-related complications (8%) at the catheterization site. Non-stent-related complications occurred in 14 (8%). CONCLUSIONS: This nationwide study demonstrates that stent-graft repair for thoracic aortic disease can be performed with acceptable postoperative morbidity. However, it is not a risk-free procedure and should continue to be used in an investigative setting.

Adult↗
PubMed2005

Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.

PURPOSE: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients were randomly assigned to six cycles of docetaxel 100 mg/m2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. RESULTS: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. CONCLUSION: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity.

Adolescent↗
PubMed2005

Infrastructure of radiation oncology in France: a large survey of evolution of external beam radiotherapy practice.

PURPOSE: To study the structural characteristics of radiation oncology facilities for France and to examine how technological evolutions had to be taken into account in terms of accessibility and costs. This study was initiated by the three health care financing administrations that cover health care costs for the French population. The needs of the population in terms of the geographic distribution of the facilities were also investigated. The endpoint was to make proposals to enable an evolution of the practice of radiotherapy (RT) in France. METHODS AND MATERIALS: A survey designed by a multidisciplinary committee was distributed in all RT facilities to collect data on treatment machines, other equipment, personnel, new patients, and new treatments. Medical advisors ensured site visits in each facility. The data were validated at the regional level and aggregated at the national level for analysis. RESULTS: A total of 357 machines had been installed in 179 facilities: 270 linear accelerators and 87 cobalt units. The distribution of facilities and megavoltage units per million inhabitants over the country was good, although some disparities existed between areas. It appeared that most megavoltage units had not benefited from technological innovation, because 25% of the cobalt units and 57% of the linear accelerators were between 6 and 15 years old. Computed tomography access for treatment preparation was not sufficient, and complete data management systems were scarce (15% of facilities). Seven centers had no treatment planning system. Electronic portal imaging devices were available in 44.7% of RT centers and in vivo dosimetry in 35%. A lack of physicians and medical physicists was observed; consequently, the workload exceeded the normal standard recommended by the French White Book. Discrepancies were found between the number of patients treated per machine per year in each area (range, 244.5-604). Most treatments were delivered in smaller facilities (61.6%). CONCLUSION: On the basis of the findings of this study, measures were taken to update the infrastructure of RT in France. A first evaluation showed an improvement of care supply in RT in the country.

Cancer Care Facilities↗
PubMed2005

Decision making process in oncology practice: is the information available and what should it consist of?

In terms of systemic chemotherapy, the oncologist is often faced with the difficulty to discriminate between several options, at least according to evidence-based medicine. The aim of the present report was to assess to what extent the efficacy-related parameters required for the decision making process are reported in clinical trials. The analysis was restricted to lung, breast, colorectal and ovarian cancers. It included 135 phase II trials published in 1999, and 79 phase III trials published between 1991 and 2000. Response duration was mentioned in one-half and one-fourth of phases II and III trials, respectively. Only one-half of the trials reported time to progression (TTP). Finally, 28% of phase II and 44% of phase III trials reported RR, TTP and progression rates. The study indicates that the information available from reported clinical trials needs to be upgraded and homogenised in order to improve the decision making process in oncology.

Clinical Trials as Topic↗
PubMed2005

Prognostic significance of a combined clinicopathologic score for response to primary systemic therapy in locally advanced breast cancer.

The response to chemotherapy is one of the best indicators of prognosis in locally advanced breast cancer (LABC). The pathologic response (pR) of 108 LABC patients was analysed and compared with their clinical response (cR). Our aim was to define a new combined clinicopathologic response score (cpR) and to explore its correlation with survival data. The 108 stage IIB to IIIB breast carcinomas were first treated with high-dose anthracycline-based chemotherapy. Standard criteria were used to assess cR. Pathologic analysis of surgical specimens allowed the definition of 5 types of pR. Three groups of combined clinicopathologic response were defined. Twenty-two patients (20%) had complete or almost complete pR. Most patients (88, 81%) had partial cR. This large group of partial cR was very heterogeneous, ranging from pR1 to pR5 and from cpR1 to cpR3. In univariate analysis, pR and cpR both strongly correlated with EFS. cR, pR and cpR all correlated with OS. Subgroups of incomplete pathologic responses were not prognostically different. In multivariate analysis, only cpR correlated strongly with both EFS and OS (p<0.002), identifying good (20%), intermediate (61%) and poor (19%) prognosis patients. In conclusion, in 108 stage IIB to IIIB breast cancer patients initially treated by high-dose chemotherapy, combined grading of clinical and pathologic responses in a single score allowed accurate prediction of outcome.

Adolescent↗
PubMed2004

Molecular profiling of inflammatory breast cancer: identification of a poor-prognosis gene expression signature.

