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Biomedical subjects

A P Sappino

Publications and source records attributed to A P Sappino.

At least 19 recordsLinked to original sources
PubMed2006

Impact of familial risk factors on management and survival of early-onset breast cancer: a population-based study.

This population-based study evaluates the impact of a strong family history of breast cancer on management and survival of women with early-onset disease. We identified all breast cancer patients </=50 years, recorded between 1990 and 2001 at the Geneva familial breast cancer registry. We compared patients at high familial risk and low familial risk in terms of tumour characteristics, method of detection, treatment, survival and breast cancer mortality risk. Compared to patients at low familial risk (n=575), those at high familial risk (n=58) received significantly more often systemic therapy, especially for node-negative or receptor-positive disease. Five-year disease-specific survival rates of patients at high vs low familial risk were 86 and 90%, respectively. After adjustment, there was no difference in breast cancer mortality in general. A strong family history nonsignificantly increased breast cancer mortality in patients </=40 years (adjusted hazard ratio (HR) 4.0, 95% CI 0.8-19.7) and in patients treated without chemotherapy (adjusted HR 2.7, 95% CI 0.6-12.5). A strong family history of breast cancer is associated with an increased use of systemic therapy in early-onset patients. Although a strong family history does not seem to affect survival in general, it may impair survival of very young patients and patients treated without adjuvant chemotherapy. Owing to the limited number of patients in this study, these results should be used only to generate hypotheses.

Adult↗
PubMed2006

Increased risk of acute myeloid leukaemia after treatment for breast cancer.

This study evaluates the risk of acute myeloid leukaemia (AML) in patients treated for breast cancer. We included all 6360 breast cancer patients that were recorded at the Geneva Cancer Registry between 1970 and 1999. Patients were followed for AML occurrence until December 2000. We calculated standardized incidence ratios of AML and identified factors modifying the risk of AML by multivariate Cox analysis. Twelve (0.2%) patients developed AML. In general, patients treated for breast cancer had a 3.5-fold (95% confidence interval (CI): 1.8-6.0) increased risk of developing AML compared with the general population. In particular, patients who were older than 70 years at breast cancer diagnosis and those treated with radiotherapy (with or without chemotherapy) had a significantly increased risk of developing AML. This population-based study confirms that radiotherapy increases the risk of AML. Due to the relatively low number of women treated with chemotherapy without radiotherapy and due to the infrequency of the disease, the question of whether chemotherapy alone increases this risk of AML cannot yet be answered.

Aged↗
PubMed2004

Set-up of a population-based familial breast cancer registry in Geneva, Switzerland: validation of first results.

BACKGROUND: This article evaluates the accuracy of family history of breast and ovarian cancer among first-degree relatives of breast cancer patients, retrospectively collected during the setting up of a population-based family breast cancer registry. PATIENTS AND METHODS: Family histories of cancer for all women with breast cancer recorded at the Geneva Cancer Registry from 1990 to 1999 were retrospectively extracted from medical files. The accuracy of these family histories was validated among Swiss women born in Geneva: all 119 with a family history of breast (n = 110) or ovarian (n = 9) cancer and a representative sample of 100 women with no family history of breast or ovarian cancer. We identified the first-degree relatives of these women with information from the Cantonal Population Office. All first-degree relatives, resident in Geneva from 1970 to 1999, were linked to the cancer registry database for breast and ovarian cancer occurrence. Sensitivity, specificity and level of overall agreement (kappa) were calculated. RESULTS: Among 310 first-degree relatives identified, 61 had breast cancer and six had ovarian cancer recorded at the Geneva Cancer Registry. The sensitivity, specificity and kappa of the reported family histories of breast cancer were 98%, 97% and 0.97, respectively. For ovarian cancer, the sensitivity, specificity and kappa were 67%, 99%, and 0.66, respectively. CONCLUSIONS: This study indicates that retrospectively obtained family histories are very accurate for breast cancer. For ovarian cancer, family histories are less precise and may need additional verification.

Adult↗
PubMed2002

Management of women with ductal carcinoma in situ of the breast: a population-based study.

