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X Sastre-Garau

Publications and source records attributed to X Sastre-Garau.

At least 37 records · Page 2Linked to original sources
PubMed2000

Low expression of bcl-2 in Brca1-associated breast cancers.

Little data are available concerning the molecular mechanisms of action of Brca1 and Brca2 in breast oncogenesis. Recent experimental results suggest that Brca1 plays a role in the regulation of apoptosis. In order to determine whether the analysis of human tumours would provide data supporting this hypothesis, we have assessed the expression of the antiapoptotic bcl-2 and of the proapoptotic p53 genes in Brca1 - and Brca2 -associated breast carcinomas. The levels of expression of these genes were compared to those observed in controls and to the mitotic and the apoptotic indexes. Our series were composed of 16 cases of breast carcinoma in women with a germline Brca1 gene mutation, and of four cases with Brca2 mutation. A group of 39 patients aged under 36 years and for whom the search for Brca1 gene mutations was negative, and a group of 36 cases of sporadic cancers without data on their Brca status were used as controls. Immunohistochemistry was used to detect p53 and bcl-2 gene products. Mitotic and apoptotic indexes were higher in Brca1 -associated tumours than in controls. No significant difference in p53 immunostaining was observed between the four groups of patients. In contrast, the rate of bcl-2 -positive tumours was lower (31%) in Brca1 -carcinomas than in carcinomas without Brca1 mutation (90%) (P< 10(-3)). A strong Bcl-2 expression was found in the four cases of Brca2 -associated carcinomas. No significant correlation was observed between p53 and Bcl-2 immunostainings, either in cases or in controls. The association between Brca1 status and Bcl-2 expression remained significant after adjustment for the oestrogen receptor status. Our study shows that a low expression of bcl-2 characterises most Brca1 -associated breast carcinomas, a biological trait which seems not to be shared by Brca2 -associated tumours nor to be related to oestrogen receptor and/or p53 status. bcl-2 might thus be one of the target genes involved in the oncogenesis related to Brca1 and its down-regulation may account for the increased apoptosis and the high proliferative rate observed in Brca1 -associated carcinomas.

Adult↗
PubMed2000

Phase I clinical trial with IL-2-transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological findings.

Various studies have emphasized an immunodepression state observed at the tumour site. To reverse this defect and based upon animal studies, we initiated a phase I clinical trial of gene therapy in which various doses of xenogeneic monkey fibroblasts (Vero cells) genetically engineered to produce human IL-2 were administered intratumorally in 8 patients with metastatic solid tumours. No severe adverse effect was observed in the 8 patients analysed during this clinical trial even in the highest dose (5 yen 107 cells) group. This absence of toxicity seems to be associated with rapid elimination of Vero-IL-2 cells from the organism. Indeed, exogenous IL-2 mRNA could no longer be detected in the peripheral whole blood 48 hours after Vero-IL-2 cell administration. In addition, we did not find any expression of exogenous IL-2 mRNA in post-therapeutic lesions removed 29 days after the start of therapy. A major finding of this trial concerns the two histological responses of two treated subcutaneous nodules not associated with an apparent clinical response. The relationship between local treatment and tumour regression was supported by replacement of tumour cells by inflammatory cells in regressing lesions and marked induction of T and natural killer cell derived cytokines (IL-2, IL-4, IFNg ...) in post-therapeutic lesions analysed 28 days after the start of Vero-IL-2 administration. Gene therapy using xenogeneic cells as vehicle may therefore present certain advantages over other vectors, such as its complete absence of toxicity. Furthermore, the in vivo biological effect of immunostimulatory genes, i.e IL-2-, may be potentiated by the xenogeneic rejection reaction.

Adenocarcinoma↗
PubMed2000

[Intraepithelial carcinoma and invasive carcinoma of the vulva, vagina and penis in Ile-de-france. Enquete PETRI on 423 cases].

