Mathematical model of T-cell lymphoblastic lymphoma: disease, treatment, cure or relapse of a virtual cohort of patients.

T lymphoblastic lymphoma (T-LBL) is a rare type of lymphoma with a good prognosis with a remission rate of 85%. Patients can be completely cured or can relapse during or after a 2-year treatment. Relapses usually occur early after the remission of the acute phase. The median time of relapse is equal to 1 year, after the occurrence of complete remission (range 0.2-5.9 years) (Uyttebroeck et al., 2008). It can be assumed that patients may be treated longer than necessary with undue toxicity.The aim of our model was to investigate whether the duration of the maintenance therapy could be reduced without increasing the risk of relapses and to determine the minimum treatment duration that could be tested in a future clinical trial.We developed a mathematical model of virtual patients with T-LBL in order to obtain a proportion of virtual relapses close to the one observed in the real population of patients from the EuroLB database. Our simulations reproduced a 2-year follow-up required to study the onset of the disease, the treatment of the acute phase and the maintenance treatment phase.

Efficiency of physical therapy on postural imbalance after stroke: study protocol for a systematic review and meta-analysis.

INTRODUCTION: Stroke frequently results in balance disorders, leading to lower levels of activity and a diminution in autonomy. Current physical therapies (PT) aiming to reduce postural imbalance have shown a large variety of effects with low levels of evidence. The objectives are to determine the efficiency of PT in recovering from postural imbalance in patients after a stroke and to assess which PT is more effective. METHODS AND ANALYSIS: We will search several databases from inception to October 2015. Only randomised controlled trials assessing PT to recover from poststroke postural imbalance in adults will be considered.Outcome measures will be the Berg Balance Scale (BBS), the Postural Assessment Scale for Stroke (PASS), the 'weight-bearing asymmetry' (WBA), the 'centre of pressure' (COP) and the 'limit of stability' (LOS). WBA, COP and LOS are measured by a (sitting or standing) static evaluation on force plate or another device.Two independent reviewers will screen titles, abstracts and full-text articles, evaluate the risk of bias and will perform data extraction. In addition to the outcomes, measures of independence will be analysed. This study will aim at determining the effects of PT on the function (WBA, COP, LOS), the activity (BBS, PASS) and the independence of patients. Subgroup analyses will be planned according to the location of brain lesion (hemispheric, brainstem or cerebellum), the time since stroke (early, late, chronic), the PT (type, main aim (direct effect or generalisation), overall duration), the type of approaches (top-down or bottom-up) and the methodological quality of studies. ETHICS AND DISSEMINATION: No ethical statement will be required. The results will be published in a peer-reviewed journal. This meta-analysis aims at managing the rehabilitation after postural imbalance by PT after a stroke. TRIAL REGISTRATION NUMBER: Prospero CRD42016037966;Pre-results.

[INSERM-FNCLCC collective expertise. Recommendations for medical management of women with genetic risk of developing breast and/or ovarian cancer]. / Expertise collectice INSERM-FNCLCC. Recommandations portant sur la prise en charge des femmes ayant un risque d'origine génétique de développer un cancer du sein et/ou de l'ovaire.

BACKGROUND: Almost 10% of breast and ovarian cancer are inherited, and the majority are linked to BRCA1 and BRCA2 germline mutations. Despite the uncertainty in the management of women gene carriers, consensus guidelines were defined to assist practitioners', and patients' decisions about the health care decisions to be made. METHODOLOGY: The Ad Hoc Committee consisted of 14 experts designated by the French National Institute for Health and Medical Research. They all attended eleven workshops at which a systematic analytical review of more than 3500 articles was carried out. Five additional experts critically analysed the first version of the report. CRITERIA AND DECISION PROCESS: Two thresholds were defined on a probability scale giving the risk of developing breast or ovarian cancer, to serve as a means of deciding as whether an intervention is worthwhile. The first threshold is that above which an intervention can be envisaged or recommended; the second is that under which an intervention can be ruled out; between the two, the decision has to be made on a each by case basis. STRATEGIES ANALYZED: About breast cancer: 1) hormonal interventions; 2) primary prevention (diet, family planning and chemoprevention); 3) screening (breast self-examination, clinician breast examination, tumor markers, imaging); 4) prophylactic mastectomy. About ovarian cancer: 1) hormonal stimulation; 2) screening (clinical screening, ultrasound and tumor markers); 3) prophylactic oophorectomy. MAIN CONCLUSIONS: With each strategy the following points were dealt with; the information to be delivered to the Consultant, the procedure and the indications. In addition, the Committee's opinion about BRCA1 and BRCA2 mutation screening is that population-based or even large scale implementation are not justified. Although no scientific evidence is available, the Committee feels that specific management is indispensable and advocates the use of defined and evaluated procedures, and involvement in clinical trials.

