Purpose: Although alterations of concentrations in circulating steroids have been linked to single nucleotide polymorphisms (SNPs) of steroidogenic enzymes, we hypothesized that SNPs of such enzymes located within the breast affect local steroid concentrations more than products of such SNPs absorbed from the circulation. Methods: Steroids (estradiol, estrone, testosterone, androstenedione, DHEA, DHEA sulfate, progesterone) in nipple aspirate fluid (NAF) were purified by HPLC and they along with serum steroids were quantified by im-munoassays. Polymorphisms of the transporter SLCO2B1 and enzymes HSD3B1, CYP19A1, HSD17B12, AKR1C3, CYP1B1, and SRD5A1 were measured in white blood cell DNA. Results: Steroid concentrations in NAF of subjects with homozygous minor genotypes differed from those with heterozygotes, i.e., SLCO2B1 (rs2851069) decreased DHEAS (p = 0.04), HSD17B12 (rs11555762) increased estradiol (p < 0.004), and CYP1B1 (rs1056836) decreased estradiol (p = 0.017) and increased progesterone (p = 0.05). Also, in serum, CYP19A1 (rs10046 and rs700518) both decreased testosterone (p = 0.02) and SRD5A1 increased androstenedione (p = 0.006). Steroids in subjects with major homozygotes did not differ from those with heterozygotes indicating recessive characteristics. Conclusions: In the breast, SNPs were associated with decreased uptake of DHEAS (SLCO2B1), increased estradiol concentrations through increased oxidoreductase activity (HSD17B12), or decreased estradiol concentrations by presumed formation of 4-hydroxyestradiol (CYP1B1). CYP19A1 was associated with decreased testosterone concentrations in serum but had no significant effect on estrogen or androgen concentrations within the breast. The hormone differences observed in NAF were not usually evident in serum, indicating the importance of assessing the effect of these SNPs within the breast.

RESULTS: Mean faculty size was 76. Overall, there were 35.4% assistant, 27.2% associate, and 37.4% full professors. Women comprised 21.8%; 5.3% were MD-PhDs, and 6.3% were PhDs. By faculty rank, publications/citations were: assistant, 14/175; associate, 39/649; and full-professor, 97/2,250. General surgery contributed most publications and citations. Highest performing groups per person were: research (58/1,683); transplantation (52/ 1,067); oncology (51/1,179); and cardiothoracic surgery (48/ 860). Overall, 23.2% of faculty were principal investigators for current/former NIH grants, and 8.9% for a current or former R01/ U01/P01. The 10 most cited faculty (MCF) within each department contributed to 42% of all publications and 55% of all citations. The MCF were most commonly general (25%), oncologic (19%), or transplant surgeons (15%). Fifty-one percent of MCF had current/former NIH funding, compared with 20% of the rest (p<0.05); and funding rates for R01/U01/P01 grants were 25.1% vs 6.8% (p<0.05). Rate of current-NIH MCF funding correlated with higher total departmental NIH rank (p<0.05).

