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Funder: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; doi: http://dx.doi.org/10.13039/501100002322, Funder: Radiumhemmets Forskningsfonder; doi: http://dx.doi.org/10.13039/501100007232, Funder: Swedish Cancer Society, Funder: Lunds Universitet Paulsson Trust, Funder: CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Funder: European Regional Development Fund; doi: http://dx.doi.org/10.13039/501100008530, Funder: Diagnoptics, Funder: CERCA Programme Generalitat de Catalunya, Funder: Esther Koplowitz Center, Barcelona, Spain, Funder: Comision Honoraria de Lucha Contra el Cancer, CSIC, Fundacion Manuel Perez, Montevideo, Uruguay, BACKGROUND: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. METHODS: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. RESULTS: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. CONCLUSIONS: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.

Background Mental illness is common amongst refugees and can differ depending on cultural background, experiences, and access to care. Given significant risk factors including high rates of exposure to sexual violence and different barriers to seeking adequate health care, refugee mothers are uniquely at risk. Methods In 2012–2013, surveys were administered to a convenience sample of Somali and systematic random sample of Iraqi refugee mothers to identify differences in mental health between the populations. The Hopkins Symptom Checklist (HSCL-25) identified respondents with major depression and emotional distress. We used multivariable logistic regression to compare these populations and identify variables associated with mental illness. Results 198 Somali and 219 Iraqi women were included. Most Iraqis (60.27%) had not seen a mental health provider while most Somalis (62.63%) had. On average, Iraqis scored 0.34 points higher (worse) on the HSCL-25 compared to Somalis (95% CI, 0.22–0.46; P < 0.001). Iraqis were more likely to have major depression (OR = 2.62, 95% CI 1.50–4.57, P = 0.001). On multivariable analysis accounting for the country of origin, those who saw a mental health provider were less likely to have major depression or emotional distress (OR 0.42, 95% CI 0.22–0.82, P = 0.011; OR 0.43, 95% CI 0.22–0.85, P = 0.015, respectively). Discussion Iraqi refugee mothers were more likely to have depression compared to Somalis. Refugee mothers who saw a mental health provider were less likely to have depression or emotional distress. These results suggest the cultural background and access to health services among refugee mothers’ impact on mental health.

The protracted conflict in Yemen-a civil war fought by proxies of Iran on one side and Saudi Arabia and the United States on the other-has ravaged the health care sector and facilitated the worst cholera outbreak on record, with more than 1 2 million people infected 2 Public health experts believe that destruction of infrastructure vital for health care delivery, such as the nation's largest seaport-an important gateway for the delivery of medical supplies and water, sanitation, and hygiene infrastructure-as well as security concerns related to ongoing violence, allowed this vaccinepreventable disease to rapidly propagate through the affected population The war, which started in 2011 as an outgrowth of the Arab Spring, marked a reversal of this trajectory 3 Perhaps most detrimental to public health in Syria are deliberate attacks on health care workers and facilities, which have been well documented since 2011 and are unprecedented in terms of scale 4 The United Nations and nongovernmental advocacy groups have documented and spoken out about the direct targeting of medical personnel, which amounts to war crimes under international law 4 Not only have these attacks limited the number of health care workers willing or able to address the health care needs ofthe besieged population, but they have created a powerful deterrent, preventing civilians from seeking care for fear of being caught in an assault- which is, perhaps, the intended goal The First Gulf War, along with crippling sanctions imposed by the United States, negatively affected Iraq's health care infrastructure, an effect that intensified during and after the 2003 US invasion 5 According to interviews with Iraqi refugee doctors, the war resulted in a substantial decline in health care services 5 In fact, four vaccinepreventable disease outbreaks- measles in 2009, mumps in 2004 and 2016, and rubella in 2004- occurred in the postinvasion period 6 Outbreaks such as these remind us that the lingering effects of conflict can last years or even decades after the declared war ends

