Met Consensus Criteria Research Articles

A Delphi study to establish an expert consensus opinion on risk factors for type 2 diabetes, and potential complications of diabetes, including brain health associations

IntroductionType 2 diabetes (T2DM) has a multifactorial aetiology, and wide-ranging potential health complications, including brain health associations.ObjectivesA number of diabetes risk factors and complications have a strong evidence base. This study will address ambiguity in the literature regarding others.AimsResults will inform development of a questionnaire for use among the public and individuals with diabetes, assessing knowledge of diabetes and brain health associations and the role of modifiable risk factors. Aiming to ultimately inform effective preventative strategies for both dementia and depression.MethodsA systematic literature review preceded this two-round modified Delphi study. Respondents rated their agreement with risk factors for T2DM, and potential complications of diabetes on an e-questionnaire.ResultsOf 46 international experts invited to participate in round-one; 14 responded (30.4%). Thirteen respondents (92.9%) completed round-two questionnaire. Consensus was pre-defined as 70% or more agreement between respondents on questionnaire items. On completion, 11/18 risk factor items for T2DM met consensus criteria however ‘depression’ did not. Of diabetes complication items, 13/16 met consensus criteria (see Table 1).ConclusionsStudy results indicate that international experts consider a number of brain health complications to be associated with diabetes. Results will be incorporated in a diabetes and brain health knowledge questionnaire for use among vulnerable populations.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Inaccurate diagnosis of paediatric anaphylaxis in three Australian Emergency Departments.

To determine the accuracy of emergency department (ED) paediatric anaphylaxis diagnosis, and to identify factors associated with misdiagnosis. Retrospective chart review of children aged 0-18 years with allergic presentations to three Victorian EDs in 2014. Cases were included if an ED diagnosis of anaphylaxis was recorded, or the presentation met international consensus criteria for anaphylaxis. Of the 60 143 paediatric ED presentations during the study period, 1551 allergy-related presentations were identified and reviewed. One hundred and eighty-seven met consensus criteria for anaphylaxis, and another 24 were diagnosed with anaphylaxis without meeting criteria. Of the 211 presentations, 105 cases were given an ED diagnosis of anaphylaxis and 106 cases were given an alternative diagnosis in ED. ED assessment had a sensitivity of 43.2% (95% confidence interval (CI) 36.1-50.7%) and specificity of 97.9% (95% CI 96.9-98.7%) for anaphylaxis. Multiple logistic regression demonstrated that an ED anaphylaxis diagnosis was associated with previous anaphylaxis (odds ratio (OR) 3.20; 95% CI 1.52-6.75), arrival by ambulance (OR 2.80; 95% CI 1.36-5.74), a high-acuity triage category (OR 4.51; 95% CI 2.20-9.25) and presentation to a tertiary hospital (OR 2.86; 95% CI 1.44-5.67). ED diagnosis of anaphylaxis was less likely in those with resolution of symptoms and signs in at least one organ system prior to arrival (OR 0.27; 95% CI 0.12-0.62). In children with allergic presentations, ED assessment has a low sensitivity but high specificity for anaphylaxis. Attention to resolved pre-hospital symptoms and awareness of diagnostic criteria are important considerations for accurate ED diagnosis of anaphylaxis.

Abstract WP232: Biomarkers of Atrial Cardiopathy and Atrial Fibrillation Detection on Mobile Continuous Outpatient Telemetry After Cryptogenic Stroke

