Citations

174 Background: AA/P is an FDA approved treatment for mCRPC. Since markers of early resistance to AA/P are unknown, we report initial findings of androgen receptor (AR) based associations with short term (12 week) progression on AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemotherapy AA/P underwent metastatic site biopsies at baseline (pre AA/P) and after 12 weeks. Baseline somatic whole exome DNA, tumor gene expression for AR full length (ARFL), AR splice variant 7 (ARV7) and ARV7/ARFL ratios were compared in progessors versus non-progressors. Progression at or within 12 weeks of AA/P therapy was defined as death or disease progression by PCWG2 “composite progression (CP)” and/or “radiographic progression” endpoints. Wilcoxon rank-sum tests were used to test for differences in the two groups for comparing ARFL, ARV7 expressions and ARV7/ARFL ratios and chi square tests were used for differences in copy number variation. Results: Between 1/2013 and 6/2014, 59 pts were enrolled of which 44 have disease assessment data at the12-week time point. CP was observed in 17/44 patients. DNA seq and clinical data was available for 42/44 pts. Using radiographic progression at 12 weeks, AR Amplification/Gain was observed in 20/26 non-progressors (13 with Amplification) and in 9/16 progressors (P-value = 0.19; OR 2.5). ARFL and ARV7 gene expressions in both groups is provided in table. Conclusions: A trend towards higher ARV7/ARFL gene expression ratio in metastases was observed with early progression on AA/P. AR gain/amplification is observed less often in pts with early progression. Validation of these findings is on-going in this prospective trial. Clinical trial information: NCT# 01953640. [Table: see text]

237 Background: AA/P is an approved treatment for mCRPC but there are no known predictive markers of response or resistance. We conducted a prospective trial to evaluate if Androgen Receptor (AR) & AR-variant (ARV) expression in tissue metastases can predict resistance to AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemo AA/P underwent metastatic site biopsies prior to (pre-AA/P) and after 12 weeks of treatment. Composite progression at 12 weeks, (primary endpoint) was evaluated with PSA, RECIST, bone scan and symptoms (per PCWG2). mRNA expressions of pre-AA/P ARFL, ARV3, ARV7, ARV9, ARV23, ARV45, four cell cycle division genes, Chromogranin-A (CHGA) together with PSA/testosterone levels, Gleason Score (GS) at initial diagnosis; high versus low volume disease; time from starting hormone therapy to mCRPC stage and serum CHGA levels were evaluated using a logistic regression model for predicting resistance at 12 weeks of therapy. A final multivariate model fitted only those factors thought to be clinically relevant or with an entry threshold of p ≤ 0.3 in univariate analysis. Results: Between 6/2013 & 3/2015, 82 pts were enrolled of which 52 had complete mRNA expression & disease assessment data at the12-week time point for analysis. Median age of the cohort was 72.5 yrs (IQR: 68.5-78); median pre-AA/P PSA was 18 ng/ml (IQR: 8.1- 46.6); GS distribution at initial diagnosis for GS 2-6; 7; 8-10 was 11; 14; 27 respectively. Progression was observed in 21/52 pts after 12 weeks. At the univariate level elevated pre-AA/P expression of ARV3 (p = 0.08), ARV7 (p = 0.26), ARV9 (p = 0.04), and cell division cycle gene CDC45 (p = 0.19) along with GS at diagnosis (p = 0.29) met the threshold for inclusion into multivariate analysis. Elevated expression of pre-therapy ARV9 in metastases alone was associated with progression at 12 weeks (OR: 3.9; CI 1.07 – 14.16; C-Index: 0.63). The 12-week biopsy of pts with progression had increased ARV9 mRNA expression compared to pts responding at 12 weeks (p = 0.14). Conclusions: Increased ARV9 mRNA expression in metastases is associated with early resistance to AA/P. This observation will need further validation in comparable datasets. Clinical trial information: NCT #0195364.

Purpose To compare the risks of serious health outcomes among hematopoietic cell transplantation (HCT) survivors versus a matched population of patients with cancer who did not undergo HCT, where the primary difference may be exposure to HCT. Methods Two-year HCT survivors treated at a comprehensive cancer center from 1992 through 2009 who were Washington State residents (n = 1,792; 52% allogeneic and 90% hematologic malignancies) were frequency matched by demographic characteristics and underlying cancer diagnosis (as applicable) to non-HCT 2-year cancer survivors, using the state cancer registry (n = 5,455) and the general population (n = 16,340) using driver’s license files. Late outcomes for all three cohorts were ascertained from the state hospital discharge and death registries; subsequent cancers were ascertained from the state cancer registry. Results After median follow-up of 7.1 years, HCT survivors experienced significantly greater rates of hospitalization compared with matched non-HCT cancer survivors (280 v 173 episodes per 1,000 person-years, P < .001) and greater all-cause mortality (hazard ratio [HR], 1.1; 95% CI, 1.01 to 1.3). HCT survivors had more hospitalizations or death with infections (10-year cumulative incidence, 31% v 22%; HR, 1.4; 95% CI, 1.3 to 1.6) and respiratory complications (cumulative incidence, 27% v 20%; HR, 1.4; 95% CI, 1.2 to 1.5). Risks of digestive, skin, and musculoskeletal complications also were greater among HCT versus non-HCT cancer survivors. The two groups had similar risks of circulatory complications and second cancers. Both HCT and non-HCT cancer survivors had significantly greater 10-year cumulative incidences of all major organ-system outcomes versus the general population. Conclusion History of HCT was associated with late morbidity and mortality among cancer survivors. In particular, clinicians who care for HCT survivors should be aware of their high rates of late respiratory and infectious complications.

