Citations

Preexposure prophylaxis (PrEP) of HIV infection with tenofovir-containing regimens is effective, but plagued by poor adherence in some studies. Options for safe, effective, and acceptable PrEP products, especially for men and women at risk of HIV via receptive anal intercourse (RAI), are needed. We performed a randomized, partially blinded, first-in-human evaluation of four candidate rectal microbicide vehicles—aqueous gel, aqueous fluid, lipid gel, and lipid fluid—to select a prototype for further clinical development. Eight seronegative participants received three doses of each product with each dose separated by at least 2 weeks: one dose was given alone without simulated RAI in clinic, another dose was followed by simulated RAI in clinic, and another dose was self-administered at home in the context of RAI with a partner. Assessments included safety, acceptability, colon histology, ex vivo HIV infectivity of colon tissue explants, and colonic luminal distribution of vehicle and HIV surrogates. Adverse events were all mild and mainly sigmoidoscopy associated. There were minor differences in colon distribution of products and little effect of RAI. Vehicle distribution covered 95% (±7% standard deviation) of the distribution of an HIV surrogate in the colonic lumen. The lipid fluid vehicle increased HIV colon tissue infectability 5-fold [log 10 p24 0.68 (95% confidence interval 0.08, 1.28)] and aqueous gel provided 6-fold protection [log 10 p24 0.80 (95% confidence interval 0.20, 1.41)] compared to no product baseline. Colon permeability of lipid vehicles was more than 10-fold greater than aqueous vehicles. All products received similar acceptability ratings, though trends favored the gel products. Intensive simultaneous assessment of safety and toxicity, luminal and tissue distribution, ex vivo HIV infectivity, and product acceptability in relevant sexual contexts provided clear differentiation among candidate gels very early in product development. We selected the aqueous gel for further development as a rectal microbicide vehicle.

Background Axillary web syndrome (AWS) is a condition that may develop following breast cancer surgery and that presents as a palpable axillary cord of tissue. Objective The purposes of this study were: (1) to determine the clinical characteristics of AWS related to movement, function, pain, and postoperative edema and (2) to define the incidence of and risk factors for AWS within the first 3 months following breast cancer surgery. Design This was a prospective cohort study with a repeated-measures design. Methods Women who underwent breast cancer surgery with sentinel node biopsy or axillary lymph node dissection (N=36) were assessed for AWS, shoulder range of motion, function, pain, and postoperative edema (using girth measurements, bioimpedance, and tissue dielectric constant) at 2, 4, and 12 weeks. Demographic characteristics were used for risk analysis. Results Seventeen women (47.2%) developed AWS, and AWS persisted in 10 participants (27.8%) at 12 weeks. Abduction range of motion was significantly lower in the AWS group compared with the non-AWS group at 2 and 4 weeks. There were no differences between groups in measurements of function, pain, or edema at any time point. Trunk edema measured by dielectric constant was present in both groups, with an incidence of 55%. Multivariate analysis determined lower body mass index as being significantly associated with AWS (odds ratio=0.86; 95% confidence interval=0.74, 1.00). Limitations Limitations included a short follow-up time and a small sample size. Conclusion Axillary web syndrome is prevalent following breast/axilla surgery for early-stage breast cancer and may persist beyond 12 weeks. The early consequences include movement restriction, but the long-term effects of persistent AWS cords are yet unknown. Low body mass index is considered a risk factor for AWS.

A mouse model for ALS A G4C2 repeat expansion in C9ORF72 is known to be the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). However, a lack of animal models recapitulating key disease features has hindered efforts to understand and prevent c9FTD/ALS-related neurodegeneration. Until now. Chew et al. describe a mouse model that mimics both neuropathological and clinical phenotypes of c9FTD/ALS. Science , this issue p. 1151

Abstract Emerging research on the long-term impact of concussions on athletes has allowed public recognition of the potentially devastating effects of these and other mild head injuries. Mild traumatic brain injury (mTBI) is a multifaceted disease for which management remains a clinical challenge. Recent pre-clinical and clinical data strongly suggest a destructive synergism between brain temperature elevation and mTBI; conversely, brain hypothermia, with its broader, pleiotropic effects, represents the most potent neuro-protectant in laboratory studies to date. Although well-established in selected clinical conditions, a systemic approach to accomplish regional hypothermia has failed to yield an effective treatment strategy in traumatic brain injury (TBI). Furthermore, although systemic hypothermia remains a potentially valid treatment strategy for moderate to severe TBIs, it is neither practical nor safe for mTBIs. Therefore, selective head-neck cooling may represent an ideal strategy to provide therapeutic benefits to the brain. Optimizing brain temperature management using a National Aeronautics and Space Administration (NASA) spacesuit spinoff head-neck cooling technology before and/or after mTBI in contact sports may represent a sensible, practical, and effective method to potentially enhance recover and minimize post-injury deficits. In this paper, we discuss and summarize the anatomical, physiological, preclinical, and clinical data concerning NASA spinoff head-neck cooling technology as a potential treatment for mTBIs, particularly in the context of contact sports.

