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Breast imaging plays an essential role in the diagnosis and management of breast disease. From screening asymptomatic patients to evaluating clinical abnormalities on diagnostic studies, breast imaging provides critical information to the breast surgeon. Available imaging studies include those that have been proved over many years, like mammography, and those that take advantage of increasingly sophisticated technology, like breast MRI. Image-guided biopsy provides a safe means of evaluating indeterminate findings on imaging. Understanding how these tools are best used can help breast surgeons provide the best care for their patients.

Supplementary Table 10 � XLXS file 35K, Metastasis rates in xenograft lines

Supplementary Fig 1 � PDF file 42K, General design of the xenografting program

Supplementary Fig 2 � PDF file 783K, Histology of unmatched xenograft lines

Supplementary Table 3 � XLXS file 39K, Patient/xenograft biomarker comparison

Supplementary Fig 4 � PDF file 123K, Treatment response concordance with the tumor of origin

Supplementary Table 2 � XLXS file 18K, STR Results

Legends to Supplementary Figures - PDF file 65K, Legends to supplementary figures

Link for Supplementary Tables 4-7 � PDF file 39K, Table 4 - Patient Clinical Treatment Response; Table 5 - Frequency of Lung Metastasis in Xenograft Lines; Table 6 - Sequenom Analysis of SNPS in Xenografts; Table 7 - Xenograft Short Tandem Repeat (STR) Profile

Supplementary Fig 3 � PDF file 31K, Demonstration of histological stability

Supplementary Table 8 � XLXS file 12K, Sequenom assays used

The US Health and Human Services Pain Management Best Practices Inter-Agency Task Force initiated a public–private partnership which led to the publication of its report in 2019. The report emphasized the need for individualized, multimodal, and multidisciplinary approaches to pain management that decrease the over-reliance on opioids, increase access to care, and promote widespread education on pain and substance use disorders. The Task Force specifically called on specialty organizations to work together to develop evidence-based guidelines. In response to this report’s recommendations, a consortium of 14 professional healthcare societies committed to a 2-year project to advance pain management for the surgical patient and improve opioid safety. The modified Delphi process included two rounds of electronic voting and culminated in a live virtual event in February 2021, during which seven common guiding principles were established for acute perioperative pain management. These principles should help to inform local action and future development of clinical practice recommendations.

Purpose/Objective: Intraoperative radiation therapy (IORT) is a form of accelerated partial breast irradiation (APBI) delivered at the time of lumpectomy for early-stage breast cancer. Upfront selection of patients based on favorable preoperative characteristics is important to achieve good outcomes. Here we present our single-institution experience in the management of invasive breast cancer with IORT. We focused on the classification of patient suitability for IORT by the American Society for Therapeutic Radiation Oncology (ASTRO) APBI consensus guidelines using preoperative and postoperative clinicopathologic factors, as well as treatment outcomes and recurrences. Materials/Methods: We reviewed our institutional prospective registry database (AAAJ8512) to identify patients with biopsy-proven invasive breast cancer treated with breast IORT between 9/2013 and 4/2020 using the Zeiss Intrabeam™. Patients received a single dose of 20Gy delivered to the lumpectomy cavity surface at the time of planned surgery. We excluded patients from analysis with prior radiation to the breast, or triple negative disease at initial diagnosis. We reviewed preoperative and postoperative clinicopathologic factors to determine each patient’s ASTRO APBI suitability (suitable, cautionary or unsuitable) based on the 2017 consensus guidelines. Results: 237 patients were treated with IORT for early stage breast cancer. Median age was 67 years (range 44-94 years). Median extent of disease by conventional imaging was 1.0 cm (range 0 - 3.0cm). 51/103 (49.5%) patients with heterogeneously or extremely dense breasts underwent a MRI preoperatively. Based on preoperative clinicopathologic characteristics, 191 (80.6%) patients were suitable according ASTRO APBI guidelines, 46 (19.4%) cautionary and no patients were unsuitable. APBI group suitability changed in 95 (40.1%) patients based on final pathology from the time of lumpectomy, summarized in Table 1. 17 (7.2%) patients underwent re-excision for close or positive margins. 39 (16.5%) patients received additional adjuvant whole breast radiotherapy including 10/18 (56%) of unsuitable patients. Of 212 (89.5%) patients who initiated hormone therapy (HT), 191 (80.6%) were compliant at last follow up. Median follow-up for all patients was 38.2 months (0.4 - 74.5). Five (2.1%) patients experienced ipsilateral breast tumor recurrence, 1 (0.4%) patient experienced new contralateral breast cancer, and 2 (1.6%) patients experienced distant recurrence with the median time to event of 27.8 months (range 6.3-50.4). Of the 5 patients with ipsilateral breast tumor recurrence, 2 (0.8%) were true local recurrences 2cm from lumpectomy bed with a different histology. Conclusion: Breast IORT is an attractive cost-effective option for women with early stage breast cancer, and our 3-year true local recurrence rate is 0.8%. Optimal patient selection is key based on preoperative characteristics. Patients who become unsuitable or cautionary for APBI based on final pathology should be considered for additional adjuvant therapy. Table 1ReasonASTRO APBI Pre-Op Suitability#SizeER (-)AgeT2ILCSuitable191Cautionary46114101122Unsuitable0ASTRO APBI Post-Op Suitability Change#SizeClose MarginsPositive MarginsLVIMultifocalILCEICSuitable to Cautionary7792023211124Suitable to Unsuitable12111Cautionary to Unsuitable624Abbreviations: ER = Estrogen Receptor; ILC = Invasive Lobular Carcinoma; LVI = Lymphovascular Invasion; EIC = Extensive Intraductal Component Citation Format: Andrea M Brown, Christine Chin, Eileen Connolly, Roshni Rao, Bret Taback, Lisa Wiechmann. Preoperative selection of patients with early-stage invasive breast cancer for intraoperative radiation therapy (IORT): A single-institution experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-19.

