Citations

Background: Osteonecrosis of the hip is the underlying etiology for 3% to 12% of total hip arthroplasties (THAs). Compared with patients who undergo THA because of osteoarthritis, those who do so because of osteonecrosis typically are younger, have a greater number of underlying diagnoses, and have inferior clinical outcomes and implant survivorship. The purpose of this study was to compare the long-term implant survivorship (median follow-up, 10 years), functional outcomes, and radiographic results of contemporary THAs with a highly cross-linked polyethylene (HXLPE) liner between patients with osteonecrosis and those with osteoarthritis. Methods: All patients who underwent primary THA with an HXLPE liner from 1999 to 2007 were identified from our institutional total joint registry. Patients with a primary diagnosis of osteonecrosis were matched 1:1, on the basis of age, sex, and body mass index (BMI), to patients with a diagnosis of osteoarthritis. This resulted in 461 hips in 413 patients with osteonecrosis matched to 461 hips in 427 patients with osteoarthritis (mean age, 59 years; 47% female; and mean BMI, 29 kg/m 2 ). Long-term implant survivorship, patient-reported outcomes, and radiographic findings were compared. In addition, a subgroup analysis of the osteonecrosis group was performed to see whether certain underlying etiologies portended poor outcomes. The median follow-up was 10 years. Results: The 15-year cumulative rates of revision were 6.6% and 4.5% in the osteonecrosis and osteoarthritis groups, respectively (hazard ratio [HR] = 1.8, p = 0.09). The 15-year cumulative rates of any reoperation were 10.5% and 6.4% in the osteonecrosis and osteoarthritis groups, respectively (HR = 2.2, p = 0.008). There were no radiographic signs of component loosening or osteolysis in the entire cohort. Despite a lower median preoperative Harris hip score (HHS) for patients with osteonecrosis, both groups had marked improvements in their scores, which were similar at all time points after surgery. The cumulative rate of reoperations at 15 years was 0% for hips with radiation-induced osteonecrosis, 6.3% for those with alcohol-induced osteonecrosis, 9.0% for those with posttraumatic osteonecrosis, 12.1% for those with steroid-induced osteonecrosis, and 25% for those with idiopathic osteonecrosis. Conclusions: Contemporary THA with an HXLPE liner offers excellent long-term implant survivorship and functional outcomes for patients with osteonecrosis; however, the risk of a reoperation is higher when compared with patients with osteoarthritis. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background: Understanding the joint effect on breast cancer risk of rare pathogenic variants in cancer predisposition genes and polygenic risk scores (PRS) from common variants can enable a precision approach to breast cancer management. Previous work found that PRS were associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers recruited from cancer genetics clinics (Kuchenbaecker et al. JNCI 2017). The joint effects of pathogenic variants and PRS have not been studied in samples drawn from the general population. There is also no existing study evaluating the effect of PRS in mutation carriers in genes other than BRCA1/2. Here we evaluate the joint effects of PRS and pathogenic mutations in established cancer predisposition genes in a population-based case-control sample. Method: We analyzed 53,199 European-ancestry individuals (20,730 controls and 21,272 cases) drawn from 7 cohorts and 2 population-based case-control studies in the CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium. Targeted sequencing was performed using dual bar-coded QIAseq. Mutation calling was conducted with Haplotype Caller and Vardict. We sequenced 18 breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHECK2, FANCC, MLH1, MSH2, MSH6, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53. The PRS was calculated based on 128 common variants using effect estimates from the largest published breast cancer GWAS. The PRS was standardized to a mean of 0 and standard deviation of 1. Logistic regression was performed to assess the combined effect of identified mutation and common variants (including main and interaction effects for carrier status and PRS). Results: A total of 1,770 pathogenic mutations were observed. About 1% of the study sample had mutations in either BRCA1 (n=209) or BRCA2 gene (n=305), and 2.2% had mutations in other genes (n=1,176). The effect of PRS in BRCA1 carriers was OR= 0.97 (95%CI: 0.62, 1.52); however, this is not statistically significantly different from the PRS in non-carriers [OR=1.23 (95%CI: 1.20, 1.25)] or previous estimates in carriers [OR: 1.14, 95%CI: 1.11-1.17]. The effect of PRS in BRCA2 carriers was OR=1.87 (95%CI: 1.31, 2.78) which was statistically significantly different from that of the non-carriers. Among the mutation carriers in genes other than BRCA, the effect of PRS on breast cancer was OR=1.00 (95%CI: 0.88,1.15). Conclusion: Consistent with previous studies, we did not find evidence that the effect of the PRS among BRCA1 carriers was statistically significantly different than non-carriers. We found some evidence that the PRS effect may be larger among BRCA2 carriers than non-carriers. Our results also suggest that PRS may not have a strong effect on breast cancer risk in mutation carriers of other predisposition genes; further work is needed for verification. Citation Format: Chi Gao, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Kun Y. Lee, Jenna Lilyquist, Nicholas J. Boddicker, Bruce Eckloff, Raed Samara, Josh Klebba, Paul Auer, Leslie Bernstein, Mia Gaudet, Hoda Anton-Culver, Amy Trentham-Dietz, Julie R. Palmer, Song Yao, Christopher Haiman, Janet E. Olson, Susan Domchek, Jeffrey Weitzel, David Goldgar, Katherine L. Nathanson, Eric C. Polley, Fergus J. Couch, Peter Kraft. The joint effects of polygenic risk scores and pathogenic variants in cancer predisposition genes on breast cancer risk in the general population: results from the CARRIERS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4177.