Background: In population-based studies, biomarkers of atrial dysfunction or “cardiopathy” have been shown to be associated with embolic stroke risk. However, it is unclear if this risk is mediated by undiagnosed paroxysmal atrial fibrillation or flutter (AF). We aim to determine whether atrial cardiopathy biomarkers predict atrial fibrillation on continuous heart-rhythm monitoring after embolic stroke of undetermined source (ESUS). Methods: This was a single-center retrospective study including all patients who met consensus criteria for ESUS and who underwent 30 days of ambulatory heart-rhythm monitoring looking for AF between Jan 1 st , 2013 and Dec 31 st , 2015. We reviewed medical records for clinical, radiographic, and cardiac variables. The primary outcome was new diagnosis of AF detected during heart-rhythm monitoring. The primary predictors were atrial biomarkers: left atrial diameter on echocardiography, P-wave terminal force in ECG lead V1 , and PR interval on ECG. Multiple logistic regression was used to assess the relationship between atrial biomarkers and AF detection. Results: Among 196 eligible patients, 23 (11.7%) were diagnosed with AF. In unadjusted analyses, patients with AF were older (72.4 vs. 61.4 years, p < 0.001) and had larger left atrial diameter (39.2 vs. 35.7 mm, p = 0.03). In a multivariable model including variables significant on univariate analyses, the only predictor of AF was age ≥ 60 years (odds ratio, 3.0; 95% CI, 1.06-8.5; p = 0.04). Atrial biomarkers were not associated with AF detection. Conclusion: Atrial biomarkers were not associated with AF after ESUS. This suggests that previously reported associations between these markers and stroke may reflect independent cardiac pathways leading to stroke. Prospective studies are needed to investigate these mechanisms and study anticoagulation versus antiplatelet treatment for secondary stroke prevention in patients with ESUS and atrial cardiopathy.

Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study.

IntroductionConsensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs).MethodsWe conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients <18 years of age were screened, and 706 with severe sepsis defined either by physician diagnosis or on the basis of 2005 International Pediatric Sepsis Consensus Conference consensus criteria were enrolled. The primary endpoint was agreement of pediatric severe sepsis between physician diagnosis and consensus criteria as measured using Cohen’s κ. Secondary endpoints included characteristics and clinical outcomes for patients identified using physician diagnosis versus consensus criteria.ResultsOf the 706 patients, 301 (42.6 %) met both definitions. The inter-rater agreement (κ ± SE) between physician diagnosis and consensus criteria was 0.57 ± 0.02. Of the 438 patients with a physician’s diagnosis of severe sepsis, only 69 % (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria alone did not have PICU mortality significantly different from that of patients identified by both physician diagnosis and consensus criteria.ConclusionsPhysician diagnosis of pediatric severe sepsis achieved only moderate agreement with consensus criteria, with physicians diagnosing severe sepsis more broadly. Consequently, the results of a research study based on consensus criteria may have limited generalizability to nearly one-third of PICU patients diagnosed with severe sepsis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-1055-x) contains supplementary material, which is available to authorized users.

Detection of microRNAs in patients with sepsis

ObjectiveTo externally validate the diagnostic and prognostic value of three previously identified microRNAs in emergency department patients with sepsis. MethodsPatients meeting consensus criteria for sepsis and septic shock were compared to controls. Three microRNAs (miR-150, miR-146a, and miR-223) were measured using real-time quantitative PCR, and levels of miRNAs were compared among the three cohorts. The association between miRNAs and both inflammatory markers and Sequential Organ Failure Assessment (SOFA) score were compared. To assess the prognostic value of each miRNA, unadjusted and adjusted logistic regression models were constructed using in-hospital mortality as the dependent variable. ResultsNinety-three patients were enrolled; 24 controls, 29 with sepsis, and 40 with septic shock. We found no difference in serum plasma miR-146a or miR-223 between cohorts, and found no association among these microRNAs and either inflammatory markers or SOFA score. miR-150 demonstrated a significant correlation with SOFA score (P= 0.31, P=0.01) and IL-10 (P=0.37, P=0.001), but no IL-6 or TNF-α (P=0.046, P=0.59). Logistic regression demonstrated miR-150 to be independently associated with mortality, even after adjusting for SOFA score (P=0.003) or initial lactate (P=0.01). ConclusionsmiR-146a and miR-223 demonstrated no significantly diagnostic or prognostic ability in this cohort. miR-150 was associated with inflammation, severity of illness, and mortality. Given the independent predictive value of miR-150, additional research regarding its role in sepsis is warranted.

Small intestinal permeability in patients with eosinophilic oesophagitis during active phase and remission

BackgroundEosinophilic oesophagitis (EoE) is presumed to be an isolated oesophageal disease; yet other allergic diseases associated with eosinophilic infiltration of target tissues, such as asthma and eczema, show perturbed functions...