111 Background: Trastuzumab in combination with chemotherapy is recommended for advanced gastric cancer positive for human epidermal growth factor receptor 2 (HER2) overexpression. Despite this recommendation, an informal pilot survey suggested that many oncologists do not include HER2 testing as part of routine practice to identify patients most likely to benefit from adding trastuzumab to chemotherapy. Methods: An interactive online educational activity was developed to provide expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer. Pre- and post-education surveys were administered as part of the activity to measure changes in participant competence. In addition, 3 months after completing the educational activity, participants were sent another follow-up survey by email to assess changes in practice. Results: To date, pre-and post-education surveys have been obtained for 122 oncologists and 3-month follow-up surveys obtained from 14 oncologists. In the pre-education survey, only 46% said they were testing all of their patients with advanced gastric or GE cancer for HER2 overexpression. However, immediately after participating in the educational intervention, this proportion increased to 93%. Importantly, a follow-up survey indicated that HER2 testing of all patients with advanced gastric or GE cancer was now part of routine practice for 79% of those surveyed. A final analysis of pre- and post-education and 3-month follow-up surveys will be presented. Conclusions: Expert guidance on HER2 testing and use of HER2-targeted agents in gastric or GE cancer provided through an interactive online educational intervention substantially improved oncologist competence and practice patterns.

Background Lower extremity peripheral arterial disease (PAD) is a common medical condition causing substantial morbidity. Limited data exist on whether discrepancies in PAD prevalence exist between the lower extremities using resting ankle-brachial indices (ABIs) and postexercise pressures. Objective We predicted the prevalence of PAD between the lower extremities. Methods and Results Consecutive patients who had undergone a noninvasive arterial lower extremity study at Mayo Clinic, Rochester, MN, between January 1996 and December 2012 with suspected PAD were retrospectively reviewed. We identified 12,312 consecutive patients who underwent an arterial lower extremity and an exercise treadmill study. Prevalence of PAD was assessed at rest and after exercise using two criteria: a resting ABI ≤ 0.90 and a postexercise pressure decrease of > 30 mm Hg. Mean age was 67 ± 12 years and there were 4,780 (39%) women studied. At rest, we found a higher prevalence of PAD on the left extremity (27.4%) compared with the right (24.6%) (p < 0.0001). After exercise, we found a higher prevalence of PAD on the right extremity (25.1%) compared with the left (19.0%) (p < 0.0001). These discrepancies between the prevalence of PAD at rest and after exercise were present in women and men. Conclusion Using validated criteria of a resting ABI of ≤ 0.90 and postexercise ankle pressure decrease > 30 mm Hg, our results suggest that there is a significantly higher prevalence of PAD in the left lower extremity at rest, in contrast to a greater prevalence of abnormal postexercise testing in the right lower extremity. The reason(s) of these discrepancies remain to be studied.

Background: Total knee arthroplasty (TKA) with a rotating-hinge prosthesis is considered a salvage procedure. While excellent immediate stability is achieved, the historically high failure rate has tempered its use. The goal of this study was to determine clinical outcomes, radiographic results, and survivorship after TKA with contemporary rotating-hinge components. Methods: We identified 408 consecutive TKAs performed with rotating-hinge components for nononcologic indications from 2002 to 2012 at a single academic institution. Two hundred and sixty-four knees (65%) had rotating-hinge TKA components implanted for aseptic etiologies, while 144 knees (35%) were managed with the components in 2-stage reimplantation following infection. Rotating-hinge TKA implants were used for complex primary procedures in 74 knees (18%) and as a revision construct in 334 knees (82%). Clinical outcomes were assessed with the Knee Society scoring system, survivorship analyses, and cumulative incidence of revision. The mean age of the patients at the time of the index arthroplasty was 69 years, and the mean duration of follow-up was 4 years (range, 2 to 12 years). Results: At the most recent follow-up, the mean Knee Society knee score had increased from 51 points preoperatively to 81 points (p < 0.0001), and the mean Knee Society functional score had increased from 26 to 36 points (p < 0.0001). At a mean of 4 years, loosening of components was observed in 13 (3.7%) of 349 knees. At the most recent follow-up, 59 revision procedures and 25 reoperations had been performed. The cumulative incidence of any revision was 9.7% at 2 years and 22.5% at 10 years. The cumulative incidence of revision for aseptic loosening was 1.7% at 2 years and 4.5% at 10 years. Metaphyseal cones were used in 114 knees (28%). Survivorship analysis revealed a trend toward a lower risk of revision (hazard ratio [HR] = 0.69; 95% confidence interval [CI] = 0.39 to 1.22; p = 0.20) and reoperation (HR = 0.51; 95% CI = 0.22 to 1.19; p = 0.12) in patients with metaphyseal cones, despite their use in the most severe of bone defects. Conclusions: Contemporary rotating-hinge TKA implants had a low 10-year cumulative incidence of revision for aseptic loosening of 4.5%. Greater use of metaphyseal fixation has aided this improvement. Patients can expect substantial improvements in clinical outcomes with this revision strategy. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract BACKGROUND: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. OBJECTIVE: To develop guidelines for CCM management. METHODS: The Angioma Alliance (www.angioma.org), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. RESULTS: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). CONCLUSION: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines.