Skin cancer risk in BRCA1/2 mutation carriers.

Women with BRCA1/2 mutations have an elevated risk of breast and ovarian cancer. These patients and their clinicians are often concerned about their risk for other cancers, including skin cancer. Research evaluating the association between BRCA1/2 mutations and skin cancer is limited and has produced inconsistent results. Herein, we review the current literature on the risk of melanoma and nonmelanoma skin cancers in BRCA1/2 mutation carriers. No studies have shown a statistically significant risk of melanoma in BRCA1 families. BRCA2 mutations have been linked to melanoma in large breast and ovarian cancer families, though a statistically significant elevated risk was reported in only one study. Five additional studies have shown some association between BRCA2 mutations and melanoma, while four studies did not find any association. With respect to nonmelanoma skin cancers, studies have produced conflicting results. Given the current state of medical knowledge, there is insufficient evidence to warrant increased skin cancer surveillance of patients with a confirmed BRCA1/2 mutation or a family history of a BRCA1/2 mutation, in the absence of standard risk factors. Nonetheless, suspected BRCA1/2 mutation carriers should be counselled about skin cancer risks and may benefit from yearly full skin examinations.

Agreement of dermatopathologists in the evaluation of clinically difficult melanocytic lesions: how golden is the 'gold standard'?

BACKGROUND: The 'gold standard' for the diagnosis of melanocytic lesions is dermatopathology. Although most of the diagnostic criteria are clearly defined, the interpretation of histopathology slides may be subject to interobserver variability. OBJECTIVES: The aim of this study was to determine the variability among dermatopathologists in the interpretation of clinically difficult melanocytic lesions. METHODS: This study used the database of MelaFind®, a computer-vision system for the diagnosis of melanoma. All lesions were surgically removed and sent for independent evaluation by four dermatopathologists. Agreement was calculated using kappa statistics. RESULTS: A total of 1,249 pigmented melanocytic lesions were included. There was a substantial agreement among expert dermatopathologists: two-category kappa was 0.80 (melanoma vs. non-melanoma) and three-category kappa was 0.62 (malignant vs. borderline vs. benign melanocytic lesions). The agreement was significantly greater for patients ≥40 years (three-category kappa = 0.67) than for younger patients (kappa = 0.49). In addition, the agreement was significantly lower for patients with atypical mole syndrome (AMS) (kappa = 0.31) than for patients without AMS (kappa = 0.76). LIMITATIONS: The data were limited by the inclusion/exclusion criteria of the MelaFind® study. This might represent a selection bias. The agreement was evaluated using kappa statistics. This is a standard method for evaluating agreement among pathologists, but might be considered controversial by some statisticians. CONCLUSIONS: Expert dermatopathologists have a high level of agreement when diagnosing clinically difficult melanocytic lesions. However, even among expert dermatopathologists, the current 'gold standard' is not perfect. Our results indicate that lesions from younger patients and patients with AMS may be more problematic for the dermatopathologists, suggesting that improved diagnostic criteria are needed for such patients.

Noninvasive genomic detection of melanoma.

BACKGROUND: Early detection and treatment of melanoma is important for optimal clinical outcome, leading to biopsy of pigmented lesions deemed suspicious for the disease. The vast majority of such lesions are benign. Thus, a more objective and accurate means for detection of melanoma is needed to identify lesions for excision. OBJECTIVES: To provide proof-of-principle that epidermal genetic information retrieval (EGIR™; DermTech International, La Jolla, CA, U.S.A.), a method that noninvasively samples cells from stratum corneum by means of adhesive tape stripping, can be used to discern melanomas from naevi. METHODS: Skin overlying pigmented lesions clinically suspicious for melanoma was harvested using EGIR. RNA isolated from the tapes was amplified and gene expression profiled. All lesions were removed for histopathological evaluation. RESULTS: Supervised analysis of the microarray data identified 312 genes differentially expressed between melanomas, naevi and normal skin specimens (P<0·001, false discovery rate q<0·05). Surprisingly, many of these genes are known to have a role in melanocyte development and physiology, melanoma, cancer, and cell growth control. Subsequent class prediction modelling of a training dataset, consisting of 37 melanomas and 37 naevi, discovered a 17-gene classifier that discriminates these skin lesions. Upon testing with an independent dataset, this classifier discerned in situ and invasive melanomas from naevi with 100% sensitivity and 88% specificity, with an area under the curve for the receiver operating characteristic of 0·955. CONCLUSIONS: These results demonstrate that EGIR-harvested specimens can be used to detect melanoma accurately by means of a 17-gene genomic biomarker.

