Clinicopathologic Features of Incident and Subsequent Tumors in Patients with Multiple Primary Cutaneous Melanomas

Background

0.6?C12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large, international, multicenter, case?Ccontrol study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas.

Methods

Multiple primary melanoma (cases) and single primary invasive melanoma (controls) patients from the Genes, Environment and Melanoma (GEM) study were included if their tumors were available for pathologic review and confirmed as melanoma. Clinicopathologic characteristics of invasive subsequent and first melanomas in cases and invasive single melanomas in controls were compared.

Results

A total of 473 pairs comprising a subsequent and a first melanoma and 1,989 single melanomas were reviewed. Forward stepwise regression modeling in 395 pairs with complete data showed that, compared with first melanomas, subsequent melanomas were more commonly contiguous with a dysplastic nevus, more prevalent on the head/neck and legs than other sites, and thinner. Compared with single primary melanomas, subsequent melanomas were more likely to be associated with a contiguous dysplastic nevus, more prevalent on the head/neck and legs, and thinner. The same differences were observed when subsequent melanomas were compared with single melanomas. First melanomas were more likely than single melanomas to have associated solar elastosis and no observed mitoses.

Conclusions

Thinner subsequent than first melanomas suggest earlier diagnosis, perhaps due to closer clinical scrutiny. The association of subsequent melanomas with dysplastic nevi is consistent with the latter being risk factors or risk markers for melanoma.     

Contribution of voltage-dependent K⁺ channels to metabolic control of coronary blood flow

The purpose of this investigation was to test the hypothesis that K(V) channels contribute to metabolic control of coronary blood flow and that decreases in K(V) channel function and/or expression significantly attenuate myocardial oxygen supply-demand balance in the metabolic syndrome (MetS). Experiments were conducted in conscious, chronically instrumented Ossabaw swine fed either a normal maintenance diet or an excess calorie atherogenic diet that produces the clinical phenotype of early MetS. Data were obtained under resting conditions and during graded treadmill exercise before and after inhibition of K(V) channels with 4-aminopyridine (4-AP, 0.3mg/kg, iv). In lean-control swine, 4-AP reduced coronary blood flow ~15% at rest and ~20% during exercise. Inhibition of K(V) channels also increased aortic pressure (P<0.01) while reducing coronary venous PO(2) (P<0.01) at a given level of myocardial oxygen consumption (MVO(2)). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous PO(2) in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a ~20% reduction in coronary K(V) current (P<0.01) and decreased expression of K(V)1.5 channels in coronary arteries (P<0.01). Together, these data demonstrate that K(V) channels play an important role in balancing myocardial oxygen delivery with metabolism at rest and during exercise-induced increases in MVO(2). Our findings also indicate that decreases in K(V) channel current and expression contribute to impaired control of coronary blood flow in the MetS. This article is part of a Special Issue entitled "Coronary Blood Flow".     

Five system barriers to achieving ultrasafe health care

Although debate continues over estimates of the amount of preventable medical harm that occurs in health care, there seems to be a consensus that health care is not as safe and reliable as it might be. It is often assumed that copying and adapting the success stories of nonmedical industries, such as civil aviation and nuclear power, will make medicine as safe as these industries. However, the solution is not that simple. This article explains why a benchmarking approach to safety in high-risk industries is needed to help translate lessons so that they are usable and long lasting in health care. The most important difference among industries lies not so much in the pertinent safety toolkit, which is similar for most industries, but in an industry's willingness to abandon historical and cultural precedents and beliefs that are linked to performance and autonomy, in a constant drive toward a culture of safety. Five successive systemic barriers currently prevent health care from becoming an ultrasafe industrial system: the need to limit the discretion of workers, the need to reduce worker autonomy, the need to make the transition from a craftsmanship mindset to that of equivalent actors, the need for system-level (senior leadership) arbitration to optimize safety strategies, and the need for simplification. Finally, health care must overcome 3 unique problems: a wide range of risk among medical specialties, difficulty in defining medical error, and various structural constraints (such as public demand, teaching role, and chronic shortage of staff). Without such a framework to guide development, ongoing efforts to improve safety by adopting the safety strategies of other industries may yield reduced dividends. Rapid progress is possible only if the health care industry is willing to address these structural constraints needed to overcome the 5 barriers to ultrasafe performance.     

UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production

Controversy continues both as to which wavelengths of sunlight cause melanoma and the mechanisms by which these different wavelengths act. Direct absorption of UVB by DNA is central in albino animal models, but melanin-pigmented models have shown major contributions by wavelengths longer than UVB that are thought to be mediated by photosensitized oxidant production. The only model for which the action spectrum of melanoma causation is known is a genetically melanoma-susceptible specific cross of Xiphophorus fish. We used electron paramagnetic resonance to quantitatively detect the UV induction of reactive melanin radicals in situ in the melanin-containing cells in the skin of this model and derived the action spectrum for melanin-photosensitized oxidant production (Phi(ox)). This action spectrum was identical to that for melanoma induction (Phi(mel)). These results confirm the hypothesis that melanin-photosensitized radical production is the major causative step of melanoma in this model and demonstrate that the wavelengths and mechanisms of melanoma causation in different models are dependent on the presence of melanin. This approach should be applicable to humans, thus providing an accurate surrogate for Phi(mel) for prevention studies.     

Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease

Our understanding of the underlying biology of Alzheimer's disease (AD) has been steadily progressing; however, this is yet to translate into a successful treatment in humans. The use of transgenic mouse models has helped to develop our understanding of AD, not only in terms of disease pathology, but also with the associated cognitive impairments typical of AD. Plaques and neurofibrillary tangles are often among the last pathological changes in AD mouse models, after neuronal loss and gliosis. There is a general consensus that successful treatments need to be applied before the onset of these pathologies and associated cognitive symptoms. This review discusses the different types of AD mouse models in terms of the temporal progression of the disease, how well they replicate the pathological changes seen in human AD and their cognitive defects. We provide a critical assessment of the behavioural tests used with AD mice to assess cognitive changes and decline, and discuss how successfully they correlate with cognitive impairments in humans with AD. This information is an important tool for AD researchers when deciding on appropriate mouse models, and when selecting measures to assess behavioural and cognitive change.     

Mutagen sensitivity as an indicator of soft tissue sarcoma risk.

The etiology of soft tissue sarcoma is poorly understood. Exposure to environmental chemicals may play a role, but the data are not clear. We compared a group of soft tissue sarcoma patients with healthy controls to determine whether the mutagen sensitivity assay, a simple chromosome aberration assay using the radiomimetic bleomycin, might be useful to identify patients at risk for soft tissue sarcoma. Patients with a diagnosis of soft tissue sarcoma at Memorial Sloan-Kettering's outpatient clinic signed informed consent and donated 30 ml of blood. Controls were selected from the general population of Connecticut by random digit dialing. Unrepaired DNA damage was assessed for 100 metaphase spreads for each individual, with the number of breaks in chromatids being counted as breaks per cell (b/c). The 20 cases with soft tissue sarcoma had 1.03 mean b/c and the controls had 0.88 b/c (P = 0.16). Patients with soft tissue sarcoma were 5.7 times more likely to be mutagen sensitive than controls (P = 0.01), as determined after dividing subjects into sensitive or not sensitive groups based on the median b/c among controls. As mutagen sensitivity has been shown to be associated with a number of cancers and appears to reflect genetic susceptibility, this assay may be an appropriate biomarker for radiation sensitivity or it may be a marker of susceptibility to soft tissue sarcoma. Larger studies should be undertaken to assess these possibilities.