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Screening for oral leukoplakia, an oral cavity cancer (OCC) precursor, could lead to earlier detection of OCC. However, the progression rate from leukoplakia to OCC and the benefits of leukoplakia screening for improving OCC outcomes are currently unclear. We conducted a case–cohort study of U.S. adults ages ≥65 years in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linkage. We identified leukoplakia diagnoses through Medicare claims, and OCC diagnoses through SEER cancer registries. Weighted Cox regression was used to estimate leukoplakia associations with OCC incidence, and the absolute OCC risk following leukoplakia diagnosis was calculated. Among OCC cases, we compared OCC stage and OCC survival between cases with a prior leukoplakia diagnosis versus those without prior leukoplakia. Among 470,266 individuals in the SEER-Medicare subcohort, 1,526 (0.3%) had a leukoplakia diagnosis. Among people with leukoplakia, the cumulative OCC incidence was 0.7% at 3 months and 2.5% at 5 years. OCC risk was most increased N = 8,927), those with prior leukoplakia were less likely to be diagnosed at regional/distant stage (OR, 0.36; 95% CI, 0.30–0.43), and had lower mortality (HR, 0.74; 95% CI, 0.65–0.84) when compared with OCC cases without a prior leukoplakia. Individuals with leukoplakia have substantially elevated risk of OCC. Lower stage and better survival after OCC diagnosis suggest that leukoplakia identification can lead to earlier OCC detection and reduced mortality. Cancer Prev Res; 8(9); 857–63. ©2015 AACR.

Supplementary Tables 1 & 2. Table 1: Comparison of American Joint Committee on Cancer (AJCC) stage to SEER historic stage within the SEER database. Table 2: Primary treatment for oral cavity cancer cases.

Background: Certain medical conditions affect risk of non-Hodgkin lymphoma (NHL), but the full range of associations is unknown. We implemented a novel method (“medical condition-wide association study,” MedWAS) to comprehensively evaluate medical risk factors for NHL documented in administrative health claims.Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we conducted a case–control study comparing NHL cases [N = 52,691, age 66+ years, with five subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), T-cell lymphoma (TCL)] to controls (N = 200,000). We systematically screened for associations with 5,926 medical conditions documented in Medicare claims more than 1 year before selection.Results: Fifty-five conditions were variously associated with NHL. Examples include well-established associations of human immunodeficiency virus, solid organ transplantation, and hepatitis C virus with increased DLBCL risk (ORs 3.83, 4.27, and 1.74, respectively), and autoimmune conditions with DLBCL and MZL (e.g., ORs of 2.10 and 4.74, respectively, for Sjögren syndrome). Risks for all NHL subtypes were increased after diagnoses of nonmelanoma skin cancer (ORs 1.19–1.55), actinic keratosis (1.12–1.25), or hemolytic anemia (1.64–4.07). Nine additional skin conditions increased only TCL risk (ORs 2.20–4.12). Diabetes mellitus was associated with increased DLBCL risk (OR 1.09). Associations varied significantly across NHL subtypes for 49 conditions (89%).Conclusion: Using an exploratory method, we found numerous medical conditions associated with NHL risk, and many associations varied across NHL subtypes.Impact: These results point to etiologic heterogeneity among NHL subtypes. MedWAS is a new method for assessing the etiology of cancer and other diseases. Cancer Epidemiol Biomarkers Prev; 25(7); 1105–13. ©2016 AACR.

Power calculations for replication analyses

3-year lag analysis

SELECT1 conditions

Immune condition associations with squamous cell carcinoma of the skin stratified by keratinocyte cancer (KC) diagnosis in Medicare prior to 2012

Background: Elevated keratinocyte carcinoma risk is present with several immune-related conditions, e.g., solid organ transplantation and non-Hodgkin lymphoma. Because many immune-related conditions are rare, their relationships with keratinocyte carcinoma have not been studied.Methods: We used Medicare claims to identify cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) cases in 2012, and controls matched on sex and age. All subjects were aged 65 to 95 years, of white race, and had attended ≥1 dermatologist visit in 2010–2011. Immune-related conditions were identified during 1999–2011 using Medicare claims. Associations were estimated with logistic regression, with statistical significance determined after Bonferroni correction for multiple comparisons.Results: We included 258,683 SCC and 304,903 BCC cases. Of 47 immune-related conditions, 21 and 9 were associated with increased SCC and BCC risk, respectively. We identified strongly elevated keratinocyte carcinoma risk with solid organ transplantation (SCC OR = 5.35; BCC OR = 1.94) and non-Hodgkin lymphoma (SCC OR = 1.62; BCC OR = 1.25). We identified associations with common conditions, e.g., rheumatoid arthritis [SCC OR = 1.06, 95% confidence interval (95% CI), 1.04–1.09] and Crohn's disease (SCC OR = 1.33, 95% CI, 1.27–1.39; BCC OR = 1.10, 95% CI, 1.05–1.15), and rare or poorly characterized conditions, e.g., granulomatosis with polyangiitis (SCC OR = 1.88; 95% CI, 1.61–2.19), autoimmune hepatitis (SCC OR = 1.81; 95% CI, 1.52–2.16), and deficiency of humoral immunity (SCC OR = 1.51, 95% CI, 1.41–1.61; BCC OR = 1.22, 95% CI, 1.14–1.31). Most conditions were more positively associated with SCC than BCC. Associations were generally consistent regardless of prior keratinocyte carcinoma history.Conclusions: Many immune-related conditions are associated with elevated keratinocyte carcinoma risk and appear more tightly linked to SCC.Impact: Immunosuppression or immunosuppressive treatment may increase keratinocyte carcinoma risk, particularly SCC. Cancer Epidemiol Biomarkers Prev; 26(7); 998–1007. ©2017 AACR.

Counts for SELECT3 conditions

OBJECTIVE Proximal junctional failure (PJF) is a severe form of proximal junctional kyphosis. Previous reports on PJF have been limited by heterogeneous cohorts and relatively short follow-ups. The authors’ objectives herein were to identify risk factors for PJF and to assess its long-term incidence and revision rates in a homogeneous cohort. METHODS The authors reviewed data from the Adult Symptomatic Lumbar Scoliosis 1 trial (ASLS-1), a National Institutes of Health–sponsored prospective multicenter study. Inclusion criteria were an age ≥ 40 years, ASLS (Cobb angle ≥ 30° and Oswestry Disability Index [ODI] ≥ 20 or Scoliosis Research Society revised 22-item questionnaire [SRS-22r] score ≤ 4.0 in pain, function, or self-image domains), and primary thoracolumbar fusion/fixation to the sacrum/pelvis of ≥ 7 levels. PJF was defined as a postoperative proximal junctional angle (PJA) change > 20°, fracture of the uppermost instrumented vertebra (UIV) or UIV+1 with > 20% vertebral height loss, spondylolisthesis of UIV/UIV+1 > 3 mm, or UIV screw dislodgment. RESULTS One hundred sixty patients (141 women) were included in this analysis and had a median age of 62 years and a mean follow-up of 4.3 years (range 0.1–6.1 years). Forty-six patients (28.8%) had PJF at a median of 0.92 years (IQR 0.14, 1.23 years) following surgery. Based on Kaplan-Meier analyses, PJF rates at 1, 2, 3, and 4 years were 14.4%, 21.9%, 25.9%, and 27.4%, respectively. On univariate analysis, PJF was associated with greater age (p = 0.0316), greater body mass index (BMI; p = 0.0319), worse baseline patient-reported outcome measures (PROMs; ODI, SRS-22r, and SF-12 Physical Component Summary [PCS]; all p < 0.04), the use of posterior column osteotomies (PCOs; p = 0.0039), and greater postoperative thoracic kyphosis (TK; p = 0.0031) and PJA (p < 0.001). The use of UIV hooks was protective against PJF (p = 0.0340). On regression analysis (without postoperative measures), PJF was associated with greater BMI (HR 1.077, 95% CI 1.007–1.153, p = 0.0317), lower preoperative PJA (HR 0.607, 95% CI 0.407–0.906, p = 0.0146), and greater preoperative TK (HR 1.362, 95% CI 1.082–1.715, p = 0.0085). Patients with PJF had worse PROMs at the last follow-up (ODI, SRS-22r subscore and self-image, and SF-12 PCS; p < 0.04). Sixteen PJF patients (34.8%) underwent revision, and PJF recurred in 3 (18.8%). CONCLUSIONS Among 160 primary ASLS patients with a median age of 62 years and predominant coronal deformity, the PJF rate was 28.8% at a mean 4.3-year follow-up, with a revision rate of 34.8%. On univariate analysis, PJF was associated with a greater age and BMI, worse baseline PROMs, the use of PCOs, and greater postoperative TK and PJA. The use of UIV hooks was protective against PJF. On multivariate analysis (without postoperative measures), a higher risk of PJF was associated with greater BMI and preoperative TK and lower preoperative PJA.