The transcriptional repressor of p16/Ink4a, Id1, is up-regulated in early melanomas.

The helix-loop-helix transcription factor Id1 coordinates cell growth and differentiation pathways within mammalian cells and has been implicated in regulating G(1)-S phase cell cycle transitions. Recently Id1 has been shown to repress Ets- and E-protein-mediated transactivation of p16/Ink4a. Because the p16/Ink4a protein has been demonstrated to be inactivated in subsets of familial and sporadic melanomas, we sought to determine whether Id1 regulation of p16/Ink4a expression might be involved in the development of this human tumor. Here we evaluate 21 melanocytic lesions at various stages of malignant progression from common melanocytic nevi to metastatic melanomas and examine these lesions for Id1 and p16/Ink4a expression. We demonstrate that Id1 expression correlates with loss of p16/Ink4a expression in melanoma in situ; however, more advanced stages of melanoma do not express Id1 except within perivascular regions, despite overall decreased p16/Ink4a expression in these lesions. Microdissected lesions were evaluated for p16/Ink4a sequence, and invasive melanomas that did not express Id1 were found to have sustained inactivating p16/ink4a mutations. These data suggest a role for Id1 in regulating p16/Ink4a expression in early melanomas and demonstrate that later genetic changes may provide for irreversible loss of p16 expression in advanced stages of this tumor.

HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma.

We investigated the role of alterations of HDM2, the human homologue of murine mdm2, in the tumorigenesis and progression of cutaneous melanoma. A well-characterized cohort of 172 cases representing different points in the spectrum of melanocyte transformation (16 dysplastic nevi, 11 melanomas in situ, 107 invasive primaries, and 38 metastatic lesions), as well as 11 human melanoma cell lines were examined by immunohistochemistry and Western blotting for HDM2 protein expression, and by either Southern blotting (SB) or fluorescence in situ hybridization for HDM2 gene amplification. HDM2 overexpression, defined as >20% tumor cells showing nuclear immunoreactivity, was observed in 1 of 16 (6%) dysplastic nevi, 3 of 11 (27%) melanomas in situ, and 81 of 145 (56%) invasive primary and metastatic melanomas. Comparable frequencies of HDM2 overexpression were observed among invasive primary cases with differing tumor thicknesses as well as among the metastatic cases: 21 of 40 (53%) at < or =1.5 mm; 31 of 50 (62%) at 1.6-3.9 mm; 10 of 17 (58%) at >4 mm; and 19 of 38 (50%) metastases. HDM2 amplification was observed in 1 of 88 (1%) primary cases using fluorescence in situ hybridization, and in 0 of 12 (0%) metastatic cases that overexpressed HDM2 using SB. Melanoma cell lines expressed HDM2 protein, but there was no evidence of amplification by SB. Our data suggest that HDM2 protein overexpression is common in invasive and metastatic melanoma. Observing HDM2 overexpression in noninvasive melanoma suggests that expression of this oncogene may play an early role in melanocyte transformation. HDM2 amplification occurs infrequently, and other mechanisms that up-regulate HDM2 expression are under investigation.

HMO penetration and the geographic mobility of practicing physicians.

In this study, we assessed the influence of changes in health maintenance organization (HMO) penetration on the probability that established patient care physicians relocated their practices or left patient care altogether. For physicians who relocated their practices, we also assessed the impact of HMO penetration on their destination choices. We found that larger increases in HMO penetration decreased the probability that medical/surgical specialists in early career stayed in patient care in the same market, but had no impact on generalists, hospital-based specialists, or mid career medical/surgical specialists. We also found that physicians who relocated their practices were much more likely to choose destination markets with the same level of HMO penetration or lower HMO penetration compared with their origin markets than they were to choose destination markets with higher HMO penetration. The largely negligible impact of changes in HMO penetration on established physicians' decisions to relocate their practices or leave patient care is consistent with high relocation and switching costs. Relocating physicians' attraction to destination markets with the same level of HMO penetration as their origin markets suggests that, while physicians' styles of medical practice may adapt to changes in market conditions, learning new practice styles is costly.

HMO growth and the geographical redistribution of generalist and specialist physicians, 1987-1997.

