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Background Time to surgery (TTS) has been suggested to have an association with mortality in early-stage breast cancer. Objective This study aims to determine the association between TTS and preoperative disease progression in tumor size or nodal status among women diagnosed with clinical T1N0M0 ductal breast cancer. Methods Women diagnosed with clinical T1N0M0 ductal breast cancer who had breast-conserving surgery as their first definitive treatment between 2010 and 2016 (n = 90,405) were analyzed using the National Cancer Database. Separate multivariable logistic regression models for hormone receptor (HR)-positive and HR-negative patients, adjusted for clinical and demographic variables, were used to assess the relationship between TTS and upstaging of tumor size (T-upstaging) or nodal status (N-upstaging). Results T-upstaging occurred in 6.76% of HR-positive patients and 11.00% of HR-negative patients, while N-upstaging occurred in 12.69% and 10.75% of HR-positive and HR-negative patients, respectively. Among HR-positive patients, odds of T-upstaging were higher for 61–90 days TTS (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.05–1.34) and ≥91 days TTS (OR 1.47, 95% CI 1.17–1.84) compared with ≤30 days TTS, and odds of N- upstaging were higher for ≥91 days TTS (OR 1.35, 95% CI 1.13–1.62). No association between TTS and either T- or N-upstaging was found among HR-negative patients. Other clinical and demographic variables, including grade, tumor location, and race/ethnicity, were associated with both T- and N-upstaging. Conclusion TTS ≥61 and ≥91 days was a significant predictor of T- and N-upstaging, respectively, in HR-positive patients; however, TTS was not associated with upstaging in HR-negative breast cancer. Delays in surgery may contribute to measurable disease progression in T1N0M0 ductal breast cancer.

Intraoperative radiation therapy (IORT) is an option for breast-conserving therapy in early-stage breast cancer. IORT is given in one fraction at the time of surgery and eliminates the need for adjuvant external beam radiation therapy. However, previous trials indicate increased local failure rates compared with whole-breast irradiation, which engenders controversy around the appropriate use of IORT. We conducted a prospective study of patients diagnosed with early-stage breast cancer (T1-T2, N0-N1) at the University of Oklahoma Health Sciences Center (OUHSC) between 2013 and 2017 and treated with lumpectomy followed by intraoperative radiation therapy (IORT). Data collected included stage of disease, tumor location, histology, tumor markers, lymph node status, surgical margin size, recurrence, cosmetic outcomes, and length of follow-up. In-breast tumor recurrence rate (IBTR) in the 77 evaluable patients was 3.9% (3 patients). Margins were close (1 mm or less) in all three recurrent patients, and two were initially diagnosed with DCIS. Recurrence rates in our patients were comparable to prior reports. All recurrences were in patients with close margins indicating that this may represent a predictive feature for exclusion from IORT; additional studies are essential to determine the recurrence rates among patients treated with IORT and to identify potential predictors of IORT eligibility.

We conducted a multiinstitutional, placebo-controlled phase IIB trial of the lignan secoisolariciresinol diglucoside (SDG) found in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from premenopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail) versus placebo for 12 months with repeat bio-specimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median baseline Ki-67 was 4.1% with no difference between arms. Median Ki-67 change was −1.8% in the SDG arm (P = 0.001) and −1.2% for placebo (P = 0.034); with no significant difference between arms. As menstrual cycle phase affects proliferation, secondary analysis was performed for 117 women who by progesterone levels were in the same phase of the menstrual cycle at baseline and off-study tissue sampling. The significant Ki-67 decrease persisted for SDG (median = −2.2%; P = 0.002) but not placebo (median = −1.0%). qRT-PCR was performed on 77 pairs of tissue specimens. Twenty-two had significant ERα gene expression changes (2.0) with 7 of 10 increases in placebo and 10 of 12 decreases for SDG (P = 0.028), and a difference between arms (P = 0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated use of SDG is tolerable and safe.

As we enter this new decade, medicine is presented with the daunting task of resolving incongruities in our existing data and the ever-increasing incidence of obesity, Coronary Artery Disease (CAD) and cancer – including but not limited to breast cancer. The consequence of our failure to quantitatively measure the impact of diets and drugs at the tissue level where the actual CAD and cancer are occurring has limited our ability to better define the dietary, lifestyle and medication changes required to limit and potentially reverse these inflammatory diseases.

