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D S Levine

Publications and source records attributed to D S Levine.

At least 37 records · Page 2Linked to original sources
PubMed1996

17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus.

Increased 4N (G2/tetraploid) cell populations have been postulated to be genetically unstable intermediates in the progression to many cancers, but the mechanism by which they develop and their relationship to instability have been difficult to investigate in humans in vivo. Barrett's esophagus is an excellent model system in which to investigate the order in which genetic and cell cycle abnormalities develop relative to each other during human neoplastic progression. Neoplastic progression in Barrett's esophagus is characterized by inactivation of the p53 gene, the development of increased 4N (G2/tetraploid) cell fractions, and the appearance of aneuploid cell populations. We investigated the hypothesis that patients whose biopsies have increased 4N (G2/tetraploid) cell fractions are predisposed to progression to aneuploidy and determined the relationship between inactivation of p53 and the development of 4N abnormalities in Barrett's epithelium. Our results indicate that increased 4N (G2/tetraploid) populations predict progression to aneuploidy and that the development of 4N abnormalities is interdependent with inactivation of the p53 gene in Barrett's esophagus in vivo.

Alleles↗
PubMed1996

Risk and natural history of colonic neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) has been suggested as a risk factor for the development of colorectal cancer in ulcerative colitis (UC); however, previous studies of this association have been limited by small numbers of patients with PSC or have been performed retrospectively. This study prospectively evaluates the risk and natural history of colonic tumorigenesis in patients with PSC and UC and compares it with patients with UC without PSC. METHODS: Twenty patients with PSC and UC and 25 control patients with UC were followed prospectively by colonoscopic surveillance using extensive mucosal biopsy sampling. All control patients with UC had disease extending beyond the sigmoid colon of > or = 8 years' duration; patients with PSC and UC were studied regardless of disease duration. RESULTS: Forty-five percent (9 of 20) of the patients with PSC and UC had dysplasia compared with 16% (4 of 25) of the control patients with UC (P < or = 0.002). Prior liver transplantation did not affect the risk of colonic dysplasia. The time course for progression to dysplasia was similar between the patients with PSC and UC and the patients with UC; however, the patients with PSC and UC were five times more likely to develop dysplasia. CONCLUSIONS: Patients with PSC and UC represent a subset of patients with UC who are at markedly increased risk for colonic neoplasia and who need close colonoscopic surveillance with extensive biopsy sampling.

Adult↗
PubMed1995

Oral beclomethasone dipropionate for treatment of human intestinal graft-versus-host disease.

Intestinal graft-versus-host disease (GVHD) causes anorexia, vomiting, abdominal pain, and diarrhea. We investigated oral beclomethasone dipropionate (BDP), a potent, topically active corticosteroid, as therapy for this disease. Forty-two allogeneic marrow-graft recipients with biopsy-proven intestinal graft-versus-host disease of mild-to-moderate severity received BDP (8 mg daily) for up to 28 days. Weekly symptom scores, oral intake, and surveillance throat and stool cultures were compared with baseline values. Adrenal testing was performed serially in patients not receiving concurrent prednisone. Improvement was seen in appetite (P < 0.001), oral intake (P < 0.001), nausea (P = 0.013), and diarrhea (P = 0.02) over the course of therapy, and an overall beneficial response was observed in 72% of 40 evaluable patients. Surveillance cultures of throat and stool showed no increase in bacterial or fungal colonization over time. The adrenal axis became suppressed in 11 of 20 evaluable patients (55%) but suppression was not a prerequisite for clinical response, as 6 of 9 patients who retained normal adrenal function improved clinically. We conclude that oral BDP is a safe and effective treatment for mild-to-moderate intestinal graft-versus-host disease. Systemic absorption probably occurs, but adrenal suppression is not a prerequisite for clinical efficacy, suggesting that the biological effect is primarily topical. BDP should be further investigated as a topical therapy for intestinal GVHD.

Administration, Oral↗
PubMed1995

A pilot study of DNA aneuploidy in colorectal adenomas and risk of adenoma recurrence.