OBJECTIVE Previous reports of rod fracture (RF) in adult spinal deformity are limited by heterogeneous cohorts, low follow-up rates, and relatively short follow-up durations. Since the majority of RFs present > 2 years after surgery, true occurrence and revision rates remain unclear. The objectives of this study were to better understand the risk factors for RF and assess its occurrence and revision rates following primary thoracolumbar fusions to the sacrum/pelvis for adult symptomatic lumbar scoliosis (ASLS) in a prospective series with long-term follow-up. METHODS Patient records were obtained from the Adult Symptomatic Lumbar Scoliosis–1 (ASLS-1) database, an NIH-sponsored multicenter, prospective study. Inclusion criteria were as follows: patients aged 40–80 years undergoing primary surgeries for ASLS (Cobb angle ≥ 30° and Oswestry Disability Index ≥ 20 or Scoliosis Research Society-22r ≤ 4.0 in pain, function, and/or self-image) with instrumented fusion of ≥ 7 levels that included the sacrum/pelvis. Patients with and without RF were compared to assess risk factors for RF and revision surgery. RESULTS Inclusion criteria were met by 160 patients (median age 62 years, IQR 55.7–67.9 years). At a median follow-up of 5.1 years (IQR 3.8–6.6 years), there were 92 RFs in 62 patients (38.8%). The median time to RF was 3.0 years (IQR 1.9–4.54 years), and 73% occurred > 2 years following surgery. Based on Kaplan-Meier analyses, estimated RF rates at 2, 4, 5, and 8 years after surgery were 11%, 24%, 35%, and 49%, respectively. Baseline radiographic, clinical, and demographic characteristics were similar between patients with and without RF. In Cox regression models, greater postoperative pelvic tilt (HR 1.895, 95% CI 1.196–3.002, p = 0.0065) and greater estimated blood loss (HR 1.02, 95% CI 1.005–1.036, p = 0.0088) were associated with increased risk of RF. Thirty-eight patients (61% of all RFs) underwent revision surgery. Bilateral RF was predictive of revision surgery (HR 3.52, 95% CI 1.8–6.9, p = 0.0002), while patients with unilateral nondisplaced RFs were less likely to require revision (HR 0.39, 95% CI 0.18–0.84, p = 0.016). CONCLUSIONS This study provides what is to the authors’ knowledge the highest-quality data to date on RF rates following ASLS surgery. At a median follow-up of 5.1 years, 38.8% of patients had at least one RF. Estimated RF rates at 2, 4, 5, and 8 years after surgery were 11%, 24%, 35%, and 49%, respectively. Greater estimated blood loss and postoperative pelvic tilt were significant risk factors for RF. These findings emphasize the importance of long-term follow-up to realize the true prevalence and cumulative incidence of RF.

OBJECTIVE Although the health impact of adult symptomatic lumbar scoliosis (ASLS) is substantial, these patients often have other orthopedic problems that have not been previously quantified. The objective of this study was to assess disease burden of other orthopedic conditions in patients with ASLS based on a retrospective review of a prospective multicenter cohort. METHODS The ASLS-1 study is an NIH-sponsored prospective multicenter study designed to assess operative versus nonoperative treatment for ASLS. Patients were 40–80 years old with ASLS, defined as a lumbar coronal Cobb angle ≥ 30° and Oswestry Disability Index ≥ 20, or Scoliosis Research Society-22 questionnaire score ≤ 4.0 in pain, function, and/or self-image domains. Nonthoracolumbar orthopedic events, defined as fractures and other orthopedic conditions receiving surgical treatment, were assessed from enrollment to the 4-year follow-up. RESULTS Two hundred eighty-six patients (mean age 60.3 years, 90% women) were enrolled, with 173 operative and 113 nonoperative patients, and 81% with 4-year follow-up data. At a mean (± SD) follow-up of 3.8 ± 0.9 years, 104 nonthoracolumbar orthopedic events were reported, affecting 69 patients (24.1%). The most common events were arthroplasty (n = 38), fracture (n = 25), joint ligament/cartilage repair (n = 13), and cervical decompression/fusion (n = 7). Based on the final adjusted model, patients with a nonthoracolumbar orthopedic event were older (HR 1.44 per decade, 95% CI 1.07–1.94), more likely to have a history of tobacco use (HR 1.63, 95% CI 1.00–2.66), and had worse baseline leg pain scores (HR 1.10, 95% CI 1.01–1.19). CONCLUSIONS Patients with ASLS have high orthopedic disease burden, with almost 25% having a fracture or nonthoracolumbar orthopedic condition requiring surgical treatment during the mean 3.8 years following enrollment. Comparisons with previous studies suggest that the rate of total knee arthroplasty was considerably greater and the rates of total hip arthroplasty were at least as high in the ASLS-1 cohort compared with the similarly aged general US population. These conditions may further impact health-related quality of life and outcomes assessments of both nonoperative and operative treatment approaches in patients with ASLS.

Background Prior US studies have shown increasing rotator cuff repair rates through 2009. We hypothesize that rotator cuff repair rates are continuing to increase and the comorbidity profiles of patients are becoming more complex over time. Methods We identified rotator cuff repairs in a large US cohort of people 18-64 years of age with ≥1 year of commercial insurance coverage. Repair rate trends across time were standardized by age, sex, and geographic region. Procedures were categorized as inpatient vs. outpatient and as arthroscopic vs. open. Prevalent comorbidities were defined as 1 inpatient diagnosis claim or 2 outpatient diagnosis claims during the year before rotator cuff repair. General population comorbidity prevalence was determined based on a random 5% sample of the commercially insured population and compared with patients with rotator cuff repair using standardized morbidity ratios. Results From 2007 to 2016, 314,239 rotator cuff repairs were identified (165 repairs per 100,000 person-years). Rotator cuff repairs were performed more frequently in men, older people, and in the Midwest. Across time, cuff repair rates increased by 1.6% per year (95% confidence interval [CI] = +1.4%-1.7%) adjusting for demographics. The highest increases in repair rates were observed among patients aged 50-64 years (+2.0%, 95% CI = +1.8%-2.2%). Rotator cuff repairs were more frequently performed using an arthroscopic approach and in an outpatient setting in later calendar years. In 2016, 83% of rotator cuff repairs were arthroscopic procedures and 99% were performed as outpatient procedures. Comorbidity prevalence in rotator cuff repair patients increased across calendar time by 4.5% per year for hypertension (95% CI = +4.2%-4.7%), 2.3% per year for diabetes (+1.9%-2.7%), 0.9% per year for hypercholesterolemia (+0.3%-1.5%), 2.9% for congestive heart failure (+0.8%-4.9%), 4.2% for peripheral vascular disease (+2.4%-6.0%), and 4.2% for chronic pulmonary disease (+3.6%-4.8%). Comorbidity prevalence in repair patients was higher than prevalence in the general population, and prevalence relative to the general population was most heightened during later calendar years. For example, hypertension prevalence was 1.58 times higher in repair patients than the general population in 2007 (95% CI = 1.53-1.62), and 2.06 times higher in 2016 (95% CI = 2.02-2.11). Conclusion Rotator cuff repair is becoming more frequent in the US commercially insured population, particularly in those 50-64 years of age. More rotator cuff repairs are being performed using an arthroscopic approach and in an outpatient setting. Over time, the comorbidity profile of patients undergoing rotator cuff repair is becoming more complex with greater prevalence of numerous conditions, including hypertension, peripheral vascular disease, and chronic pulmonary disease.

Objectives: physically-demanding occupations may increase rotator cuff disease (RCD) risk and need for surgery. We linked a job-exposure matrix (JEM) to the UK Biobank cohort study to measure physical occupational exposures and estimate associations with RCD surgery.Methods: jobs and UK Standard Occupational Classification (SOC) codes were recorded during the UK Biobank verbal interview. Lifetime job histories were captured through a web-based survey. UK SOC codes were linked to a JEM based on the US O*NET database. O*NET-based scores [static strength, dynamic strength, general physical activities, handling/moving objects (range=1-7), time spent using hands, whole body vibration, and cramped/awkward positions (range=1-5)] were assigned to jobs. RCD surgeries were identified through linked national hospital inpatient records. Multivariable Cox regression was used to calculate hazard ratios (HR) as estimates of associations with RCD surgery. Among those with lifetime job histories, associations were estimated for duration of time with greatest exposure (top quartile of exposure).Results: of 277 808 people reporting jobs, 1997 (0.7%) had an inpatient RCD surgery. After adjusting for age, sex, race, education, area deprivation, and body mass index, all O*NET variables considered were associated with RCD surgery (HR per point increase range=1.10-1.45, all P10 years of work (eg, HR for 11-20 versus 0 years with static strength score ≥4 = 2.06, 95% confidence interval 1.39-3.04).Conclusions: workplace physical demands are an important risk factor for RCD surgery, particularly for workers with more than a decade of exposure.