Understanding word preference for description of exercise interventions as a means for enhancing recruitment and acceptability of exercise treatment among adults treated for depression

BackgroundThe importance of consumer preferences in the marketing and design of exercise and other health promotion interventions has received increasing attention. This study examined word preference for descriptions of an exercise intervention among 464 adults treated for depression. We also explored differences in word preference by current depression status, current smoking status and other demographic characteristics. MethodsRespondents completed a mailed survey. They were asked to rate the likelihood of seeking out an exercise program described by 14 different adjectives (i.e., realistic and innovative) on a 5 point scale. Scale responses were dichotomized as 0, 1, 2 (not at all/a little/moderately) versus 3, 4 (quite a bit/extremely). Words endorsed as quite a bit/extremely likely in over half of the sample indicated consensus. ResultsRespondents were 82% female, 95% Caucasian, 22% were currently depressed (PHQ-2 score), and 14% were current smokers. Only 4 words met consensus criteria for likelihood of seeking out an exercise program: realistic, doable, fun and energizing. Programs described as novel, new, innovative along with vigorous or intense were not rated highly. Currently depressed individuals were less likely than non-depressed respondents to seek out an exercise program described as energizing (p = 0.014), but there were no differences in endorsing realistic, doable, or fun by current depression status. No significant differences were detected between current smokers and nonsmokers in likelihood of seeking out exercise programs being realistic, doable, fun, or energizing. ConclusionAs a preliminary study, the results suggest there is a clear preference profile for exercise program descriptions which could be tapped to promote such programs and enhance recruitment.

Metabolic syndrome in antipsychotic naïve patients with schizophrenia: pooled analysis of data from three Indian studies

This study aimed to assess the prevalence of metabolic syndrome (MS) and subthreshold MS in antipsychotic naïve patients with schizophrenia by pooling the data from three different centres in India. One hundred thirty-seven antipsychotic naïve patients with schizophrenia were evaluated for MS using common criteria for clinical diagnosis. Twenty-six patients (19%) met consensus criteria. Additionally, 56 patients (40.9%) fulfilled one criterion and 32 patients (23.3%) fulfilled two criteria of MS out of five criteria. One-fifth of antipsychotic naïve patients with schizophrenia had MS and another two-third had at least one metabolic abnormality. Awareness of such a high risk is vitally important for rational selection of antipsychotic medications as well as effective implementation of preventive measures.

Diagnostic Stringency and Healthcare Needs in Patients with Biliary Dyskinesia

We have recently shown an increase in cholecystectomies for biliary dyskinesia. Based on these results, we hypothesized that diagnostic criteria are less stringently applied which may contribute to ongoing resource utilization. Using billing codes, patients seen for biliary dyskinesia were identified and data were extracted from the electronic medical record to confirm the diagnosis, obtain demographic and clinical data and assess resource utilization 1 year prior to and after cholecystectomy. A total of 972 patients were identified, with 894 undergoing cholecystectomy. In 259 patients, symptoms had started <3 months prior to evaluation. Functional gallbladder imaging revealed a mean gallbladder ejection fraction of 23.1 ± 0.7 %; of the patients undergoing surgery, 116 had a normal gallbladder ejection fraction. Sufficient up data for pre- and post-operative assessment of resource utilization was available for 368 patients. Emergency room (ER) visits decreased from 0.86 ± 0.07 to 0.69 ± 0.03 (P < 0.05), while hospitalization rates remained unchanged after surgery. Patients not meeting consensus criteria for the diagnosis of biliary dyskinesia were more likely to use opioids and have ER visits prior to and after cholecystectomy. Using multiple logistic regression benzodiazepine use, migraine history and prior ER visits independently predicted postoperative resource utilization. Our data demonstrate that a significant number of patients undergo cholecystectomy for biliary dyskinesia, even though they do not meet currently accepted diagnostic criteria. While healthcare resource utilization drops within the first year after surgery, ER visits and hospitalizations remain common, suggesting a more limited benefit of surgical approaches in these patients.

