Dermoscopy, a useful tool for general practitioners in melanoma screening: a nationwide survey.

BACKGROUND: Dermoscopy improves diagnostic accuracy in melanoma, as shown by several meta-analyses. Although it is used by general practitioners (GPs) in Australia, Canada and Italy, no published data on this topic are available in France. OBJECTIVES: To review the opinions and use of dermoscopy by GPs in France and to understand their practice of skin examination. METHODS: We designed a descriptive and cross-sectional survey and conducted it between 26 November and 26 December 2014. An anonymous, multiple-choice questionnaire about the demographic characteristics, skin examination modalities and use and training in dermoscopy was sent to 4057 GPs in four large regions of France. Pearson, χ(2) , Student, Welch and Fisher tests were used for cross-tabulation statistical analysis. RESULTS: Only 8% of respondents had access to a dermoscope; most were male practitioners and aged > 50 years. Dermoscopy increased self-confidence in analysing pigmented lesions (P = 0·004), and dermoscopy users referred fewer patients to dermatologists. The number of biopsies was reduced in the dermoscopy users group (P = 0·004). In total, 425 questionnaires were returned and analysed. Dermoscopy users took more time to evaluate a single pigmented lesion (P = 0·015). Only 16·9% of physicians declared having received some training on dermoscopy, yet this number reached 47% for those owning a dermoscope. Their training was mostly short and recent. Overall 29·2% of the respondents said the main advantage was to reduce the number of referrals to the dermatologists (P = 0·004), while its main disadvantage was the necessity of training (54·6%). Our responders declared they could spend seven working days on a dermoscopy training course. CONCLUSIONS: Our study demonstrates positive opinions regarding dermoscopy, despite a minority of French GPs using this technique in the areas surveyed. The need for formal training appears to be the main limitation to wider use. Appropriate and specifically designed training programmes should be offered.

Corpus callosum abnormalities in Wilson's disease.

INTRODUCTION: Wilson's disease (WD) with neurological presentation is associated with brain lesions classically localised in globus pallidus, putamen, thalamus, mesencephalon, pons and dentate nucleus. Lesions of corpus callosum (CC) have not been studied in a broad population of patients with WD. OBJECTIVE: Evaluation of the frequency of CC lesions in patients with neurological symptoms related to WD. METHOD: The authors included all patients with neurological expression of WD, followed in the French national centre for WD who had a brain MRI between March 2006 and December 2008. The localisation of brain lesions was analysed and the frequency of lesions in CC evaluated. All patients were assessed using the Unified Wilson's Disease Rating Scale. For patients with abnormalities located in CC, a clinical dysconnexion syndrome was investigated. RESULTS: Among 81 patients (45 men, mean age: 34.8 years, from 12 to 74 years) with neurological expression, 42% had white-matter lesions on fluid-attenuated inversion recovery MRI. 23.4% of patients presented CC lesions, limited to the posterior part (splenium). The severity of disability estimated by Unified Wilson's Disease Rating Scale was correlated with the presence of CC lesions on MRI. CONCLUSION: Abnormalities in CC are not unusual (23.4%). Together with lesions of basal ganglia, CC signal changes should suggest the diagnosis of WD.

[Lynch syndrome: when pathologist and clinician have the opportunity to reduce the risk of developing cancer]. / Le syndrome de lynch: pathologiste et praticien peuvent ensemble éduire le risque de cancer.

Lynch syndrome is an autosomal dominant disease associated with an important risk of cancer, mainly endometrial and colorectal-cancer. This risk can be efficiently lessen by an appropriate screening as far as the mutations carriers are identified. As current clinicopathological recommendations lack sensitivity, a systematic pre-screening of every patient with a colorectal or endometrial cancer can be proposed. Oncogenetic units of the HUG in Geneva and ICHV in Valais have set up a population-based study to evaluate the efficacy of such a strategy. Whatever the approach, the pathologist is directly implicated as Lynch syndrome harbors specific histological aspects that can help to its identification, but also as pre-screening tests are directly realized on tumor-tissue.

Hormonal therapy for oestrogen receptor-negative breast cancer is associated with higher disease-specific mortality.

BACKGROUND: Tamoxifen has a remarkable impact on the outcome of oestrogen receptor (ER)-positive breast cancer. Without proven benefits, tamoxifen is occasionally prescribed for women with ER-negative disease. This population-based study aims to estimate the impact of tamoxifen on the outcome of ER-negative disease. METHODS: We identified all women (n = 528) diagnosed with ER-negative invasive breast cancer between 1995 and 2005. With Cox regression analysis, we calculated breast cancer mortality risks of patients treated with tamoxifen compared with those treated without tamoxifen. We adjusted these risks for the individual probabilities (propensity scores) of having received tamoxifen. RESULTS: Sixty-nine patients (13%) with ER-negative disease were treated with tamoxifen. Five-year disease-specific survival for women treated with versus without tamoxifen were 62% [95% confidence interval (CI) 48% to 76%] and 79% (95% CI 75% to 83%), respectively (P(Log-rank) < 0.001). For ER-negative patients, risk of death from breast cancer was significantly increased in those treated with tamoxifen compared with patients treated without tamoxifen (adjusted hazard ratio = 1.7, 95% CI 1.1-2.9, P = 0.031). CONCLUSION: Our results show that patients with ER-negative breast cancer treated with tamoxifen have an increased risk of death from their disease. Tamoxifen use should be avoided for these patients.

