Citations

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on translational research on Barrett's esophagus that address evidence for genetic instability in esophageal cancer; the role of microsatellite instability; the use of histologic and serum Doublecortin‐like kinase 1 expression for progression of Barrett's esophagus to adenocarcinoma; the oxidative stress in Barrett's tumorigenesis; the genomic alterations in esophageal cancer; in vivo modeling in Barrett's esophagus; epigenetic and transcriptional regulation in Barrett's esophagus and esophageal adenocarcinoma; and normal and disordered regeneration in Barrett's esophagus.

PurposeAdvanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown.Patients and MethodsIn a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non–mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC).ResultsResponses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response.ConclusionAlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

Abstract Background: Breast and other solid tumors exhibit high and varying degrees of intra-tumor heterogeneity that make the management and treatment of these diseases rather difficult. In order to study clinically relevant tumor heterogeneity in detail we performed an in-depth analysis of the clonal architecture of primary chemoradiation-naive breast cancers and their lymph node metastases. We combined DNA content-based flow cytometry and ploidy analysis with high-definition array comparative genomic hybridization (aCGH) and next-generation sequencing technologies to interrogate the genomes and transcriptomes of multiple biopsies from the tumors and involved lymph nodes. Thus rather than inferring the presence of distinct tumor cell populations, our flow-sorting based approach of first identifying and defining the clonal populations and then interrogating their genomes provides a highly objective method of exploring the clinical significance of tumor heterogeneity in solid tumors. Material and methods: We used DAPI-based DNA content measurements and flow sorting to isolate nuclei from distinct clonal populations of diploid and aneuploid tumor cells in surgical tumor samples and distant lymph nodes from chemoradiation naive patients. In parallel, matching samples were processed for pathological, transcriptome, and IHC based assays. Each distinct sorted tumor cell population was then interrogated with aCGH and next generation sequencing. For each patient, the detailed profiles of ploidy, copy number aberrations and mutations were used to recreate and map the lineages present in the primary tumor and lymph. In one detailed case, we used 12 fresh frozen sections morphologically mapped from within a chemo-naïve primary invasive ductal carcinoma of histological grade 3 with lymph node involvement, 2-3 fresh frozen sections from 2 out of 5 lymph nodes with metastatic carcinoma, formalin-fixed paraffin-embedded (FFPE) tissue sections from 2 more of the involved lymph nodes and 5 morphologically mapped FFPE samples of normal tissue adjacent to the tumor. Results: We identified multiple coexisting aneuploid populations within biopsies from individual patients. Our clonal analysis determined the genomic aberrations arising in lineages that spread throughout the primary tumor and later bifurcated to distinct lymph nodes, revealing distinct therapeutic targets in the trunk and branches of the tumor. We identified driver events including high-level focal amplifications (e.g. SARC) and homozygous deletions (e.g. ROBO1 and ROBO2), that converge on distinct cellular signaling pathways. Conclusion: The approach highlighted here has broad implications in the study of tumor heterogeneity in breast and other solid tumors by providing a unique ultra-high resolution view of tumor heterogeneity that can advance more effective treatment and clinical management of patients with this disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD4-7.

This study examined the possibility that hearing-impaired listeners, in addition to displaying poorer-than-normal recognition of speech presented in background noise, require a larger signal-to-noise ratio for the detection of the speech sounds. Psychometric functions for the detection and recognition of stop consonants were obtained from both normal-hearing and hearing-impaired listeners. Expressing the speech levels in terms of their short-term spectra, the detection of consonants for both subject groups occurred at the same signal-to-noise ratio. In contrast, the hearing-impaired listeners displayed poorer recognition performance than the normal-hearing listeners. These results imply that the higher signal-to-noise ratios required for a given level of recognition by some subjects with hearing loss are not due in part to a deficit in detection of the signals in the masking noise, but rather are due exclusively to a deficit in recognition.

