Biomedical subjects

Jacques Medioni

Publications and source records attributed to Jacques Medioni.

9 recordsLinked to original sources

PubMed2006

Phase II multi-step planning methods in oncology: comparison, recommendations and potential applications.

Phase II clinical trials in oncology are commonly used to determine whether a new treatment has a sufficient response rate to be compared with the best standard therapy in phase III. The multi-step planning methods such as Fleming's procedure and the triangular test adapted for phase II trials were elaborated to terminate phase II trials early. We compared these methods considering a fixed number of steps (4 or 5) on their statistical properties: overall type II error and observed type II error, average number of subjects necessary to conclude, probability to conclude at each step and maximum number of subjects necessary to conclude. Fleming's procedure has an actual power similar to the theoretical power for low to high response rate. In contrast, triangular test has an actual power different from the theoretical power in a few situations: it was very high in case of a very low minimum response rate and very low (<20%) in case of a very high minimum response rate (>80%). In these situations, Fleming's procedure and triangular test were not compared and triangular test cannot be recommended. For intermediate response rate, triangular test required a lower average number of subjects to conclude, a larger number of subjects at each step and thus a larger maximum number of subjects. It provided a larger probability to conclude during the first steps. These advantages should be balanced with the risk to have to include a larger number of patients. Multi-step methods, when correctly used are useful for cytotoxic development when response rate is the end point. They can also be used in trials where toxicity is the end point, and could be of great interest for cytostatic development for example with biological surrogate endpoints. An example using real phase II data is also presented.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Increased risk of relapse after stopping nicotine replacement therapies: a mathematical modelling approach.

AIMS: To describe the effect of nicotine replacement therapy (NRT) on the risk of relapse as a function of time since the quit date. DATA SOURCES: Meta-analysis of 21 published, randomized, controlled clinical trials, comparing NRT to placebo. DATA EXTRACTION: A total of 6644 smokers were treated with NRT and 2766 smokers treated with placebo. DATA SYNTHESIS: During treatment with the medication, NRT reduced the hazard ratio (HR) significantly compared with placebo [early HR = 0.62 (95% CI: 0.58-0.67)]. At the end of the average treatment duration (145 days), the HR was 0.81 (95% CI: 0.71-0.94), showing that the benefit was still present at this time. After stopping treatment, the HR increased progressively up to a value of 1.44 (95% CI, 1.18-1.76) showing that the risk of relapse was higher after stopping NRT than after stopping placebo. If NRT and placebo had not been stopped, the HR of smoking relapse would have been established at 0.95 (95% CI: 0.76-1.18, P = 0.64), indicating a similar risk of relapse with NRT and placebo. Moreover, the observed HR of smoking relapse was significantly higher than the expected HR of smoking relapse if NRT had been continued: the difference in HR is 1.51 (95% CI: 1.16-1.98, P < 0.003). This suggests that if NRT had been been continued, around 50% of relapses could have been prevented. CONCLUSION: The protective effect of NRT against relapse slowly decreases as a function of time. After stopping NRT, the risk of relapse increases. It may be more beneficial not to stop NRT after the usual 3-6-month treatment period but to use NRT for longer periods of time.

Adult↗

PubMed2005

[Prostate cancer: update].

The study of mitotic transduction of the signal showed that overexpression of pAkt and reduction in pERK expression would be associated a biological relapse. For tumors T1-3 N0M0 at the high risk of local relapse after prostatectomy, an immediate radiotherapy compared with a differed radiotherapy (at the time of PSA relapse), showed a significant reduction in the rate of local relapse and an ameliorated progression free survival. The effectiveness of the docetaxel was confirmed in two phase III randomized clinical trials : TAX-327 with 3 arms compared docetaxel every 21 days, docetaxel every 7 days and mitoxantrone. All arms were prednisone-based. An increase in overall survival, PSA progression free survival, PSA response rate and a pain reduction were highlighted in the docetaxel arm every 21 days. Docetaxel obtained at the end of this study the marketing authorization in this indication and became the treatment of reference. The SWOG 99-16 study compared the docetaxel estramustine association with the same arm of reference, mitoxantrone and prednisone, with similar results. The addition of estramustine to the docetaxel seems to improve the PSA response rate and progression free survival, but with a greater embolic toxicity. The addition of an antiangiogenic agent, the thalidomide, to docetaxel, improves progression free survival and overall survival. PSA responses were observed with an inhibitor of the proteasome, the bortezomib, in monotherapy, contrary to the imatinib which in monotherapy didn't have any effectiveness. Studies in association with docetaxel are ongoing. Some biological responses were observed with a vaccine anti MUC-1 and must be confirmed on a greater series of patients. The docetaxel impact on localized disease is actually evaluated.

