The aim of the study was to compare costs associated with excision of routine cavity shave margins (CSM) versus standard partial mastectomy (PM) in patients with breast cancer.Excision of CSM reduces re-excision rates by more than 50%. The economic implications of this is, however, unclear.Between October 21, 2011 and November 25, 2013, 235 women undergoing PM for Stage 0-III breast cancer were randomized to undergo either standard PM ("no shave", n = 116) or have additional CSM taken ("shave", n = 119). Costs from both a payer and a hospital perspective were measured for index surgery and breast cancer surgery-related care through subsequent 90 days.The 2 groups were well-matched in terms of baseline characteristics. Those in the "shave" group had a longer operative time at the initial surgery (median 76 vs 66 min, P < 0.01), but a lower re-excision rate for positive margins (13/119 = 10.9% vs 32/116 = 27.6%, P < 0.01). Actual direct hospital costs associated with operating room time ($1315 vs. $1137, P = 0.03) and pathology costs ($1195 vs $795, P < 0.01) were greater for the initial surgery in patients in the "shave" group. Taking into account the index surgery and the subsequent 90 days, there was no significant difference in cost from either the payer ($10,476 vs $11,219, P = 0.40) or hospital perspective ($5090 vs $5116, P = 0.37) between the "shave" and "no shave" groups.Overall costs were not significantly different between the "shave" and "no shave" groups due to significantly fewer reoperative surgeries in the former.
e13541 Background: Recent evidence suggests that black cohosh (Cimicifuga racemosa) may prevent and treat breast cancer through anti-proliferative, pro-apoptotic, anti-estrogenic, and anti-inflammatory effects. We sought to determine the efficacy of black cohosh (BC) as a potential chemoprevention agent by evaluating its ability to decrease the cell proliferation biomarker Ki67 in a pre-operative window trial of ductal carcinoma in situ (DCIS) patients. Methods: Patients were treated pre-operatively with commercial standardized isopropanolic black cohosh extract (20 mg orally twice daily) for 2-5 weeks. Ki67 in DCIS regions was measured using automated quantitative immunofluorescence (AQUA) pre- and post-operatively. A sample size of 22 patients, assuming a 10% drop-out rate, was estimated to achieve 91% power to detect a 0.8 standard deviation of difference with a two-sided significance level at 0.05 using Wilcoxon signed-rank test. Eligible subjects were women newly diagnosed with DCIS on core biopsy, prior to definitive excision (NCT01628536). Results: Of 32 patients enrolled, 24 patients were available for Ki67 analysis; 5 patients’ samples were unevaluable by AQUA and 3 patients lacked DCIS post-treatment. Mean duration of BC therapy was 23 days (range; 13-35 days). Among evaluable patients, we found no significant change in Ki67 values in areas of DCIS with pre-operative exposure to BC (Z = -.9714, p = .33), though a downward trend was observed. Eleven of the 32 patients (34%) were found to have invasive disease at the time of surgery, nine of whom had grade 2-3 DCIS at biopsy; these observations are similar to expected DCIS upgrade rates published in the literature. BC was well tolerated; no related adverse events were above grade 1. Conclusions: Pre-operative exposure to BC did not significantly decrease Ki67 in patients with DCIS, although a downward trend was seen. Our findings suggest that BC is safe for use in breast cancer patients and could be explored as a potential chemoprevention agent. Clinical trial information: NCT01628536.Disease # of patients Avg. Ki67 pre Avg. Ki67 post % decrease p-value DCIS 14 1700 1327 21.94 .68 Invasive 10 1413 1076 23.82 .28 All patients 24 1581 1223 22.64 .33
The objective of this study was to determine the effects of rasagiline as monotherapy on quality of life (QOL) in patients with early Parkinson's disease (PD). Rasagiline, a potent, second-generation, irreversible, selective monoamine oxidase B inhibitor improves PD symptoms in patients with early PD. Patients with early untreated PD were randomly assigned to once-daily rasagiline 1 mg/day, rasagiline 2 mg/day, or placebo in a 6-month, double-blind trial (n=404). At the end of 6 months, patients entered the preplanned, active-treatment phase in which those receiving 1 mg/day and 2 mg/day of rasagiline continued on their previously assigned dosages and those receiving placebo switched to rasagiline 2 mg/day, while maintaining blinding to treatment assignments. QOL was measured with the Parkinson's Disease Quality of Life questionnaire (PDQUALIF) at 0, 14, 26, and 52 weeks after randomization. Analysis of the change in PDQUALIF scores from baseline to 6 months showed adjusted treatment effects (with 95% confidence interval) favoring rasagiline over placebo of -2.91 units (-5.19, -0.64, P=0.01) for the 1 mg/day group and -2.74 units (-5.02, -0.45, P=0.02) for the 2 mg/day. Subscore analysis attributed most of this benefit to the self-image/sexuality domain. At 12 months (n=266), with all groups receiving rasagiline for at least 6 months, no significant differences in PDQUALIF scores were seen between groups. Rasagiline improved QOL compared with placebo. This QOL improvement appears to be accounted for primarily by the symptomatic benefit of rasagiline.