[Inserm ad hoc committee: Recommendations for the management of women with a genetic risk for developing cancer of the breast and/or the ovary]. / Expertise collective Inserm-FNCLCC: recommandations portant sur la prise en charge des femmes ayant un risque d'origine génétique de développer un cancer du sein et/ou de l'ovaire.

BACKGROUND: Almost 10% of breast and ovarian cancer are inherited, and the majority are linked to BRCA1 and BRCA2 germline mutations. Despite the uncertainty, consensus guidelines were defined to assist practitioners', and patients' decisions about the health care decisions to be made. METHODOLOGY: The ad hoc committee consisted of 14 experts designated by the French National Institute for Health and Medical Research. They all attended eleven workshops at which a systematic analytical review of more than 3,500 articles was carried out. Five additional experts critically analyzed the first version of the report. PROCESS: Two thresholds were defined on a probability scale giving the risk of developing breast or ovarian cancer, to serve as a means of deciding as whether an intervention is worthwhile. The first threshold is that above which an intervention can be envisaged or recommended; the second is that under which an intervention can be ruled out; between the two, the decision has to be made on a each by case basis. SCREENING AND PREVENTIVE STRATEGIES ANALYZED: About breast cancer: 1) hormonal interventions; 2) primary prevention (diet, family planning and chemoprevention); 3) screening (breast self-examination, clinician breast examination, tumor markers, imaging); 4) prophylactic mastectomy. About ovarian cancer: 1) hormonal stimulation; 2) screening (clinical screening, ultrasound and tumor markers); 3) prophylactic oophorectomy. MAIN CONCLUSIONS: With each strategy the following points were dealt with: the information to be delivered to the consult and, the procedure and the indications. The committee's opinion about BRCA mutation screening is that population-based or even large scale implementation are not justified. The committee feels that specific management is indispensable and advocates the use of defined and evaluated procedures, and involvement in clinical trials.

Recommendations for medical management of hereditary breast and ovarian cancer: the French National Ad Hoc Committee.

BACKGROUND AND PURPOSE: Almost 10% of breast and ovarian cancers are familial, and the majority are linked to BRCA1 and BRCA2 germline mutations. Despite uncertainty about the management of female gene carriers, consensus guidelines have been established to assist practitioners and consultees in making health care decisions. METHODOLOGY: The Ad Hoc Committee was composed of 14 experts appointed by the French National Institute for Health and Medical Research, all of whom attended eleven workshops at which more than 3500 articles were systematically analyzed. Five additional experts critically analysed the first version of the report. CRITERIA AND DECISION PROCESS: On a probability scale of the risk of developing breast or ovarian cancers, two thresholds were defined for use in determining whether an intervention would be worthwhile. The first is the threshold above which an intervention can be envisaged or recommended, and the second is the one below which an intervention can be ruled out; between the two, the decision has to be made on a case-by-case basis. SCREENING AND PREVENTIVE STRATEGIES ANALYZED: With respect to breast cancer: 1) hormonal interventions; 2) primary prevention (diet, family planning and chemoprevention); 3) screening (breast self-examination, clinician breast examination, tumor markers, imaging); 4) prophylactic mastectomy. With respect to ovarian cancer: 1) hormonal stimulation; 2) screening (clinical screening, ultrasound and tumor markers); 3) prophylactic oophorectomy. MAIN CONCLUSIONS: For each strategy the following points were addressed: the information to be given to the consultee, the procedure and the indications. In addition, the committee's opinion about BRCA1 and BRCA2 mutation screening is that population-based, or even large-scale, implementation are not justified. Although no scientific evidence is available, the committee feels that specific management is indispensable and advocates the use of defined and evaluated procedures, and participation in clinical trials.

[INSERM-FNCLCC collective expert's report. Recommendations for management of women having a genetic risk of developing breast and/or ovarian cancer. National Federation of Centers of the Fight Against Cancer]. / Expertise collective INSERM-FNCLCC. Recommandations portant sur la prise en charge des femmes ayant un risque d'origine génétique de développer un cancer du sein et/ou de l'ovaire.