Androgen Antagonists↗

PubMed2004

Distinct responses of xenografted gliomas to different alkylating agents are related to histology and genetic alterations.

A series of 12 human gliomas was established as xenografts in nude mice and used to evaluate the relationship between histology, genetic parameters, and response to alkylating agents. Eight were high-grade oligodendroglial tumors, and four were glioblastoma. They were characterized for their genetic alterations, including those considered as "early" alterations, namely loss of chromosome 1 +/- loss of chromosome 19q, TP53 mutation, and those considered as "late" alterations, namely loss of chromosome 10, loss of chromosome 9p, EGFR genomic amplification, PTEN mutation, CDKN2A homozygous deletion, and telomerase reactivation. Chemosensitivity of xenografts to four alkylating agents, temozolomide (42 mg/kg, days 1-5, p.o.), 1,3-bis(2-chloroethyl)-1-nitrosourea (5 mg/kg, day 1, i.p.), Ifosfamide (90 mg/kg, days 1-3, i.p.), and carboplatin (66 mg/kg, day 1, i.p.) was tested by administration of drugs to tumor-bearing mice. Although each tumor presented an individual response pattern, glioblastoma had a lower chemosensitivity than oligodendrogliomas, and temozolomide was the most effective drug. Deletion of 1p +/- 19q was associated with higher chemosensitivity, whereas late molecular alterations, particularly EGFR amplification, were associated with chemoresistance. These results suggest that the combined use of histology and molecular markers should eventually be helpful selecting the most appropriate agents for treatment of malignant oligodendrogliomas and astrocytomas.

Animals↗

PubMed2003

Three irradiation treatment options including radiosurgery for brain metastases from primary lung cancer.

PURPOSE: To determine local control and survival rates in 92 patients with 145 brain metastases treated with three options of radiotherapy including stereotactic radiosurgery (SR). METHODS: Between July 1994 and August 2002, 92 consecutive patients with 145 metastases were treated with a SR, 34 with initially SR alone, 22 initially with an association of whole-brain radiotherapy (WBRT) and 36 with SR alone for recurrent new brain metastasis after WBRT. At time of treatment, extracranial disease was controlled in 46 (50%) and uncontrolled in 46 (50%). Pathologies were adenocarcinoma in 54 cases (59%), squamous cell carcinoma in 14 cases (15%), small cell carcinoma in 10 cases (11%) and miscellaneous in 14 cases (15%). All patients underwent only one treatment fraction for 1 or 2 metastases in 73 cases (83%) and for more than 2 metastases for the others. RESULTS: The characteristics of patients and metastases in the group treated initially with SR alone and in the group treated initially with WBRT+SR were comparable. Median follow-up was 29 months (18-36). Overall, the median and the 1- and 2-year rates of overall survival were, respectively, 9 months, 37 and 20%. A controlled extracranial disease, a high Karnofsky index and a low number of metastasis were independent prognostic factor of overall survival, respectively, HR 0.53 (95% CI 0.31-0.90, P=0.01), HR 0.95 (95% CI 0.92-0.97, P=0.0002), and HR 0.48 (95% CI 0.25-0.90, P=0.02). Thirteen metastases were not controlled (9%). Six-month and 1-year local control rate were, respectively, 93 and 86%. High delivered dose was an independent prognostic factor of local control, HR 0.41 (95% CI 0.18-0.95, P=0.03). A controlled extracranial disease was favourable independent prognostic factor of brain free-disease free survival, HR 0.47 (95% CI 0.2-0.98, P=0.04). Although there was a trend of a better local control, overall and brain disease free survivals rates in the WBRT+SR group compared to SR alone one, the difference were not statistically different. CONCLUSION: Local control and survival rates are acceptable for a palliative treatment for the three option of treatment. In this series, the number of patients is not enough great to conclude to the necessity of the association of WBRT to SR. Re-irradiation is a safe treatment after new metastases appeared in previously irradiated area.

Adult↗

PubMed2003

Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients.

OBJECTIVES: To evaluate the occurrence of autoimmune and inflammatory complications in Wiskott-Aldrich syndrome (WAS) and to determine risk factors and the prognosis of such complications with the aim of improving the definition of treatment options. METHODS: We reviewed the records of 55 patients with WAS evaluated at Necker-Enfants Malades Hospital (Paris) from 1980 to 2000. RESULTS: Forty patients (72%) had at least 1 autoimmune or inflammatory complication. Autoimmune hemolytic anemia was detected in 20 cases (36%); in all cases, onset occurred before the age of 5 years. Other complications included neutropenia (25%), arthritis (29%), skin vasculitis (22%), cerebral vasculitis (7%), inflammatory bowel disease (9%), and renal disease (3%). The median survival of the entire population was 14.5 years. Two autoimmune complications and 1 biological factor were predictive of a poor prognosis in this population: autoimmune hemolytic anemia, severe thrombocytopenia recurring after splenectomy, and high serum immunoglobulin M (IgM) levels before splenectomy. Autoimmune hemolytic anemia was significantly more observed in patients with high serum IgM level. CONCLUSIONS: High serum IgM concentration before splenectomy was identified as a risk factor for autoimmune hemolytic anemia; however, it must be confirmed. Autoimmune hemolytic anemia and severe thrombocytopenia recurring after splenectomy were 2 indicators of a poor prognosis. Those results suggest that patients with WAS and IgM levels more than mean + 2 standard deviations before splenectomy should be placed under strict surveillance. Furthermore, severe autoimmune complications should lead, as early as possible, to hematopoietic stem cell transplantation using the best available donor.

