Biomedical subjects

S R Hamilton

Publications and source records attributed to S R Hamilton.

At least 145 records · Page 8Linked to original sources

PubMed1993

Idiopathic hypertrophic cranial pachymeningitis.

We evaluated 3 patients with biopsy-proven hypertrophic cranial pachymeningitis apparently unrelated to any systemic disease. Each patient had chronic headache, cranial neuropathy, an elevated ESR, and a mild CSF pleocytosis. Neuro-ophthalmic findings included bilateral sixth nerve palsies in two patients and the third had bilateral optic neuropathies. MR imaging revealed thickened dura that enhanced with Gd-DTPA administration. Histologic examination showed thickened, fibrotic dura with a sterile, chronic, nongranulomatous inflammation. The response to treatment was variable with corticosteroids, immunosuppressive drugs, or radiation. The distinctive MR appearance should help physicians recognize this rarely reported disease.

Abducens Nerve↗

PubMed1992

APC mutations occur early during colorectal tumorigenesis.

Human tumorigenesis is associated with the accumulation of mutations both in oncogenes and in tumour suppressor genes. But in no common adult cancer have the mutations that are critical in the early stages of the tumorigenic process been defined. We have attempted to determine if mutations of the APC gene play such a role in human colorectal tumours, which evolve from small benign tumours (adenomas) to larger malignant tumours (carcinomas) over the course of several decades. Here we report that sequence analysis of 41 colorectal tumours revealed that the majority of colorectal carcinomas (60%) and adenomas (63%) contained a mutated APC gene. Furthermore, the APC gene met two criteria of importance for tumour initiation. First, mutations of this gene were found in the earliest tumours that could be analysed, including adenomas as small as 0.5 cm in diameter. Second, the frequency of such mutations remained constant as tumours progressed from benign to malignant stages. These data provide strong evidence that mutations of the APC gene play a major role in the early development of colorectal neoplasms.

Adenoma↗

PubMed1992

Molecular genetics of colorectal carcinoma.

The molecular genetics of colorectal carcinoma are among the best understood of any common human cancer. Reported molecular genetic abnormalities involve tumor-suppressor genes that undergo inactivation (e.g., apc, mcc, dcc, p53, and possibly genes on chromosomes 8p, 1p, and 22q) and dominant-acting oncogenes (e.g., ras, src, and myc). Multiple clonal genetic abnormalities accumulate during the development of colorectal carcinoma in adenomas. Altered DNA methylation is an early event, and the specific genetic alterations occur in a preferential order. However, the clinical application of molecular genetics in patients who are at risk for or have colorectal carcinoma is in its infancy. Patients with a predisposition to colorectal carcinoma caused by inheritance of familial adenomatous polyposis can be identified by genetic analysis of the apc gene on chromosome 5q21. In patients who undergo curative resection of colorectal cancer, deletion of the p53 gene on chromosome 17p, deletion of the dcc gene on 18q, and high fractional allelic loss (fraction of nonacrocentric autosomal arms with deletion) in the primary tumor appear to indicate an increased likelihood of occult disseminated disease and thus a poor prognosis. Additional studies are needed to establish the role of the molecular genetics of colorectal carcinoma in the management of patients who are at risk for or already have neoplasia of the large bowel.

Colorectal Neoplasms↗

PubMed1992

Evidence that the MCC-APC gene region in 5q21 is not the site for susceptibility to hereditary nonpolyposis colorectal carcinoma.

