Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure.

BACKGROUND: Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose use for ATP generation. We hypothesized that cardiac accumulation of toxic lipid intermediates inhibits insulin signaling in advanced heart failure and that mechanical unloading of the failing myocardium corrects impaired cardiac metabolism. METHODS AND RESULTS: We analyzed the myocardium and serum of 61 patients with heart failure (body mass index, 26.5±5.1 kg/m(2); age, 51±12 years) obtained during left ventricular assist device implantation and at explantation (mean duration, 185±156 days) and from 9 control subjects. Systemic insulin resistance in heart failure was accompanied by decreased myocardial triglyceride and overall fatty acid content but increased toxic lipid intermediates, diacylglycerol, and ceramide. Increased membrane localization of protein kinase C isoforms, inhibitors of insulin signaling, and decreased activity of insulin signaling molecules Akt and Foxo were detectable in heart failure compared with control subjects. Left ventricular assist device implantation improved whole-body insulin resistance (homeostatic model of analysis-insulin resistance, 4.5±0.6-3.2±0.5; P<0.05) and decreased myocardial levels of diacylglycerol and ceramide, whereas triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/phosphatidylinositol-3 kinase/Akt signaling cascade after left ventricular assist device implantation was confirmed by increased phosphorylation of Akt and Foxo, which was accompanied by decreased membrane localization of protein kinase C isoforms after left ventricular assist device implantation. CONCLUSIONS: Mechanical unloading after left ventricular assist device implantation corrects systemic and local metabolic derangements in advanced heart failure, leading to reduced myocardial levels of toxic lipid intermediates and improved cardiac insulin signaling.

Post-mastectomy radiation therapy: translating local benefits into improved survival.

Several randomized trials and the most recent meta-analysis from the Oxford Overview have confirmed the efficacy of post-mastectomy radiation therapy (PMRT) in improving local control and long-term survival. The survival advantage of PMRT has been established in patients with a 10% risk of local regional recurrence. Patients with four or more positive lymph nodes fall in this category, even with effective systemic therapy. However, it remains difficult to identify the subset of patients with 1-3 positive lymph nodes at highest risk of local recurrence, who would most likely demonstrate a survival benefit with PMRT. When PMRT is used, careful treatment planning, particularly with regard to cardiac dose, is critical to minimizing serious late effects of treatment. Further developments in pathologic stratification of these patients, guided by expression profiles or novel biologic markers, are required to enable individualized assessment of long-term therapeutic risks and benefits.

Influence of follow-up bias on PSA failure after external beam radiotherapy for localized prostate cancer: results from a 10-year cohort analysis.

PURPOSE: To estimate the biases inherent in prostate cancer outcome that arise from different failure end points and variations in follow-up time and intensity using a cohort of men with long follow-up. METHODS AND MATERIALS: The study cohort consisted of 205 men with T1-T2N0-Nx prostate cancer treated with conventional radiotherapy between 1991 and 1993. The median follow-up was 103 months. Outcome was assessed using different definitions of biochemical failure, including the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria and the "nadir plus two" criteria (any rise of 2 ng/mL greater than the current nadir). Patient subgroups were created according to where patients had received their last 2 years of follow-up. Patients were also stratified according to whether they were initially present in the departmental database (under regular surveillance) or were uncovered after more vigorous investigation (previously "lost to follow-up"). RESULTS: In this series with maximized follow-up, the 10-year biochemical disease-free survival rate did not change significantly with varying definitions of failure, 49% and 45% for ASTRO and "nadir plus two" criteria, respectively. Patients followed by outside physicians (n = 99) were faring better at 10 years than those followed at the treating institution by either their radiation oncologist (n = 50) or their medical oncologist or urologist (n = 52). This was by all measures of outcome, including overall survival, and metastasis-free survival. Patients previously lost to follow-up (n = 43) who were tracked down also appeared to be doing better than those on our database for whom information had been readily available (n = 161). This, however, may have been an artifact of the ASTRO criteria, which underestimates failure when insufficient prostate-specific antigen values are available. CONCLUSION: The ASTRO definition of failure underestimates late failure. This bias may be compensated for by the use of cohorts with long follow-up or the use of the "nadir plus two" definition of failure. The use of institutional prostate cancer databases may overestimate failure rates because patients followed outside of the treating institution fared better with respect to both survival and biochemical recurrence. Vigorous attempts to obtain follow-up beyond the hospital walls may correct this bias.

Informed consent and the process of cadaver donation.