PURPOSE The 80-gene molecular subtyping signature (80-GS) reclassifies a proportion of immunohistochemistry (IHC)-defined luminal breast cancers (estrogen receptor–positive [ER+], human epidermal growth factor receptor 2–negative [HER2–]) as Basal-Type. We report the association of 80-GS reclassification with neoadjuvant treatment response and 5-year outcome in patients with breast cancer. METHODS Neoadjuvant Breast Registry Symphony Trial (NBRST; NCT01479101 ) is an observational, prospective study that included 1,069 patients with early-stage breast cancer age 18-90 years who received neoadjuvant therapy. Pathologic complete response (pCR) and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed in 477 patients with IHC-defined ER+, HER2– tumors and in a reference group of 229 patients with IHC-defined triple-negative breast cancer (TNBC). RESULTS 80-GS reclassified 15% of ER+, HER2– tumors (n = 73) as Basal-Type (ER+/Basal), which had similar pCR compared with TNBC/Basal tumors (34% v 38%; P = .52), and significantly higher pCR than ER+/Luminal A (2%; P < .001) and ER+/Luminal B (6%; P < .001) tumors. The 5-year DMFS (%, [95% CI]) was significantly lower for patients with ER+/Basal tumors (66% [52.6 to 77.3]), compared with those with ER+/Luminal A tumors (92.3% [85.2 to 96.1]) and ER+/Luminal B tumors (73.5% [44.5 to 79.3]). Importantly, patients with ER+/Basal or TNBC/Basal tumors that had a pCR exhibited significantly improved DMFS and OS compared with those with residual disease. By contrast, patients with ER+/Luminal B tumors had comparable 5-year DMFS and OS whether or not they achieved pCR. CONCLUSION Significant differences in chemosensitivity and 5-year outcome suggest patients with ER+/Basal molecular subtype may benefit from neoadjuvant regimens optimized for patients with TNBC/Basal tumors compared with patients with ER+/Luminal subtype. These data highlight the importance of identifying this subset of patients to improve treatment planning and long-term survival.

The Neoadjuvant Breast Symphony Trial (NBRST) demonstrated the 70-gene risk of distant recurrence signature, MammaPrint, and the 80-gene molecular subtyping signature, BluePrint, precisely determined preoperative pathological complete response (pCR) in breast cancer patients. We report 5-year follow-up results in addition to an exploratory analysis by age and menopausal status.The observational, prospective NBRST (NCT01479101) included 954 early-stage breast cancer patients aged 18-90 years who received neoadjuvant chemotherapy and had clinical and genomic data available. Chemosensitivity and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed. In a post hoc subanalysis, results were stratified by age (≤ 50 vs. 50 years) and menopausal status in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors.MammaPrint and BluePrint further classified 23% of tumors to a different subtype compared with immunohistochemistry, with more precise correspondence to pCR rates. Five-year DMFS and OS were highest in MammaPrint Low Risk, Luminal A-type and HER2-type tumors, and lowest in MammaPrint High Risk, Luminal B-type and Basal-type tumors. There was no significant difference in chemosensitivity between younger and older patients with Low-Risk (2.2% vs. 3.8%; p = 0.64) or High-Risk tumors (14.5% vs. 11.5%; p = 0.42), or within each BluePrint subtype; this was similar when stratifying by menopausal status. The 5-year outcomes were comparable by age or menopausal status for each molecular subtype.Intrinsic preoperative chemosensitivity and long-term outcomes were precisely determined by BluePrint and MammaPrint regardless of patient age, supporting the utility of these assays to inform treatment and surgical decisions in early-stage breast cancer.

Clinical efforts to diagnostically evaluate women-and men-with breast cancer have resulted in various degrees of success. The use of external radiographic sources to look for tissue abnormalities-mammography - has according to the Cochrane Collaboration not been able to demonstrate a reduction in mortality [1]; a position also held by the National Cancer Institute and The Canadian Trial [2].

Background We hypothesize that women undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis from appendiceal cancer will have a survival advantage compared to men. Methods The National Cancer Database (NCDB) public user file (2004–2014) was used to select patients with PC undergoing CRS and HIPEC from appendiceal cancer. Univariate and multivariable analyses were performed. Results 1,190 patients with PC from appendiceal cancer underwent HIPEC and CRS. OS was significantly longer for women than for men, with mean and median OS being 73.8 months and 98.2 months for women vs 58.7 months and 82.5 months for men, respectively (p = 0.0032). On multivariable analysis, male sex (HR: 1.444, 95% CI: 1.141–1.827, p = 0.0022) and increasing age (HR: 1.017, 95% CI: 1.006–1.027, p = 0.0017) were both found to be independent risk factors for worse OS. Conclusion Women undergoing CRS and HIPEC for PC from appendiceal origin live longer than men undergoing the same treatment. Increasing age was also found to be independent risk factors for worse survival

The risk of inflammatory changes, potential autoimmune diseases and breast cancer in women with breast implants are now well recognized..

Diagnostic evaluation of patients with chest pain may include myocardial perfusion imaging. During the initial stress imaging evaluation, differences in regional blood flow and metabolism differentiates normal coronary blood flow from abnormal – viz..

The clinical treatment of coronary (heart) artery disease (CAD) for hundreds of thousands to millions of people

Beginning in 1999, Fleming, et al. began the development of the first quantitative nuclear imaging method

Monday 4 February 2019 was yet another World Cancer Day. We celebrated our efforts to find and eradicate cancer without admitting to ourselves that cancer isn’t a single disease, but rather a group of diseases all caused by our bodies responding to the toxic environment we are exposing ourselves to, just as our planet is responding to the toxic wastes we are dumping into it.