BACKGROUND: Almost 10% of breast and ovarian cancer are inherited, and the majority are linked to BRCA1 and BRCA2 germline mutations. Despite the uncertainty, consensus guidelines were defined to assist practitioners', and patients' decisions about the health care decisions to be made. METHODOLOGY: The Ad Hoc Committee consisted of 14 experts designated by the French National Institute for Health and Medical Research. They all attended eleven workshops at which a systematic analytical review of more than 3500 articles was carried out. Five additional experts critically analyzed the first version of the report. PROCESS: Two thresholds were defined on a probability scale giving the risk of developing breast or ovarian cancer, to serve as a means of deciding as whether an intervention is worthwhile. The first threshold is that above which an intervention can be envisaged or recommended; the second is that under which an intervention can be ruled out; between the two, the decision has to be made on a each by case basis. SCREENING AND PREVENTIVE STRATEGIES ANALYZED: About breast cancer: 1) hormonal interventions; 2) primary prevention (diet, family planning and chemoprevention); 3) screening (breast self-examination, clinician breast examination, tumor markers, imaging); 4) prophylactic mastectomy. About ovarian cancer: 1) hormonal stimulation; 2) screening (clinical screening, ultrasound and tumor markers); 3) prophylactic oophorectomy. MAIN CONCLUSIONS: With each strategy the following points were dealt with: the information to be delivered to the consultant, the procedure and the indications. The Committee's opinion about BRCA mutation screening is that population-based or even large scale implementation are not justified. The Committee feels that specific management is indispensable and advocates the use of defined and evaluated procedures, and involvement in clinical trials.

Effect of retroviral integration on control of expression of a tumor marker in HeLa cells.

Fusion between HeLa cells and normal human fibroblasts results in the suppression of tumorigenicity. Under prolonged culture conditions, rare tumorigenic segregants arise and have been shown to reexpress a cell surface antigen, p75, which is also present in the HeLa parent but not in the fibroblast parent or in the nontumorigenic HeLa x fibroblast hybrid. Expression of p75 strictly correlates with tumorigenicity in HeLa and human somatic cell hybrids, as has been shown by chromosomal segregation and after gamma-irradiation. Using insertional mutagenesis, we induced expression of p75 in the nontumorigenic hybrid. Three cell clones were isolated that expressed p75 at different levels. Two of these clones exhibited a high level of p75 expression and displayed an altered morphology similar to that of the previously characterized tumorigenic segregants and consistent with the appearance of tumorigenicity. When injected into athymic nude mice, two clones were found to be tumorigenic, one from the onset of subculturing and the second only after further propagation for approximately 50 population doublings. The third clone showed very low p75 expression, had no altered morphology, and was nontumorigenic.

Qualitative differences in effects of recombinant alpha-, beta- and gamma-interferons on human peripheral blood leukocytes in vitro.

The in vitro effects of bacteria-produced human interferons alpha 2, beta and gamma on several properties of peripheral blood leukocytes from different healthy donors were compared. Treatment with HuIFN-alpha 2 or HuIFN-beta resulted in inhibition of the proliferative response to phytohaemagglutinin and in closely parallel induction of 2'-5'-oligoadenylate synthetase activity. In contrast, HuIFN-gamma had no significant effect on these two activities. However, all three HuIFN were able to enhance natural killer cell cytotoxicity and the expression of HLA-DR surface antigens, with only quantitative variations from donor to donor. Similar results were observed with glycosylated recombinant hamster-cell-derived HuIFN-gamma and with natural HuIFN-gamma. These data demonstrate qualitative differences in the effects of HuIFN-gamma compared to those of HuIFN-alpha 2 or -beta on cells of the immune system.

The cytotoxicity of bleomycin A2 on adult rat liver epithelial cell lines at different stages of spontaneous cell transformation.

Cytotoxic effects of Bleomycin A2 on adult rat liver epithelial cell lines were evaluated by three methods: the incorporation rate of (3H) thymidine for DNA biosynthesis, the incorporation rate of L-(3H) leucine for protein biosynthesis and Giemsa dye staining of surviving cells. Chromosome investigations at successive passages of cell lines have shown that spontaneous chromosome abnormalities in distribution and structure after 15-20 passages, i.e. 50 to 60 cell generations, were the earliest morphological sign of spontaneous transformation. In this study a highly spontaneously transformed cell line was very sensitive to the drug. Another cell line at the beginning of spontaneous transformation appeared to be insensitive although on further passage it became more sensitive. The use of microtitration plates made it easier for us to undertake a comparative study of the different parameters. Following Bleomycin A2 exposure, Giemsa staining gave the best evaluation of cell killing whereas thymidine incorporation allowed the estimation of cell recovery. The antineoplastic effect of Bleomycin A2 can probably be used to evaluate the malignant potential of different rat liver epithelial cell lines.

Melanogenesis in cultured human neuroblastomas.