Abstract Introduction: Histologic characteristics of nonmalignant breast tissues (epithelial proliferation and involution) are associated with future breast cancer (BC) risk. We evaluated immune infiltration (lobulitis) in benign breast lobules and its association with features of BC risk. Methods: We analyzed archived nonmalignant breast tissue samples from 81 women in age-matched groups of varying cancer risk: 27 with benign breast disease (BBD) who later developed BC (cases), 27 with BBD without subsequent BC (controls), and 27 normal women without clinical breast disease from the Komen Tissue Bank at Indiana University (KTB). Up to 10 lobules in each sample were characterized by H&E for lobulitis, involution (none, partial, complete), and fibrocystic (FC) status (normal, nonproliferative, proliferative). Lobulitis was defined by H&E staining as lymphocyte nuclei in the intralobular stroma at low magnification and between adjacent acini at high magnification. Data was analyzed by mixed effects logistic regression. Results: Median age was 57 years (range 37-70). Among 81 breast tissue samples, 750 lobules were evaluated: 249 in BBD Cases, 265 in BBD Controls, and 236 in KTB donors. 56% of lobules were normal and 44% were FC, with 87% of FC lobules occurring in BBD samples. Lobulitis was present in 44% of lobules and varied according to subject age and individual lobule features. Younger women were more likely to have lobulitis (p=0.002); among women <50 the median proportion of lobules with lobulitis was 50%, versus 30% among women 50+. Lobulitis was less frequent in lobules with complete involution (37%) compared to partial (74%) or no involution (84%), p<0.0001. Lobulitis was common in normal lobules (52%) and decreased with increasing epithelial abnormality-39% of nonproliferative lobules and 27% of proliferative lobules (p<0.0001). In multivariate analysis including all 3 variables, all 3 remained significantly associated with lobulitis: age (p=0.03), proliferation (p<0.0001), and involution (p=0.0001). Lobules with lobulitis were less frequent in groups of women with increased breast cancer risk-55% of lobules in normal KTB samples, 43% in BBD controls, and 35% in BBD cases (p = 0.02). Conclusion: Lobulitis is common in normal and benign breast tissue lobules but varies with age, involution status, and epithelial abnormality. Further work is needed to understand the role of immune infiltrates in breast cancer risk. Citation Format: Rushin D. Brahmbhatt, Daniel W. Visscher, Tanya L. Hoskin, Derek C. Radisky, Linda M. Murphy, Melody L. Stallings Mann, Erin Miller, Vernon S. Pankratz, Lynn C. Hartmann, Marlene H. Frost, Amy C. Degnim. Immune infiltration of normal and benign breast lobules varies in breast tissues based on cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1652. doi:10.1158/1538-7445.AM2014-1652

