[Muir-Torre syndrome and Turcot syndrome]. / Syndrome de Muir-Torre et syndrome de Turcot.

INTRODUCTION: Lynch syndrome (LS) is a syndrome that carries a genetic predisposition to certain cancers associating, either in a single individual or in a family, a visceral tumour, mainly colorectal, with a high risk of other synchronous or metachronous cancers. LS is linked with mutations in the genes coding for proteins in the DNA repair system. Phenotypic variants of SL exist, including Muir-Torre syndrome (MTS) and Turcot syndrome (TS), both of which predispose to colorectal cancer. They may be distinguished by the presence of benign or malignant sebaceous tumours in MTS, and tumours of the central nervous system in TS. PATIENTS AND METHODS: A 59-year-old man, with a history of right colon cancer at the age of 36 years, consulted for a nose lesion shown by histopathological examination to be a sebaceous tumour. Immunohistochemistry revealed loss of expression of proteins MSH2 and MSH6, strongly suggesting a diagnosis of MTS. Eight years earlier, the man's son had developed a fatal glioblastoma; given the paternal phenotype of MTS, the hypothesis of TS in the son is probable. DISCUSSION: This case suggests that several variants of Lynch syndrome may be seen within the same family. It raises the issue of screening for cerebral tumours in patients with MTS and in their family members, even though such a recommendation does not exist; current recommendations in fact consist primarily of gastrointestinal and gynaecological monitoring.

Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.

French women's breast self-examination practices with time after undergoing BRCA1/2 genetic testing.

To assess the impact of BRCA1/2 genetic test results on cancer-free women's breast-self-examination (BSE) practices and to prospectively determine their influence on psychological functioning. A prospective longitudinal study on French women's BSE practices and frequencies in BRCA1/2 carriers (N = 217) and non-carriers (N = 313) 1 and 2 years following disclosure of the test results, along with psychological factors predicting BSE practices. Before disclosure, BSE was practised by 47.2% of the women, and increased to 57.3% 1 year later. No change in the women's practices was noted between 12 and 24 months after the test. Carriers and non-carriers practicing regularly BSE at baseline were, respectively 8 to 6 times more likely to be practising BSE regularly at 12 months after being tested. Among the carriers, having fewer depressive symptoms at baseline and believing in the ability of BSE to detect breast cancer were found to be the most decisive factors associated with BSE practices 1 year after disclosure, following adjustment for BSE baseline practices. Among the non-carriers, believing in the ability of BSE to detect breast cancer, greater post-test anxiety, and a higher perceived risk of breast cancer were found to be predictors of post-test BSE practices after adjusting for BSE baseline practices. In France, where performing BSE is neither mandatory nor recommended, an increase in BSE practices was found to occur after disclosure of women's genetic test results, regardless of their carrier status.

The contribution of germline rearrangements to the spectrum of BRCA2 mutations.

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.

[Li-Fraumeni syndrome: update, new data and guidelines for clinical management]. / Le syndrome de Li-Fraumeni: mise au point, données nouvelles et recommandations pour la prise en charge.

The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.

[Germ-line mutations of the BRCA1 gene in northeastern France]. / Mutations germinales du gène BRCA1 dans le Nord-Est de la France.

Thirty-seven breast/ovarian or breast-only cancer families selected on a regional basis have been analyzed for mutations at BRCA1. By combining direct sequence analysis and protein truncation test, mutations were detected in 14 families (38%). We found seven different mutations, two of which have not been described before. Mutations at BRCA1 were present in 60% of breast/ovarian and 32% of breast-only cancer families. Mutations were frequent in families with at least one breast cancer case before age 40 (44%) and/or one bilateral breast cancer case (54%). Two mutations, namely 3600del11 and G1710X, are frequent in the population native from northeastern France. Oriented BRCA1 analysis should facilitate carrier detection in breast and/or ovarian cancer families stemming from this French area.

[Congenital hypertrophy of retinal pigment epithelium: a marker in familial adenomatous polyposis]. / L'hypertrophie congénitale de l'épithélium pigmenté rétinien: un marqueur de la polypose adénomateuse familiale.

PURPOSE: Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder with marked propensity for malignant transformation. The potential for congenital hypertrophy of retinal pigment epithelium (CHRPE) as a phenotypic marker for this disease is recognized. MATERIAL AND METHODS: We report our investigations in 11 families with familial adenomatous polyposis. CHRPE characteristics were described and the relations between genotype and phenotype and those between CHRPE and severity of FAP are discussed. DISCUSSION: All members of the family should undergo retinal examination at the earliest age possible. The results give an indication of the severity of the intestinal disease and allow an approximate localization of the mutation in the coding sequence, leading to a more rapid genetic analysis.

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.