Impaired financial abilities in Parkinson's disease patients with mild cognitive impairment and dementia

PurposeFinancial capacity (FC) is an instrumental activity of daily living (IADL) critical to independent functioning and sensitive to cognitive impairment in dementia. Little is known about FC in cognitively impaired patients with Parkinson's disease (PD). The present study investigated FC in PD patients with prodromal and clinical dementia. MethodsParticipants were 20 older controls and 35 PD patients who met consensus criteria for either mild cognitive impairment (PD-MCI, n = 18) or PD dementia (PDD, n = 17). FC was assessed using a standardized performance based measure consisting of 9 domain and two global scores (Financial Capacity Instrument; FCI) (1). FCI domain and global performance scores were compared across groups. Capacity impairment ratings (no impairment, mild/moderate impairment, severe impairment) were calculated for each PD patient's domain and global scores. ResultsRelative to controls, PD-MCI patients were impaired on both FCI global scores and domains of basic monetary skills, financial concepts, and investment decision-making. Relative to both controls and PD-MCI patients, PDD patients were impaired on virtually all FCI variables. With respect to impairment ratings, greater than 50% of PD-MCI patients and greater than 90% of PDD patients were classified as either mild/moderate or severely impaired on the two FCI global scores. ConclusionsImpairment of financial capacity is already present in PD-MCI and is advanced in PDD. Complex cognitively-mediated IADLs such as financial capacity appear to be impaired early in the course of PD dementia.

Alcohol screening scores and 90-day outcomes in patients with acute lung injury.

The effects of excess alcohol consumption (alcohol misuse) on outcomes in patients with acute lung injury have been inconsistent, and there are no studies examining this association in the era of low tidal volume ventilation and a fluid conservative strategy. We sought to determine whether validated scores on the Alcohol Use Disorders Identification Test that correspond to past-year abstinence (zone 1), low-risk drinking (zone 2), mild to moderate alcohol misuse (zone 3), and severe alcohol misuse (zone 4) are associated with poor outcomes in patients with acute lung injury. Secondary analysis. The Acute Respiratory Distress Syndrome Network, a consortium of 12 university centers (44 hospitals) dedicated to the conduct of multicenter clinical trials in patients with acute lung injury. Patients meeting consensus criteria for acute lung injury enrolled in one of three recent Acute Respiratory Distress Syndrome Network clinical trials. None. Of 1,133 patients enrolled in one of three Acute Respiratory Distress Syndrome Network studies, 1,037 patients had an Alcohol Use Disorders Identification Test score available for analysis. Alcohol misuse was common with 70 (7%) of patients having Alcohol Use Disorders Identification Test scores in zone 3 and 129 (12%) patients in zone 4. There was a U-shaped association between validated Alcohol Use Disorders Identification Test zones and death or persistent hospitalization at 90 days (34% in zone 1, 26% in zone 2, 27% in zone 3, 36% in zone 4; p < 0.05 for comparison of zone 1 to zone 2 and zone 4 to zone 2). In a multiple logistic regression model, there was a significantly higher odds of death or persistent hospitalization in patients having Alcohol Use Disorders Identification Test zone 4 compared with those in zone 2 (adjusted odds ratio 1.70; 95% confidence interval 1.00, 2.87; p = 0.048). Severe but not mild to moderate alcohol misuse is independently associated with an increased risk of death or persistent hospitalization at 90 days in acute lung injury patients.

A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method

Astrocytic tumors account for 42% of childhood brain tumors, arising in all anatomical regions and associated with neurofibromatosis type 1 (NF1) in 15%. Anatomical site determines the degree and risk of resectability; the more complete resection, the better the survival rates. New biological markers and modern radiotherapy techniques are altering the risk assessments of clinical decisions for tumor resection and biopsy. The increasingly distinct pediatric neuro-oncology multidisciplinary team (PNMDT) is developing a distinct evidence base. A multidisciplinary consensus conference on pediatric neurosurgery was held in February 2011, where 92 invited participants reviewed evidence for clinical management of hypothalamic chiasmatic glioma (HCLGG), diffuse intrinsic pontine glioma (DIPG), and high-grade glioma (HGG). Twenty-seven statements were drafted and subjected to online Delphi consensus voting by participants, seeking >70% agreement from >60% of respondents; where <70% consensus occurred, the statement was modified and resubmitted for voting. Twenty-seven statements meeting consensus criteria are reported. For HCLGG, statements describing overall therapeutic purposeand indications for biopsy, observation, or treatment aimed at limiting the risk of visual damage and the need for on-going clinical trials were made. Primary surgical resection was not recommended. For DIPG, biopsy was recommended to ascertain biological characteristics to enhance understanding and targeting of treatments, especially in clinical trials. For HGG, biopsy is essential, the World Health Organization classification was recommended; selection of surgical strategy to achieve gross total resection in a single or multistep process should be discussed with the PNMDT and integrated with trials based drug strategies for adjuvant therapies.

