Citations

Abstract Introduction A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Methods Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web‐based quantitative survey regarding symptom frequency and the conceptualization of PCA. Results A three‐level classification framework for PCA is described comprising both syndrome‐ and disease‐level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico‐radiological syndrome. Classification level 2 (PCA‐pure, PCA‐plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA‐AD], Lewy body disease [PCA‐LBD], corticobasal degeneration [PCA‐CBD], prion disease [PCA‐prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome‐level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. Discussion There was strong agreement regarding the definition of the core clinico‐radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single‐center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.

422 Background: There is significant variability in the response to VEGF-TT in mRCC with no validated predictive biomarkers. We hypothesized that whole exome analysis might identify markers of response and resistance to VEGF-TT in mRCC. Methods: mRCC patients who received first-line sunitinib or pazopanib and were in two extreme phenotypes of response were identified. Extreme responders (ER) were defined as PR or CR for ≥3 years (n=10) and primary refractory patients (PRP) were defined as PD within the first 3 months of therapy (n=10). WES was performed in pre-treatment specimens and established Broad Institute analytical pipelines were utilized to identify point mutations and copy number alterations across the exome. ER (n=4) and PRP (n=4) who were part of TCGA project for clear-cell RCC were included in this analysis. Nonsense, missense and indel mutations in established or novel RCC genes were investigated. Results: IMDC prognostic scores were not significantly different between the two groups. VHL mutations were observed at similar frequency in ER and PRP, overall 57%. Mutations in PBRM1 were identified in 7 ER (50%) vs. 1 PRP (7%) (p=0.03). In addition, mutations in TP53 were only found in PRP (p=0.09). No other gene had mutations that were associated with either response or primary refractory disease (Table). Conclusions: In this pilot study, PBRM1 mutations were associated with extreme response to VEGF-TT. However, this was exploratory, and multivariable analysis was not performed. Analysis of additional patient samples is ongoing to confirm or refute this association. If true it suggests that epigenetic effects of PBRM1 mutation may contribute to response to VEGF-TT in mRCC. [Table: see text]

443 Background: Identification of a sensitive and specific prognostic marker would aid in the management of patients (pts) with standard histopathology node negative colon cancer (CC). We conducted a pooled individual pt data analysis to confirm the prognostic value of GCC for disease recurrence in untreated stage II CC. Methods: GCC mRNA was quantified by RT-qPCR using formalin-fixed LN from 310 stage II pts diagnosed from 1991-2006 enrolled in two studies (Sargent 2011 [study1] and Haince 2009 [study2]). Patients were classified by GCC LN ratio (LNR) (high risk: LNR ≥ 0.1; low risk: LNR < 0.1), with LNR defined as number of GCC positive LN divided by number of informative LNs. Clinical outcomes included time to recurrence (TTR), overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS). Stratified log-rank tests and multivariate Cox models assessed the association between clinical outcomes and GCC LN status. Results: The 5-year recurrence rate in study 1 (n=241) was 15.8%, 24.9% in study 2 (n=69). GCC LNR high risk pts had significantly higher risk of TTR, OS, DSS and DFS, which remained after adjusting for age, T stage, grade, number of LNs examined, and presence of lymphovascular invasion ( Table ). In a secondary analysis of low risk stage II pts (T3, ≥12 LNs examined, and negative surgical margins, n=241), a strong relationship between GCC LNR and each endpoint remained (TTR HR=4.34, 95% CI=2.07 – 9.13, p<0.001). Conclusions: Pts with GCC LNR high risk status have significantly poorer outcomes compared to pts with low risk status, particularly among those traditionally considered to be low risk. [Table: see text]

369 Background: A multi-center prospectively specified retrospective study Validating Indicators to Associate Recurrence (VITAR) is assessing the relationship between guanylyl cyclase C (GCC) gene expression in formalin fixed LNs and recurrence risk in stage II CC pts not treated with adjuvant chemotherapy. Here we report the preplanned initial analysis performed with 241 pts. Methods: GCC mRNA was quantified by RT-qPCR using FFPE LNs tissues from untreated stage II CC pts diagnosed from 1999-2006 with at least 10 LN examined blinded to clinical outcomes. Cox regression models examined the relationship between GCC nodal status and the prespecified primary endpoint of recurrence risk. Results: Twenty-ninepts (12%) had a disease recurrence or cancer death, median follow-up was 60 months and median LNs examined was 15. The ratio of the number of GCC+ LNs over the total number of informative LNs (LNR) significantly predicted higher recurrence risk for 84 pts classified as high risk (HR, 2.38; p=0.02). The estimated 5-yr recurrence rates were 10% and 27% for the low and high risk group, respectively. After adjusting for age, T stage, number of LNs assessed, and MMR status, the significant association remained (HR, 2.61; 95% CI, 1.17-5.83; p=0.02). In a subset of 181 pts with negative margin, T3 tumor only and ≥12 LN examined, the GCC LNR had a HR for recurrence of 5.06 (95% CI 1.61-15.91, p=0.003), translating into 5-yr recurrence rates of 4% among low risk pts and 27% for the high-risk group. Conclusions: Our results suggest that GCC expression in LNs is a significant determinant of recurrence in appropriately staged CC pts not treated with adjuvant chemotherapy. The validation component of the study is ongoing. [Table: see text] [Table: see text]

