Citations

Purpose Recent changes have occurred in the presurgical planning for breast cancer, including the introduction of preoperative breast magnetic resonance imaging (MRI). We sought to analyze the trends in mastectomy rates and the relationship to preoperative MRI and surgical year at Mayo Clinic, Rochester, MN. Patients and Methods We identified 5,405 patients who underwent surgery between 1997 and 2006. Patients undergoing MRI were identified from a prospective database. Trends in mastectomy rate and the association of MRI with surgery type were analyzed. Multiple logistic regression was used to assess the effect of surgery year and MRI on surgery type, while adjusting for potential confounding variables. Results Mastectomy rates differed significantly across time (P < .0001), and decreased from 45% in 1997% to 31% in 2003, followed by increasing rates for 2004 to 2006. The use of MRI increased from 10% in 2003% to 23% in 2006 (P < .0001). Patients with MRI were more likely to undergo mastectomy than those without MRI (54% v 36%; P < .0001). However, mastectomy rates increased from 2004 to 2006 predominantly among patients without MRI (29% in 2003% to 41% in 2006; P < .0001). In a multivariable model, both MRI (odds ratio [OR], 1.7; P < .0001) and surgical year (compared to 2003 OR: 1.4 for 2004, 1.8 for 2005, and 1.7 for 2006; P < .0001) were independent predictors of mastectomy. Conclusion After a steady decline, mastectomy rates have increased in recent years with both surgery year and MRI as significant predictors for type of surgery. Further studies are needed to evaluate the role of MRI and other factors influencing surgical planning.

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 Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that inhibit T-cell activity and contribute to the immune suppression characteristic of most tumors. We discovered that bone marrow (BM) progenitor cells from the Muc1 knockout (KO) mice differentiated into CD11b+Gr1+ MDSCs in vitro under granulocyte macrophage colony-stimulating factor and interleukin-4 signaling. MUC1 is a tumor-associated mucin and its cytoplasmic tail (MUC1-CT) can regulate β-catenin to promote oncogenesis. Given the importance of β-catenin in hematopoiesis, we hypothesized that the MUC1 regulation of β-catenin is important for MDSC development. Our current study shows that the aberrant development of BM progenitors into CD11b+Gr1+ MDSCs is dependent on the down-regulation of β-catenin levels that occurs in the absence of Muc1. In light of this, KO mice showed enhanced EL4 tumor growth and were able to better tolerate allogeneic BM185 tumor growth, with an accumulation of CD11b+Gr1+ cells in the blood and tumor-draining lymph nodes. WT mice were able to similarly tolerate allogeneic tumor growth when they were injected with CD11b+Gr1+ cells from tumor-bearing KO mice, suggesting that tolerance of allogeneic tumors is dependent on MDSC-mediated immune suppression. This further delineates the ability of Muc1 to control MDSC development, which could directly affect tumorigenesis. Knowledge of the biology by which Muc1 regulates the development of myeloid progenitors into MDSCs would also be very useful in enhancing the efficacy of cancer vaccines in the face of tumor immune suppression. [Cancer Res 2009;69(8):3554–62]

Purpose An accurate estimate of a woman's breast cancer risk is essential for optimal patient counseling and management. Women with biopsy-confirmed atypical hyperplasia of the breast (atypia) are at high risk for breast cancer. The Gail model is widely used in these women, but has not been validated in them. Patients and Methods Women with atypia were identified from the Mayo Benign Breast Disease (BBD) cohort (1967 to 1991). Their risk factors for breast cancer were obtained, and the Gail model was used to predict 5-year–and follow-up–specific risks for each woman. The predicted and observed numbers of breast cancers were compared, and the concordance between individual risk levels and outcomes was computed. Results Of the 9,376 women in the BBD cohort, 331 women had atypia (3.5%). At a mean follow-up of 13.7 years, 58 of 331 (17.5%) patients had developed invasive breast cancer, 1.66 times more than the 34.9 predicted by the Gail model (95% CI, 1.29 to 2.15; P < .001). For individual women, the concordance between predicted and observed outcomes was low, with a concordance statistic of 0.50 (95% CI, 0.44 to 0.55). Conclusion The Gail model significantly underestimates the risk of breast cancer in women with atypia. Its ability to discriminate women with atypia into those who did and did not develop breast cancer is limited. Health care professionals should be cautious when using the Gail model to counsel individual patients with atypia.