Abstract Background: In CALGB-49907 (NEJM 2009;360:2055), older patients (pts) with ESBC were randomized to standard adjuvant chemo (AC or CMF versus capecitabine). The objective of this secondary QoL analysis is to assess if pts’ BL chemo preference (CP, defined as high or low), is associated with the following during and after completion of chemo: self and professional-reported toxicity, changes in mental health, function, QoL, recurrence-free (RFS) and overall (OS) survival. Patients and Methods: Of 633 trial pts 350 participated in the QoL substudy; 145/350 pts completed the BL assessment regarding CP. CP was measured by asking the amount of benefit women would require to choose adjuvant chemo in a hypothetical situation, irrespective of chemo agents. Women who chose chemo for an increase in OS of ≤12 months (mo) were designated as high chemo preference (HCP) and those who chose >12 mo were designated low chemo preference (LCP). CP associations were evaluated with: BL perception of self-health and perceived QoL on chemo; patient reported outcomes (PROs), changes in function and QoL (based on EORTC-QLQ-C30); anxiety and depression (Hospital Anxiety and Depression Scale); observed grade 3-5 adverse events (AEs) by NCI common toxicity criteria (CTC v2.0). Pts were assessed at midtreatment and at 1, 12, 18 and 24 mo post-treatment. Chi-square tests, t-tests, and Cox models were used for categorical, continuous, and time-to-event variables, respectively. Results: The demographic and tumor characteristics of women (median age 71) who provided CP at BL were not different from women in the QoL subset or from non-QoL pts. 68/145 (47%) women had a HCP. CP groups did not differ based on age, surgery type, tumor and nodal stage, hormone receptor status, performance status, chemo assignment, education, marital or employment status except the LCP group had a higher proportion of white women (95% vs. 78%, p=0.004). At BL, there were no differences in perception of self-health based on CP but women with LCP predicted QoL on chemo to be worse than women with HCP (p=0.006) and reported greater nausea/vomiting. Mid-treatment, LCP pts reported worse nausea/vomiting, financial worries, and cancer symptoms. Post-treatment, LCP pts had worse constipation (at 1 mo) and financial worries (at 24 mo). There were no differences based on CP for dyspnea, pain, fatigue, insomnia, anxiety or depression at any timepoint. Mid-treatment, LCP women reported lower QoL and worse social, emotional and physical function compared to HCP women. These scores were not significantly different after treatment completion. LCP women had significantly higher rates of grade 3-5 AEs (53 vs. 34%, p=0.02) during treatment but these did not persist post-therapy. CP was not significantly associated with OS (HR =0.75, p=0.36) or RFS (HR=0.94, p=0.84). Conclusions: LCP at BL was associated with lower QoL, worse physical symptoms, AEs and function mid-therapy, but not mental health. Mid-therapy declines in women with LCP largely reversed post-therapy. This information may be useful for oncology professionals to counsel older ESBC pts with LCP receiving adjuvant chemo. Citation Format: Ajeet Gajra, Linda McCall, Hyman B Muss, Harvey J Cohen, Aminah Jatoi, Karla V Ballman, Ann H Partridge, Linda Sutton, Barbara A Parker, Gustav Magrinat, Jaqueline M Lafky, Arti Hurria. Association of patient preference for adjuvant chemotherapy (chemo) at baseline (BL) with toxicity, mental health, function, quality of life (QoL) and survival in older women with early stage breast cancer (ESBC) [CALGB 49907 Alliance] [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-07.

Abstract Background. Locally advanced breast cancer (LABC) and inflammatory breast cancer (IBC) remain difficult challenges despite progress in multimodality treatment. The SWOG trial S0800 (clinicaltrial.gov NCT00856492) compared bevacizumab in combination with weekly nab-paclitaxel followed by dose-dense AC to nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative IBC/LABC. The rationale was based on the proposed role of angiogenesis, potential role of improved flow and oxygenation in enhancing the delivery of chemotherapy agents, and the proapoptotic effect with certain chemotherapeutic agents, particularly taxanes. Methods. This was a randomized open-label Phase II trial with an accrual goal of 200 patients equally allocated to either bevacizumab (Arm 1) or no bevacizumab.Two patients were ineligible and five withdrew consent leaving 208 for analysis. The no bevacizumab group was further randomized to two sequences (Arm 2: nab-paclitaxel - AC+PEG-G versus Arm 3: AC+PEG-G- nab-paclitaxel) with 50 patients expected in each sequence. The primary endpoint of this study was pathologic complete response (pCR) defined as no evidence of invasive tumor at the primary site and axillary lymph nodes in the surgical specimen. The power for the primary comparison of bevacizumab (bev) versus no bevacizumab (no bev) ignoring sequence was 80% with a 1-sided α = 0.10. Randomization was stratified by hormone receptor status and type of disease (IBC or LABC). Results 215 patients were accrued May 2010 - September 2012. Most had LABC (88%) versus IBC (12%) and most tumors were hormone-receptor (HR) positive (67%). Fourteen (7%) patients had no definitive surgery (included as no pCR); 135 (65%) had residual disease (no pCR) and 59 (28%) had pCR. The bevacizumab pCR rate was higher (35/96; 38%) than that in the non-bevacizumab arms (24/112; 21%) (exact p=0.021; stratified p=0.015). In HR-positive disease there was slight improvement that was not statistically significant (bev 25% vs. non-bev 18%; p=0.41) while the difference was larger in HR-negative disease (bev 59% vs. non-bev 28%; p=0.014). In LABC the overall pCR rate was 29% with a higher rate in the bevacizumab patients (37% vs. 22%; p=0.035). For IBC there was improvement (30% vs. 14%), but not statistically significant (p=0.61) in a small sample. Overall, Grade 3 and 4 events were common in both (bev 67%; non-bev 65%), but did not differ by treatment. There were 21 deaths with 3-year overall survival (OS) of 87% and 83% for bevacizumab and non-bevacizumab, respectively (log-rank p=0.57). Conclusion Compared with combination anthracycline-taxane neoadjuvant chemotherapy, the Bev-Nab-paclitaxel-AC regimen significantly improved pCR rate overall, primarily for triple negative (TNBC) patients. This neoadjuvant regimen could be a good choice for TNBC/IBC . The observed pCR rate in ER negative disease (59%) suggests that the addition of bevacizumab to a standard chemotherapy backbone may improve outcome in this subset, and justifies further testing of such an approach. Correlative science studies to further delineate the biology of TNBC and the effects of bevacizumab are ongoing. Citation Format: Zeina A Nahleh, William E Barlow, Daniel F Hayes, Anne F Schott, Julie R Gralow, Edith A Perez, William M Sikov, Sudhathi Chennuru, Hamid Mirshahidi, Sarah Vidito, Danika L Lew, Lajos Pusztai, Robert B Livingston, Gabriel N Hortobagyi. S0800: Nab-paclitaxel, doxorubicin, cyclophosphamide, and pegfilgrastim with or without bevacizumab in treating women with inflammatory or locally advanced breast cancer (NCI CDR0000636131) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-16.