Impact of a positive family history on diagnosis, management, and survival of breast cancer: different effects across socio-economic groups.

BACKGROUND: This study aims to investigate whether increased awareness of breast cancer, due to a positive family history (FH), reduces diagnostic, therapeutic, and survival differences between women of low versus high socio-economic status (SES). METHODS: All breast cancer patients registered between 1990 and 2005 at the population-based Geneva Cancer Registry were included. With multivariate logistic and Cox regression analysis, we estimated the impact of SES and FH on method of detection, treatment, and mortality from breast cancer. RESULTS: SES discrepancies in method of detection and suboptimal treatment, as seen among women without a FH, disappeared in the presence of a positive FH. SES differences in stage and survival remained regardless of the presence of a positive FH. Overall, positive FH was associated with better survival. This effect was the strongest in women of high SES (age-adjusted Hazard Ratio [HR(ageadj)] 0.54 [0.3-1.0]) but less pronounced in women of middle (0.77 [0.6-1.0]), and absent in women of low SES (0.80 [0.5-1.2]). CONCLUSION: A positive FH of breast cancer may reduce SES differences in access to screening and optimal treatment. However, even with better access to early detection and optimal treatment, women of low SES have higher risks of death from their disease than those of high SES.

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.

[Epigenetics and cancer]. / Epigénétique et cancer.

Since the early 80's, cancer research has been dominated by scientific breakthroughs demonstrating the genetic origin of cancer. Thousands of genetic alterations have been identified, affecting more than one hundred cell regulating genes. In the past ten years, our understanding of carcinogenesis has evolved: cancer is both a genetic and an epigenetic disease. Epigenetic modifications play a fundamental biological role in the initiation and progression of cancer by altering the expression of cell cycle regulation genes. Unlike genetic mutations, epigenetic modifications are potentially reversible. Thus, epigenetic inhibitors are currently evaluated as anticancer drugs. Moreover, DNA methylation study holds promise as biological marker for classification, diagnostic and prognostic purposes in clinical practice.

[Wilson disease]. / La maladie de Wilson.

Wilson disease is an autosomal recessive disorder of copper overload. A principal characteristic of this disease is its wide phenotypic and genotypic variability. Its results from mutations of the ATP 7B gene located on chromosome 13, that encodes a hepatic copper transport protein. More than 300 mutations of this gene have been identified. This protein ensures the transport of copper in the hepatocyte, its incorporation with the apoceruloplasmin and its biliary excretion. The clinical manifestations are heterogeneous as well in their presentation, dominated by the neuropsychiatric and hepatic symptoms, as in the age of the first symptoms. Early recognition and initiation of therapy with chelators or zinc are essential for prognosis. Liver transplantation is indicated in cases with fulminant hepatitis, end-stage liver cirrhosis and should be considered in the therapy resistant neurological forms. A regular follow-up with monitoring of adverse effects of treatment and compliance is essential. Any discontinuation of treatments will involve, within a very variable time, but in constant manner, a reappearance or a reaggravation of the signs. Such relapses are often brutal and can be extremely serious, especially since response to subsequent treatment is often poor.

N-acetyltransferase 2 influences cancer prevalence in hMLH1/hMSH2 mutation carriers.

Hereditary nonpolyposis colorectal cancer (HNPCC), an inherited cancer predisposition syndrome, has been associated with germline mutations in DNA mismatch repair (MMR) genes. Because a deficiency in MMR does not predict a specific cancer phenotype, modifying genes may account in part for the variation in disease expression. We determined the N-acetyltransferase 2 (NAT2) genotype in 26 unaffected and 52 cancer-affected hMLH1/hMSH2 mutation carriers coming from 21 Swiss HNPCC families. Slow acetylators were found to be significantly (P < 0.03) more prevalent in the group of affected mutation carriers. Our results suggest a protective effect of the NAT2 rapid acetylator phenotype, an observation that could have implications for genetic counseling and management of MMR gene mutation carriers.

TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germ-line mutations: distinctive spectrum and structural distribution.