Objective To assess the safety and efficacy of single-fraction, intra-operative radiation therapy (IORT) delivered with the Xoft® Axxent® Electronic Brachytherapy System® (eBx®) immediately following surgical resection for treatment of early stage breast cancer. Methods This phase 4, open-label, single-arm, prospective, non-randomized trial is still enrolling participants and is currently being conducted at 26 hospitals in the USA (25) and Portugal (1). 878 participants with biopsy-proven ductal carcinoma in situ (DCIS) or invasive ductal carcinoma who met the inclusion criteria underwent lumpectomy followed by single-fraction IORT to the lumpectomy cavity. Briefly, a small, presterilized lead shield piece was placed on the chest wall to reduce the dose to the ribs, and then a balloon applicator, suitable to the surgical bed, was placed in the lumpectomy cavity and inflated with saline (30-75 cc); skin was temporarily closed over the balloon and ultrasound was used to confirm a balloon surface-to-skin distance ≥ 1.0 cm. The Xoft System was used to deliver the 20 Gy dose at the balloon applicator surface. The balloon was deflated, lead shield and balloon removed and the surgical site sutured. The prespecified primary outcome of this 10-year follow-up study is recurrence of ipsilateral breast tumor at 5 years. Prespecified secondary outcomes include 10-year recurrence and cosmesis (Harvard Scale). Trial Registry: ClinicalTrials.gov; Identifier: NCT01644669. Findings Of the 878 participants treated, 877 participants received the prescribed 20 Gy dose with a mean radiation treatment time of 594.5 seconds, whereas one participant received 14 Gy due to a source failure. 569 participants have reached 18-month (333), 2-year (199), and 3-year (37) follow-up. The mean age at enrollment was 65 years (range 41-90). 219 participants had DCIS and 658 had invasive ductal carcinoma. The DCIS nuclear grade was high (N=79), intermediate (N=100), or low (N=40). Invasive cancers were Grade 1 (N=282), 2 (N=282), or 3 (N=94). 664 participants had T1 lesions, 56 had T2 lesions, and 3 were unknown. The mean tumor size was 12.33 ± 10.5 mm. Cosmesis was excellent to good in 90% of participants who reached 2-year follow-up. To date, 155 reported adverse events were Grade 2 or higher. The most frequent side effects were breast pain, seroma, induration, and erythema. There were nine deaths, none of which were breast cancer related, four ipsilateral breast recurrences, and three new contralateral breast cancers. Conclusions Early results from this multi-center trial demonstrate that IORT using the Xoft Axxent eBx System at the time of breast conservation surgery continues to be a promising treatment option for early stage breast cancer. The short course of radiation therapy for select patients has excellent to good cosmetic results and a low rate of high-grade adverse events and recurrences. Funding Funded by Xoft, Inc., a subsidiary of iCAD, Inc. Acknowledgement Medical writing support from Dr. Theresa E. Singleton, Singleton Science, LLC. Citation Format: Syed AMN, Chang H, Schwartzberg BS, Bremmer AK, Boylan S, Lopez-Penalver C, Vito CA, Davis M, Dooley WC, Chakravarthy AB, Croomer C, Proulx GM, Golder SL, Ivanov O, Fernandez KL, Farha M, Gonzalez V, Wengler C, Bhatnagar A, Neuner G, Kopkash K, Rahman S, Corn C, Costa P, Ellenhorn J, Cox C. Two-year follow-up results of a multi-center trial of intra-operative electronic brachytherapy during breast conservation surgery for early stage breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-19.