Adolescent↗

PubMed2003

[Testicular metastasis of alveolar rhabdomyosarcoma: clinical case of a 19-year-old man].

The authors report a case of a 19-year-old man with alveolar rhabdomyosarcoma with an unusual clinical presentation. The diagnosis was established on lymph node biopsy performed on admission of the patient in a context simulating leukaemia. The patient achieved complete remission in response to high-dose chemotherapy. A recurrence in the form of an intratesticular metastasis demonstrated a periorbital tumour that was probably the primary tumour. The authors present the radiological and histological findings and a molecular biology study of the testicular metastasis, eliminating a primary testicular tumour.

Adult↗

PubMed2002

Outcome of suprarenal localized masses diagnosed during the perinatal period: a retrospective multicenter study.

BACKGROUND: The growing use of abdominal ultrasonography during pregnancy and in the postnatal period is leading to the discovery of an increasing number of suprarenal masses. The optimal diagnosis and treatment of these masses has not yet been determined. METHODS: The authors reviewed the files of patients with suprarenal masses detected prenatally or during the first 3 months of life, between 1986 and 1999, in the pediatric surgery and oncology departments of Paris hospitals. RESULTS: Thirty masses were detected prenatally and 23 postnatally. In the latter group of patients, the diagnosis was based on ultrasound in 8 cases and on the palpation of a mass in 15 cases, 13 of which were neuroblastoma. At birth, the masses were cystic in 19 cases, solid in 17, and mixed in 13. Sensitivities of methyliodobenzylguanidine and urinary catecholamine assay were 70% and 52% respectively. Surgery was performed in 38 cases with a median age of 42 days. Histologic analysis showed 31 neuroblastomas, 1 adrenal hemorrhage, 2 necrotic masses, 1 bronchogenic cyst, and 3 sequestrations. All the patients were alive and disease free, at a follow-up ranging from 3 months to 13 years. CONCLUSIONS: In this series, 58% of the suprarenal masses diagnosed perinatally were localized neuroblastoma with a favorable outcome. All other cases either regressed spontaneously or turned out to be benign lesion. Thus, the management of these masses must strike a compromise between aggressive treatment and a wait-and-see attitude. This requires appropriate initial assessment and a close follow-up in a specialized center.

Adrenal Gland Neoplasms↗

PubMed2002

Association between genetically determined pancreatic status and lung disease in adult cystic fibrosis patients.

STUDY OBJECTIVES: The association between genotype and phenotype in cystic fibrosis (CF) has been clearly established for pancreatic status, but not for lung disease. DESIGN: Retrospective study. SETTING: A respiratory unit of a teaching hospital. PATIENTS: We studied 51 adult CF patients for whom current data and genotype were available. Thirty-seven patients carried two severe mutations associated with pancreatic insufficiency phenotype (group S). Fourteen patients carried at least one mild (and dominant) mutation associated with pancreatic sufficiency phenotype (group M). MEASUREMENTS: We compared the course of the disease between the two groups, looking for a genotype/phenotype association for lung disease. RESULTS: The mean age of the population was 30 years. Patients with two severe mutations presented more severe disease with earlier onset (1.7 years vs 7.9 years, p = 0.0001). They presented with a more severe respiratory impairment, with a lower mean FEV(1) (29% of predictive value vs 58% of predictive value, p < 0.001); a higher Pseudomonas colonization rate (97% vs 57%, p < 0.01); a more frequent end-stage respiratory insufficiency, defined by a FEV(1) < 30% (73% vs 29%, p < 0.05); and a more marked yearly decline of FEV(1) (3% vs 1.4%, p < 0.001). By multivariate logistic regression analysis, carrying two severe mutations was the only independent predictor of a terminal respiratory insufficiency (relative risk, 6.75; 95% confidence interval, 1.79 to 26.50; p = 0.003). CONCLUSION: This study suggests that pulmonary disease appears to be associated with the severity of CF transmembrane regulator mutations.

Adolescent↗