Several groups have studied the molecular pathology of inherited breast cancer. By combining several such studies, we show in this study that somatic TP53 abnormalities are more common in breast cancer associated with BRCA1 or BRCA2 germ-line mutations than in sporadic breast cancers (odds ratio, 2.8; P = 0.0003). Then, we compared the spectrum of TP53 mutations for breast cancers in the IARC TP53 mutation database with the 82 mutations reported in BRCA1/2-associated breast cancers. The spectrum differed significantly both in distribution (P < 1 x 10(-6)) and in base changes (P = 0.025). Mutations at A:T bp were more common in BRCA1/2-associated tumors and strand bias suggesting DNA repair abnormalities was found. Changes were common at TP53 codons that are not mutation hotspots. Structural modeling showed that most of these p53 non-hotspot amino acids characterized in breast tumors isolated from patients with deficient BRCA1/2 function are distributed in a region of the protein on the opposite side of the p53 DNA-binding surface. Our results suggest that BRCA1/2 mutations influence the type and distribution of TP53 mutations seen in breast cancer.

[Breast cancer screening different from that used for the general population: who is concerned and with which approach?]. / Un dépistage du cancer du sein différent de celui de la population générate: pour quelles femmes et avec quelles mesures?

One of the major risk factors for developing breast cancer is a positive family history for this disease. A detailed family history is critical for breast cancer risk evaluation and for evaluation of the probability of a genetic predisposition to breast cancer in the family (the hereditary breast/ovarian cancer syndrome). Various models have been developed to evaluate these risks. The diagnosis of a low, moderate or high breast cancer risk is associated with adapted breast cancer screening procedures. Screening with magnetic resonance imaging (MRI) is recommended only for women identified as high risk. Genetic testing of the main breast cancer susceptibility genes, BRCA1 and BRCA2, is now available in a clinical setting.

[Colorectal cancer: a risk-adapted screening and the role of the physician in the prevention of this cancer]. / Cancer colorectal: dépistage adapté au risque et rôle du médecin traitant dans la prévention de ce cancer.

The benefit of colorectal cancer screening in the average-risk population, as well as in the presence of high risk genetic predispositions, has been validated by a significant reduction of the mortality associated with the disease. Several screening options are recognized and compliance with these measures remains a public health problem. The physician plays a key role in the promotion of the colorectal cancer screening. Collecting a precise family history is crucial for the identification of individuals at high risk. Validated clinical criteria are helpful for the identification of individuals with a genetic predisposition to colorectal cancer. Molecular screening for the main colorectal cancer predisposing genes should now be integrated in the clinical management of these patients and their families.

Right colon cancer: Left behind.

INTRODUCTION: Prognosis of colon cancer (CC) has steadily improved during the past three decades. This trend, however, may vary according to proximal (right) or distal (left) tumor location. We studied if improvement in survival was greater for left than for right CC. METHODS: We included all CC recorded at the Geneva population-based registry between 1980 and 2006. We compared patients, tumor and treatment characteristics between left and right CC by logistic regression and compared CC specific survival by Cox models taking into account putative confounders. We also compared changes in survival between CC location in early and late years of observation. RESULTS: Among the 3396 CC patients, 1334 (39%) had right-sided and 2062 (61%) left-sided tumors. In the early 1980s, 5-year specific survival was identical for right and left CCs (49% vs. 48%). During the study period, a dramatic improvement in survival was observed for patients with left-sided cancers (Hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.29-0.62, p < 0.001) but not for right CC patients (HR: 0.76, 95% CI: 0.50-1.14, p = 0.69). As a consequence, patients with distal CC have a better outcome than patients with proximal CC (HR for left vs. right CC: 0.81, 95% CI: 0.72-0.90, p < 0.001). CONCLUSION: Our data indicate that, contrary to left CC, survival of patients with right CC did not improve since 1980. Of all colon cancer patients, those with right-sided lesions have by far the worse prognosis. Change of strategic management in this subgroup is warranted.

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.

Germline BRCA1/2 mutations and p27(Kip1) protein levels independently predict outcome after breast cancer.

PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27(Kip1) in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27(Kip1) protein levels, and outcome has not been studied. PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27(Kip1) expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27(Kip1) expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P =.009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P =.003). Similar results were seen for women whose tumors expressed low levels of p27(Kip1), compared with those with high levels (5-year DDFS, 68% v 93%; P<.0001). In a multivariate analysis, both BRCA1/2 mutation and low p27(Kip1) expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P =.05; and RR, 3.9; 95% CI, 1.4 to 11.1; P =.01, respectively). CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27(Kip1) in breast cancer. Both BRCA1/2 and p27(Kip1) status were identified as independent prognostic factors.

[Wilson disease: clinical and biological aspects]. / La maladie de Wilson: aspects clinicobiologiques.