Abstract Introduction: Preoperative MRI of the breast is the most sensitive imaging modality in the detection of multifocal or multicentric breast cancer, as well as simultaneous contralateral breast cancer. The aim of this retrospective review was to evaluate the effect of preoperative MRI on local control for patients with breast cancer. Methods: The Enterprise Data Warehouse of Northwestern Medicine was searched for women who underwent breast conserving surgery for ductal carcinoma in situ (DCIS) or primary invasive breast cancer in the interval of 2004-2010. The use of preoperative MRI, and the clinical and therapeutic details of the patients thus identified were extracted by direct review of the electronic medical record. A breast event was defined as a local recurrence in the treated breast more than six months after completion of treatment (ipsilateral) or a new breast cancer in the untreated breast (contralateral). Differences in the frequency of all events (local and distant), for ipsilateral breast events, and for contralateral breast events was evaluated with Cox proportional hazards model, adjusting for patient age, tumor size, nodal status, the presence of triple negative disease, and the use of radiotherapy and systemic therapy. Results: In our cohort of 1097 patients, 526 had preoperative MRI and 571 had no MRI. The patients who had preoperative MRI were younger (59 vs. 66 years, p<0.0001), were more commonly premenopausal (37.8% vs. 27.3%, p=0.0004), were more likely to present with palpable tumors (34.8% vs. 26.6%, p=0.004), were more likely to have invasive lobular disease (16% vs. 11.6%), and less likely to have DCIS (16.5% vs. 29%, p=0.001 for differences in histologic pattern). Mean tumor size was equivalent in the two groups (17.5 and 17.3 mm), but nodes were more frequently positive in the MRI group (23.9% vs. 19.1%, p=0.045). Triple negative tumors were more frequent in the MRI group (14.1% vs. 7.5%, p=0.0003). Mean follow up was 51.5 months in the MRI group and 59.4 months in the no MRI (p<0.0001). The number of events was 49 in the MRI group and 68 in the no MRI group. The Cox hazard ratio (HR) for all events (adjusted for follow-up duration and factors described in the Methods) was equivalent between the two groups (HR 0.90, 95% CI 0.59-1.36, p=0.61). The HR for ipsilateral (HR 0.93, 95% CI 0.57-1.51, p=0.76) and contralateral events (HR 1.22, 95% CI 0.57-2.62, p=0.61) was equivalent between the two groups. Conclusions: In analyses adjusted for important prognostic features, the use of preoperative breast MRI was not associated with a reduced hazard of any breast cancer event, or of in-breast events (ipsilateral or contralateral). However, the MRI group had a more adverse tumor and patient profiles; a propensity score analysis will be performed, to further adjust for these differences. These findings add weight to the position that routine use of preoperative MRI for all breast cancer patients is not beneficial. Citation Format: Amanda L Amin, Irene B Helenowski, Thomas E Kmiecik, Shruti R Zaveri, Nora M Hansen, Kevin P Bethke, Seema A Khan. Effects of preoperative MRI on rate of ipsilateral and contralateral recurrence of breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-01-05.

Background:Postoperative venous thromboembolism (VTE) is important clinically, and VTE quality metrics are used in public reporting and pay-for-performance programs. However, current VTE outcome measures are not valid due to surveillance bias, and the Surgical Care Improvement Project (SCIP-VTE-2) process measure only requires prophylaxis within 24 hours of surgery. Objectives:We sought to (1) develop a novel measure of VTE prophylaxis that requires early ambulation, mechanical prophylaxis, and chemoprophylaxis throughout the hospitalization, and (2) compare hospital performance on the SCIP-VTE-2 process measure to this novel measure. Research Design:A new composite measure of ambulation, sequential compression device (SCD), and chemoprophylaxis component measures was developed. The ambulation component required daily ambulation, the SCD component required documentation of continuous use, and the chemoprophylaxis component required patient-appropriate and medication-appropriate dosing and administration. Requirements could also be met with component-specific exceptions. Surgical patients at an academic center from 2012 to 2013 were assessed for SCIP-VTE-2 and composite measure adherence. Results:Of 786 patients, 589 (74.9%) passed the ambulation measure, 494 (62.8%) passed the SCD measure, and 678 (86.3%) passed the chemoprophylaxis measure. A total of 268 (91.8%) SCD failures and 46 (42.6%) chemoprophylaxis failures were ordered but not administered. When comparing the 2 measures, 784 (99.7%) passed SCIP-VTE-2, whereas only 364 (46.3%) passed the composite measure (P<0.001). Conclusions:This new measure incorporates the critical aspects of VTE prevention to ensure defect-free care. After additional evaluation, this composite VTE prophylaxis measure with appropriate exclusion criteria may be a better alternative to existing VTE process and outcome measures.