PURPOSE: Inflammatory breast cancer (IBC) is a rare but particularly aggressive form of primary breast cancer. The molecular mechanisms responsible for IBC are largely unknown. EXPERIMENTAL DESIGN: To obtain further insight into the molecular pathogenesis of IBC, we used real-time quantitative reverse transcription (RT)-PCR to quantify the mRNA expression of 538 selected genes in IBC relative to non-IBC. RESULTS: Twenty-seven (5.0%) of the 538 genes were significantly up-regulated in IBC compared with non-IBC. None were down-regulated. The 27 up-regulated genes mainly encoded transcription factors (JUN, EGR1, JUNB, FOS, FOSB, MYCN, and SNAIL1), growth factors (VEGF, DTR/HB-EGF, IGFBP7, IL6, ANGPT2, EREG, CCL3/MIP1A, and CCL5/RANTES) and growth factor receptors (TBXA2R, TNFRSF10A/TRAILR1, and ROBO2). We also identified a gene expression profile, based on MYCN, EREG, and SHH, which discriminated subgroups of IBC patients with good, intermediate, and poor outcome. CONCLUSION: Our study has identified a limited number of signaling pathways that require inappropriate activation for IBC development. Some of the up-regulated genes identified here could offer useful diagnostic or prognostic markers and could form the basis of novel therapeutic strategies.

Breast Neoplasms↗
PubMed2003

Two prognostic groups of inflammatory breast cancer have distinct genotypes.

PURPOSE: The prognosis of inflammatory breast cancer (IBC) remains poor despite the use of multimodality treatments, with a 10-year survival rate of not >30%. Clinicopathological and biological predictors of outcome are inadequate in this setting. Analysis of loss of heterozygosity (LOH) can provide a molecular portrait of the genetic alterations underlying stepwise cancer progression. We tested the value of LOH patterns as diagnostic and prognostic markers in IBC. EXPERIMENTAL DESIGN: In a previous study of 64 patients with IBC who were treated homogeneously between 1988 and 1999, we determined LOH frequencies at 71 loci located in 20 chromosomal regions associated with primary breast cancer. Six of these regions bore alterations that were less frequent in non-IBC. In the present study, we sought correlations between these molecular data and the clinicopathological features and clinical outcome of the same 64 patients. RESULTS: With the exception of stage IV disease, extensive breast inflammation at first clinical examination was the main factor associated with poor outcome (P = 0.00065 versus localized inflammation). The overall frequency of LOH was also higher in this group (P = 0.000073). LOH patterns differed between patients with localized and extensive breast inflammation. CONCLUSION: Patients with IBC can be separated into two major prognostic groups on the basis of initial clinical signs, which appear to be subtended by different molecular alterations.

Adult↗
PubMed2003

Use of abdominal aortic endovascular prostheses in France from 1999 to 2001.

BACKGROUND: Since the introduction of endovascular repair (EVR) for infrarenal abdominal aortic aneurysm (AAA), clinical evaluation has been under way in many countries throughout the world. The main purpose of this retrospective study was to determine outcome of EVR with aortic endovascular prostheses (AEPs) and to evaluate the extent to which French practitioners have complied with regulatory and clinical guidelines for the use of these trial devices. METHODS: This retrospective study was conducted by the French National Health Insurance Fund for Salaried Workers. Data were compiled on EVR procedures performed at health care institutions all over mainland France between June 1999 and May 2001. RESULTS: A total of 1012 AEPs were deployed for AAA repair in France during the study period. Only 151 (14.9%) of these EVR procedures were carried out within an approved investigational setting with informed patient consent. Only 149 of the 861 patients (17.3%, 95% confidence interval [CI], 14.9 to 19.9%) who underwent endovascular repair in noninvestigational settings signed informed consent forms. In 452 cases (46.5%), the diameter of the AAA was 50 mm or less. Complete outcome data for the first year were available for 891 patients (88%). Complications occurred in 177 of these patients (19.9%, 95% CI, 17.3 to 22.6%). There were a total of 47 deaths (5.3%, 95% CI, 3.9 to 6.9%), including 27 during the first 30 postoperative days. Other major events during the first year after AEP implantation were ruptured AAA in 5 patients, conversion to open operation in 15, and additional endovascular treatment in 52. Data on clinical surveillance were available for 987 patients (97.5%) with a mean follow-up of 345 days. Only 294 patients (29.8%, 95% CI, 27.0 to 32.7%) underwent complete imaging within the first month after AEP implantation. A total of 184 patients (18.6%, 95% CI, 16.3 to 21.2%) received no surveillance at all. CONCLUSION: This study shows the need for improvement in the clinical evaluation of new devices and medical technologies in France. Study findings also confirm the significant incidence of adverse outcomes and necessity for routine surveillance after EVR of AAA with AEP. However, risk/benefit analysis is difficult because most procedures were not carried out within a proper investigational context.

