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N Harpaz

Publications and source records attributed to N Harpaz.

At least 19 recordsLinked to original sources
PubMed2006

Crohn's-like colitis, enterocolitis and perianal disease in Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessively inherited disorder consisting of the triad of oculocutaneous tyrosinase-positive albinism, prolonged bleeding time secondary to platelet storage pool defect and ceroid depositions within the reticuloendothelial system. Some patients also reportedly have gastrointestinal (GI) complications related to chronic granulomatous colitis, enterocolitis and extensive granulomatous perianal disease, the later previously unreported in the literature. These observations suggest that the GI complications of HPS are due to the development of classical Crohn's disease. The implications for disease pathogenesis and surgical management are discussed.

Adult↗
PubMed2005

Segmentation of intestinal gland images with iterative region growing.

A region growing algorithm for segmentation of human intestinal gland images is presented. The initial seeding regions are identified based on the large vacant regions (lumen) inside the intestinal glands by fitting with a very large moving window. The seeding regions are then expanded by repetitive application of a morphological dilate operation with a much smaller round window structure set. False gland regions (nongland regions initially misclassified as gland regions) are removed based on either their excessive ages of active growth or inadequate thickness of dams formed by the strings of goblet cell nuclei sitting immediately outside the grown regions. The goblet cell nuclei are then identified and retained in the image. The gland contours are detected by applying a large moving round window fitting to the enormous empty exterior of the goblet cell nucleus chains in the image. The assumptions based on real intestinal gland images include the closed chain structured goblet cell nuclei that sit side-by-side with only small gaps between the neighbouring nuclei and that the lumens enclosed by the goblet cell nucleus chains are most vacant with only occasional run-away nuclei. The method performs well for most normal and abnormal intestinal gland images although it is less applicable to cancer cases. The experimental results show that the segmentations of the real microscopic intestinal gland images are satisfactorily accurate based on the visual evaluations.

Adenocarcinoma↗
PubMed2004

Histological criteria for the identification of acute cellular rejection in human small bowel allografts: results of the pathology workshop at the VIII International Small Bowel Transplant Symposium.

Acute cellular rejection remains a serious and frequent complication during the posttransplant course of small bowel allograft recipients. Currently, small bowel biopsies are the optimal method to identify this form of rejection. The morphological criteria for this diagnosis have been known for some time; however, no consensus study has classified these changes. To address issues in bowel transplant pathology, several pathologists experienced in this particular subdiscipline participated in a Pathology Workshop preceding the VIIIth International Small Bowel Transplant Symposium in Miami, Florida. Among the results of this workshop was the development a standardized grading scheme for acute cellular rejection in small bowel transplants.

Biopsy↗
PubMed2004

Grb7 expression and cellular migration in chronic lymphocytic leukemia: a comparative study of early and advanced stage disease.

Grb7, a noncatalytic intracellular adaptor protein involved in cell migration, is overexpressed in certain invasive and metastatic solid tumors. We found a highly significant difference in the level of expression of Grb7 between chronic lymphocytic leukemia (CLL) cells obtained from stage I and stage IV patients (P<0.001). Using semiquantitative RT-PCR, we detected high levels of Grb7 in 88% of stage IV patients vs only 18% in stage I patients. A corresponding increase was found in the in vitro migration of stage IV CLL cells in comparison to stage I cells. The statistically significant difference in the expression of Grb7 between stage IV and stage I patients was preserved even when tested specifically in the ZAP70-positive group (P<0.01). These findings show that Grb7 levels reflect the severity of the disease, and may be used, in conjunction with ZAP70, to predict disease progression.

Case-Control Studies↗
PubMed2001

Screening and surveillance colonoscopy in chronic Crohn's colitis.

