Biomedical subjects

Bruce D Greenwald

Publications and source records attributed to Bruce D Greenwald.

10 recordsLinked to original sources

PubMed2006

Reprimo methylation is a potential biomarker of Barrett's-Associated esophageal neoplastic progression.

PURPOSE: Reprimo, a candidate tumor-suppressor gene, regulates p53-mediated cell cycle arrest at G2 phase, and tumor-suppressor gene methylation is involved in the pathogenesis and progression of esophageal cancer. Our aim was to determine whether and at what phase of neoplastic progression Reprimo methylation occurs in Barrett's adenocarcinogenesis, as well as its columnar or squamous cell-type specificity. We also sought to determine whether Reprimo expression could be restored in vitro by the demethylating agent 5-aza-deoxycytidine (5AzaC). EXPERIMENTAL DESIGN: Quantitative methylation-specific PCR for Reprimo was done using an ABI7700 (Taqman) apparatus on 175 endoscopic biopsy specimens. In addition, reverse transcription-PCR and quantitative methylation-specific PCR were done on esophageal carcinoma cells before and after treatment with 5AzaC. RESULTS: In Barrett's esophagus (BE; P=0.001), high-grade dysplasia (HGD; P=0.001), and esophageal adenocarcinoma (EAC; P=0.00003), the level and frequency of Reprimo methylation were significantly higher than in normal esophagus (NE). There was no statistically significant difference between BE and EAC, HGD and EAC, or NE and esophageal squamous cell carcinoma (ESCC). Reprimo methylation occurred in 0 of 19 NE samples, 6 (13%) of 45 ESCC, 9 (36%) of 25 BE, 7 (64%) of 11 HGD, and 47 (63%) of 75 EAC. Analysis of Reprimo methylation in EAC versus NE revealed an area under the receiver-operator characteristic curve of 0.812 (P<0.00001; 95% confidence interval, 0.73-0.90). In vitro 5AzaC treatment of OE33 EAC cells reduced Reprimo methylation and increased Reprimo expression. CONCLUSIONS: Reprimo methylation occurs significantly more frequently in BE, HGD, and EAC than in NE or ESCC, suggesting that this epigenetic alteration is a specialized columnar, cell-specific early event with potential as a biomarker for the early detection of esophageal neoplasia.

Adenocarcinoma↗

PubMed2006

Promoter methylation and response to chemotherapy and radiation in esophageal cancer.

BACKGROUND & AIMS: Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to find methylation markers that could be used to predict response to chemoradiation. METHODS: Tumor specimens were obtained before treatment from 35 patients enrolled in a uniform chemoradiation treatment protocol. Methylation-specific quantitative polymerase chain reaction was performed on all samples. Pathology reports from esophagectomy specimens were used to define response to treatment. RESULTS: Thirteen (37%) of 35 patients were responders, and 22 (63%) of 35 patients were nonresponders. The number of methylated genes per patient was significantly lower in responders than in nonresponders (1.4 vs 2.4 genes per patient; Student t test, P = .026). The combined mean level of promoter methylation of p16, Reprimo, p57, p73, RUNX-3, CHFR, MGMT, TIMP-3, and HPP1 was also lower in responders than in nonresponders (Student t test, P = .003; Mann-Whitney test, P = .001). The frequency (15% of responders vs 64% of nonresponders; Fisher exact test, P = .01) and level (0.078 in responders vs 0.313 in nonresponders; Mann-Whitney test, P = .037) of Reprimo methylation was significantly lower in responders than in nonresponders. CONCLUSIONS: Reprimo methylation occurred at significantly lower levels and less frequently in chemoradioresponsive than in nonresponsive esophageal cancer patients, suggesting potential clinical application of this single-gene biomarker in defining prognosis and management. In addition, increased methylation of a 9-gene panel correlated significantly with poor responsiveness to chemoradiation.

Adenocarcinoma↗

PubMed2006

Quality assessment of colonoscopic cecal intubation: an analysis of 6 years of continuous practice at a university hospital.