Background: TNF inhibitors (TNFi) effectively treat rheumatoid arthritis but may increase patient risk of some malignancies, particularly lymphomas or skin cancers. Methods: We used Surveillance, Epidemiology, and End Results (SEER)–Medicare data to conduct a case–control study in patients with rheumatoid arthritis (2007–2015). Cases were individuals with a first cancer diagnosed in SEER registries (ages 66–99, 22 cancer sites, N = 10,263). Skin cancer cases [nonmelanoma skin cancer (NMSC, N = 501), basal cell carcinoma (BCC, N = 161), squamous cell carcinoma (SCC, N = 150)] and cancer-free controls (N = 30,475) were selected from Medicare beneficiaries residing in SEER areas. Cases and controls had prior Medicare claims-based evidence for rheumatoid arthritis, and TNFi exposure was ascertained from part B and part D claims. Logistic regression was used to estimate adjusted odds ratios (aOR). Results: TNFi exposure was present in 16.2% of controls and 12.8% to 33.7% of cancer cases, varying by site. TNFi use was associated with increased risk of NMSC overall (aOR 1.32, 95% confidence interval 1.06–1.63), non-Hodgkin lymphoma (NHL) overall (1.28, 1.06–1.56) and, specifically, follicular lymphoma (2.63, 1.63–4.24). TNFi exposure was not associated with other SEER cancer sites, BCC or SCC specifically, or other common NHL subtypes. Conclusions: Among older adults with rheumatoid arthritis, TNFi exposure was associated with elevated risk of NMSC and NHL, driven specifically by follicular lymphoma. Exposure was not associated with increased risk for other cancer sites. Impact: Our results support a role for TNF in lymphomagenesis. Given the association with NMSC, patients initiating TNFi therapy may benefit from skin cancer screening and sun protection measures.

OBJECTIVE Although short-term adult symptomatic lumbar scoliosis (ASLS) studies favor operative over nonoperative treatment, longer outcomes are critical for assessment of treatment durability, especially for operative treatment, because the majority of implant failures and nonunions present between 2 and 5 years after surgery. The objectives of this study were to assess the durability of treatment outcomes for operative versus nonoperative treatment of ASLS, to report the rates and types of associated serious adverse events (SAEs), and to determine the potential impact of treatment-related SAEs on outcomes. METHODS The ASLS-1 (Adult Symptomatic Lumbar Scoliosis–1) trial is an NIH-sponsored multicenter prospective study to assess operative versus nonoperative ASLS treatment. Patients were 40–80 years of age and had ASLS (Cobb angle ≥ 30° and Oswestry Disability Index [ODI] ≥ 20 or Scoliosis Research Society [SRS]–22 subscore ≤ 4.0 in the Pain, Function, and/or Self-Image domains). Patients receiving operative and nonoperative treatment were compared using as-treated analysis, and the impact of related SAEs was assessed. Primary outcome measures were ODI and SRS-22. RESULTS The 286 patients with ASLS (107 with nonoperative treatment, 179 with operative treatment) had 2-year and 5-year follow-up rates of 90% (n = 256) and 74% (n = 211), respectively. At 5 years, compared with patients treated nonoperatively, those who underwent surgery had greater improvement in ODI (mean difference −15.2 [95% CI −18.7 to −11.7]) and SRS-22 subscore (mean difference 0.63 [95% CI 0.48–0.78]) (p < 0.001), with treatment effects (TEs) exceeding the minimum detectable measurement difference (MDMD) for ODI (7) and SRS-22 subscore (0.4). TEs at 5 years remained as favorable as 2-year TEs (ODI −13.9, SRS-22 0.52). For patients in the operative group, the incidence rates of treatment-related SAEs during the first 2 years and 2–5 years after surgery were 22.38 and 8.17 per 100 person-years, respectively. At 5 years, patients in the operative group who had 1 treatment-related SAE still had significantly greater improvement, with TEs (ODI −12.2, SRS-22 0.53; p < 0.001) exceeding the MDMD. Twelve patients who received surgery and who had 2 or more treatment-related SAEs had greater improvement than nonsurgically treated patients based on ODI (TE −8.34, p = 0.017) and SRS-22 (TE 0.32, p = 0.029), but the SRS-22 TE did not exceed the MDMD. CONCLUSIONS The significantly greater improvement of operative versus nonoperative treatment for ASLS at 2 years was durably maintained at the 5-year follow-up. Patients in the operative cohort with a treatment-related SAE still had greater improvement than patients in the nonoperative cohort. These findings have important implications for patient counseling and future cost-effectiveness assessments.

Machine learning, combined with a proliferation of electronic healthcare records (EHR), has the potential to transform medicine by identifying previously unknown interventions that reduce the risk of adverse outcomes. To realize this potential, machine learning must leave the conceptual 'black box' in complex domains to overcome several pitfalls, like the presence of confounding variables. These variables predict outcomes but are not causal, often yielding uninformative models. In this work, we envision a 'conversational' approach to design machine learning models, which couple modeling decisions to domain expertise. We demonstrate this approach via a retrospective cohort study to identify factors which affect the risk of hospital-acquired venous thromboembolism (HA-VTE). Using logistic regression for modeling, we have identified drugs that reduce the risk of HA-VTE. Our analysis reveals that ondansetron, an anti-nausea and anti-emetic medication, commonly used in treating side-effects of chemotherapy and post-general anesthesia period, substantially reduces the risk of HA-VTE when compared to aspirin (11% vs. 15% relative risk reduction or RRR, respectively). The low cost and low morbidity of ondansetron may justify further inquiry into its use as a preventative agent for HA-VTE. This case study highlights the importance of engaging domain expertise while applying machine learning in complex domains.

BACKGROUND While evidence indicates that familial predisposition influences the risk of developing degenerative rotator cuff disease (RCD), knowledge of specific genetic markers is limited. We conducted a genome-wide association study of RCD surgery using the UK Biobank, a prospective cohort of 500,000 people (40 to 69 years of age at enrollment) with genotype data. METHODS Cases with surgery for degenerative RCD were identified using linked hospital records. The cases were defined as an International Classification of Diseases, Tenth Revision (ICD-10) code of M75.1 determined by a trauma/orthopaedic specialist and surgery consistent with RCD treatment. Cases were excluded if a diagnosis of traumatic injury had been made during the same hospital visit. For each case, up to 5 controls matched by age, sex, and follow-up time were chosen from the UK Biobank. Analyses were limited to European-ancestry individuals who were not third-degree or closer relations. We used logistic regression to test for genetic association of 674,405 typed and >10 million imputed markers, after adjusting for age, sex, population principal components, and follow-up. RESULTS We identified 2,917 RCD surgery cases and 14,158 matched controls. We observed 1 genome-wide significant signal (p < 5 × 10-8) for a novel locus tagged by rs2237352 in the CREB5 gene on chromosome 7 (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.11 to 1.24). The single-nucleotide polymorphism (SNP) rs2237352 was imputed with a high degree of confidence (info score = 0.9847) and is common, with a minor allele frequency of 47%. After expanding the control sample to include additional unmatched non-cases, rs2237352 and another SNP in the CREB5 gene, rs12700903, were genome-wide significant. We did not detect genome-wide significant signals at loci associated with RCD in previous studies. CONCLUSIONS We identified a novel association between a variant in the CREB5 gene and RCD surgery. Validation of this finding in studies with imaging data to confirm diagnoses will be an important next step. CLINICAL RELEVANCE Identification of genetic RCD susceptibility markers can guide understanding of biological processes in rotator cuff degeneration and help inform disease risk in the clinical setting. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

STUDY DESIGN Prospective longitudinal cohort. OBJECTIVES The aim of this study was to determine whether functional treadmill testing (FTT) demonstrates differences between patients treated operatively and nonoperatively for adult symptomatic lumbar scoliosis (ASLS). SUMMARY OF BACKGROUND DATA ASLS has become increasingly prevalent as the population ages. ASLS can be accompanied by neurogenic claudication, leading to difficulty walking. FTT may provide a functional tool to evaluate patients with ASLS. METHODS One hundred and eighty-seven patients who underwent nonoperative (n = 88) or operative treatment (n = 99) of ASLS with complete baseline and 2-year post-treatment FTTs and concurrent patient-reported outcomes were identified. FTT parameters included maximum speed, time to onset of symptoms, distance ambulated, time ambulated, and Back and Leg pain severity before and after testing. RESULTS At baseline, patients treated operatively reported worse post-FTT back pain (4.39 vs. 3.45, P = 0.032) than those treated nonoperatively, despite similar ODI, SRS-22 Pain and Activity domain scores. Mean time ambulated (+2.15 vs. -1.20 P = 0.001), pre-FTT back pain (+0.19 vs. -1.60, P

