Long-term risk of recurrence and mortality due to melanoma is potentially an important factor in the US presidential race because one candidate, Senator John McCain, had a high-risk cutaneous melanoma removed about 8 years ago. I have done an evidence-based analysis of the available information to calculate the mortality risk for McCain due to melanoma. McCain's physicians provided a brief summary of his health status in May, 2008.1Statement of health status: prepared by Mayo Clinic at the request of Senator John McCain.http://www.johnmccain.com/mccainrecords/Google Scholar Although the summary presents limited information on the lesion removed in August, 2000 (ulceration status and histology are not provided), sufficient information is given to use the 10-year survival prognostic model developed by Schuchter.2Schuchter L Schultz DJ Synnestvedt M et al.A prognostic model for predicting 10-year survival in patients with primary melanoma.Ann Intern Med. 1996; 125: 369-375Crossref PubMed Scopus (157) Google Scholar McCain's melanoma fell into the higher-risk categories identified in that study: the tumour was 2·2 mm thick, placing it into the second highest risk category (T3); McCain was older than 60 years at diagnosis; he is male; and his lesion was not on an extremity. As a result, using the prognostic model, his predicted 10-year survival at the time of diagnosis was only 24%. With regard to future risk, Kolmel and colleagues3Kolmel KF Kulle B Lippold A Seebacher C Survival probabilities and hazard functions of malignant melanoma in Germany 1972–1996, an analysis of 10433 patients. Evolution of gender differences and malignancy.Eur J Cancer. 2002; 38: 1388-1394Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar have shown that for male patients with thickness T3 melanoma the increased mortality associated with such tumours is relatively constant and remains so for 15 years from diagnosis (risk of death was highest 7 years from diagnosis, and decreased only minimally over the next 8 years). If we then apply a constant risk assumption to the prediction from the Schuchter model, the mortality risk for McCain for the remaining 2 years to the 10-year point would be about 12% per year, and would remain so for several years. A limitation of the evidence for long-term mortality risk in melanoma is that the patient cohorts are generally from the period before sentinel lymph node (SLN) biopsy was used. Because McCain underwent SLN biopsy, with results negative for metastatic disease, his prognosis should be better than for the overall population in the Schuchter model. An estimate of how much better is provided by two reports,4Leong SP Accortt NAQ Essner R et al.Impact of sentinel node status and other risk factors on the clinical outcome of head and neck melanoma patients.Arch Otolaryngol Head Neck Surg. 2006; 132: 370-373Crossref PubMed Scopus (84) Google Scholar, 5Gomez-Rivera F Santillan A McMurphey AB et al.Sentinel node biopsy in patients with cutaneous melanoma of the head and neck: recurrence and survival study.Head Neck. 2008; 30: 1284-1294Crossref PubMed Scopus (54) Google Scholar each with a median of about 3 years of follow-up, which indicate that the mortality risk in SLN-negative patients was about half that in SLN-positive patients. If we assume that this trend is maintained long term, McCain's mortality risk due to melanoma is better but not eliminated, remaining at 6% per year. I have made voluntary contributions to the to the Democratic party and its candidate, but otherwise declare that I have no conflict of interest.

05G. Viral Hepatitis' (g) Hepatitis' C Clinical therapy$223 postulating a direct interference of C virus on the different liver cell metabolic pathways.Nevertheless, data is still controversial.This study was aimed to confirm those hypothesises by comparing the prevalence of the insulin-resistant parameters and iron metabolism alterations between CHC and chronic hepatitis B (CHB).We retrospectively evaluated 842 consecutive patients (726 CHC and 116 CHB) who had undergone liver biopsy.We evaluated age, sex, ALT, type 2 diabetes and/or metabolic syndrome (MS), serum iron (IC) and ferritin concentration (FC) as well as and transferrin saturation, BMI, apparent duration of disease.Age, ADD, and BMI were significantly higher in CHC (p < 0.05) and the prevalence of metabolic syndrome (p < 0.005) but not diabetes were higher in CHC.No differences were found at liver biopsies.At the univariate analysis age, sex, BMI, ALT, Diabetes, MS, IC and FC were significantly related to liver fibrosis in CHC whereas only age, sex, steatosis and FC were related to fibrosis in CHB.At the multivariate analysis independent risk factors of fibrosis in CHC were age, sex, BMI, ALT and MS, whereas in CHB only age and sex seemed related to liver fibrosis.We also evaluated the association between significant degrees of steatosis (>30%) and age, sex, BMI, diabetes, metabolic syndrome, staging, Fe, Ferritin, Transferrin saturation in the two groups.In HCV positive patients, diabetes an staging were significantly associated to steatosis >30% at the multivariate analysis, whereas none of the parameters were found related to steatosis in CHB.This data confirms the higher association between obesity, insulin resistance (MS), iron overload and HCV-related hepatitis.Nevertheless, iron overload is not related to a worsening of liver fibrosis and/or clinical significant steatosis.Surprisingly, the prevalence of diabetes is higher, when compared to the prevalence in the general population (4 5%), both CHC and CHB subjects documenting that more than the virus, the liver damage might be responsible for the deranged glucose metabolism.