BACKGROUND: Despite increased emphasis on endoscopic performance indicators, e.g., cecal intubation rates, limited data from actual clinical practice have been published. OBJECTIVES: Retrospective database review to determine the rate and documentation of cecal intubation during colonoscopy at the University of Maryland Medical Center. METHODS: We reviewed 5,477 consecutive colonoscopies performed by 10 faculty gastroenterologists at a University hospital over a 6-yr period (March 1, 1999 to February 28, 2005). Unadjusted cecal intubation rates were analyzed as were rates that were adjusted based on the U.S. Multi-Society Task Force on Colorectal Cancer recommendations. We analyzed trends in overall and individual cecal intubation rates, circumstances that impact these rates, and the quality of documentation of cecal intubation. RESULTS: The overall adjusted cecal intubation rate for the entire 6 yr was 90.3%, and increased over the study period with the highest adjusted rate (93.7%) in the most recent year studied. There was no correlation between cecal intubation rate and patient age, gastroenterology fellow involvement, or endoscopist experience and number of procedures/year. In contrast, colon cancer screening, male gender, outpatient colonoscopy, and adequate bowel preparation predicted a higher cecal intubation rate. Written and photographic documentation of cecal intubation improved significantly after 2002. CONCLUSIONS: Our analysis revealed cecal intubation and documentation rates that meet current guidelines, and identified factors that may cause substantial variance in these rates depending on the nature of the practice. The present analysis confirms that computerized databases can be used to assess individual and group cecal intubation and documentation rates on an annual basis, and to make these data available to the public.

Aged↗

PubMed2005

Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk.

Patients with Barrett's esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EAC). Clinical neoplastic progression risk factors, such as age and the length of the esophageal BE segment, have been identified. However, improved molecular biomarkers predicting increased progression risk are needed for improved risk assessment and stratification. Using real-time quantitative methylation-specific PCR, we screened 10 genes (HPP1, RUNX3, RIZ1, CRBP1, 3-OST-2, APC, TIMP3, p16, MGMT, p14) for promoter hypermethylation in 77 EAC, 93 BE, and 64 normal esophagus (NE) specimens. A subset of genes manifesting significant differences in methylation frequencies between BE and EAC was then analysed in 20 dysplastic specimens. All 10 genes except p14 were frequently methylated in EACs, with RUNX3, HPP1, CRBP1, RIZ1, and OST-2 representing novel methylation targets in EAC and/or BE. p16, RUNX3, and HPP1 displayed increasing methylation frequencies in BE vs EAC. Furthermore, these increases in methylation occurred early, at the interface between BE and low-grade dysplasia (LGD). To demonstrate the silencing effect of hypermethylation, we selected the EAC cells BIC1, in which the HPP1 promoter is natively methylated, and subjected them to 5-aza-2'-deoxycytidine (Aza-C) treatment. Real-time RT-PCR indicated increased HPP1 mRNA levels after 3 days of Aza-C treatment, as well as decreased levels of methylated HPP1 DNA. Hypermethylation of a subset of six genes (APC, TIMP3, CRBP1, p16, RUNX3, and HPP1) was then tested in a retrospective longitudinal study of 99 BE and nine LGD specimens obtained from 53 BE patients undergoing surveillance endoscopy. Only high-grade dysplasia (HGD) or EAC were defined as progression end points. Two patient groups were compared: eight progressors (P) and 45 nonprogressors (NP), using Cox proportional hazards models to determine the relative progression risks of age, BE segment length, and methylation events. Multivariate analyses revealed that only hypermethylation of p16 (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.33-2.20), RUNX3 (OR 1.80, 95% CI 1.08-2.81), and HPP1 (OR 1.77, 95% CI 1.06-2.81) were independently associated with an increased risk of progression, whereas age, BE segment length, and hypermethylation of TIMP3, APC, or CRBP1 were not independent risk factors. In combined analyses, risk was detectable up to, but not earlier than, 2 years preceding neoplastic progression. Hypermethylation of p16, RUNX3, and HPP1 in BE or LGD may represent independent risk factors for the progression of BE to HGD or EAC. These findings have implications regarding risk stratification, early EAC detection, and the appropriate endoscopic surveillance interval for patients with BE.

Adenocarcinoma↗

PubMed2005

The utility of EUS-guided FNA in the diagnosis of metastatic breast cancer to the esophagus and the mediastinum.