BACKGROUND & AIMS: Unlike ulcerative colitis, there are few reports on the efficacy of surveillance colonoscopy in patients with chronic Crohn's colitis and therefore little agreement as to whether routine surveillance is indicated. We report on 259 patients with chronic Crohn's colitis who underwent screening and subsequent surveillance colonoscopy and biopsy since 1980. METHODS: Biopsies were performed at 10-cm intervals and from strictures and polypoid masses. Pathology was classified as normal, dysplasia (indefinite, low-grade, high-grade), or carcinoma. RESULTS: A total of 663 examinations were performed on 259 patients. The median interval between examinations was 24 months; examinations were performed more frequently (1-6 months) in patients with dysplasia on biopsy. A thinner-caliber colonoscope was required to complete 12% of screening examinations and 23% of surveillance examinations. The pediatric colonoscope helped increase our yield of neoplasia by 19%. The screening and surveillance program detected dysplasia or cancer in 16% (10 indefinite, 23 low-grade, and 4 high-grade dysplasias and 5 cancers). A finding of definite dysplasia or cancer was associated with age >45 years and increased symptoms. By life table analysis, the probability of detecting dysplasia or cancer after a negative screening colonoscopy was 22% by the fourth surveillance examination. CONCLUSIONS: Colonoscopic surveillance should be strongly considered in chronic extensive Crohn's colitis.

Adolescent↗
PubMed2001

Treatment responses in collagenous colitis.

OBJECTIVE: In the nearly 20 yr since collagenous colitis was first recognized, the results of therapies have not been systematically described in substantial numbers of patients. We have therefore conducted a retrospective analysis of 26 patients treated in this institution during the years 1991-1994. METHODS: Twenty-nine cases of collagenous colitis were obtained by review of biopsy specimens collected between 1991 and 1994 at The Mount Sinai Hospital. Each chart was reviewed for patient demographics, symptoms, coexisting conditions, specific therapies, and therapeutic outcomes. Additional data were obtained from telephone calls to patients when deemed necessary. Three patients were exeluded from the study because of lack of follow-up. Therapeutic outcomes were defined as follows: Complete Remission (CR): normalization of bowel function; Partial Remission (PR): 50% reduction in frequency of bowel movements; Failure: <50% reduction in frequency of bowel movements; or Relapse: return of symptoms after cessation of treatment. Median follow-up was 58 wk from time of diagnosis, with a range of 22-376 wk. RESULTS: The 26 patients (25 women, one man) had a mean age of 62 yr (range, 22-85 yr) at diagnosis. Of 26 patients, 22 responded to some form of therapy and one had spontaneous remission. Six of the responders ultimately remained in CR with no therapy. Twelve are maintained on 5-aminosalicylic acid (5-ASA) and or antidiarrheals to control symptoms. An additional six required prednisone throughout the follow-up period to remain in CR or PR. Two patients failed all therapy. CONCLUSION: Collagenous colitis is a treatable condition in most patients. We recommend initial therapy with antidiarrheals, followed by a trial of 5-ASA agent. A trial of 5-ASA in combination with prednisone should be attempted in patients refractory to 5-ASA alone, with subsequent attempts in the responders to taper prednisone and maintain remission with no therapy, if possible, or with 5-ASA and/or antidiarrheal agents if necessary.

Adult↗
PubMed2000

Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1.