Inhibition of inosine monophosphate dehydrogenase (IMPDH) is one of several proposed mechanisms of action for ribavirin (RBV), a critical component of the current treatment for chronic hepatitis C (CHC). This study was a double-blind, placebo-controlled dose-escalation study of a novel, selective, orally active small molecule inhibitor of IMPDH, merimepodib (VX-497 or MMPD) in combination with standard interferon-alpha (IFN-alpha). Fifty-four treatment-naive patients with genotype-1 CHC were randomized to receive IFN-alpha 3 MIU subcutaneously three times a week, alone or in combination with 100 mg or 300 mg (every 8 h) of MMPD for 4 weeks. At the end of 4 weeks, all patients were offered 48 weeks of treatment with IFN-alpha/RBV. The objectives of the study were to evaluate the tolerability of the IFN-alpha/MMPD combination and to evaluate whether MMPD had an on-treatment effect on HCV-RNA, similar to RBV when added to IFN-alpha. The drug combination was generally well tolerated; one patient at the higher dose discontinued because of elevated alanine aminotransferase levels. No pharmacokinetic interactions were evident between the two drugs. Analysis of covariance that adjusted for a baseline imbalance in HCV-RNA in the intent-to-treat population did not show any significant differences between the treatment groups, or between MMPD plus IFN-alpha compared with IFN-alpha alone. However, the per-protocol primary efficacy analysis based on treatment-compliant patients demonstrated a greater reduction in mean HCV-RNA in the combination of 100 mg MMPD plus IFN-alpha compared with IFN-alpha alone (-1.78 log vs -0.86 log, P=0.037). In conclusion, the addition of a selective IMPDH inhibitor to IFN-alpha was well tolerated. In a low-dose range, the addition of MMPD may have the potential to add to the antiviral efficacy of IFN-alpha. Larger, longer duration trials incorporating pegylated IFN would be required to determine whether this combination, alone or with RBV, would increase either early or sustained virological response rates.

AIMS:Interferon alpha monotherapy induces a sustained response in less than 20% of patients treated for chronic hepatitis C. Interferon beta represents a potential therapeutic alternative for the treatment of chronic hepatitis C. The aim of this pilot study was to evaluate the efficacy and tolerance of recombinant interferon beta-la administered subcutaneously.METHODS:Twenty-one drug-naive patients with chronic hepatitis C were treated with recombinant interferon beta-la administered, subcutaneously, for 24 weeks using two different regimens: 9 MU, three times per week (n=11) and 12 MU, three times per week (n=10).RESULTS:At the end of the treatment period, nine (43%) patients had a biochemical and virological response (i.e. normal ALT and absence of hepatitis C virus RNA by PCR). Four of these patients were in the 9 MU group and five in the 12 MU group. A biochemical and virological sustained response occurred in four (19%) patients, all in the 9 MU dose group. The 4 patients with a sustained response maintained their response during a follow-up period of 33 to 58 months. Side effects were mild and 19 (90%) patients completed the treatment period.CONCLUSIONS:The results of this pilot study indicate that interferon beta-la administered subcutaneously is an effective therapy for some patients with chronic hepatitis C, and suggest that interferon beta-1a deserves further evaluations in larger trials especially in combination with ribavirin.