This case-control study examined whether DNA aneuploidy in colorectal adenomas is a risk factor for subsequent adenoma recurrence. Cases (recurrent polyp formers) were defined as persons with diagnoses of new adenomas at 2 colonoscopies following the index (first) adenoma diagnosis; controls were persons with no new adenomas at a follow-up at least 1 year after the index diagnosis. Cases (n = 22) and up to 3 controls (n = 29) were matched for factors known to be associated with polyp recurrence or aneuploidy: (a) age; (b) histology; (c) number of index polyps; and (d) size of largest index polyp. The largest adenoma from the index colonoscopy was removed from the paraffin block and analyzed for DNA content abnormalities by flow cytometry. On the basis of the observed distribution of aneuploidy in case-control sets, the point estimate for the relative odds of recurrence given aneuploidy in the index polyp was infinity (P < 0.035), and the lower bound for the 95% confidence interval was 2.02. We conclude that in this convenience sample, DNA aneuploidy increased the risk of recurrent colorectal adenomas. Larger, preferably prospective studies are needed before DNA content flow cytometric analysis of colorectal adenomas can be recommended as a routine clinical practice, but these results do suggest that polyp ploidy should be assessed in research studies using adenomas as end points or intermediate end point markers.

Adenoma↗
PubMed1995

Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis.

OBJECTIVE: Colonoscopic biopsy surveillance to detect dysplasia, defined as a neoplastic change of the epithelium without invasion into the lamina propria, in patients with ulcerative colitis has become a widespread practice. We undertook a survey study to determine physicians' perceptions of, and approaches to, dysplasia surveillance colonoscopy in ulcerative colitis. METHODS: Members of two regional gastroenterology associations in the United States, including both academic and private practice-based gastroenterologists, and a group of senior gastroenterology trainees were surveyed by means of a written questionnaire. The questionnaires were distributed at three separate meetings of practicing gastroenterologists or trainees: 1) a Gastrointestinal pathology course for second-year gastroenterology fellows from training programs around the United States (February 1993, Los Angeles, CA); 2) a meeting of the Southern California Gastroenterology Society (March 1993, Los Angeles, CA); and 3) a meeting of the Pacific Northwest Gastroenterology Society (June 1993, Seattle, Washington). The percentages of all responses were tallied and analyzed for the group as a whole as well as by subgroup analysis. Understanding of the definition of dysplasia and specific practice techniques and approaches were the main outcomes sought. RESULTS: Only 19% of respondents correctly identified the definition of dysplasia. More respondents (48%) correctly defined high grade dysplasia specifically compared with only 16% who correctly defined low grade dysplasia. The majority of respondents (69%) recommended colectomy when high grade dysplasia was diagnosed, yet nearly one-third of respondents pursued continued surveillance in this setting. Almost uniformly, respondents pursued continued surveillance and not colectomy when low grade dysplasia was diagnosed. Nearly one-half of the respondents thought that there was only < 20% chance of finding invasive cancer in patients with preoperative diagnoses of high grade dysplasia. On average, respondents performed surveillance colonoscopy every 1-2 yr and took an average of three biopsies per site, at approximately eight sites in the colon, and most respondents confidently relied on their local pathologist at making the diagnosis. There were, however, wide variations in the practice of dysplasia surveillance. CONCLUSIONS: The majority of respondents did not know the definition of dysplasia, and most viewed it as a preneoplastic lesion. Furthermore, there was a lack of appreciation that the difference between low grade and high grade dysplasia is one of degree or severity of neoplastic change and for the likelihood of finding invasive cancer at surgery if there is only a diagnosis of dysplasia preoperatively. Dysplasia surveillance colonoscopy in ulcerative colitis is not a well standardized, clearly understood screening tool, and continued education of the gastroenterology community regarding its outcomes and pitfalls is needed.

Colectomy↗
PubMed1994

The management of high grade dysplasia and early cancer in Barrett's esophagus. A multidisciplinary problem.