The catecholic amino acids, dopa and 5-S-cysteinyldopa, and the dopamine metabolite, homovanillic acid, were determined in 8 neuroblastomas. 5-S-Cysteinyldopa and/or dopa were detected in all cases and homovanillic acid was present in 5. Dopa was also found in two tumours in which no definite histological diagnosis could be made. Neuroblastoma cells were cultured from 7 patients. The ageing of human sympathoblasts in culture was accompanied by modifications in the ability to synthetize dopa, which is a precursor of catecholamines as well as of melanins, and the metabolite homovanillic acid. An increase in the levels of 5-S-cysteinyldopa, a metabolite of the melanocytes, has been observed. Concurrent modifications of ultrastructural morphology with the disappearance of granular vesicles and appearance of melanosomes were noticed. This modulation of the original phenotypic expression commonly resulted in cell death, but in one case of metastatic adenopathy of a neuroblastoma we have been able to establish a permanent pigmented cell line.

Biotransformation of allylbenzene analogues in vivo and in vitro through the epoxide-diol pathway.

1. The epoxidation of allylbenzene, safrole, estragole, eugenol and eugenol methyl ether was investigated in rats pretreated with these compounds and also in vitro using hepatic microsomal preparations and adult rat liver cell cultures. 2. Dihydrodiols were detected in the urine and liver of rats pretreated with allylbenzene compounds. Similarly, incubation of allylbenzene epoxides with hepatic microsomal preparations and adult rat liver cell cultures gave rise to the formation of dihydrodiols.

[The occurrence of glucuroconjugated metabolites of safrole in the urine of treated rats]. / Présence de métabolites glucuroconjugués du safrol dans l'urine de rats traités.

The glucuronides of safrole were studied with GC-MS. At least seven compounds were identified, among then isomers of allylcatechol and mono-hydroxysafrol glucuronides. The presence of a glucuronide of hydroxysafrole-2',3' oxide will be especially discussed.

[Mutagenicity of the metabolites of the epoxide-diol pathway of safrole and its analogs. Study on Salmonella typhimurium]. / Pouvoir mutagène de métabolites de la voie époxyde-diol du safrol et d'analogues. Etude sur Salmonella typhimurium.

Mutagenicity of the metabolites of the expoxide-diol pathway of safrole and analogues was studied on Ames' strains with Ames' method. Safrole, eugenol, eugenolmethylether, estragol, allylbenzene and 1'-hydroxysafrole, are not mutagen on TA 1535, TA 100 (point mutation) and TA 1537, TA 1538, TA 98 (frameshift mutations) without activation system. The corresponding epoxides that we have synthetized, are mutagens and inducers of point mutation in TA 1535 and TA 100. Dose-effect curves show differences between the mutagen efficiencies of these epoxides probably in relation with their electrophilic properties. On the other hand the 2', 3'-dihydro-2',3'-dihydroxisafrole was not mutagen in Ames' test. These results confirm the promutagen character of safrole and analogues and the role of the epoxides as proximate carcinogens.

[Metabolic activation of a natural promutagen, eugenol, by replicative cultures of adult rat liver epithelial cells]. / Activation métabolique d'un promutagène naturel, l'eugénol, par des cultures réplicatives de cellules épithéliales de foie de rat adulte.

The metabolism of eugenol via the epoxide-diol pathway has been characterized by the incubation of this compound in replicative cultures of epithelial cells from sexed rat liver. It is a naturally occuring compound which has been found as the second metabolite of a known hepatocancerogen: safrole. Eugenol did not appear as a mutagen while epoxyeugenol was mutagenic using the Ames Test.

[A comparative study in cultured rat liver cells of the metabolism of different analogues and metabolites of a natural hepatocarcinogen: safrol]. / Etude comparative en culture cellulaire de foie de rat du métabolisme de différents analogues et métabolites d'un dépatocancérogène naturel: le safrol

Metabolism by sexed rat liver cell lines of safrole, a natural hepatocancerogen and of metabolites and analogs were studied and compared by gas chromatography-mass spectrometry. The epoxide-diol route was evidenced for safrole, isosafrole and eugenol as well as the induction of drug metabolizing enzymes by tested compounds.

[Perturbations of the levels of hypophyseal serotonin induced by oral administration of a single dose of 7, 12-dimethyl 1-2 benz(a)anthracene in rats].

Pituitary serotonin was estimated by fluorescence technique in rats fed with DMBA at 30 days, 60 days or 90 days age. In the rats most receptive to this carcinogen, serotonin was found to be decreased to 40% of control values, for the 8 days period studied. A possible mechanism leading to hormonal unbalance is proposed.