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common form of hereditary colon cancer. Autosomal dominant inheritance is evident from pedigrees but the genetic basis of the disorder is otherwise unknown. Recently, two genes in 5q21 involved in colon carcinogenesis, APC and MCC, were identified, and APC was shown to be the gene predisposing to familial adenomatous polyposis. To determine if these genes also confer susceptibility to HNPCC we performed linkage analyses in nine affected families. The MCC-APC region could be formally excluded as the locus for HNPCC in seven families. In one family the results were suggestive of exclusion, although they were not conclusive. The remaining family was uninformative. We used two alternative definitions of affected status. Based on haplotypes for MCC and APC the added pairwise logarithm-of-odds score for all nine families was -22.57 at the recombination fraction of 0.00 using more stringent criteria for the HNPCC phenotype and -22.67 for less stringent criteria. In addition to blood DNA samples from living family members, DNA from formaldehyde-fixed archival pathology specimens from decreased individuals contributed to these linkage results.

Base Sequence↗

PubMed1992

Expression and different polarity of aminopeptidase N in normal human colonic mucosa and colonic tumors.

Expression and cellular localization of brush-border enzymes (aminopeptidase N, dipeptidylpeptidase IV, lactase, maltase) in normal human colon, colonic polyps and malignant intestinal tumors were investigated with a panel of monoclonal antibodies reacting with either native or denatured proteins. The enzymes were detected on cryostat sections by indirect immunofluorescence staining, or affinity-purified and analyzed by gel electrophoresis and immunoblotting. Dipeptidylpeptidase IV, lactase and maltase were absent from all samples examined, while aminopeptidase N (APN) was detected at the basal membrane of the epithelial cells in most specimens of colon obtained from individuals free of intestinal tumors. In contrast, APN was frequently localized at the luminal membrane of the surface epithelium in large-intestinal mucosa distal to tumors, adenomas and hyperplastic polyps, and from members of hereditary colon cancer syndrome families. APN was also expressed in colonic tumors, where it was present in an apical cell membrane location in 3/23 adenomas and 14/35 adenocarcinomas examined. No correlation was found between tumor-cell invasiveness (classified by "Dukes" stage) and expression or cellular location of aminopeptidase N. Histologically, all positive tumors were moderately or well differentiated. These results suggest that aminopeptidase N is normally expressed in adult human colon, but epithelial cells in the large and small intestine differ in their ways of sorting this enzyme intracellularly and eventually inserting it into different aspects of their surface membrane, a process which may be altered at an early stage of carcinogenesis.

Aminopeptidases↗

PubMed1992

Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors.

Colorectal (CR) tumors are usually curable if detected before metastasis. Because genetic alterations are associated with the development of these tumors, mutant genes may be found in the stool of individuals with CR neoplasms. The stools of nine patients whose tumors contained mutations of K-ras were analyzed. In eight of the nine cases, the ras mutations were detectable in DNA purified from the stool. These patients included those with benign and malignant neoplasms from proximal and distal colonic epithelium. Thus, colorectal tumors can be detected by a noninvasive method based on the molecular pathogenesis of the disease.

Adult↗

PubMed1992

Molecular genetic alterations as potential prognostic indicators in colorectal carcinoma.

The molecular genetic alterations in colorectal carcinoma are among the best understood of any common human cancer. Identified abnormalities include both dominant-acting oncogenes (ras, myc, src) and suppressor genes which undergo inactivation or deletion (deleted in colorectal carcinoma gene [DCC], p53, adenomatous polyposis coli gene [APC], and probably loci on chromosomes 1p and 22q). Accumulation of multiple abnormalities is evident in the adenoma-carcinoma sequence with a preferential order, and alteration of DNA methylation is an especially early event. Identification of molecular genetic markers useful for classification and staging of colorectal carcinoma is in its infancy. Deletion of the p53 gene on chromosome 17p, deletion of the DCC gene on 18q, and high fractional allelic loss (fraction of evaluable nonacrocentric autosomal arms with deletion) have been associated with distant metastases and with poorer prognosis in patients without initial evidence of disseminated disease. Additional studies are needed to determine the possible role of these alterations in clinical management.

Chromosome Deletion↗

PubMed1992

The adenoma-adenocarcinoma sequence in the large bowel: variations on a theme.

