The Genes and Genetics of Malignant Melanoma

Background: Population-based studies have identified several clinical variables associated with an increased risk of developing cutaneous melanoma that include phenotype, amount of and response to sun exposure, and family history. However, these observations are of limited relevance to clinical practice as the risk associated with each factor is individually modest and the characteristics of these variables lack precision when applied to a particular individual. Objective: To review the literature regarding recent advances made in the understanding of the genes and genetics of clinical variables associated with an increased risk of melanoma. Conclusion: Variants of the MC1R (melanocortin-1 receptor) have been identified as major determinants of high-risk phenotypes, such as red hair and pale skin, and the ability to tan in response to UV exposure. Several studies also suggest that such variants may increase melanoma risk independent of their contribution to phenotype. A strong genetic basis for both nevus density and size has been demonstrated and the link between nevi and the development of MM has become better defined. Finally, germline defects in several genes involved in cell cycle regulation, namely, p16 and CDK4, have been demonstrated in many familial melanoma kindreds. This progress has introduced the prospect of genetic testing as a means of identifying a limited number of high-risk individuals who can be targeted with regular screening and education regarding UV exposure and skin self-examination. Ultimately, through rational genetic therapy targeted to correcting the underlying molecular defect, altering the natural history of melanoma development may be possible.     

Peripheral amino acid and fatty acid infusion for the treatment of necrolytic migratory erythema in the glucagonoma syndrome

Necrolytic migratory erythema (NME), the characteristic rash associated with the glucagonoma syndrome, is a cause of substantial morbidity among patients with this rare malignancy. Treatment options are suboptimal, and often useful for only short or moderate durations. We report the effective, long-term (> 1 year) use of intermittent infusions of amino acids (AA) and fatty acids (FA) administered via peripheral intravenous access for the treatment of NME in the glucagonoma syndrome. Despite resolution of the NME, serum amino acid (initially subnormal) and fatty acid (initially normal) levels remained unchanged. Tumour growth and other symptoms related to the glucagonoma syndrome appear unaffected by such infusions.     

Interactions of human antibodies,epitope exposure,antibody binding and neutralization of primary isolate HIV-1 virions

OBJECTIVE: Development of an effective HIV vaccine has been limited because of the inherent structural properties of the HIV envelope on native virions and the failure of the immune system to respond in an effective manner. Identification of the interactions of human antibodies with virions resulting in neutralization will facilitate vaccine design. DESIGN: Combinations of human monoclonal antibodies (hMAb) were studied for binding to and neutralization of primary isolate virions. METHODS: Virion binding and neutralization were measured using primary isolate virions. RESULTS: Antibodies and combinations of antibodies to epitopes exposed upon CD4 binding (CD4i) and V3 loop antibodies resulted in additive binding and neutralization of R5X4 virus. Antibodies did not bind to or neutralize R5 virus as well. The combination of V3 loop antibody with 2G12 resulted in enhanced neutralization and binding to the R5X4 isolate but not the R5 isolate. Preincubation of the R5X4 isolate with F240, a non-neutralizing anti-gp41 antibody, significantly enhanced binding and neutralization by CD4i hMAb and 2F5. F240 also enhanced the binding of 2F5 to the R5 isolate and the neutralization of the R5 isolate mediated by 2G12. CONCLUSIONS: Neutralizing epitopes are obscured on intact primary isolate virions and are dynamically exposed upon ligand (CD4) interactions. Interestingly, a non-neutralizing antibody to gp41 also increased binding and neutralizing activity of some hMAb that poorly neutralized R5 virus. These data suggest that non-neutralizing epitopes may be appropriate targets for vaccine design and epitope exposure should be considered in the development of immunotherapeutic strategies for HIV.     

Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis

OBJECTIVE: To review the effect of calcitonin on bone density and fractures in postmenopausal women. DATA SOURCE: We searched MEDLINE and EMBASE from 1966 to 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies and primary authors for unpublished data. STUDY SELECTION: We included 30 studies that randomized women to calcitonin or an alternative (placebo or calcium and/or vitamin D) and measured bone density or fracture incidence for at least 1 yr. DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: Calcitonin reduced the incidence of vertebral fractures, with a pooled relative risk (RR) of 0.46 [95% confidence interval (CI) 0.25-0.87, P = 0.02, n = 1404, 4 trials]. However, the RR from the one relatively large randomized controlled trial (RCT) was 0.79 (95% CI 0.62-1.00, P = 0.05, n = 1108). For nonvertebral fractures, the pooled RR was 0.52 (95% CI 0.22-1.23, P = 0.14, n = 1481, 3 trials). Once again, the single large trial showed a less impressive effect than the smaller trials (RR 0.80, 95% CI 0.59-1.09, P = 0.16, n = 1245). For bone density of the lumbar spine, the pooled weekly dose of 250 to 2800 IU per week resulted in significant increase in the weighted mean difference (WMD) of 3.74 (2.04-5.43, P < 0.01, n = 2260, 24 trials). The combined forearm showed a similar effect, with a WMD of 3.02 (95% CI 0.98-5.07, P < 0.01, n = 468, 9 trials). At the femoral neck, the pooled weighted mean difference showed a nonsignificant trend toward benefit, WMD 3.80 (95% CI -0.32-7.91, P = 0.07, 9 trials, n = 513). Methodologically weaker studies tended to show greater effects on bone density, and the lumbar spine results suggested the possibility of publication bias. CONCLUSIONS: Calcitonin likely increases bone density in postmenopausal women predominantly at the lumbar spine and forearm for weekly doses of greater than 250 IU, although the true effect may be smaller than the pooled estimate would suggest. Calcitonin likely reduces the risk of vertebral fracture; its effect on nonvertebral fracture remains uncertain.     

