RESUMO
OBJECTIVE: Based on an updated review of the international literature covering the different surgical techniques and complications of risk reducing mastectomies (RRM) in non-genetic context, the Commission of Senology (CS) of the College National des Gynécologues Obstétriciens Français (CNGOF) aimed to establish recommendations on the techniques to be chosen and their implementation. DESIGN: The CNGOF CS, composed of 24 experts, developed these recommendations. A policy of declaration and monitoring of links of interest was applied throughout the process of making the recommendations. Similarly, the development of these recommendations did not benefit from any funding from a company marketing a health product. The CS adhered to and followed the AGREE II (Advancing guideline development, reporting and evaluation in healthcare) criteria and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method to assess the quality of the evidence on which the recommendations were based. The potential drawbacks of making recommendations in the presence of poor quality or insufficient evidence were highlighted. METHODS: The CS considered 6 questions in 4 thematic areas, focusing on oncologic safety, risk of complications, aesthetic satisfaction and psychological impact, and preoperative modalities. RESULTS: The application of the GRADE method resulted in 7 recommendations, 6 with a high level of evidence (GRADE 1±) and 1 with a low level of evidence (GRADE 2±). CONCLUSION: There was significant agreement among the CS members on recommendations for preferred surgical techniques and practical implementation.
Assuntos
Mastectomia , Escolaridade , HumanosRESUMO
OBJECTIVES: Implementing fully automated analyzers has become a crucial safety step in blood donation centers. The Elecsys® assays were evaluated on the cobas e 801 module (Roche Diagnostics) for routine first-time blood donor screening. MATERIALS & METHODS: Five Elecsys infectious disease assays were tested on the cobas e 801 module at Etablissement Français du Sang, Montpellier, France (March-April 2018). The performance of Elecsys HIV Duo, Anti-HCV II, HBsAg II, Anti-HBc II, and Syphilis assays was compared with PRISM HIV O Plus, HCV, HBsAg, HBcore, and newbio pk TPHA assays (specificity analyses)/ARCHITECT Syphilis TP (sensitivity analyses), respectively. Specificity was determined in residual fresh serum samples from unselected first-time blood donors (n≥5195 per parameter). Elecsys assay sensitivity was tested using 30 preselected, positively characterized samples per assay and compared with archived routine testing data for comparator assays. RESULTS: Across all parameters, specificities for repeatedly reactive samples ranged from 99.81-100.00% for Elecsys assays and 99.71-99.98% for comparator assays. Sensitivities of Elecsys and comparator assays were the same for hepatitis C (85.19%), hepatitis B surface antigen (70.00%), hepatitis B core antigen antibodies (100.00%), and syphilis (100.00%). The sensitivity of the Elecsys HIV Duo assay was higher than the comparator assay (83.33% vs. 76.67%), but the difference was not statistically significant. CONCLUSIONS: Elecsys infectious disease assays on the cobas e 801 module demonstrated high specificity and sensitivity for screening first-time blood donor samples, and were comparable with other commercially available assays. The Elecsys assays are reliable tests for screening blood donations.
Assuntos
Infecções por HIV , Hepatite B , Sífilis , Doadores de Sangue , Infecções por HIV/diagnóstico , Hepatite B/diagnóstico , Antígenos de Superfície da Hepatite B , Humanos , Sensibilidade e Especificidade , Sífilis/diagnósticoRESUMO
The objective of this review was to identify recurrences (ipsilateral, contralateral, metastases and deaths) occurring after controlled ovarian hyperstimulation (COH) or cryopreservation of ovarian tissue (CPTO) for patients treated for a breast cancer. METHODS: We performed a bibliographical research through the Pubmed/Medline database, including all the references from January 2006 until September 2016, in French or in English, after exclusion of animal studies. The keywords association "breast neoplasms", "fertility preservation", "reproductive techniques", "ovarian cryopreservation" and "in vitro fertilization" allowed the selection of 852 publications among which only 6 were selected because they included data on recurrence and long term follow up. Four publications involved HSC (3 before breast cancer treatment and 1 after) and 2 concerned CPTO with re-implantation. RESULTS: This analysis has not shown increasing of breast recurrences after HSC and CPTO. However, results were not statistically significant, due to several biases in particular heterogeneousness of the groups of patients. CONCLUSION: A survey of patients who used fertility preservation or assisted reproductive technologies after breast cancer would be helpful to better estimate their oncological risk.