IMPORTANCE Individualized risk prediction tools have an important role as decision aids for use by patients and surgeons before surgery. Patient-centered outcomes should be incorporated into such tools to widen their appeal and improve their usability.OBJECTIVE To develop a patient-centered outcome for the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator, a web-based, individualized risk prediction tool.DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study using data from the ACS NSQIP, a national clinical data registry. A total of 973 211 patients from July 2010 to June 2012, encompassing 392 hospitals, were used in this analysis.MAIN OUTCOMES AND MEASURES Risk of discharge to a postacute care setting.RESULTS The overall rate of discharge to postacute care was 8.8%. Significant predictors of discharge to postacute care included being 85 years or older (odds ratio [OR] = 9.17; 95% CI, 8.84-9.50), the presence of septic shock (OR = 2.43; 95% CI, 2.20-2.69) or ventilator dependence (OR = 2.81; 95% CI, 2.56-3.09) preoperatively, American Society of Anesthesiologists class of 4 or 5 (OR = 3.59; 95% CI, 3.46-3.71), and totally dependent functional status (OR = 2.27; 95% CI, 2.11-2.44). The final model predicted risk of discharge to postacute care with excellent accuracy (C statistic = 0.924) and calibration (Brier score = 0.05).CONCLUSIONS AND RELEVANCE Individualized risk of discharge to postacute care can be predicted with excellent accuracy. This outcome will be incorporated into the ACS NSQIP Surgical Risk Calculator.

551 Background: The National Quality Forum has endorsed the use of adjuvant chemotherapy in stage III colon cancer yet a substantial treatment gap exists in the United States. Our objective was to evaluate the contribution of postoperative complications on the use of adjuvant therapy after colectomy for cancer. Methods: Patients from the ACS NSQIP and the NCDB who underwent colon resection for cancer were linked (2006-2008) to create a novel dataset containing robust information on comorbidities, complications, and oncologic variables. The association of complications on adjuvant chemotherapy use was assessed using multivariable regression models. Results: From 140 hospitals, 2414 patients underwent resection for stage III colon adenocarcinoma (open colectomy: 64%, laparoscopic colectomy: 36%). Overall, 896 (37.1%) patients were not treated with adjuvant therapy, of which 116 (12.9%) had documented severe comorbidities or advanced age as the reason for no adjuvant therapy receipt. Of the remaining 780 patients, 202 (25.9%) had a potential complication that could account for not receiving adjuvant therapy: 33 perioperative deaths and 169 patients with ≥1 serious complications including organ space infection (n=32), wound dehiscence (n=12), respiratory failure (n=48), pneumonia (n=45), renal failure (n=22) and septic shock (n=38). The remaining 611 patients did not have a documented reason for not receiving adjuvant chemotherapy. Complications independently associated with decreased adjuvant therapy use were renal failure (OR 0.17, 95% CI 0.0-0.59), respiratory failure (OR 0.23, 95% CI 0.11-0.51) and pneumonia (OR 0.36, 95% CI 0.18-0.75). Organ space infection was not associated with decreased use of adjuvant therapy, but significantly increased time to treatment (69 vs. 45 days, P<0.05). Superficial SSI did not decrease adjuvant therapy use or delay treatment. Conclusions: Serious postoperative complications explained one quarter of the adjuvant chemotherapy treatment gap among stage III colon cancer patients and should be considered in quality assessment of colon cancer care. Judging provider performance on quality metrics is challenging without clinical data.

BACKGROUND: Accurately estimating surgical risks is critical for shared decision making and informed consent. The Centers for Medicare and Medicaid Services may soon put forth a measure requiring surgeons to provide patients with patient-specific, empirically derived estimates of postoperative complications. Our objectives were to develop a universal surgical risk estimation tool, to compare performance of the universal vs previous procedure-specific surgical risk calculators, and to allow surgeons to empirically adjust the estimates of risk.STUDY DESIGN: Using standardized clinical data from 393 ACS NSQIP hospitals, a web-based tool was developed to allow surgeons to easily enter 21 preoperative factors (demographics, comorbidities, procedure). Regression models were developed to predict 8 outcomes based on the preoperative risk factors. The universal model was compared with procedure-specific models. To incorporate surgeon input, a subjective surgeon adjustment score, allowing risk estimates to vary within the estimate's confidence interval, was introduced and tested with 80 surgeons using 10 case scenarios.RESULTS: Based on 1,414,006 patients encompassing 1,557 unique CPT codes, a universal surgical risk calculator model was developed that had excellent performance for mortality (c-statistic = 0.944; Brier score = 0.011 [where scores approaching 0 are better]), morbidity (c-statistic = 0.816, Brier score = 0.069), and 6 additional complications (c-statistics > 0.8). Predictions were similarly robust for the universal calculator vs procedure-specific calculators (eg, colorectal). Surgeons demonstrated considerable agreement on the case scenario scoring (80% to 100% agreement), suggesting reliable score assignment between surgeons.CONCLUSIONS: The ACS NSQIP surgical risk calculator is a decision-support tool based on reliable multi-institutional clinical data, which can be used to estimate the risks of most operations. The ACS NSQIP surgical risk calculator will allow clinicians and patients to make decisions using empirically derived, patient-specific postoperative risks. ((C) 2013 by the American College of Surgeons)