INTRODUCTION Up to 6% of opioid naive patients who undergo surgery become chronic opioid users. The aim of this study was to determine if formal opioid prescribing education of general surgery residents is associated with decreased opioid prescribing postoperatively. METHODS We surveyed surgery residents at 3 general surgery programs in the United States and 1 in Israel. Residents were divided into 2 groups based on whether or not they received formal opioid prescribing education. RESULTS Of those surveyed, 107 (50%) responded. 45% of residents had formal opioid prescribing education, which included instructional videos, current literature, and hospital guidelines. For the 4 operations analyzed, residents who received no formal teaching prescribed a higher number of opioids (lumpectomy p = 0.001, open inguinal hernia repair p = 0.004, laparoscopic appendectomy p = 0.007, thyroidectomy p = 0.002). The largest difference in opioid prescribing was seen in “high prescribers,” defined as residents prescribing 15 or more opioid pills. For thyroidectomy, 24.4% of residents without formal education prescribed 20 or more oxycodone 5mg pills compared to 0% of residents with formal education. The Israeli cohort was less likely to receive a pain focused education and was also less likely to prescribe opioids to their patients for all 4 procedures evaluated. CONCLUSIONS Although a minority of general surgery residents are receiving an opioid prescribing education, a formal educational program was associated with significantly decreased opioid prescribing. There is a need for a generalizable educational opioid program for surgery residents.

Background Growing evidence suggests a possible sex disparity in COVID-19 disease related outcomes. Objective To explore the sex disparity in COVID-19 cases and outcomes using New York City (NYC) population level data. Setting NYC surveillance data from February 29 to June 12, 2020. Participants Individuals tested for COVID-19 in metropolitan NYC.Outcome Measurements and Statistical Analysis: Outcomes of interest included rates of COVID-19 case positivity, hospitalization and death. Relative risks and case fatality rates were computed for all outcomes based on sex and were stratified by age groups. Results and limitations 911,310 individuals were included, of whom 434,273 (47.65%) were male and 477,037 (52.35%) were female. Men represented the majority of positive cases (n=106,275, 51.36%), a majority of hospitalizations (n=29,847, 56.44%), and a majority of deaths (n=13,054, 59.23%). Following population level adjustments for age and sex, testing rates of men and women were equivalent. The majority of positive cases and hospitalizations occurred in men for all age groups except age g75 years, and death was more likely in men of all age groups. Men were at a statistically significant greater relative risk of case positivity, hospitalization, and death across all age groups except those l18 years of age. The most significant difference for case positivity was observed in the 65n74 age group (RR 1.22, 95%CI 1.19n1.24), for hospitalization in the 45n65 age group (RR 1.85, 95% 1.80n1.90), and for death in the 18n44 age group (RR 3.30, 95% CI 2.82n3.87). Case fatality rates were greater for men in all age-matched comparisons to women. Limitations include the use of an evolving surveillance data set and absence of further demographic characteristics such as ethnographic data. Conclusion Men have higher rates of COVID-19 positivity, hospitalization, and death despite greater testing of women; this trend remains after stratification by age. J Drugs Dermatol. 2020;19(10):960-967. doi:10.36849/JDD.2020.5590.

