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R C Haggitt

Publications and source records attributed to R C Haggitt.

At least 37 records · Page 2Linked to original sources
PubMed1995

Microsatellite instability and K-ras mutations associated with pancreatic adenocarcinoma and pancreatitis.

ras oncogene mutations and microsatellite instability (MIN) have been described in pancreatic cancer studies from paraffin blocks and fresh frozen tissue. We sought to determine whether they could be detected in endoscopic retrograde cholangiopancreatography-derived pancreatic juice. ras mutations were detected in the pancreatic juice of 40% (2 of 5) of patients with pancreatic cancer and 2 of 5 patients with pancreatitis. MIN was detected at a single locus in the pancreatic juice of 40% of pancreatic cancer patients and at > or = 2 loci of 100% of pancreatitis patients. The finding of MIN in pancreatitis specimens was verified in studies performed on paraffin blocks. MIN was not detected in normal pancreas controls. All of the cancer patients who had ras mutations in their pancreatic juice also had evidence of MIN at one or more loci (P < or = 0.05), suggesting that MIN is associated with the development of a ras mutation. More importantly, the finding of MIN in pancreatitis specimens suggests that MIN can occur in nonneoplastic conditions of the pancreas and may represent the saturation of an intact mismatch repair system.

Adenocarcinoma↗
PubMed1995

A germline substitution in the human MSH2 gene is associated with high-grade dysplasia and cancer in ulcerative colitis.

BACKGROUND & AIMS: The DNA mismatch repair gene human MSH2 shows a germline mutation in certain family members with hereditary nonpolyposis colorectal cancer. There is an increased risk of colorectal cancer in patients with ulcerative colitis (UC) with extensive disease of > 8 years' duration; however, specific constitutional predisposing genetic abnormalities have not yet been identified. METHODS: A germline human MSH2 abnormality was sought in patients with UC with high-grade dysplasia or carcinoma. RESULTS: After direct sequencing of exon 13 and flanking regions of human MSH2, a germline T to C substitution was shown at the -6 intronic splice acceptor site of exon 13. This substitution was found in 14 of 53 patients with UC with high-grade dysplasia or carcinoma (26%) compared with 4 of 36 high-risk patients with UC without dysplasia or cancer (11%) (P < or = 0.04) and in 7 of 80 healthy adult blood donors (9%) (P < or = 0.003). The patients with UC who had the substitution were three times more likely to develop neoplasia than patients with UC who did not carry it. CONCLUSIONS: An intronic splice-site substitution in the human MSH2 gene is present in the general population but may predispose to cancer in the setting of UC.

Adult↗
PubMed1995

Pneumatosis intestinalis: a review.

Pneumatosis intestinalis (PI) is an uncommon but important condition in which gas is found in a linear or cystic form in the submucosa or subserosa of the bowel wall. PI is a sign, not a disease; therefore, its relevance should be interpreted within the whole clinical context. PI has been found in several distinctive clinical settings: 1) in premature infants with necrotizing enterocolitis; 2) in adults with obstructive pulmonary disease; 3) in adults and children with a wide variety of associated conditions, including pyloric stenosis, jejunoileal bypass, progressive systemic sclerosis, transplantation, ischemic bowel, and drug therapy, particularly steroids, chemotherapy, and immunosuppression; 4) in adults as a primary benign problem; and 5) as an incidental finding in endoscopic mucosal biopsies. The two most important tasks of the physician include: 1) recognition of the entity of PI so that patients are not misdiagnosed and mismanaged as having malignancy or polyposis; and 2) differentiation of the benign variety, in which no intervention is indicated, from the life-threatening form, in which immediate surgery is necessary. Once life-threatening illnesses such as bowel necrosis, perforation, and infections are excluded, patients symptomatic from the cysts per se may be treated with oxygen and/or antibiotics. Because the reports of treatment of PI are at best anecdotal, the decision to treat and the treatment chosen should be carefully balanced with the risks.

Humans↗
PubMed1994

Mucosal biopsy diagnosis of colitis: acute self-limited colitis and idiopathic inflammatory bowel disease.