Introduction BO is the strongest precursor of oesophageal adenocarcinoma. Participation patterns and effectiveness of BO community screening using unsedated transnasal endoscopy (uTNE) is unknown. Feasibility of mobile van screening closer to home is also unknown. We aimed to assess the effectiveness of this technique compared to sedated endoscopy (SE). Methods A population cohort ≥50 years of age, with no history of endoscopic evaluation, was identified from a group of subjects who previously completed a validated symptom questionnaire. Patients were randomised (stratified by age, sex and reflux symptoms) and invited to undergo either uTNE in a mobile research van (muTNE), uTNE in outpatient endoscopy suite (huTNE) or SE. uTNE was performed using a portable oesophagoscope with a disposable sheath. Procedure performance characteristics and validated tolerability scales (0 = none and 10 = severe) were recorded. Results 459 subjects were contacted and 209 (46%) agreed to undergo study procedures (muTNE n = 76, huTNE n = 72, SE n = 61). Baseline characteristics were comparable among the three groups. Participation rates were numerically higher in the unsedated arms (muTNE 47.5%, huTNE 45.7%) than in the SE arm (40.7%) (p = 0.27). Patients with acid reflux symptoms ≥1/week were more likely to participate (odds ratio 2.94, 95% confidence interval 1.47, 5.88). Complete evaluation of the oesophagus was comparable using muTNE (99%), huTNE (96%) and SE (100%) techniques. Successful biopsy acquisition was lower in the muTNE (79%) and huTNE (83%) groups compared to SE (100%) (p = 0.001). Mean duration (minutes) of examination was shorter in the SE arm (4.7) than in muTNE (8.0) and huTNE (8.5) groups (p < 0.001). However, recovery time was much longer for SE (67.3) compared to muTNE (15.5) and huTNE (18.5) techniques (p < 0.001). While overall tolerability for SE was better than muTNE and huTNE (mean score 0.4 vs. 1.9 and 2.2 respectively, p < 0.001), the majority of patients who underwent muTNE and huTNE were willing to undergo the same procedure again in future (79% and 83%, respectively). No serious adverse events were reported. 16 subjects (7.6%) were diagnosed with BO. Conclusion In this first large randomised trial evaluating novel approaches for community screening for BO, unsedated mobile van and clinic screening with TNE was feasible and effective. The patients’ visit was significantly shorter with adequate tolerability, acceptability and safety profiles. Mobile and outpatient techniques may provide a cost-effective alternative to SE for BO screening. Disclosure of Interest S. Sami: None Declared, K. Dunagan: None Declared, M. Johnson: None Declared, C. Schlek: None Declared, A. Zinsmeister: None Declared, L. M. Wong Kee Song: None Declared, K. Wang: None Declared, D. Katzka: None Declared, K. Ragunath Grant/research support from: Olympus (keymed, UK) and Intromed Ltd. (Seoul, South Korea), P. Iyer: None Declared.

Abstract Islet allografts are subject to rapid rejection through host cellular immune responses involving mononuclear cell recruitment and tissue injury. Interruption of leukocyte recruitment through chemokine receptor targeting is of therapeutic benefit in various experimental models, but little is known about the contribution of chemokine pathways to islet allograft rejection. We found that murine islets produce monocyte chemoattractant protein-1 (MCP-1; CCL2) in vitro and that islet allograft rejection was associated with intragraft expression of MCP-1 and its receptor, CCR2. We therefore investigated whether MCP-1 and CCR2 are required for the rejection of fully MHC-disparate islet allografts. Wild-type mice treated with blocking anti-MCP-1 mAb plus a brief, subtherapeutic course of rapamycin had long-term islet allograft survival, in contrast to the effect of treatment with either mAb or rapamycin alone. CCR2−/− mice treated with rapamycin also maintained islet allografts long-term. Both MCP/CCR2- and rapamycin-sensitive signals were required for maximal proliferation of alloreactive T cells, suggesting that MCP-1/CCR2 induce rejection by promoting alloreactive T cell clonal expansion and homing and migration. Prolonged islet allograft survival achieved by blockade of the MCP-1/CCR2 pathway plus rapamycin therapy was accompanied by a mononuclear cell infiltrate expressing the inhibitory receptor, programmed death-1 (PD-1), and its ligand (PD-L1, B7-H1), and prolongation of islet allograft survival was abrogated by anti-PD-L1 mAb therapy. These data show that the blockade of MCP-1 binding to CCR2 in conjunction with subtherapeutic immunosuppression can have profound effects on islet allograft survival and implicate the expression of the PD-1/PD-L1 pathway in the regulation of physiologic responses in vivo.

Stroke remains an exceedingly incident and prevalent public health burden across the globe, with an estimated 16 million new strokes per annum and prevalence over 60 million, and extracranial internal carotid artery atherosclerotic disease is an important risk factor for stroke. Randomized trials of surgical treatment were conducted (North American Symptomatic Carotid Endarterectomy Trial, European Carotid Surgery Trial) and demonstrated efficacy of carotid endarterectomy for secondary prevention of stroke in patients with cerebrovascular events (e.g. ipsilateral stroke, transient ischemic attack, and/or amaurosis fugax) attributable to a diseased artery with 50–99% stenosis. Therapeutic clarity, however, proved elusive with asymptomatic carotid artery disease. Asymptomatic Carotid Atherosclerosis Study (ACAS), Asymptomatic Carotid Surgery Trial, and Veterans Affairs Cooperative Study (VACS) suggested only modest benefit from surgical intervention for primary stroke prevention and the best medical therapy at the time of these trials is not comparable to modern medical therapy. ACT-1, Asymptomatic Carotid Surgery Trial-2, Stent-Protected Angioplasty in asymptomatic Carotid artery stenosis versus Endarterectomy Trial-2, European Carotid Surgery Trial-2, Carotid Revascularization Endarterectomy Versus Stenting Trial-2 are trials that are recent, ongoing, or in development that include diverse populations across Europe and North America, complementary trial designs, and a collaborative spirit that should provide clinicians with evidence that informs best clinical practice for asymptomatic carotid artery disease.