Most adenocarcinomas of the colorectum arise in a visible benign precursor lesion, the adenoma, which is a monoclonal proliferation of dysplastic nonmalignant epithelial cells. The resultant adenoma-adenocarcinoma sequence represents the predominant pathogenetic pathway, in contrast to de novo carcinoma. Therefore, the adenoma is a tempting endpoint for chemoprevention trials. The adenoma-adenocarcinoma sequence occurs in diverse clinical settings. In familial adenomatous polyposis (FAP) syndrome, autosomal dominant inheritance of the mutated APC (adenomatous polyposis coli) gene on chromosome 5q21 typically results in thousands of adenomas in the colorectum and in lesser numbers in the proximal small bowel. Adenocarcinoma usually develops in only a few of these adenomas, typically in the left colon and duodenum. In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, autosomal dominant inheritance of an unidentified gene appears to result in small numbers of adenomas which progress frequently to adenocarcinoma, predominantly in the right or transverse colon. In familial aggregation of colorectal cancer without a recognizable syndrome, cancer and/or adenomas occur in pedigree members. In "sporadic" cancers and adenomas, family history is absent and the tumors are mainly in the left colon. Colorectal adenomas have variable characteristics including size, shape (polypoid vs. flat), villous architecture, and dysplasia. A variety of oncogenes and tumor suppressor genes are altered during progression. Epigenetic factors are important as evidenced by the disappearance of adenomas in FAP patients after ileorectal anastomosis or treatment with the nonsteroidal antiinflammatory drug sulindac. Several variations on the theme of the adenoma-carcinoma sequence are evident. Identification of the inherited and acquired genetic alterations as well as the interacting environmental factors will provide a rational basis for chemoprevention.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMed1992

The risk of upper gastrointestinal cancer in familial adenomatous polyposis.

Adenomas with potential for malignancy occur frequently in the upper gastrointestinal tract of patients with familial adenomatous polyposis. However, an assessment of relative risk of upper gastrointestinal cancer in patients with adenomatous polyposis has never been performed. Therefore, the incidence rate of upper gastrointestinal cancer in patients with familial adenomatous polyposis in The Johns Hopkins Registry was compared with the rate of the general population through person-year analysis with adjustment for demographics. There was an increased relative risk of duodenal adenocarcinoma (relative risk, 330.82; 95% confidence limits, 132.66 and 681.49; P less than 0.001) and ampullary adenocarcinoma (relative risk, 123.72; 95% confidence limits, 33.65 and 316.72; P less than 0.001). No significant increased risk was found for gastric or nonduodenal small intestinal cancer. These results indicate that periodic surveillance of the upper gastrointestinal tract for duodenal and periampullary cancer is needed in patients with familial adenomatous polyposis. Prophylactic duodenectomy is a consideration when large adenoma(s) with high-grade dysplasia are identified but awaits risk benefit analysis.

Adenomatous Polyposis Coli↗

PubMed1992

The relationship of DNA aneuploidy to molecular genetic alterations in colorectal carcinoma.

Altered total nuclear DNA content is frequent in colorectal carcinomas, but the mechanisms producing aneuploidy are unknown. Therefore, DNA ploidy by flow cytometry was correlated with molecular genetic alterations and tumor characteristics in 50 colorectal carcinomas. The prognostic value of these alterations was also evaluated because aneuploidy has been associated with poor prognosis. Thirty-nine of the carcinomas (78%) were DNA aneuploid. When compared with diploid carcinomas, aneuploid tumors had greater mean fractional allelic loss, defined as the fraction of evaluable nonacrocentric autosomal arms with deletion (0.25 +/- 0.15, range 0-0.667, vs. 0.12 +/- 0.10, range 0-0.345; P = 0.006). DNA index by flow cytometry correlated with fractional allelic loss (r = 0.38, P = 0.006). Aneuploid tumors also had more frequent allelic loss on chromosome 17p (87% vs. 55%; P = 0.017), but less frequent ras gene mutation (44% vs. 82%; P = 0.025). Among the 25 right-sided and 25 left-sided tumors, DNA diploid tumors were more frequent on the right side (P = 0.002), whereas deletion of 17p was found predominantly on the left side. Aneuploidy was associated with moderate and poor differentiation of the carcinomas but not with distant metastasis. By contrast, high fractional allelic loss, deletion of 17p, and deletion of 18q were associated with distant metastasis. In survival analysis of patients with Dukes' B or C carcinoma, DNA aneuploidy was not a significant discriminator, but patients whose tumor had deletion of 17p or deletion of both 17p and 18q had poorer survival (P = 0.045 and 0.022, respectively). The results suggest that DNA aneuploidy is associated with some of the molecular genetic alterations and phenotypic characteristics of colorectal carcinomas but is not a reliable indicator of metastatic potential.