BACKGROUND/AIMS: Rectal biopsy specimen changes distinguish acute self-limited colitis (ASLC) from idiopathic inflammatory bowel disease (IBD). This study aimed to determine whether these histological criteria are also valid for acute-onset IBD. METHODS: Blind analysis of colorectal biopsy specimens from 52 patients with ASLC, 51 patients with acute-onset (< 3 months) IBD, and 30 patients with chronic IBD was performed. RESULTS: Histological features of ASLC are normal crypt architecture and acute lamina propria inflammation, but mixed acute and chronic inflammation can be found. Histological features of IBD are diffusely abnormal crypt architecture, crypt atrophy, mixed lamina propria inflammation, basal plasmacytosis, basal lymphoid aggregates, basal lymphoid hyperplasia, isolated giant cells, epithelioid granulomas, goblet cell mucus depletion, and reactive epithelial hyperplasia. Changes of chronic IBD were present in biopsy specimens as early as 7 days after the onset of symptoms. CONCLUSIONS: Rectal biopsy specimens are useful in distinguishing ASLC from acute-onset IBD even if the biopsy specimens are not obtained during the first 4 days of the illness. There were no significant differences in histology between acute-onset and chronic IBD.

Acute Disease↗
PubMed1994

Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis.

BACKGROUND/AIMS: In long-term extensive ulcerative colitis, aneuploidy occurs earlier and loss of heterozygosity for p53 (p53 LOH) later during histological progression towards carcinoma. This study determined the time of onset of p53 mutation in this progression. METHODS: We developed a rapid, sensitive screening assay for p53 mutations at codon 248. The geographic distribution of this p53 mutation was mapped in two fresh colectomy specimens with mutations of codon 248 (1 cancer, 1 dysplasia) and correlated with patterns of clonal expansion, histological progression, and allelic loss. Numerous samples from throughout both colons were analyzed (216 for histology, 142 for DNA content, 104 for mutation, and 41 for p53 LOH). RESULTS: p53 mutation correlated highly with histological grade and was distributed more extensively than p53 LOH. Mutation, but not LOH, was also found in diploid, nondysplastic colonic mucosa adjacent to dysplastic areas. CONCLUSIONS: These findings suggest that p53 mutation appears to be an early genetic event that precedes p53 LOH. The very close correlation of p53 mutation with aneuploidy (P > 0.0001) emphasizes the role of normal p53 at the G1 checkpoint to help prevent entry of genetically damaged cells into the cell cycle.

Aneuploidy↗
PubMed1994

Barrett's esophagus, dysplasia, and adenocarcinoma.

In Barrett's esophagus the normal stratified squamous epithelium lining the esophagus becomes replaced by metaplastic columnar epithelium containing goblet cells; it develops as a complication of chronic gastroesophageal reflux disease and predisposes the patient to adenocarcinoma. The frequency with which it leads to adenocarcinoma is not established with certainty, but the reported prevalence averages approximately 10% when the diagnosis of Barrett's esophagus is first made. The estimated incidence of adenocarcinoma varies from one in 152 to one in 441 cases per patient year, or a 30- to 125-fold excess risk. Esophageal adenocarcinoma arises only in patients with metaplastic columnar epithelium. Dysplasia precedes adenocarcinoma in Barrett's esophagus and arises from the metaplastic epithelium; it has been proposed as a marker for detecting patients at high risk for developing carcinoma. Problems with the use of dysplasia as a marker for cancer risk include difficulty in differentiating it from reactive change, variability in diagnosis and grading between observers and when the same observer interprets the sections on different occasions, and lack of understanding of its natural history. Methods other than dysplasia for detecting patients at highest risk for developing carcinoma have been sought, but flow cytometric analysis of DNA content is the only one proven to be valuable to date. Flow cytometric abnormalities correlate well with histological progression in Barrett's esophagus. The prevalence of elevated S phase and G2/tetraploid fractions and of aneuploid cell populations increases with histological progression from metaplasia to indefinite/low grade dysplasia to high grade dysplasia and cancer. Flow cytometric abnormalities in endoscopic biopsy specimens identify those patients with a higher risk of progression to high grade dysplasia or adenocarcinoma.

Adenocarcinoma↗
PubMed1994

Mesenteric inflammatory veno-occlusive disease. A seldom recognized cause of intestinal ischemia.