Incidence of melanoma has been constantly growing during the last decades. Although most of the new diagnoses are represented by thin melanomas, the number of melanoma-related deaths in 2018 was 60,712 worldwide (Global Cancer Observatory, 2019). Until 2011, no systemic therapy showed to improve survival in patients with advanced or metastatic melanoma. At that time, standard of care was chemotherapy, with very limited results. The identification of BRAF V600 mutation, and the subsequent introduction of BRAF targeting drugs, radically changed the clinical practice and dramatically improved outcomes. In this review, we will retrace the development of molecular-target drugs and the current therapeutic scenario for patients with BRAF mutated melanoma, from the introduction of BRAF inhibitors as single agents to modern clinical practice. We will also discuss the resistance mechanisms identified so far, and the future therapeutic perspectives in BRAF mutated melanoma.

The incidence of melanoma, among the most lethal cancers, is widespread and increasing. Metastatic melanoma has a poor prognosis, representing about 90% of skin cancer mortality. The increased knowledge of tumor biology and the greater understanding of the immune system role in the anti-tumor response has allowed us to develop a more rational approach to systemic therapies. The discovery of activating BRAF mutations in half of all melanomas has led to the development of molecularly targeted therapy with BRAF and MEK inhibitors, which dramatically improved outcomes of patients with stage IV BRAF-mutant melanoma. More recently, the results of clinical phase III studies conducted in the adjuvant setting led to the combined administration of BRAF and MEK inhibitors also in patients with resected high-risk melanoma (stage III). Therefore, BRAF mutation testing has become a priority to determine the oncologist's choice and course of therapy. In this review, we will report the molecular biology-based strategies used for BRAF mutation detection with the main advantages and disadvantages of the most commonly used diagnostic strategies. The timing of such molecular assessment in patients with cutaneous melanoma will be discussed, and we will also examine considerations and approaches for accurate and effective BRAF testing.

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Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.

Background: In the midst of a global refugee crisis, addressing mental health is critical for refugee health care delivery. Understanding efficacy of mental health interventions is more important t...

// William Bruno 1 , Claudia Martinuzzi 1 , Virginia Andreotti 1 , Lorenza Pastorino 1 , Francesco Spagnolo 2 , Bruna Dalmasso 1 , Francesco Cabiddu 3 , Marina Gualco 3 , Alberto Ballestrero 1 , Giovanna Bianchi-Scarra 1 , Paola Queirolo 2 , Federica Grillo 4, * , Luca Mastracci 4, * , Paola Ghiorzo 1, * on behalf of the Italian Melanoma Intergroup (IMI) 1 Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy 2 Department of Medical Oncology, IRCCS AOU San Martino-IST, Genoa, Italy 3 Department of Pathology, IRCCS AOU San Martino-IST, Genoa, Italy 4 Department of Surgical and Diagnostic Sciences, Pathology Unit, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy * These authors have contributed equally to this work Correspondence to: Martinuzzi Claudia, email: claudia.martinuzzi@edu.unige.it Keywords: BRAF, primary melanoma, PNA-clamping, immunohistochemistry, heterogeneity Abbreviations: PNA: peptide nucleic acid – PNA-clamping real-time PCR; IHC: immunohistochemistry; NGS: next generation sequencing; FFPE: formalin-fixed, paraffin embedded Received: September 20, 2016 Accepted: November 24, 2016 Published: December 22, 2016 ABSTRACT Finding the best technique to identify BRAF mutations with a high sensitivity and specificity is mandatory for accurate patient selection for target therapy. BRAF mutation frequency ranges from 40 to 60% depending on melanoma clinical characteristics and detection technique used. Intertumoral heterogeneity could lead to misinterpretation of BRAF mutational status; this is especially important if testing is performed on primary specimens, when metastatic lesions are unavailable. Aim of this study was to identify the best combination of methods for detecting BRAF mutations (among peptide nucleic acid – PNA-clamping real-time PCR, immunohistochemistry and capillary sequencing) and investigate BRAF mutation heterogeneity in a series of 100 primary melanomas and a subset of 25 matched metastatic samples. Overall, we obtained a BRAF mutation frequency of 62%, based on the combination of at least two techniques. Concordance between mutation status in primary and metastatic tumor was good but not complete (67%), when agreement of at least two techniques were considered. Next generation sequencing was used to quantify the threshold of detected mutant alleles in discordant samples. Combining different methods excludes that the observed heterogeneity is technique-based. We propose an algorithm for BRAF mutation testing based on agreement between immunohistochemistry and PNA; a third molecular method could be added in case of discordance of the results. Testing the primary tumor when the metastatic sample is unavailable is a good option if at least two methods of detection are used, however the presence of intertumoral heterogeneity or the occurrence of additional primaries should be carefully considered.