Purpose: To study the association of recurrent symptomatic urinary tract infections (UTIs) with the long-term use of clean intermittent catheterization (CIC) for the management of neurogenic bladder in patients with spinal cord injury (SCI). Methods: Retrospective study of 61 SCI patients with neurogenic bladder managed by CIC. Subjects were selected from 210 SCI patients seen at the Yale Urology Medical Group between 2000 and 2010. Medical UTI prophylaxis (PRx) with oral antimicrobials or methenamine/ascorbic acid was used to identify patients with recurrent UTI. The number of positive cultures (≥103 cfu/mL) within a year prior to starting PRx was used to confirm the recurrence of UTI. Results: Fifty-one male and 10 female subjects were managed with CIC. Forty-one (67%) subjects were placed on medical PRx for symptomatic recurrent UTI. Seventeen (28%) subjects had at least 3 positive cultures within the year prior to starting PRx. Fifteen of 20 (75%) subjects not on PRx had no complaints of UTI symptoms in the final year of follow-up. Conclusion: Recurrent symptomatic UTIs remain a major complication of long-term CIC in SCI patients. Although CIC is believed to have the fewest number of complications, many SCI patients managed with long-term CIC are started on medical PRx early in the course of management. Future studies are needed to determine the efficacy of routine UTI PRx in these patients as well as determine what factors influence why many patients on CIC experience frequent infections and others do not.
Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that occurrence of breast cancer should be associated with an acceleration of epigenetic aging in normal breast tissue. Ninety-six normal breast tissue samples were obtained from 88 subjects (breast cancer = 35 subjects/40 samples, unaffected = 53 subjects/53 samples). Normal tissue samples from breast cancer patients were obtained from distant non-tumor sites of primary mastectomy specimens, while samples from unaffected women were obtained from the Komen Tissue Bank (n = 25) and from non-cancer-related breast surgery specimens (n = 28). Patients were further stratified into four cohorts: age < 50 years with and without breast cancer and age ≥ 50 with and without breast cancer. The Illumina HumanMethylation450k BeadChip microarray was used to generate methylation profiles from extracted DNA samples. Data was analyzed using the "Epigenetic Clock," a published biomarker of aging based on a defined set of 353 CpGs in the human genome. The resulting age estimate, DNA methylation age, was related to chronological age and to breast cancer status. The DNAmAge of normal breast tissue was strongly correlated with chronological age (r = 0.712, p < 0.001). Compared to unaffected peers, breast cancer patients exhibited significant age acceleration in their normal breast tissue (p = 0.002). Multivariate analysis revealed that epigenetic age acceleration in the normal breast tissue of subjects with cancer remained significant after adjusting for clinical and demographic variables. Additionally, smoking was found to be positively correlated with epigenetic aging in normal breast tissue (p = 0.012). Women with luminal breast cancer exhibit significant epigenetic age acceleration in normal adjacent breast tissue, which is consistent with an analogous finding in malignant breast tissue. Smoking is also associated with epigenetic age acceleration in normal breast tissue. Further studies are needed to determine whether epigenetic age acceleration in normal breast tissue is predictive of incident breast cancer and whether this mediates the risk of chronological age on breast cancer risk.