Lack of Standardization in Exception Points for Patients With Primary Sclerosing Cholangitis and Bacterial Cholangitis

For conditions that the Model for End-Stage Liver Disease (MELD) score does not accurately predict waitlist mortality, transplant centers may apply to regional review boards for exception points. For patients with primary sclerosing cholangitis (PSC) suffering from bacterial cholangitis, consensus recommendations published in December 2006 are to grant exception points for recurrent cholangitis with ≥ 2 episodes of bacteremia or ≥ 1 episode septic complications. Using data provided by the United Network for Organ Sharing, we evaluated PSC patients who applied for exception points due to bacterial cholangitis from February 27, 2002 to March 14, 2011. Before publication of the recommendations, 66.0% of applications were accepted, compared with 80.1% after (p < 0.001). Focusing on applications after publication of the recommendations, 311 (74.6%) did not meet the recommended criteria, and 250 (80.4%) of these were approved. Of patients with approved applications, those not meeting consensus criteria were more likely to be transplanted, (77.4% vs. 62.8%, p = 0.043), whereas those with denied applications for approved indications were more liked to die/be removed (44.4% vs. 9.5%, p = 0.49). Although data are needed to properly identify those patients at highest risk for waitlist mortality, standardized criteria or a centralized review board should be adopted to ensure consistency in the granting of exception points.

Surgery for Primary Hyperparathyroidism

To determine parathyroidectomy (PTx) rates in patients who satisfy the consensus guidelines for surgical treatment of primary hyperparathyroidism (PHPT). Surgery for PHPT is recommended for all symptomatic patients and select asymptomatic patients meeting established consensus criteria. Adherence to the consensus guidelines has not been examined systematically, because of inadequate information regarding patients managed nonoperatively. All nonuremic patients with PHPT during the period 1995-2008 were identified using the Kaiser Permanente-Southern California laboratory database, encompassing 3.5 million individuals annually. Multivariate logistic regression was used to examine predictors of PTx. We found 3388 patients with PHPT, of whom 265 (8%) were symptomatic (nephrolithiasis). Nephrolithiasis was predictive of PTx (OR 2.94 vs asymptomatic), with 51% of symptomatic patients undergoing surgery. Among asymptomatic patients, the proportion meeting consensus criteria was 39% during the early period (1995-2002) and 51% during the late period (2003-2008). The PTx rate for these patients exceeded that for asymptomatic patients not meeting consensus criteria but remained low (early 44% vs 19%, P < 0.0001; late 39% vs 16%, P < 0.0001). The following individual criteria were predictive of PTx: calcium >11.5 mg/dL (OR 2.27), hypercalciuria (OR 3.28, P < 0.0001), and age < 50 years (OR 1.54, P < 0.0001). However, the absolute PTx rates associated with satisfaction of these criteria were in the 50% range. Bone density scores did not influence likelihood of PTx and renal impairment predicted against PTx (OR 0.35, P < 0.0001). The consensus guidelines regarding PHPT have not been followed in our study population. PTx appears to be underutilized in both asymptomatic and symptomatic patients.