Abstract [Background] Patient advocates bring a unique, valuable perspective and presence to SPOREs. However, although patient advocates are recommended members of SPORE grants, guidelines are not given on the role of advocates or on measurement of the performance of advocates. [Methods] The Mayo Clinic Breast Cancer SPORE Patient Advocate Advisory Committee has developed a participation measurement tool. This tool will underpin and augment evaluations of the individual advocate contributions by the program PI and the SPORE project leaders. The Advocate Advisory Committee Chair will review the evaluations with the individual advocates. Annually, the advocate committee will review the performance of the group by the standard of the metrics. [Results] Advocates kept a log of their SPORE activities for four months then worked with a statistician to discern patterns of measurable, evaluable behaviors. The determined evaluable areas are training, scientific activity, meeting attendance, communication. Currently, those metrics are being tracked. Advocates developed the metrics together and report activities at the monthly advocate meetings. Currently, activities are simply tracked and categorized. No minimum standards are set. This will be the third step in the development of the metrics. [Conclusions] This approach is the first step in the development of meaningful evaluation of advocate SPORE activities. It quantifies the participation of advocates in the SPORE and provides the basis for developing a qualitative performance evaluation. The SPORE PI and the Committee Chair will use the evaluations to interpret the involvement of advocates in SPORE research and activities and to plan interventions to strengthen the advocate contributions to the SPORE. Citation Format: Cynthia Chauhan, Wayland Eppard, Lori Denison, Debra Gearhart, Lawanna Holmes, Ruth Kraft, Linda Miller, Mary A Sitta, Mary L Smith, James Ingle, Matthew Goetz. Measurements of advocate participation in and contributions to the Mayo Clinic breast cancer SPORE [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-09-04.