Assuntos
Neoplasias da Mama/terapia , Criopreservação , Preservação da Fertilidade/efeitos adversos , Recidiva Local de Neoplasia/epidemiologia , Ovário , Indução da Ovulação/efeitos adversos , Feminino , Preservação da Fertilidade/métodos , Fertilização in vitro , Humanos , MEDLINE , Técnicas de Reprodução Assistida/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND: Muir-Torre syndrome (MTS), a cutaneous variant of Lynch syndrome, consists of hereditary predisposition to cutaneous tumours and gastrointestinal and gynaecological neoplasms, with autosomal dominant transmission. It is associated with mutations in genes coding for proteins in the DNA mismatch repair system. PATIENTS AND METHODS: Herein, we report a case of a male patient presenting Waldenstrom's macroglobulinemia since the age of 50 and which, after the age of 65 years, developed into sebaceous tumours (5 sebaceous adenomas, 1 sebaceoma, 1 sebaceous carcinoma) and colonic lesions (4 adenomas). The clinical phenotype was consistent with MTS. Somatic analysis carried out on one sebaceous tumour showed instability of the microsatellites with loss of expression of MSH2 and MSH6 although constitutional genetic analysis showed no germline mutations known to be harmful. DISCUSSION: This noteworthy case raises a number of questions, including the possibility of association between STM and Waldenstrom's macroglobulinemia, which is discussed herein.
Assuntos
Síndrome de Muir-Torre/complicações , Macroglobulinemia de Waldenstrom/complicações , Adenoma/genética , Idoso , Carcinoma/genética , Neoplasias do Colo/genética , Humanos , Masculino , Instabilidade de Microssatélites , Síndrome de Muir-Torre/genética , Neoplasias das Glândulas Sebáceas/genéticaRESUMO
Women with a BRCA1 or BRCA2 mutation are at an elevated risk of developing breast and ovarian cancer; however, it is unclear to what extent family history influences the uptake of cancer prevention options. Women with a BRCA1/2 mutation completed a follow-up questionnaire that assessed uptake of cancer preventive options. The pedigree of each woman was reviewed, and information was recorded on cancers diagnosed in relatives. Five hundred and seventeen women were included in the study. Women with a sister with breast cancer were more likely to have a prophylactic mastectomy than those without a sister with breast cancer [odds ratios (OR) = 2.4, p = 0.003]. Uptake of prophylactic mastectomy was significantly lower in women with a mother with ovarian cancer compared with those whose mother did not have ovarian cancer (OR = 0.4, p = 0.01). Having a mother or sister with ovarian cancer significantly predicted the uptake of prophylactic oophorectomy (OR = 1.6, p = 0.04). Women with a BRCA2 mutation were less likely to have a prophylactic oophorectomy than those with a BRCA1 mutation (OR = 0.49, p = 0.0004). Among women with a BRCA1 or BRCA2 mutation, family history predicts the uptake of prophylactic mastectomy and prophylactic oophorectomy.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Ovariectomia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Feminino , Testes Genéticos , Humanos , Mastectomia , Linhagem , PrognósticoRESUMO
BACKGROUND: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. OBJECTIVE: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. METHODS: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2. RESULTS: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. CONCLUSION: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.