Adult↗

PubMed1992

Patterns of ileal recurrence in Crohn's disease. A prospective randomized study.

To gain information on the pathogenesis of ileal recurrence, 86 patients with Crohn's disease undergoing their first ileocolic resection were randomized to receive either an end-to-end (n = 47) or side-to-end (n = 39) anastomosis. The demographic and clinical characteristics of both groups were similar. There were no statistically significant differences between the two groups in postoperative complications or in the subsequent development of symptomatic or documented recurrences. Among the 43 patients with follow-up in the end-to-end anastomosis group, there were 10 documented ileal recurrences (23%), and all involved distal ileum in the characteristic preanastomotic location. Among the 35 patients with follow-up in the side-to-end anastomosis group, there were 11 documented recurrences (31%, not significant). The ileal recurrence pattern could be determined accurately in five of these 11 patients and involved the ileum adjacent to the colon, but spared the distal ileum in the blind pouch. This study suggests that the fecal stream and reflux of colonic contents are important factors in determining the pattern of ileal recurrence after ileocolectomy for Crohn's disease.

Adult↗

PubMed1992

The relationship of quantitative nuclear morphology to molecular genetic alterations in the adenoma-carcinoma sequence of the large bowel.

The relationship of abnormal nuclear morphology to molecular genetic alterations that are important in colorectal tumorigenesis is unknown. Therefore, Feulgen-stained isolated nuclei from 22 adenomas and 42 carcinomas that had been analyzed for ras gene mutations and allelic deletions on chromosomes 5q, 18q, and 17p were characterized by computerized image analysis. Both nuclear area and the nuclear shape factor representing irregularity correlated with adenoma-carcinoma progression (r = 0.57 and r = 0.52, P < 0.0001), whereas standard nuclear texture, a parameter of chromatin homogeneity, was inversely correlated with progression (r = -0.80, P < 0.0001). The nuclear parameters were strongly interrelated (P < 0.0005). In multivariate analysis, the nuclear parameters were predominantly associated with adenoma-carcinoma progression (P < or = 0.0001) and were not influenced significantly by the individual molecular genetic alterations. Nuclear texture, however, was inversely correlated with fractional allelic loss, a global measure of genetic changes, in carcinomas (r = -0.39, P = 0.011). The findings indicate that nuclear morphology in colorectal neoplasms is strongly related to tumor progression. Nuclear morphology and biologic behavior appear to be influenced by accumulated alterations in cancer-associated genes.

Adenoma↗

PubMed1991

Recurrent idiopathic lateral rectus muscle palsy in adults.

Recurrent, unilateral, isolated, idiopathic lateral rectus muscle palsy is an uncommon but well-recognized disorder in children that has not been recognized as well in other age groups. We studied five cases of this uncommon entity that we encountered in adults and adolescents. Ages at onset ranged from 15 to 72 years and there were three to eight episodes per patient. Most of the patients shared the following features with the previously reported pediatric cases: ipsilateral recurrence, lack of pain, spontaneous recovery within six months, and no clear cause. Unlike the children, females or left-eye involvement was not preponderant in adults.