SummaryBackgroundDuodenal injury persists in some coeliac disease patients despite gluten‐free diet, and is associated with adverse outcomes.AimTo determine the prevalence and clinical risk factors for persistent villus atrophy among symptomatic coeliac disease patients.MethodsA nested cross‐sectional analysis was performed on coeliac disease patients with self‐reported moderate or severe symptoms while following a gluten‐free diet, who underwent protocol‐mandated duodenal biopsy upon enrolment in the CeliAction clinical trial. Demographic factors, symptom type, medication use, and serology were examined to determine predictors of persistent villus atrophy.ResultsOf 1345 symptomatic patients, 511 (38%, 95% CI, 35–41%) were found to have active coeliac disease with persistent villus atrophy, defined as average villus height to crypt depth ratio ≤2.0. On multivariable analysis, older age (OR, 5.1 for ≥70 vs. 18–29 years, 95% CI, 2.5–10.4) was a risk factor while longer duration on gluten‐free diet was protective (OR, 0.37, 95% CI, 0.24–0.55 for 4–5.9 vs. 1–1.9 years). Villus atrophy was associated with use of proton‐pump inhibitors (PPIs; OR, 1.6, 95% CI, 1.1–2.3), non‐steroidal anti‐inflammatory drugs (NSAIDs; OR, 1.64, 95% CI, 1.2–2.2), and selective serotonin reuptake inhibitors (SSRIs; OR, 1.74, 95% CI, 1.2–2.5). Symptoms were not associated with villus atrophy after adjusting for covariates.ConclusionsA majority of symptomatic coeliac disease patients did not have active disease on follow‐up histology. Symptoms were poorly predictive of persistent mucosal injury. The impact of NSAIDs, PPIs, and SSRIs on mucosal healing in coeliac disease warrants further study.

Background: The objective of this study is to determine the time-dependent dissipation of extrinsic wrist ligament tension following the application external fixation with axial distraction of the wrist in a cadaveric model. Methods: Six paired fresh-frozen cadaveric specimens underwent mechanical testing simulating external fixation with 1 arm of each pair osteotomized to simulate a distal radius fracture. The change in tension was then recorded over 24 hours. Results: The rate of stress relaxation decreased with time. The average loss in tension in the control arms and osteotomized arms was 55% and 59%, respectively, over a 24-hour period. There was no statistically significant difference in the stress relaxation behavior between the 2 groups. Conclusion: This study further supports the recommendation that comminuted distal radius fractures treated with an external fixator should have Kirschner wire augmentation or other additional means of fixation to help maintain fracture length and alignment. The results of this study call in to question the efficacy of ligamentotaxis alone through external fixation as the sole means of maintaining reduction of displaced, unstable distal radius fractures.

ABSTRACTObjectives:Celiac disease (CD) is a common immune‐mediated disorder that affects up to 1% of the general population. Recent reports suggest that the incidence of CD has reached a plateau in many countries. We aim to study the incidence and altered presentation of childhood CD in a well‐defined population.Methods:Using the Rochester Epidemiology Project, we retrospectively reviewed Mayo Clinic and Olmsted Medical Center medical records from January 1994 to December 2014. We identified all CD cases of patients ages 18 years or younger at the time of diagnosis. Incidence rates were calculated by adjusting for age, sex, and calendar year and standardizing to the 2010 US white population.Results:We identified 100 patients with CD. Incidence of CD has increased from 8.1 per 100,000 person‐years (2000–2002) to 21.5 per 100,000 person‐years (2011–2014). There was an increase in CD prevalence in children from 2010 (0.10%) to 2014 (0.17%). Thirty‐four patients (34%) presented with classical CD symptoms, 43 (43%) had nonclassical CD, and 23 (23%) were diagnosed by screening asymptomatic high‐risk patients. Thirty‐six patients (36%) had complete villous atrophy, 51 (51%) had partial atrophy, and 11 (11%) had increased intraepithelial lymphocytes. Two patients were diagnosed without biopsy. Most patients (67%) had a normal body mass index, 17% were overweight/obese, and only 9% were underweight.Conclusions:Both incidence and prevalence of CD have continued to increase in children during the past 15 years in Olmsted County, Minnesota. Clinical and pathologic presentations of CD are changing over time (more nonclassical and asymptomatic cases are emerging).

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.