We describe seven patients (three men, four women; ages 27-78) who presented with signs of intestinal ischemia requiring surgical intervention. In each case, the resected colon, small bowel, or both showed striking phlebitis and venulitis affecting veins of the bowel and mesentery and resulting in ischemic injury of the bowel. In each case, this vasculopathy was the only demonstrable cause of ischemia. Arteritis involving the bowel or the mesentery was not found in any patient, and none had clinical evidence or a history of extraintestinal vasculitis. The composition of the inflammatory infiltrate was variable; in four patients, it was predominantly lymphocytic, in two necrotizing and in one lymphocytic/granulomatous. In addition, three patients also had myointimal hyperplasia of the affected mesenteric veins. Six of seven patients recovered uneventfully after surgery, suggesting a self-limited or indolent process, and the seventh died of an unknown cause. We propose the name mesenteric inflammatory veno-occlusive disease (MIVOD) to describe this unusual and previously unrecognized cause of intestinal ischemia. Its etiology is unknown, and MIVOD may represent a precursor of the recently described idiopathic myointimal hyperplasia of mesenteric veins.

Adult↗
PubMed1994

Deletion mapping of chromosome 8p in colorectal carcinoma and dysplasia arising in ulcerative colitis, prostatic carcinoma, and malignant fibrous histiocytomas.

Short tandem repeat polymorphism markers on the short arm of chromosome 8 were used to search for loss of heterozygosity (LOH) in colorectal carcinoma and dysplasia complicating ulcerative colitis, in prostatic carcinoma, and in malignant fibrous histiocytoma (MFH). Fifty percent of prostatic carcinomas (13/26), 44% of carcinomas or dysplasias arising in ulcerative colitis (7/16), and 30% (4/12) of MFH cases showed LOH for markers on 8p. Detailed mapping demonstrated variability in the size of the chromosomal region showing LOH; however, the data suggest a common 30-centimorgan region of LOH on chromosome 8p between the LPL locus and pter in colorectal and prostatic cancers. In addition, LOH was observed on 8p in both high-grade and low-grade dysplasia in ulcerative colitis, indicating that LOH on 8p may occur at an early stage of neoplastic development in this disorder. In contrast, MFH cases exhibited LOH for marker D8S87, which has been identified as being near the putative Werner's syndrome locus. These results suggest that a tumor suppressor gene, located on the distal portion of chromosome 8p, exists in common for prostatic and colorectal carcinomas, and a second tumor suppressor gene may exist linked to the Werner's syndrome locus.

Chromosome Deletion↗
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

Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis.

BACKGROUND: To control the increased risk of colorectal carcinoma in patients with long-standing ulcerative colitis, surveillance colonoscopy is widely recommended. METHODS: To assess the role of colonoscopic surveillance in affecting colorectal carcinoma-related mortality, an outcome analysis was performed. RESULTS: Among the total of 41 patients who developed carcinoma associated with ulcerative colitis, 19 patients were under colonoscopic surveillance and 22 patients were not. Carcinoma was detected at a significantly earlier Dukes' stage in the surveillance group (P = 0.039). Four patients in the surveillance group died, compared with 11 patients in the no-surveillance group. The 5-year survival rate was 77.2% for the surveillance group and 36.3% for the no-surveillance group (P = 0.026). CONCLUSIONS: These results suggest that colonoscopic surveillance reduces colorectal carcinoma-related mortality by allowing the detection of carcinoma at an earlier Dukes' stage.

Adolescent↗
PubMed1993

Experimental use of high-frequency ultrasound to image bowel wall after porcine intestinal transplantation.

A means to monitor intestinal allografts will be crucial for the future success of small bowel transplantation. We have previously demonstrated the ability of high-frequency ultrasound (US) to diagnose porcine intestinal ischemia in vitro. The aim of this study was to compare the histologic appearance of normal porcine small bowel versus bowel undergoing acute rejection, using 8.5-MHz US images. We allowed porcine heterotopic small bowel allograft transplants to reject and then removed, at scheduled intervals from postoperative day 0 to 12, specimens of both the transplanted bowel and the native bowel. We examined the tissues in vitro with an 8.5-MHz linear array US system then studied them histologically. Histologically, the earliest changes of rejection occurred at days 4 to 5, with mild submucosal edema, endotheliitis, and vasculitis affecting the small vessels; the mucosa remained normal. By days 7 to 8, the submucosal endotheliitis became more prominent, with focal thrombosed small vessels; the mucosa now appeared abnormal with flattened villi, erosions, and necrosis. By days 10 to 12, marked submucosal edema, vasculitis, endotheliitis, and necrotic mucosa were present. Ultrasonically, normal intestinal wall has five wall layers, corresponding to mucosa, submucosa, muscularis propria, and subserosal fat. The US criteria for abnormality were loss of folds, decreased numbers of echo layers, discontinuity of layers, and a homogeneous appearance. Using these US criteria, blinded observers differentiated normal from abnormal bowel wall after transplantation with a sensitivity of 84% and a specificity of 81%. Most of the errors occurred with the day 4 and 5 specimens, which appeared nearly normal on US.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Persistent clonal areas and clonal expansion in Barrett's esophagus.