Abstract Background: The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial (Alliance) reported a false negative rate (FNR) of 12.6% with sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy in women presenting with node-positive breast cancer. Proposed methods to decrease the FNR include clip placement in the positive node at initial diagnosis with confirmation of resection of the clipped node at surgery and inclusion of residual metastatic cells identified by immunohistochemistry (IHC) for cytokeratins and disease measuring <0.2mm on H&E in the definition of node positivity after chemotherapy. Herein we evaluate the impact of these methods on FNR. Methods: Z1071 was a prospective multi-institutional trial in which women with clinical T0-4,N1-2,M0 breast cancer underwent both SLN surgery and axillary dissection (ALND) after neoadjuvant chemotherapy. The primary endpoint defined nodal metastasis as disease >0.2mm on H&E. Slides were submitted for central IHC staining when H&E-negative, unless performed locally. For this analysis, we expanded the definition of node positivity to include metastases less than 0.2mm on H&E and metastatic deposits identified by IHC. In 171 cases, a clip was placed in the node at initial biopsy and in these cases the SLNs and ALND were evaluated by x-ray or pathology to document clip location. FNR in the clip cohort is reported using the primary endpoint definition of node positive disease (>0.2mm on H&E). Results: In the 113 cases where the clip was found in the SLN the FNR was 6.4% (1.8-15.5%). In the 29 cases where the clip was found in the ALND specimen, the FNR was 22.2% (6.4-47.6%). IHC was available on 470 of 525 patients with cN1 disease and 2 SLNs resected. Using the definition of H&E metastasis >0.2mm, the FNR in these patients was 11.3% (34/301, 8.0-15.4%) which decreased to 8.7% (27/311, 5.6-11.8%) when including any disease <0.2mm. SLNs from 16 patients had disease <0.2mm in size. Seven patients previously classified as false negative SLN changed to true positive with identification of disease in the SLN. Nine patients changed from node-negative to node-positive with the only disease being <0.2mm disease found in the SLN. Nodal pathologic complete response rate changed from 36.0% to 33.8% with the inclusion of metastases <0.2mm. NResidual disease identified in SLNs or ALNDFNR (%)95% CINode positive definitionSLN metastases >0.2mm by H&E470301 (64.0%)11.38.0-15.4SLN metastasis any size on IHC or H&E470311 (66.2%)8.75.6-11.8Clip locationClip in SLN11462 (54.4%)6.41.8-15.5Clip in ALND2918 (62.1%)22.26.4-47.6Clip location unknown2920 (69.0%)14.33.0-36.3Clip not placed354207 (58.5%)13.59.1-18.9 Conclusion: Placement of a clip at initial diagnosis of node positive disease with identification of the clip during the SLN surgery reduces the FNR. Use of IHC with inclusion of metastases <0.2mm in the definition of residual nodal disease in women with node positive breast cancer after chemotherapy also improves the accuracy of SLN surgery. Use of one or both of these methods should be considered when performing SLN in this setting. Citation Format: Judy C Boughey, Karla V Ballman, William F Symmans, Linda M McCall, Elizabeth A Mittendorf, Gretchen M Ahrendt, Lee G Wilke, Bret Taback, Kelly K Hunt. Methods impacting the false negative rate of sentinel lymph node surgery in patients presenting with node positive breast cancer (T0-T4,N1-2) who receive neoadjuvant chemotherapy – Results from a prospective trial – ACOSOG Z1071 (Alliance) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-01-02.

Abstract Background: The development of distant metastases is the strongest prognostic factor associated with cancer mortality. Customization of treatment based on molecular profiling of a patient’s primary tumor has yielded promising results and has opened a new paradigm for treating patients with advanced disease. Nevertheless profiling the primary tumor may not reflect the actionable molecular drivers of the metastatic lesions. In the last few years a large number of genomic and proteomic studies have demonstrated that at the molecular level metastatic lesions significantly differ from matched primary tumors. The impact of metastasis site organ microenvironments on breast cancer primary tumors has been only partially explored. Since most targeted therapies work by modulating aberrantly-activated protein kinase signaling, the aim of this study was to utilize reverse phase protein arrays (RPPA) to explore whether metastatic lesions derived from different patients, but invading the same host target organ showed similarities in their signaling architecture and presented with organ-specific targetable signatures. Methods: Snap frozen material collected from 14 metastatic breast cancer patients enrolled in a prospective phase II trial ("Side Out II") were used for this analysis. Sites of metastasis were: liver (n=7), skin/chest wall (n=4), and lung (n=3). All samples were subjected to Laser Capture Microdissection (LCM) and RPPA to measure the activation/phosphorylation levels of 12 FDA approved drug targets and linked substrates. Results: Among the 7 patients with liver metastases, p70S6K, c-Abl, ERK 1/2 were highly phosphorylated in 5 cases (71.4%), ErbB2/HER2 in 4 cases (57.1%), and AKT in 3 cases (42.8%). On the contrary, of the 4 patients with skin/chest wall lesions 3 showed high activation of ErbB2/HER2, ErbB3/HER3, and ERK 1/2 (75.0%) and 2 of EGFR (50.0%). Of note, none of the skin/chest wall lesions showed activation of AKT and only 1 case presented with activated p70S6K (25.0%). Lung metastasis showed an overall low activation of all 12 analytes measured. Discussion: Although this data is based on a relatively small number of samples and needs further validation, our initial analysis revealed potentially important trends that could have an impact in the prioritization and selection of targeted agents for metastatic breast cancer trials. We found that the distribution of the 12 FDA approved drug targets and downstream substrates varies between different metastatic sites. Thus, the emergent hypothesis from this work is that breast cancer patients with liver metastases may be more susceptible to AKT-mTOR directed targeted therapeutics and patients with skin/chest wall metastasis may benefit from therapies that target EGFR and/or downstream ERK signaling. Citation Format: Mariaelena Pierobon, Stephen P Anthony, K Alex Reeder, Nicholas J Robert, Donald W Northfelt, Mohammad Jahanzeb, Linda Vocila, Julia D Wulfkuhle, Bryant Dunetz, Lance A Liotta, Emanuel F Petricoin. Pathway activation mapping of metastatic breast cancer identifies potential organ-specific signatures: Implications for patient stratification to targeted treatment [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-23.