[Thromboembolic accidents in postmenopausal patients with adjuvant treatment by tamoxifen. Frequency, risk factors and prevention possibilities]. / Accidents thromboemboliques chez les patientes ménopausées sous traitement adjuvant par tamoxifène. Fréquence, facteurs de risque et possibilités de prévention.

Tamoxifen is the anti-estrogen the most widely used in breast cancer. The duration of its prescription, as adjuvant treatment, tends to increase (5 years, and even more) and now it is used in chemoprevention. A slight increase of thromboembolic complications was noted in some studies. This article evaluates the frequency of thromboembolic accidents (TEA) in 441 postmenopausal patients treated by an association of conservative radiosurgery, tamoxifen +/- chemotherapy, for a breast carcinoma T0, T1T2 < 4 cm. Nineteen patients (4.3%), all in remission, presented a TEA, between 1 and 44 months after the beginning of the tamoxifen treatment. We observed seven pulmonary embolisms (PE), 11 deep venous thromboses (DVT) and an acute arterial ischemia. Two patients aged 74 and 80 years died, the others had a favourable evolution under anticoagulant treatment. Among these 19 patients, six presented known risks factors (phlebitis, cardiovascular disorders) and ten had a "favouring circumstance" aggravating the risk of TEA (surgical operation, severe infection, fracture). Their median age was 65 years (61 for all the 441 patients). We noted eight cases of breast lobular cancer (42%) among these 19 patients (11% for all the patients). Among postmenopausal patients, the indication of tamoxifen must be evaluated according to the benefits expected in those with high risk factors of TEA (history of heart failure, obesity, spread varix, age > 65 years). In case of DVT and/or PE, this treatment seems contra-indicated. In case of "favouring circumstances", a hypocoagulant or systematic anticoagulant treatment must be proposed. In case of combined chemotherapy, it is better to start tamoxifen at the end of the treatment. These simple prophylactic measures should allow to reduce significantly the risk of TEA in postmenopausal patients with adjuvant anti-estrogenotherapy.

The bond strength of a glass polyalkenoate cement to enamel and stainless steel.

An in vitro evaluation of bond strength of a glass polyalkenoate cement to human dental enamel and stainless steel is reported. Shear testing of adhesive strength was measured over time at 23 degrees C following a one minute mixing time. It was found that there is a significant difference in bond strengths between enamel and stainless steel with strength to enamel the greater. Bond strength increases with time with very low strength measured within 30 minutes from commencement of mixing.

Low dose heparin versus low molecular weight heparin (Kabi 2165, Fragmin) in the prophylaxis of thromboembolic complications of abdominal oncological surgery.

Eighty patients undergoing pelvic or abdominal surgery for cancer were randomized in two groups for prevention of postoperative thromboembolism: 40 patients received a 15,000 IU day-1 Calciparine prophylaxis and 40 patients a 5000 anti-Xa U/d Fragmin prophylaxis for 10 days. In the Calciparine group, two patients (5%) developed postoperative pulmonary embolism but none developed it in the Fragmin group. Two patients in the Fragmin group (5%) developed isotopic DVT, which was not confirmed by phlebography. There was no deep vein thrombosis of the lower limbs in the two groups. Important postoperative bleeding (one patient in the Calciparine group and two patients in the Fragmin group) was similar in both groups. Moderate and minor bleeding were significantly lower in the Fragmin group. Haemoglobin and haematocrit changes, total blood loss and transfusion requirements were not different in both groups. It is concluded that, over a 10-day period, one daily 5000 U Fragmin prophylaxis was as effective and safe as three daily 5000 IU Calciparine injections.

Adhesion of human breast cancer cell line MCF-7 to human vascular endothelial cells in culture. Enhancement by activated platelets.

The interactions of MCF-7 tumor cells with human vascular endothelial cells (EC) and subendothelial extracellular matrices (ECM) were morphologically observed by electron microscopy and quantitatively evaluated by labelling tumor cells with 111Indium-oxine. MCF-7 tumor cells adhered more rapidly to ECM than to the apical surface of a confluent monolayer of EC. The affinity of MCF-7 cells for type-IV collagen was greater than for fibronectin, suggesting that type-IV collagen contributes to the higher rate of adhesion of MCF-7 cells to the subendothelial ECM. Otherwise, the attachment of tumor cells to EC was increased in the presence of both washed platelets and 0.1% citrated platelet-poor plasma (cPPP), a condition accelerating platelet aggregation by tumor cells. The enhancement of MCF-7 adhesion to EC in the presence of platelets and cPPP was completely blocked by the addition of prostacyclin, or hirudin, a specific thrombin inhibitor. In ultrastructural studies, MCF-7 initiated EC retraction, and firm attachment and flattening occurred on exposed ECM. When MCF-7 cells were incubated with platelets and cPPP, most of the tumor cells adhering to the EC and inducing disruption of endothelial monolayer were closely packed and associated with platelet aggregates. MCF-7 cells appeared to adhere more efficiently to exposed subendothelial ECM when they were associated into multicellular aggregates containing platelets and trapped in a fibrin thrombus. Thus, this homologous human system of cultured vascular EC and breast carcinoma line MCF-7 cells may be used to assess anti-aggregant compounds for their ability to alter tumor-cell implantation on EC-lined surfaces.