BACKGROUND: The incidence of Barrett's-associated esophageal adenocarcinoma is rising, but experience in the treatment of high-grade dysplasia (HGD) or early cancer is limited. Based on an endoscopic surveillance program, the authors developed a systematic multidisciplinary approach to this problem. METHODS: Surgical resection was considered if biopsies of the Barrett's segment, performed according to a published protocol, showed invasive cancer, intramucosal carcinoma, or repeated evidence of HGD. The type of resection was based on the length of the Barrett's segment and included an en bloc lymph node dissection for staging purposes. Careful intraoperative pathologic evaluation ensured that all of the Barrett's mucosa was resected. RESULTS: From 1984 to 1993, 27 consecutive patients (23 men, 4 women), with median age of 61 years (range, 45-75 years) underwent surgical exploration. Indications for operation were invasive cancer in 17 patients, intramucosal carcinoma in 5 patients, and HGD in 5 patients. Median length of the Barrett's segment was 9 cm (range, 1-17 cm). Only 15 patients (55%) had abnormalities visible with endoscopic examination that were potentially suspicious for malignancy. Twenty-six patients underwent resection with complete removal of the Barrett's mucosa, 20 by Ivor Lewis esophagogastrectomy, and 6 by transhiatal esophagectomy. Pathologic tumor stages were: TisN0M0 in 10 patients; T1N0M0 in 11 patients; T2N0M0 in 2 patients; T3N0M0 in 3 patients; and T1NXM1 in 1 patient. There were no postoperative deaths or anastomotic leaks. Major complications occurred in 4 patients. With a median follow-up of 3.7 years, 22 patients were alive, and only 2 patients had recurrences. CONCLUSIONS: This increasingly important group of patients with HGD or early carcinoma in the Barrett's esophagus has a high chance of cure but requires careful multidisciplinary treatment by the surgeon, gastroenterologist, and pathologist.

Adenocarcinoma↗
PubMed1994

17p allelic losses in diploid cells of patients with Barrett's esophagus who develop aneuploidy.

Inactivation of the p53 gene, located on chromosome 17p, leads to genetic instability and aneuploidy in vitro. Aneuploid cell populations from Barrett's adenocarcinomas have a high prevalence of 17p allelic losses, and there is substantial evidence that the target of these losses is the p53 gene. If 17p allelic losses lead to aneuploidy in Barrett's esophagus, then they should be present in diploid cells from patients who develop aneuploidy. We detected 17p allelic losses in diploid cells from 10 of 11 patients (91%) with Barrett's esophagus who developed aneuploid cell populations. Our data strongly suggest that 17p allelic losses precede the development of aneuploidy during neoplastic progression in Barrett's esophagus in vivo and, therefore, support in vitro evidence for the role of p53 in genetic instability.

Adenocarcinoma↗
PubMed1994

p53 mutations in Barrett's adenocarcinoma and high-grade dysplasia.

BACKGROUND/AIMS: Allelic losses of chromosome 17p and overexpression of p53 protein have been reported in Barrett's adenocarcinomas. This study aimed to determine the stage in which p53 mutations arise in neoplastic progression in Barrett's esophagus and their relationship to the clonal evolution of cancer. METHODS: Fourteen patients with high-grade dysplasia, adenocarcinoma, or both arising in Barrett's esophagus were evaluated. Flow cytometric cell sorting was used to obtain purified populations of neoplastic cells for analysis of p53 mutations. DNA was extracted, and exons 5 through 9 of the p53 gene were amplified by polymerase chain reaction. Amplified DNA was sequenced and analyzed by automated sequencing. RESULTS: Nine of the 14 patients had p53 mutations. Six of the 9 patients had regions of high-grade dysplasia that could be evaluated; all 6 had p53 mutations in high-grade dysplasia. In 3 patients, the same p53 mutations were found in both high-grade dysplasia and adenocarcinoma. All 14 patients had aneuploidy. In 4 patients, diploid cell populations could also be evaluated for p53 mutations; 3 of the 4 patients had p53 mutations in diploid cell populations. In 2 patients, the same p53 mutation was found in multiple aneuploid cell populations within a cancer. CONCLUSIONS: p53 mutations occur frequently in Barrett's adenocarcinomas. They develop in diploid cell populations. The same p53 mutations are then found in aneuploid cell populations in high-grade dysplasia, in cancer, and in multiple aneuploid cell populations in cancer.