Whole-Genome Sequencing Results From 30 Patients with Waldenstrom's Macroglobulinemia

Abstract 434 Introduction:The primary oncogenetic event resulting in malignant transformation in Waldenstrom's Macroglobulinemia (WM) remains to be delineated. We therefore employed whole genome sequencing (WGS) to help identify potential somatic variants in WM. Patients and Methods:Thirty patients meeting consensus criteria for the diagnosis of WM were included for these studies, whose characteristics are depicted in Table 1. CD19-magnetic bead sorting was used for isolation of bone marrow LPC. CD19-depleted PB mononuclear cells were collected as matched normal tissue. For 10 patients, WGS of tumor and matched normal samples was performed, and for 20 additional patients tumor samples alone were completely sequenced. Library construction and WGS was performed by Complete Genomics Inc. Read sequences were aligned to the NCBI Build 37. High confidence somatic variants were identified using cgatools version 1.3. Novel non-synonymous exonic variants for familial and sporadic LPL/WM patients were identified using ANNOVAR using to filter against several large databases including dbSNP version 132, the November 2010 release version of the 1,000 genomes project, and a 46 healthy donor dataset from Complete Genomics, Inc. based on KnownGene annotations. Variants filtered out in this process were checked against the dbSNP132 flagged SNP database for potential clinical significance. Data was further annotated against the Database of Genomic Variants and the Segmental Duplication Database, TargetScan, and transcription factor binding site data from the ENCODE project. When applicable, variants were scored using SIFT, PolyPhen2 and Mutation Taster. Copy number neutral loss of heterozygosity (CNLOH) was identified from the rate of heterozygous variants per 500,000 base pairs, CG content adjusted coverage data, and allele imbalance calculated from the percentage of total reads supporting the less covered allele.Table 1Clinical and laboratory characteristics for 30 WM patients whose lymphoplasmacytic cells were used in WGS studies.MedianRangeAge6241–87Familial WM9 (30%)NAUntreated26 (87%)NABone Marrow Involvement (%)65%5–95%Clonal B–cells(%)196.355.5–100IgM (mg/dL)3,970590–6,580IgMκ/IgMλ monoclonal protein24/6NAIgA (mg/dL)4111–516IgG (mg/dL)519215–3,120Serum B2M (mg/L)3.551.50–12.1Hematocrit (%)31.424.0–41.51Determined by light chain restriction using flow cytometry. Results:Tumor and normal genomes were both sequenced to an average of 66X (range 60–91X) coverage of mapped individual reads. The average gross mapped yield for these genomes was 186.89 (range 171.56–262.03 Gb). Acquired copy number changes were common, and included losses in chromosome 6q (13/30; 43%), gains in chromosome 4 (7/30; 23%), and gains in 6p (3/30; 10%). Large regions of CNLOH were observed in 9/30 (30%) of patients occurring in chromosomes 1, 2, 3, 5, 9, 11, 17, 21, and X. The most frequent somatic variant occurred at position 38182641 in chromosome 3p22.2 in the myeloid differentiation primary response (MYD88) gene, resulting in a non-synonymous change at amino acid position 265 from leucine to proline (L265P) in 26/30 (86.7%) patients. Of these, 4/26 (15%) had a CNLOH covering this position making the variant effectively homozygous. Additional somatic variants occurred in transporter 2, ATP-binding cassette, sub-family B (TAP2) gene in 7/30 (23%) patients; chemokine (C-X-C motif) receptor 4 (CXCR4) gene in 6/30 (20%) patients. Somatic variants were also identified in the coding regions of low density lipoprotein receptor-related protein 1B (LRP1B) gene in 5/30 (17%) patients; mesothelin (MSLN) gene in 4/30 (13%) patients; AT rich interactive domain 1A (ARID1A) gene in 3/30 (10%) patients; histone cluster 1, H1e (HIST1H1E) in 3/30 (10%) patients, and Rap guanine nucleotide exchange factor 3 (RAPGEF3) in 3/30 (10%) patients. Conclusions:The results of this study provide the first reporting of comprehensive WGS efforts in patients with WM, and reveal recurring somatic variants in genes with important regulatory functions including MYD88, TAP2, and CXCR4. Structural and functional validation studies are ongoing and will be updated at the meeting. The results of these studies provide important new insights into the pathogenesis of WM. Disclosures:No relevant conflicts of interest to declare.

