Citations

104 Background: Lymphedema (LE), a side effect of BC treatment, affects 8%–56% of women. The study tested the effectiveness of an education only vs education + exercise intervention on LE incidence in a group randomized trial (NCT00376597) of 38 cooperative group sites. Methods: Newly diagnosed women with stage I-III BC were consented and arm circumference and range of motion were measured pre-surgery. After surgery, patients (pts) were enrolled based on the randomization assignment of their treating institution, stratified by their type of node dissection (sentinel or axillary), and received either: education only: its causes, signs, symptoms and risk reduction strategies, or education + personalized exercise instruction from a physical therapist, with elastic compression garments to wear during heavy arm use and air travel. Pts completed surveys and arm measurements at baseline (BL), 12 and 18 months with the LE endpoint defined as ≥ 10% difference in limb volume at any time from BL to 18 months or physician diagnosis of LE. Cochran-Mantel-Haenszel (CMH) tests were used to compare the LE-free rate between arms, adjusted for type of biopsy. Logistic regression assessed predictors of LE. Results: 568 pts were enrolled, 45% in education only, and 55% in education + exercise, with 554 (98%) included in the analyses. Pts were on average 57.7 years, White (83%), non-Hispanic (92%) and married (62%). 47% only had sentinel node dissection, 35% had mastectomy, and 37% had chemotherapy. The LE-free rate was 58% in education only vs 55% in education + exercise (CMH p = 0.73). Predictors of LE included surgery type (lumpectomy vs mastectomy, OR = 2.22, p < 0.001) and chemotherapy (no vs yes, OR = 1.73, p = 0.02), after adjusting for BMI and type of node dissection. Only one-third wore the sleeve at least 75% of the time and only 50% did LE exercises at least weekly. Conclusions: There was no difference by intervention arm in LE incidence by 18 months. Poor adherence in the education + exercise arm may have been a factor. Additional analyses will assess quality of life, body image and knowledge about LE by arm. Further research is needed to effectively prevent LE in pts after BC surgery. Research Support: UL1TR001409; U10CA037447, UG1CA189823 Clinical trial information: NCT00376597.

685 Background: RAS/BRAF mutations constitutively activate the MAPK pathway in colorectal cancer, and may promote resistance to CRT. We propose that trametinib, a MEK1/2 inhibitor, in combination with 5FU CRT for patients with LARC will improve outcome. Methods: Phase I study with standard 3+3 design in patients with Stage II/III rectal cancer with 3 dose levels of trametinib: 0.5, 1, and 2mg daily with 5FU 225mg/m2/day and 50.4 Gy. Trametinib was given over a 5-day lead-in and continued through the course of CRT. Patients undergo surgery 6-10 weeks after the completion of CRT. An expansion cohort at the maximum tolerated dose (MTD) with 12 patients is ongoing. Tumor tissue is collected prior to therapy, at day 4/5 of trametinib, and at surgery. The primary endpoint is to determine the MTD of trametinib with CRT. Results: 15 patients (10 males, 5 females) have been enrolled and 14 patients are evaluable for toxicities to date. Median age is 53 years (range 35-74). Patients have completed enrollment to all dose levels, with 1 dose-limiting toxicity of diarrhea attributed to 5FU CRT. No grade 4/5 toxicities, and toxicities are shown in the table. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient, and was held 3 days for 2 patients. At the trametinib dose level of 2mg, 3 out of 7 (43%) patients had a pathological complete response and the average neoadjuvant rectal (NAR) score is 8.1. Tumor RAS/BRAF mutation status is determined. Analysis of tumor tissue shows dose-dependent decrease in phosphorylated-ERK1/2 with increasing doses of trametinib. Conclusions: Initial evaluation shows that the combination of trametinib with 5FU CRT is tolerable and effective, and warrants further investigation in LARC. Clinical trial information: NCT01740648. [Table: see text]

Background: Second anterior cruciate ligament (ACL) tears after reconstruction occur at a reported rate of 20% to 30%. This high frequency indicates that there may be factors that predispose an athlete to graft failure and ACL tears of the contralateral knee. Purpose: To determine the incidence of second ACL injuries in a geographic population-based cohort over a 10-year observation period. Study Design: Descriptive epidemiological study. Methods: International Classification of Diseases, 9th Revision (ICD-9) codes relevant to the diagnosis of an ACL tear and the procedure code for ACL reconstruction were searched across the Rochester Epidemiology Project, a multidisciplinary county database, between the years of 1990 and 2000. This cohort of patients was tracked for subsequent ACL injuries through December 31, 2015. The authors identified 1041 patients with acute, isolated ACL tears. These patients were stratified by primary and secondary tears, sex, age, activity level, side of injury, sex by side of injury, and graft type. Results: Of the 1041 unique patients with a diagnosed ACL tear in Olmsted County, Minnesota, from 1990 to 2000, there were 66 (6.0%) second ACL tears; 66.7% of these tears occurred on the contralateral side. A second ACL injury was influenced by graft type ( P < .0001), election of ACL reconstruction ( P = .0060), and sex by side of injury ( P = .0072). Nonparametric analysis of graft disruption by graft type demonstrated a higher prevalence of second ACL tears with allografts compared with hamstring ( P = .0499) or patellar tendon autografts ( P = .0012). Conclusion: The incidence of second ACL tears in this population-based cohort was 6.0%, with 66.7% of these tears occurring on the contralateral side from the original injury. There was a high population incidence of second ACL injuries in female patients younger than age 20 years. The utilization of patellar tendon autografts significantly reduced the risk of second ACL injuries compared with allografts or hamstring autografts in this cohort.