OBJECTIVE: Precancerous and invasive carcinoma of the external genitalia and of the vagina are rare tumors and their incidence is not very well known in the Paris region. The objective of this study was to evaluate the frequency of precancerous and invasive lesions of the vulva, the vagina and the penis as well as their variation according to age. METHODS: A prospective study was conducted implicating private and public pathology laboratories in Paris and the seven departments around. Four hundred and twenty three genital biopsies have been analyzed: 160 from the vulva, 151 from the vagina and 112 from the penis. RESULTS: The mean age of the patients was 45 years. The highest frequency of genital biopsies was similar for the three anatomical sites and concerned patients of 25-34 years old. intraepithelial neoplasias represented 77p. 100 of the biopsies (32p. 100 of low grade and 45p. 100 of high grade), invasive squamous carcinoma and adenocarcinoma represented 21p. 100 and 2p. 100 of cases, respectively. The mean age of the patients with low grade vulvar intraepithelial neoplasia, low grade vaginal intraepithelial neoplasia and low grade penile intraepithelial were 34, 40 and 33 years old, respectively. An interval of three to seven years separates the mean age of low grade intraepithelial neoplasia from the mean age of high grade. High grade intraepithelial neoplasia present a peak of frequency in the same class of age for the three localizations (25-34 years) and the risk of developing a high grade intraepithelial neoplasia of the external genital was higher between 25 and 35 years and between 35-45 years of the vagina. The mean age of invasive vulvar carcinoma, vagina carcinoma and penile carcinoma was 62, 59 and 68 years old, respectively. CONCLUSIONS: The correlation between the development of intraepithelial neoplasia of the vulva and the penis supposes a common aetiologic factor in the majority of the cases. The diagnosis of a intraepithelial neoplasia implies a clinical, colposcopic and follow-up of the entire genital area.

Adenocarcinoma↗
PubMed2000

[Value of macroscopic analysis for authentification of axillary sentinel nodes detected by Patent Blue dye alone during breast cancer surgery].

Assessment sentinel node coloration by the patent blue dye technique during breast carcinoma surgery largely depends upon the surgeon. It would therefore be valuable to define a procedure to validate the quality of the surgical specimen. With this aim, we have analyzed a series of 141 cases of sentinel nodes and determined whether the blue color of the node persisted after formalin fixation and could be assessed by examination of the tissue blocks. The pathologist's macroscopic control confirmed blue coloring in 114/141 cases (81%). This rate was similar when the sentinel node was metastatic (82.5%) (40 cases) or non metastatic (81%) (101 cases). Checking the color of the lymph node is a simple method to verify the quality of the surgical specimen. This item should be included in the pathologist's report. Several mechanisms can account for the lack of coloring of true sentinel nodes.

Breast Neoplasms↗
PubMed1999

Quantitative PCR analysis of c-erb B-2 (HER2/neu) gene amplification and comparison with p185(HER2/neu) protein expression in breast cancer drill biopsies.

A PCR assay using capillary electrophoresis was designed for the detection of c-erbB-2 gene amplification in alcohol-formalin-acetic acid (AFA)-fixed, paraffin-embedded biopsies from 81 consecutive breast tumors. c-erbB-2 expression was analyzed in the same samples using immuno-histochemistry (IHC). In the competitive PCR assay, a single pTag plasmid containing a 4-nucleotide (nt)-deleted copy of a 124-nt sequence of c-erbB-2 and a 4-nt-deleted copy of a 120-nt sequence of GAPDH was co-amplified with genomic DNA extracted from 3 10-micrometer-thick tissue sections of the tumor biopsy. The percentage of tumor cells in the biopsy specimen and the percentage of tumor cells stained with the membrane anti-c-erbB-2 monoclonal antibody CB11 were recorded by a single pathologist on 2 consecutive sections. Among 81 consecutive tumor biopsies assayed by PCR, 21 (26%) displayed unequivocal c-erbB-2 amplification (actual gene copy number, AGCN > 4), 47 (58%) displayed no c-erbB-2 amplification (AGCN </= 2) and 7 (9%) could not be analyzed due to an insufficient amount of DNA. Six samples (7%) were considered inconclusive since the percentage of tumor cells was <20%. Analysis of c-erbB-2 expression by IHC showed that among the 21 amplified specimens 15 displayed strong staining, while all non-amplified samples (47) displayed no or only weak staining. The concordance of the 2 techniques was 91%. We conclude that c-erbB-2 gene amplification can be accurately quantitated by competitive PCR performed on small, fixed and embedded tumor samples.

Adenocarcinoma↗
PubMed1999

Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice.

Interleukin (IL) 17 is a proinflammatory cytokine secreted mainly by activated human memory CD4 T cells that induces IL-6, IL-8, and nitric oxide. Because IL-6 and IL-8 have been implicated in the pathogenesis of cervical cancer, we investigated the action of IL-17 on human cervical tumor cell lines in vitro and in vivo. We showed that in vitro, IL-17 increases IL-6 and IL-8 secretion by cervical carcinoma cell lines at both protein and mRNA levels. No direct effect of IL-17 on in vitro proliferation of cervical tumor cell lines could be demonstrated. However, two cervical cell lines transfected with a cDNA encoding IL-17 exhibited a significant increase in tumor size as compared to the parent tumor when transplanted in nude mice. This enhanced tumor growth elicited by IL-17 was associated with increased expression of IL-6 and macrophage recruitment at the tumor site. A potential role of IL-17 in modulation of the human cervical tumor phenotype was also supported by its expression on the cervical tumor in patients with CD4 infiltration. IL-17 therefore behaves like a T-cell-specific cytokine with paradoxical tumor-promoting activity. This may partially explain previous reports concerning the deleterious effect of CD4 T cells in cancer.