Twelve to 15% of sporadic colorectal cancers display defective DNA mismatch repair (MMR), manifested as microsatellite instability (MSI). In this group of cancers, promoter hypermethylation of the MMR gene hMLH1 is strongly associated with, and believed to be the cause of, MSI. A subset of colorectal neoplastic lesions arising in inflammatory bowel disease (IBD) is also characterized by MSI. We wished to determine whether hMLH1 hypermethylation was associated with diminished hMLH1 protein expression and MSI in IBD neoplasms. We studied 148 patients with IBD neoplasms, defined as carcinoma or dysplasia occurring in patients with ulcerative colitis or Crohn's disease. MSI was evaluated using multiplex fluorescent PCR to amplify loci D2S123, BAT-25, BAT-26, D5S346, and D17S250 in all cases. Lesions were characterized as high-frequency MSI (MSI-H) if they manifested instability at two or more loci, low-frequency MSI (MSI-L) if unstable at only one locus, or MS-stable (MSS) if showing no instability at any loci. Methylation-specific PCR was performed to determine the methylation status of the hMLH1 promoter region. hMLH1 protein expression was also evaluated by immunohistochemistry. Thirteen (9%) of 148 neoplasms arising in IBD were MSI-H, comprising 11 carcinomas and 2 dysplastic lesions. Sixteen additional lesions (11%) were MSI-L, comprising 11 carcinomas and 5 dysplastic lesions. The remaining 118 neoplasms (80%) were MSS. Six (46%) of 13 MSI-H, 1 (6%) of 16 MSI-L, and 4 (15%) of 27 MSS lesions showed hMLH1 hypermethylation (P = 0.013). Diminished hMLH1 protein expression in neoplastic cell nuclei relative to surrounding normal cell nuclei was demonstrated immunohistochemically in four of four (100%) hypermethylated lesions tested. In IBD neoplasia, hMLH1 promoter hypermethylation occurs frequently in the setting of MSI, particularly MSI-H. Furthermore, hMLH1 hypermethylation and MSI are strongly associated with diminished hMLH1 protein expression in IBD neoplasms. These findings suggest that hMLH1 hypermethylation causes defective DNA MMR in at least a subset of IBD neoplasms.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Low prevalence of the APC I1307K sequence in Jewish and non-Jewish patients with inflammatory bowel disease.

A germline sequence alteration at codon 1307 of the APC gene (I1307K) has been reported in 6-7% of the Ashkenazi Jewish population in the United States. This alteration is believed to predispose the APC gene to a secondary mutation at the same locus, resulting in an increased risk of colorectal carcinoma. There is an increased risk of colorectal carcinoma in patients with inflammatory bowel disease (IBD), a relatively large proportion of whom are Ashkenazi Jews. We therefore sought to determine whether the I1307K sequence variant occurred in the germline DNA of IBD patients. To our surprise, we found this sequence in only two of 267 patients with IBD (0.7%), occurring in only 1.5% of Jewish IBD patients. The I1307K sequence variant was not found in 67 patients with esophageal cancer, 53 patients with gastric carcinoma (13 MSI-H and 44 MSI-negative), or ten patients with sporadic MSI-H colon cancer. These findings suggest that the I1307K sequence is relatively rare in the germline of Jewish as well as non-Jewish IBD patients. It does not appear to contribute to the increased colorectal cancer risk present in these patients.

Colorectal Neoplasms↗
PubMed1999

Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps.

BACKGROUND & AIMS: Adenomatous polyps are by definition dysplastic and pathologically indistinguishable from the dysplasia-associated lesion or mass (DALM) described in 1981. Yet, adenomatous polyps in noncolitic colons are usually removed definitively endoscopically, whereas DALMs are regarded as harbingers of colon cancer, mandating colectomy. METHODS: Since 1988, all of our patients with chronic ulcerative or Crohn's colitis and dysplastic polyps and no coexistent dysplasia in flat mucosa underwent colonoscopic polypectomy. Biopsy specimens were obtained also adjacent to polypectomy sites, from strictures, and throughout the colon at 10-cm intervals. Follow-up colonoscopies and biopsies were performed within 6 months after polypectomy and yearly thereafter. RESULTS: Colonoscopy in 48 patients with chronic colitis (mean duration, 25.4 years) resected 70 polyps (60 in colitic and 10 in noncolitic mucosa). Polyps were detected on screening colonoscopies (29%) and on surveillance (71%). Pathology was tubular adenoma in all polyps from noncolitic mucosa and low-grade dysplasia (57), high-grade dysplasia (2), or carcinoma (1) in polyps from colitic mucosa. Subsequent colonoscopies (mean follow-up, 4.1 years) revealed additional polyps in 48% but no carcinomas. Surgical resection (6 patients) for recurrent polyps confirmed colonoscopic findings. No dysplasia or cancers in flat mucosa were found at surgery or on follow-up colonoscopies. CONCLUSIONS: In patients with chronic colitis who have no dysplasia in flat mucosa, colonoscopic resection of dysplastic polyps can be performed effectively, just as in noncolitic colons.