Assuntos
Genes BRCA2 , Mutação em Linhagem Germinativa/genética , Éxons/genética , Feminino , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Deleção de Sequência/genéticaRESUMO
The BRCAPRO, Couch, Myriad I and II, Ontario Family History Assessment Tool (FHAT), and Manchester models have been used to predict BRCA1 or BRCA2 mutation carrier status of women at high risk for developing the heritable form of breast and ovarian cancers. We have evaluated these models for their accuracy in classifying 224 French Canadian families with at least three cases of breast cancer (diagnosed before the age of 65 years), ovarian cancer, or male breast cancer where mutation status was known for an index affected case used to assess the model. This series includes 44 BRCA1 and 52 BRCA2 mutation-positive families. Using receiver operator characteristics analyses, the C-statistics were found to be 0.81, 0.80, 0.79, and 0.74 for the BRCAPRO, FHAT, Manchester, and Myriad II models, respectively, when incorporating both BRCA1 and BRCA2 mutation carrier predictions. For the BRCAPRO model, 75% scored greater than a 0.43 probability in the mutation-positive group and 75% scored less than 0.50 in the mutation-negative group. Only 38 of 128 (30%) mutation-negative group had a probability greater than 0.43 with the BRCAPRO model. While all models were highly predictive of carrier status, the BRCAPRO model was the most accurate where a cut-off of 10% would have eliminated 60 of 128 (47%) mutation-negative families for genetic testing and only miss 10 of 96 (10%) mutation-positive families. A review of the cancer phenotypes with high BRCAPRO probabilities showed that significantly more metachronous bilateral breast cancer cases occurred in BRCA1/2 mutation carrier families in comparison to mutation-negative families, a feature which is not discriminated in the BRCAPRO model.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Modelos Genéticos , Neoplasias Ovarianas/genética , Neoplasias da Mama/etnologia , Neoplasias da Mama Masculina/etnologia , Neoplasias da Mama Masculina/genética , Canadá , Feminino , Predisposição Genética para Doença/etnologia , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/etnologia , Linhagem , Probabilidade , Quebeque , Curva ROCRESUMO
To address the cellular basis for the response to ovarian cancer treatment, we characterized the chemosensitivity and radiosensitivity of four human epithelial ovarian cancer cell lines that harbor different genetic alterations. The TOV-21G, TOV-81D, OV-90, and TOV-112D cell lines were derived from ovarian tumors (TOV) or ascites (OV) from chemotherapy- and radiotherapy-naive patients and were characterized by their mutation spectrum of BRCA2, TGFbeta-RII, KRAS2, TP53, and CDKN2A. Cells were monitored for survival following exposure at various concentrations to different cytotoxic agents including cisplatin, camptothecin or paclitaxel or to different doses of gamma-irradiation. At the lowest doses, the TGFbeta-RII-mutated and KRAS2-mutated cell line, TOV-21G, and the BRCA2-mutated cell line, TOV-81D, demonstrated a significantly higher sensitivity to cisplatin and gamma-irradiation than the TP53-mutated cell lines, TOV-112D and OV-90. At higher doses, differences between the TP53-mutated lines were observed with TOV-112D being less sensitive to cisplatin than OV-90 that also harbors a CDNK2A mutation. All cell lines were similarly sensitive to high doses of gamma-irradiation. In contrast, sensitivity to camptothecin or paclitaxel was not significantly different between all cell lines, irrespective of the mutation status of BRCA1, BRCA2, TGFbeta-RII, KRAS2, TP53, and CDKN2A. The observed responses to treatment are consistent with the current knowledge concerning BRCA2, TGFbeta-RII, KRAS2, TP53, and/or CDKN2A aberrant function.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Ovarianas/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Genes BRCA2 , Genes p16 , Genes p53 , Humanos , Mutação , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Tolerância a Radiação , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Células Tumorais Cultivadas , Proteínas rasRESUMO
Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.
Assuntos
População Negra/genética , Frequência do Gene , Predisposição Genética para Doença , Neoplasias/genética , Polimorfismo Genético , População Branca/genética , Sistema Enzimático do Citocromo P-450/genética , Bases de Dados Factuais , Ligação Genética , HumanosRESUMO
The isolation of full-length cDNAs of naturally occurring GSTP1 gene variants, and the demonstration that these alleles are distributed in the normal population, have provided conclusive evidence that the human GSTP1 gene locus is polymorphic and that specific GSTP1 alleles may be associated with different risk for cancers or other diseases. Recent data have indicated that the different GSTP1 alleles encode proteins with different enzymatic activities against carcinogens. In this case-control study, we examined the effect of the GSTP1 genetic polymorphism and its interaction with other factors to determine breast cancer risk. GSTP1 and GSTM1 genotypes of 220 breast cancer patients and 196 controls, all residents of western France, were examined. Data on menopausal status and family cancer history were obtained from 195 patients and 147 controls. Exons 5 and 6 of the GSTP1 gene, which contain the polymorphic nucleotide transitions, were analyzed by DNA polymerase chain reaction-restriction fragment length polymorphism to distinguish between the GSTP1 alleles. In the control population, GSTP1 allelic frequencies were 64.3%, 26.0% and 9.7%, respectively, for GSTP1*A, GSTP1*B and GSTP1*C. In the breast cancer patients, the frequencies were 67.9% for GSTP1*A, 26.8% for GSTP1*B and 5.3% for GSTP1*C. In multivariate analysis, breast cancer risk increased by 7.7-fold (p < 0.001) in women with a family history of cancers and 2.18-fold (p = 0.026) in non-GSTP1*C individuals. GSTM1 genotypes did not emerge as risk factor. Our results show that in addition to well-known risk factors, in particular, a family history of cancer, GSTP1 allelopolymorphism is a significant modifier of breast cancer risk. The results also suggest a protective role against breast cancer for the GSTP1*C allele.
