Biomedical subjects
P Watson
Publications and source records attributed to P Watson.
Colon cancer genetics.
The terms "hereditary," "sporadic," and "familial" colorectal cancer (CRC) suggest a knowledge of causation; however, current understanding of CRC does not permit categorization of differing CRC risks in accord with their cause per se. Despite these serious shortcomings, these terms are defined operationally on the basis of a family history of cancer, and when available, additional phenotypic information. The sporadic type occurs in the absence of a family history of CRC in a first-degree relative. The familial type occurs when at least one first-degree relative has CRC. Both these categories require the exclusion of hereditary CRC. In the case of hereditary CRC, this type is defined as a family history of CRC occurring in a pattern that indicates autosomal-dominant inheritance, which also may involve certain phenotypic signs (depending on the specific disorder, i.e., florid adenomatous polyps, benign and malignant extracolonic lesions, cancer of unusually early onset, and multiple primary cancer, particularly synchronous and metachronous CRC). Although this operational classification does not produce etiologically homogeneous groups, it is believed to have pragmatic utility with respect to planning targeted surveillance and management strategies. Because of the distinctive natural history of CRC in hereditary syndromes, it is of paramount clinical importance to identify hereditary CRC when it does occur. Even in patients with no evidence of hereditary CRC syndrome, their family history may be second only to age in determining the best CRC screening program for those who are asymptomatic. In an attempt to provide a perspective on the clinical evaluation of CRC risk, research was reviewed on pathologic features and biomarkers that may be related to CRC causes, especially the genetic basis of CRC susceptibility. The long-term objective of studies on the genetic epidemiology of CRC is primary and secondary prevention through development of targeted management and surveillance recommendations (based on an understanding of CRC causation) that is relevant to hereditary, familial, and sporadic CRC.
Medical records in general practice.
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Genetic counselling and hereditary breast ovarian cancer.
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Natural history and age at onset of hereditary breast cancer.
Hereditary breast cancer (HBC) is noteworthy for certain unique facets of its natural history and heterogeneity. Interfamily heterogeneity in age at initial breast cancer diagnosis was investigated in 217 family members with HBC. The mean age at diagnosis was 44.9 years (standard deviation +/- 12.5 years). A one-way analysis of variance in ages at diagnosis, using the family as a random effect factor, indicated that between-family differences were significant (P less than 0.002) and accounted for approximately 18% of the variance in ages at diagnosis. A subset of families with HBC was characterized by an extraordinarily early onset of breast cancer. A knowledge of the natural history of HBC with particular attention to age at onset allows for the development of more accurately targeted surveillance, genetic counselling, and management strategies.
Hereditary flat adenoma syndrome: a variant of familial adenomatous polyposis?
We describe the clinical and pathologic features in four extended kindreds that are consistent with the hereditary flat adenoma syndrome (HFAS). This colon cancer susceptibility disorder is believed to be inherited as an autosomal dominant. The principal phenotypic marker is multiple colonic adenomas (usually less than 100), with a tendency for proximal location. The majority of these adenomas are flat or slightly raised and plaquelike, as opposed to polypoid. Colon cancers have typically developed in middle age and show no unusual histologic features. There are a variety of extracolonic manifestations, including adenomas and carcinomas of the small bowel and fundic gland polyps. The HFAS is contrasted with hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis (FAP) and shown to be distinct from both in the numbers and distribution of colonic adenomas and the typical age of cancer diagnosis. The clinical implications of these findings are discussed. Given its linkage to the FAP locus on 5q and the phenotypic parallels between HFAS and FAP, we conclude that HFAS is a variant of FAP.
Epidemiologic characteristics of the flat adenoma of Muto. A prospective study.