Abstract Lipocalin-2 (LCN2) promotes malignant development in many cancer types. LCN2 is upregulated in patients with pancreatic ductal adenocarcinoma (PDAC) and in obese individuals, but whether it contributes to PDAC development is unclear. In this study, we investigated the effects of Lcn2 depletion on diet-induced obesity, inflammation, and PDAC development. Mice with acinar cell–specific expression of KrasG12D were crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of fat content. Pancreas were collected and analyzed for inflammation, pancreatic intraepithelial neoplasia (PanIN), and PDAC. We also used a syngeneic orthotopic PDAC mouse model to study tumor growth in the presence or absence of Lcn2 expression. In addition, to understand the mechanistic role of how LCN2 could be mediating PDAC, we studied LCN2 and its specific receptor solute carrier family 22 member 17 (SLC22A17) in human pancreatic cancer stellate cells (PSC), key mediators of the PDAC stroma. Depletion of Lcn2 diminished extracellular matrix deposition, immune cell infiltration, PanIN formation, and tumor growth. Notably, it also increased survival in both obesity-driven and syngeneic orthotopic PDAC mouse models. LCN2 modulated the secretion of proinflammatory cytokines in PSC of the PDAC tumor microenvironment, whereas downregulation of LCN2-specific receptor SLC22A17 blocked these effects. Our results reveal how LCN2 acts in the tumor microenvironment links obesity, inflammation, and PDAC development. Cancer Res; 77(10); 2647–60. ©2017 AACR

Abstract Background: Triple negative breast cancer (TNBC) is a heterogeneous disease. Amplification of chromosome 9p24.1 encoding JAK2 and PD-L1 has been reported in up to 25% of TNBC and is associated with poor clinical outcome. In lymphoma, JAK2 is a transcriptional activator of both PD-1 ligands, and chromosome 9p copy number gain has been associated with therapeutic activity of nivolumab. We evaluated the interaction of JAK2 and PD-L1 expression in TNBC. Methods: 9p24.1 amplification in 4 TNBC cell lines (MDA-MB-231, MDA-MB-436, HCC1937, and HCC70) was measured using array comparative genomic hybridization (aCGH). Amplification was defined as aCGH log2ratio&gt;2.0. Cell surface expression of PD-L1 was detected by flow cytometry and compared with the median fluorescence intensity (MFI) of isotype control Ig. To selectively inhibit JAK2, lentiviral vectors encoding two different shRNA were generated. JAK2, pSTAT1 and pSTAT3 expression were measured by immunoblot. The effects of the anti-JAK1/2 inhibitor ruxolitinib and interferon-gamma (IFN-γ) induction of PD-L1 was measured. Results: 9p24.1 copy number loss was measured in MDA-MB-231 (log2ratio =-1), neutral in HCC1937 ((log2ratio =0), gained in MDA-MB-436 ((log2ratio =+1) and amplified in HCC70 ((log2ratio =+2). No correlation was observed between PD-L1 expression and the 9p24.1 amplification, with the MFI ratio range from 5 to 16.5, mean 8.3 by flow cytometry. TNBC cell lines had higher baseline expression of PD-L1 compared to the ER+ cell lines T47D and MCF-7 (ratio, 0 p=0.1). Low dose IFN-γ (1.0-10.0 ng/ml) rapidly induced expression of PD-L1 in MDA-MB-231 (1.5 fold increase) and HCC70 (3.3 fold increase) with significant activation of the JAK2/STAT1 pathway. The induction of pSTAT1 and PD-L1 expression by IFN-γ was blocked with low dose (1mM) JAK1/2 inhibitor ruxolitinib. Knockdown of JAK2 with shRNA (&gt;80%) did not impact PD-L1 baseline expression in MDA-MB-231 and HCC70 but abrogated IFN-γ –mediated induction of PD-L1 and the phosphorylation of STAT1. Conclusion: These data suggest that TNBC cell lines have baseline PD-L1 expression, but the cells with 9p24.1 amplification are highly sensitive to PD-L1 induction with IFN-γ which can be abrogated with inhibition with a JAK1/2 inhibitor or shRNA. Synergistic inhibition of PD1/PD-L1 and JAK2 may have therapeutic efficacy in the subset of TNBC with 9p24.1 amplification, and the dynamic effects of tumor PD-L1 expression in response to local inflammation should be considered in the evaluation of PD-1/PD-L1 checkpoint blockade. Citation Format: Chen M, Pockaj B, Andreozzi M, Barrett MT, Ocal IT, McCullough AE, Krishna S, Anderson KS. JAK2 and PD-L1 amplification enhance the dynamic expression of PD-L1 in triple negative 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 P2-04-18.