Abstract INTRODUCTION: Taking routine cavity shave margins (CSM) reduces positive margin and re-excision rates by 50%, but the impact of this technique on operative time and overall costs have not been well-elucidated. METHODS: The SHAVE trial randomized 235 Stage 0-3 breast cancer patients undergoing partial mastectomy 1:1 to either have further cavity shave margins resected ("shave") or not ("no shave"). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Intraoperative time as well as actual direct costs incurred by the hospital were measured, for both the index case as well as any surgeries over the subsequent 90 days. RESULTS: Median patient age was 61 (range; 33-94). 54 patients (23%) had invasive cancer, 45 (19%) had DCIS, and 125 (53%) had both. Median invasive tumor size was 1.1 cm (range; 0-6.5), and median DCIS size was 1.0 cm (range; 0-9.3). The "shave" and "no shave" groups were well-matched in terms of baseline characteristics, including the proportion having a sentinel node biopsy (75.6% vs. 69.8%, p=0.32) and/or axillary node dissection (9.2% vs. 7.8%, p=0.68) at the time of the initial surgery. The median number of additional CSM in the "shave" group was 4 (range; 3-6). At the initial surgery, those in the "shave" group had a longer operative time (median 76 vs. 66 minutes, p=0.005), and higher OR, pathology and total costs (see table). 48 patients required a subsequent surgery; 45 (93.8%) for margin clearance, 3 for sentinel lymph node biopsy alone (2 in the "shave" and 1 in the "no shave" group, p=1.00). There was a significantly lower re-excision rate for margins in the "shave" group (10.9% vs. 27.6%, p=0.001). Median time to re-excision was 22 days (range; 10-62). The mean cost of additional surgeries for those who required them was no different between the "shave" and "no shave" groups ($2636 vs. $3453, p=0.12); however, given the overall lower reoperation rate in the "shave" group (12.6% vs. 28.4%, p=0.003), the mean cost per patient for additional surgeries was significantly lower in the "shave" vs. "no shave" group. Taking into account all surgeries (including the index case and any additional surgeries within 90 days), there was no significant difference in cost (from a hospital perspective) between the two groups. Mean (± SE) Costs per patient"Shave" (n=119)"No Shave" (n=116)p-valueIndex surgery: OR costs$1315 (± $69)$1138 (± $52)0.042Pathology costs$1195 (± $43)$795 (± $48)< 0.001Total costs$4758 (± $123)$4133 (± $119)< 0.001Additional surgery: OR costs$94 (± $24)$247 (± $44)0.003Pathology costs$51 (± $18)$112 (± $21)0.031Total costs$332 (± $88)$983 (± $189)0.002Total 90 day surgery costs: OR costs$1409 (± $76)$1385 (± $64)0.808Pathology costs$1247 (± $49)$909 (± $52)< 0.001Total costs$5090 (± $166)$5116 (± $214)0.925 CONCLUSIONS: Taking routine CSM is associated with increased time and cost for the index surgery, but this is offset by the cost savings of reduced re-excision rates. While the strategies of "shave" and "no shave" are similar in terms of 90 day hospital-related costs, taking CSM is associated with a lower need for reoperative surgery, thereby reducing patient angst and improving utilization of surgeon and OR time. Citation Format: Chagpar AB, Longley PB, Horowitz NR, Killelea BK, Tsangaris TN, Li F, Butler M, Stavris K, Yao X, Harigopal M, Bossuyt V, Lannin DR, Pusztai L, Loftus M, Davidoff AJ, Gross CP. Impact of routine cavity shave margins on time and money: Results from the SHAVE trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-13-01.
1012 Background: Considerable controversy exists regarding the utility of routine CSM in patients undergoing partial mastectomy for breast cancer. We performed a prospective RCT to determine whether this practice results in a lower positive (+) margin rate. Methods: 251 patients with preoperative Stage 0-3 breast cancer undergoing partial mastectomy were randomized 1:1 to SPM or CSM (80% power to detect a reduction in (+) margin rate from 30% to 15%). Prior to intraoperative randomization, surgeons performed SPM per their usual practice. The sealed randomization envelope was then opened and surgeons were instructed either to take circumferential CSM or close. (+) margins were defined as tumor at ink for invasive cancer, and < 1 mm for DCIS. Results: The median patient age was 61 (range; 33-94). 61 (24.3%) had invasive cancer only, 50 (19.9%) had DCIS alone, and 129 (51.4%) had a combination of both. The median invasive tumor size was 1 cm (range; 0-6.5), and median DCIS size was 0.9 cm (range; 0-9.3). The groups were well-matched in terms of baseline characteristics (see table below). Margin status prior to randomization was not significantly different between the two groups (34.9% vs. 33.6%, p = 0.894). After randomization, those randomized to CSM had a significantly lower (+) margin rate than SPM (18.3% vs. 33.6%, p = 0.006). This was the primary endpoint of the study. Not all (+) margins were re-excised due to anatomic considerations; however, CSM resulted in a significantly lower re-excision rate than SPM (9.5% vs. 20.8%, p = 0.014). Conclusions: This is the first RCT to conclusively demonstrate that CSM halves the (+) margin and re-excision rate of SPM. Use of routine CSM may significantly reduce morbidity and cost of reoperation for margin clearance. Clinical trial information: NCT01452399. CSM (n = 126) SPM (n = 125) p-value Age (yrs); median 62 60 0.525 Invasive tumor size (cm); median (range) 1.0 (0 – 6.0) 1.0 (0 – 6.5) 0.639 Palpable (%) 20.6% 22.4% 0.761 Invasive lobular histology (%) 11.0% 7.8% 0.744 DCIS component (%) 69.0% 73.6% 0.486 DCIS size (cm); median (range) 0.9 (0 – 9.3) 1.0 (0 – 8.1) 0.775 Node positive 10.3% 10.4% 1.000 ER+ 90.6% 87.5% 0.527