Disease flare after tyrosine kinase inhibitor (TKI) discontinuation in patients with EGFR-mutant lung cancer and acquired resistance.

e18001 Background: Treatment of oncogene-addicted malignant neoplasms with targeted kinase inhibitors is biologically and clinically different than treatment with cytotoxic chemotherapy. We have observed that some patients (pts) with acquired resistance to EGFR TKI (initial response followed by RECIST disease progression) have accelerated progression of disease after discontinuation of EGFR TKI. The risk of a serious disease flare after discontinuing erlotinib or gefitinib in EGFR-mutant lung cancer despite acquired resistance has not been systematically evaluated. Methods: We identified pts with EGFR-mutant lung adenocarcinoma enrolled in 6 trials for treatment of acquired resistance which mandated TKI discontinuation prior to treatment. Disease flare was defined as symptomatic progression of disease leading to hospitalization or death during the washout period. All pts met consensus criteria for acquired resistance (Jackman, JCO, 2010). Results: 55 pts were eligible, (age range: 27-82, women: 76%). Baseline EGFR mutations were exon 19 deletions (36) and L858R (19). The median time on TKI before discontinuation was 19 months (range 7-78). 12 pts (22%; 95% CI 13-35%) experienced a disease flare after discontinuation of EGFR TKI. The median time to disease flare from discontinuation of TKI was 8 days (range 3-21). Of these 12, all were hospitalized and 3 died. Flare was associated with a preceding shorter initial time to progression on TKI, median 9 vs. 13 months, p=0.015 (Wilcoxon). There was no association between disease flare and EGFR sensitizing mutation, presence of secondary T790M mutation, sites of disease, or performance status. Conclusions: In pts with EGFR-mutant lung cancer with acquired resistance to EGFR TKI, discontinuation of erlotinib or gefitinib prior to initiation of an alternative treatment is associated with a clinically significant risk of accelerated disease progression. There is a need to identify clinical and molecular characteristics that predict this phenomenon. Future clinical trials targeting this patient population should eliminate or minimize protocol-mandated washout periods. Funded by NIH T32 CA009207, P01 CA129243.

Pilot study of neoadjuvant FOLFIRINOX in unresectable locally advanced (LA) pancreatic carcinoma (PC).

324 Background: 5-flourouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients (pts) with advanced PC who have a good performance status (Conroy et al, ACCORD 11 trial, ASCO 2010). After the initial data on FOLFIRINOX were presented at ASCO 2007, we began using it off-protocol as neoadjuvant therapy for LAPC. We report our experience herein. Methods: In this retrospective series, we included pts with unresectable LAPC who received neoadjuvant FOLFIRINOX. The doses were identical to the ACCORD 11 trial, with G-CSF prophylaxis from cycle 1. The primary endpoint was R0 resection rate. Secondary endpoints were overall survival (OS), safety and tolerability. Results: Between 5/2008 and 9/2010, we treated 12 pts with LAPC with neoadjuvant FOLFIRINOX. All pts met consensus criteria for unresectability after multidisciplinary review. The median age was 57.5 years and 9/12 were men. All had ECOG PS of 0 or 1. Two pts received gemcitabine prior to FOLFIRINOX and 10 were treatment-naive. Two pts are still on therapy and 10 completed a median of 6 cycles (range 3-17) and were evaluable; 6 were felt to have converted to resectability by imaging and were taken for surgery. Four had R0 resections (40% of evaluable, 33% of all patients), 1 had R1 resection, and 1 had unresectable disease at laparotomy. To date, 2 pts have died and 10 remain alive with a Kaplan-Meier estimated median OS of 20.7 months (95% CI 18.8-22.6). All 4 pts with R0 resections are alive and disease- free. Grade 3/4 chemotherapy-related toxicities were neutropenia (17%), neutropenic fever (8%) and fatigue (17%). Common grade 1/2 toxicities were neutropenia (42%), anemia (92%), thrombocytopenia (50%), fatigue (92%), nausea (58%), diarrhea (42%) and neuropathy (33%). Two of the 6 surgical pts had significant postoperative complications - 1 with C. Difficile colitis, gastroparesis and a subhepatic collection and another with an infected pancreatic bed collection requiring percutaneous drainage 3 times. Conclusions: FOLFIRINOX is feasible as neoadjuvant therapy in patients with unresectable LAPC, with manageable toxicities. In this small series, the R0 resection rate was at least 33%. A prospective trial is warranted. No significant financial relationships to disclose.