Three patients with Barrett's esophagus who had cytogenetic abnormalities detected in their metaplastic epithelium developed high-grade dysplasia or adenocarcinoma during prospective surveillance over a period of 1.5 to 6 years. In the 3 cases, cytogenetic abnormalities that were associated with the most advanced histological lesions were present in samples obtained 11, 25, and 48 months prior to the diagnosis of high-grade dysplasia or carcinoma. In a fourth patient, marker chromosomes found in a Barrett's adenocarcinoma were also present in an esophageal region spatially removed from the tumor. In all four patients, clonal cytogenetic abnormalities were present in samples obtained at widespread locations in the Barrett's segment. These observations suggest that in some patients with Barrett's esophagus clonal proliferations arise in regions of benign histology and spread to involve large areas of Barrett's mucosa. These clones persisted when the disease progressed to high-grade dysplasia or adenocarcinoma.

Adenocarcinoma↗
PubMed1992

Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers.

The tumor suppressor gene APC was recently identified, and the cDNA was cloned from chromosome 5q21. Point mutations affecting APC are seen in the hereditary syndrome familial adenomatous polyposis, and point mutations in APC and a closely linked gene, MCC, as well as loss of heterozygosity involving chromosome 5q have been reported in sporadic colon cancer. To our knowledge, loss of heterozygosity involving APC or MCC or both has not yet been described in any other human cancer besides lung cancer. We used the polymerase chain reaction and DNA content flow cytometric nuclear sorting to examine 30 primary human esophageal cancers for loss of heterozygosity of APC or MCC or both. Loss of one allele was detected in 77% of 26 informative cases. These data suggest that loss of heterozygosity of regions on 5q including the APC and MCC genetic loci is involved in the development and/or progression of most human esophageal cancers. They imply that inactivation of APC, MCC, and/or a linked gene on chromosome 5q plays a role in the pathogenesis of some cancers of the upper gastrointestinal tract, as well as in colon cancer and familial adenomatous polyposis.

Adenocarcinoma↗
PubMed1992

Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele.

Neoplastic progression in patients with chronic ulcerative colitis (UC) is characterized by the development of epithelial dysplasia, which is accompanied by genetic abnormalities that can be detected by flow cytometric and molecular biologic methods. Distribution of and correlation between histologic abnormalities, DNA content, and loss of heterozygosity for a p53 allele (p53 LOH) in the colons of nine UC patients were analyzed. Loss of a p53 allele was found in 85% (22/26) of biopsy specimens classified histologically as carcinoma, 63% (25/40) of biopsy specimens with high grade dysplasia, and 33% (7/21) of biopsy specimens with low grade dysplasia. Loss of heterozygosity for p53 was also found in 9% (5/57) of biopsy specimens indefinite for dysplasia and in 1/18 biopsy specimens negative for dysplasia, showing that this genetic change may occur early in the histological progression towards carcinoma. Aneuploid DNA contents were more common than p53 LOH in regions with negative, indefinite or low grade dysplastic histology; moreover, p53 LOH was detected only in aneuploid cells and not in diploid epithelium. Aneuploidy alone was not as specific a marker for the concomitant presence of dysplasia or carcinoma in a biopsy sample as aneuploidy combined with p53 LOH. These findings show that aneuploidy may precede both p53 LOH and epithelial dysplasia. Two UC patients' colons contained geographically separated clones of cells with different aneuploidies that also showed loss of different p53 alleles, suggesting that neoplasia may arise within different populations of cells in separate areas of the same colon.

Adult↗
PubMed1992

DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis.