Background: Nipple aspiration fluid (NAF) use as a biosample is limited by the variable yield across studies. We investigated the endocrine determinants of yield in an ongoing breast cancer case–control study. Methods: One-hundred and eighteen women yielding ≥2 μL NAF and 120 non-yielders were included; serum hormones were measured; differences in median hormones were assessed using the Wilcoxon rank-sum test. ORs and 95% confidence intervals (95% CI) for yielder status relative to hormone levels were estimated using logistic regression, adjusting for parity and lactation, and, in premenopausal women, menstrual cycle phase (MCP). Results: Prolactin concentrations were higher in yielders than non-yielders (premenopausal: 7.6 and 2.5 ng/mL, P < 0.01; postmenopausal 5.3 and 2.2 ng/mL; P < 0.01). Among premenopausal-yielders, estradiol was lower (64.3 vs. 90.5 pg/mL, MCP-adjusted P = 0.02). In separate menopausal status and parity-adjusted models, significant case–control differences persisted in prolactin: case OR 1.93 (95% CI, 1.35–2.77), control OR 1.64 (95% CI, 1.17–2.29). Premenopausal control yielders had higher progesterone (OR, 1.70; 95% CI, 1.18–2.46) and sex-hormone binding-globulin (OR, 2.09; 95% CI, 1.08–4.05) than non-yielders. Among parous women, further adjustment for lactation suggested a stronger positive association of serum prolactin with yield in cases than controls. Conclusion: NAF-yielders show higher prolactin than non-yielders, regardless of menopause and parity; implications of this and other endocrine differences on NAF biomarkers of breast cancer risk deserve further study. Impact: NAF yield is associated with a distinct endocrine environment that must be considered in studies of NAF-based breast cancer risk markers. Cancer Epidemiol Biomarkers Prev; 22(12); 2277–84. ©2013 AACR.

1 Title: Hormonal determinants of nipple aspirate fluid yield among breast cancer cases and screening controls.

BACKGROUND:The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) generally has not collected cancer-specific variables. Because increasing numbers of studies are using ACS NSQIP data to study cancer surgery, the objectives of the current study were 1) to examine differences between existing ACS NSQIP variables and cancer registry variables, and 2) to determine whether the addition of cancer-specific variables improves modeling of short-term outcomes. METHODS:Data from patients in the ACS NSQIP and National Cancer Data Base (NCDB) who underwent colorectal resection for cancer were linked (2006-2008). By using regression methods, the relative importance of cancer staging and neoadjuvant therapy variables were assessed along with their effects on morbidity, serious morbidity, and mortality. RESULTS:From 146 hospitals, 11,405 patients were identified who underwent surgery for colorectal cancer (colon, 85%; rectum, 15%). The NCDB metastatic cancer variable and the ACS NSQIP disseminated cancer variables agreed marginally (Cohen kappa coefficient, 0.454). For mortality, only the ACS NSQIP disseminated cancer variable and the NCDB stage IV variable were identified as important predictors; whereas the variables stage I through III, tumor (T)-classification, and lymph node (N)-classification were not selected. Cancer stage variables were inconsistently important for serious morbidity (stage IV, T-classification), superficial surgical site infection (N-classification), venous thromboembolism (metastatic cancer), and pneumonia (T-classification). With respect to neoadjuvant therapy, ACS NSQIP and NCDB variables agreed moderately (kappa, 0.570) and predicted superficial surgical site infection, serious morbidity, and organ space surgical site infection. The model fit was similar regardless of the inclusion of stage and neoadjuvant therapy variables. CONCLUSIONS:Although advanced disease stage and neoadjuvant therapy variables were predictors of short-term outcomes, their inclusion did not improve the models.