Significant knowledge gaps exist in the perioperative pain management of patients with a history of chronic pain, substance use disorder, and/or opioid tolerance as highlighted in the US Health and Human Services Pain Management Best Practices Inter-Agency Task Force 2019 report. The report emphasized the challenges of caring for these populations and the need for multidisciplinary care and a comprehensive approach. Such care requires stakeholder alignment across multiple specialties and care settings. With the intention of codifying this alignment into a reliable and efficient processes, a consortium of 15 professional healthcare societies was convened in a year-long modified Delphi consensus process and summit. This process produced seven guiding principles for the perioperative care of patients with chronic pain, substance use disorder, and/or preoperative opioid tolerance. These principles provide a framework and direction for future improvement in the optimization and care of ‘complex’ patients as they undergo surgical procedures.

Re-excision for positive margins (margins where tumor is positive) after breast conserving surgery (BCS) is common and burdensome for breast cancer patients. Routine shave margins can reduce positive margins and re-excision rates. Cavity shaving margin (CSM) removes margins from the lumpectomy cavity edges, whereas specimen shave margin (SSM) requires ex vivo removal of margins from the resected specimen.We assessed breast cancer patients undergoing BCS who received CSM or SSM procedures from 2017 to 2019. CSM and SSM techniques were compared by analyzing positive rates of primary and final shaved margins, re-excision rates, and tissue volumes removed.Of 116 patients included in this study, 57 underwent CSM and 59 underwent SSM. Primary margins were positive or close in 19 CSM patients and 21 SSM patients (33% versus 36%; P = 0.798). Seventeen CSM patients had a tumor in shaved margin specimens, compared to four patients for SSM (30% versus 7%; P 0.001); however, final shave margins were similar (5% versus 5%; P = 0.983). Volumes of shave specimens were higher with SSM (40.7 versus 13.4 cmCSM and SSM are effective techniques for achieving low re-excision rates. Our findings suggest that surgeons performing either CSM or SSM may maintain operative preferences and achieve similar results.

Background Intraoperative radiation therapy (IORT) has gained popularity for early stage breast cancer treatment. Few studies have examined the relationship between complications and both demographic and technical factors. The objective of the current study was to determine if applicator size or distances to the skin were significant risk factors for complications. Methods Data was prospectively collected on patients who underwent lumpectomy followed by IORT from November 1, 2013 to August 31, 2018. Exclusion criteria included any prior radiation exposure or personal history of breast cancer. Comorbid conditions such as body mass index, diabetes, and smoking as well as technical specifications such as applicator size and distances to the skin were included for investigation. Student's t-test, Fisher's exact test, and odds ratios were utilized for statistical analysis. Results The study was comprised of 219 patients. None developed Clavien-Dindo grade 2 or above complications. Of 21.0% (n = 46) had minor complications. The most common complication was a palpable breast seroma (n = 37). Diabetes was the only comorbid condition with increased risk for complications (OR 3.2; 95% CI1.3-7.5; P = 0.008). The applicator sizes and average skin distances were similar between groups. Surprisingly, the closest skin distance was not a significant risk factor for post-operative complications (1.4 +/- 1.6 versus 1.4 +/- 1.9 cm; P = 1.0). Conclusion Neither applicator size nor the closest skin distance were associated with increased complications. Traditionally described risk factors such as BMI and smoking were not predictive. This data provides support for potentially expanding the utilization for IORT without increasing complications.

Summary The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes.

