Citations

Background— The relationship between neutrophils and outcomes post–myocardial infarction (MI) is not completely characterized. We examined the associations of neutrophil count with mortality and post-MI heart failure (HF) and their incremental value for risk discrimination in the community. Methods and Results— MI was diagnosed with cardiac pain, biomarkers, and Minnesota coding of the ECG. Neutrophil count at presentation, reported as counts ×10 9 /L, was categorized by tertiles (lower tertile, <5.7; middle tertile, 5.7 to 8.5; upper tertile, >8.5). From 1979 to 2002, 2047 incident MIs occurred in Olmsted County, Minn (mean age, 68±14 years; 44% women). Median (25th to 75th percentile) neutrophil count was 7.0 (5.1 to 9.5). Within 3 years post-MI, 577 patients died, and 770 developed HF. Overall survival and survival free of HF decreased with increased neutrophil tertile ( P <0.001). Compared with the lower tertile, the age and sex adjusted hazard ratio for death was 1.44 (95% CI, 1.14 to 1.81) for the middle tertile and 2.60 (95% CI, 2.10 to 3.22) for the upper tertile ( P <0.001). Similarly, for HF, the hazard ratio was 1.32 (95% CI, 1.09 to 1.59) for the middle and 2.12 (95% CI, 1.77 to 2.53) for the upper tertile ( P <0.001). These associations persisted after adjustment for risk factors, comorbidities, Killip class, revascularization, and ejection fraction. Neutrophil count improved risk discrimination as indicated by increases in the area under the receiver operating characteristic curves (all P <0.05) and by the integrated discrimination improvement analysis (all P <0.001). Conclusions— In the community, the neutrophil count was strongly and independently associated with death and HF post-MI and improved risk discrimination over traditional predictors.

Background— There have been significant bidirectional changes in the prevalence of cardiovascular (CV) risk factors over time in the United States, making the net trend in risk for incident CV disease unknown. We assessed these trends by applying the Framingham Heart Study prediction model to national data. Methods and Results— The National Health and Nutrition Examination Survey (NHANES) II (1976–1980), NHANES III (1988–1994), and NHANES 1999–2004 are cross-sectional representative samples of the noninstitutionalized population of the United States. We excluded people with a history of CV disease, pregnant women, participants with missing CV risk factors data, and individuals outside the Framingham age range of 30 to 74 years. The Framingham risk function was used to estimate the 10-year risk for incident symptomatic CV disease. We calculated the slope of change or rate of change per year between NHANES II and III, and between NHANES III and 1999–2004. The difference between slopes was calculated and compared to zero. The average age-adjusted 10-year CV risk between NHANES II and III decreased from 10.0% to 7.9% between NHANES II and III, with a statistically significant slope ( P <0.001). However, the average age-adjusted CV risk decreased at a lesser magnitude between NHANES III and NHANES 1999–2004 from 7.9% to 7.4% ( P <0.001). These slopes were significantly different ( P <0.0001). In women and middle-aged participants, CV risk did not change between NHANES III and NHANES 1999–2004 ( P =0.40). Conclusions— The estimated net risk for CV disease in the US population decreased from 1976–1980 to 1988–1994 but has changed minimally from 1988–1994 to 1999–2004, particularly in women and middle-aged people.

Abstract Purpose: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need. Experimental Design: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials. Results: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2. Conclusions: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics. (Clin Cancer Res 2009;15(16):5032–9)