Background Cyclin dependent kinase inhibitor 2A gene (CDKN2A) germline mutations have recently been associated with poor survival in patients with melanoma. Despite the high mutation rate in our cohort (up to 10% in patients with apparently sporadic melanoma), information on the impact of CDKN2A on survival in this cohort is lacking. Objective To investigate whether poor survival associated with CDKN2A germline mutations was confirmed in a high mutation–prevalence cohort of Italian patients with melanoma undergoing a mutation-based follow-up. Methods A total of 1239 patients with cutaneous melanoma were tested for CDKN2A mutational status and then assigned to a follow-up scheme according not only to family history but also to CDKN2A mutational status, as follow-up intervals were more frequent for CDKN2A germline mutation–positive (MUT+) patients. From this cohort, we selected 106 MUT+ patients (with familial melanoma or apparently sporadic melanoma) and 199 CDKN2A germline mutation–negative (MUT–) patients with sporadic melanoma who were matched by age and sex and had a similar tumor stage distribution. Results We found no difference in overall survival (hazard ratio, 0.85; 95% confidence interval, 0.48-1.52; P = .592,) or melanoma-specific survival (hazard ratio, 0.86; 95% confidence interval, 0.38-1.95; P = .718,) between MUT+ and MUT– patients. MUT+ patients were more likely to develop multiple melanomas and to undergo surgical excision of dysplastic nevi than were MUT– patients. Limitations Retrospective study. Conclusion CDKN2A mutations were not associated with survival in our cohort.

Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes. Guidelines for melanoma genetic testing have been published as an informal “rule of twos and threes,” but these guidelines apply to CDKN2A testing and are not intended for the more recently described non-CDKN2A melanoma syndromes. In order to develop an approach for the full spectrum of hereditary melanoma patients, we have separated melanoma syndromes into two types: “melanoma dominant” and “melanoma subordinate.” Syndromes in which melanoma is a predominant cancer type are considered melanoma dominant, although other cancers, such as mesothelioma or pancreatic cancers, may also be observed. These syndromes are associated with defects in CDKN2A, CDK4, BAP1, MITF, and POT1. Melanoma-subordinate syndromes have an increased but lower risk of melanoma than that of other cancer(s) seen in the syndrome, such as breast and ovarian cancer or Cowden syndrome. Many of these melanoma-subordinate syndromes are associated with well-established predisposition genes (e.g., BRCA1/2, PTEN). It is likely that these predisposition genes are responsible for the increased susceptibility to melanoma as well but with lower penetrance than that observed for the dominant cancer(s) in those syndromes. In this review, we describe our extension of the “rule of twos and threes” for melanoma genetic testing. This algorithm incorporates an understanding of the spectrum of cancers and genes seen in association with melanoma to create a more comprehensive and tailored approach to genetic testing.

Background Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A ( CDKN2A ) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral. Objective We sought to determine the CDKN2A / CDK4 /microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history. Methods In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A , CDK4 , and microphthalmia-associated transcription factor. Results CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether. Limitations The study was hospital based, not population based. Rare novel susceptibility genes were not tested. Conclusion Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.