Background: The PI3K/Akt/mTOR pathway is an important oncogenic driver in BC. A major hurdle in clinical Akt inhibitor development has been dose-limiting toxicities, such as rash. To facilitate the risk assessment of Akt inhibitor associated toxicity, we hypothesize that circulating biomarkers can be identified in proteins secreted by the tumor or tumor microenvironment and systemic response after treatment. Exosomes are small membrane bound vesicles containing proteins, mRNA, miRNA, and lipids that are secreted from host cells and remain viable after long-term storage of blood. In this study, we focused on identifying biomarkers associated with drug rash from serum exosomes in BC patients treated with the Akt inhibitor MK-2206. Methods: In an open-label pre-surgical trial, 2 doses of weekly MK2206 were administered to patients (pts) with stage I-III invasive BC: first at day -9 and second at day -2 from surgery. Sera were collected before and after MK2206. 200 μL of serum was used to isolate total exosomes by precipitation and centrifugation, followed by trypsin digestion and multiplexing labeling analysis. The Orbitrap mass spectrometer was used to acquire LC-MS/MS data. 1,053 unique proteins were identified from the uniProt database. Maximum false discovery rate level (FDR) for predictive biomarkers was controlled at 26% (q Results: The study was discontinued after 12 pts were enrolled due to toxicity. Notably, an acneiform/maculopapular rash was observed in 5 pts. Unsupervised principal component analysis on the pre-MK-2206 specimens and the entire set of 1,053 proteins demonstrated that 4 of the 5 pts with rash formed a distinct cluster. 30 proteins were differentially expressed in pre-MK-2206 samples from pts who developed rash vs. no rash (q Conclusions: We demonstrated that mass spectrometry-based proteomic analysis of patient-derived serum exosomes is a promising approach to study drug-induced toxicity. We found significant changes of circulating proteins before and after MK-2206. Increased expression of different proteins involved in lipid metabolism appears to predict skin toxicity, commonly seen with PI3K/Akt pathway inhibitors. Since the PI3K/Akt signaling pathway plays a role in physiological regulation of lipid metabolism, lipid metabolic profiles of BC patients might be important for predicting the risk and controlling toxicity induced by Akt inhibitors. These toxicity-associated biomarkers should be validated and then assessed prospectively in clinical trials. Citation Format: Mundi PS, Chen E, Sparano J, Andreopoulou E, Taback B, Wiechmann L, Feldman S, Ananthakrishnan P, Hibshoosh H, Connolly E, Crew K, Maurer M, Hershman DL, Kalinsky K. Identification of serum biomarkers associated with Akt inhibitor MK-2206-induced toxicity in a pre-surgical breast cancer (BC) 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 P3-07-52.

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m(2) every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo.

Oncogenic targets acting in both tumor cells and tumor stromal cells may offer special therapeutic appeal. Interrogation of the Oncomine database revealed that 52 of 53 human breast carcinomas showed substantial upregulation of WNT family ligand WNT7B. Immunolabeling of human mammary carcinoma showed that WNT7B immunoreactivity was associated with both tumor cells and with tumor-associated macrophages. In the MMTV-PymT mouse model of mammary carcinoma, we found tumor progression relied upon WNT7B produced by myeloid cells in the microenvironment. Wnt7b deletion in myeloid cells reduced the mass and volume of tumors due to a failure in the angiogenic switch. In the tumor overall, there was no change in expression of Wnt/β-catenin pathway target genes, but in vascular endothelial cells (VEC), expression of these genes was reduced, suggesting that VECs respond to Wnt/β-catenin signaling. Mechanistic investigations revealed that failure of the angiogenic switch could be attributed to reduced Vegfa mRNA and protein expression in VECs, a source of VEGFA mRNA in the tumor that was limiting in the absence of myeloid WNT7B. We also noted a dramatic reduction in lung metastasis associated with decreased macrophage-mediated tumor cell invasion. Together, these results illustrated the critical role of myeloid WNT7B in tumor progression, acting at the levels of angiogenesis, invasion, and metastasis. We suggest that therapeutic suppression of WNT7B signaling might be advantageous due to targeting multiple aspects of tumor progression. Cancer Res; 74(11); 2962–73. ©2014 AACR.

Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of severe combined immunodeficient (SCID)/Beige and nonobese diabetic (NOD)/SCID/IL-2γ-receptor null (NSG) mice under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (∼21% and ∼19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were “triple-negative” [estrogen receptor (ER)−progesterone receptor (PR)−HER2+; n = 19]. However, we established lines from 3 ER−PR−HER2+ tumors, one ER+PR−HER2−, one ER+PR+HER2−, and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biologic consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including 2 ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis. Cancer Res; 73(15); 4885–97. ©2013 AACR.

Introduction Translational breast cancer research is hampered severely by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that accurately reflect patient tumor biology. These limitations are due, in part, to the fact that traditional immunocompromised mouse models are not generally permissive for growth. We sought to circumvent some of these limitations by transplanting and growing human mammary tumors in the mammary fat pad of SCID/Beige immunocompromised mice in the absence of exogenous human fibroblasts. Aims and Methods To establish a set of stable human breast cancer xenografts for preclinical studies. Human breast cancer biopsies were received, minced into small fragments and then transplanted directly into “cleared” fat pads of recipient SCID/Beige immunocompromised mice. Transplanted fat pads were checked weekly. After initial tumor was palpated and harvested, tumor fragments were transplanted into new SCID/Beige hosts for subsequent transplant generations. Serial immunohistochemical evaluations were performed to confirm human origin and biomarker status. Analytical flow cytometry for evaluating expression of proposed “cancer stem cell” markers, and gene and protein expression analysis were carried out on all stable lines. Results and Conclusions Xenograft lines were established directly from breast cancer patient samples, without intervening culture in vitro, using the epithelium-free mammary fat pad as the transplantation site. Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet without exogenous human fibroblasts. Thirty six stably transplantable xenograft lines representing 27 patients were established, using pre-treatment, mid-treatment, and/or post-treatment samples. Most patients yielding xenografts were “triple-negative” (ER-PR-HER2−) (n=21), we were able to establish lines from three ER-PR-HER2+ patients, one ER+PR+HER2−, one ER+PR-HER2−and one “triple-positive” (ER+PR+HER2+) patients. Serially passaged xenografts show phenotypic consistency with the tumor of origin at the histopathology level, and remarkable stability across multiple transplant generations at both the genomic, transcriptomic, and proteomic levels. Of 27 lines evaluated fully, thirteen xenografts showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource, and should prove useful for preclinical evaluation of experimental therapeutics. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-21-01.

The tumor microenvironment is a complex network of cells that support tumor progression and malignancy. It has been demonstrated that tumor cells can educate the immune system to promote a tumor-friendly environment. Among all these immune cells, tumor-associated macrophages (TAMs) are well represented and their presence in mouse models has been shown to promote tumor progression and metastasis. These effects are through the stimulation of angiogenesis, enhancement of tumor cell invasion and intravasation, immunosuppression, and at the metastatic site tumor cell extravasation and growth. However, the precise mechanisms are not fully understood. Furthermore there is limited information on TAMs derived from human cancers. For this reason it is important to be able to extract TAMs from tumors in order to compare their phenotypes, functions, and transcriptomes with normal resident tissue macrophages. Isolation of these cells is challenging due to the lack of markers and standardized protocols. Here we show an optimized protocol for the efficient isolation and extraction of resident macrophages and TAMs from human and mouse tissues by using multicolor flow cytometry. These protocols allow for the extraction of thousands of macrophages in less than 5 h from tissues as small as half a gram. The isolated macrophages can then be used for both “omics” and in vitro studies.

Breast cancer evolution and tumor progression are governed by the complex interactions between steroid receptor [estrogen receptor (ER) and progesterone receptor] and growth factor receptor signaling. In recent years, the field of cancer therapy has witnessed the emergence of multiple strategies targeting these specific cancer pathways and key molecules (ER and growth factor receptors) to arrest tumor growth and achieve tumor eradication; treatment success, however, has varied and both de novo (up front) and acquired resistance have proven a challenge. Recent studies of ER biology have revealed new insights into ER action in breast cancer and have highlighted the role of an intimate crosstalk between the ER and HER family signaling pathways as a fundamental contributor to the development of resistance to endocrine therapies against the ER pathway. The aim of this review article is to summarize the current knowledge on mechanisms of resistance of breast cancer cells to endocrine therapies due to the crosstalk between the ER and the HER growth factor receptor signaling pathways and to explore new available therapeutic strategies that could prolong duration of response and circumvent endocrine resistant tumor growth.