Assuntos
Neoplasias da Mama/genética , Genótipo , Glutationa Transferase/genética , Isoenzimas/genética , Proteínas de Neoplasias/genética , Polimorfismo Genético , Adulto , Idoso , Alelos , Análise de Variância , Estudos de Casos e Controles , Família , Feminino , Glutationa S-Transferase pi , Humanos , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Fatores de RiscoAssuntos
Neoplasias da Mama/genética , Frequência do Gene/genética , Genes BRCA1/genética , Repetições de Microssatélites/genética , Mutação/genética , Expansão das Repetições de Trinucleotídeos/genética , Alelos , Proteína BRCA1/química , Proteína BRCA1/genética , Sítios de Ligação , Análise Mutacional de DNA , Feminino , França , Mutação em Linhagem Germinativa/genética , Humanos , Perda de Heterozigosidade/genética , Neoplasias Ovarianas/genética , Estrutura Terciária de Proteína , Dedos de Zinco/genéticaRESUMO
Investigation of early breast carcinogenesis is limited by the difficulty in obtaining cell cultures or adequate fresh frozen material and by the fact that available data from in situ techniques are interpreted in terms of various classification systems. Our studies in a series of pure ductal carcinomas in situ (DCIS) were conducted in accordance with the recommendations of the international Consensus Conference (Hum. Pathol., 28, 122-125, 1997) relative to processing, determination of lesion extent, and histological stratification primarily on nuclear grade (NG). A multifactorial study performed in 15 low- and 16 high-NG DCIS (68% detected by mammography) included the following: (1) morphological analysis of NG, necrosis, and architectural pattern; (2) detection of numerical genomic abnormalities at ERBB2, MYC, CCND1, Xq1.2 and 20q13 loci by fluorescence in situ hybridization on interphase nuclei; and (3) immunohistochemical determination of cell proliferation, p53 accumulation, hormonal receptors and bcl-2 expression on serial sections of formalin-fixed, paraffin-embedded specimens. High NG, comedo/solid pattern and necrosis were significantly associated with amplification at one or more loci, the number of amplified loci, amplification at the ERBB2 locus, absence of bcl-2 and hormonal receptor expression and high cell proliferation (p < 0.05). High NG and comedo/solid pattern were significantly associated with MYC amplification and p53 accumulation, and necrosis with CCND1 amplification (the only gene amplification detected in low NG DCIS). These data provide additional information on the early steps of breast carcinogenesis, in accordance with currently recognized criteria of histological classification.
Assuntos
Neoplasias da Mama/genética , Carcinoma in Situ/genética , Carcinoma Ductal de Mama/genética , Amplificação de Genes , Hibridização in Situ Fluorescente , Proto-Oncogenes , Adulto , Idoso , Neoplasias da Mama/patologia , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/patologia , Divisão Celular , Ciclina D1/genética , Feminino , Genes erbB-2 , Genes myc , Humanos , Imuno-Histoquímica , Pessoa de Meia-IdadeRESUMO
PURPOSE: Cancer patients frequently experience anemia as a consequence of myelosuppressive therapy or bone marrow invasion. PATIENTS AND METHODS: A risk model for chemotherapy-induced severe anemia requiring RBC transfusions (SARRT) within 31 days after the administration of chemotherapy was delineated in the cohort of cancer patients treated with chemotherapy in the Department of Medicine of Centre Léon Bérard in 1996 (CLB-1996). The risk model was tested on a series of 797 patients treated in 1997 (CLB-1997) and on 295 patients included in a multicenter prospective series (ELYPSE 1). RESULTS: One hundred seven of the 1,051 patients of the CLB-1996 cohort (10%) experienced SARRT. In univariate analysis, only female sex, performance status greater than 1, hemoglobin level less than 12 g/dL before chemotherapy on day 1 (d1), and d1 lymphocyte count < or = 700/microL significantly correlated with the risk of SARRT. Using logistic regression, d1 hemoglobin level less than 12 g/dL (odds ratio [OR] = 14.0; 95% confidence interval [CI], 7 to 30), performance status greater than 1 (OR = 2.2; 95% CI, 1.4 to 3.5), and d1 lymphocyte count < or = 700/microL (OR = 1.7; 95% CI, 1. 1 to 2.6) were identified as independent risk factors for SARRT. These three factors were given arbitrary risk coefficients of 3, 1, and 1 respectively, and a risk score for each individual patient was obtained by adding the coefficients. The calculated probability of RBC transfusions was 30% for patients with a score > or = 4, and 11%, 4%, and 1% in patients with a score of 2 or 3, 1, and 0 respectively. This model was then tested and validated in the CLB-1997 and ELYPSE 1 series. CONCLUSION: This risk index could be useful to identify patients at high risk for chemotherapy-induced SARRT who might be appropriate candidates for prophylactic erythropoietin treatment.