Preoperative and early postoperative magnetic resonance imaging in two cases of childhood choroid plexus carcinoma

We present and illustrate the MRI appearances of two children with choroid plexus carcinoma. The MRI characteristics of these rare tumours are reviewed. Since total surgical resection is a significant prognostic factor, early postoperative MRI was performed in both cases to ensure surgical clearance. In one case a complete resection was documented and this patient remains well at short-term follow-up. Residual tumour was noted in the second case, but despite "second look" surgery there was subsequent local relapse.     

How to detect hepatocellular carcinoma in cirrhosis

Cirrhosis predisposes to hepatocellular carcinoma (HCC) which develops by sequential steps of de-differentiation of hepatocytes from regenerative nodules via borderline (dysplastic) nodules to frankly malignant HCC. Effective treatment depends on early recognition of HCC, so the key tasks for imaging are firstly recognising the presence of a suspicious lesion, and secondly differentiating between benign, borderline and malignant nodules. Screening of high-risk cirrhotic patients with sonography and measurement of alpha fetoprotein (AFP) is helpful but will not reliably differentiate small HCC from benign or dysplastic nodules. Large HCCs can usually be recognised by their characteristic morphology on imaging, but the appearances of smaller benign and malignant nodules show considerable overlap on unenhanced sonography, CT and MRI. Increasing degrees of histological malignancy are associated with increasing arterialisation and loss of portal blood supply, so the recognition of HCC requires the use of dynamic imaging with contrast-enhanced CT or T1-weighted MRI with gadolinium enhancement. Sonography with microbubble contrast media now offers another method for detecting arterialised nodules; however, some non-malignant nodules show arterial hypervascularity and a minority of HCCs are hypovascular, so the assessment of perfusion does not conclusively distinguish benign from malignant lesions. Kupffer cell function is another attribute of liver tissue which can be explored using MRI with superparamagnetic iron oxide particles (SPIO). Experience thus far suggests that uptake of SPIO is an effective discriminator between benign and malignant nodules. The combination of SPIO with gadolinium-enhanced MRI offers the opportunity for imaging characterisation of cirrhotic nodules by cellular function as well as by blood supply, and this approach is now proposed as the examination of choice for detecting HCC in cirrhosis.     

Energy intake deficit and physical performance at altitude

BACKGROUND: Physical performance of sea-level (SL) residents acutely exposed to altitude (ALT) is diminished and may improve somewhat with ALT acclimatization. HYPOTHESIS: A large reduction in lean body mass (LBM), due to severe energy intake deficit during the first 21 d of ALT (4300 m) acclimatization, will adversely affect performance. METHODS: At ALT, 10 men received a deficit (DEF) of 1500 kcal x d(-1) below body weight (BW) maintenance requirements and 7 men received adequate (ADQ) kcal x d(-1) to maintain BW. Performance was assessed by: 1) maximal oxygen uptake (VO2max); 2) time to complete 50 cycles of a lift and carry task (L+C); 3) number of one-arm elbow flexions (10% BW at 22 flexions x min(-1); and 4) adductor pollicis (AP) muscle strength and endurance time (repeated 5-s static contractions at 50% of maximal force followed by 5-s rest, to exhaustion). Performance and body composition (using BW and circumference measures) were determined at SL and at ALT on days 2 through 21. RESULTS: At SL, there were no between-group differences (p > 0.05) for any of the performance measures. From SL to day 21 at ALT, BW and LBM declined by 6.6 +/- 3 kg and 4.6 kg, respectively, for the DEF group (both p < 0.01), but did not change (both p > 0.05) for the ADQ group. Performance changes from day 2 or 3 to day 20 or 21 at ALT were as follows (values are means +/- SD): VO2max (ml x min(-1)): DEF = +97 +/- 237, ADQ = +159 +/- 156; L + C (s): DEF = -62 +/- 35*, ADQ = -35 +/- 20* (*p < 0.05; improved from day 3); arm flex (reps): DEF = -2 +/- 7, ADQ = +2 +/- 8; AP endurance (min): DEF = +1.4 +/- 2, ADQ = + 1.9 +/- 2; AP strength (kg): DEF = -0.7 +/- 4, ADQ = -1.2 +/- 2. There were no differences in performance between groups. CONCLUSIONS: A significant BW and LBM loss due to underfeeding during the first 21 d of ALT acclimatization does not impair physical performance at ALT.     

Incidence of symptomatic thrombosis in a stable population of 650,000: travel and other risk factors

Despite recent intensive media interest, the incidence of traveler's thrombosis is unknown. We have undertaken a study of all symptomatic cases of venous thrombosis, presenting to a hospital, in a fixed population of 650,000. There were 1,250 cases of venous thromboembolism diagnosed over a 2-yr period. Of these, only 47 (3.8%) answered positively to the question" did you make a journey of more than 100 mi in the 4 wk prior to diagnosis?" Among the travelers, 60% had traveled by air, 36% by road, and the remainder by rail. At least one medical risk factor for venous thrombosis was present in all but three of our cohort. We conclude that, taking into consideration the enormous number of passengers who travel, the relative risk of traveler's thrombosis is likely to be low. The incidence of this complication in the North East of England is 1 per 27,660 of the whole population.