Objective: To investigate the acute effects of low-dose caffeine and aminophylline on cerebral blood flow in preterm infants, using both near-infrared spectroscopy (NIRS) and cerebral Doppler ultrasonography. Methods: Preterm infants with a gestational age of 2Hb), deoxygenated hemoglobin (HHb), oxidized-reduced cytochrome aa3 (CtOx), and mean cerebral oxygen saturation (SmO2 = O2Hb/total Hb). Changes in cerebral blood volume (ΔCBV) after caffeine or aminophylline administration were calculated. Cerebral blood flow velocity (CBV) in the pericallosal artery was evaluated by cerebral Doppler ultrasounds. Results: Data collected by NIRS and cerebral Doppler ultrasounds did not show significant differences before and after caffeine treatment. We observed a significant increase in O2Hb and HHb concentration and in CBV at 30 min after the infusion of aminophylline, which tended to return to baseline at the end of the study period. Conclusion: Caffeine does not significantly affect brain hemodynamics, while aminophylline induces a significant transient increase in O2Hb and HHb concentration and CBV.

Background: Breast and endometrial cancers are two of the most frequently diagnosed reproductive cancers in women in the western world. Previously, research has focused on cancer cells, however increasing evidence shows that the tumour microenvironment plays an important role in cancer progression. Macrophages are almost entirely derived from circulating monocytes and are recruited into tumour sites. In murine studies, tumour-associated macrophages (TAMs) have been implicated in promoting angiogenesis, immune suppression and resistance to treatment. Their density has been associated with poor prognosis in breast cancer and decreased survival in endometrial cancer. However, little is known about the function of TAMs in humans. The aim of this study is to examine the transcriptional profiles of human TAMs in order to investigate their biological relevance and potential for therapeutic intervention. Methods: RNA-sequencing was performed on purified normal macrophages and TAMs from breast tissue (4 breast cancer and 4 healthy breast) and endometrium tissue (5 endometrial cancer and 9 healthy endometrium). Statistical analysis using Limma was used to identify significantly differentially expressed genes (FDR< 0.05) with a minimum log2 fold change of 1.5. Gene set enrichment (GSEA) analysis and gene ontologies (GO) were employed for functional analysis and identification of important biological pathways. Results: Transcriptome profiling revealed a significantly altered gene expression profile of TAMs when compared to normal macrophages. Furthermore, comparison of TAMs between breast and endometrial cancer also revealed differences suggesting that different tumour microenvironments induce different gene expression profiles in TAMs. Interestingly, comparison of normal macrophages between breast and endometrial tissue also revealed differences in gene expression suggesting tissue specificity for macrophages. Functional analysis of significant genes revealed similar biological pathways to those of murine studies suggesting that TAMs in humans may have similar functions. We were able to extract TAM-specific genes by comparing with publicly available datasets that could serve as markers for their identification. Finally, we identified a list of transmembrane receptors that could act as potential targets for targeted killing of TAMs. Conclusion: This is the first study to carry out genome-wide profiling of TAMs in human breast and endometrial cancer. Expression profiles differed between TAMs and healthy patients, as well as between breast and endometrial cancer suggesting cancer specificity for TAMs and revealing not only potential TAM-specific markers, but also identifying possible cancer- and TAM-specific therapeutic targets. Citation Format: Matina Fragkogianni, Luca Cassetta, Agnieszka Swierczak, Lisa Wiechmann, Harriet O. Smith, Andrew H. Sims, Hui Zhang, Lisa M. Coussens, J. W. Pollard. Transcriptional profiling of human TAMs highlights differences in breast and endometrial tumour microenvironments. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2698.