Abstract Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. Pathogenic mutations in cancer predisposition genes are associated with established risks of breast cancer and are actively used for risk management of breast cancer for women qualifying for genetic testing because of a family history of breast and/or ovarian cancer or young age of diagnosis. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study was to estimate breast cancer risks associated with mutations in hereditary cancer panel genes. Germline DNA from 32,298 breast cancer patients and 31,869 matched unaffected controls enrolled in cohorts and population-based case-control studies were sequenced to identify pathogenic mutations in 37 cancer predisposition genes.The average age at diagnosis was 61.2 years and the average age of last follow-up was 62.1 years. DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions in 37 predisposition genes. Products from 768 samples were pooled and sequenced in a single lane of a HiSeq 4000 system. Mutations were called by GATK Haplotype Caller and Vardict.High quality sequence data was obtained for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified in 6.2% of all breast cancer cases and 2.1% of controls; and in 6.7% of African American breast cancer cases and 1.8% of controls. In case-control association analyses adjusted for age at diagnosis or last follow up and family history of breast and ovarian cancer, mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (odds ratio (OR)>4.0). Mutations in CHEK2 and BARD1 were associated with moderate risks of breast cancer (OR>2.0), whereas mutations in ATM had lower clinical relevance (OR=1.6). Stratification by ER, PR, and HER2 status of tumors found that BRCA1, BRCA2, PALB2 and TP53 were associated with high risks of studies of triple negative breast cancer (TNBC), and that BARD1, BRIP1, FANCM, and RAD51C were associated with moderate risks of TNBC. Overall, results from the CARRIERS study establish that mutations in predisposition genes are associated with lower risks of breast cancer in the general population than in high-risk families. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform on the use of cancer screening and other risk management strategies for women in the general population with mutations in predisposition genes. Citation Format: Fergus J. Couch, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Jenna Lilyquist, Kun Y. Lee, Chi Gao, Bruce Eckloff, Hoda Anton-Culver, Paul Auer, Leslie Bernstein, Mia Gaudet, Christopher Haiman, Julie Palmer, Amy Tentham-Dietz, Song Yao, Susan Domchek, Jeffrey N. Weitzel, David E. Goldgar, Katherine L. Nathanson, Peter Kraft, Eric C. Polley. Population-based breast cancer risk estimates associated with cancer predisposition gene mutations from 32,298 breast cancer patients and 31,869 matched unaffected controls from the CARRIERS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4169.

Background and objectives Dialysis is a preference-sensitive decision where prognosis may play an important role. Although patients desire risk prediction, nephrologists are wary of sharing this information. We reviewed the performance of prognostic indices for patients starting dialysis to facilitate bedside translation. Design, setting, participants, & measurements Systematic review and meta-analysis following the PRISMA guidelines. We searched Ovid MEDLINE, Ovid Embase, Ovid Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus for eligible studies of patients starting dialysis published from inception to December 31, 2018. Selection Criteria: Articles describing validated prognostic indices predicting mortality at the start of dialysis. We excluded studies limited to prevalent dialysis patients, AKI and studies excluding mortality in the first 1–3 months. Two reviewers independently screened abstracts, performed full text assessment of inclusion criteria and extracted: study design, setting, population demographics, index performance and risk of bias. Pre-planned random effects meta-analysis was performed stratified by index and predictive window to reduce heterogeneity. Results Of 12,132 articles screened and 214 reviewed in full text, 36 studies were included describing 32 prognostic indices. Predictive windows ranged from 3 months to 10 years, cohort sizes from 46 to 52,796. Meta-analysis showed discrimination area under the curve (AUC) of 0.71 (95% confidence interval, 0.69 to 073) with high heterogeneity ( I 2 =99.12). Meta-analysis by index showed highest AUC for The Obi, Ivory, and Charlson comorbidity index (CCI)=0.74, also CCI was the most commonly used (ten studies). Other commonly used indices were Kahn-Wright index (eight studies, AUC 0.68), Hemmelgarn modification of the CCI (six studies, AUC 0.66) and REIN index (five studies, AUC 0.69). Of the indices, ten have been validated externally, 16 internally and nine were pre-existing validated indices. Limitations include heterogeneity and exclusion of large cohort studies in prevalent patients. Conclusions Several well validated indices with good discrimination are available for predicting survival at dialysis start.

PURPOSE Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician’s choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer–specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.

