Citations

463 Background: The genomic assessment of cancer has been revolutionized by next-generation sequencing and is increasingly being applied in the clinic to guide therapeutic decision-making. Time to reporting of results, specimen quantity, and analyte quality have constrained initial clinical applications to gene panels and whole exome based strategies. Methods: Patients underwent surgical resection, excisional or core biopsies, or bone marrow biopsy. Samples were analyzed by whole genome or exome sequencing and RNA sequencing, bioinformatics analysis, and therapeutic target prioritization by a multi-disciplinary Clinical Genomics Board. All prioritized targets were CLIA validated using Sanger sequencing, RT-qPCR, FISH, or IHC as appropriate. Treatment was delivered using off-label FDA approved drugs, clinical trials, or single patient INDs. Results: We have enrolled 40 patients with advanced, treatment-refractory cancers of whom sequencing data is available on 33. The initial 6 patients were evaluated in a non-CLIA pilot phase and 27 in the CLIA enabled phase. Upon availability of the initial report, identified targets of putative therapeutic relevance were then prioritized by the CGB in 22/27 patients (81%) for subsequent CLIA validation. Eleven patients have been treated with genomically selected therapy with partial response in 3/10 assessed patients. A testicular cancer patient had aberrations in two testes specific genes, a copy number gain in TSSK6 and a novel gene fusion between thyroid hormone receptor associated protein 3 (THRAP3) and Tektin 2 (TEKT2). Additionally, a case of papillary renal cell carcinoma had an amplification of YAP1 and a previously unreported P287T mutation in CCND1, suggesting potential benefit with a CDK4/6 inhibitor. Treatment is ongoing and results will be reported. Conclusions: Integrated whole genome analysis in a CLIA setting is feasible. Integration of SNV, copy number and transcriptional data may allow for selection of putative driver genes to enhance targeted therapy decisions. Barriers for future broader implementation include the need for reduced time from biopsy to report and availability of therapies.

11 Background: Acid-suppressive medications, particularly proton pump inhibitors (PPI), may modify risk of esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus (BE). We performed a systematic review and meta-analysis of studies evaluating the association between PPIs and histamine receptor antagonists (H2RA) and risk of EAC or high-grade dysplasia (BE-HGD) in patients with BE. Methods: Through a systematic search up to June 2013, we identified 7 observational studies (5 cohort studies and 2 case-control studies; 2,813 patients with BE, 317 cases of EAC and/or BE-HGD, 84.4% PPI users) reporting the association between PPIs or H2RA and EAC in patients with BE. Summary odds ratio (OR) with 95% confidence intervals (CI) was estimated using random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, PPI use was associated with 71% reduction in EAC risk in patients with BE (adjusted OR, 0.29; 95% CI, 0.12-0.71). There was a trend toward a dose-response relationship with PPI use for >2 years protective against EAC [3 studies; PPI use >2 years vs. <2 years (as compared to no use): OR, 0.45 (0.19-1.06) vs. 1.09 (0.47-2.56)]. Considerable heterogeneity was observed in the overall analysis (I2=81%). On restricting analysis to 5 cohort studies, use of PPIs was consistently associated with a lower risk of EAC and/or BE-HGD (adjusted OR, 0.33; 95% CI, 0.19-0.58; I2=9%). H2RA use was not associated with decreased risk of EAC in patients with BE based on 2 studies (adjusted OR, 1.15; 95% CI, 0.77-1.72). Using a 67% summary risk reduction (derived from cohort studies) of EAC and/or BE-HGD with PPI use in patients with BE, and observed cumulative incidence rates of EAC and/or BE-HGD in patients with BE overall as 10.2 per 1,000 patient years, we estimate the number needed to treat with PPIs to prevent 1 case of EAC or BE-HGD in BE patients at 147. Conclusions: Based on meta-analysis of observational studies, the use of PPI, but not H2RA appears to be associated with a decreased risk of EAC and/or BE-HGD in patients with BE. PPI use should be considered in BE, and chemopreventive trials of PPIs in patients with BE are warranted.