Adenoma↗
PubMed1997

FHIT gene alterations in esophageal cancer and ulcerative colitis (UC).

FHIT (fragile histidine triad gene), a candidate tumor suppressor gene, was recently identified and cloned at chromosome 3p14.2. Alterations of this gene have been reported in a number of primary human tumors, including colorectal, esophageal, gastric and lung carcinomas. However, some reports have found no abnormalities in this gene. We investigated a total of 63 primary esophageal tumors, nine esophageal cancer cell lines and 17 ulcerative colitis-associated neoplasms (UCANs) for alterations of FHIT. In 13 esophageal tumors, we employed overlapping reverse transcriptase-PCRs (RT-PCRs) to amplify and sequence the complete open reading frame of FHIT. One of 13 primary esophageal tumors analysed by RT-PCR expressed no detectable FHIT transcript; the remaining 12 expressed normal-sized transcripts with wild-type open reading frame sequences. In an additional 50 esophageal tumors, the polymorphic microsatellite loci D3S1300 and D3S1313 were used to evaluate loss of heterozygosity (LOH) at 3p14.2. Eleven of these 50 tumors showed LOH at one or both loci. In all these 11 tumors, genomic PCR and direct sequencing of FHIT exons 5-9 was performed. This analysis revealed that none of these 11 primary esophageal tumors contained any alterations in the FHIT open reading frame or adjacent intron sequences. Finally, among 17 UCANs, the in vitro synthesized protein (IVSP) assay detected no truncated protein products, nor were there any abnormalities in size or DNA sequence of FHIT RT-PCR products. However, in six of nine esophageal carcinoma cell lines, no FHIT RT-PCR product was detectable using either of the overlapping primer sets. Genomic PCR and direct sequencing of exons 5-9, also performed in these nine cell lines, revealed wild-type sequence in eight cell lines; however, one cell line contained no exon 5 PCR product. This cell line also lacked detectable FHIT transcript. These data suggest that the open reading frame of FHIT is not important in the development or progression of most primary esophageal carcinomas or UCANs, although lack of expression of the FHIT transcript may be common in esophageal cancer-derived cell lines. The possibility of an additional tumor suppressor gene at chromosome 3p14.2 remains to be evaluated.

Acid Anhydride Hydrolases↗
PubMed1997

Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.

The E2F group of transcription factors transactivates genes that promote progression through the G1-S transition of the cell cycle. Members of the retinoblastoma (Rb) family of proteins bind to E2Fs and inhibit this function. E2F-4, one example of the E2F group, functions as an oncogene when transfected into nontransformed cells in vitro. On the other hand, mice that are homozygously lacking a normal E2F-1 gene develop cancers, consistent with a tumor-suppressive role for this gene. The exact function of E2Fs has thus been unclear; moreover, direct involvement of this gene in primary human tumorigenesis has not been shown. We, therefore, investigated mutation within the E2F-4 coding region in 16 primary gastric adenocarcinomas, 12 ulcerative colitis-associated neoplasms, 46 sporadic colorectal carcinomas, 9 endometrial cancers, and 3 prostatic carcinomas. We limited our investigation to the serine repeat within E2F-4, reasoning that this tract might be altered in genetically unstable tumors (replication error-positive, or RER+). All tumors were RER+, with the exception of a control group of 15 RER- sporadic colorectal carcinomas. PCR with incorporation of [32P]dCTP was performed using primers flanking the serine trinucleotide (AGC) repeat. Twenty-two of 59 gastrointestinal tumors (37%) contained E2F-4 mutations; these comprised 5 of 16 gastric tumors (31%), 4 of 12 ulcerative colitis-associated neoplasms (33%, including 1 dysplastic lesion), and 13 of 31 sporadic colorectal cancers (42%). No mutation was present in any of the endometrial, prostate, or RER- colorectal tumors. Of note, homozygous mutations occurred in three cases, and two of seven informative patients showed loss of one E2F-4 allele in their tumors. Furthermore, the RER+ sporadic colorectal tumors were evaluated at trinucleotide repeats within the genes for N-cadherin and B-catenin; no tumors demonstrated mutation of these genes. These data suggest that E2F-4 is a target of defective DNA repair in these tumors.