Lynch syndrome is an inherited cancer syndrome caused by germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. LS predisposes to high risk of early-onset colorectal, endometrial and other tumors. Patients with Lynch syndrome have also been shown to have an elevated risk for pancreatic cancer (PC). In this study, we aimed to estimate the frequency of suspected Lynch syndrome among a series of 135 PC patients. Further, we wanted to determine the frequency of MMR gene mutations in the suspected Lynch syndrome cases. We also aimed to verify the pathogenicity of any novel non-truncating variants we might detect with a functional assay. Based on personal and/or familial cancer history, 19 patients were classified as suspected Lynch syndrome cases. DNA material for mutation analysis was available for eleven of them. Four patients were found to carry a total of five MLH1 or MSH2 variants. Of these, MSH2-Q402X, MSH2-G322D, and MLH1-K618A had been previously reported, while the MSH2-E205Q and MSH2-V367I variants were novel. MSH2-Q402X is a known stop mutation and reported here for the first time here in association with PC. MLH1-K618A was found in the unaffected branch of a kindred, suggesting that it may be a polymorphism or a low penetrance variant. MSH2-G322D likely does not cause a MMR defect, although this variant has also been associated with breast cancer as indeed seen in our patient. The novel variants MSH2-E205Q and MSH2-V367I were found in the same patient. Both novel variants were however functional in the applied MMR assay. Our findings suggest that only a small subset of pancreatic cancer patients carry pathogenic MMR mutations.

Purpose: We aimed to test the hypothesis that medulloblastoma (MB) variants show a different age distribution and clinical behavior reflecting their specific biology, and that MB occurring at very young age is associated with cancer predisposition syndromes such as Gorlin syndrome (GS). Experimental Design: We investigated the frequency, age distribution, location, response to treatment, outcome, and association with familial cancer predisposition syndromes in a series of 82 cases of MB in patients ages Results: Desmoplastic MB and MB with extensive nodularity (MBEN), were present in 22 of 82 cases (27%) and were more frequent in children ages ≤3 years (13 of 25; 52%). In this age group, MBEN was significantly more frequent than desmoplastic MB and classic MB (P < 0.001) and had a good prognosis. MBEN was associated with GS in 5 of 12 cases. Overall, 8 cases occurred in the context of familial tumor predisposition syndromes (5 GS, 1 each NF1, Li-Fraumeni, and Fragile X) and 7 of these patients were ages ≤3 years at diagnosis. Desmoplastic histology and a more intensive treatment represented independent favorable prognostic factors in multivariate analysis (P = 0.003 and P = 0.0139, respectively). Metastasis was a predictor of bad outcome (P = 0.0001). Conclusions: Our data indicate that biologically different MB entities warrant risk-adapted treatment and that MBEN is strongly associated with GS. Patients, ages ≤3 years, with MB and their families should be investigated for tumor predisposition syndromes such as GS.

Although the genetic bases of most hereditary cancer syndromes are known, and genetic tests are available for them, the incidence of the most rare of these syndromes is likely underestimated, partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs, though not necessarily tumors, that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis, and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects.

Entrapment of the ulnar nerve that leads to cubital tunnel syndrome is a common and often disabling disease. Current surgical treatment options involve simple decompression, medial epicondylectomy, or a variety of anterior transposition procedures. Such techniques often involve extensive exposure of the ulnar nerve with prolonged periods of immobilization. Because of this, patients may often experience significant postoperative pain, scarring, and joint stiffness. In this paper, we describe a minimally invasive technique for treating cubital tunnel syndrome using endoscopic assistance. This procedure enables complete ulnar nerve decompression through one small incision. Direct visualization of all potential anatomic compression sites for a distance of 20 cm around the medial epicondyle is possible. This endoscopic approach to cubital tunnel release is appealing, especially to those patients with mild to moderate symptoms who may otherwise be reluctant to undergo a more involved conventional surgery. It decreases postoperative pain, reduces scarring, and promotes an earlier return to activity than traditional open techniques allow, due to a decreased immobilization period.