CONTEXT: Informed consent entails more than signing a document. Ideally, it should involve a process in which individuals are given sufficient information to make a voluntary decision. Little is known about the process of informed consent for cadaver donation. OBJECTIVE: To assess existing consent procedures for cadaver donation in a sample of US medical schools. DESIGN: Cross-sectional survey and content analysis of informational brochures and consent forms given to potential cadaver donors. SETTING AND PARTICIPANTS: The 22 largest medical schools in the United States, as ranked by the number of medical students in the Association of American Medical Colleges Institutional Profile System Annual Report 1995-1996. MAIN OUTCOME MEASURES: Description of dissection procedure, information provided about dissection, and the process for obtaining consent. RESULTS: Of the 22 schools studied, 18 schools (82%) mentioned the altruistic nature of cadaver donation. Twenty-one schools (96%) specified that bodies would be used to teach students, and 16 schools (73%) specified that bodies would be used for research. One school (4%) noted that organs could be permanently preserved for teaching purposes. Only 2 schools (9%) provided any description of the dissection procedures to be performed on the cadavers. Seven schools (32%) used the term dissect at least once. None of the schools offered to provide a complete account of the dissection procedure. CONCLUSIONS: The existing consent procedures for cadaver donations at US medical schools do not provide sufficient information to potential donors to constitute a fully informed consent.

Incidence of second malignancies among patients treated with proton versus photon radiation.

PURPOSE: Proton radiation, when compared with photon radiation, allows delivery of increased radiation dose to the tumor while decreasing dose to adjacent critical structures. Given the recent expansion of proton facilities in the United States, the long-term sequelae of proton therapy should be carefully assessed. The objective of this study was to compare the incidence of second cancers in patients treated with proton radiation with a population-based cohort of matched patients treated with photon radiation. METHODS AND MATERIALS: We performed a retrospective cohort study of 558 patients treated with proton radiation from 1973 to 2001 at the Harvard Cyclotron in Cambridge, MA and 558 matched patients treated with photon therapy in the Surveillance, Epidemiology, and End Results (SEER) Program cancer registry. Patients were matched by age at radiation treatment, sex, year of treatment, cancer histology, and site. The main outcome measure was the incidence of second malignancies after radiation. RESULTS: We matched 558 proton patients with 558 photon patients from the Surveillance, Epidemiology, and End Results registry. The median duration of follow-up was 6.7 years (interquartile range, 7.4) and 6.0 years (interquartile range, 9.3) in the proton and photon cohorts, respectively. The median age at treatment was 59 years in each cohort. Second malignancies occurred in 29 proton patients (5.2%) and 42 photon patients (7.5%). After we adjusted for sex, age at treatment, primary site, and year of diagnosis, proton therapy was not associated with an increased risk of second malignancy (adjusted hazard ratio, 0.52 [95% confidence interval, 0.32-0.85]; P=.009). CONCLUSIONS: The use of proton radiation therapy was not associated with a significantly increased risk of secondary malignancies compared with photon therapy. Longer follow-up of these patients is needed to determine if there is a significant decrease in second malignancies. Given the limitations of the study, these results should be viewed as hypothesis generating.

Time to prostate-specific antigen nadir after androgen suppression therapy for postoperative or postradiation PSA failure and risk of prostate cancer-specific mortality.

OBJECTIVES: To examine whether the time to the prostate-specific antigen (PSA) nadir was associated with prostate cancer-specific mortality (PCSM) in men with PSA failure after radical prostatectomy or radiotherapy who do not achieve an undetectable PSA level (PSA level of 0.2 ng/mL or less) after 8 months of androgen suppression therapy (AST). METHODS: The cohort included 162 men with localized prostate cancer treated with AST for an increasing PSA level after radical prostatectomy or radiotherapy. Gray's analysis was used to evaluate for an association between the time to PSA nadir after 8 months of AST and the time to PCSM, adjusting for established prognostic factors. The median age and follow-up after 8 months of AST was 71.2 and 1.8 years, respectively. RESULTS: After adjusting for Gleason score, pre-AST PSA doubling time, PSA at AST, PSA nadir value, time to PSA failure, initial treatment, and age, the time to PSA nadir was significantly associated with PCSM (adjusted hazard ratio 2.53, 95% confidence interval 1.24 to 5.14, P = 0.01). Men with a PSA nadir greater than the median value of 0.9 ng/mL and the time to PSA nadir longer than the median of 4 months had significantly greater PCSM estimates (P <0.001) compared with men with a PSA nadir of 0.9 ng/mL or less. CONCLUSIONS: The time to PSA nadir, combined with the PSA nadir level, can be used to identify men who are at high risk of PCSM after a short course of AST for entry onto clinical trials using novel systemic agents with AST.