OBJECTIVE: To assess the impact of the growth in HMO penetration in different metropolitan areas on the change in the number of generalists, specialists, and total physicians, and on the change in the proportion of physicians who are generalists. DATA SOURCES/STUDY SETTING: The American Medical Association Physician Masterfile, to obtain the number of patient care generalists and specialists in 1987 and in 1997 who were practicing in each of 316 metropolitan areas in the United States. Additional data for each metropolitan area were obtained from a variety of sources, and included HMO penetration in 1986 and 1996. STUDY DESIGN: We estimated multivariate regression models in which the change in the number of physicians between 1987 and 1997 was a function of HMO penetration in 1986, the change in HMO penetration between 1986 and 1996, population characteristics and physician fees in 1986, and the change in population characteristics and fees between 1986 and 1996. Each model was estimated using ordinary least squares (OLS) and two-stage least squares (TSLS). PRINCIPAL FINDINGS: HMO penetration did not affect the number of generalist physicians or hospital-based specialists, but faster HMO growth led to smaller increases in the numbers of medical/surgical specialists and total physicians. Faster HMO growth also led to larger increases in the proportion of physicians who were generalists. Our best estimate is that an increase in HMO penetration of .10 between 1986 and 1996 reduced the rate of increase in medical/surgical specialists by 10.3 percent and reduced the rate of increase in total physicians by 7.2 percent. CONCLUSIONS: The findings of this study support the notion that HMOs reduce the demand for physician services, particularly for specialists' services. The findings also imply that, during the past decade, there has been a redistribution of physicians-especially medical/surgical specialists-from metropolitan areas with high HMO penetration to low-penetration areas.

A comparison of preference assessment instruments used in a clinical trial: responses to the visual analog scale from the EuroQol EQ-5D and the Health Utilities Index.

OBJECTIVES: To compare preference assessments that were made by using the EuroQol EQ-5D and the Health Utilities Index Mark II. SUBJECTS: 561 patients in a randomized trial of tirilazad mesylate for aneurysmal subarachnoid hemorrhage. MEASURES: Three preference assessments (a value score for the EuroQol instrument and value and utility scores for the Health Utilities Index) made three months after randomization. The averages for each of the three scores, stratified by clinical outcomes and attributes of the Health Utilities Index health status classification system, were compared. To evaluate potential sources of difference between the instruments, the authors estimated two alternative Health Utilities Index scoring rules that were based on patient responses to the EuroQol instrument. RESULTS: Patients' ratings of their current health made by using the 100-point visual analog scale from the EuroQol instrument were more similar to the utility scores for the Health Utilities Index than they were to the value scores for the Health Utilities Index. The biggest differences between the visual analog scores for the EuroQol instrument and the utility scores for the Health Utilities index were seen at higher levels of functioning. CONCLUSION: For states representing higher levels of functioning, differences were seen between patients' self-ratings obtained by using the EuroQol instrument and the patients' utility scores on the Health Utilities Index; for states representing lower levels of functioning, substantial agreement was observed between these two scores. Differences observed at the higher levels of functioning suggest that further research is needed to determine whether the Health Utility Index's assignment of a score of 1.0 to the reference state representing being healthy is appropriate.

How managed care growth affects where physicians locate their practices.

Managed care has had a profound effect on physician practice. It has altered patterns in the use of physician services, and consequently, the practice and employment options available to physicians. But managed care growth has not been uniform across the United States, and has spawned wide geographic disparities in earning opportunities for generalists and specialists. This Issue Brief summarizes new information on how managed care has affected physicians' labor market decisions and the impact of managed care on the number and distribution of physicians across the country.

Altered patterns of RB expression define groups of soft tissue sarcoma patients with distinct biological and clinical behavior.

BACKGROUND: Function of the retinoblastoma tumor suppressor protein (pRB) may be compromised at a genetic level by gene loss or mutation or at a post-translational level by hyperphosphorylation. In this study, we examined adult soft tissue sarcomas (ASTS) to determine if alterations of pRB were associated with distinct patterns of pRB expression and clinical outcome. DESIGN: We investigated 86 ASTS patients using monoclonal antibodies that distinguish between hyperphosphorylated and underphosphorylated pRB products. We also used microsatellite analysis to investigate the genetic status of the RB locus. We correlated pRB alterations with proliferative activity, and with clinicopathological outcomes. RESULTS: Altered patterns of pRB expression are common in ASTS occurring in 84% of cases, and it is significantly associated with proliferative activity (p<0.001). Patients whose tumors either lack expression of pRB, or express hyperphosphorylated forms of pRB, have poor survivals compared to patients whose tumors exhibit a normal, underphosphorylated pattern of pRB expression (p=0.03). In addition, 63% of cases lacking expression of pRB showed loss-of-heterozygosity at the locus. CONCLUSIONS: Inactivation of pRB is common in adult STS, which may be due to either gene loss or post-translational modification, namely hyper-phosphorylation. Both mechanisms are associated with tumor cell proliferation and poor survival.