Breast cancer prevention strategies for young pre-menopausal women must have minimal side effects and accommodate potential future child-bearing. Based on epidemiologic evidence and informed by a single-arm pilot study, we conducted a multi-institutional, placebo-controlled Phase IIB trial of the lignan secoisolariciresinol diglycoside (SDG) found in high concentrations in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from pre-menopausal women at increased risk for breast cancer during the follicular phase as estimated by dates. Those with cytologic hyperplasia and ≥2% positive cells by Ki-67 immunocytochemistry were eligible for randomization 2:1 to daily Brevail® (50 mg SDG) or placebo. After 12 months, RPFNA and blood for hormone assays were repeated. The primary endpoint was difference in change in Ki-67 between the randomization groups. A planned accrual of 230 was to provide an 80% power of detecting a 2.5% reduction in Ki-67 for the SDG group vs no reduction in the placebo group. Accrual was slower than anticipated and the study was closed with 180 enrollees at five sites. 152 (51 placebo, 101 SDG) sets of paired specimens were evaluable for the primary endpoint. Baseline Ki-67 was a median of 4.1% (range, 2.0 - 26.8%), with no difference between arms (Mann-Whitney nonparametric test, p=0.34). Both arms showed a decrease in percent Ki-67 over time (Wilcoxon signed rank test; p=0.034 for placebo, p=0.001 for SDG). Although Ki-67 reduction was greater in the SDG arm (median of -1.8% vs -1.2%), there was no statistically significant difference between the two arms (Mann-Whitney, p=0.72). Since luteal phase progesterone affects proliferation, we excluded 35 women that by serum progesterone levels could not be confirmed to be in the same phase of the menstrual cycle at baseline and off-study. Analyzing the remaining 117 for Ki-67 (42 placebo, 75 SDG), there was no significant change for the placebo arm (Wilcoxon, p=0.14) but the significant change in the SDG arm persisted (p=0.002). As an exploratory analysis, assessment of gene expression was performed by RT-qPCR on 77 pairs of non-bloody RPFNA specimens. 22 had significant ERα gene expression changes (defined 2.0 fold changes). There was no significant change over time for the placebo group (7/10 increases, Wilcoxon, p=0.16), but there was significant change for the SDG group (10/12 decreases, p=0.027). There was also a significant difference between the groups (Mann-Whitney, p=0.018). While the primary trial result is null, there is supportive evidence SDG may favorably affect cell proliferation and estrogen signaling in premenopausal women at high risk for development of breast cancer. Supported by Susan G. Komen Promise Grant KG101039. Study agent (Brevail®, placebo) provided by Lignan Research Inc. (later Barlean's Oils) which was otherwise not involved in the design, conduct, or analysis of the study. Citation Format: Carol J. Fabian, Seema A. Khan, Judy E. Garber, William C. Dooley, Lisa D. Yee, Carola M. Zalles, Trina Metheny, Teresa A. Phillips, Jinxiang Hu, Brian K. Petroff, Stephen D. Hursting, Bruce F. Kimler. Randomized clinical trial of a flaxseed lignan in pre-menopausal women at high risk for development of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1120.

Until quite recently, diagnostic imaging has relied upon lqualitativer imaging methods limited by linattention blindnessr, reader expectation bias and the ability to define disease as either present or absent...

Women with both dense breasts and breast implants present a special challenge for consideration due to the increased incidence of false-positives and false-negatives with mammography [1]. Molecular Breast Imaging [MBI] has provided limited proven benefit until recently, when improvements in camera calibration, enhancement and quantification [2,3], resulted in the ability to differentiate tissue based upon measurable changes in regional blood flow and metabolism [4].

Background: Scientifically published studies have demonstrated that all isotopes, including Sestamibi redistribute. Measurement of this redistribution using FMTVDM©℗ provides an accurate method for determining wash-in and washout. Methods: Using FMTVDM©℗ 1040 human coronary arteries were studied to determine their wash-in and washout redistribution measured on a pixel-by-pixel basis. From FMTVDM©℗ the percent diameter stenosis (%DS) for each artery was determined. This %DS was then used to calculate coronary flow reserve (Calculated SFR) using a proprietary quadratic equation (QCFR©, FCFR©) previously derived from quantitative coronary arteriography (QCA) measurements. These calculated CFR values were then compared with the actual measured CFR obtained directly from QCA. Results: The results of the calculated CFR from FMTVDM©℗ with that obtained by direct QCA measurement showed a regression analysis of y= (0.8758•x)+0.4291, where y=the QCFR© and x=the QCA measured CFR. The R2 value (coefficient of determination) for this demonstrated a strong relationship at 0.87582. Conclusions: The use of the FMTVDM©℗ for measurement of isotope redistribution, including Sestamibi, provides an accurate quantitative method for determining both redistribution wash-in and redistribution washout, from which %DS can be calculated on a pixel-by-pixel basis. This %DS can then be used with the proprietary equation (QCFR©, FCFR©) to calculate the CFR directly from the MPI result using FMTVDM©℗. The implementation of this power tool, will provide for additional determination of the physiological effect of CAD without requiring additional QCA equipment and expertise costs, making QCFR© possible in most if not all hospitals with nuclear medicine departments.