20 Background: Esophageal adenocarcinoma (EAC) incidence is rising and prognosis is uniformly poor, even with early stage disease. Barrett esophagus (BE) serves as a premalignant marker for EAC, with an estimated progression of 0.5% per year. Low-grade (LGD) and high-grade dysplasia (HGD) confer a higher risk of progression, providing an opportunity for intervention and surveillance. Aims: To evaluate a large cohort of patients undergoing endoscopic evaluation of BE and thereby better understand the natural history of BE and dysplasia. Methods: A retrospective review of endoscopic databases was conducted for all patients with the diagnosis of BE undergoing upper endoscopy at a tertiary academic medical center from 1991-2010. All endoscopy and accompanying pathology reports were reviewed. Only those patients with 2 biopsies documenting specialized intestinal metaplasia were analyzed. Results: 848 patients underwent upper endoscopy for evaluation of BE. Of these, 674 patients met inclusion criteria, at a mean follow up of 66.6 months. Table 1 depicts the distribution of patients according to their histology at presentation. 22 (3.2%) patients presented with established EAC, while EAC developed in 51 (7.6%). Of patients with HGD, LGD, or no dysplasia (ND) at presentation, EAC ultimately developed in 30.6%, 6.6%, and 2.7%, respectively. EAC developed in 4 patients despite RFA treatment for ND (2) or LGD (2). HGD developed in 6 such patients after treatment for ND (3) and LGD (3). Only 1 patient in each RFA-treated cohort required esophagectomy, while the others cleared dysplasia or EAC with continuous treatment. Conclusions: In this large cohort of patients with Barrett’s esophagus, higher grade of dysplasia at first endoscopy was associated with development of EAC. Continuous surveillance during and after endoscopic treatment is necessary and often results in clearance of dysplasia and EAC. [Table: see text]

248 Background: Improved understanding of TME in CCA may allow for development of novel therapeutics targeting stromal components. Hyaluronic acid (HA) is a polysaccharide that has been found in the TME of a number of solid tumors characterized by desmoplastic stroma, such as pancreatic cancer. Elevated HA levels were prognostic in these malignancies. HA prevalence and association with clinic-pathological features in CCA is unknown. Methods: A retrospective study was conducted using clinically annotated formalin-fixed paraffin embedded tissue from resected intrahepatic CCA samples. Specimens were analyzed for HA, scored using a positive pixel count algorithm (Aperio Imagescope) and positivity was calculated as % of total pixel count. Clinical variables were examined by chi-square or ANOVA F-test. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier method and compared via log-rank test. Multivariate analysis was conducted using Cox proportional hazards regression models. Results: 142 patient samples were stained for HA. HA was identified in all samples (100%), with a range of HA positivity of 32.8 – 91.8%. Median HA value was 67.1% and 95% of patients had HA positivity ≥ 45%. Factors associated with higher than median HA ( > 67%) included perineural invasion (PNI) (40% vs. 21%, p = 0.011), necrosis (67% vs. 41%, p = 0.003), lymph node positivity (32% vs. 14%, p = 0.027), and small tumor size ( < 6.8 cm vs. > 8.4cm, p = 0.014). Stratification of HA staining by median positivity value was not an independent predictor of survival based on multivariate analysis. OS for patients with HA > 67% was 40.1 months (mo) vs 48.5 mo with HA ≤ 67%, p = 0.537. PFS for patients with HA > 67% was 14.4 mo vs. 25.7 mo with HA ≤ 67%, p = 0.177. Conclusions: Prevalence of HA staining in resected CCA is higher than seen in many solid tumors and is ubiquitous in our study. Absence of statistically significant association with OS and PFS might be attributable to ubiquitous prevalence, narrow signal range, and association with known negative prognostic factors. Further pre-clinical and clinical evaluation would be warranted.

9 Background: We examined patient-reported fatigue scores and overall survival (OS) in patients with esophageal cancer (EC) enrolled in the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry (EABE). Methods: 1,481 patients enrolled in the EABE between September 2001 and January 2009 returned a baseline quality of life questionnaire including a Linear Analog Self Assessment (LASA) fatigue score which was scored on a 0-10 scale, with 0 as the most extreme fatigue. Patients were categorized as having clinically deficient fatigue (DF) if they reported a score of ≤ 5 and clinically non-deficient fatigue (nDF) if they reported a score of > 5. Kaplan-Meier methodology and Cox models explored OS in relation to fatigue scores in patients with EC. Results: A total of 667 patients with EC were included in the EABE, of which 659 returned a registry questionnaire with a valid LASA fatigue score recorded. Median age at the time of registry entry was 65 years (range 23-92). A total of 392 (59%) and 267 patients (41%) reported DF and nDF, respectively. On univariate analysis, patients with nDF had improved 5-year survival compared to patients with DF. In patients having esophagectomy prior to LASA, those reporting nDF had improved survival compared to patients with DF. Similarly, in patients having no esophagectomy prior to LASA, those with nDF had improved survival compared to those with DF. Among the 368 patients with locally advanced EC (LAEC), those reporting nDF had improved 5-year overall survival compared to patients with DF (28% vs 17%, HR = 0.67, p = 0.003). This remained significant on multivariate analysis (HR = 0.71, p = 0.015). Conclusions: Patient-reported fatigue is associated with overall survival in patients with LAEC. As a result, fatigue scores should be considered as a stratification factor in future clinical trial design. [Table: see text] No significant financial relationships to disclose.