The objective of the present study was to determine whether abnormal epithelial DNA content (aneuploidy) in colonic biopsy specimens from ulcerative colitis (UC) patients correlated with and predicted histological progression to dysplasia. Aneuploidy was absent in 20 low-cancer risk patients. In 81 high-cancer risk patients aneuploidy correlated significantly with the severity of histological abnormality (negative, indefinite, dysplasia, or cancer). Statistically our data suggest that many more biopsy specimens than are usually taken are needed to detect focal dysplastic lesions. Prospective study of 25 high risk patients without dysplasia revealed 5 with aneuploidy, all of whom progressed to dysplasia in 1-2.5 years, whereas 19 patients without aneuploidy did not progress to either aneuploidy or dysplasia within 2-9 years. Our data indicate that aneuploidy in mucosal biopsy specimens correlates with histological grade and identifies a subset of patients without dysplasia who are more likely to develop it. It was concluded that more frequent and extensive colonoscopic surveillance of this minority subset of high risk patients and less frequent surveillance in the remaining majority may reduce cost and detect more curable lesions.

Adolescent↗
PubMed1992

Use of ultrasound to detect intestinal wall ischemia in piglets.

To evaluate the use of ultrasound (US) to detect intestinal wall ischemia, we isolated segments of jejunum on single vascular pedicles in five piglets. We sequentially clamped these segments in intervals of 0 to 6 h, reperfused them for 24 h, and then examined them in vitro histologically and with an 8.5 MHz US scan. All segments were grossly viable except those with 6 h of ischemia. Histologically, mild submucosal edema developed after 1 to 2 h of ischemia; after 3 to 4 h, mucosal necrosis, loss of folds, worsening submucosal edema, and prominent neutrophilic infiltration occurred; after 5 to 6 h, severe mucosal necrosis with hemorrhage and submucosal edema was present. Ultrasonically, we saw five wall layers in the control group corresponding to mucosa, submucosa, muscularis propria, and subserosal fat. After mild (1 to 2 h) ischemia, all layers were present except for a discontinuity in layer 3. After moderate (3 to 4 h) ischemia, the five layers persisted but with a markedly thickened submucosal layer, reduced echogenicity, and flattened mucosal folds. With severe (5 to 6 h) ischemia, we observed a loss of all normal layers with no discernible architecture. Using these US criteria, blinded observers were able to differentiate normal/mild from moderate/severe ischemia with a sensitivity and specificity of 100%. These data suggest that US can differentiate, in vitro, normal from moderate and severe degrees of intestinal wall ischemia that correlates well with the histological appearance. Endoscopic US or surgically implantable US probes can potentially help diagnose clinical intestinal wall ischemia.

Animals↗
PubMed1992

Flow-cytometric and histological progression to malignancy in Barrett's esophagus: prospective endoscopic surveillance of a cohort.

To determine whether or not flow-cytometric evidence of aneuploidy and increased G2/tetraploid fractions predispose to neoplastic progression in Barrett's esophagus, 62 patients with Barrett's esophagus were evaluated prospectively for a mean interval of 34 months. Nine of 13 patients who showed aneuploid or increased G2/tetraploid populations in their initial flow-cytometric analysis developed high-grade dysplasia or adenocarcinoma during follow-up; none of the 49 patients without these abnormalities progressed to high-grade dysplasia or cancer (P less than 0.0001). Neoplastic progression was characterized by progressive flow-cytometric and histological abnormalities. Patients who progressed to high-grade dysplasia and carcinoma frequently developed multiple aneuploid populations of cells that were detectable flow-cytometrically. Similarly, patients appeared to progress through a phenotypic sequence that could be recognized histologically by the successive appearance of Barrett's metaplasia negative for dysplasia, abnormalities in the indefinite/low-grade dysplasia range, high-grade dysplasia, and eventually adenocarcinoma. These and prior results suggest that neoplastic progression in Barrett's esophagus occurs in a subset of patients who have an acquired genomic instability that generates abnormal clones of cells, some of which have aneuploid or increased G2/tetraploid DNA contents. With continued genomic instability, multiple aneuploid subclones may evolve, one of which may ultimately acquire the ability to invade and become an early carcinoma. The combination of histology and flow cytometry can be used to identify a subset of patients with Barrett's esophagus who merit more frequent endoscopic surveillance for the early detection of high-grade dysplasia or carcinoma.

Aneuploidy↗