ObjectiveTo evaluate the use of monosyllabic word recognition versus sentence recognition to determine candidacy and long‐term benefit for cochlear implantation.Study DesignProspective multi‐center single‐subject design.MethodsA total of 21 adults aged 18 years and older with bilateral moderate to profound sensorineural hearing loss and low monosyllabic word scores received unilateral cochlear implantation. The consonant‐nucleus‐consonant (CNC) word test was the central measure of pre‐ and postoperative performance. Additional speech understanding tests included the Hearing in Noise Test sentences in quiet and AzBio sentences in +5 dB signal‐to‐noise ratio (SNR). Quality of life (QoL) was measured using the Abbreviated Profile of Hearing Aid Benefit and Health Utilities Index.ResultsPerformance on sentence recognition reached the ceiling of the test after only 3 months of implant use. In contrast, none of the participants in this study reached a score of 80% on CNC word recognition, even at the 12‐month postoperative test interval. Measures of QoL related to hearing were also significantly improved following implantation.ConclusionResults of this study demonstrate that monosyllabic words are appropriate for determining preoperative candidate and measuring long‐term postoperative speech recognition performance.Level of Evidence2c. Laryngoscope, 127:2368–2374, 2017

251 Background: To assess the effect of adjuvant therapy in gallbladder adenocarcinoma (GBC). Methods: Retrospective review was conducted at five institutions to identify pts who had surgery for confirmed dx of GBC from 1985-2008 (N = 189). Pts were excluded if they had chemo alone (N = 8), path other than adenoca (N= 7), carcinoma in situ (N=1), < 30 days of follow-up (N = 2), or missing data (N=14). Of the remaining 156 pts, 58 received surgery only and 98 received adj RT ± chemo. Kaplan-Meier was used for overall survival (OS) and Cox proportional hazards to compare risk factors. Results: Median age of dx was 64.4, 68.0% were female, 37.9% had ≥ stage 2b, 37.2% had + nodes, and 32.1% had + margins. Overall, 35.9% of the patients had simple cholecystectomy (SC) only and 64.1% had radical resection (ER). mOS for pts treated with surgery alone was 49.7 months (95% CI: 24.8 to Inf). On univariate analysis, + margins (HR 2.72, p<0.001) was associated with worse OS, whereas ER compared to SC improved survival in both univariate (HR 0.46, p<0.001) and multivariate (HR 0.53, p=0.033) analyses after adjusting for node/margins, T-stage, adj RT, age, gender, and institution. mOS for the entire cohort vs. adj RT (median 50.4 Gy) ± chemo was 30.7 months (95% CI: 19.2 to 46.9) vs. 26.9 months (95% CI: 15.5 to 39.1). But, compared to surgery alone, the adj group was more likely to have had node +, margin +, or T-stage 3+ (all p<0.001). The adj RT group was also less likely than surgery alone pts to have undergone ER (p = 0.007). On multivariate analysis, decreased OS was also found for node + (HR 2.09, p=0.004), margin + (HR 1.84, p=0.043), and T3/T4 disease (HR 2.37, p=0.002). After adjusting for surgical extent, node, margin, T stage, age, gender, and institution, there was improved OS with adj therapy (HR: 0.43, p = 0.020). When stratified by surgical extent, the risk estimate for adj RT improved OS among those with SC (n=56; HR 0.20, p=0.135) and ER (n=100; HR 0.46, p=0.067), but was not statistically significant. Conclusions: ER was associated with improved OS, whereas node/margin+ and T-stage 3+ were associated with worse survival. In multivariate analysis, adj RT improved OS after surgery. Given the poor prognosis of GBC patients with advanced disease, consideration of adj therapy is appropriate. No significant financial relationships to disclose.

Background: Preventive medicine techniques have alleviated billions of dollars’ worth of the economic burden in the medical care system through the implementation of vaccinations and screenings before the onset of disease symptoms. Knowledge of biomechanical tendencies has progressed rapidly over the past 20 years such that clinicians can identify, in healthy athletes, the underlying mechanisms that lead to catastrophic injuries such as anterior cruciate ligament (ACL) ruptures. As such, preventive medicine concepts can be applied to noncontact musculoskeletal injuries to reduce the economic burden of sports medicine treatments and enhance the long-term health of athletes. Purpose: To illustrate the practical medical benefits that could be gained from preventive biomechanics applied to the ACL as well as the need and feasibility for the broad implementation of these principles. Study Design: Literature review. Methods: The recent literature pertinent to the screening and prevention of musculoskeletal injuries was reviewed and compiled into a clinical commentary on the current state and applicability of preventive biomechanics. Results: Investigators have identified neuromuscular training protocols that screen for and correct the underlying biomechanical deficits that lead to ACL injuries. The literature shows that when athletes comply with these prescribed training protocols, the incidence of injuries is significantly reduced within that population. Such preventive biomechanics practices employ basic training methods that would be familiar to athletic coaches and have the potential to save billions of dollars in cost in sports medicine. Conclusion: The widespread implementation of preventive biomechanics concepts could profoundly affect the field of sports medicine with a minimum of initial investment.