Citations

Abstract Purpose: Esophageal adenocarcinoma is a highly aggressive malignancy that frequently develops from Barrett's esophagus, a premalignant pathologic change occurring in the lower end of the esophagus. Identifying Barrett's esophagus patients at high risk of malignant transformation is essential to the prevention of esophageal adenocarcinoma. Although microRNA (miRNA) expression signatures have been associated with the etiology and prognosis of several types of cancers, their roles in the development of esophageal adenocarcinoma have not been extensively evaluated. Experimental Design: In this study, we analyzed the expression patterns of 470 human miRNAs using Agilent miRNA microarray in 32 disease/normal-paired tissues from 16 patients diagnosed with Barrett's esophagus of either low- or high-grade dysplasia, or esophageal adenocarcinoma. Results: Using unsupervised hierarchical clustering and class comparison analyses, we found that miRNA expression profiles in tissues of Barrett's esophagus with high-grade dysplasia were significantly different from their corresponding normal tissues. Similar findings were observed for esophageal adenocarcinoma, but not for Barrett's esophagus with low-grade dysplasia. The expression patterns of selected miRNAs were further validated using quantitative reverse transcription real-time PCR in an independent set of 75 pairs of disease/normal tissues. Finally, we identified several miRNAs that were involved in the progressions from low grade-dysplasia Barrett's esophagus to esophageal adenocarcinoma. Conclusions: We showed that miRNAs were involved in the development and progression of esophageal adenocarcinoma. The identified significant miRNAs that may become potential targets for early detection, chemoprevention, and treatment of esophageal cancer. (Clin Cancer Res 2009;15(18):5744–52)

Background and Purpose— Predictive models of outcome after ischemic stroke have incorporated acute diffusion-weighted MRI (DWI) information with mixed results. We hypothesized that serial measurements of DWI infarct volume would be predictive of functional outcome after ischemic stroke. Methods— The prospective Acute Stroke Accurate Prediction (ASAP) Study included a prespecified serial imaging subgroup who underwent DWI studies at baseline (<24 hours after symptom onset) and Day 5 (±2 days). DWI infarct volumes were calculated using the Analyze software (Rochester, Minn). Clinical outcomes were assessed at 3 months. Univariate and multivariable regression analysis was performed to assess the relationship between change in DWI lesion volume and excellent neurological outcome (modified Rankin Scale 0, 1, and Barthel Index ≥95). Results— In total, 169 cases from the ASAP study had serial DWI scans with a measurable lesion at baseline, follow-up, or both. The median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 3 to 13). For each 10 cm 3 of growth in DWI infarct volume, the OR for achieving an excellent outcome by modified Rankin Scale was 0.52 (95% CI, 0.38 to 0.71) and for the Barthel Index was 0.64 (95% CI, 0.51 to 0.79). Adjusting for clinically important covariates, the OR for an excellent modified Rankin Scale outcome was 0.57 (95% CI, 0.37 to 0.88) and excellent Barthel Index outcome was 0.75 (95% CI, 0.56 to 1.01). Conclusions— Based on these data, the likelihood of achieving an excellent neurological outcome diminishes substantially with growth in DWI infarct volume in the first 5 days after ischemic stroke of mild to moderate severity.

Abstract Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P &lt; 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P &lt; 0.001, &lt;0.001, and &lt;0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Δ-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. A methylation biomarker–based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia. [Cancer Res 2009;69(10):4112–5]

Abstract Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138+ MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P < .01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-κB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.

Abstract Waldenström's macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM paraprotein production. Cytogenetic analyses were historically limited by difficulty in obtaining tumor metaphases, and the genetic basis of the disease remains poorly defined. Here, we performed a comprehensive analysis in 42 WM patients by using a high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of cases have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%), and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in tumor necrosis factor (TNF) receptor–associated factor 3 and TNFα-induced protein 3, two negative regulators of the nuclear factor-κB (NF-κB) signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-κB target genes. Mutational activation of the NF-κB pathway, which is normally activated by ligand receptor interactions within the BM microenvironment, highlights its biological importance, and suggests a therapeutic role for inhibitors of NF-κB pathway activation in the treatment of WM. [Cancer Res 2009;69(8):3579–88]

Abstract Purpose: Photodynamic therapy (PDT) is used to treat Barrett's esophagus with high-grade dysplasia and mucosal carcinoma. Outcomes are variable with some patients having persistent disease, whereas others develop strictures. The aims of this study were (a) to compare porfimer sodium tissue uptake, light dose, and esophageal thickness with clinical outcomes and (b) to determine the selectivity of porfimer sodium uptake in diseased and normal epithelium. Experimental Design: Forty-eight hours after porfimer sodium infusion, patients underwent mucosal biopsy for quantification of the porfimer sodium. Laser light was delivered at 48 hours and again 24 or 48 hours later. Porfimer sodium was extracted from the biopsy samples and quantified using fluorescence spectroscopy. The enhanced photodynamic dose was determined as [porfimer sodium content * light dose/esophageal thickness]. PDT efficacy was determined 6 to 8 weeks later based on persistence or complete ablation of dysplasia or carcinoma. Results: Mean porfimer sodium content of 6.2 mg/kg (range, 2.6-11.2 mg/kg) and mean total light dose of 278 J/cm (range, 225-360 J/cm) resulted in a complete treatment. Mean porfimer sodium tissue content of 3.9 mg/kg (range, 2.1-8.1 mg/kg) and mean total light dose of 268 J/cm (range, 250-350 J/cm) resulted in an incomplete treatment. The total esophageal thickness (range, 1.7-6.0 mm) and enhanced photodynamic dose were correlated with treatment outcome. Conclusions: Esophageal thickness is the strongest predictor of treatment outcome. The porfimer sodium content of Barrett's and normal tissue is not significantly different. “Photodynamic dose” for esophageal PDT should incorporate the esophageal thickness.

Background and Purpose— A simple, easily measured surrogate outcome measure for use in early treatment trials for acute ischemic stroke therapies would be highly valued. We hypothesized that day-5 NIH stroke scale score (NIHSS) and day-5 diffusion weighted imaging (DWI) volume would predict clinical outcome better than either alone and could be considered as a possible surrogate outcome in early phase acute stroke trials. Methods— The prospective Acute Stroke Accurate Prediction (ASAP) trial included a prespecified subgroup evaluated for early outcome. Logistic regression analysis was used to assess the prediction of modified Rankin (mRankin) of 0 or 1. Results— A total of 204 subjects completed the substudy, and 116 (57%) had excellent outcome at 3 months. The area under the ROC curve (AUC) for day-5 NIHSS predicting 3-month excellent outcome was 0.84; for DWI volume predicting outcome was 0.76, and for the multivariable model combining both was 0.84. Conclusions— The results of the early outcome substudy of the ASAP trial suggest that early stroke severity and infarct volume measures are predictive of 3-month excellent outcome. In our data set the DWI volume does not add clinically relevant information in predicting 3-month outcome. Validation of these results is required.

AbstractDo some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]–matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P < .001) and relapse (RR, 1.50; P < .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P < .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

Abstract Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid–induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving IκB kinases β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKKβ inhibitor Bay 11-7082 suppressed bile acid–induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKKβ (pIKKβ) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKKβ expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKKβ signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus–associated EAC. [Cancer Res 2008;68(8):2632–40]

Coronary artery disease (CAD) accounts for a large fraction of the morbidity, mortality, and cost of diabetes. Recognizing this, nearly 10 years ago the American Diabetes Association published a consensus recommendation that clinicians consider a risk factor–guided screening approach to early diagnosis of CAD in both symptomatic and asymptomatic patients. Subsequent clinical trial results have not supported those recommendations. Since the prior consensus statement, newer imaging methods, such as coronary artery calcium scoring and noninvasive angiography with computed tomography (CT) techniques, have come into use. These technologies, which allow quantitation of atherosclerotic burden and can predict risk of cardiac events, might provide an approach to more widespread coronary atherosclerosis screening. However, over this same time interval, there has been recognition of diabetes as a cardiovascular disease (CVD) equivalent, clear demonstration that medical interventions should provide primary and secondary CVD risk reduction in diabetic populations, and suggestive evidence that percutaneous coronary revascularization may not provide additive survival benefit to intensive medical management in patients with stable CAD. This additional evidence raises the question of whether documenting asymptomatic atherosclerosis or ischemia in people with diabetes is warranted. More data addressing this issue will be forthcoming from the BARI 2-D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. Until then, for patients with type 2 diabetes who are asymptomatic for CAD, we recommend that testing for atherosclerosis or ischemia, perhaps with cardiac CT as the initial test, be reserved for those in whom medical treatment goals cannot be met and for selected individuals in whom there is strong clinical suspicion of very-high-risk CAD. Better approaches to identify such individuals based on readily obtained clinical variables are sorely needed.