e22515 Background: Soft tissue sarcomas (STS) are heterogeneous solid tumors of mesenchymal cell origin, often difficult to manage. Local recurrence of extremity STS with surgery alone ranges from 5-20% with amputation ; 40% with wide excision. Neoadjuvant therapies are used to improve surgical outcomes. There is currently no recognized optimal neoadjuvant chemoradiation regimen prior to resection of STS. At our institution, we have piloted a neoadjuvant regimen of daily Cisplatin with infusional Adriamycin concurrent with radiation to assess its impact on surgical outcomes and tumor control. Methods: Patients diagnosed with STS of any site were treated neoadjuvantly with Cisplatin 6mg/m2 IV over 3-5 mins given 20 to 30 minutes before radiation (5 days) for 6 weeks. Adriamycin was given in the inpatient setting at 12.5 mg/m2 IV over 24 hours on days 1-4, weeks 1 and 4. The radiation dose was 54 Gy in 30 fractions. More than 50% of patients were treated with IMRT planning. Results: Since 2011, 12 STS patients were treated preoperatively with this regimen. Of these patients, 9 underwent surgery. Six of the 9 surgical patients received this neoadjuvant protocol followed by resection in the upfront setting. All of the 6 upfront patients had negative surgical margins; all of these patients had grade 3 tumors. Necrosis was reported based on the FNCLCC grading system. The average percent of necrosis was 96.3% (95% confidence interval 50.4%, 99.8%). Toxicity: Reported according to the RTOG/EORTC Radiation toxicity grading system. Of all patients, grade 1-2 skin toxicity predominated (75%). No grade 4 toxicity reported. Hematologic toxicity: Of all patients, grade 2-3 hematologic toxicity during neoadjuvant chemotherapy was reported in 83% of patients; grade 4 in 1 patient. No febrile neutropenia occurred. Post-operative complications: Seroma/hematoma formation was the most common post-operative complication in the surgical patients. No severely delayed healing was noted. Survival:Nine of 12 patients were dead (6 of 9 surgical patients) at the time of this analysis, all of metastatic disease. Mean time to DM 7.4 months. Mean OS 10 months. Conclusions: Our novel regimen achieved high necrosis rates, and all surgical patients achieved negative margin status. These factors are prognostic and correlate with local control. The predominant pattern of failure was distant. With its acceptable toxicity, this regimen of neoadjuvant Cisplatin, Adriamycin and radiation should be examined in a randomized fashion versus neoadjuvant radiation alone to determine the long term outcomes.

Background: The diagnostic testing for breast cancer has been limited by the absence of a method, which can quantitatively differentiate tissue differences; specifically differentiation between calcium deposits, normal breast tissue, inflammatory changes in breast tissue and breast cancer. Such a quantitative method would remove the issue of sensitivity and specificity errors and allow for diagnostic decision-making including treatment monitoring. Method: A series of investigations were conducted over an 18-year period of time looking at more than 1000 women and men suspected of having breast tissue abnormalities. The studies compared pathologic tissue results with outcomes using other diagnostic studies and FMTVDM-BEST©℗ Imaging. The studies began with asking the fundamental questions necessary to produce such a quantitative diagnostic test, followed by correcting for errors encountered by other methods. Following the initial work comparing FMTVDM-BEST©℗ Imaging with other tests and tissue pathology results, the investigations turned to monitoring changes in women over time, demonstrating the ability to monitor treatment results from surgery, chemotherapy, radiation therapy, immune therapy, diet and lifestyle changes. Further work was conducted to assure that the time within a woman’s cycle did not affect FMTVDM-BEST©℗ Imaging. The next series of studies looked at the effect that soy protein, smoking and hormone treatment (HRT) had on breast tissue health and the relationship between breast cancer and these influences. The summation of all of these studies included looking at breast density and breast implants as well as male patients. Results: FMTVDM-BEST©℗ Imaging quantitatively differentiates between breast calcium deposits, normal breast tissue, inflammatory changes and breast cancer. It can monitor transitions in tissue showing both the progression and regression of disease allowing clinicians to monitor treatment outcomes independent of the treatment approach used. FMTVDM-BEST©℗ Imaging is not affected by breast density, breast implants, mastectomy or size of breast; including male patients. : FMTVDM-BEST©℗ Imaging provides the first and only quantitative method, which can differentiate tissues based upon changes in measurements obtained from this patented method. As such, it can detect changes in tissue leading to breast cancer allowing for greater treatment opportunities, as well as monitoring outcomes of treatment for breast cancer and other abnormalities (e.g. fibrocystic disease). FMTVDM-BEST©℗ Imaging works independent of whether the patient has dense breast tissue, breast implants, is on HRT, smokes or has undergone previous treatment in both men and women.

Background microRNAs are promising candidate breast cancer biomarkers due to their cancer-specific expression profiles. However, efforts to develop circulating breast cancer biomarkers are challenged by the heterogeneity of microRNAs in the blood. To overcome this challenge, we aimed to develop a molecular profile of microRNAs specifically secreted from breast cancer cells. Our first step towards this direction relates to capturing and analyzing the contents of exosomes, which are small secretory vesicles that selectively encapsulate microRNAs indicative of their cell of origin. To our knowledge, circulating exosome microRNAs have not been well-evaluated as biomarkers for breast cancer diagnosis or monitoring. Methods Exosomes were collected from the conditioned media of human breast cancer cell lines, mouse plasma of patient-derived orthotopic xenograft models (PDX), and human plasma samples. Exosomes were verified by electron microscopy, nanoparticle tracking analysis, and western blot. Cellular and exosome microRNAs from breast cancer cell lines were profiled by next-generation small RNA sequencing. Plasma exosome microRNA expression was analyzed by qRT-PCR analysis. Results Small RNA sequencing and qRT-PCR analysis showed that several microRNAs are selectively encapsulated or highly enriched in breast cancer exosomes. Importantly, the selectively enriched exosome microRNA, human miR-1246, was detected at significantly higher levels in exosomes isolated from PDX mouse plasma, indicating that tumor exosome microRNAs are released into the circulation and can serve as plasma biomarkers for breast cancer. This observation was extended to human plasma samples where miR-1246 and miR-21 were detected at significantly higher levels in the plasma exosomes of 16 patients with breast cancer as compared to the plasma exosomes of healthy control subjects. Receiver operating characteristic curve analysis indicated that the combination of plasma exosome miR-1246 and miR-21 is a better indicator of breast cancer than their individual levels. Conclusions Our results demonstrate that certain microRNA species, such as miR-21 and miR-1246, are selectively enriched in human breast cancer exosomes and significantly elevated in the plasma of patients with breast cancer. These findings indicate a potential new strategy to selectively analyze plasma breast cancer microRNAs indicative of the presence of breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0753-x) contains supplementary material, which is available to authorized users.