STUDY DESIGN: Longitudinal Comparative Cohort OBJECTIVE: The purpose of this study is to report on the cost-effectiveness of surgical versus nonsurgical treatment for Adult Symptomatic Lumbar Scoliosis (ASLS) using the as-treated data and provide a comparison to previously reported intent-to-treat (ITT) analysis. SUMMARY OF BACKGROUND DATA: Adult spinal deformity is a relatively prevalent condition for which surgical treatment has become increasingly common but concerns surrounding complications, revision rates and cost-effectiveness remain unresolved. Of these issues, cost-effectiveness is perhaps the most difficult to quantify as the requisite data is difficult to obtain. The purpose of this study is to report on the cost-effectiveness of surgical versus nonsurgical treatment for Adult Symptomatic Lumbar Scoliosis (ASLS) using the as-treated data and provide a comparison to previously reported intent-to-treat (ITT) analysis. METHODS: Patients with at least five-year follow-up data within the same treatment arm were included. Data collected every three months included use of nonoperative modalities, medications and employment status. Costs for surgeries and non-operative modalities were determined using Medicare Allowable rates. Medication costs were determined using the RedBook and indirect costs were calculated based on reported employment status and income. Quality Adjusted Life Years (QALY) was determined using the SF-6D. RESULTS: Of 226 patients, 195 patients (73 Non-op, 122 Op) met inclusion criteria. At five years, 29 (24%) patients in the Op group had a revision surgery of whom two had two revisions and one had three revisions. The cumulative cost for the Op group was $111,451 with a cumulative QALY gain of 2.3. The cumulative cost for the Non-Op group was $29,124 with a cumulative QALY gain of 0.4. This results in an ICER of $44,033 in favor of Op treatment. CONCLUSION: This as-treated cost effectiveness analysis demonstrates that surgical treatment for adult lumbar scoliosis becomes favorable at year-three, one year earlier than suggested by a previous intent-to-treat analysis. LEVEL OF EVIDENCE: II

OBJECTIVEAdult symptomatic lumbar scoliosis (ASLS) is a common and disabling condition. The ASLS-1 was a multicenter, dual-arm study (with randomized and observational cohorts) examining operative and nonoperative care on health-related quality of life in ASLS. An aim of ASLS-1 was to determine patient and radiographic factors that modify the effect of operative treatment for ASLS.METHODSPatients 40–80 years old with ASLS were enrolled in randomized and observational cohorts at 9 North American centers. Primary outcomes were the differences in mean change from baseline to 2-year follow-up for the SRS-22 subscore (SRS-SS) and the Oswestry Disability Index (ODI). Analyses were performed using an as-treated approach with combined cohorts. Factors examined were prespecified or determined using regression tree analysis. For each potential effect modifier, subgroups were created using clinically relevant cutoffs or via regression trees. Estimates of within-group and between-group change were compared using generalized linear mixed models. An effect modifier was defined as a treatment effect difference greater than the minimal detectable measurement difference for both SRS-SS (0.4) and ODI (7).RESULTSTwo hundred eighty-six patients were enrolled and 256 (90%) completed 2-year follow-up; 171 received operative treatment and 115 received nonoperative treatment. Surgery was superior to nonoperative care for all effect subgroups considered, with the exception of those with nearly normal pelvic incidence−lumbar lordosis (PI–LL) match (≤ 11°). Male patients and patients with more (> 11°) PI–LL mismatch at baseline had greater operative treatment effects on both the SRS-SS and ODI compared to nonoperative treatment. No other radiographic subgroups were associated with treatment effects. High BMI, lower socioeconomic status, and poor mental health were not related to worse outcomes.CONCLUSIONSNumerous factors previously related to poor outcomes with surgery, such as low mental health, lower socioeconomic status, and high BMI, were not related to outcomes in ASLS in this exploratory analysis. Those patients with higher PI–LL mismatch did improve more with surgery than those with normal alignment. On average, none of the factors considered were associated with a worse outcome with operative treatment versus nonoperative treatment. These findings may guide future prospective analyses of factors related to outcomes in ASLS care.

Aims Few risk factors for rotator cuff disease (RCD) and corresponding treatment have been firmly established. The aim of this study was to evaluate the relationship between numerous risk factors and the incidence of surgery for RCD in a large cohort. Methods A population-based cohort of people aged between 40 and 69 years in the UK (the UK Biobank) was studied. People who underwent surgery for RCD were identified through a link with NHS inpatient records covering a mean of eight years after enrolment. Multivariate Cox proportional hazards regression was used to calculate hazard ratios (HRs) as estimates of associations with surgery for RCD accounting for confounders. The risk factors which were considered included age, sex, race, education, Townsend deprivation index, body mass index (BMI), occupational demands, and exposure to smoking. Results Of the 421,894 people who were included, 47% were male. The mean age at the time of enrolment was 56 years (40 to 69). A total of 2,156 people were identified who underwent surgery for RCD. Each decade increase in age was associated with a 55% increase in the incidence of RCD surgery (95% confidence interval (CI) 46% to 64%). Male sex, non-white race, lower deprivation score, and higher BMI were significantly associated with a higher risk of surgery for RCD (all p < 0.050). Greater occupational physical demands were significantly associated with higher rates of RCD surgery (HR = 2.1, 1.8, and 1.4 for ‘always’, ‘usually’, and ‘sometimes’ doing heavy manual labour vs ‘never’, all p < 0.001). Former smokers had significantly higher rates of RCD surgery than those who had never smoked (HR 1.23 (95% CI 1.12 to 1.35), p < 0.001), while current smokers had similar rates to those who had never smoked (HR 0.94 (95% CI 0.80 to 1.11)). Among those who had never smoked, the risk of surgery was higher among those with more than one household member who smoked (HR 1.78 (95% CI 1.08 to 2.92)). The risk of RCD surgery was not significantly related to other measurements of secondhand smoking. Conclusion Many factors were independently associated with surgery for RCD, including older age, male sex, higher BMI, lower deprivation score, and higher occupational physical demands. Several of the risk factors which were identified are modifiable, suggesting that the healthcare burden of RCD might be reduced through the pursuit of public health goals, such as reducing obesity and modifying occupational demands. Cite this article: Bone Joint J 2020;102-B(3):352–359

Background: No previous study has investigated how the Patient-Reported Outcomes Measurement Information System (PROMIS) performs compared with legacy patient-reported outcome measures in patients with symptomatic acetabular dysplasia treated with periacetabular osteotomy (PAO). Purpose: To (1) measure the strength of correlation between the PROMIS and legacy outcome measures and (2) assess floor and ceiling effects of the PROMIS and legacy outcome measures in patients treated with PAO for symptomatic acetabular dysplasia. Study Design: Cohort study (Diagnosis); Level of evidence, 2. Methods: This study included 220 patients who underwent PAO for the treatment of symptomatic acetabular dysplasia. Outcome measures included the Hip disability and Osteoarthritis Outcome Score (HOOS) pain, HOOS activities of daily living (ADL), modified Harris Hip Score (mHHS), PROMIS pain, and PROMIS physical function subsets, with scores collected preoperatively and/or postoperatively at a minimum 12-month follow-up. The change in mean scores from preoperatively to postoperatively was calculated only in a subgroup of 57 patients with scores at both time points. Distributions of the PROMIS and legacy scores were compared to evaluate floor and ceiling effects, and Pearson correlation coefficients were calculated to evaluate agreement. Results: The mean age at the time of surgery was 27.7 years, and 83.6% were female. The mean follow-up time was 1.5 years. Preoperatively, neither the PROMIS nor the legacy measures showed significant floor or ceiling effects. Postoperatively, all legacy measures showed significant ceiling effects, with 15% of patients with a maximum HOOS pain score of 100, 29% with a HOOS ADL score of 100, and 21% with an mHHS score of 100. The PROMIS and legacy instruments showed good agreement preoperatively and postoperatively. The PROMIS pain had a moderate to strong negative correlation with the HOOS pain ( r = −0.66; P < .0001) and mHHS ( r = −0.60; P < .0001) preoperatively and the HOOS pain ( r = −0.64; P < .0001) and mHHS ( r = −0.64; P < .0001) postoperatively. The PROMIS physical function had a moderate positive correlation with the HOOS ADL ( r = 0.51; P < .0001) and mHHS ( r = 0.49; P < .0001) preoperatively and a stronger correlation postoperatively with the HOOS ADL ( r = 0.56; P < .0001) and mHHS ( r = 0.56; P < .0001). Conclusion: We found good agreement between PROMIS and legacy scores preoperatively and postoperatively. PROMIS scores were largely normally distributed, demonstrating an expanded ability to capture variability in patients with improved outcomes after treatment.