Background: Povidone-iodine (PI) irrigation is often used prior to wound closure in total joint arthroplasty, but there are limited reports evaluating its efficacy in decreasing joint infections. The goal of this study was to compare the rate of any reoperation for infection (both superficial and deep) in primary total hip arthroplasty (THA) and primary total knee arthroplasty (TKA) among patients who did and did not receive PI irrigation prior to wound closure. Methods: Using our institution’s total joint registry, we identified 5,534 primary THA and 6,204 primary TKA procedures performed from 2013 to 2017. Cases were grouped on the basis of whether or not the wound was irrigated with 1 L of 0.25% PI prior to closure. PI irrigation was used in 1,322 (24%) of the THA cases and in 2,410 (39%) of the TKA cases. The rates of reoperation for infection at 3 months and 1 year were compared between the 2 groups. The same comparisons were then performed using propensity scores to account for differences in baseline characteristics. Results: The rate of reoperation for infection as assessed at 3 months following THA was similar between those who received dilute PI irrigation (0.9%) and who did not (0.7%) (p = 0.7). At 1 year, the rate of reoperation for infection was similar between those who received dilute PI irrigation (0.7%) and those who did not (0.9%) (p = 0.6). After using the propensity score, there was no difference between the groups in the risk of septic reoperations. For TKA, the rate of reoperation as assessed at 3 months was similar between those who received dilute PI irrigation (0.8%) and those who did not (0.3%) (p = 0.06). At 1 year, there was a greater rate of reoperations for infection among those who received dilute PI irrigation (1.2%) compared with those who did not (0.6%) (p = 0.03). However, there was no difference in the risk of septic reoperations between the groups after using the propensity score. Conclusions: Despite enthusiasm for and progressive adoption of the use of dilute PI irrigation at our institution, there was not a significant reduction in the risk of reoperation for infection as assessed at 3 months and 1 year following primary THA and TKA. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Postoperative infection remains a major challenge in revision total hip arthroplasty (THA) and revision total knee arthroplasty (TKA). Wound irrigation with dilute povidone-iodine (PI) solution has emerged as a simple, inexpensive, and potentially successful means of reducing postoperative infections. The aim of this study was to assess its effectiveness in reducing infection following revision THA and TKA in, to our knowledge, the largest revision cohort to date. Methods: Using our institution’s total joint registry, we identified 1,402 revision THAs and 1,482 revision TKAs performed during the study period (2013, when the PI irrigation protocol was first implemented, to 2017). The PI lavage protocol was employed in 27% of the revision THA cases and 34% of the revision TKA cases; in the remaining cases, the protocol was not used. Demographics, comorbid conditions, underlying surgical diagnoses, and whether the revision was for a septic or an aseptic etiology were compared between the groups (use or no use of PI irrigation). Any reoperation due to infection, as assessed at 3 and 12 months following revision arthroplasty, was compared between the groups and propensity scores were calculated to account for differences in baseline characteristics between the groups. Results: After adjusting for baseline differences between the groups using the propensity-score weighted models, we found no significant difference in the rate of reoperation for infection at 3 months (p = 0.58 for revision THA, and p = 0.06 for revision TKA) and at 12 months (p = 0.78 for revision THA, and p = 0.06 for revision TKA). Nonetheless, the hazard ratios from the propensity-score model trended higher for patients who received PI lavage: 1.6 and 1.3 for revision THA at 3 and 12 months, respectively, and 2.9 at both 3 and 12 months for revision TKA. Conclusions: PI wound lavage demonstrated no benefit in reducing any reoperation for infection following revision THA and TKA. Moreover, the trend toward higher rates for reoperation for infection among patients who received PI irrigation merit further consideration. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

AbstractIntroduction:Patients with end‐stage renal disease (ESRD) experience frequent hemodialysis (HD) complications. Intradialytic hypotension (IDH) is a common complication presenting in approximately between 20 and 50% of HD sessions. Available interventions such as volume replacement or vasoactive medications are associated with significant side effects.Intermittent pneumatic compression (IPC) has been proposed as a feasible intervention for the prevention of IDH, treatment of peripheral arterial disease and venous ulcers. These devices apply intermittent pressure to the legs improving arterial blood flow, mobilization of pooled blood with an increase in venous return increasing the effective circulatory volume.Our goal was to identify the published clinical evidence on whether IPC has a circulatory benefit and is it well‐tolerated among patients receiving HD.Methods:We conducted a systematic review to identify studies assessing the efficacy and safety of IPC in patients with ESRD. Our primary outcome was IDH. Secondary outcomes such as HD comfort, ultrafiltration volume, and physical activity were collected. No restrictions where used and we included all observational and interventional studies. Two reviewers performed screening and study quality assessment.Findings:We included seven studies. Out of the seven studies, five addressed IDH, and the rest were included for secondary outcomes such as physical capacity and HD comfort. In one randomized crossover trial comparing exercise against IPC, 21 patients were randomized to 3 different arms (no intervention, cycling, IPC) a decrease in the rates of IDH with IPC was described (43%, 38%, and 24% respectively P = 0.014). The smaller studies corroborated these results. All studies where at high risk of bias.Discussion:IPC might offer significant benefits for patients undergoing HD not limited to prevention of IDH but also improvement of hemodialysis comfort and physical capacity. However, our results should be interpreted in the context of its limitations.

Introduction: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. Methods: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. Results: The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. Discussion: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.