Context: Obesity attenuates spontaneous GH secretion and the GH response to exercise. Obese individuals often have low fitness levels, limiting their ability to complete a typical 30-min bout of continuous exercise. An alternative regimen in obese subjects may be shorter bouts of exercise interspersed throughout the day. Objective: The objective of the study was to examine whether intermittent and continuous exercise interventions evoke similar patterns of 24-h GH secretion and whether responses are attenuated in obese subjects or affected by gender. Design: This was a repeated-measures design in which each subject served as their own control. Setting: This study was conducted at the University of Virginia General Clinical Research Center. Subjects: Subjects were healthy nonobese (n = 15) and obese (n = 14) young adults. Interventions: Subjects were studied over 24 h at the General Clinical Research Center on three occasions: control, one 30-min bout of exercise, and three 10-min bouts of exercise. Main Outcome Measures: Twenty-four hour GH secretion was measured. Results: Compared with unstimulated 24-h GH secretion, both intermittent and continuous exercise, at constant exercise intensity, resulted in severalfold elevation of 24-h integrated serum GH concentrations in young adults. Basal and pulsatile modes of GH secretion were attenuated both at rest and during exercise in obese subjects. Conclusions: The present data suggest that continuous and intermittent exercise training should be comparably effective in increasing 24-h GH secretion.

Background and Purpose— Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The c ombined approach to l ysis utilizing e ptifibatide a nd r ecombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination. Methods— The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke–funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 μg/kg bolus followed by 0.75 μg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy. Results— Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 ( P =0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 ( P =0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA–only arm ( P =0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group. Conclusions— The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.

Background and PurposeEarly physical functional changes after gastric bypass surgery (GBS) are unclear, and the relationship between these changes and health-related quality of life (HR-QOL) has not been reported. We measured distances from a 6-minute walk test (6MWT) and scores on the 36-Item Short-Form Health Survey (SF-36) before and after GBS.Subjects and MethodsTwenty-five people undergoing GBS completed the SF-36 and 6MWT presurgically and at the 3-month and 6-month follow-up visits. Ratings of perceived exertion (RPE) were measured during 6MWTs.ResultsPresurgical walking distance (X̅±SD; 414.1±103.7 m) was 55%±14% of normative values. Distances increased significantly at 3 months (505.2±98.0 m) and at 6 months (551.5±101.2 m). Final RPEs decreased significantly, and HR-QOL improved significantly. Both physical and mental health components of the SF-36 improved significantly. Distance was inversely correlated with body mass throughout the study and positively correlated with the SF-36 Physical Component Summary change from 3 to 6 months.Discussion and ConclusionsImproved functional capacity was associated with enhanced HR-QOL. At 6 months, walking distances remained 75% of those for age-matched peers who had normal weight.

Questions remain as to whether pediatric sleep disordered breathing increases the risk for elevated blood pressure and blood pressure–dependent cardiac remodeling. We tested the hypothesis that activity-adjusted morning blood pressure surge, blood pressure load, and diurnal and nocturnal blood pressure are significantly higher in children with sleep disordered breathing than in healthy controls and that these blood pressure parameters relate to left ventricular remodeling. 24-hour ambulatory blood pressure parameters were compared between groups. The associations between blood pressure and left ventricular relative wall thickness and mass were measured. 140 children met the inclusion criteria. In children with apnea hypopnea index <5 per hour, a significant difference from controls was the morning blood surge. Significant increases in blood pressure surge, blood pressure load, and in 24-hour ambulatory blood pressure were evident in those whom the apnea hypopnea index exceeded 5 per hour. Sleep disordered breathing and body mass index had similar effect on blood pressure parameters except for nocturnal diastolic blood pressure, where sleep disordered breathing had a significantly greater effect than body mass index. Diurnal and nocturnal systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure predicted the changes in left ventricular relative wall thickness. Therefore, sleep disordered breathing in children who are otherwise healthy is independently associated with an increase in morning blood pressure surge, blood pressure load, and 24-hour ambulatory blood pressure. The association between left ventricular remodeling and 24-hour blood pressure highlights the role of sleep disordered breathing in increasing cardiovascular morbidity.

Learning Objectives After completing this course, the reader will be able to: Discuss the role of radiation therapy in the adjuvant treatment of DCIS.Describe the impact of tamoxifen in the treatment of DCIS.Discuss evolving strategies in neoadjuvant treatment for DCIS. Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com