In 2007, professional collaborations developed a unified set of quality standards for breast cancer care.This was an Institutional Review Board-approved, retrospective review of all breast cancer patients treated initially at University of Oklahoma Medical Center from 2000 to 2008. All tumor registry data were reviewed to test compliance with the Center for Medicare and Medicaid Services (CMS) (Medicare) quality standards.Overall and disease-free survival was better for patients meeting the radiation for breast conservation standard (P.02). Whether estrogen receptor positive (ER+) or estrogen receptor negative, there were similar statistically significant benefits of combination chemotherapy in overall and disease-free survival rates for all patients with tumors greater than 1 cm in size (P.05). Hormonal therapy was associated with an overall survival benefit (P.005) but only a trend toward improvement in disease-free survival (P = .076).We believe the current CMS standards are a reasonable first step at monitoring breast cancer quality of care. Our data suggest that these may be improved by including combination chemotherapy in ER+ disease when data show a net survival benefit over hormonal therapy alone.

This report describes a novel HLA/peptide complex with potential prognostic and therapeutic roles for invasive breast cancer. Macrophage migration inhibitory factor (MIF) mediates inflammation and immunity, and MIF overexpression is observed in breast cancer. We hypothesized that the HLA class I of cancerous breast epithelial cells would present MIF-derived peptides. Consistent with this hypothesis, the peptide FLSELTQQL (MIF19–27) was eluted from the HLA-A*0201 (HLA-A2) of breast cancer cell lines. We posited that if this MIF19–27/HLA-A2 complex was exclusively found in invasive breast cancer, it could be a useful prognostic indicator. To assess the presentation of MIF peptides by the HLA of various cells and tissues, mice were immunized with the MIF19–27/HLA-A2 complex. The resulting mAb (RL21A) stained invasive ductal carcinoma (IDC) but not ductal carcinoma in situ, fibroadenoma, or normal breast tissues. RL21A did not stain WBCs (total WBCs) or normal tissues from deceased HLA-A2 donors, substantiating the tumor-specific nature of this MIF/HLA complex. As this MIF/HLA complex appeared specific to the surface of IDC, RL21A was tested as an immunotherapeutic for breast cancer in vitro and in vivo. In vitro, RL21A killed the MDA-MB-231 cell line via complement and induction of apoptosis. In an in vivo orthotopic mouse model, administration of RL21A reduced MDA-MB-231 and BT-20 tumor burden by 5-fold and by >2-fold, respectively. In summary, HLA-presented MIF peptides show promise as prognostic cell surface indicators for IDC and as targets for immunotherapeutic intervention.

Prior multi-institutional studies have reported a survival benefit of breast cancer treatment by surgical oncologists (SO) over general surgeons (GS).Retrospective review tumor registry data of all breast cancer patients receiving primary treatment at a single institution from January 1, 1995, to December 31, 2008.During the time period, there were 2192 patients who received primary breast cancer treatment at this institution. The mean age was 57 years and the mean follow-up was55 months. Stage distribution was similar between GS and SO. Overall survival (SO 83.8% vs. GS 75.6%) and disease-free survival (SO 80.7% vs. GS 72.0%) was highly statistically significant (P0.0001). For stages 1, 2a, 2b, 3a, and 3b there were statistically significant (P0.05) differences for overall and disease-free survival. Overall, the use of breast conservation was more likely by SO-52.6 vs. 38.3% all stages and 65.8 vs. 54.0% for stage 0-2. The compliance with all systemic therapies (chemotherapy and hormone therapy) was more likely if being treated by SO-77.3 vs. 68.5% (P0.02). The use of radiotherapy for breast conservation and in stage 3 mastectomy patients was higher for SO (P0.001). Participation in clinical trials was far higher for SO patients-56.2 vs. GS 7.0% (P0.001).The value added by having primary breast cancer treatment by a SO seems to arise from the more successful completion of multidisciplinary care in a timely fashion and higher rates of clinical trial involvement.