Adenocarcinoma↗
PubMed1997

A transforming growth factor beta 1 receptor type II mutation in ulcerative colitis-associated neoplasms.

BACKGROUND & AIMS: Numerous gastrointestinal tumors, notably sporadic and ulcerative colitis (UC)-associated colorectal carcinomas and dysplasias, gastric cancers, and esophageal carcinomas, manifest microsatellite instability. Recently, a transforming growth factor beta 1 type II receptor (TGF-beta 1RII) mutation in a coding microsatellite was described in colorectal carcinomas showing instability. One hundred thirty-eight human neoplasms (61 UC-associated, 35 gastric, 26 esophageal, and 16 sporadic colorectal) were evaluated for this TGF-beta 1RII mutation. METHODS: Whether instability was present at other chromosomal loci in these lesions was determined. In lesions manifesting or lacking instability, the TGF-beta 1RII coding region polydeoxyadenine (poly A) microsatellite tract was polymerase chain reaction amplified with 32P-labeled deoxycytidine triphosphate. Polymerase chain reaction products were electrophoresed on denaturing gels and exposed to radiographic film. RESULTS: Three of 18 UC specimens with instability at other chromosomal loci (17%) showed TGF-beta 1RII poly A tract mutation, including 2 cancers and 1 dysplasia; moreover, 2% of UC specimens without instability (1 of 43) (1 cancer), 81% of unstable sporadic colorectal cancers (13 of 16), and none of the 61 stable or unstable gastric or esophageal cancers contained TGF-beta 1RII mutations. CONCLUSIONS: Mutational inactivation of the poly A microsatellite tract within TGF-beta 1RII occurs early and in a subset of unstable UC neoplasms and commonly in sporadic colorectal cancers but may be rare in unstable gastric and esophageal tumors.

Activin Receptors, Type I↗
PubMed1997

Carcinoid tumor and inflammatory bowel disease: a study of eleven cases and review of the literature.

OBJECTIVES: To determine the frequency and outcome of carcinoid tumors in a large series of patients with inflammatory bowel disease (IBD). METHODS: Eleven patients with carcinoid tumors associated with IBD were admitted or readmitted to The Mount Sinai Hospital between 1960 and 1995. These cases were derived from two sources, seven from our clinical series of 3326 IBD patients (0.2%) and four more recent cases from the records of our Pathology Department. Six of the cases were associated with Crohn's disease and five with ulcerative colitis. RESULTS: Nine of the 11 carcinoids were found in the appendix, and 2 were found in the ileum. All carcinoids were found incidentally after surgery for IBD; none of the patients had distant metastases or carcinoid syndrome. Of the 11 cases, 3 were associated with an additional noncarcinoid tumor: 2 with adenocarcinoma of the colon and 1 with endometrial carcinoma. CONCLUSIONS: There appears to be no evidence to substantiate a direct association between IBD and carcinoid tumor, because almost all cases were found incidentally after surgery for IBD, with a frequency in operated IBD patients similar to that reported for patients without IBD.

Adenocarcinoma↗
PubMed1996

Infrequent DPC4 gene mutation in esophageal cancer, gastric cancer and ulcerative colitis-associated neoplasms.