BACKGROUND: Increasing incidence of ductal carcinoma in situ (DCIS) confronts patients and clinicians with optimal treatment decisions. This multidisciplinary study investigates therapeutic modalities of DCIS in daily practice and provides recommendations on how to increase quality of care. PATIENTS AND METHODS: All women (n = 116) with unilateral DCIS recorded in the Geneva Cancer Registry from 1995 to 1999 were considered. Information concerned patient and tumor characteristics, treatment and outcome. Factors linked to therapy were determined using a case-control approach. Cases were women with treatment of interest and controls other women on the study. RESULTS: Most DCIS cases (62%) were discovered by mammography screening. Ninety (78%) women had breast-conserving surgery (BCS), 18 (16%) mastectomy and seven (6%) bilateral mastectomy. Eight (7%) patients had tumor-positive margins, 18 (16%) lymph node dissection and two (1.7%) chemotherapy. Twenty-five per cent of women with BCS had no radiotherapy, three had radiotherapy after mastectomy. Less than 50% underwent breast reconstruction after mastectomy. Method of discovery, multifocality, tumor localization, size and differentiation were linked to the use of BCS or lymph node dissection. CONCLUSIONS: Because of important disparities in DCIS management, recommendations are made to increase quality of care, in particular to prevent axillary dissection or bilateral mastectomy and to increase the use of radiotherapy after BCS.

Adult↗
PubMed2001

Adjuvant chemotherapy for colon carcinoma with positive lymph nodes: use and benefit in routine health care practice.

In 1990, an international consensus was reached on the efficacy of adjuvant chemotherapy for lymph node positive (stage III) colon carcinoma (CC). This study evaluates the use and benefit of such therapy in routine health care practice. The study includes all patients with stage III CC treated by putative curative surgery (n = 182) recorded at the Geneva cancer registry between 1990 and 1996. Factors modifying chemotherapy use were determined by logistic regression, considering patients with chemotherapy as cases (n = 55) and others as controls (n = 127). The effect of chemotherapy on the 5-year survival was evaluated by the Cox model. Analyses were adjusted for possible confounders. The use of chemotherapy increased over the period (P(trend) < 0.001). Age strongly modulated chemotherapy use. In 1996, 54% of eligible patients received chemotherapy, this proportion fell to 13% after age 70. Decisions to use chemotherapy significantly depended on stage, grade and cancer site. The chance to be treated was non-significantly lower among individuals of low social class, widowed and foreigners. Chemotherapy significantly decreased mortality rates (Hazard ratio: 0.35, 95%CI: 0.18-0.68), independently of the prognostic factors and with similar benefit regardless of stage and age group. Strong beneficial effect of adjuvant chemotherapy on stage III CC can be achieved in routine practice. However, this study shows that it is probably not optimally utilised in Switzerland, particularly among the elderly.

Adult↗
PubMed2001

Functional evaluation of plasmin formation in primary breast cancer.

PURPOSE: Plasmin generation is controlled by the plasminogen activators (PA)/plasmin system, which comprises proteases (urokinase-type PA [uPA] and tissue-type PA [tPA]) and antiproteases (PA inhibitors, PAI-1 and PAI-2). The tumoral content of uPA and PAI-1 has been shown to carry prognostic value in breast cancer; however, because most assays used so far have relied on immunometric determinations, we have explored the enzymatic activities governing plasmin formation in breast cancer specimens. PATIENTS AND METHODS: We applied semiquantitative histochemical zymography to 201 primary breast cancer tissue sections. Enzymatic activities were correlated with histopathologic parameters and clinical outcome. The median follow-up was 91 months. RESULTS: A wide range of PA-mediated catalytic activities was detected. The overall survival was significantly worse for patients with tumors showing tPA in the lowest quartile of activity (P =.003). The 5-year overall survival of patients with tPA activity in the lowest quartile was 58% compared with 81% for patients with tPA value in the other three quartiles. Tumor size, axillary lymph node metastasis, histologic grade, lymphovascular infiltration, TP53 mutation, and tPA activity were all major risk factors in univariate analysis. tPA activity was an independent prognostic factor in a multivariate Cox regression model, both in the whole population (relative risk = 0.5, 95% confidence interval, 0.3 to 0.9; P =.02) and in the node-negative subgroup (relative risk = 0.2, 95% confidence interval, 0.08 to 0.6; P =.004). CONCLUSION: By using a zymographic assay performed directly on primary tumor tissue sections, we demonstrate that reduced tPA-mediated plasmin production is an independent adverse prognostic factor in breast cancer.