Nursing shortages and international nurse migration.

BACKGROUND: The United Kingdom and the United States are among several developed countries currently experiencing nursing shortages. While the USA has not yet implemented policies to encourage nurse immigration, nursing shortages will likely result in the growth of foreign nurse immigration to the USA. Understanding the factors that drive the migration of nurses is critical as the USA exerts more pull on the foreign nurse workforce. AIM: To predict the international migration of nurses to the UK using widely available data on country characteristics. METHOD: The Nursing and Midwifery Council serves as the source of data on foreign nurse registrations in the UK between 1998 and 2002. We develop and test a regression model that predicts the number of foreign nurse registrants in the UK based on source country characteristics. We collect country-level data from sources such as the World Bank and the World Health Organization. RESULTS: The shortage of nurses in the UK has been accompanied by massive and disproportionate growth in the number of foreign nurses from poor countries. Low-income, English-speaking countries that engage in high levels of bilateral trade experience greater losses of nurses to the UK. CONCLUSION: Poor countries seeking economic growth through international trade expose themselves to the emigration of skilled labour. This tendency is currently exacerbated by nursing shortages in developed countries. Countries at risk for nurse emigration should adjust health sector planning to account for expected losses in personnel. Moreover, policy makers in host countries should address the impact of recruitment on source country health service delivery.

Evaluation of germline CDKN2A, ARF, CDK4, PTEN, and BRAF alterations in atypical mole syndrome.

Atypical mole syndrome is a sporadic or an inherited condition with an increased risk of melanoma. Germline mutations in the CDKN2A, ARF, CDK4 and somatic mutations in the PTEN and BRAF genes have been associated with melanoma. In this study, we evaluated genes associated with familial and sporadic melanoma for mutations in 28 probands with the atypical mole syndrome. No sequence alterations in the coding regions or in the splice junctions of CDKN2A, ARF, CDK4, PTEN or BRAF were identified. These data suggest that genes evaluated in this study are unlikely to be candidate genes for atypical mole syndrome and support the notion that unknown susceptibility gene/s for this disease exist.

Specialty care by child neurologists: a workforce analysis.

OBJECTIVE: To provide a current profile of the practice of child neurology, report the attitudes of child neurologists toward practice, and analyze the supply of child neurologists. METHODS: In March 2002, a questionnaire was sent to all active members of the Child Neurology Society (n = 1,051) and to nonmember physicians under age 70 who listed child neurology as a primary or secondary specialty on the American Medical Association Masterfile (n = 433). The response rate was 65%. Eligibility criteria were then applied to arrive at the sample of main specialty in child neurology working at least 20 hours per week in patient care. The final population was 604. Differences in practice characteristics were tested by practice type, and the number of full-time patient care child neurologists was projected by extrapolating to nonrespondents. RESULTS: There are 904 full-time patient care child neurologists in the United States and 1.27 per 100,000 children. Career satisfaction is 90%, yet no growth in the supply is projected over the next 20 years. Wait times for an appointment average 53 and 44 days for a new and return visit, with longer wait times in university settings. Average annual income is 151,000 dollars. CONCLUSION: The practice characteristics of child neurologists suggest that the specialty will be challenged to meet patient demands.

Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi--results from the NYU-LCMN registry.

BACKGROUND: Large congenital melanocytic naevi (LCMN), which develop in utero and are present in approximately one in 20,000 newborns, are associated with markedly increased risks of cutaneous melanoma, leptomeningeal melanoma and neurocutaneous melanocytosis (NCM). OBJECTIVES: This study examined clinical characteristics associated with melanoma and NCM among patients with LCMN, and estimated the risk of developing melanoma and NCM in these patients. METHODS: Two hundred and five LCMN patients enrolled in the New York University registry were studied. One hundred and seventy of these patients were followed prospectively. The remaining 35 patients had either melanoma at the time of entry into the registry (n = 6), or had insufficient follow-up information (n = 29). The outcome measures were the occurrence of melanoma and NCM. The associations between these outcomes and the clinical covariates (anatomical location of the LCMN, size of the LCMN, number of satellite lesions, family history of melanoma, patient sex and treatment) were assessed. RESULTS: Four of 170 (2.3%) prospectively followed patients developed melanomas, representing a standardized morbidity ratio of 324. Among the entire cohort (n = 205), there were associations between increasing numbers of satellite naevi and the occurrence of melanoma (P = 0.04), and the presence of NCM (P = 0.06). Compared with patients who did not develop these diseases, median LCMN diameters were larger among patients who developed melanoma (49 vs. 39 cm) and NCM (55 vs. 46 cm). CONCLUSIONS: In LCMN patients, increasing numbers of satellite lesions and larger LCMN diameters are associated with melanoma and NCM.