Assuntos
Anemia/terapia , Antineoplásicos/efeitos adversos , Transfusão de Eritrócitos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Anemia/sangue , Anemia/induzido quimicamente , Estudos de Coortes , Feminino , Hemoglobina A/análise , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Probabilidade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome characterized by familial predisposition to colorectal carcinoma and extracolonic cancers of the gastrointestinal, urological, and female reproductive tracts. This dominant disorder is caused by germline defects in one of at least five DNA mismatch repair (MMR) genes: hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 (GTBP). Germline mutations of hMSH2 and hMLH1 are also frequently identified in families not fulfilling all the Amsterdam criteria, thereby demonstrating that the involvement of these genes is not confined to typical HNPCC. To evaluate the respective involvement of the various MMR genes in typical and incomplete HNPCC syndromes, we have performed an analysis of the hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in a large series of French kindreds (n=75) with colorectal tumors and/or aggregation of extracolonic cancers belonging to the HNPCC spectrum. Mutational analysis has been performed in all families, without preselection for the tumor phenotype. We have detected 26 pathogenic germline mutations of the hMLH1 and hMSH2 genes and several novel variants of the hPMS1, hPMS2, and hMSH6 genes. Our data confirm that, regardless of the type of families and the tumor phenotype, hPMS1, hPMS2, and hMSH6 germline mutations are rare in familial aggregation of colorectal cancers. Furthermore, they suggest that the presence of multiple primary malignancies in a single individual and the observation of extracolonic tumors in relatives of a colorectal cancer patient should be included among the guidelines for referring patients for genetic testing.
Assuntos
Adenosina Trifosfatases , Neoplasias Colorretais Hereditárias sem Polipose/genética , Enzimas Reparadoras do DNA , Mutação em Linhagem Germinativa , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Idade de Início , Proteínas de Transporte , Neoplasias do Colo/genética , Proteínas de Ligação a DNA/genética , França , Deleção de Genes , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteínas MutL , Proteína 2 Homóloga a MutS , Proteínas Nucleares , Ácidos Nucleicos Heteroduplexes , Mutação Puntual , Prevalência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/genética , Neoplasias Urológicas/genéticaRESUMO
p53 tumor-suppressor gene mutation and p53 protein over-expression have been reported with higher frequency in early-onset breast carcinomas (EOBC). Given the role attributed to normal p53 protein in DNA-repair mechanisms, other somatic genomic alterations would be expected to be associated with this abnormality. Amplification of the c-erbB-2 (HER-2/neu) oncogene and over-expression of the corresponding p185erbB-2 protein have been linked to prognosis and response to therapy in breast cancer. In a retrospective study of 62 formalin-fixed paraffin-embedded invasive EOBC (diagnosed at 35 years or less), the amplification status of the c-erbB-2 gene detected by fluorescence in situ hybridization (FISH) using a unique sequence probe was compared with p53 protein accumulation measured by immunohistochemistry (IHC) and phenotypic features. p185erbB2-protein expression was also detected by immunohistochemistry, together with estrogen-receptor (ER) and progesterone-receptor (PR) expression. The data for a sub-set of 33 node-negative EOBC cases were compared with 70 node-negative tumors diagnosed in women above 36 years of age. Compared with node-negative BC in older women, node-negative EOBC was significantly more likely to feature high grade, high proliferation rate, negative ER and/or PR and p53 over-expression (p < 0.05). A trend toward a higher incidence of c-erbB-2 amplification in EOBC (21% vs. 9%) reached near-significance (p = 0.07). In EOBC, c-erbB-2 amplification and p53 over-expression were not associated with high tumor grade or high cell-proliferation rate, in contrast to the significant associations of these markers in tumors in older women. Abnormalities in tumor markers, including c-erbB-2 gene amplification and p53-protein over-expression, occur at different rates in women with EOBC as compared with BC developing in older women. This finding may reflect a different pathogenesis for EOBC, and warrants further investigation.