Predictive Value of Symptoms for Early Detection of Ovarian Cancer

A recent consensus statement encouraged use of certain symptoms to diagnose ovarian cancer earlier. We assessed the sensitivity, specificity, and positive predictive value of a proposed symptom index and of symptoms included in the consensus recommendation. In-person interviews were conducted with 812 case patients, aged 35-74 years, who had epithelial ovarian cancer that was diagnosed from January 1, 2002, through December 31, 2005, and with 1313 population-based control subjects. The symptom index was considered positive when pelvic or abdominal pain or bloating or feeling full was reported at least daily for at least 1 week, with an onset of less than 12 months before diagnosis or a reference date (for control subjects). The consensus criteria were considered fulfilled when any symptom above or urinary urgency or frequency was reported for at least 1 month, with an onset of less than 12 months before diagnosis or a reference date. Positive predictive value was calculated by use of external estimates of cancer prevalence. Most case patients who had a positive index or met consensus criteria did so only within 5 months before diagnosis. Symptoms (except nausea) were somewhat less likely to have occurred among women diagnosed with early-stage than late-stage ovarian cancer. The estimated positive predictive value of the symptom index or symptoms meeting the consensus criteria was 0.6%-1.1% overall and less than 0.5% for early-stage disease. Use of symptoms to trigger medical evaluation for ovarian cancer is likely to result in diagnosis of the disease in only one of 100 women in the general population with such symptoms.

Patterns of cortical thinning in the language variants of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous neurodegenerative disorder. Two subtypes commonly present with a language disorder: semantic dementia (SemD) and progressive nonfluent aphasia (PNFA). Patients meeting consensus criteria for PNFA and SemD who had volumetric MRI of sufficient quality to allow cortical thickness analysis were recruited from a tertiary referral clinic: 44 (11 pathologically confirmed) patients with SemD and 32 (4 pathologically confirmed) patients with PNFA and 29 age-matched and gender-matched healthy controls were recruited. Cortical thickness analysis was performed using the Freesurfer software tools. Patients with SemD had significant cortical thinning in the left temporal lobe, particularly temporal pole, entorhinal cortex, and parahippocampal, fusiform, and inferior temporal gyri. A similar but less extensive pattern of loss was seen in the right temporal lobe and (with increasing severity) also in left orbitofrontal, inferior frontal, insular, and cingulate cortices. Patients with PNFA had involvement particularly of the left superior temporal lobe, inferior frontal lobe, and insula, and (with increasing severity) other areas in the left frontal, lateral temporal, and anterior parietal lobes. Similar patterns were seen in the pathologically confirmed cases. Patterns of cortical thinning differed between groups: SemD had significantly more cortical thinning in the temporal lobes bilaterally while PNFA had significantly more thinning in the frontal and parietal lobes. The language variants of frontotemporal lobar degeneration have distinctive and significantly different patterns of cortical thinning. Increasing disease severity is associated with spread of cortical thinning and the pattern of spread is consistent with progression of clinical deficits.

A Study of the Treatment of Rett Syndrome With Folate and Betaine

We tested the hypothesis that increasing methyl-group pools might promote transcriptional repression by other methyl-binding proteins or by mutant methyl-CpG-binding protein 2 with altered affinity, ameliorating the clinical features of Rett syndrome. A 12-month, double-blind, placebo-controlled folate-betaine trial enrolled 73 methylCpG-binding protein 2 mutation positive female participants meeting consensus criteria for Rett syndrome. Participants were randomized as young (< age 5 years) or old (>or= age 5 years). Structured clinical assessments occurred at baseline, 3, 6, and 12 months. Primary outcome measures included quantitative evaluation of breathing and hand movements during wakefulness, growth, anthropometry, motor/behavioral function, and qualitative evaluations from electroencephalograms and parent questionnaires. In all, 68 participants completed the study. Objective evidence of improvement was not found. Subjective improvement from parent questionnaires was noted for the <5 years group. This study should inform future treatment trials regarding balancing participants with specific mutations and comparable severity to minimize selection bias.