Purpose: We have shown that incomplete blockade of the human epidermal growth factor (HER) pathway is a mechanism of resistance to treatment with trastuzumab (T) in HER2-overexpressing tumor xenografts. We now investigate whether the addition of lapatinib (L), a dual HER1/2 kinase inhibitor, to T results in more potent inhibition of the pathway and therefore inhibition of tumor growth, and whether reduced dose and intermittent treatment with the combination is equally effective. Experimental Design: Nude mice bearing HER2-overexpressing MCF7/HER2–18 or BT-474 xenograft tumors were treated with L and T, alone or in various combinations with other HER inhibitors. L + T for short duration (14 and 42 days), intermittent administration (14 days on/off), and reduced dosing (half dose) was also investigated. Inhibition of tumor growth, downstream signaling, proliferation, and induction of apoptosis were assessed. All statistical tests were two-sided. Results: L + T was the most effective regimen in both MCF7/HER2–18 and BT-474 xenografts with complete regression (CR) of tumor observed in all mice. Intermittent and reduced dose treatment (½ dose) resulted in high rates of CR and low rates of tumor recurrence that were comparable to full dose continuous treatment. L + T resulted in significantly reduced downstream signaling and proliferation, and increased apoptosis. Conclusions: L + T is a potent and effective combination even when given in reduced dose or intermittent schedule potentially resulting in lower toxicity and reduced cost if translated to patients. These findings warrant timely clinical testing. Clin Cancer Res; 17(6); 1351–61. ©2011 AACR.

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of mammographically detected breast cancers. DCIS can recur or progress to invasive breast cancer, but the ability to predict the outcome of patients with DCIS remains limited, leading to inappropriate treatment choices. To the authors' knowledge to date, the hunt for molecular prognostic markers for DCIS has been unsuccessful. Emerging technologies, however, are shedding new light on the biologic course of DCIS. In the current study, the authors review recent findings elucidating the molecular journey from DCIS to invasive cancer and discuss how these findings will lead to more effective treatment with minimization of morbidity.

2613 Background: The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). MK-2206 is the first allosteric Akt inhibitor in clinical development. The purpose of this p...

Objective.To evaluate whether fiberoptic phototherapy influences the postprandial increase in mesenteric blood flow velocity similarly to conventional phototherapy in preterm infants.Patients and Methods.With the use of Doppler color ultrasonography, blood flow velocity in the superior mesenteric artery was measured both preprandially and postprandially in 19 preterm infants during and after conventional phototherapy, and in 20 preterm infants during and after fiber-optic phototherapy. The mean arterial blood pressure/mean flow velocity ratio was calculated as an estimate of relative vascular resistance of the superior mesenteric artery.Results.The study shows that conventional phototherapy blunts the postprandial mesenteric blood flow response to feeding in preterm infants. Furthermore, it shows that the postprandial increase in intestinal blood flow is not attenuated when fiber-optic phototherapy is administered, and that such postprandial increase of blood flow is significantly greater than in infants receiving conventional phototherapy. During and after fiber-optic phototherapy, a significant reduction in postprandial relative vascular resistance was found; such reduction was significantly greater than during conventional phototherapy.Conclusions.Fiber-optic phototherapy is preferable to conventional phototherapy for the treatment of hyperbilirubinemia in preterm infants because it does not affect the physiologic postprandial redistribution of blood flow from the periphery to the gastrointestinal system as does conventional phototherapy.

Background Expression of the Epidermal Growth Factor Receptor ligand, Amphiregulin, has been associated with estrogen receptor positive breast cancer. As Amphiregulin is proteolytically released from the surface of breast cancer cells, we investigated the levels of Amphiregulin in the serum of breast cancer patients and cancer-free women to evaluate its potential utility as a breast cancer biomarker. Findings Serum Amphiregulin levels were quantified by ELISA from 125 cancer-free women and 114 breast cancer patients. No significant association between serum Amphiregulin levels and breast cancer status was detected at two cut-points evaluated. Conclusions Measurement of serum Amphiregulin levels lacks the necessary sensitivity and specificity for breast cancer screening in the general population.