Adult↗
PubMed2003

[Anti-epidermal growth factor receptor treatment: a new paradigm for conducting therapeutic trials].

Agents which modify biological properties of tumour tissue can target many tenths of functions over- or underexpressed in human tumours. In general these agents are cytostatic rather than cytotoxic and will affect only that fraction of human tumours where the target plays and important and unique role for the viability of the tumour tissue. Alternatively it is expected that acute toxicity will not be observed at active dose-time exposure; rather subacute or chronic toxicity can be observed with these agents. Clinical studies will have to follow the following rules: characterisation of the pharmacological target and of its functional role on tumour tissue; definition of an optimal biological dose rather than a maximum tolerated dose; importance of validated pharmacodynamic endpoints; importance and thus need for early studies of combination regimens. It is still too early to define general guidelines for the study of these different therapeutic families. Nevertheless, studies already conducted with agents interfering with EGF mediated signalization have already permitted preliminary indications on pharmacodynamics, target assessment, level of activity and conduct of clinical trials with combination regimens.

Antineoplastic Agents↗
PubMed2002

Evidence of chromosome regions and gene involvement in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is a rare but particularly aggressive form of primary breast cancer. In contrast to noninflammatory breast cancer (non IBC), the molecular alterations underlying IBC are poorly known. We postulated that the kind and frequency of these alterations might differ between IBC and non IBC and account for its particular aggressiveness. We investigated allelic losses associated with primary breast cancer (on chromosome arms 1p, 3p, 6p, 6q, 7q, 8p, 9p, 11p, 11q, 16q, 17p and 17q) by analyzing 71 microsatellite markers in 66 cases of IBC. Loss of heterozygosity (LOH) was frequent, with a mean fractional allelic loss (FAL) index of 52%. Relative to published data on non IBC, allelic loss was particularly frequent at 3p21-p14, 6p, 8p22, 11q, 13q14 and 17q21, suggesting the presence of genes that are markedly altered in IBC. In contrast, the DNA amplification levels of ERBB2, MYC and CCND1, as measured by real-time quantitative PCR, did not differ between IBC and non IBC.

Breast Neoplasms↗
PubMed2002

Increased incidence of ERBB2 overexpression and TP53 mutation in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. We studied the biological characteristics of these tumours by comparing the overexpression of oncogenes ERBB2, MYC, CCND1 and RHOC and TP53 gene mutation rates in IBC with those found in locally advanced and not otherwise specified breast cancers. The prevalence of the TP53 mutation was much higher in IBC than in the two other types of cancer (57% vs 30). Unexpectedly, however, in IBC tumours, histological grade was independent of TP53 status. In addition, ERBB2 overexpression was twice as frequent in inflammatory as in non-inflammatory tumours, whereas the frequencies of MYC, CCND1 and RHOC overexpression did not vary significantly among the three types of breast cancer. These findings suggest that IBC tumours constitute a distinct subset with a specific pathogenesis. Given the importance of TP53 and ERBB2 in the response to treatments, our observations have important therapeutic implications for the clinical management of IBC patients.

Breast Neoplasms↗
PubMed2002

Chemotherapy for metastatic breast cancer-report of a European expert panel.

The anthracyclines doxorubicin and epirubicin, and the taxanes paclitaxel and docetaxel, are effective chemotherapeutic agents for the first-line and second-line treatment of metastatic breast cancer, and their clinical use is widespread. However, for women whose disease has progressed despite receiving these drugs, treatment options are limited. These women often have a good performance status, and may survive for many months or even years, so they should be given the opportunity to benefit from further chemotherapy. The goals of chemotherapy in these patients are to obtain maximum control of symptoms, prevent serious complications, and increase survival without diminishing quality of life. Several agents are used for this purpose, including fluorouracil, docetaxel (in patients who have already received paclitaxel), vinorelbine, and mitomycin c, but because data from controlled trials are limited, a standard regimen has not yet been established. Moreover, these agents may be inconvenient to administer and can be associated with adverse events requiring hospitalisation. Therefore, there is a clear need for additional therapeutic options for patients with metastatic breast cancer. Ideally, agents should have a convenient method of administration, eg, oral, and should be suitable for home-based rather than hospital-based therapy. Treatment should control disease in at least 20-30% of patients with an acceptable side-effect profile. Novel oral therapies have now been developed and are being used increasingly in patients whose disease has progressed following taxane therapy.

Antibiotics, Antineoplastic↗