Breast Neoplasms↗
PubMed2000

A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer.

Germ-line mutations in MLH1 and MSH2 genes predispose to hereditary non-polyposis colorectal cancer (HNPCC) syndrome, but they do not predict a specific phenotype of the disease. We speculated that the ataxia-telangiectasia mutated gene (ATM) was a candidate gene to modulate the phenotypic expression of HNPCC, as heterozygous individuals for germ-line ATM mutations have been considered at higher risk of developing epithelial malignancies. The frequency of the ATM D1853N polymorphism was evaluated in 167 individuals from 20 HNPCC families in which MLH1 or MSH2 germ-line mutations co-segregated with the disease. Among the 67 MLH1 or MSH2 mutation carriers, the ATM 1853N variant was associated with a significantly higher incidence of colorectal and other HNPCC-related cancers, when compared with individuals carrying the ATM 1853D variant [12/13 (92%) vs. 31/54 (57.5%); p = 0.02]. MLH1 and MSH2 mutation carriers who concomitantly carried the ATM 1853N variant, had an 8 times increased risk of developing colorectal and other HNPCC-related cancers (OR: 8.9; p = 0.02), when compared with MLH1 or MSH2 mutation carriers with the ATM 1853D variant. Our results suggest that the ATM D1853N polymorphism modulates the penetrance of MLH1 and MSH2 germ-line mutations.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Elevated levels of angiogenic cytokines in the plasma of cancer patients.

Although in the normal healthy organism angiogenesis is a tightly regulated process, under a variety of circumstances it may contribute to disease states. These include the growth of solid tumors, the hematogenous spread of tumor cells and the growth of metastasis. Our aim was to measure the levels of 5 angiogenic cytokines in the plasma of patients with a variety of cancers, to establish a plasmatic angiogenic profile. We prospectively obtained blood samples in citrated tubes from 40 healthy individuals and 75 patients with a variety of solid tumors. Patients who had received any form of treatment in the preceeding 6 months were excluded from the study. Plasma levels of the following 5 cytokines were determined by ELISA: vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), basic fibroblast growth factor, transforming growth factor-beta and tumor necrosis factor-alpha. In some cases, additional samples were taken 4 and 15 days after surgical removal of the tumor. Our findings demonstrate, that firstly, compared to the tumor group VEGF was almost always undetectable or present at very low levels in healthy individuals; secondly, a threshold value for HGF was found to exist between the 2 groups (healthy vs. tumor); and thirdly, there was a clear relationship between plasma levels of VEGF and HGF and extension of disease (i.e., without or with metastases). The timing of blood sampling in the post-operative period was found to be critical, particularly with regard to VEGF and HGF. The existence of a systemic angiogenic profile in the plasma of cancer patients may be useful as a diagnostic and prognostic tool and may help in the future to monitor the responses of individual patients to anti-tumor and, particularly, anti-angiogenic therapy.

Adult↗
PubMed2000

Repression of the putative tumor suppressor gene Bard1 or expression of Notch4(int-3) oncogene subvert the morphogenetic properties of mammary epithelial cells.