585 Background: For patients undergoing surgery for cancer, it has been suggested that risk-adjustment with cancer-specific variables is needed when evaluating short-term outcomes. Our objectives were to assess the influence of cancer-related variables on postoperative complications and hospital quality comparisons. Methods: Patients from ACS NSQIP and NCDB who underwent colorectal resection for cancer were linked (2006-2008) to create a dataset containing robust information on comorbidities, complications, and oncologic variables. Three hierarchical models were developed predicting the NSQIP outcome 30-day mortality or any serious morbidity using variables from (1) NSQIP only, (2) NCDB only, and (3) a combined model using NSQIP and NCDB. Models were compared with fit statistics and hospital outlier agreement. Results: From 146 NSQIP hospitals, 11401 patients underwent a colorectal resection for cancer, of which, 1954 (17%) experienced a mortality or serious morbidity event. The first five variables selected in the NCDB-only model were Charlson comorbidity score, neoadjuvant therapy use, T stage, primary payer, and M stage (c-statistic, 0.64; AIC, 9886). The first five variables selected in the NSQIP-only model were ASA class, preop sepsis, albumin, surgical procedure, and COPD (c-statistic, 0.66; AIC, 9787). In the combined model, neoadjuvant therapy use was the only cancer-specific variable selected in the top five. The remaining variables were ASA class, preop sepsis, albumin, and wound class (c-statistic, 0.67; AIC, 9455). At the hospital-level, the NCDB-only model identified three high outliers (worse than expected) and one low outlier (better than expected). Both the NSQIP-only and combined models identified the same four high and two low outlying hospitals (kappa: 1.0), which agreed marginally with the NCDB-only model (kappa: 0.59). Conclusions: Addition of cancer-specific variables to NSQIP models slightly improved model fit; however, hospital outcome comparisons were identical. For patients with colorectal cancer undergoing resection, cancer-related factors have limited predictive ability for short-term outcomes and did not influence hospital quality comparisons.

71 Background: Nipple aspirate fluid (NAF) is an attractive biosample for the investigation of breast cancer risk factors. The reported NAF yield rate varies from 30% to 90% in various studies, raising questions about its value as a risk assessment and about the generalizability of data generated in NAF-yielders to non-yielders. To date, there is no data regarding the characteristics of breast cancers that arise in NAF-yielders and non-yielders. Methods: We examined breast cancer characteristics in NAF yielders and the non NAF yielders in an on-going case control study assessing the hormone concentrations of NAF in breast cancer cases and healthy screening controls. 299 women with recently diagnosed breast cancer were recruited from the Lynn Sage Breast Center. NAF collection was performed from the non cancer breast in the clinic, either before surgery or more than one week post-operatively. NAF yielders produced at least 2 ul of NAF. Each patient completed a detailed study questionnaire. Breast cancer characteristics were recorded on each participant. Results: Among 299 recruited patients 130 (40%) were non NAF yielders (group A) and 169 (60%) were NAF yielders (group B). The association of breast cancer risk factors was compared between them. There were no significant differences in the tumor characteristics. The tumor size, grade, number of positive lymph nodes, and fraction of hormone receptor positive, HER2 positive, and triple negative tumors was similar in NAF-yielders and non-yielders (smallest p value 0.295, for histology, ductal versus lobular). Among the major breast cancer risk factors, the only significant differences were that NAF yielders were younger than non-yielders (50.8 vs. 53.6 years, p < 0.0001) and were more likely to have a history of post-menopausal hormone use (27% among NAF yielders and 7% among non-yielders, p < 0.0001). Conclusions: Tumor characteristics of NAF-yielders and non-yielders are similar, suggesting that there is no qualitative difference between these two groups. The risk predictors developed in yielders can apply to non-yielders.