Homozygously Deleted in Pancreatic Cancer 4 (DPC4), a recently identified candidate tumor suppressor gene, was previously shown to be altered in human pancreatic cancers. We examined DPC4 mutation in 30 examples of three other types of gastrointestinal malignancy: 10 esophageal cancers, 10 gastric cancers and 10 colorectal cancers occurring in the preneoplastic condition, ulcerative colitis. The entire coding region of DPC4 (including all 11 exons) was analysed by either direct sequencing of PCR product or the in vitro synthesized protein assay. No coding region mutations of DPC4 were found in any of the samples examined. Our results suggest that inactivation of DPC4 may not be important in the majority of these types of gastrointestinal cancer.

Colitis, Ulcerative↗
PubMed1996

Sialosyl-Tn antigen is prevalent and precedes dysplasia in ulcerative colitis: a retrospective case-control study.

BACKGROUND & AIMS: Expression of the carbohydrate-associated sialosyl-Tn (STn) antigen has been correlated with carcinogenesis in sporadic colon cancer. This retrospective study analyzed surveillance colonoscopy biopsy specimens to determine whether STn antigen could serve as a marker for neoplasia risk in patients with long-standing ulcerative colitis. METHODS: Eleven patients who developed dysplasia or cancer and who had undergone at least three surveillance colonoscopies were matched with 11 controls who had not developed neoplasia. Sections from 969 available surveillance biopsy specimens were stained immunohistochemically with monoclonal antibody TKH2 and were interpreted blindly. RESULTS: Compared with controls, patients expressed STn antigen more frequently in their biopsy specimens (44% patient biopsy specimens vs. 11% control biopsy specimens). Patients were also more likely to undergo colonoscopies with two or more colonic segments expressing STn antigen (73% vs. 22%), repeated STn antigen expression in two or more consecutive colonoscopies (91% vs. 27%), and STn antigen expression proximal to the hepatic flexure (64% vs. 0%). STn antigen appearance preceded the detection of neoplasia by 7 or fewer years, and its preferential expression in patients was not confounded by the degree of active inflammation. CONCLUSIONS: Repeated STn antigen expression in nondysplastic colonic mucosa may presage the development of neoplasia in long-standing ulcerative colitis and may be a useful adjunct to dysplasia during colonoscopic surveillance.

Adult↗
PubMed1996

Colorectal adenocarcinoma in Crohn's disease.

OBJECTIVE: The authors' aim was to review the clinical features and estimate the long-term survival of patients with colorectal carcinoma complicating Crohn's disease. SUMMARY BACKGROUND DATA: Recent studies have demonstrated a significantly increased risk of colorectal carcinoma in patients with Crohns disease. METHODS: The authors reviewed retrospectively the medical records of 30 patients with Crohn's disease admitted to The Mount Sinai Hospital between 1960 and 1989 in whom colorectal adenocarcinoma developed. All patients were operated on and follow-up was complete for all patients to 10 years after operation, to the time of death, or to the closing date of the study in December 1989. RESULTS: The 30 patients in the series had 33 colorectal adenocarcinomas; three patients (10%) presented with two synchronous cancers. The patients were relatively young (mean age, 53 years) and had long-standing Crohn's disease (duration >20 years in 87%). The 5-year actuarial survival was 44% for the overall series: 100% for stage A, 86% for stage B, 60% for stage C. All five patients with excluded bowel tumor died of large bowel cancer within 2.4 years; by contrast, the actuarial 5-year survival for patients with in-continuity tumors was 56%. CONCLUSIONS: The incidence, characteristics, and prognosis of colorectal carcinoma complicating Crohn's disease are similar to the features of cancer in ulcerative colitis, including young age, multiple neoplasms, long duration of disease, and greater than a 50% 5-year survival rate (without excluded loops). These observations suggest the advisability of surveillance programs for Crohn's disease of the colon similar to those for ulcerative colitis of comparable duration and extent.

Adenocarcinoma↗