Routine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and reexcision among patients undergoing partial mastectomy for breast cancer.In this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no-shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Positive margins were defined as tumor touching the edge of the specimen that was removed in the case of invasive cancer and tumor that was within 1 mm of the edge of the specimen removed in the case of ductal carcinoma in situ. The rate of positive margins was the primary outcome measure; secondary outcome measures included cosmesis and the volume of tissue resected.The median age of the patients was 61 years (range, 33 to 94). On final pathological testing, 54 patients (23%) had invasive cancer, 45 (19%) had ductal carcinoma in situ, and 125 (53%) had both; 11 patients had no further disease. The median size of the tumor in the greatest diameter was 1.1 cm (range, 0 to 6.5) in patients with invasive carcinoma and 1.0 cm (range, 0 to 9.3) in patients with ductal carcinoma in situ. Groups were well matched at baseline with respect to demographic and clinicopathological characteristics. The rate of positive margins after partial mastectomy (before randomization) was similar in the shave group and the no-shave group (36% and 34%, respectively; P=0.69). After randomization, patients in the shave group had a significantly lower rate of positive margins than did those in the no-shave group (19% vs. 34%, P=0.01), as well as a lower rate of second surgery for margin clearance (10% vs. 21%, P=0.02). There was no significant difference in complications between the two groups.Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy. (Funded by the Yale Cancer Center; ClinicalTrials.gov number, NCT01452399.).
Abstract BACKGROUND: Increasing evidence suggests that epigenetic mechanisms play critical roles in the development of breast cancer. However, precise DNA methylation signatures associated with breast cancer susceptibility remain unknown. We sought to compare DNA methylation changes in the normal breast tissue of women with and without breast cancer to identify patterns of aberrant DNA methylation in women with breast cancer. METHODS:Samples of normal breast tissue were collected from four cohorts of women: age < 50 years with and without breast cancer, and age ≥50 years with and without breast cancer. Normal breast tissue from healthy women was obtained from the Komen Tissue Bank at IU Simon Cancer Center and from women presenting for reduction mammoplasty at Yale New Haven Hospital. Normal breast tissue from women with breast cancer was obtained from patients undergoing adjuvant total mastectomy at Yale Breast Center. DNA was extracted using Qiagen AllPrep Universal kit. Raw data files in idat format were imported to Partek Genomics Suite 6.6 for normalization and differential methylation analysis. Raw intensities were normalized using With Array Normalization (SWAN) method. Principal component analysis (PCA) were performed as quality control. Differentially methylated loci (DML) between control and breast cancer groups were detected when False discovery rate (FDR) < 0.05 and fold change > 1.5. Functional enrichment analysis of genes with DML in the gene body were conducted using METACORE™. Pathways with FDR < 0.05 were selected. RESULTS: Ninety-three normal breast tissue samples from 89 subjects were analyzed (breast cancer=40, unaffected=53). Comparison of DNA methylation patterns between women with and without breast cancer revealed 200 DMLs. The majority of DMLs (186) were hyper-methylated in breast cancer patients, and 48 DMLs locate in enhancers of genes. 170 DMLs locate in 134 genes, enriched in two pathways: (1) Cell adhesion_Endothelial cell contacts by junctional mechanisms, and (2) Neurophysiological process_Constitutive and regulated NMDA receptor trafficking. Genes associated with cell adhesion and cell contacts included: ACTN2, GJA4, GJA7 and MAGI1. Two hyper-methylated loci were found in enhancers of ACTN2. In addition, one hyper-methylated locus in GJA4, one hyper-methylated and one hypo-methylated loci in GJA7, and two hyper-methylated loci in MAGI1 were detected in breast cancer patients. Genes associated with NMDA receptor trafficking include: TPK1, ADCY4 and LIN7C. One and two loci were found in TPK1 and ADCY4, respectively, that were hyper-methylated in normal breast tissue from cancer patients in the gene body, while a hypo-methylated locus in breast cancer patients was identified in LIN7C. CONCLUSIONS: Comparison of DNA methylation patterns of normal breast tissue from women with and without breast cancer reveal specific mechanistic pathways and genes that are differentially methylated in women with breast cancer. DNA methylation of normal breast tissue deserves further study as a potential biomarker for breast cancer risk stratification and may lend new insight into mechanisms of breast cancer development. Citation Format: Hofstatter EW, Zhu Y, Horvath S, Chagpar AB, Wali VB, Bossuyt V, Storniolo AM, Hatzis C, Patwardhan G, Von Wahlde M-K, Butler M, Epstein L, Stavris K, Sturrock T, Au A, Kwei S, Pusztai L. Comparison of DNA methylation patterns in normal breast tissue from women with and without breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-04-02.