We have investigated whether repression of the putative tumor suppressor gene BARD1 or expression of the Notch4(int-3) oncogene in non-tumorigenic mammary epithelial cells affects their in vitro morphogenetic properties. Bard1 (Brca1-associated ring domain) is a protein interacting with Brca1 and thought to be involved in Brca1-mediated tumor suppression. To investigate the potential role of Bard1 in mammary gland development, we repressed its expression in TAC-2 cells, a murine mammary epithelial cell line which, when grown in three-dimensional collagen gels, forms branching ducts in response to hepatocyte growth factor (HGF) and alveolar-like cysts in response to hydrocortisone. Whereas Bard1 repression did not markedly modify the tubulogenic response of TAC-2 cells to HGF, it dramatically altered cyst development, resulting in the formation of compact cell aggregates devoid of central lumen. In addition, when grown to post-confluence in two-dimensional cultures, Bard1-suppressed TAC-2 cells overcame contact-inhibition of cell proliferation and formed multiple cell layers. The Notch4(int-3) oncogene, which codes for a constitutively activated form of the Notch4 receptor, has been reported to induce undifferentiated carcinomas when expressed in the mammary gland. The potential effect of activated Notch4 on mammary gland morphogenesis was investigated by retroviral expression of the oncogene in TAC-2 cells. Notch4(int-3) expression was found to significantly reduce HGF-induced tubulogenesis and to markedly inhibit hydrocortisone-induced cyst formation. In addition, Notch4(int-3) expressing TAC-2 cells formed multilayers in post-confluent cultures and exhibited an invasive behavior when grown on the surface of collagen gels. Taken together, these results indicate that both repression of Bard1 and expression of Notch4(int-3) disrupt cyst morphogenesis and induce an invasive phenotype in TAC-2 mammary epithelial cells.

Breast↗
PubMed2000

Primary care physicians' knowledge and attitudes towards genetic testing for breast-ovarian cancer predisposition.

BACKGROUND: Primary health care providers are expected to be directly involved in the genetic testing for cancer susceptibility. This study assessed physicians' knowledge, attitude and perception of their role towards testing for hereditary breast ovarian cancer. DESIGN: A mail-in survey was sent to all general practitioners, internists, obstetrician-gynecologists and oncologists in private practice in Geneva county, Switzerland. Questions included socio-demographic variables, knowledge about hereditary breast ovarian cancer, attitude towards testing and assessment of their role in the pre- and post-test procedure. RESULTS: Two hundred fifty-nine (65%) of four hundred questionnaires were returned of which two hundred forty-three (61%) were analysed. Response rates were similar between specialties; women answered more frequently. The majority of the respondents (87%) approved of genetic susceptibility testing. The most common objection to testing was the absence of approved strategies for the prevention and detection of early breast cancer. Most physicians felt they had an active part to play in the pre-test procedure, the disclosure of results, and especially the consultants' long-term care and support (99%). Physicians correctly answered a third (32%) of the knowledge questions. The abstention rate for individual items ranged from 13% to 60%. Scores varied by specialty. Oncologists were more knowledgeable than gynecologists, internists and general practitioners. CONCLUSIONS: The majority of the primary care physicians in this study have a favourable attitude and are ready to play a prominent role in genetic counseling and testing for breast ovarian cancer predisposition. Defective knowledge scores, however, underline the need for targeted educational programs.

Attitude of Health Personnel↗
PubMed2000

Infusional ECarboF in patients with advanced breast cancer: a very active and well-tolerated out-patient regimen.

We performed a trial using the combination of epirubicin 50 mg/m2/day 1, carboplatinum AUC 5/day 1 and continuous 5-fluorouracil (5-FU) 200 mg/m2/day (every 4 weeks for 6 months) to confirm the efficacy and low toxicity profile of this regimen in breast cancer. In 51 patients with metastatic (n = 33) or locally advanced (n = 18) breast cancer the overall response rate was 86% (95% confidence interval (95% CI): 73%-94%): 94% in locally advanced and 81% metastatic disease. Grade 3-4 toxicity was low: 4% of patients presented with febrile neutropenia, 16% with severe palmar-plantar syndrome, 10% with Port-a-cath thrombosis. This study confirms the high efficacy of infusional 5-FU-based regimens and justifies further research into novel promising oral 5-FU derivatives.

Adult↗
PubMed1999

Prognostic significance of p53 mutation in breast cancer: frequent detection of non-missense mutations by yeast functional assay.

p53 status was tested in 180 patients with primary breast cancer using a yeast functional assay. Mutations were identified in 32% of cases. Only half were point missense mutations; the remainder were nonsense, insertion, deletion and splice site mutations. Twenty-two percent of mutations were located outside exons 5-8. For a median follow-up of 88 months, survival analysis showed that p53 mutation conferred a worse prognosis in the whole population and the node-positive subgroup but not in node-negative patients. p53 status, tumour size >2 cm, axillary lymph node metastasis and high histological grade were major adverse risk factors in univariate analysis. Multivariate analysis of 153 patients for whom full data were available showed that p53 status contributed prognostic information when tumour size and lymph node status were taken into account but not when histological grade was included. p53 status thus contributes only limited new prognostic information in breast cancer when established prognostic factors are taken into account. Int. J. Cancer (Pred. Oncol.) 84:587-593, 1999.

