Citations

AbstractIntroductionAfrican Americans' (AAs) late‐onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power.MethodsWe conducted a genome‐wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome‐wide set of single‐nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs.ResultsTwo SNPs at novel loci, rs112404845 (P = 3.8 × 10−8), upstream of COBL, and rs16961023 (P = 4.6 × 10−8), downstream of SLC10A2, obtained genome‐wide significant evidence of association with the posterior liability.DiscussionAn informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

ObjectiveIn observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL‐C; as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH.MethodsWe performed 2 candidate‐gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk.ResultsTwelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10−4) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10−6).InterpretationGenetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730–740

ObjectivesTo examine outcomes of selective neck dissection (SND) in patients with human papillomavirus (HPV)‐related oropharyngeal squamous cell carcinoma (OPSCC) who present with clinical neck disease.Study DesignMulti‐institutional retrospective review.MethodsTwo institutional databases of patients with HPV‐related OPSCC were reviewed to identify patients with clinical (c) N1‐N3 neck disease who underwent SND ± adjuvant therapy.ResultsThree hundred and twenty‐four patients were identified with a median follow‐up of 49 months (range 3–199 months). All patients underwent transoral resection of the primary tumor and SND, including levels II–IV and ± levels I or V, with resection of additional nonlymphatic tissue (extended SND) as indicated by extent of disease, including the spinal accessory nerve (7%), the internal jugular vein (13%), and the sternocleidomastoid muscle (8%). Two hundred and seventy (83%) patients underwent adjuvant radiation. There were 13 (4%) regional recurrences and 19 (6%) distant recurrences. Regional control following salvage was 98%. On univariable analysis, absence of radiation was associated with regional recurrence (odds ratio [OR] 9.2, 95% confidence interval [CI] 2.9–29.4). On multivariable analysis, adjuvant radiation was associated with improved disease‐free survival (DFS) (OR 0.27, 95% CI 0.14–0.53) but lost significance for overall (OS) and disease‐specific survival (DSS) (P > 0.05). Five‐year Kaplan‐Meier estimates for OS, DSS, and DFS were 88% (95% CI 84%–92%), 93% (95% CI 89%–96%), and 83% (95% CI 78%–87%), respectively.ConclusionIn HPV‐related OPSCC presenting with clinical neck disease, a SND ± additional tissue resection and adjuvant therapy, when indicated, provides excellent long‐term regional control. Omission of radiotherapy increases the risk of regional recurrence, although it may not significantly impact OS or DSS. It appears unnecessary to routinely perform a comprehensive neck dissection.Level of Evidence4. Laryngoscope, 127:623–630, 2017

Healthcare workers suffer musculoskeletal disorders at rates that exceed most other industries. Despite this, many healthcare facilities do not follow best practices that are proven to reduce risk of injury. This discussion panel will explore the reasons for why the healthcare industry struggles to prevent injuries and will outline successful strategies for protecting workers. The panelists are leaders and advisors for large medical systems and their specialties include ergonomics, safe patient handling, and patient safety. The panelists relate the critical challenges faced when preventing caregiver injuries. Such challenges include underreporting of staff injuries, lack of funding or administrative support, and inability to sell the connections among caregiver safety, caregiver productivity, and patient safety. The panelists also share success stories of when they have achieved positive change and explain the strategies that were effective. Practitioners should gain new insights for implementing successful change, and researchers will be exposed to new and important research questions.

Abstract Context: Type VIII osteogenesis imperfecta (OI; OMIM 601915) is a recessive form of lethal or severe OI caused by null mutations in P3H1, which encodes prolyl 3-hydroxylase 1. Objectives: Clinical and bone material description of non-lethal type VIII OI. Design: Natural history study of type VIII OI. Setting: Pediatric academic research centers. Patients: Five patients with non-lethal type VIII OI, and one patient with lethal type VIII OI. Interventions: None. Main Outcome Measures: Clinical examinations included bone mineral density, radiographs, and serum and urinary metabolites. Bone biopsy samples were analyzed for histomorphometry and bone mineral density distribution by quantitative backscattered electron imaging microscopy. Collagen biochemistry was examined by mass spectrometry, and collagen fibrils were examined by transmission electron microscopy. Results: Type VIII OI patients have extreme growth deficiency, an L1–L4 areal bone mineral density Z-score of −5 to −6, and normal bone formation markers. Collagen from bone and skin tissue and cultured osteoblasts and fibroblasts have nearly absent 3-hydroxylation (1–4%). Collagen fibrils showed abnormal diameters and irregular borders. Bone histomorphometry revealed decreased cortical width and very thin trabeculae with patches of increased osteoid, although the overall osteoid surface was normal. Quantitative backscattered electron imaging showed increased matrix mineralization of cortical and trabecular bone, typical of other OI types. However, the proportion of bone with low mineralization was increased in type VIII OI bone, compared to type VII OI. Conclusions: P3H1 is the unique enzyme responsible for collagen 3-hydroxylation in skin and bone. Bone from non-lethal type VIII OI children is similar to type VII, especially bone matrix hypermineralization, but it has distinctive features including extremely thin trabeculae, focal osteoid accumulation, and an increased proportion of low mineralized bone.