Extracranial internal carotid artery atherosclerotic occlusive disease is a common ischemic stroke mechanism. Vascular risk factor control remains the cornerstone of stroke prevention in patients with both asymptomatic and symptomatic carotid occlusive diseases. Intensive medical therapy refers to the contemporary approach of antiplatelet therapy, blood pressure control, low-density lipoprotein reduction, and lifestyle modification to reduce stroke risk. Carotid revascularization with endarterectomy or angioplasty and stenting are established treatments for patients with symptomatic carotid stenosis ≥70%. Previously accepted ischemic stroke preventative strategies, such as carotid revascularization for asymptomatic carotid stenosis, require reassessment given advances in both medical therapy and surgical techniques. The purpose of this review is to describe contemporary approaches to the management of extracranial carotid atherosclerotic occlusive disease and the basis of these recommendations. Results from recently published clinical trials will be highlighted in addition to updated information from clinical trials addressing knowledge gaps in prevention of stroke caused by extracranial disease.

AbstractCytogenetics can inform risk stratification in pediatric acute myeloid leukemia (AML). We describe the first case of a newborn with leukemia cutis found to have AML harboring a cryptic insertional t(8;16)(p11.2;p13.3) with associated KAT6A/CREBBP fusion identified exclusively by fluorescence in situ hybridization (FISH). Expectant management resulted in spontaneous leukemia resolution. The identification of t(8;16)(p11.2;p13.3) may serve as a biomarker for spontaneous remission in congenital AML. FISH for this translocation is warranted in congenital AML with a normal karyotype, and patients with KAT6A/CREBBP fusion should be conservatively managed. While 50% of spontaneously remitting congenital AML with t(8;16)(p11.2;p13.3) may recur, high salvage rates are attained with standard therapy.

SummaryBackgroundThe proportion of oesophageal adenocarcinoma that is detected concurrently with initial Barrett's oesophagus diagnosis is not well studied.AimTo compare the proportion of prevalent adenocarcinoma vs. incident adenocarcinoma found during surveillance of Barrett's.MethodsWe performed a systematic search of MEDLINE, EMBASE and Web of Science (from their inception to 31 May 2015) for cohort studies in adults with Barrett's (nondysplastic Barrett's ± Barrett's with low‐grade dysplasia) with minimum average follow‐up of 3 years, and providing numbers of prevalent adenocarcinoma detected (concurrently with Barrett's diagnosis and up to 1 year afterwards) vs. incident adenocarcinoma detected (greater than 1 year after Barrett's diagnosis). Pooled weighted proportions of prevalent and incident adenocarcinoma were calculated, using a random effects model.ResultsOn meta‐analysis of 13 studies reporting on 603 adenocarcinomas in 9657 Barrett's patients, 85.1% of adenocarcinomas were classified as prevalent [95% confidence interval (CI), 78.1–90.2%) and 14.9% as incident (95% CI, 9.8–21.9%), with substantial heterogeneity (I2 = 66%). Among nine studies reporting on 787 high‐grade dysplasia and oesophageal adenocarcinomas in 8098 Barrett's patients, the proportion of prevalent high‐grade dysplasia‐oesophageal adenocarcinoma was similar at 80.5% (95% CI, 68.1–88.8%, I2 = 87%). These results remained stable across multiple subgroup analyses including study quality, setting, duration of follow‐up and presence of baseline dysplasia.ConclusionsIn our meta‐analysis, four of five patients diagnosed with adenocarcinoma or high‐grade dysplasia at index endoscopy or within 1 year of Barrett's follow‐up were considered to be prevalent cases. Continued efforts are needed to identify patients with Barrett's before the development of adenocarcinoma.

Objective Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. Design We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. Results We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10−5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. Conclusions This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.