Adolescent↗

PubMed1991

Ethnic differences in the anatomical location of colorectal adenomatous polyps.

The ratio of right- to left-sided colonic cancer is increasing, but data on the distribution of its usual precursor lesion, the colorectal adenoma, are contradictory. Therefore, we investigated the prevalence of right- and left-sided colorectal adenomatous polyps from January 1, 1970, to September 30, 1989, using the study design of "epidemiologic necropsy" and the autopsy files of The Johns Hopkins Hospital. Compared with the decade of the 1970's, the 1980's showed a slight decrease in the overall prevalence of right-sided adenomas (6.4 per 1,000, 95% confidence limits 4.7-8.8 vs. 5.1 per 1,000, 95% CL 3.6-6.5), but a marked decrease occurred in left-sided adenomas (11.8 per 1,000, 95% CL 9.3-14.3 vs. 6.7 per 1,000, 95% CL 4.8-8.6). As a result, the ratio of right-sided to left-sided adenomas increased from 0.55 in the 1970's to 0.77 in the 1980's. This increased ratio occurred in both sexes, although prevalences were lower in females, and in whites. Unexpectedly, blacks had a ratio of right-sided to left-sided adenomas greater than unity in both the 1970's and 1980's (1.19 vs. 1.79) due to a relatively high prevalence of right-sided adenomas (5.8 per 1,000, 95% CL 3.6-8.0 in 1970's; 5.8 per 1,000, 95% CL 3.3-8.3 in 1980's), but low prevalences of left-sided adenomas (4.9 per 1,000, 95% CL 3.0-6.8 in 1970's; 3.2 per 1,000, 95% CL 1.2-5.2 in 1980's). The overall adenoma prevalence in blacks was lower than in whites. We conclude that the right-sided predominance of colorectal adenomas in blacks suggests ethnic differences in the pathogenesis of colorectal adenomas. This observation may have important implications for secondary prevention of colorectal cancer.

Adenoma↗

PubMed1991

Identification of p53 gene mutations in bladder cancers and urine samples.

Although bladder cancers are very common, little is known about their molecular pathogenesis. In this study, invasive bladder cancers were evaluated for the presence of gene mutations in the p53 suppressor gene. Of 18 tumors evaluated, 11 (61 percent) were found to have genetic alterations of p53. The alterations included ten point mutations resulting in single amino acid substitutions, and one 24-base pair deletion. In all but one case, the mutations were associated with chromosome 17p allelic deletions, leaving the cells with only mutant forms of the p53 gene products. Through the use of the polymerase chain reaction and oligomer-specific hybridization, p53 mutations were identified in 1 to 7 percent of the cells within the urine sediment of each of three patients tested. The p53 mutations are the first genetic alterations demonstrated to occur in a high proportion of primary invasive bladder cancers. Detection of such mutations ex vivo has clinical implications for monitoring individuals whose tumor cells are shed extracorporeally.

Alleles↗

PubMed1991

High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer.

DNA methylation abnormalities occur consistently in human neoplasia including widespread hypomethylation and more recently recognized local increases in DNA methylation that hold potential for gene inactivation events. To study this imbalance further, we have cloned and localized to chromosome 19 a portion of the human DNA methyltransferase gene that codes for the enzyme catalyzing DNA methylation. Expression of this gene is low in normal human cells, significantly increased (30- to 50-fold by PCR analysis) in virally transformed cells, and strikingly elevated in human cancer cells (several hundredfold). In comparison to colon mucosa from patients without neoplasia, median levels of DNA methyltransferase transcripts are 15-fold increased in histologically normal mucosa from patients with cancers or the benign polyps that can precede cancers, 60-fold increased in the premalignant polyps, and greater than 200-fold increased in the cancers. Thus, increases in DNA methyltransferase gene expression precede development of colonic neoplasia and continue during progression of colonic neoplasms. These increases may play a role in the genetic instability of cancer and mark early events in cell transformation.

