Citations

Abstract Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab. Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS). Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57–0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50–0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66–0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59–0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40–0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25–0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations. Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777–83. ©2017 AACR.

BACKGROUND It is possible that the relative lack of progress in treatment outcomes among adolescent and young adult (AYA) patients with cancer is caused by a difference in disease biology compared with the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive and has a poorer prognosis in AYA patients than in older adult patients. METHODS To further understand the molecular basis for this difference, whole‐exome sequencing was conducted on a cohort of 30 adult, 30 AYA, and 2 pediatric colon cancers. RESULTS A statistically significant difference in mutational frequency was observed between AYA and adult samples in 43 genes, including ROBO1 , MYC binding protein 2 ( MYCBP2 ), breast cancer 2 (early onset) ( BRCA2 ), MAP3K3, MCPH1, RASGRP3, PTCH1, RAD9B, CTNND1, ATM, NF1 ; KIT, PTEN , and FBXW7 . Many of these mutations were nonsynonymous, missense, stop‐gain, or frameshift mutations that were damaging. Next, RNA sequencing was performed on a subset of the samples to confirm the mutations identified by exome sequencing. This confirmation study verified the presence of a significantly greater frequency of damaging mutations in AYA compared with adult colon cancers for 5 of the 43 genes ( MYCBP2, BRCA2, PHLPP1, TOPORS , and ATR ). CONCLUSIONS The current results provide the rationale for a more comprehensive study with a larger sample set and experimental validation of the functional impact of the identified variants along with their contribution to the biologic and clinical characteristics of AYA colon cancer. Cancer 2018;124:1070‐82. © 2017 American Cancer Society .

Objective: Activation encompasses energy and activity and is a central feature of bipolar disorder. However, the impact of activation on treatment response of bipolar depression requires further exploration. The aims of this study were to assess the association of decreased activation and sustained remission in bipolar depression and test for factors that could affect this association. Methods: We assessed participants with Diagnostic and Statistical Manual of Mental Disorders (4th ed) bipolar depression ( n = 303) included in a comparative effectiveness study of lithium- and quetiapine-based treatments (the Bipolar CHOICE study). Activation was evaluated using items from the Bipolar Inventory of Symptoms Scale. The selection of these items was based on a dimension of energy and interest symptoms associated with poorer treatment response in major depression. Results: Decreased activation was associated with lower remission rates in the raw analyses and in a logistic regression model adjusted for baseline severity and subsyndromal manic symptoms (odds ratio = 0.899; p = 0.015). The manic features also predicted lower remission (odds ratio = 0.934; p < 0.001). Remission rates were similar in the two treatment groups. Conclusion: Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression. Patients with these features may require specific treatment approaches, but new studies are necessary to identify treatments that could improve outcomes in this population.

Background: Femoral retroversion has been noted as a possible risk factor for poor clinical results after hip arthroscopic surgery. Purpose: To compare the outcomes of the arthroscopic treatment of hip abnormalities in patients with femoral retroversion to patients with femoral anteversion between 10° and 20°. Study Design: Cohort study; Level of evidence, 3. Methods: Between November 2011 and September 2013, 790 hip arthroscopic procedures were performed at a single institution. Of these, 59 hips (7.5%) were located in patients with femoral version ≤0°, calculated using preoperative magnetic resonance imaging. These patients were pair matched, based on body mass index ±5 kg/m 2 , age ±5 years, and Tönnis grade, with 59 patients with femoral anteversion between 10° and 20°. Exclusion criteria included Perthes disease, inflammatory arthritis, slipped capital femoral epiphysis, previous hip surgery, abductor repair, lateral center-edge angle <20°, Tönnis grade >1, and acetabular profunda or protrusio. Patient-reported outcomes (PROs) were recorded preoperatively, at 3 months postoperatively, and annually thereafter. The PROs utilized were the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), and Hip Outcome Score–Sports-Specific Subscale (HOS-SSS). The visual analog scale (VAS) was collected to assess the patients’ pain; patient satisfaction scores (0-10) were also collected. Radiographs were collected at the above time intervals as well. Results: Two patients from the control group and 1 patient from the retroverted group required total hip arthroplasty at a mean 19.5 and 26.3 months, respectively. Both groups demonstrated significant improvement from their preoperative state in all PRO and VAS scores ( P < .001). No differences in preoperative, postoperative, or change in PRO and VAS scores between the groups were noted. Conclusion: Patients with femoral retroversion reported similar outcomes compared to patients with normal femoral version when undergoing hip arthroscopic surgery. Both groups had similar improvements from the preoperative state.

Abstract This article presents the authors' technique for evaluation of possible abductor tears with magnetic resonance imaging (MRI). By using T2 fat‐saturated coronal and axial slices of the hip and T1 coronal images of the pelvis, the authors show how to visualize all tears of the abductor tendons and signs of chronic abductor deficiency. After diagnosis has been made, signs that may help the surgeon determine if open or arthroscopic surgery would be best used are reviewed. Finally, the author reviews indications for a gluteus medius repair with concomitant gluteus maximus reconstruction. Technique Video video See video under supplementary data.

