Citations

Abstract Background: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made. Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 20(8); 1690–702. ©2011 AACR.

Object Neuromuscular choristoma (NMC) is a rare peripheral nerve lesion in which mature skeletal muscle fibers lie within the nerve and its fascicles. Given limited follow-up, its natural history is poorly understood. The occurrence of aggressive fibromatosis in one of the authors' patients and its occurrence in reported cases suggests an etiological relationship between the 2 lesions. This study attempts to explain the association and its frequency. Methods All cases of NMCs seen in consultation or treated at the Mayo Clinic were identified. Demographic and clinical data were reviewed in cases with coexistent aggressive fibromatosis. Pathology and neuroimaging studies were reexamined. In addition, an extensive literature review was performed to explore the association of NMC with aggressive fibromatosis, with special attention given to pathological and imaging characteristics and the development of aggressive fibromatosis. Results The authors identified 10 patients with a diagnosis of NMC who were treated at the Mayo Clinic between 1992 and 2010. Four of 5 with adequate follow-up had developed a definite or suspected aggressive fibromatosis. A review of the initial pathological specimens in these cases revealed no evidence of fibromatosis, but all of the lesions exhibited accompanying hypocellular collagenous tissue. On MR images, all cases showed areas of low signal intensity, which significantly differed from muscle, nerve, and NMC components. On available serial MR imaging studies, aggressive fibromatosis seemed to originate in such lower-intensity regions. In the 18 previously reported cases of NMC, 5 patients developed recurrent masses diagnosed as either definite (2 cases) or possible (3 cases) fibromatosis. Review of the published imaging studies in these cases suggests the presence of lower intensity areas similar to those observed in the 10 patients treated at the Mayo Clinic. Conclusions This study confirms that the development of aggressive fibromatosis in patients with NMC has been underreported. A direct relationship between the NMC and the development of aggressive fibromatosis is suggested by pathological and neuroimaging evidence.

AbstractFree light chains (FLCs) are the most commonly detected paraproteins in chronic lymphocytic leukemia (CLL). We examined the types of FLC abnormalities and prognostic utility of the FLC assay compared with standard prognostic biomarkers in a prospective cohort of 339 patients with newly diagnosed CLL. Three types of FLC abnormalities were identified: monoclonal elevated FLC (elevated κ and/or λ with abnormal FLC ratio), polyclonal elevated FLC (elevated κ and/or λ with normal FLC ratio), and ratio-only FLC abnormality (normal range κ and λ with abnormal FLC ratio). One hundred sixty-five patients (49%) had a FLC abnormality with approximately equal distribution among monoclonal elevation, polyclonal elevation, and ratio-only abnormality. All FLC abnormalities were associated with poor time to first treatment: monoclonal FLC (hazard ratio [HR], 4.99; 95% confidence interval [CI], 2.94-8.48), polyclonal FLC (HR, 2.40; 95% CI, 1.24-4.64), ratio-only FLC (HR, 2.57; 95% CI, 1.40-4.69). Monoclonal FLC and polyclonal FLC were associated with poor overall survival compared with patients with normal FLC. Results remained significant after adjusting for Rai stage. The FLC assay is a simple, widely available clinical test with similar prognostic utility as routinely used prognostic biomarkers for CLL. Among persons with FLC abnormalities, the type of abnormality affects prognostic significance.