[Preliminary results of a randomized trial comparing the efficacy of standard heparin with that of fragmine, a low molecular weight heparin, in the prevention of postoperative thrombosis in cancer surgery]. / Résultats préliminaires d'un essai randomisé comparant l'efficacité d'une héparine standard à celle de la fragmine, une héparine de bas poids moléculaire, dans la prophylaxie des thromboses post-opératoires en chirurgie oncologique.

Low molecular weight heparins have stimulated much interest because of their supposedly more selective action on Xa factor. A randomized study in 50 patients compared efficacy of low doses of a standard heparin, calciparin (5,000 IU/8 h) with that of a low molecular weight heparin, fragmine (Kabi 2165) (5,000 anti-Xa U/24 h), in the prophylaxis of postoperative thrombosis after oncologic surgery. Three of 25 patients receiving calciparin developed pulmonary embolism, as against one of 25 treated with fragmine who developed a periphlebitis. Hemorrhagic complications were comparable in the two groups. Anti-Xa activity was significantly higher in the fragmine group, whereas platelet counts, cephalin times with activator and anti-IIa activity were similar. These findings indicate equal efficacy of fragmine and calciparin in the prophylaxis of post-oncology surgery venous thrombosis.

Rapid and sensitive photometric quantification of the proliferation of adherent vascular endothelial and smooth muscle cells in 96-multiwell plates after may-grünwald giemsa staining.

A simple, sensitive, and rapid photometric method has been developed to measure the proliferation of adherent cells in 96-multiwell plates quantitatively. The cultured cells were fixed with methanol and stained with May-Grünwald Giemsa. The multiwell plate was scanned at two wavelengths (lambda max 540 nm and lambda reference 405 nm or 690 nm). The correlation coefficient (r) between cell densities measured by direct microscopic cell counting or photometric light absorbance was greater than 0.9, in the range 400 to 66,000 cells/cm2. The method is applicable to adherent cells such as vascular endothelial cells, vascular smooth muscle cells, fibroblasts, or the breast adenocarcinoma cell line MCF-7. In addition, the morphology of the fixed and stained cells was examined and 3H-thymidine incorporation in cells was studied by radioactive counting of solubilized cells.

Characterization of cell types in human breast tumor primary cultures.

Primary cultures of cells from breast carcinomas were attempted in 74 cases. Growth was observed in 46 cases. Using immunochemical demonstration of keratin proteins (KER), epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), three morphologically distinct cell populations were characterized and described. Two cell types (E- and E'-cells) were identified as epithelial by their positive staining for KER and EMA. The third type (F cells) displayed a negative staining for these two epithelial markers; they were considered as stromal cells (fibroblasts). More than 50% of the cultures consisted of pure epithelial cells. Positive CEA staining was observed only in KER- and EMA-positive cells. Out of the 30 cultures, 15 displayed positive staining for CEA. In 7 of these, 30-50% of cells displayed positive, diffuse staining for CEA. The other 8 cultures consisted of more than 50% CEA-positive cells. Strong and homogeneous positivity was restricted to the E-cells, while in the same cultures, E'-cells displayed heterogeneous and diffuse staining. Efficiency and value of this cell culture system are discussed, in comparison with other human breast tumor cell (HBTC) culture techniques. Identification of growing cells and cellular composition of primary cultures are emphasized.

Proteinases and sialyltransferase in human breast tumors.

Proteolytic and sialyltransferase activities were determined in extracts of 65 human primary breast tumors, 6 lymph node metastases, 6 fibroadenomas and 27 normal tissues. Using proteins and synthetic selective substrates, we observed the presence of collagen-peptidases, plasminogen activator, cathepsin-B and cathepsin-D-like enzymes, and sialyltransferase. No active or trypsin-activatable type-IV collagenase activity was detected. Although individual variations between tumors were large, proteinase and sialyltransferase contents were significantly elevated in malignant breast tissues. Enzyme activities were found to be related to the epithelial volume of the tumor. No significant correlation was found between the proteinase or sialyltransferase activities and the degree of differentiation of the tumor cells, or the degree to which tumors had metastasized to regional lymph nodes. Since large variations of enzyme levels apparently reflect the heterogeneity of epithelial cell densities in tumor samples, proteolytic or sialyltransferase activities cannot therefore be used as a measure of quantitative evaluation of invasive properties in breast cancer.