Animals↗
PubMed1998

No significant predictive value of c-erbB-2 or p53 expression regarding sensitivity to primary chemotherapy or radiotherapy in breast cancer.

To document whether c-erbB-2 over-expression or p53 accumulation in tumour cells was predictive of response to chemo- or radiotherapy, we analyzed a population of patients with breast cancer assigned to neo-adjuvant therapy (median follow-up: 54 months). T2/T3-N0N1b-M0 tumours (329 cases) were treated either by FAC chemotherapy or by radiotherapy before surgery, and the clinical response was classified as complete or incomplete. Expression of c-erbB-2 and p53 was retrospectively evaluated by immunohistochemistry. Proliferation rate was assessed by means of MIB-1 antibody and by S-phase fraction. A complete response to chemotherapy was observed in 38/167 patients (23%). Complete response rate was 20% in c-erbB-2-negative tumours, and rose to 31% in tumours with c-erbB-2 over-expression, but this trend was not statistically significant. There was no correlation between p53 staining and response to treatment, whereas chemosensitivity was found correlated with histological grade and S-phase. A complete response to radiotherapy was observed in 64 of the 156 evaluable patients (41%). Complete response rate was 41% in c-erbB-2- or p53-negative tumours, 54% in tumours with c-erb-B-2 over-expression, and 44% in tumours with p53 accumulation. There was no correlation between response to radiotherapy and histological grade or proliferative rate. No prognostic value was found for c-erbB-2 or p53 expression, whereas the 5-year survival rate was 85% for patients presenting a tumour with a low proliferating index (MIB-1 < 10%), and 68% for patients presenting a tumour with a high proliferative index. In multivariate analysis, node status (RR = 2), MIB-1 immunostaining (RR = 2), and tumour size (RR = 1.8) were found to be associated with survival. These results indicate that c-erbB-2 or p53 expression is not significantly associated with tumour response to neo-adjuvant chemo/radiotherapy in our series of breast cancers.

Breast Neoplasms↗
PubMed1998

Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas.

BACKGROUND: The production of the cytokine interferon gamma (IFN gamma) by activated peripheral blood mononuclear cells may be reduced in patients with invasive cervical carcinoma. This study was designed to assess the prognostic value of intratumoral IFN gamma messenger RNA (mRNA) levels in such patients. METHODS: Biopsy specimens of primary cervical lesions were obtained from 27 patients with invasive squamous cell carcinoma before they received any therapy. Two prognostic groups were considered: 1) a group of 14 patients who had no apparent disease recurrence and who were alive 2 years after diagnosis (good-prognosis group) and 2) a group of 13 patients who had disease recurrence or died during the 2-year follow-up (poor-prognosis group). A competitive reverse transcription-polymerase chain reaction assay was used to measure levels of IFN gamma and beta actin mRNA. The expression of human leukocyte antigen (HLA) class II proteins (which is stimulated by IFN gamma) in tumor cells was studied by immunostaining. RESULTS: Tumor specimens from all 14 patients in the good-prognosis group contained more than 10(3) IFN gamma mRNA copies per 5 x 10(5) beta actin mRNA copies, whereas tumor specimens from only six of the 13 patients in the poor-prognosis group contained this level of IFN gamma mRNA (two-sided P = .006). No clear relationship was observed between levels of IFN gamma mRNA and T-cell or natural killer cell infiltration in tumors; however, a statistically significant association was observed between HLA class II expression on tumor cells and IFN gamma mRNA levels (two-sided P = .01). CONCLUSIONS: A subgroup of poor-prognosis cervical carcinoma patients who have low levels of intratumoral IFN gamma mRNA was identified.

Carcinoma, Squamous Cell↗
PubMed1998

Human papillomavirus genotype as a major determinant of the course of cervical cancer.

PURPOSE: To determine whether the prognosis of invasive cancers of the uterine cervix is related to the type of human papillomavirus (HPV) associated with the tumor. PATIENTS AND METHODS: Two hundred ninety-seven patients with invasive cervical cancer were prospectively registered from 1986 to 1994. HPV typing was performed on DNA extracted from frozen tumor specimens by means of Southern blot hybridization (SBH) and polymerase chain reaction (PCR) techniques. The median follow-up was 38 months. RESULTS: HPV sequences were detected in 246 patients (83%): 150 patients had HPV16, 31 patients had HPV18, and 14 patients had one of the intermediate-oncogenic-risk HPV types (HPV31, 33, 35, 52, 58). In 51 patients, HPV type remained undetermined, and in 51 patients, no viral sequences were found. No significant associations were observed between virologic data and tumor stage or node status. The 5-year disease-free survival (DFS) rate was 100% for patients with intermediate-risk HPV-associated tumors, 58% for patients with HPV16-positive tumors, and 38% for patients with HPV18-positive tumors (P = .02). In multivariate analysis, patients with HPV18-associated tumors had a relative risk (RR) of death 2.4 times greater (95% confidence interval [CI], 1.29-4.59) than that for patients with HPV16, and 4.4 times greater (95% CI, 3.48-5.32) than that for patients with a tumor associated with a viral type different from HPV16/18. CONCLUSION: The prognosis for invasive cancers of the uterine cervix is dependent on the oncogenic potential of the associated HPV type. HPV typing may provide a prognostic indicator for individual patients and is of potential use in defining specific therapies against HPV-harboring tumor cells.