Abstract Objective: Determine whether differences in serum hormone concentrations explain the lack of NAF yield among women participating in a study of NAF hormone concentrations in breast cancer cases and screening controls. Methods: 80 NAF yielders (Y) and 80 non-yielders (NY) were randomly selected from women who had completed participation in an ongoing case-control study, equally divided by menopausal status and case-control status (only the contralateral breast was aspirated in cases). Average age of premenopausal women was 45.95 years and of postmenopausal women was 57.54 years. The percentage of African American and Caucasian subjects was similar among those who yielded NAF and those who did not. Serum was collected on the same day that nipple aspiration was attempted and the serum was assayed for estradiol, progesterone, and FSH by standard immunoassays. Hormonal concentrations were compared among 80 subjects who produced >2 microliters of NAF and 80 who did not. Wilcoxon tests were used to compare rank distributions of the values for yielders and non-yielders within each menopausal and case/control category. Results: Hormonal data were analyzed in quintiles with the following comparisons: premenopausal cases Y vs NY; postmenopausal cases Y vs NY; premenopausal controls N vs NY; postmenopausal controls N vs NY. Among premenopausal cases estradiol was significantly greater at the P = 0.0067 level among those who did not produce NAF. This remained significant after correction for multiple comparisons. The difference remained significant after combining cases and controls at the P = 0.021 level. The other comparisons were not significant. Analyses of progesterone and FSH yielded no significant differences. Discussion: The inhibition of breast fluid accumulation by estradiol is consistent with the effect of ovarian steroids on milk secretion observed after parturition. The observation that this effect was greater in cases is interesting and will be investigated further to ascertain whether other factors associated with breast cancer may play a role in the observed inhibition. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B33.

Bilimoria, Karl MD; Kmiecik, Thomas PhD; DaRosa, Debra PhD; Bell, Richard MD, FACS; Soper, Nathaniel MD, FACS; Wayne, Jeffrey MD, FACS Author Information

Previous studies have shown that carboxyl-terminal mutation of pp60C-srC can activate its transforming ability. Conflicting results have been reported for the transforming ability of pp6Oc-sr mutants having only mutations outside its carboxyl-terminal region. To clarify the effects of such mutations, we tested the activities of chimeric v(amino)and c(carboxyl)-src (v/c-src) proteins at different dosages in NIH 3T3 cells. The focus-forming activity of Rous sarcoma virus long terminal repeat (LTR)-src expression plasmids was significantly reduced when the v-src 3' coding region was replaced with the corresponding c-src region. This difference was masked when the Rous sarcoma virus LTR was replaced with the Moloney murine leukemia virus LTR, which induced approximately 20-fold more protein expression, but even focus-selected lines expressing v/c-src proteins were unable to form large colonies in soft agarose or tumors in NFS mice. This suggests that pp60(csrc is not equally sensitive to mutations in its different domains and that there are at least two distinguishable levels of regulation, the dominant one being associated with its carboxyl terminus. vlc-src chimeric proteins expressed with either LTR had high in vitro specific kinase activity equal to that of pp6Ov-s' but, in contrast, were phosphorylated at both Tyr-527 and Tyr-416. Total cell protein phosphotyrosine was enhanced in cells incompletely transformed by v/c-src proteins to the same extent as in v-src-transformed cells, suggesting that the carboxyl-terminal region may affect substrate specificity in a manner that is important for transformation.

To develop a rapid preclinical in vivo model to study gene transfer into human hematopoietic progenitor cells, MO-7e cells (CD-34+, c-kit+) were infected with multidrug resistance (MDR1)-containing retroviruses and then transplanted into nonobese diabetic severe combined immunodeficient mice (NOD SCID). MO-7e cells infected with a retrovirus encoding the human MDR1 cDNA showed integration, transcription, and expression of the transfered MDR1 gene. This resulted in a 20-fold increase in the resistance of MO-7e cells to paclitaxel in vitro. The expression of the MDR1 gene product was stable over a 6-month period in vitro without selection in colchicine. MO-7e and MDR1-infected MO-7e cells were transplanted into NOD SCID mice to determine whether MDR1 could confer drug resistance in vivo. A sensitive polymerase chain reaction method specific for human sequences was developed to quantitate the level of human cell engraftment in NOD SCID bone marrow (BM) cells. The percentage of human DNA in BM cells from MO-7e- transplanted mice was 10.9% and decreased to 0.7% in mice treated with paclitaxel. The percentage of human DNA in infected-MO-7e transplanted mice was 7.6% and that level was unchanged in mice treated with paclitaxel. These results show that expression of the MDR1 gene in human hematopoietic progenitor cells can confer functional drug resistance in an in vivo model.