William C Dooley1, James C Wurzer2, Mohamed Megahy3, Gary Schreiber4, Tapan Roy5, Gary Proulx6, Susan Laduzinsky7, Steven Lane8, James Dalzell9, Kambiz Dowlatshahi10, Dwelvin Simmons11, John P Thropay12, Harish Ahuja13, Peter Beitsch14, Randall W Holt15, Charles A Lee161Oklahoma University Health Sciences Center, Oklahoma City, OK, USA; 2Atlanticare, Egg Harbor Township, NJ, USA; 3Maryville Oncology, Maryville, IL, USA; 4Swedish Covenant Hospital, Chicago, IL, USA; 5Cape Girardeau Cancer Center, Cape Girardeau, MO, USA; 6Exeter Hospital, Exeter, NH, USA; 7St. Elizabeth's Medical Center, Swansea, IL, USA; 8Brockton Hospital, Brockton, MA, USA; 9Nazha Cancer Center, Northfield, NJ, USA; 10Rush University Medical Center, Chicago, IL, USA; 11Florida Radiation Oncology Group, Jacksonville, FL, USA; 12Beverly Oncology and Imaging Center, Montebello, CA, USA; 13Aspirus Cancer Center, Wausau, WI, USA; 14Dallas Surgical Group, Dallas, TX, USA; 15Pacific Crest Medical Physics, Chico, CA, USA; 16Gulf Coast Cancer Treatment Center, Panama City, FL, USAPurpose: This multicenter, retrospective study evaluated treatment and clinical outcomes of patients with early stage breast cancer who received adjuvant high-dose rate (HDR) electronic brachytherapy (EBT) treatment post-lumpectomy using the Axxent® EBT system. Dosimetric data from the EBT treatment plans were compared with those based on iridium-192 HDR brachytherapy.Material and methods: Medical records of 63 patients with early stage breast cancer (Tis, T1a, T1b, T1c, and T2) who were treated post-lumpectomy with EBT alone or in combination with external beam radiation therapy were reviewed. The prescribed EBT dose was 34 Gy (10 fractions over 5 days, 3.4 Gy each) to 1 cm from the balloon surface. Dosimetry data from 12 patients were compared with these of treatment plans using an iridium-192 source prepared for the same 12 patients.Results: The majority of patients (90.5%) were older than 50 years and had one or more risk factors for breast cancer (80.6%). Tumor sizes were 0.1 cm to 3.5 cm (mean 1.3 cm). Median follow-up was 7 months (1 to 18 months) post-EBT. Balloon applicators were implanted 0 to 85 days (mean 13.4 days) post-lumpectomy/re-excision. The most common adverse events were erythema, rash dermatitis, and pain or breast tenderness. No recurrences were reported. Dosimetric analyses demonstrated comparable target coverage, increased high-dose regions, and a significantly reduced dose to the ipsilateral breast and lungs as well as the heart with EBT as compared with the iridium-192 treatment plans.Conclusion: This retrospective, multicenter study showed that postsurgical adjuvant radiation therapy for early stage breast cancer can be administered using the EBT system with similar toxicity outcomes to those reported with iridium-192 brachytherapy. EBT offers a convenient, portable, nonisotope alternative to HDR brachytherapy using iridium-192.Keywords: electronic brachytherapy, breast cancer, radiation therapy

William C Dooley1, John P Thropay2, Gary J Schreiber3, Mohamed Y Puthawala4, Steven C Lane5, James C Wurzer6, Charles E Stewart7, Gordon L Grado8, Harish G Ahuja9, Gary M Proulx101University of Oklahoma Health Sciences Center, Oklahoma City, OK; 2Beverly Oncology and Imaging Center, Montebello, CA; 3Swedish Covenant Medical Center, Chicago, IL; 4Rhode Island Hospital, Providence, RI; 5Signature Healthcare Brockton Hospital, Brockton, MA; 6AtlantiCare Regional Medical Center, Egg Harbor Township, NJ; 7St Francis Medical Center, Tulsa, OK; 8Southwest Oncology Centers, Scottsdale, AZ; 9Aspirus Regional Medical Center, Wausau, WI; 10Exeter Hospital, Exeter, NH, USABackground: This retrospective, multicenter study evaluated the feasibility and safety of high-dose rate electronic brachytherapy (EBT) as a postsurgical adjuvant radiation therapy for endometrial cancer.Methods: Medical records were reviewed from 41 patients (age 40–89 years) with endometrial cancer (Federation of International Gynecology and Obstetrics stages IA–IIIC) treated at nine centers between April 2008 and October 2009. Treatment included intracavitary vaginal EBT alone (n = l6) at doses of 18.0–24.0 Gy in 3–4 fractions and EBT in combination with external beam radiation therapy (EBRT, n = 25) at a total radiation dose range of 40.0–80.4 Gy. Doses were prescribed to a depth of 5 mm from the applicator surface and to the upper third (n = 15) and the upper half (n = 26) of the vagina.Results: Median follow-up was 3.8 (range 0.5–12.0) months. All 41 patients received the intended dose of radiation as prescribed. Adverse events occurred in 13 of 41 patients and were mild to moderate (Grade 1–2), consisting primarily of vaginal mucositis, rectal mucosal irritation and discomfort, and temporary dysuria and diarrhea. There were no Grade 3 adverse events in the EBT-only treatment group. One patient, who was being treated with the combination of EBT and EBRT for recurrent endometrial cancer, had a Grade 3 adverse event. No recurrences have been reported to date.Conclusion: Electronic brachytherapy provides a feasible treatment option for postoperative adjuvant vaginal brachytherapy as sole radiation therapy and in combination with EBRT for primary endometrial cancer. Early and late toxicities were mild to moderate.Keywords: endometrial cancer, electronic brachytherapy, radiation therapy