Background Despite guideline recommendations, a significant number of patients with non– ST elevation myocardial infarction ( NSTEMI ) do not receive dual antiplatelet therapy ( DAPT ) before angiography “pretreatment.” While there may be valid clinical reasons to not pretreat, such as concern for bleeding or multivessel disease warranting coronary artery bypass graft surgery, the degree of variability and factors associated with DAPT pretreatment are unknown. Methods and Results From the multicenter TRIUMPH registry, 1632 NSTEMI patients were not taking DAPT on admission and were included in the study cohort. Among the study patients, only 22% patients received DAPT pretreatment. A multivariable logistic regression model showed that race other than white or black (odds ratio [ OR] 0.41, 95% CI 0.21–0.83), hemoglobin level ( OR 1.18, 95% CI 1.08–1.29), patients’ bleeding risk (assessed with NCDR Cath PCI Bleeding Risk Score) ( OR 0.85, 95% CI 0.74–0.99), and severe left ventricular dysfunction ( OR 0.3, 95% CI 0.13–0.65) were the main predictors of pretreatment with DAPT , whereas likelihood of needing coronary artery bypass graft surgery ( GRACE prediction model) was not ( OR 1.09, 95% CI 0.88–1.35). Median ORs were calculated to assess variability of receiving DAPT pretreatment across sites after adjustment for patient characteristics. Receiving DAPT pretreatment varied substantially across sites (range 0–100%, mean OR 3.94, P <0.0001). Conclusions While deviating from guideline‐recommended DAPT pretreatment in patients with NSTEMI was associated with patient factors (eg, bleeding risk), marked variation was present across sites after accounting for patient‐level characteristics. This suggests that site‐level interventions are needed to improve concordance with current guidelines.

Abstract Background ER+ BC is associated with activated CDK4/6. The CDK4/6 inhibitor palbociclib (P) markedly improves time to progression in advanced ER+HER2- BC. We conducted a neoadjuvant phase II trial to determine the activity of P in primary breast cancer as a prelude to adjuvant studies. Methods To assess molecular changes induced by anastrozole (A) or P+A, patients (pts) were treated initially with A alone (1mg PO daily) for 28 days in cycle 0 (C0) before the addition of P (125mg PO daily on D1-21 each cycle) on C1D1. P+A was administered for 4 28-day cycles followed by C5 with A alone for 2-4 weeks (wks) before surgery. P was added in C5 for 10-12 days immediately prior to surgery in the last 20 pts enrolled to assess molecular changes induced by A, either alone or in combination with P immediately prior to surgery, in resected tumor. Goserelin was added in premenopausal pts. Research tumor biopsies were obtained at baseline, C1D1, and C1D15. Central Ki67 analysis was performed at all timepoints, those with Ki67 &gt;10% at C1D15 went off study treatment. The primary endpoint was complete cell cycle arrest (CCA), defined as Ki67 &lt;2.7%, at C1D15. Patient stratification was based on PIK3CA mutation status with an initial focus on PIK3CA wild type (WT) disease. Pts with PIK3CA mutant (Mut) tumors enrolled to a separate cohort. A sample size of 33 pts in the PIK3CA WT cohort was chosen based on the Fleming's single-stage phase II design to test the hypothesis that P+A leads to &gt; 50% improvement over A in CCA rate on C1D15 biopsy (44% with A alone based on historical data, vs 66% with P+A, power = 0.8, alpha=0.05). The primary endpoint is met if &gt;20 pts achieved CCA in this cohort. Correlative endpoints included assessment of markers of proliferation, apoptosis, senescence, Rb, gene expression microarray, intrinsic subtype, and next generation sequencing of 83-gene panels, which will be reported at the meeting. Results Between 4/23/2013 and 4/24/2015, 50 pts (33 PIK3CA WT, 11 PIK3CA Mut, 2 pending, 4 tissue quantity or quality not sufficient for sequencing (QNS)) were enrolled to the study. Median age was 57.5 (range: 34.1–79.6) years. Four pts, all with WT PIK3CA, went off study due to Ki67 &gt;10% on C1D15 biopsy, 26 pts completed treatment and surgery, 1 refused surgery, 3 withdrew study treatment in C1, and 16 continued to receive study drug (2 in C0, 3 in C1, 4 in C2, 5 in C3, 1 in C4, and 1 in C5). Among the 40 pts currently evaluable for the primary endpoint (C1D15 Ki67), CCA occurred in 34 (85%) pts, including 9 of 9 (100%) PIK3CA Mut, 22 of 28 (78.5%) WT, and 3 of 3 QNS pts. Preliminary analysis of available data indicated a significantly lower Ki67 value after 2 wks of P+A (C1D15) compared to that on A alone (C1D1) (p=0.034, n=18). Conclusion This study met the primary endpoint demonstrating that P+A is a highly effective anti-proliferative combination. The sequential biopsy design clearly demonstrated that P+A increased cell cycle control over A alone. P+A was effective regardless of PIK3CA mutation status and these results support the evaluation of this combination in the adjuvant setting for ER+HER2- BC. Citation Format: Ma CX, Gao F, Northfelt D, Goetz M, Forero A, Naughton M, Ademuyiwa F, Suresh R, Anderson KS, Margenthaler J, Aft R, Hobday T, Moynihan T, Gillanders W, Cyr A, Eberlein TJ, Hieken T, Krontiras H, Hoog J, Han J, Guo Z, Vij K, Mardis E, Al-Kateb H, Sanati S, Ellis MJ. A phase II trial of neoadjuvant palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with anastrozole for clinical stage 2 or 3 estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-05.