Background— Data on the association between myocardial infarction (MI) and fractures are scarce. Recent changes in the epidemiology of MI justify exploring this relationship. We evaluated whether MI constitutes a risk factor for osteoporotic fracture and examined secular trends in this association. Methods and Results— Consecutive Olmsted County, Minnesota, residents with incident MI diagnosed in 1979 to 2006 and community control subjects individually matched (1:1) to cases on age, sex, and year of onset (n=6642) were followed up through 2009. Outcome measures were time to osteoporotic fracture, overall and by anatomic site, and death. Fracture incidence rates were stable in controls but increased markedly over time among MI cases. Accordingly, although an overall excess of fracture risk after MI was observed (adjusted hazard ratio, 1.32; 95% confidence interval, 1.12 to 1.56), substantial temporal variations were noted (1979 to 1989: hazard ratio, 0.81; 95% confidence interval, 0.58 to 1.12; 1990 to 1999: hazard ratio, 1.47; 95% confidence interval, 1.10 to 1.96; 2000 to 2006: hazard ratio, 1.73; 95% confidence interval, 1.32 to 2.27; P for trend <0.001). Trends were similar regardless of age, sex or fracture site. Conversely, the overall hazard ratio for death in MI cases versus controls did not change materially despite a continuous decline in 30-day case fatality rate (12.5% in 1979 to 1989; 6.7% in 2000 to 2006). Observed changes in the baseline prevalence of cardiovascular risk factors, MI characteristics, and comorbidities did not fully account for the trends in fracture risk. Conclusions— Over the past decades, the association between MI and osteoporotic fractures increased steadily. The trend is consistent with the displacement of post-MI outcomes toward noncardiovascular events, highlighting the need for comprehensive prevention strategies to accommodate the changing epidemiology of MI.

Abstract Purpose: p53 as a prognostic and predictive factor in early-stage breast cancer has had mixed results. We studied p53 protein expression, by immunohistochemistry, in a randomized clinical trial of stage II patients treated with adjuvant doxorubicin and cyclophosphamide with or without paclitaxel [Cancer and Leukemia Group B (CALGB) 9344, INT0148]. Patients and Methods: Epithelial p53 expression was evaluated using two immunohistochemical antibodies (DO7 and 1801) in formalin-fixed, paraffin-embedded tissue from patients with node-positive breast cancer who were randomized to four cycles of cyclophosphamide and one of three doses of doxorubicin (60, 75, or 90 mg/m2; AC) and to receive four subsequent cycles of paclitaxel (T) or not. Prognostic and predictive value of p53 protein expression was assessed, independent of treatment assignment, for escalating doses of doxorubicin or addition of T with endpoints of relapse-free (RFS) and overall survival (OS). Results: Of 3,121 patients, 1,887 patient specimens treated on C9344 were obtained, passed quality control, and evaluated for p53 expression. Expression was 23% and 27% for mAbs 1801 and D07, respectively, with 92% concordance. In univariate analysis, p53 positivity was associated with worse OS with either antibody, but only p53 staining with monoclonal antibody 1801 had significantly worse RFS. In multivariate analysis, p53 was not predictive of RFS or OS from either doxorubicin dose escalation or addition of paclitaxel regardless of the antibody. Conclusion: Nuclear staining of p53 by immunohistochemistry is associated with worse prognosis in node-positive patients treated with adjuvant doxorubicin-based chemotherapy but is not a useful predictor of benefit from doxorubicin dose escalation or the addition of paclitaxel. Clin Cancer Res; 17(15); 5170–8. ©2011 AACR.

Abstract In April 2010, a NIH workshop was convened to discuss the current state of understanding of lung cell plasticity, including the responses of epithelial cells to injury, with the objectives of summarizing what is known, what the field needs to know, and how to get there. The proximal stimulus for this workshop is the body of recent evidence suggesting that plasticity is a prominent but incompletely characterized property of lung epithelial cells, and that a focus on understanding this aspect of epithelial cell biology in particular, may be an important window into disease pathobiology and pathogenesis. In addition to their many vital functions in maintaining tissue homeostasis, epithelial cells have emerged as both a central target of disease initiation and an active contributor to disease progression, making a workshop to investigate the role of cell plasticity in lung injury and repair timely. The workshop was organized around four major themes: lung epithelial cell plasticity, signaling control of plasticity, fibroblast plasticity and crosstalk, and translation to human disease. Although this breakdown was recognized to be somewhat artificial, it was felt that this approach would promote cross-fertilization among groups that ordinarily do not communicate and lend itself to the generation of new approaches. The summary reports of individual group discussions below are followed by consensus priorities and recommendations of the workshop participants.