Preoperative focused microwave thermotherapy (FMT) is a promising method for targeted treatment of breast cancer cells. Results of four multi-institutional clinical studies of preoperative FMT for treating invasive carcinomas in the intact breast are reviewed.Externally applied wide-field adaptive phased-array FMT has been investigated both as a preoperative heat-alone ablation treatment and as a combination treatment with preoperative anthracycline-based chemotherapy for breast tumors ranging in ultrasound-measured size from 0.8 to 7.8 cm.In phase I, eight of ten (80%) patients receiving a single low dose of FMT prior to receiving mastectomy had a partial tumor response quantified by either ultrasound measurements of tumor volume reduction or by pathologic cell kill. In phase II, the FMT thermal dose was increased to establish a threshold dose to induce 100% pathologic tumor cell kill for invasive carcinomas prior to breast-conserving surgery (BCS). In a randomized study for patients with early-stage invasive breast cancer, of those patients receiving preoperative FMT at ablative temperatures, 0 of 34 (0%) patients had positive tumor margins, whereas positive margins occurred in 4 of 41 (9.8%) of patients receiving BCS alone (P = 0.13). In a randomized study for patients with large tumors, based on ultrasound measurements the median tumor volume reduction was 88.4% (n = 14) for patients receiving FMT and neoadjuvant chemotherapy, compared with 58.8% (n = 10) reduction in the neoadjuvant chemotherapy-alone arm (P = 0.048).Wide-field adaptive phased-array FMT can be safely administered in a preoperative setting, and data from randomized studies suggest both a reduction in positive tumor margins as a heat-alone treatment for early-stage breast cancer and a reduction in tumor volume when used in combination with anthracycline-based chemotherapy for patients with large breast cancer tumors. Larger randomized studies are required to verify these conclusions.

Interest in breast endoscopy came from Oriental investigators in the early 1990s where bloody nipple discharge is a more common presentation of breast cancer. The early techniques using a single microfiber scope without ductal distension was successful in navigating only the first 1-3 cm of the ducts and fraught with technical problems such as scope breakage and poor image quality. In spite of these barriers there has been increasing use of this technology in Japan and more widespread acceptance as the technology of scope design improved. Dooley and others tested a new method of obtaining a rich cytologic specimen from the ducts of high-risk women known as ductal lavage recently. The success of this procedure was that it detected severe cytologic and malignant atypia in clinically and radiographically normal breasts. Reproducibly, the same breast duct could be cannulated and severely atypical cytology obtained. The problem arose in identifying the lesion within the breast, which was the source for the atypia. New American multi-fiber microendoscopes were applied to solve this problem in an initial series of patients with abnormal cytology to identify the lesions. Success of that series lead to wider application of the imaging technology and eventual adoption of this imaging modality help to guide during all non-mastectomy breast surgery where fluid could be elicited from the nipple to identify the duct connecting to the lesion for which surgery was being performed. Initial reports have demonstrated the types of operative findings in certain sub-populations early in the use of this technology.

Diagnostic breast biopsy is one of the most common medical procedures, and a variety of methods have been developed in the last 30 years to augment classic surgical incisional and excisional biopsies. Fine-needle aspiration (FNA) has an important historical role and remains among the most cost-effective methods but is limited by the weakness of current breast cytology to adequately reproduce all information provided by traditional histopathology. FNA continues to play an important role in assessing risk. Core biopsies ranging from the use of simple needle cores to larger coring devices to remove spaghetti- to macaroni-sized pieces have become the mainstay of current biopsy techniques for most palpable and non-palpable lesions. Surgical incisional and excisional biopsies, which are the classic standards, are reserved for a few exceptional circumstances, including the removal of symptomatic benign lesions or when coring biopsy tools fail to provide adequate diagnostic information and material. Ductoscopy, which was initially developed as a tool to investigate pathological nipple discharge, is an evolving technology that may have an increasing role in research and prevention as tools and techniques become more refined. Failure of biopsy to accurately diagnose breast problem remains a small but persistent problem requiring the diligent methodical use of biopsy methods and the careful consideration of issues such as sample bias when the entire lesion is not removed and there is discordance between clinical expectations and biopsy pathology.

Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)–/CD44+ hormone-independent breast cancer cells, but not of the ER+/CD44-/low hormone-dependent breast cancer cells. Coincidentally, CD44+ breast cancer cells were abundant in metastatic lung and brain lesions in ER– breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER–/CD44+ breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44+ cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER–/CD44+ breast cancer.