Abstract Background Activating mutations in PIK3CA occur in approximately 40% ER+BC. MK-2206 (M), a pan-AKT inhibitor, induced apoptosis of ER+ BC under estrogen deprivation in preclinical studies. We conducted this neoadjuvant trial to determine the pathologic complete response (pCR) rate of M plus anastrozole (A) for PIK3CA mutant (Mut) ER+ BC. Methods This single arm open label study of M+A used a 2-stage Simon phase II design (stage 1, n=16; stage 2, n=13, alpha=0.10, power=0.90) to test whether pCR rate &lt;1% (based on historical data with A alone), against the alternative that pCR rate ≥15% in PIK3CA Mut ER+ BC. At least 1 pCR in stage 1 was required to proceed to stage 2. Eligible patients (pts) with clinical stage II or III ER+HER2- BC were pre-registered and proceeded to a research tumor biopsy for PIK3CA sequencing, followed by treatment with daily A monotherapy for 28 days (cycle 0). Pts with PIK3CA Mut BC were subsequently registered, underwent a second biopsy, and started M (150mg PO weekly) with daily A on cycle 1 day 1 (C1D1) for a maximum of four 28-day cycles followed by surgery. Goserelin was added for premenopausal pts. A tumor biopsy on C1D17, 17 days post the start of M, was performed. Those with C1D17 Ki67 &gt;10% discontinued study treatment. pCR was defined as no invasive cancer in the breast and the lymph nodes. Tumor specimens collected at all timepoints are being analyzed for markers of proliferation, apoptosis, and PI3K pathway activity, gene expression microarray, intrinsic subtypes, and next generation sequencing of 83 genes. Results Of the 51 pts pre-registered, 35 pts did not register due to no PIK3CA mutation (n=22), inadequate specimen for testing (n=6), physician/pt decision (n=7). The remaining 16 pts (median age: 58, range: 40-77 years) received combination therapy. Three pts did not complete 4 cycles due to C1D17 Ki67 &gt;10% (n=2) and intolerability (grade (Gr) 4 transaminase elevation in C1, n=1). Other severe toxicities possibly related to M included Gr 3 rash (25%) and pruritus (12.5%). Of the 13 pts completed study therapy and underwent surgery, all had residual disease in the breast and 7 also had positive nodes. Table 1 summarized changes in Ki67 during treatment. ComparisonsnAbsolute changes in Ki67 median (range)Wilcoxon signed rank p-valueC1D1 relative to pre-registration11-17.0% (-49.8 to 4.1%)0.0020C1D17 relative to pre-registration14-16.4% (-51.4 to 4.1%)0.0004C1D17 relative to C1D112-1.5% (-18.6 to 15.8%)0.9697C1D1, biopsy post 28 days of A alone; C1D17 biopsy post 17 days on combination therapy Although Ki67 levels post A monotherapy (C1D1) or M+A (C1D17) were significantly lower than that of pre-registration samples, Ki67 did not differ between C1D17 and C1D1 samples. Other correlative studies are ongoing and results will be presented. Conclusion Despite the small sample size, biomarker analysis on serial biopsy specimens demonstrated that M+A is unlikely to be more effective than A alone in PIK3CA Mut ER+ BC. This trial demonstrated the feasibility of genomic sequencing for pt selection and the value of a small, well-designed proof-of-principle neoadjuvant trial for the evaluation of targeted agents. Citation Format: Ma CX, Suman VJ, Goetz M, Northfelt D, Burkard M, Ademuyiwa F, Naughton M, Margenthaler J, Aft R, Gray R, Tavaarwerk A, Wilke L, Haddad T, Moynihan T, Loprinzi C, Hieken T, Hoog J, Guo Z, Han J, Vij K, Mardis E, Sanati S, Al-Kateb H, Doyle L, Erlichman C, Ellis MJ. A phase II neoadjuvant trial of MK-2206, an AKT inhibitor, in combination with anastrozole for clinical stage 2 or 3 PIK3CA mutant estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-13-04.