Assuntos
Neoplasias da Mama/genética , Amplificação de Genes , Genes erbB-2 , Hibridização in Situ Fluorescente , Proteína Supressora de Tumor p53/análise , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Fenótipo , Receptor ErbB-2/análiseRESUMO
This study was conducted to determine the maximum tolerated dose of an intensified MAID (mesna, adriamycin, ifosfamide, dacarbazine) regimen with the support of lenograstim in patients with advanced soft tissue sarcomas. Following 1 cycle of MAID at the standard dose, four patients were to be treated at each of five dosage levels: +25%, +45%, +65%, +85%, +100%. Sixteen patients were treated. Because there were no significant differences in hematologic toxicity between patients receiving lenograstim 5 or 10 microg/kg/day (levels 1-5 and 1-10), the data were pooled for comparison with level 2. The median duration of absolute neutrophil count < 0.5 x 10(9)/l was 3 days at level 1 and 7 days at level 2 (p < 0.01). The median platelet nadir was 25 x 10(9)/l at level 1 and 10 x 10(9)/l at level 2 (p < 0.01). The median duration of toxicity-related hospitalization was 3.5 days and 11 days at levels 1 and 2, respectively, (p < 0.001). Mucositis > or = grade III occurred after 3/29 cycles at level 1 and 10/15 cycles at level 2 (p < 0.001). After 4 cycles at level 1, 8/8 patients still had performance status scores < or = 2, and only 4/8 had performance status scores < or = 2 after the second cycle at level 2. Lenograstim enabled an increase of 25% of the MAID regimen. At higher dose levels, severe mucositis and deterioration in performance status were dose limiting.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Ifosfamida/administração & dosagem , Lenograstim , Masculino , Mesna/administração & dosagem , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Análise de SobrevidaRESUMO
The influence of polymorphisms of the glutathione S-transferase gene GSTM1 in breast cancer susceptibility has been assessed in this study. Previous studies correlated the absence of the GSTM1 protein with an increased risk of developing some cancers, especially lung or bladder cancers, in heavy smokers. In this study, we determined GSTM1 polymorphisms in a population of 437 female controls from the west of France and 361 community breast cancer patients. Three distinct alleles of this gene exist: GSTM1*A, GSTM1*B and GSTM1*0 (deleted allele). Null subjects (GSTM1 null) are homozygous for this deletion. The comparative analysis of GSTM1 allelotypes in our two populations did not demonstrate a statistically significant difference in distribution (P = 0.22), although the null genotype was more frequent in cancer patients. However, breast cancer risk was increased in null subjects > or = 50 years of age compared with non-null subjects [odds ratio = 1.99 (1.19-3.32), P = 0.009], but not in null subjects < 50 years of age compared with non-null subjects (P = 0.86). Our results suggest that the GSTM1 null genotype may play a role in post-menopausal breast cancer development. They also point to a putative protective role of the A allele in the older female control group, especially in hemizygous subjects [odds ratio = 0.42 (0.23-0.77), P = 0.03].