This study reviews the various microsurgical techniques available to reanimate the paralyzed eye sphincter. Traditional as well as several innovative procedures are described that the senior author has used over the past 20 years. The methods of evaluating such outcomes are discussed and analyzed with regard to eye reanimation. An independent panel of reviewers evaluated standardized preoperative and postoperative videos documenting eye closure and blink in patients with lagophthalmos. A significant difference in overall postoperative outcome of both eye closure and blink was demonstrated. In this particular population, those patients who underwent dynamic procedures more often yielded better results than those who did not. Detailed video documentation and independent grading of outcomes of eye closure and blink are necessary to assist in developing effective surgical treatments for paralytic lagophthalmos. Accurate measurement of the results of these interventions remains a considerable challenge in the field of eye reanimation microsurgery.

In their interesting paper “Definitions of genetic testing in European legal documents,” Varga et al. (2012) provide an extensive assessment of how European and other legislation and policy instruments define genetic testing. They found that the definitions used across documents lacked a general consensus, showed that a definition of genetic testing was more often provided in non-binding than in binding instruments, and emphasized that a differentiation needs to be made between clinical genetic testing, genetics laboratory-based genetic testing, and genetic information. Overall, the authors analyzed 59 legal documents; one of which is a policy instrument by the Italian National Bioethics Committee (NBC) (1999). However, four further Italian legal documents (two policy papers and two binding instruments) define genetic testing. We thus provide a brief description of these documents and of the definitions for genetic testing they set forth and compare them with the findings of Varga et al., with the aim of contributing to a more complete and accurate view of how European legislation and policy instruments define genetic testing. The first policy instrument we refer to is the 1998 paper by the Italian National Committee for Biosecurity, Biotechnology and Life Sciences (NCBBLS) entitled “Guidelines for Genetic Testing” (Italian National Committee for Biosecurity 1998). The aim of this paper was to provide a reference framework to healthcare and laboratory professionals involved in genetic testing, with the overall purpose of ensuring that genetic testing is safe and effective, is used appropriately, is performed in accordance with high quality standards, and is offered to users whose decisional autonomy is fully respected and who are given appropriate social and psychological support. The second policy instrument is the 2011 position paper “Genetic Susceptibility Testing and Personalized Medicine” (Italian National Bioethics Committee and Italian National Committee for Biosecurity and Life Sciences Joint Working Group 2010) by the NBC/NCBBLS joint working group. The aim of this paper was to provide the general public with a critical assessment of the current and potential value of genome-wide testing in terms of clinical validity and clinical utility. Of the two binding instruments, the first is an agreement reached in 2004 by the Italian Ministry of Health and regional health authorities, the “Guidelines for Medical Genetics Activities” (Permanent Conference of the State and the Regions and the Autonomous Provinces of Trento and Bolzano 2004), which regulates medical genetics services. This binding instrument mainly focuses on the organization of clinical medical genetic services and laboratories, on the requirements that such facilities must meet, and on the training of medical genetic professionals. The second binding document is a regulation that is periodically issued by the Italian Data Protection Authority, the “General Authorization for the Processing of Genetic Data” (Italian Data Protection Authority 2011). The main purpose of the authorization is to establish the purposes for and mechanisms whereby genetic data can be processed. It is a soft-law instrument that would typically lack binding force but benefits from a hybrid status, as the Italian Data Protection Code confers such force to provisions dealing with genetic information (Republic of Italy 2003). In its current version (Italian Data Protection Authority 2011), the authorization sets forth an extensive list of definitions for genetic testing and related concepts (Battistuzzi et al. 2012). We have analyzed the definitions of genetic testing laid out in these documents according to the criteria applied by Vargas et al.; the results are shown in Table 1. Table 1 Items covered by the definitions of genetic testing contained in Italian policy and legislation documents We observed that none of the Italian documents, including those that are specifically concerned with data protection, personal rights, and privacy, mention family history or routine laboratory tests as sources of genetic information. Interestingly, the analysis of Varga et al. shows that roughly a third of the European documents (21/59) include family history, and only nine mention routine laboratory tests, as “materials” or “methods” from which genetic information can be obtained. It has been suggested that definitions associated with genetic information often center on genetic testing because it may be easier to specify and control due to its more recent and less well-established medical and social role, as opposed to family history or routine tests (Parthasarathy 2004). However, because family pedigrees can be important indicators of genetic risk and genetic information can be derived from nongenetic laboratory tests, the absence of these contexts of application from the definitions of genetic testing contained in the Italian instruments we identified, as well as from most of the European documents reviewed by Varga et al., seems to reflect an incomplete understanding of what the term genetic testing may encompass. Another result worth pointing out has to do with prenatal genetic testing and preimplantation genetic diagnosis (PGD). Prenatal testing is included as one of the possible types of testing in the definition of genetic testing provided by just one of the Italian documents. The others discuss prenatal testing, but place it under the wider umbrella of diagnostic and presymptomatic testing. As for PGD, it is completely absent from all of the Italian instruments. According to the review of Varga et al., just over half (34/59) of the European documents’ definitions of genetic testing include either PGD or prenatal testing. In the case of PGD, this may be explained by the fact that its legal status has seen numerous, often controversial, developments, both in Italy (Levi Setti et al. 2011; Republic of Italy 2004) and in other European countries such as Germany (Tuffs 2011). Prenatal testing, however, is one of the most widely employed clinical applications of molecular genetics. That it is not mentioned as one of the settings for genetic testing in so large a subset of the legal instruments discussed here indicates that widespread difficulties exist in the use of appropriate, well-defined terminology. Overall, despite the shortcomings described above, we found that the four Italian documents clearly distinguish between clinical and nonclinical genetic testing, take into account the setting for clinical applications, and discriminate between diagnostic testing and the range of predictive tests conducted in healthy individuals. Most importantly, their definitions of genetic testing show a good degree of consensus, providing a framework that appears to be both coherent and enforceable (Sequeiros 2010). These results contrast with the conclusions of Varga et al. that the definitions set forth in the European instruments they surveyed suffered from extreme variability, and sometimes displayed a lack of clarity and precision, and point to how eliminating language barriers and providing international accessibility of national hard- and soft-law instruments would allow for more accurate analyses of legal data coming from different sources.