Abstract Excessive femoral anteversion may lead to increasing stress placed on the anterior acetabulum and soft tissues, which can predispose to intra‐articular hip pathology. By addressing the excessive femoral anteversion in combination with intra‐articular hip pathology, the results will be durable over time. This technique details how to perform a femoral derotation osteotomy for excessive femoral anteversion after addressing intra‐articular pathology with hip arthroscopy in one surgical intervention. This allows the surgeon to address both the underlying pathoanatomy and the resultant intra‐articular sequelae. Technique Video video See video under supplementary data.

Abstract Background: Estrogen receptor (ER) status in breast cancer is strongly associated with etiologic factors, prognosis and treatment response. Data suggest that population-based incidence rates of ER-positive (ER+) tumors are increasing and ER-negative (ER-) cancers have fallen over time in the United States (US), Denmark and Scotland. Whether these trends are consistent in other populations with different etiologic exposures and across ER±/HER2± subtypes is unknown. We, therefore, analyzed breast cancer secular trends in Ireland by ER expression; and for the first time, by joint expression of ER±/HER2±, a well-established clinical marker of uncertain etiological significance. Methods: This study included invasive breast cancers (n=24,845; 2004-2013) among women aged 20-84 years within the population-based National Cancer Registry of Ireland (97% coverage). The general population at risk (n=10,401,986) was obtained from the Irish Central Statistics Office. Using a validated approach to account for missing ER/HER2-status, we assessed ER± and ER±/HER2± secular trends with age-standardized incidence rates (ASR) and estimated annual percentage change (EAPC) with 95% confidence intervals (95%CI). Results: Over the 10-year follow-up period, 19,264 ER+ and 4,161 ER- breast cancers were diagnosed (1,420 were ER-unknown). ASRs increased significantly for ER+ (EAPC: 2.20%/year (95%CI: 0.97, 3.45%/year)) and decreased significantly for ER- cancers (EAPC: -3.43%/year (95%CI: -5.05, -1.78%/year)). The ER-specific trends were qualitatively similar among three age groups (&lt;50, 50-64 and ≥65 years). With further stratification by HER2± expression, ER+/HER2- cancers rose (EAPC: 2.87%/year (95%CI: 1.33, 4.44%/year)), ER+/HER2+ cancers were statistically flat, while ER-/HER± cancers significantly declined. Conclusion: Secular trends for ER± cancers in Ireland were similar to those previously observed in the US and Denmark. Further, trends for ER/HER2 followed those for ER, although rates were constant for ER+/HER+ tumors. The divergence of cancer incidence patterns by ER among independent populations over time could reflect comparable changes in risk factor exposures with dual or opposite effects for risk of ER+ and ER- cancers (e.g., obesity, age at first birth/parity). Additionally, although HER2 is a well-established clinical predictive and prognostic marker for breast cancer outcome, it did not appear to substantively impact breast cancer incidence trends. Citation Format: Maeve Mullooly, Jeanne Murphy, Gretchen L. Gierach, Brittny Davis, Paul Walsh, Sandra Deady, Thomas I. Barron, Mark E. Sherman, Philip S. Rosenberg, William F. Anderson. Estrogen receptor positive and negative breast cancer secular trends in Ireland (2004-2013) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 257. doi:10.1158/1538-7445.AM2017-257

Abstract Rationale Usual interstitial pneumonia (UIP) is the histopathologic hallmark of idiopathic pulmonary fibrosis. Although UIP can be detected by high-resolution computed tomography of the chest, the results are frequently inconclusive, and pathology from transbronchial biopsy (TBB) has poor sensitivity. Surgical lung biopsy may be necessary for a definitive diagnosis. Objectives To develop a genomic classifier in tissue obtained by TBB that distinguishes UIP from non-UIP, trained against central pathology as the reference standard. Methods Exome enriched RNA sequencing was performed on 283 TBBs from 84 subjects. Machine learning was used to train an algorithm with high rule-in (specificity) performance using specimens from 53 subjects. Performance was evaluated by cross-validation and on an independent test set of specimens from 31 subjects. We explored the feasibility of a single molecular test per subject by combining multiple TBBs from upper and lower lobes. To address whether classifier accuracy depends upon adequate alveolar sampling, we tested for correlation between classifier accuracy and expression of alveolar-specific genes. Results The top-performing algorithm distinguishes UIP from non-UIP conditions in single TBB samples with an area under the receiver operator characteristic curve (AUC) of 0.86, with specificity of 86% (confidence interval = 71–95%) and sensitivity of 63% (confidence interval = 51–74%) (31 test subjects). Performance improves to an AUC of 0.92 when three to five TBB samples per subject are combined at the RNA level for testing. Although we observed a wide range of type I and II alveolar–specific gene expression in TBBs, expression of these transcripts did not correlate with classifier accuracy. Conclusions We demonstrate proof of principle that genomic analysis and machine learning improves the utility of TBB for the diagnosis of UIP, with greater sensitivity and specificity than pathology in TBB alone. Combining multiple individual subject samples results in increased test accuracy over single sample testing. This approach requires validation in an independent cohort of subjects before application in the clinic.