Wilson disease is an autosomal recessive disorder of copper excess. This illness results from mutations of the ATP7B gene (chromosome 13, MIM# 277900). The discovery of the gene allowed a better understanding of cytosolic copper trafficking and its relationship with ceruloplasmin synthesis. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Clinical and phenotypic evidences provide only presumptive arguments for this disease which can be routinely assessed by molecular analysis. This genetic disease which can be efficiently treated was formerly biologically suspected after a careful but sometimes invasive study of copper metabolism. Genetic advances can now give a definite answer using linkage analysis and research for disease-causing mutations. However, this diagnosis strategy is limited since currently over 320 mutations and 80 polymorphisms have been currently identified.

Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis.

Germ-line mutations in the 5' half of the Adenomatous Polyposis Coli (APC) gene are found in about 80% of the patients affected with familial adenomatous polyposis (FAP). The vast majority of these are nonsense or frameshift mutations which result in the loss of the carboxyl terminus of the APC protein. Using an in vivo assay in yeast, we have identified pathogenic germ-line mutations in 26 of 32 (81%) unrelated Swiss families affected with FAP. Nine mutations were novel and eight families were shown to harbor two recurrent mutations. Correlations were attempted between the location of APC germ-line mutations and clinical manifestations of the disease.

Increased risk for nonmedullary thyroid cancer in the first degree relatives of prevalent cases of nonmedullary thyroid cancer: a hospital-based study.

The genetic basis for nonmedullary forms of thyroid cancer (NMTC) is less well established than that of medullary thyroid cancer. However, epidemiological and family studies suggest that a proportion of NMTC may be due to inherited predisposition. To estimate the familial risk of thyroid cancer, we conducted a hospital-based case-control study at the Princess Margaret Hospital in Toronto, Ontario, Canada, and at 2 university hospitals in Montréal, Québec, Canada. We obtained pedigrees from 339 unselected patients diagnosed with NMTC and from 319 unaffected ethnically matched controls. Family histories of cancer were obtained from the cases and controls for 3292 first degree relatives of cases and controls. Seventeen cases (5.0%) and 2 controls (0.6%) reported at least one first degree relative with thyroid cancer. In relatives of patients with thyroid cancer, the incidence of any type of cancer (including NMTC) was 38% higher than in relatives of controls (incidence rate ratio, 1.4; 95% confidence interval, 1.1-1.7). The relative risk for thyroid cancer was 10-fold higher in relatives of cancer patients than in controls (incidence rate ratio, 10.3; 95% confidence interval, 2.2-47.6). Our findings suggest that hereditary or other familial factors are important in a small proportion of NMTC. Molecular studies are needed to determine the genetic basis of cancer susceptibility in these families.

A physiological amount of zinc supplementation: effects on nutritional, lipid, and thymic status in an elderly population.

Forty-four institutionalized elderly subjects with body mass indexes (BMI) of either > or = 24 or < or = 21 participated in a 16-wk crossover study designed to determine the effects of low-dose zinc supplementation [306 mumol (20 mg)/d] on food intake, anthropometry, and biochemical and immunological indexes. Initial serum zinc concentrations were low in both groups and increased by approximately 20% after zinc supplementation. Zinc supplementation allowed a partial but significant restoration of serum thymulin activity and improved nutritional status (food intake and serum albumin and transthyretin concentrations) but had no effect on anthropometric indexes or serum apolipoproteins, except apolipoprotein CII and apolipoprotein CIII. After zinc supplementation, serum copper concentration decreased but there was no change in the ratio of low-density-lipoprotein cholesterol to high-density-lipoprotein cholesterol. Low-dose zinc supplementation allows restoration, at least partially, of nutritional and thymic status without the known disadvantages of high doses of zinc.

Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis).

Strontium ranelate (S12911) has previously been shown to stimulate bone formation and inhibit bone resorption in rats. To determine whether strontium ranelate affects normal bone remodeling, we studied the effect of strontium ranelate on alveolar bone in monkeys. Strontium ranelate, at dosages of 100, 275, and 750 mg/kg per day, or vehicle, were given by gavage to 31 normal adult monkeys (Macaca fascicularis) (15 males, 16 females), aged 3-4 years. Treatment for 6 months with strontium ranelate resulted in an increase in plasma strontium concentration. Histomorphometric analyses of indices of bone formation and resorption were determined in standardized areas of alveolar bone. Treatment with strontium ranelate decreased the histomorphometric indices of bone resorption (osteoclast surface and number) with a maximal significant effect at the highest dose tested. In contrast to this inhibitory effect on bone resorption, strontium ranelate maintained bone formation. Although the amount of osteoid tended to increase, strontium ranelate, even at the highest dose, had no deleterious effect on bone mineralization, as evaluated by mineral apposition rate and osteoid thickness. These findings show that strontium ranelate decreases indices of bone resorption while maintaining bone formation in the alveolar bone in monkeys.