Adenocarcinoma↗
PubMed1993

An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett's esophagus.

BACKGROUND: Surveying vs. performing resection in patients with high-grade dysplasia in Barrett's esophagus is debated because of concern about the accuracy of endoscopic biopsy diagnosis. The aim of this study was to investigate the accuracy of an endoscopic biopsy protocol in patients with neoplastic abnormalities in Barrett's epithelium without obvious esophageal cancer. METHODS: Preoperative and postoperative diagnoses in 28 patients who underwent surgery for high-grade dysplasia or early adenocarcinoma in Barrett's esophagus and compared them with 22 other patients with high-grade dysplasia who were maintained under prospective endoscopic surveillance. All 50 patients lacked gross lesions to suggest esophageal cancer. The endoscopic protocol involved rigorous, systematic acquisition of multiple, large biopsy samples. RESULTS: Overall, 64% of patients had minimal but distinct endoscopic abnormalities that were targeted for biopsies. High-grade dysplasia alone (7 patients) was differentiated from early adenocarcinoma (19 patients). Two patients with preoperative diagnoses of intramucosal adenocarcinoma had high-grade dysplasia in their resection specimens. CONCLUSIONS: This endoscopic protocol accurately detects and differentiates high-grade dysplasia from early adenocarcinoma in Barrett's esophagus. Patients with high-grade dysplasia alone in Barrett's esophagus detected by such a protocol do not necessarily require surgical resection to rule out an undiagnosed adenocarcinoma; electing for surgery should be based on other clinical considerations.

Adenocarcinoma↗
PubMed1993

Barrett's esophagus: cell cycle abnormalities in advancing stages of neoplastic progression.

BACKGROUND: Abnormal proliferation in Barrett's esophagus may predispose to the development of esophageal adenocarcinoma, but previous studies have not determined the specific cell cycle abnormalities that were associated with neoplastic progression. METHODS: Ki67/DNA content multiparameter flow cytometry and DNA content flow cytometry were used to investigate G0, G1, and S phase fractions in advancing stages of neoplastic progression in Barrett's esophagus. RESULTS: In control biopsy specimens from gastric mucosa, G1, S phase, and total Ki67-positive proliferative fractions were low, suggesting that cells were predominantly in G0. Ki67-positive G1 fractions were increased in Barrett's metaplasia. More advanced stages of neoplastic progression were characterized by a subset of biopsy specimens that had aneuploid cell populations, increased S phase fractions, or both. CONCLUSIONS: The development of increased G1 fractions is an early event in Barrett's metaplasia. Increased S phase fractions occur in a subset of specimens typically at more advanced stages of neoplastic progression and often in association with the development of aneuploidy. Neoplastic progression in Barrett's esophagus is associated with at least three types of cell cycle abnormalities: (1) mobilization from G0 into G1; (2) loss of control of the G1/S phase transition; and (3) accumulation in G2.

Aneuploidy↗
PubMed1993

Methodological and theoretical issues in neural network models of frontal cognitive functions.

Neural network models have made significant strides in recent years toward modeling of neuropsychological data. In particular, three different research groups, including that of the present authors, have simulated in model networks some of the behavioral effects of frontal lobe damage. In this article we review these models and discuss their significance in terms of hierarchical organization in the nervous system. These models, to varying degrees, incorporate several widely used neural network principles that have also been used to model a wide range of data in other areas such as categorization, conditioning, and motor control. These principles include associative learning, competition, opponent processing, neuromodulation, and interlevel resonant feedback. Specifically, we show how combinations of these principles serve to model the attentional requirements of cognitive tasks and motor plans.

Animals↗