Importance Time to surgery (TTS) is of concern to patients and clinicians, but controversy surrounds its impact on breast cancer survival. There remains little national data evaluating the association. Objective To investigate the relationship between the time from diagnosis to breast cancer surgery and survival, using separate analyses of two of the largest cancer databases in the United States. Design Two independent population-based studies of prospectively-collected national data utilizing the Surveillance Epidemiology and End Results (SEER)-Medicare-linked database (SMDB), and the National Cancer Database (NCDB). Setting The SMDB cohort included Medicare patients >65 years of age, and the NCDB cohort included patients cared for at Commission on Cancer-accredited facilities throughout the United States. Each analysis assessed overall survival as a function of time between diagnosis and surgery by evaluating intervals encompassing ≤30, 31–60, 61–90, 91–120, and 121–180 days in length, and disease-specific survival at 60-day intervals. Participants All patients were diagnosed with noninflammatory, nonmetastatic, invasive breast cancer and underwent surgery as initial treatment. Main Outcomes and Measures Overall and disease-specific survival as a function of time between diagnosis and surgery, after adjusting for patient, demographic and tumor-related factors. Results The SMDB cohort had 94,544 patients ≥66 years old, diagnosed 1992 – 2009. With each interval delay increase, overall survival was lower overall (hazard ratio [HR] 1.09, p<0.001), and in stage I (HR 1.13, p<0.001) and II (HR 1.06, p=0.010) patients. Breast cancer-specific mortality increased with each 60-d interval (subhazard ratio [sHR] 1.26, p= 0.03). The NCDB study evaluated 115,790 patients ≥18 years old, diagnosed 2003 – 2005. The overall mortality HR was 1.10 (p<0.001) for each increasing interval, significant in stages I (HR 1.16, p<0.001) and II (1.09, p<0.001) only, adjusting for demographic, tumor and treatment factors. Conclusions and Relevance Greater TTS confers lower overall and disease-specific survival, and a shortened delay is associated with benefits comparable to some standard therapies. Although time is required for preoperative evaluation and consideration of some options such as reconstruction, efforts to reduce TTS should be pursued where possible to enhance survival.

Objective— The mechanism of neovascularization during the proliferative phase of infantile hemangioma is poorly understood. It is known that circulating bone marrow-derived endothelial progenitor cells (EPCs) form new blood vessels in ischemic tissues using mediators regulated by the transcription factor, HIF-1α. Mobilization of EPCs is enhanced by VEGF-A, matrix metalloproteinase (MMP)-9, and estrogen, whereas homing is secondary to localized expression of stromal cell-derived factor-1α (SDF-1α). We examined whether these mediators of EPC trafficking are upregulated during the proliferation of infantile hemangioma. Methods and Results— Surgical specimens and blood samples were obtained from children with proliferating hemangioma and age-matched controls (n=10, each group). VEGF-A and MMP-9 levels were measured in blood, and tissue sections were analyzed for SDF-1α, MMP-9, VEGF-A, and HIF-1α. The role of estrogen as a modulator of hemangioma endothelial cell growth was also investigated. We found that all these mediators of EPC trafficking are elevated in blood and specimens from children with proliferating infantile hemangioma. In vitro, the combination of hypoxia and estrogen demonstrated a synergistic effect on hemangioma endothelial cell proliferation. Conclusions— These findings demonstrate that proliferating hemangiomas express known mediators of vasculogenesis and suggest that this process may play a role in the initiation or progression of this disease.

Background-Advanced age is known to impair neovascularization. Because endothelial progenitor cells (EPCs) participate in this process, we examined the effects of aging on EPC recruitment and vascular incorporation. Methods and Results-Murine neovascularization was examined by use of an ischemic flap model, which demonstrated aged mice (19 to 24 months) had decreased EPC mobilization (percent mobilized 1.4Ϯ0.2% versus 0.4Ϯ0.1%, PϽ0.005) that resulted in impaired gross tissue survival compared with young mice (2 to 6 months). This decrease correlated with diminished tissue perfusion (PϽ0.005) and decreased CD31 ϩ vascular density (PϽ0.005). Gendermismatched bone marrow transplantation demonstrated significantly fewer chimeric vessels in aged mice (PϽ0.05), which confirmed a deficit in bone marrow-mediated vasculogenesis. Age had no effect on total EPC number in mice or humans. Reciprocal bone marrow transplantations confirmed that impaired neovascularization resulted from defects in the response of aged tissue to hypoxia and not from intrinsic defects in EPC function. We demonstrate that aging decreased hypoxia-inducible factor 1␣ stabilization in ischemic tissues because of increased prolyl hydroxylasemediated hydroxylation (PϽ0.05) and proteasomal degradation. This resulted in a diminished hypoxia response, including decreased stromal cell-derived factor 1 (PϽ0.005) and vascular endothelial growth factor (PϽ0.0004). This effect can be reversed with the iron chelator deferoxamine, which results in hypoxia-inducible factor 1␣ stabilization and increased tissue survival. Conclusions-Aging impairs EPC trafficking to sites of ischemia through a failure of aged tissues to normally activate the hypoxia-inducible factor 1␣-mediated hypoxia response.

Preoperative, patient-specific CT modeling, and cutting guide fabrication outweigh the costs associated with the additional technology without jeopardizing overall outcomes or increasing complication rates.