Adult↗
PubMed1999

Pediatric medulloblastoma: prognostic value of p53, bcl-2, Mib-1, and microvessel density.

The aim of this study was to retrospectively assess the prognostic value of p53 and bcl-2 protein expression, cell proliferation index (Mib-1 index), and tumor microvessel density (factor VIII-related antigen) in pediatric medulloblastoma patients. Tumor specimens of 55 patients (age 2-18 years) with medulloblastoma treated with a curative intent between 1972 and 1991 were studied. Slides of paraffin embedded tissue were stained with monoclonal antibodies (mAb) and examined under high power light microscopy for the presence of immunoreactivity. Microvessel density was scored both in the area of most intense staining ('Angio-max') and in 3 additional randomly selected areas. The sum of these 4 scores was termed 'Angio-total'. 'Angio-max' and 'Angio-total' were evaluated separately by two independent investigators to assess reproducibility. None of the parameters studied, i.e. p53 or bcl-2 expression, Mib-1 index or microvessel density scores were associated with patient survival. Microvessel scores between observers were significantly but weakly correlated, with correlation coefficients (r) < 0.5 for both 'Angio-max' and 'Angio-total'. Leptomeningeal spread at diagnosis was the only independent factor associated with a poor survival (p = 0.003). There was no association of leptomeningeal metastasis with any of the biological markers tested in this study.

Adolescent↗
PubMed1999

Plasminogen activation in human acute leukaemias.

Plasminogen activation is implicated in solid tumour growth, invasion and metatastic spread. However, little is known about its role in leukaemia. We investigated the production by leukaemic cells of plasminogen activators [urokinase (uPA) and tissue-type PA (tPA)], cell surface receptor for uPA (uPAR) and PA inhibitors (PAI-1 and PAI-2). Leukaemic cells from 37 patients [26 with acute myeloid leukaemia (AML) and 11 with acute lymphoid leukaemia (ALL)] were analysed for mRNA content and enzymatic activities. High levels of uPA mRNA were found in M1, M2, M3 and M4-M5 AMLs, whereas tPA mRNA was not detected in any of the analysed cases. uPAR mRNA was confined to subtypes M4-M5. PAI-1 mRNA was detected in M3 and M4-M5. PAI-2 mRNA was found predominantly in M2 and M4-M5. SDS-PAGE/zymography analyses of cell extracts and supernatants after 24 and 48 h of culture confirmed the production of active uPA by AML cells (mainly M4-M5). but not by ALL. The finding of uPA, uPAR, PAI-1 and PAI-2 synthesized by leukaemic cells suggests that plasminogen activation may contribute to the invasive behaviour of these cells, the fibrinolytic imbalance observed in leukaemic patients and the differentiation and proliferation of M4-M5 by interaction of uPA with uPAR.

Acute Disease↗
PubMed1998

Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer.

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a consequence of a dominantly inherited susceptibility to accumulate somatic mutations. The disorder is manifested as a familial aggregation of colorectal cancers diagnosed at an early age and, to a lesser degree, of cancers of the endometrium, ovary, urinary tract, and organs of the gastrointestinal tract other than the colon. In more than half of the HNPCC families investigated, the cancer predisposition has been linked to germline mutations in one of the 2 genes hMLHI or hMSH2, involved in post-replicative DNA-mismatch repair. Twenty-four Swiss families affected with colorectal cancer were screened for germline mutations in these 2 genes, and pathogenic mutations were identified in over 70% of the families fulfilling the Amsterdam criteria (AC), but in only 10% of the families not completely fulfilling these criteria. One of the reported mutations, discovered in an extended HNPCC kindred from the Swiss Alps, is shown to be a founding mutation. Unexpectedly, all the mutations identified are in the hMLHI gene, where all but one are novel sequence alterations. Our data suggest that an unusually high proportion of Swiss HNPCC patients may harbour a germline mutation in the hMLHI gene.

Adaptor Proteins, Signal Transducing↗