STUDY DESIGN Secondary analysis of prospective multicenter cohort. OBJECTIVE To assess effect of serious adverse events (SAEs) on 2- and 4-year patient-reported outcomes measures (PROMs) in patients surgically treated for adult symptomatic lumbar scoliosis (ASLS). SUMMARY OF BACKGROUND DATA Operative treatment for ASLS can improve health-related quality of life, but has high rates of SAEs. How these SAEs effect health-related quality of life remain unclear. METHODS The ASLS study assessed operative versus nonoperative ASLS treatment, with randomized and observational arms. Patients were 40- to 80-years-old with ASLS, defined as lumbar coronal Cobb ≥30° and Oswestry Disability Index (ODI) ≥20 or Scoliosis Research Society-22 (SRS-22) ≤4.0 in pain, function, and/or self-image domains. SRS-22 subscore and ODI were compared between operative patients with and without a related SAE and nonoperative patients using an as-treated analysis combining randomized and observational cohorts. RESULTS Two hundred eighty-six patients were enrolled, and 2- and 4-year follow-up rates were 90% and 81%, respectively, although at the time of data extraction not all patients were eligible for 4-year follow-up. A total of 97 SAEs were reported among 173 operatively treated patients. The most common were implant failure/pseudarthrosis (n = 25), proximal junctional kyphosis/failure (n = 10), and minor motor deficit (n = 8). At 2 years patients with an SAE improved less than those without an SAE based on SRS-22 (0.52 vs. 0.79, P = 0.004) and ODI (-11.59 vs. -17.34, P = 0.021). These differences were maintained at 4-years for both SRS-22 (0.51 vs. 0.86, P = 0.001) and ODI (-10.73 vs. -16.69, P = 0.012). Despite this effect, patients sustaining an operative SAE had greater PROM improvement than nonoperative patients (P

BACKGROUND Acetabular cartilage damage has been described in patients with femoroacetabular impingement (FAI). However, most reports of articular cartilage damage in hip FAI have been focused on the acetabular cartilage and derived from single-center, retrospective studies of relatively small patient cohorts. Identifying patterns of articular cartilage wear is important in patient selection, treatment prognosis, and determining whether patterns of intraarticular cartilage wear are secondary to abnormal hip morphology. Using a multicenter, observational cohort, we sought to determine whether there was a specific pattern of cartilage wear across acetabular and femoral articular cartilage among patients with symptomatic FAI. QUESTIONS/PURPOSES (1) Is there is a specific pattern of cartilage wear in the acetabulum and femoral head, assessed during hip arthroscopy, in cam FAI, pincer, and mixed-type hip pathologies? (2) Are there specific patterns of cartilage wear associated with duration of symptoms, age, and/or body mass index (BMI)? METHODS A multicenter observational cohort and a hip preservation database from a senior author were used to identify 802 patients who underwent hip arthroscopy for the treatment of symptomatic FAI. The diagnosis of cam, pincer, or mixed-type FAI was determined by each treating surgeon at each institution using the minimum basic criteria of pain in the affected hip for a period of > 3 months, hip ROM, and radiographic findings. Acetabular and femoral head cartilage lesions were classified arthroscopically by location and severity for each group (cam, pincer, or mixed FAI). Cartilage wear was classified using the Beck classification and defined as cartilage lesions greater than Grade 1 (normal macroscopically sound cartilage). The assessment of cartilage wear was performed arthroscopically by experienced hip preservation surgeons who are a part of ANCHOR, a multicenter group that uses a longitudinally maintained database to investigate issues related to hip preservation surgery. Clinical characteristics, radiographic findings, and acetabular and femoral head damage by location and severity of wear were reported based on patient diagnoses of cam (n = 472), mixed (n = 290), and pincer (n = 40) FAI hip pathologies. Wald chi-square tests were used to test for differences in the presence of wear in each cartilage quadrant across hip pathologies, duration of symptoms, age, and BMI. One-way analysis of variance tests were used to test for differences in average grade of wear in each cartilage quadrant across hip pathologies, duration of symptoms, age, and BMI. A bivariate logistic regression model was used to identify factors independently associated with the presence of cartilage wear in the acetabulum and femoral head. Acetabular cartilage wear was present in 743 of 802 patients (93%) in the cohort. Femoral head cartilage wear was observed in only 130 (16%). RESULTS We found significant associations between acetabular patterns of wear and FAI hip pathologies; specifically, we observed more frequent and severe debonding of acetabular cartilage in patients with symptomatic cam (93%, 1.7 ± 1.1 grade) and mixed (97%, 1.7 ± 1.2 grade) FAI compared with Pincer (75%, 1.5 ± 0.9 grade) FAI hip pathologies (p < 0.001). Superolateral peripheral cartilage lesions occurred more frequently and with greater severity in patients with cam (90% [416 of 472] prevalence, 3.1 ± 1.1 grade) and mixed (91% [260 of 290] prevalence, 3.1 ± 1.1 grade) FAI than in pincer (60% [24 of 40] prevalence, 2.2 ± 1.1 grade) FAI hip pathologies (p < 0.0001). Conversely, patients with pincer FAI most commonly demonstrated cartilage lesions with an even distribution at the anterior and superolateral acetabular rim: 64% (25 of 40) (mean grade 2.1 ± 1.0) and 60% (24 of 40) mean grade 2.2 ± 1.1, respectively. Age was associated with increased presence of wear in both the acetabulum (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.2-1.7; p = 0.005) and femoral head (OR, 1.08; 95% CI, 1.6-1.1; p < 0.001). BMI was associated with a greater presence of wear only in the femoral head (OR, 1.1; 95% CI, 1.2-1.1; p = 0.002). Specifically, compared with patients with a BMI < 30 kg/m, patients with a BMI ≥ 30 kg/m presented with more frequent and more severe lesions in the posterior peripheral acetabular rim (42% [47 of 117] versus 26% [171 of 677], p = 0.0006; grade 1.9 ± 1.3 versus grade 1.4 ± 0.9, p < 0.001), the anterolateral femoral head (22% [20 of 117] versus 9% [60 of 67], p = 0.006), and the anteromedial femoral head (15% [16 of 117] versus 6% [39 of 677], p = 0.002; grade 1.3 ± 0.8 versus grade 1.1 ± 0.6, p = 0.04). In general, we found that older patients (≥ 50 years old) presented with more frequent and more severe lesions in both the acetabulum and femoral head. We found no association between hip pathology and cartilage wear patterns in the examined femoral heads. CONCLUSIONS Hip morphology affects the pattern of acetabular cartilage wear. More frequent and severe cartilage lesions were observed in patients with symptomatic FAI cam and mixed-type hip pathologies. Surgical attempts to restore normal anatomy to avoid FAI should be performed to potentially improve long-term joint homeostasis. Increasing age is an independent risk for cartilage wear in both the acetabulum and femoral head. Additionally, increased BMI is an independent risk factor for cartilage wear in the femoral head. In the future, prospective studies should provide further insight into the pathomechanics of early degenerative changes associated with hip FAI deformities. LEVEL OF EVIDENCE Level III, prognostic study.