Background— Mortality among patients with heart failure is high. Though individual biomarkers have been investigated to determine their value in mortality risk prediction, the role of a multimarker strategy requires further evaluation. Methods and Results— Olmsted County residents presenting with heart failure from July 2004 to September 2007 were recruited to undergo biomarker measurement. We investigated whether addition of C-reactive protein, B-type natriuretic peptide, and troponin T to a model including established risk indicators improved 1-year mortality risk prediction using the c statistic, integrated discrimination improvement, and net reclassification improvement. Among 593 participants, the mean age was 76.4 years, and 48% were men. After 1 year of follow-up, 122 (20.6%) participants had died. Patients with C-reactive protein (<11.8 mg/L), B-type natriuretic peptide (<350 pg/mL), and troponin T (≤0.01 ng/mL) less than the median had low 1-year mortality (3.3%), whereas those with 2 or 3 biomarkers greater than the median had markedly increased mortality (30.8% and 35.5%, respectively). The addition of 2 or more biomarkers to the model offered greater improvement in 1-year mortality risk prediction than use of a single biomarker. The combination of C-reactive protein and B-type natriuretic peptide resulted in an increase in the c statistic from 0.757 to 0.810 ( P <0.001), an integrated discrimination improvement gain of 7.1% ( P <0.001), and a net reclassification improvement of 22.1% ( P <0.001). Use of all 3 biomarkers offered no incremental gain (integrated discrimination improvement gain 0.7% versus C-reactive protein+B-type natriuretic peptide, P =0.065). Conclusions— Biomarkers improved 1-year mortality risk prediction beyond established indicators. The use of a 2-biomarker combination was superior to a single biomarker in risk prediction, though addition of a third biomarker conferred no added benefit.

Abstract Data on long-term follow-up for definitive therapy of prostate cancer are limited, especially for radiation therapy. Either surgery or radiation was used in 322 patients for treatment with curative intent, and follow-up was for a minimum of 15 years. Overall survival was nearly identical to that in an age-matched cohort. 5-, 10-, and 15-year recurrence-free survival rates were 77%, 63% and 53%, respectively. Grade and stage were significant prognostic factors for both recurrence and survival. More than 60% of the initial failures were local, and more than 25% of the failures occurred after 10 years. Radiation therapy was used in 137 patients with clinically staged disease. Radical retropubic prostatectomy and perineal prostatectomy were performed in 133 and 44 patients, respectively. In this group, pathological staging was used. Survival rates for surgically treated patients were better than those in the cohort population. In conclusion, overall long-term follow-up demonstrates that definitive treatment does not have an adverse effect on survival from prostate cancer. Local recurrence is a frequent cause of failure. Caution must be used in interpreting any prostate study with less than 10 years of follow-up, because 25% to 50% of the failures occur after that time.

Abstract Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]

Abstract Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610–6)

Abstract Background. The anticancer multikinase inhibitors (MKIs) are associated with cutaneous adverse events, including hand–foot skin reaction (HFSR), a condition affecting 20%–40% of patients. Symptoms are usually mild, but can evolve into a painful condition that limits function and impacts quality of life (QoL), resulting in shortened cancer treatment duration or intensity. The goal of this study was to systematically review the literature on the prevention and palliation of MKI-associated HFSR, to identify areas for further clinical study, and to provide a foundation for evidence-based guidelines for HFSR management. Methods. Systematic searches of the National Library of Medicine’s PubMed database, Cochrane Reviews, BIOSIS, CancerLit, and the American Society of Clinical Oncology website were conducted using search terms for cutaneous toxicities associated with chemotherapeutic agents. Articles were categorized (C) based on type of agent and cutaneous reaction as: C1 (MKI and HFSR); C2 (MKI and other cutaneous toxicity); C3 (other antineoplastic agents and HFSR); and C4, other. Results. Of the 2,069 abstracts screened, 350 (17%) met the criteria for C1–C4, with 56 (16%) coded as C1 with details of HFSR histology, pathogenesis, clinical outcome, QoL impact, and/or prevention and treatment approaches in MKI-treated patients. No randomized, controlled trials (RCTs) on prevention/palliation of HFSR were identified. Anecdotal evidence or expert opinion advocated protective measures, preventive and therapeutic skin care, systemic analgesics for pain, vitamin B6, and MKI dose modification. Conclusion. No articles containing evidence from RCTs on preventive/palliative approaches to MKI-associated HFSR have been published. Systematic study of optimal treatment strategies for HFSR is needed to advance development of evidence-based treatment guidelines.