Citations

Objectives: Arthroscopic treatment for femoroacetabular impingement (FAI) generally has good results, but the outcome can worsen with increasing arthritis, largely defined as joint space narrowing. There remains a subset of hips with maintained joint space but with subchondral edema and cystic change of the acetabulum on MRI, with unknown outcome. Therefore, the purpose of this study was (1) to determine if postoperative outcome was worse for patients with subchondral edema on preoperative MRI compared to a matched control group and (2) to identify risk factors on MRI leading to inferior outcome. Methods: A review of patients who underwent arthroscopic hip surgery for FAI between 2007 and 2013 identified 530 patients. Of these, 39 patients had evidence of subchondral edema or subchondral cyst on the preoperative MRI with maintained joint space on preoperative radiographs. Lesions were characterized by grade, location and type using an established radiographic MRI classification system. A matched cohort of patients without evidence of subchondral edema or cyst was identified, and 2:1 matching was based on patient age, surgeon, surgery year within one year, surgical procedure, Tegner activity score, and Tonnis grade osteoarthritis changes on preoperative x-ray. Outcome was compared using the Hip Outcome Score and Modified Harris Hip Score between the two groups. Risk factors were then analyzed for type of lesion, grade and location of bone marrow lesion. Results: Thirty-nine patients (20 males, 19 females) showed preoperative MRI evidence of subchondral edema, and were followed for a mean of 23 months postoperatively (range, 12 - 60 months). Patients had an average age of 41 years (range, 19 - 67) and a preoperative Tegner score of 3.8 (range, 1 - 9). 87% of patients with subchondral cystic change had evidence of a grade IV full thickness cartilage lesion at the time of hip arthroscopy. Average Modified Harris Hip Scores were inferior for the subchondral group (79.9 ± 18.7) compared to the control group (86.6 ± 12.5; p = 0.027). In addition, Sport sub-scales of the Hip Outcome Score showed significantly lower scores for the subchondral group for both score (69.1 ± 27.0 vs. 79.5 ± 21.4, p = 0.018) and rating (66.7 ± 27.5 vs. 78.0 ± 20.8, p = 0.044). No radiographic risk factors, including type, location, or size of lesion were significant predictors of outcome. Two patients in the subchondral group were later converted to a total hip replacement. Conclusion: The presence of a subchondral acetabular cyst on MRI is indicative of a full thickness cartilage lesion at the time of arthroscopy. These patients have inferior outcomes for arthroscopic treatment of FAI compared to patients with similar age and activity level without MRI subchondral changes. Therefore, we recommend caution with consideration of hip arthroscopy in this patient subset.

Trafficking from bedside to bench Typically in translational research, a discovery in cell or molecular biology is later exploited to improve patient care. Occasionally, information flows in the opposite direction. Lo et al. found that patients with an autoimmune disorder caused by deficiency of a protein called LRBA responded dramatically to the drug abatacept (see the Perspective by Sansom). Abatacept contains a segment of a potent inhibitory immune receptor, CTLA4. Experiments prompted by this observation revealed the relationship between the two proteins: LRBA controls the intracellular trafficking and degradation of CTLA4. This information may further improve patient care, because other clinically approved drugs have the desired mechanism of action with potentially fewer side effects. Science , this issue p. 436 ; see also p. 377

Abstract Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

Background: The medial collateral (MCL) and anterior cruciate ligaments (ACL) are, respectively, the primary and secondary ligamentous restraints against knee abduction, which is a component of the valgus collapse often associated with ACL rupture during athletic tasks. Despite this correlation in function, MCL ruptures occur concomitantly in only 20% to 40% of ACL injuries. Hypothesis/Purpose: The purpose of this investigation was to determine how athletic tasks load the knee joint in a manner that could lead to ACL failure without concomitant MCL failure. It was hypothesized that (1) the ACL would provide greater overall contribution to intact knee forces than the MCL during simulated motion tasks and (2) the ACL would show greater relative peak strain compared with the MCL during simulated motion tasks. Study Design: Controlled laboratory study. Methods: A 6-degrees-of-freedom robotic manipulator articulated 18 cadaveric knees through simulations of kinematics recorded from in vivo drop vertical jump and sidestep cutting tasks. Specimens were articulated in the intact-knee and isolated-ligament conditions. After simulation, each ACL and MCL was failed in uniaxial tension along its fiber orientations. Results: During a drop vertical jump simulation, the ACL experienced greater peak strain than the MCL (6.1% vs 0.4%; P < .01). The isolated ACL expressed greater peak anterior force (4.8% vs 0.3% body weight; P < .01), medial force (1.6% vs 0.4% body weight; P < .01), flexion torque (8.4 vs 0.4 N·m; P < .01), abduction torque (2.6 vs 0.3 N·m; P < .01), and adduction torque (0.5 vs 0.0 N·m; P = .03) than the isolated MCL. During failure testing, ACL specimens preferentially loaded in the anteromedial bundle failed at 637 N, while MCL failure occurred at 776 N. Conclusion: During controlled physiologic athletic tasks, the ACL provides greater contributions to knee restraint than the MCL, which is generally unstrained and minimally loaded. Clinical Relevance: Current findings support that multiplanar loading during athletic tasks preferentially loads the ACL over the MCL, leaving the ACL more susceptible to injury. An enhanced understanding of joint loading during in vivo tasks may provide insight that enhances the efficacy of injury prevention protocols.

Background and Purpose— The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Methods— Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P <10 −6 for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. Results— The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P =3.9×10 −8 ) in African Americans. Nominal associations ( P <10 −6 ) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing ( PTPRG , CDC5L ), platelet function ( HPS4 ), blood–brain barrier permeability ( CLDN17 ), immune response ( ELTD1, WDFY4 , and IL1F10-IL1RN ), and histone modification ( HDAC9 ). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 ( P =0.03), and 1p31.1 ( P =0.018). Four of 7 previously reported ischemic stroke loci ( PITX2, HDAC9, CDKN2A/CDKN2B , and ZFHX3 ) were nominally associated ( P <0.05) with stroke in COMPASS. Conclusions— We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

Abstract A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P &lt; 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 783