OBJECTIVE To examine the frequency and correlates of skin examination behaviors in an international sample of individuals at varying risk of developing melanoma. DESIGN A cross-sectional, web-based survey. SETTING Data were collected from the general population over a 20-month period on behalf of the Melanoma Genetics Consortium (GenoMEL). PARTICIPANTS A total of 8178 adults from Northern (32%), Central (33%), and Southern (14%) Europe, Australia (13%), and the United States (8%). MAIN OUTCOME MEASURES Self-reported frequency of skin self-examination (SSE) and clinical skin examination (CSE). RESULTS After adjustment for age and sex, frequency of skin examination was higher in both Australia (odds ratio [OR]SSE=1.80 [99% CI, 1.49-2.18]; ORCSE=2.68 [99% CI, 2.23-3.23]) and the United States (ORSSE=2.28 [99% CI, 1.76-2.94]; ORCSE=3.39 [99% CI, 2.60-4.18]) than in the 3 European regions combined. Within Europe, participants from Southern Europe reported higher rates of SSE than those in Northern Europe (ORSSE=1.61 [99% CI, 1.31-1.97]), and frequency of CSE was higher in both Central (ORCSE=1.47 [99% CI, 1.22-1.78]) and Southern Europe (ORCSE=3.46 [99% CI, 2.78, 4.31]) than in Northern Europe. Skin examination behavior also varied according to melanoma history: participants with no history of melanoma reported the lowest levels of skin examination, while participants with a previous melanoma diagnosis reported the highest levels. After adjustment for region, and taking into account the role of age, sex, skin type, and mole count, engagement in SSE and CSE was associated with a range of psychosocial factors, including perceived risk of developing melanoma; perceived benefits of, and barriers to, skin examination; perceived confidence in one's ability to engage in screening; and social norms. In addition, among those with no history of melanoma, higher cancer-related worry was associated with greater frequency of SSE. CONCLUSIONS Given the strong association between psychosocial factors and skin examination behaviors, particularly among people with no history of melanoma, we recommend that greater attempts be made to integrate psycho-education into the fabric of public health initiatives and clinical care, with clinicians, researchers, and advocacy groups playing a key role in guiding individuals to appropriate tools and resources.