Assuntos
Neoplasias da Mama/genética , Deleção de Genes , Predisposição Genética para Doença/genética , Glutationa Transferase/genética , Polimorfismo Genético , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Homozigoto , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Reprodutibilidade dos TestesRESUMO
The use of mutation screening of BRCA1 and BRCA2 genes as a genetic test is still to a certain extent limited and the oncogeneticist may want to use complementary approaches to identify at-risk individuals. In a series of 23 families with at least three breast or ovarian cancer cases, screened for mutations at BRCA1 and BRCA2 and typed for markers at both loci, we investigated the usefulness of marker segregation information at two levels: 1) to what extent can the indirect approach identify the mutation carrier status of screened cases and their first-degree relatives, and 2) in what way does it help to identify the gene implicated in a family in which neither BRCA1 nor BRCA2 mutation has been detected? Using the indirect approach, the carrier status of the screened case could be determined with quasi certainty in three families and with a high probability in eight families. This status could be inferred in unaffected first-degree relatives as almost certain in one family and as highly probable in six families. Fourteen mutations were found concurrently in our series. Among the nine mutation-negative families, we were able to conclude that a BRCA1 mutation most probably segregated in one and that a mutation other than BRCA1 and BRCA2 was probably involved in two families. Our results show that, in small families, little help is to be expected from linkage data and mutation screening is the only way of identifying the origin of a genetic predisposition in a family. Marker segregation information may be useful in some large breast/ovarian cancer families in which no BRCA1 or BRCA2 mutation has been detected.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Aconselhamento Genético , Neoplasias Ovarianas/genética , Proteína BRCA1/genética , Proteína BRCA2 , Segregação de Cromossomos/genética , Feminino , Ligação Genética , Testes Genéticos , Heterozigoto , Humanos , Proteínas de Neoplasias/genética , Linhagem , Fatores de Transcrição/genéticaRESUMO
Glutathione S-transferases (GSTs) are a family of isoenzymes involved in cellular detoxification. Previous studies have correlated the absence of the GSTM1 protein with an increased risk of developing some cancers, especially lung or bladder cancer, in heavy smokers. In this study, we determined GSTM1 gene polymorphisms in a French western population of 437 female controls and 361 community breast cancer patients. Three distinct alleles of this gene may be identified: GST M1* A allele, GST M1* B allele, and GST M1* 0 allele (which is deleted). Null patients (GSTM1 0) are homozygous for the deletion. We determined in our two populations, patients with no, one or two GSTM1 alleles. The comparative analysis of our two populations did not demonstrate any statistically significant difference in GSTM1 allelotype distribution between the two groups (P = 0.43), although the null genotype was the more frequent in patients. The predominance of the null genotype was significant in the oldest group of patients (> or = 55) (P = 0.006), suggesting that GSTM1 null genotype may play an important role in breast cancer susceptibility in the elderly. This was not observed in the youngest age group, i.e. < 40 year old patients (P = 0.25), or in the patients aged from 40 to 55 years old (P = 0.37). Our results also point out a putative protective role of the A allele in the older female control group (P = 0.02), especially in subjects hemizygous for these alleles (P = 0.03). A prospective study will be of interest to investigate the effect of dosage of the gene.
Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Deleção de Genes , Glutationa Transferase/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , França , Frequência do Gene , Genótipo , Heterozigoto , Homozigoto , Humanos , Pessoa de Meia-IdadeRESUMO
Severe thrombocytopenia is a rare but life-threatening side effect of cytotoxic chemotherapy for which risk factors are not well known. Our objective was to delineate a risk model for chemotherapy-induced thrombocytopenia requiring platelet transfusions in cancer patients. Univariate and multivariate analysis of risk factors for chemotherapy-induced thrombocytopenia requiring platelet transfusions were performed on the cohort of the 1,051 patients (CLB 1996) treated with chemotherapy in the Department of Medicine of the Centre Léon Bérard (CLB) in 1996. In univariate analysis, performance status (PS) greater than 1, platelet count less than 150, 000/microL at day 1 (d1) before the initiation of chemotherapy, d1 lymphocyte count < or = 700/microL, d1 polymorphonuclear leukocyte count less than 1,500/microL, and the type of chemotherapy (high risk v others) were significantly associated (P < .01) with an increased risk of severe thrombocytopenia requiring platelet transfusions. Using logistic regression, d1 platelet count less than 150,000/microL (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.9 to 9.6), d1 lymphocyte counts < or = 700/microL (OR, 3.37; 95% CI, 1.77 to 6.4), the type of chemotherapy (OR, 3.38; 95% CI, 1.77 to 6.4), and PS greater than 1 (OR, 2.23; 95% CI, 1.22 to 4.1) were identified as independent risk factors for platelet transfusions. The observed incidences of platelet transfusions were 45%, 13%, 7%, and 1.5% for patients with > or = 3, 2, 1, or 0 risk factors, respectively. This model was then tested in 3 groups of patients treated with chemotherapy used as validation samples: (1) the series of 340 patients treated in the CLB in the first 6 months of 1997, (2) the prospective multicentric cohort of 321 patients of the ELYPSE 1 study, and (3) the series of 149 patients with non-Hodgkin's lymphoma treated in the CLB within prospective phase III trials (1987 to 1995). In these 3 groups, the observed incidences of platelet transfusions in the above-defined risk groups did not differ significantly (P > .1) from those calculated in the model. This risk index could be useful to identify patients at high risk for chemotherapy-induced thrombocytopenia requiring platelet transfusions.