Adult↗
PubMed1998

Highly recurrent der(1;16)(q10;p10) and other 16q arm alterations in lobular breast cancer.

Cytogenetic data on infiltrating lobular carcinomas (ILCs) of the breast are described. In addition to 9 tumors, including 2 bilateral ones, with apparently normal chromosomes, recurrent chromosome alterations were found among 18 tumors. A der(1;16)(q10;p10), resulting in 1q gain and 16q loss, was observed in 11 tumors. Chromosome arm 16q was lost by other rearrangements in 3 other tumors. Thus, the deletion of 16q appears to be highly recurrent in ILCs. Compared to infiltrating ductal carcinomas (IDCs), ILCs have fairly simple karyotypes that remain pseudo- or near-diploid in most cases. This finding is confirmed by DNA ploidy studied by flow cytometry, which shows that about half of the tumors are diploid. This makes the der(1;16)(q10;p10) and other alterations of the 16q arm an early alteration of tumor progression, possibly related to the loss of expression of E-cadherin, whose gene is mapped on the 16q arm.

Adult↗
PubMed1997

Predictive factors for complete removal in soft tissue sarcomas: a retrospective analysis in a series of 592 cases.

BACKGROUND AND OBJECTIVES: In order to specify the indications for conservative surgery and preoperative therapeutic approaches of soft tissues sarcomas (STS), we looked for the clinico-pathological parameters associated with the failure to obtain a complete removal (CRm) of the tumor. METHODS: We retrospectively analyzed a series of 592 cases of primary non-metastatic STS. Surgery was performed in 495 cases as a primary treatment and in 88 cases after chemo- or radiotherapy. Nine patients were treated by chemotherapy-radiotherapy. In a univariate analysis, 20 parameters were tested for their association with CRm. A multivariate analysis was then used to define the independent parameters linked to the achievement of a CRm. RESULTS: In the univariate analysis, 15 parameters were found to be linked to the achievement of a CRm. Three of them proved to be independent in the multivariate analysis: T in the TNM classification, tumor location, and tumor necrosis. By the combination of these risk factors, four groups of patients were defined, with respective rates of CRm of 97% (no factor), 95% (one factor), 70% (two factors), and 48% (three factors). CONCLUSIONS: The achievement of a CRm after surgery of STS depends not only on the accessibility of the lesion, but also on tumor aggressiveness, a reflection of which is necrosis. The detection of necrosis by imaging procedures may thus help predicting the resectability of tumors and defining the indications for neoadjuvant therapies, likely to broaden the use of conservative surgery.

Adolescent↗
PubMed1997

Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma.

PURPOSE: Several histologic grading systems have been validated in soft tissue sarcomas (STS), but no system is currently accepted worldwide. The National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems were examined comparatively in the same population of patients with STS to determine which system is the best prognosticator with regard to metastasis development and tumor mortality. PATIENTS AND METHODS: Four hundred ten adult patients with nonmetastatic STS were examined. Histologic grade was established according to the NCI and FNCLCC systems in each case. The prognostic value of both systems was examined using univariate and multivariate (Cox's model) analyses, and special attention was devoted to tumors with discordant grades. RESULTS: In univariate analysis, both the NCI and FNCLCC systems were of prognostic value to predict metastasis development and tumor mortality. In multivariate analysis, high-grade tumors, irrespective of the system used, size > or = 10 cm, and deep location were found to be independent prognostic factors for the advent of metastases. Tumor grade had a higher predictive value than size or depth, and higher prognostic weight was assigned to the FNCLCC grading system in Cox models. Grade discrepancies were observed in 34.6% of the cases. An increased number of grade 3 STS, a reduced number of grade 2 STS, and a better correlation with overall and metastasis-free survival within subpopulations with discordant grades were observed in favor of the FNCLCC system. CONCLUSION: The FNCLCC system showed slightly increased ability to predict distant metastasis development and tumor mortality. The use of this system to evaluate STS aggressiveness might be favored.

Adolescent↗