Suppression of H-2b-associated resistance to Friend erythroleukemia virus by a class I gene from the H-2d major histocompatibility complex haplotype.

Mice homozygous for the H-2d haplotype at the major histocompatibility complex are markedly more susceptible to erythroleukemia induction by the Friend isolate of murine leukemia retrovirus (FV) than are congenic mice homozygous for the H-2b haplotype. The resistance conferred by the H-2b haplotype is recessive in this cross, since heterozygous F1 mice are as susceptible as parental strain H-2d homozygotes. However, H-2b-associated resistance is not an intrinsically recessive trait, since H-2b/H-2dm1 heterozygotes resemble H-2b homozygotes in their relative resistance to FV; the mutant H-2dm1 haplotype lacks the entire D region of the parental haplotype except for a single class I gene formed by the fusion of its terminal D-region genes to produce a class I gene differing from both parental genes, and thus this finding indicates that one or more D-region genes of the H-2d haplotype can actively suppress H-2b-associated resistance. Unlike H-2dm1, the mutant H-2dm2 haplotype, which retains only the class IDd gene in the D region of the H-2d haplotype, strongly suppresses resistance in H-2b/H-2dm2 heterozygotes, and the presence of Dd as a transgene significantly reduces the resistance of H-2b homozygotes. Since H-2b-associated resistance to FV appears to be due mainly to the capacity of Lb (also called Db), the only class I molecule encoded in the D region of the H-2b haplotype, to present viral epitopes for recognition by FV-specific cytotoxic T lymphocytes, suppression of resistance to FV by the Dd molecule implies that the presence of one class I molecule of the major histocompatibility complex can interfere with either the presentation of viral epitopes by another class I molecule or the generation of T cells that recognize viral epitopes so presented.

Analytic approaches for the evaluation of costs.

Currently, economic evaluation of new medical therapies is conducted routinely. Development of an analysis plan before performance of the analysis is a first step in the analysis of data from such evaluations. Univariate analysis of costs can be performed with both parametric and nonparametric tests. Potential multivariable analyses include ordinary least squares regression, nonparametric hazard models, parametric failure time models, Cox semiparametric regression, and joint distributions of survival and cost. In addition to developing point estimates for economic outcomes, 95% confidence intervals for cost-effectiveness ratios should be developed to evaluate the level of uncertainty that surrounds these estimates. Sensitivity analysis should be used to address other sources of uncertainty.

Confidence intervals for cost-effectiveness ratios: a comparison of four methods.

We evaluated four methods for computing confidence intervals for cost-effectiveness ratios developed from randomized controlled trials: the box method, the Taylor series method, the nonparametric bootstrap method and the Fieller theorem method. We performed a Monte Carlo experiment to compare these methods. We investigated the relative performance of each method and assessed whether or not it was affected by differing distributions of costs (normal and log normal) and effects (10% absolute difference in mortality resulting from mortality rates of 25% versus 15% in the two groups as well as from mortality rates of 55% versus 45%) or by differing levels of correlation between the costs and effects (correlations of -0.50, -0.25, 0.0, 0.25 and 0.50). The principal criterion used to evaluate the performance of the methods was the probability of miscoverage. Symmetrical miscoverage of the intervals was used as a secondary criterion for evaluating the four methods. Overall probabilities of miscoverage for the nonparametric bootstrap method and the Fieller theorem method were more accurate than those for the other the methods. The Taylor series method had confidence intervals that asymmetrically underestimated the upper limit of the interval. Confidence intervals for cost-effectiveness ratios resulting from the nonparametric bootstrap method and the Fieller theorem method were more dependably accurate than those estimated using the Taylor series or box methods. Routine reporting of these intervals will allow individuals using cost-effectiveness ratios to make clinical and policy judgments to better identify when an intervention is a good value for its cost.

Quantifying stochastic uncertainty and presenting results of cost-effectiveness analyses.

In the last decade, major advances have been made in the statistical methods for quantifying uncertainty in stochastic cost-effectiveness studies. In this paper, we provide a guide to the literature in which we highlight the preferred methods for confidence interval estimation, new developments in the formulation of the cost-effectiveness problem, suggested ways for presenting results and the areas in which future research may develop. The overall approach taken is nontechnical, with an emphasis on graphical rather than algebraic presentation of methods.