BACKGROUND: Breast cancer can metastasize to the esophagus and the mediastinum. EUS-guided FNA (EUS-FNA) is being used increasingly as a less invasive alternative to mediastinoscopy for procuring a tissue diagnosis of mediastinal disease and may be useful for the diagnosis of breast cancer metastatic to the esophagus and the mediastinum. METHODS: Twelve women (age range 54-82 years) with a history of breast cancer presented with dysphagia or other symptoms between 1 and 15 years after initial diagnosis and treatment. CT and endoscopy with biopsies suggested a mediastinal mass or lymphadenopathy with extrinsic esophageal compression but failed to provide a tissue diagnosis. EUS-FNA was performed for diagnosis. RESULTS: Cytologic evaluation of specimens obtained by EUS-FNA confirmed breast cancer metastases in 11 of 12 patients (91%). Recurrent disease was found in intramural masses and periesophageal lymph nodes. No complication resulted from any EUS-FNA procedure. CONCLUSIONS: EUS-FNA is safe and effective for the diagnosis of breast cancer metastases to the esophagus and the mediastinum. EUS-FNA may be useful as a first-line method of evaluation when breast cancer metastasis to the esophagus and the mediastinum is suspected.

Aged↗

PubMed2003

An LOH and mutational investigation of the ST7 gene locus in human esophageal carcinoma.

Frequent loss of heterozygosity (LOH) on human chromosome 7q31 has been reported in numerous malignancies. Suppressor of tumorigenicity 7 (ST7) has been identified as a candidate tumor suppressor gene in this region. To identify whether 7q31 and genetic alterations of ST7 were involved in human esophageal carcinogenesis, we performed LOH mapping of a 5.4 cM region at 7q31-q35 in 43 primary esophageal carcinomas, as well as mutational analyses of the ST7 gene in tumors with LOH in this region. Of 43 tumors, 12 (28%) showed LOH at 7q31-q35. These included four (22%) of 18 squamous cell carcinomas and eight (32%) of 25 adenocarcinomas. The peak LOH locus was D7S480, lying 4.2 Mb telomeric to ST7 and showing LOH in eight of 37 informative tumors, or 22%. No mutations were found in the entire coding or flanking intronic regions of the ST7 gene among 12 tumors with 7q-LOH. In addition, quantitative RT-PCR analyses of ST7 mRNA expression levels in 11/13 normal-tumor pairs failed to show more than a 50% decrease in tumor ST7 mRNA relative to matched normal tissues. These data suggest that LOH at 7q31-q35 is involved in the origin or progression of at least a subset of esophageal carcinomas, but that ST7 is not the target gene of this somatic event.

Adenocarcinoma↗

PubMed2003

N-2-butyl-cyanoacrylate for bleeding gastric varices: a United States pilot study and cost analysis.

OBJECTIVES: N-butyl-2-cyanoacrylate has been reported to be effective for bleeding varices but is not available in the United States. We report the initial US experience with cyanoacrylate in this prospective trial and evaluate its safety, efficacy, and relative costs. METHODS: Patients with active or recent gastric variceal bleeding were eligible. Cyanoacrylate therapy was performed until variceal occlusion was achieved. Rebleeding was assessed at 72 h (acute phase), 6 wk (subacute phase), and 1 yr (chronic phase). Survival was assessed at 3 months and 1 yr. Cost analysis was performed comparing the first 17 patients to historical control patients not treated with cyanoacrylate. RESULTS: A total of 44 patients were enrolled, 37 with cirrhosis and seven with noncirrhotic portal hypertension (NCPH). In cirrhotic patients, rebleeding was seen in two of 37 (5%) at 72 h, one of 30 (3%) at 6 wk, and five of 28 (18%) at 1 yr. Survival without shunt at 3 months was 30 of 34 (88%) and at 1 yr was 24 of 31 (77%). In NCPH patients, rebleeding was seen in two of seven (29%) at 72 h. These patients received definitive therapy for NCPH after diagnosis. Mortality and costs were substantially higher in the non-cyanoacrylate group. The odds of death were greater by 7-fold in the non-cyanoacrylate group than within the cyanoacrylate group (95% CI = 1.18-41.36, p = 0.0318). At 3 months, there was a 3.18-fold difference (95% CI = 1.05-9.64, p = 0.0411) in accrued costs; at 1 yr, the difference was 2.55-fold (95% CI = 0.96-6.94, p = 0.0585). The cost-effective ratio was estimated as 108,237 US dollars/death averted, reflecting marked cost reduction with improved survival in the cyanoacrylate-treated group. This is believed to result largely from avoidance of shunt interventions. CONCLUSIONS: Cyanoacrylate treatment of gastric varices is safe, clinically effective, and cost effective.