UpdateThis article was updated on November 12, 2019, because of a previous error. On page 349, in Table VII, the column heads “2 Yr”, “Mean Change from Baseline (SE)”, “Difference in Mean Change (95% CI)”, and “P Value” that had been aligned with the content in the second to fourth columns have now

BackgroundThe optimal clinical management of oral precancer remains uncertain. We investigated the natural history of oral leukoplakia, the most common oral precancerous lesion, to estimate the relative and absolute risks of progression to cancer, the predictive accuracy of a clinician’s decision to biopsy a leukoplakia vis-à-vis progression, and histopathologic predictors of progression.MethodsWe conducted a retrospective cohort study (1996–2012) of patients with oral leukoplakia (n = 4886), identified using electronic medical records within Kaiser Permanente Northern California. Among patients with leukoplakia who received a biopsy (n = 1888), we conducted a case-cohort study to investigate histopathologic predictors of progression. Analyses included indirect standardization and unweighted or weighted Cox regression.ResultsCompared with the overall Kaiser Permanente Northern California population, oral cancer incidence was substantially elevated in oral leukoplakia patients (standardized incidence ratio = 40.8, 95% confidence interval [CI] = 34.8 to 47.6; n = 161 cancers over 22 582 person-years). Biopsied leukoplakias had a higher oral cancer risk compared with those that were not biopsied (adjusted hazard ratio = 2.38, 95% CI = 1.73 to 3.28). However, to identify a prevalent or incident oral cancer, the biopsy decision had low sensitivity (59.6%), low specificity (62.1%), and moderate positive–predictive value (5.1%). Risk of progression to oral cancer statistically significantly increased with the grade of dysplasia; 5-year competing risk-adjusted absolute risks were: leukoplakia overall = 3.3%, 95% CI = 2.7% to 3.9%; no dysplasia = 2.2%, 95% CI = 1.5% to 3.1%; mild-dysplasia = 11.9%, 95% CI = 7.1% to 18.1%; moderate-dysplasia = 8.7%, 95% CI = 3.2% to 17.9%; and severe dysplasia = 32.2%, 95% CI = 8.1%–60.0%. Yet 39.6% of cancers arose from biopsied leukoplakias without dysplasia.ConclusionsThe modest accuracy of the decision to biopsy a leukoplakia vis-à-vis presence or eventual development of oral cancer highlights the need for routine biopsy of all leukoplakias regardless of visual or clinical impression. Leukoplakia patients, particularly those with dysplasia, need to be closely monitored for signs of early cancer.

This population-based cohort study examines associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas in recipients of lung transplants., Key Points Question What is the association between voriconazole, an antifungal used to treat aspergillosis infections, and the risk of keratinocyte carcinomas among recipients of lung transplants? Findings In a population-based cohort study of 9599 non-Hispanic white recipients of 9793 lung transplants in the United States (2007-2016) with linkage to pharmacy claims, increasing cumulative voriconazole exposure was associated with an increased risk of cutaneous squamous cell carcinoma. Meaning These findings suggest that physicians caring for lung transplant recipients at high risk for aggressive keratinocyte carcinomas should limit voriconazole exposure when possible and encourage skin protection behaviors and more frequent cancer screenings., Importance The antifungal medication voriconazole is used to prevent and treat aspergillosis, a major cause of mortality among recipients of lung transplants (hereinafter referred to as lung recipients). Small studies suggest that voriconazole increases risk of cutaneous squamous cell carcinoma (SCC). Objective To examine associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas (SCC and cutaneous basal cell carcinoma [BCC]) in lung recipients. Design, Setting, and Participants This population-based cohort study included non-Hispanic white patients (n = 9599) who underwent lung transplant in the United States from January 1, 2007, to December 31, 2016, identified through the national Scientific Registry of Transplant Recipients with data linkable to pharmacy claims. Data were analyzed from March 1, 2018, to February 13, 2019. Exposures Antifungal medication use, including voriconazole, itraconazole, posaconazole, and other antifungals, was ascertained from pharmacy claims and treated as a time-varying exposure (assessed every 30 days). Cumulative antifungal exposure was calculated as the total number of exposed months. Main Outcomes and Measures Primary outcomes were the first SCC or BCC reported to the transplant registry by transplant centers. Follow-up began at transplant and ended at SCC or BCC diagnosis, transplant failure or retransplant, death, loss to follow-up, or December 31, 2016. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (AHRs) for each antifungal medication. Results Among the 9793 lung transplants in 9599 recipients included in the analysis, median age at transplant was 59 (interquartile range [IQR], 48-65) years, 5824 (59.5%) were male, and 5721 (58.4%) reported ever smoking. During a median follow-up of 3.0 (IQR, 1.4-5.0) years after transplant, 1031 SCCs (incidence, 322 per 10 000 person-years) and 347 BCCs (incidence, 101 per 10 000 person-years) were reported. Compared with lung recipients with no observed voriconazole use, those with 1 to 3 months of voriconazole use experienced increased AHR for SCC of 1.09 (95% CI, 0.90-1.31); 4 to 7 months, 1.42 (95% CI, 1.16-1.73); 8 to 15 months, 2.04 (95% CI, 1.67-2.50); and more than 15 months, 3.05 (95% CI, 2.37-3.91). Ever itraconazole exposure was associated with increased SCC risk (AHR, 1.20; 95% CI, 1.00-1.45). For BCC, risk was not associated with voriconazole use but was increased with itraconazole use (AHR, 1.74; 95% CI, 1.27-2.37) or posaconazole use (AHR, 1.55; 95% CI, 1.00-2.41). Conclusions and Relevance In this study, voriconazole use was associated with increased SCC risk among lung recipients, especially after prolonged exposure. Further research evaluating the risk-benefit ratio of shorter courses or alternative medications in transplant recipients at high risk for SCC should be considered.

BACKGROUND Cutaneous melanoma incidence may be modestly elevated in people with HIV (PWH) vs. people without HIV. However, little is known about the relationship of immunosuppression, HIV replication, and antiretroviral therapy (ART) with melanoma risk. METHODS PWH of white race in the North American AIDS Cohort Collaboration on Research and Design were included. A standardized incidence ratio was calculated comparing risk with the white general population, standardizing by age, sex, and calendar period. Associations between melanoma incidence and current, lagged, and cumulative measures of CD4 count, HIV RNA level, and ART use were estimated with Cox regression, adjusting for established risk factors such as age and annual residential ultraviolet B (UVB) exposure. RESULTS Eighty melanomas were diagnosed among 33,934 white PWH (incidence = 40.75 per 100,000 person-years). Incidence was not elevated compared with the general population [standardized incidence ratio = 1.15, 95% confidence interval (95% CI) = 0.91 to 1.43]. Higher melanoma incidence was associated with older age [adjusted hazard ratio (aHR) per decade increase = 1.50, 95% CI = 1.20 to 1.89] and higher UVB exposure (aHR for exposure ≥35 vs.

STUDY DESIGN Level III, Retrospective observational study. OBJECTIVE To determine if there is an increased risk of developing cancer after exposure to high-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) and if risk is dose and/or exposure-dependent. SUMMARY OF BACKGROUND DATA Concerns have been raised regarding a relationship between rhBMP-2 and cancer. METHODS A total of 642 adult deformity patients from a single institution receiving a cumulative rhBMP-2 dose ≥40 mg from July, 2002 to July, 2009 were identified. Patients with a history of surveillance, epidemiology, and end result (SEER) cancer before rhBMP-2 exposure were excluded. To determine the occurrence of a cancer event, questionnaires were mailed and telephone follow up attempted for nonresponders. Only cancers tracked by the National Cancer Institute (NCI) SEER registry were included. Observed cancer counts were compared to expected cancer counts based on general population incidence rates within 5-year age strata. Cumulative incidence competing risk (CICR) modeling was used to evaluate the association between rhBMP-2 exposure and cancer controlling for potential confounding variables. RESULTS Forty-nine patients were lost-to-follow up, leaving 593 patients (92.4%; 138 males/455 females) available for analysis. Mean age was 52.8 years at the time of first exposure. Mean cumulative rhBMP-2 dose was 113.5 mg with 85% having one exposure (range: 1-8). Mean follow-up [date of exposure to date of death (regardless of cause) or returned completed questionnaire] was 5.6 ± 1.9 years; median follow up was 5.4 years. A total of 342 patients have greater than 5-year follow up. Minimum follow up was 2.0 years or until occurrence of a SEER cancer. Our total 8-year cumulative incidence of new SEER cancer accounting for the competing risk of death was 7.4% for 30 cancers in 593 patients. Fewer cancers were observed than expected based on general population rates, though the difference was not statistically significant (expected = 34; standardized incidence ratio = 0.88, 95% confidence interval, CI = 0.60-1.26). CICR found neither cumulative rhBMP-2 dose (hazard ratio, HR = 0.995, 95% CI 0.988-1.003; P = 0.249) nor number of exposures (HR = 0.776, 95% CI 0.359-1.677; P = 0.519) increased the risk of developing a postexposure cancer after controlling for known cancer risk factors. CONCLUSION The incidence of a SEER cancer after rhBMP-2 exposure was similar to incidence reported by the NCI. There were no significant rhBMP-2 dose or multi-exposure related risks of developing a life-threatening cancer. LEVEL OF EVIDENCE 3.