Cutaneous melanoma continues to increase in incidence in many countries, and intentional tanning is a risk factor for melanoma. The aim of this study was to understand how melanoma risk factors, perceived threat and preferences for a suntan relate to intentional tanning. Self-report data were collected on behalf of GenoMEL (www.genomel.org) from the general population using an online survey. A total of 8178 individuals completed the survey, with 72.8% of respondents being from Europe, 12.1% from Australia, 7.1% from the US, 2.5% from Israel and 5.5% from other countries. Seven percent of respondents had previously been diagnosed with melanoma and 8% had at least one first-degree relative with a previous melanoma. Overall, 70% reported some degree of intentional tanning during the past year, and 38% of respondents previously diagnosed with melanoma had intentionally tanned. The total number of risk factors was positively correlated with perceived risk of melanoma [correlation coefficient (rho) = 0.27], and negatively correlated with intentional tanning (rho = -0.16). Preference for a dark suntan was the strongest predictor of intentional tanning [regression coefficient (beta)= 0.35, P

Background: The incidence of melanoma continues to increase in many countries, and primary prevention of melanoma includes avoidance of sunburn as well as adequate sun protection behavior. The aim of this study was to examine the prevalence of self-reported sun protection behaviors and sunburn in users of the Internet, and to identify the demographic, clinical, and attitudinal/motivational correlates of sun protection behaviors. Methods: Self-report data were gathered on behalf of the GenoMEL consortium using an online survey available in 10 different languages, and 8,178 individuals successfully completed at least 80% of survey items, with 73% of respondents from Europe, 12% from Australia, 7% from the United States, 2% from Israel, and 6% from other countries. Results: Half of all respondents and 27% of those with a previous melanoma reported at least one severe sunburn during the previous 12 months. The strongest factors associated with sun protection behavior were perceived barriers to protection (β = −0.44/β = −0.37), and respondents who reported a positive attitude toward suntans were less likely to protect (β = −0.16/β = −0.14). Reported use of protective clothing and shade, as well as avoidance of midday sun exposure, were more strongly related to reduced risk of sunburn than sunscreen use. Conclusions: Despite widespread dissemination of public health messages about the importance of sun protection, a substantial proportion of this international sample, including respondents with a previous melanoma, reported inadequate sun protection behaviors resulting in severe sunburn. Impact: Future strategies to decrease sunburn should target the practical, social, and psychological barriers associated with nonuptake of sun protection. Cancer Epidemiol Biomarkers Prev; 19(9); 2199–210. ©2010 AACR.

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available. (Cancer Res 2006; 66(20): 9818-28)

Over the last decade, the sural flap has been popularized as a suitable alternative to free-tissue transfer for soft-tissue coverage of the lower extremity. However, flap failure rates may be increased especially if patients have certain risk factors, such as age over 40 years, peripheral artery disease, venous insufficiency, diabetes mellitus, and others. This article describes a sural flap delay procedure to avoid flap necrosis in this potentially "high-risk" patient population.

Approximately 5% to 10% of melanoma may be hereditary in nature, and about 2% of melanoma can be specifically attributed to pathogenic germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A). To appropriately identify the small proportion of patients who benefit most from referral to a genetics specialist for consideration of genetic testing for CDKN2A, we have reviewed available published studies of CDKN2A mutation analysis in cohorts with invasive, cutaneous melanoma and found variability in the rate of CDKN2A mutations based on geography, ethnicity, and the type of study and eligibility criteria used. Except in regions of high melanoma incidence, such as Australia, we found higher rates of CDKN2A positivity in individuals with 3 or more primary invasive melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of invasive melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family. The work summarized in this review should help identify individuals who are appropriate candidates for referral for genetic consultation and possible testing.