Background: To serve as a bridge between pre-clinical and early clinical testing, pre-surgical studies are being designed to expose patients to a limited duration of an anti-cancer agent before launching a lengthy clinical trial program. In this model, modulation of predictive tissue and serum biomarkers are assessed. At Columbia University, we have completed 3 pre-surgical studies. The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). The first allosteric Akt inhibitor to enter clinical development, MK-2206 is well-tolerated and has demonstrated anti-cancer properties in pre-clinical and early-phase clinical studies. The purpose of this study (NCI P8740) is to determine the effects of MK-2206 on women with newly diagnosed BC between breast biopsy and surgery. Trial Design: Patients (n=30) will receive 2 doses of weekly MK-2206 (200 mg): first dose at day −9 and second at day −2 from surgery. This drug administration consistency will decrease the potential for noise in detecting true biomarker response. This time period was selected based upon the pharmacokinetic profile of weekly MK-2206. The main eligibility criteria for this open-label pre-surgical trial include operable, clinical stage I (at least T1c) to IIIC invasive BC. Patients not considered for neoadjuvant chemotherapy are eligible. Specific Aims: Our hypothesis is that MK-2206 will decrease phospho-AktSer473 in tumor tissue after 2 weekly doses. To maintain sample quality and ensure that phospho-Akt evaluated on formalin-fixed paraffin-embedded (FFPE) tissue is comparable across samples (given the 20 minute half life of AKT), all samples will be processed rapidly by a standardized protocol. Secondary objectives include the following in FFPE: modulation of downstream PI3K/Akt pathway signaling [immunohistochemistry and reverse phase-protein microarray analysis (RPPA)]; change in tumor proliferation (Ki-67 staining); and exploration of whether PI3K/Akt signaling change depends upon tumor genetics (PIK3CA mutation or PTEN loss) or expression (Hormone Receptor/HER2 status). Pre- and post-MK-2206 blood will be collected for phospho-expression analysis in peripheral blood mononuclear cells (RPPA and western blotting). Statistical Methods: With the expectation that 20% of the matched pre- and post-treatment tissue samples will not be analyzable, we will enroll 30 patients to ensure that matched tumor samples from 24 patients are available for our primary analysis. A sample size of 24 patients will yield greater than 90% power to detect a difference in the mean score between pre-and-post treatment samples of 60 units, paired t-test (2-sided, 0.05 significance level). This trial was recently activated by the NCI and currently ready to accrue patients. Patients will be enrolled and treated at affiliated institutions in the New York Cancer Consortium. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-03.

Abstract #706 Background In preclinical studies of HER2 positive breast cancer, combination antiHER therapy with lapatinib (L) and trastuzumab (T), is more promising than monotherapy. To reduce side effects, cost and increase patient compliance, we investigated novel dosing and scheduling of the L and T combination to find alternative treatment approaches. Methods Mice bearing xenograft tumors of BT474 (ER+/HER2-amplified) cells were treated with control estrogen supplementation, with estrogen withdrawal alone, or with estrogen withdrawal in combination with one or two HER inhibitors (T-10mg/Kg biweekly, L-100mg/Kg 5d/wk) continuously. Alternative dosing regimens included limited treatment duration (14, 42 days), intermittent administration (14 days on/ 14 days off L+T treatment), and dose adjustments (1/2L + 1/2T). Tumor volumes and weights were evaluated weekly. Results were analyzed with the Fisher's exact test or survival analysis methods (Kaplan-Meier estimates) and generalized Wilcoxon test. Group sizes were designed to rule out relatively large decrements in efficacy [i.e. 99% complete regression (CR) vs 65% CR]. All statistical tests were two-sided. Results At day 140 of the experiment, BT474 xenografts demonstrate de novo resistance to estrogen deprivation (ED) and respond more rapidly to the drug combination (L+T) compared to L or T alone. CR rates for xenograft tumors treated for 14 or 42 days are similar to full therapy, although relapses occur earlier (47% relapses at day 140 for 14 day treatment, compared to 20% and 0% for 42 day or full treatment, respectively). Intermittent treatment is as effective as full dose (one mouse demonstrating small palpable growth following CR died before confirmation of relapse). Decreasing the dose did not substantially change the percentage of tumors that undergo complete regression (CR) and did not accelerate treatment failure [Progression Free Survival (PFS) at day 140], but was associated with longer time to complete tumor regression (TTR). Conclusion Intermittent treatment with combined T and L is a promising strategy that warrants further investigation. Though 42 days of therapy led to complete tumor regression, our preliminary data suggest that a sustained response is more likely to be achieved by treatment >42 days. Longer follow up is needed to determine the effectiveness of decreased dose regimens. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 706.