BACKGROUND Pediatric solid organ transplant recipients have a 100 to 200 times higher risk of non-Hodgkin lymphoma (NHL) than the general pediatric population. Consequently, transplant-related NHL may contribute considerably to the pediatric NHL burden in the United States. METHODS A cohort study using a linkage between the US transplant registry and 16 cancer registries was conducted. Cancer incidence rates were calculated for people less than 20 years old in the transplant and general populations. Rates were applied to transplant registry and US census data to estimate pediatric NHL counts for transplant recipients and the general population. RESULTS During 1990-2012, an estimated 22,270 NHLs were diagnosed in US children and adolescents; they included 628 cases diagnosed in transplant recipients. Thus, 2.82% of pediatric NHL diagnoses in the general population (95% confidence interval [CI], 2.45%-3.19%) occurred in transplant recipients. Among transplant recipients, the most common subtypes were diffuse large B-cell lymphoma (DLBCL; 64.5% of cases) and Burkitt lymphoma (BL; 8.6%). For DLBCL and BL, transplant recipients contributed 7.62% (95% CI, 6.35%-8.88%) and 0.87% (95% CI, 0.51%-1.23%) of diagnoses, respectively. The proportion of NHLs that occurred in transplant recipients was highest among children less than 5 years old (4.46%; 95% CI, 3.24%-5.69%) and in more recent calendar years (3.73% in 2010-2012; 95% CI, 2.07%-5.39%). DLBCL patterns were similar, with transplant recipients contributing 19.78% of cases among children less than 5 years old (95% CI, 12.89%-26.66%) and 11.4% of cases in 2010-2012 (95% CI, 5.54%-17.28%). CONCLUSIONS Among children and adolescents, solid organ transplant recipients contribute a substantial fraction of NHL diagnoses, particularly DLBCL diagnoses. This fraction has increased over time. Prevention efforts targeted toward this group could reduce the overall pediatric NHL burden. Cancer 2017. © 2017 American Cancer Society.

STUDY DESIGN Secondary analysis using data from the NIH-sponsored study on adult symptomatic lumbar scoliosis (ASLS) that included randomized and observational arms. OBJECTIVE The aim of this study was to perform an intent-to-treat cost-effectiveness study comparing operative (Op) versus nonoperative (NonOp) care for ASLS. SUMMARY OF BACKGROUND DATA The appropriate treatment approach for ASLS continues to be ill-defined. NonOp care has not been shown to improve outcomes. Surgical treatment has been shown to improve outcomes, but is costly with high revision rates. METHODS Patients with at least 5-year follow-up data were included. Data collected every 3 months included use of NonOp modalities, medications, and employment status. Costs for index and revision surgeries and NonOp modalities were determined using Medicare Allowable rates. Medication costs were determined using the RedBook and indirect costs were calculated based on reported employment status and income. Qualityadjusted life year (QALY) was determined using the SF6D. RESULTS There were 81 of 95 cases in the Op and 81 of 95 in the NonOp group with complete 5-year follow-up data. Not all patients were eligible 5-year follow-up at the time of the analysis. All patients in the Op and 24 (30%) in the NonOp group had surgery by 5 years. At 5 years, the cumulative cost for Op was $96,000 with a QALY gain of 2.44 and for NonOp the cumulative cost was $49,546 with a QALY gain of 0.75 with an incremental cost-effectiveness ratio (ICER) of $27,480 per QALY gain. CONCLUSION In an intent-to-treat analysis, neither treatment was dominant, as the greater gains in QALY in the surgery group come at a greater cost. The ICER for Op compared to NonOp treatment was above the threshold generally considered cost-effective in the first 3 years of the study but improved over time and was highly cost-effective at 4 and 5 years. LEVEL OF EVIDENCE 2.

Background In the United States, incidence and mortality rates of hepatocellular carcinoma (HCC) are increasing in older individuals. Chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) are important causes of HCC; however, the contribution of viral hepatitis to recent trends in HCC incidence among older Americans is unclear. Methods Data from the Surveillance, Epidemiology, and End Results-Medicare linkage (SEER-Medicare) for the years 2001 through 2013 were used to identify HCC cases among individuals aged ≥66 years and Medicare files were used to assess the HCV and HBV status of these HCC cases. Age-standardized incidence rates of HCV-attributable, HBV-attributable, and HCV/HBV-unrelated HCC were estimated overall and by age group, sex, and race/ethnicity. The authors also calculated annual percent changes (APCs) in HCC incidence. Results Between 2001 and 2013, a total of 15,300 HCC cases occurred in this population. Overall HCC rates increased 43% from 16.3 to 23.3 per 100,000 population (APC, 3.40% per year), whereas HCV-attributable HCC rates nearly doubled from 4.2 to 8.2 per 100,000 population (APC, 5.62% per year). HCC rates increased more slowly for HBV-attributable HCC (1.3 to 1.8 per 100,000 population; APC, 3.17% per year) and HCV/HBV-unrelated HCC (11.3 to 14.1 per 100,000 population; APC, 2.35% per year). The percentage of HCC cases with evidence of HCV infection increased from 25.7% in 2001 through 2004 to 32.3% in 2011 through 2013, whereas the percentage with HBV remained stable at 8%. In 2013, higher rates for both HCV-attributable and HBV-attributable HCC were noted among individuals aged 66 to 75 years, men, and individuals of Asian ancestry. Conclusions Among Americans aged ≥66 years, HCC rates increased rapidly between 2001 and 2013. Although HCV-attributable cases contributed substantially to this increase, rates of HBV-attributable and HCV/HBV-unrelated HCC also rose during this period.

Background Appropriate patient-reported outcome measures are paramount to determine the clinical relevance of change experienced by patients after a surgical procedure. The purpose of this study was to evaluate the psychometric properties of 3 patient-reported outcome measures (Hip disability and Osteoarthritis Outcome Score [HOOS], modified Harris hip score, and Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) in a large population of patients treated with periacetabular osteotomy for symptomatic developmental dysplasia of the hip. Methods Patients who underwent a periacetabular osteotomy for acetabular dysplasia between October 2011 and October 2016 completed multiple questionnaires preoperatively and at the 1-year follow-up. Internal consistency for subscores was evaluated with the Cronbach alpha. Validity was assessed against the Short Form-12. Interpretability included the calculation of the distribution of scores, floor and ceiling effects, and the minimal clinically important difference. Responsiveness was assessed by correlating the score changes with the Global Perceived Effect score. Results Of 294 patients, 246 (84%) were female. The median age was 21 years (interquartile range, 17 to 29 years). All WOMAC and HOOS subscores demonstrated adequate internal consistency, and none of the modified Harris hip score components did. All scores except the WOMAC stiffness score exhibited adequate validity and interpretability, with no floor and ceiling effects over 15%. For the HOOS subscores, the minimal clinically important difference was 10.3 for pain, 10.2 for symptoms, 12.6 for sports and recreation, 11.2 for quality of life, and 10.8 for activities of daily living. The minimal clinically important difference for the modified Harris hip score was 7.4. For the WOMAC subscores, the minimal clinically important difference was 10.8 for pain, 12.9 for stiffness, 10.8 for physical, and 10.4 for total. All scores demonstrated adequate responsiveness. Conclusions The HOOS, WOMAC, and modified Harris hip score have adequate psychometric properties for use in patients undergoing periacetabular osteotomy, with minor shortcomings. Among the scores analyzed, the HOOS appears to be the most appropriate measure of patient-reported outcome in patients undergoing periacetabular osteotomy. Clinical relevance By establishing the psychometric properties of patient-reported outcome measures for periacetabular osteotomy, this study enables a more informed choice of measures for clinical practice and research. The estimated minimal clinically important difference values will facilitate understanding the importance of change in patient-reported outcomes after a surgical procedure in a clinical setting and sample size calculation for further studies.

US transplant centers are required to report cancers in transplant recipients to the transplant network. The accuracy and completeness of these data, collected in the Scientific Registry of Transplant Recipients (SRTR), are unknown. We compared diagnoses in the SRTR and 15 linked cancer registries for colorectal, liver, lung, breast, prostate and kidney cancers; melanoma; and non-Hodgkin lymphoma (NHL). Among 187 384 transplants, 9323 cancers were documented in the SRTR or cancer registries. Only 36.8% of cancers were in both, with 47.5% and 15.7% of cases additionally documented solely in cancer registries or the SRTR, respectively. Agreement between the SRTR and cancer registries varied (kappa = 0.28 for liver cancer and kappa = 0.52-0.66 for lung, prostate, kidney, colorectum, and breast cancers). Upon evaluation, some NHLs documented only in cancer registries were identified in the SRTR as another type of posttransplant lymphoproliferative disorder. Some SRTR-only cases were explained by miscoding (colorectal cancer instead of anal cancer, metastases as lung or liver cancers) or missed matches with cancer registries, partly due to recipients' outmigration from catchment areas. Estimated sensitivity for identifying cancer was 52.5% for the SRTR and 84.3% for cancer registries. In conclusion, SRTR cancer data are substantially incomplete, limiting their usefulness for surveillance and research.