Animals↗

PubMed1991

Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers.

Recent studies have suggested the existence of a tumor suppressor gene located at chromosome region 5q21. DNA probes from this region were used to study a panel of sporadic colorectal carcinomas. One of these probes, cosmid 5.71, detected a somatically rearranged restriction fragment in the DNA from a single tumor. Further analysis of the 5.71 cosmid revealed two regions that were highly conserved in rodent DNA. These sequences were used to identify a gene, MCC (mutated in colorectal cancer), which encodes an 829-amino acid protein with a short region of similarity to the G protein-coupled m3 muscarinic acetylcholine receptor. The rearrangement in the tumor disrupted the coding region of the MCC gene. Moreover, two colorectal tumors were found with somatically acquired point mutations in MCC that resulted in amino acid substitutions. MCC is thus a candidate for the putative colorectal tumor suppressor gene located at 5q21. Further studies will be required to determine whether the gene is mutated in other sporadic tumors or in the germ line of patients with an inherited predisposition to colonic tumorigenesis.

Adenomatous Polyposis Coli↗

PubMed1991

Evaluation of dietary dehydroepiandrosterone for chemoprotection against tumorigenesis in premalignant colonic epithelium of male F344 rats.

Epidemiological and experimental studies suggest that dehydroepiandrosterone (DHEA), an adrenal cortical steroid, has chemoprotective properties. Rat colonic epithelium which had been induced to a premalignant state by the colonic carcinogen azoxymethane was used as a model for patients at high risk of colorectal carcinoma, and the efficacy of dietary DHEA for chemoprotection against tumorigenesis was evaluated. Ten-week-old male F344 rats (n = 100) were given 10 weekly s.c. injections of azoxymethane at a dose of 10 mg/kg/week. One day after the final dose of carcinogen, DHEA was added to the diet of 50 rats (0.5% DHEA chow), and the other rats were used as pair-fed controls. DHEA-fed rats lost body weight throughout the 17-week study, in contrast to their pair-fed controls. Serum DHEA in DHEA-fed rats at the end of the study was 6 times that of controls (120 +/- 30 versus 18 +/- 14 pmol/ml), and serum DHEA sulfate was 23 times that of controls (1311 +/- 13 versus 55 +/- 13 pmol/ml). Addition of DHEA to the diet produced no significant chemoprotection in our model. Tumor-related mortality was somewhat increased in DHEA-fed rats (20% versus 6% in week 16 of DHEA feeding, P not significant). The cumulative prevalence of left colonic tumors, identified by weekly colonoscopic examinations, was somewhat lower in DHEA-fed rats than in controls during weeks 10 through 13 (17% versus 33% in week 12, P not significant), but in week 14 the prevalence in DHEA-fed rats became similar to that in controls (39% versus 41%). Growth curves of autochthonous left colonic tumors, as assessed for 8 weeks by computerized image analysis of colonoscopic photographs, were similar for DHEA-fed and control rats. Prevalence, mean frequency, multiplicity, and diameter of colonic tumors at necropsy of colonoscopically negative rats in week 17 were somewhat lower in the DHEA-fed rats (e.g., prevalence of 47% versus 67%), but the differences from controls were not significant. Parameters of colonic epithelial proliferation after tritiated thymidine incorporation in DHEA-fed rats were similar to those in control rats (labeling index of 8.3 +/- 0.7% versus 8.4 +/- 0.6% in week 17), despite higher serum DHEA and DHEA sulfate levels. Our findings indicate that DHEA did not have significant postinduction chemoprotective activity against azoxymethane-induced colonic tumorigenesis in this model utilizing pair-fed controls. Further preclinical studies appear to be needed before dietary DHEA can be recommended for chemoprotection trials in patients with premalignant colorectal epithelium.

1,2-Dimethylhydrazine↗