Adult↗

PubMed2002

Artificial neural networks and gene filtering distinguish between global gene expression profiles of Barrett's esophagus and esophageal cancer.

cDNAmicroarrays, combined with bioinformatics analyses, are becomingincreasingly used in current medical research. Existing analytic methods,particularly those that are unsupervised, often have difficulty recognizing subtle differences among predefined subgroups. In contrast, supervised methods, such as Artificial Neural Networks (ANNs), are able to recognize subtly different biological entities. We applied ANNs in a proof-of-principle study of cDNA microarray data in esophageal cancer (CA) and premalignancy. cDNA microarrays, each containing 8064 clones, were hybridized to RNAs from 22 esophageal lesions, including 14 Barrett's esophagus (BA) metaplasias and 8 esophageal carcinomas (3 squamous cell carcinomas and 5 adenocarcinomas). Scanned cDNA microarray data were analyzed using the bioinformatics software Cluster/TreeView, Significance Analysis of Microarrays (SAM), and ANNs. Cluster analysis based on all 8064 clones on the microarrays was unable to correctly distinguish BA specimens from CA specimens. SAM then selected 160 differentially expressed genes between Barrett's and cancer. Cluster analysis based on this reduced set still misclassified 2 Barrett's as cancers. The ANN was trained on 12 samples and tested against the remaining 10 samples. Using the 160 selected genes, the ANN correctly diagnosed all 10 samples in the test set. Finally, the 160 genes selected by SAM may merit further study as biomarkers of neoplastic progression in the esophagus, as well as in elucidating pathological mechanisms underlying BA and CA.

Adenocarcinoma↗

PubMed2002

EUS-guided fine needle aspiration of the liver: indications, yield, and safety based on an international survey of 167 cases.

BACKGROUND: The liver is a common site of metastases for various malignancies. EUS-guided fine needle aspiration (EUS-FNA) of liver masses has only been reported in small series from single centers. METHODS: A retrospective questionnaire was sent by e-mail to 130 EUS-FNA centers around the world regarding indications, complications, and findings of EUS-FNA of the liver. RESULTS: Twenty-one centers reported 167 cases of EUS-FNA of the liver. A complication was reported in 6 (4%) of 167 cases including the following: death in 1 patient with an occluding biliary stent and biliary sepsis, bleeding (1), fever (2), and pain (2). EUS-FNA diagnosed malignancy in 23 of 26 (89%) cases after nondiagnostic fine needle aspiration under transabdominal US guidance. EUS localized an unrecognized primary tumor in 17 of 33 (52%) cases in which CT had demonstrated only liver metastases. EUS image characteristics were not predictive of malignant versus benign lesions. CONCLUSION: EUS-guided FNA of the liver appears to be a safe procedure with a major complication rate of approximately 1%. EUS-FNA should be considered when a liver lesion is poorly accessible to US-, or CT-guided FNA should be considered when US- or CT-guided FNA fail to make a diagnosis, when a liver lesion(s) is detected (de novo) by EUS, and for investigation of possible upper GI primary tumors in the setting of liver metastases.

Attitude of Health Personnel↗

PubMedDate not supplied

Endoscopic oncology.

Endoscopy plays a critical role in the management of patients with malignancies involving the gastrointestinal tract. Endoscopic ultrasound has provided essential staging information, made more complete by the ability to perform fine needle aspiration of suspicious lymph nodes. Novel endoscopic resection and ablative techniques are expanding therapeutic choices in premalignant and malignant conditions. Obstruction, virtually anywhere along the length of the gastrointestinal tract, can be relieved with new stents. All of these advances have made the therapeutic gastroenterologist a key member of the team managing patients with tumors of the gastrointestinal tract.

Biopsy, Needle↗