Objective HIV-infected people and elderly people have higher cancer risk, but the combined effects of aging and HIV are not well described. We aimed to evaluate the magnitude of cancer risk in the HIV-infected elderly population. Design We conducted a case-cohort study including a 5% sample of U.S. Medicare enrollees and all cancer cases aged at least 65 in linked cancer registries. Methods HIV was identified through Medicare claims. Among the HIV-infected, absolute cancer risk was calculated accounting for the competing risk of death. Associations between HIV and cancer were estimated with weighted Cox regression adjusting for demographic characteristics. Results Among 469 954 people in the 5% sample, 0.08% had an HIV diagnosis. Overall, 825 776 cancer cases were identified in cancer registries. Over 5 years, 10.1% of the HIV-infected elderly developed cancer, the most common diagnoses comprising lung (5-year cumulative incidence=2.2%), prostate (2.7%, among men), and colorectal cancer (0.9%), and non-Hodgkin lymphoma (0.8%). HIV was strongly associated with incidence of Kaposi sarcoma [adjusted hazard ratio (aHR)=94.4, 95% confidence interval (95%CI)=54.6-163], anal cancer (aHR=34.2, 95%CI=23.9-49.0) and Hodgkin lymphoma (aHR=6.3, 95%CI=2.8-14.3). HIV was also associated with incidence of liver cancer, non-Hodgkin lymphoma and lung cancer (aHR=3.4, 2.6, and 1.6, respectively). Conclusion In the elderly, HIV infection is associated with higher risk for many cancers, although some associations were weaker than expected, perhaps reflecting effects of non-HIV pathways on cancer development. Due to the effects of HIV and aging, the HIV-infected elderly have a sizeable absolute risk, highlighting a need for cancer prevention.

BACKGROUND There are limited data on outcomes in transplant recipients with a history of pretransplant melanoma. OBJECTIVE To determine whether pretransplant melanoma is associated with differences in survival or posttransplant melanoma risk. MATERIALS AND METHODS We evaluated the outcomes of 185,039 US transplant recipients from the Transplant Cancer Match Study. We also evaluated the impact of transplantation on 141,441 patients with melanoma identified in cancer registries. RESULTS There were 336 transplant recipients (0.18%) with pretransplant melanoma; they had increased risk of melanoma-specific mortality (hazard ratio [HR], 27; 95% confidence interval [CI], 11-64, p < .0001), overall mortality (HR, 1.3; 95% CI, 1.0-1.5, p = .02), and incident melanoma (HR, 5.4; 95% CI, 2.9-9.8, p < .0001) after transplant, compared with recipients without pretransplant melanoma. The 10-year absolute risk difference was 2.97% for melanoma-specific mortality, 3.68% for incident melanoma, and 14.32% for overall mortality. Among the 141,441 patients with melanoma in the general population, 68 (0.05%) subsequently received a transplant. Transplantation increased melanoma-specific mortality, but not significantly (HR, 1.7; 95% CI, 0.61-4.5, p = .32). CONCLUSION Pretransplant melanoma is associated with increased melanoma-specific mortality, overall mortality, and incident melanoma after transplant. Nonetheless, the rarity of melanoma-related events supports the current practice for listing transplant candidates with a history of melanoma.

Background: Herpes zoster (HZ) arises in older people due to age-related decline in immunity. We assessed whether HZ, as a marker of immune suppression, is associated with increased cancer risk. Methods: We conducted a case–control study in U.S. adults with ages ≥ 65 years using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database. Cases (n = 1,108,986) were people with first cancers identified in cancer registries (1992–2005). Controls (n = 100,000) were cancer-free individuals frequency matched to cases on age, sex, and year of selection. We identified HZ diagnosis using Medicare claims. Logistic regression models were constructed to determine adjusted associations between cancer and HZ. Results: HZ prevalence was modestly higher in cases than controls (1.4% vs. 1.2%). We identified significant associations between HZ and oral cavity/pharyngeal [adjusted OR (aOR) = 1.21], colon (aOR = 1.10), lung (aOR = 1.11), and non-melanoma skin (aOR = 1.46) cancers; myeloma (aOR = 1.38); diffuse large B-cell lymphoma (aOR = 1.30); lymphoplasmacytic lymphoma (aOR = 1.99); and chronic lymphocytic leukemia/small lymphocytic lymphoma (aOR = 1.55). Among solid cancers, HZ was mostly associated with regional and/or distant stage tumors. Associations were strongest when HZ was diagnosed 13 to 35 months before cancer diagnosis/selection; they were significant for some cancers in the 36 to 59 months period, and 60+ months for lymphoplasmacytic lymphoma (OR = 1.99). Conclusion: HZ is associated with modestly increased risk of a few cancers, particularly hematologic malignancies. Associations were strongest at short latency intervals for many cancers, and for regional/distant stages among solid cancers, perhaps reflecting reverse causality. Impact: Age-related immune decline does not play a major role in cancer development in older people, but it may be important for some lymphomas. Cancer Epidemiol Biomarkers Prev; 25(1); 28–35. ©2015 AACR.

BACKGROUND CONTEXT Adult spinal deformity is a relatively prevalent condition for which surgical treatment has become increasingly common but concerns surrounding complications, revision rates and cost-effectiveness remain unresolved. Of these issues, cost-effectiveness is perhaps the most difficult to quantify as the requisite data is difficult to obtain. PURPOSE The purpose of this study is to report on the cost-effectiveness of surgical vs nonsurgical treatment for adult symptomatic lumbar scoliosis (ASLS) using the as-treated data and provide a comparison to previously reported intent-to-treat (ITT) analysis. STUDY DESIGN/SETTING Secondary analysis of data from the NIH sponsored study on ASLS that included randomized and observational arms. PATIENT SAMPLE Patients enrolled in the NIH sponsored study on ASLS that included randomized and observational cohorts with at least five-year follow-up data within the same treatment arm. OUTCOME MEASURES Quality Adjusted Life Years (QALY) derived from the SF-6D. METHODS Patients with at least five-year follow-up data within the same treatment arm were included. Data collected every three months included use of nonoperative modalities, medications and employment status. Costs for surgeries and nonoperative modalities were determined using Medicare allowable rates. Medication costs were determined using the RedBook and indirect costs were calculated based on reported employment status and income. Quality Adjusted Life Years (QALY) was determined using the SF-6D. RESULTS Of 286 patients, 195 patients (73 Nonop, 122 Op) met inclusion criteria. At five years, 29 (24%) patients in the Op group had a revision surgery of whom two had two revisions and one had three revisions. The cumulative cost for the Op group was $111,451 with a cumulative QALY gain of 2.29. The cumulative cost for the Non-Op group was $29,124 with a cumulative QALY gain of 0.41. This results in an ICER of $44,033 in favor of Op treatment. CONCLUSIONS This as-treated cost effectiveness analysis demonstrates that surgical treatment for adult lumbar scoliosis becomes favorable at year-three, one year earlier than suggested by a previous intent-to-treat analysis. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Background Posttransplant lymphoproliferative disorder (PTLD) is a neoplastic complication of transplantation, with early cases largely due to immunosuppression and primary Epstein-Barr virus infection. Etiology may differ for later-onset cases, but the contributions of immunosuppression, immune reactivity to the donor organ, and chronic B cell activation are uncertain. Methods We conducted a case-control study of late-onset PTLD (diagnosed >1 year posttransplant) in a cohort of liver recipients. We assessed serum samples (obtained >6 months before diagnosis in cases) from N = 60 cases and N = 166 matched controls for donor-specific antibodies (DSAs, evaluable for N = 221 subjects), immunoglobulin kappa and lambda free light chains (FLCs, N = 137), and B cell activating factor (BAFF, N = 226). Conditional or unconditional logistic regression was used to calculate adjusted odds ratios (aORs). Results Circulating DSAs were less common in PTLD cases than controls (18% vs 30%), although this difference was borderline significant (aOR, 0.51; 95% confidence interval [CI], 0.24-1.10; P = 0.09). Donor-specific antibodies against class II HLA antigens predominated and likewise showed a borderline inverse association with PTLD (aOR, 0.58; 95% CI, 0.27-1.24). The FLC levels were less frequently abnormal in cases than controls, but measurements were available for only a subset and confidence intervals were wide (elevated kappa: aOR, 0.57; 95% CI, 0.15-2.12; P = 0.40; elevated lambda: aOR, 0.68; 95% CI, 0.30-1.50; P = 0.34). B cell-activating factor levels were not associated with PTLD. Conclusions Our results suggest that circulating DSAs are associated with decreased risk of late-onset PTLD. Because DSAs may develop in the setting of underimmunosuppression, the inverse association with DSAs supports a role for immunosuppression in the etiology of late-onset PTLD.