UNLABELLED: The flat adenoma is an endoscopically visible lesion that histologically consists of adenomatous change near the luminal surface of colonic tubules. We have described three families with hereditary colon cancer with later age of onset than familial adenomatous polyposis (FAP) and with multiple proximal colonic flat adenomas. These families have been linked to the FAP locus on chromosome 5. Our aim was to determine whether the flat adenoma is pathognomonic of this hereditary flat adenoma syndrome (HFAS) or merely an atypical or early tubular adenoma with occurrence in patients other than those from colon cancer-prone families. METHODS: We prospectively examined a population referred for colonoscopy within a one-year period. During colonoscopy, flat adenomas were specifically sought and all lesions were removed endoscopically and evaluated histologically. Members of known hereditary colon cancer families were excluded. RESULTS: One hundred forty-eight patients underwent colonoscopy (64 men and 84 women). Median age was 61 years. Fifty-seven patients had 157 polyps. One hundred thirty-six polyps were reviewed histologically. Thirty-five (23.6 percent) of the referred patients had adenomas, of whom twelve patients had only flat adenomas while six had both flat and other adenomas (18 = 12 percent of 148). The associations between flat adenoma occurrence and various predictors (sex, race, prior colonic neoplasms, family history of cancer, synchronous adenomas) were similar to those seen with other adenomas. Flat adenomas were found in nearly equal proportions of patients under or over age 61 years (11 percent and 13 percent, respectively). Other adenomas were significantly more common in the older group (6 percent vs. 25 percent; P less than 0.002 by Fisher's exact test). CONCLUSION: In a referral practice, the flat adenoma has the same prevalence and associated risk factors as other adenomas, except for younger age of onset. Our data suggest that the flat adenoma represents an early stage of adenoma development that is manifested in a subset of patients from the general population and that, as an isolated event, does not provide a marker for a hereditary colon cancer-prone syndrome.
Hereditary ovarian cancer: a clinicopathological study.
Hereditary ovarian cancer (HOC) is rare and little recognized. Over the years, we have identified 37 HOC patients from HOC syndrome kindreds with documented cancers of ovary, breast, colon, or endometrium in two or more first-degree relatives. The age and clinical stage at diagnosis and overall 5-year survival of HOC patients were compared with those of ovarian cancers in the unselected patients. The gross and microscopic features of the tumors are compared with a set of 34 consecutively chosen ovarian cancer cases with documented negative family histories. The mean age of HOC patients at diagnosis was significantly lower (50.2 years) than that of the unselected control population (59 years) (p less than 0.001). Detailed pedigree analysis breaks down the HOC group into (a) site-specific ovarian cancer, 5 cases, 56.4 years mean age; (b) breast-ovarian cancer syndrome, 28 cases, 50.46 years mean age; and (c) Lynch syndrome II (colon/endometrial cancer), 4 cases, mean age 41 years. The age differences were statistically significant (p = 0.050). The most prevalent International Federation of Gynecology and Obstetrics clinical stage at diagnosis of HOC (stage III) was the same as for the control group. Histologically, all (100%) HOC tumors were surface epithelial cancers with predominance of serous papillary type moderate to high grade (89 versus 71% in control, p = 0.07). No other pathologic features appeared to be significant. In conclusion, HOC is a serous papillary tumor and characterized by early age of onset and excess of breast/ovary/colon-endometrial cancers in first-degree relatives of patients with specific HOC syndromes.
Surgically induced necrotising sclerokeratitis (SINS)--precipitating factors and response to treatment.
The clinical features, treatment, and visual outcome of 52 eyes from 43 patients who developed scleritis following surgery were reviewed. In all patients the scleral inflammation developed adjacent to a surgical wound. Ninety six per cent had necrotising disease and 23% also had evidence of secondary posterior scleritis. Many different types of ocular surgery were implicated and the majority (75%) of the patients had two or more surgical procedures before the onset of the scleritis. Although cataract extraction through a limbal incision resulted in the largest subgroup, scleritis also followed glaucoma, strabismus, and retinal detachment surgery. The latent period between surgery and the appearance of inflammation was short (mean 9 months) except for a small group in whom scleritis occurred many years after squint surgery. Sixty three per cent of patients had evidence of a systemic disease. Early diagnosis and aggressive medical treatment significantly improved the visual outcome. The precipitating factors, pathogenesis, and course of this condition are discussed.
Linkage of a variant or attenuated form of adenomatous polyposis coli to the adenomatous polyposis coli (APC) locus.
Adenomatous polyps are an intermediate in the pathway to colon carcinoma. An inherited disorder, familial adenomatous polyposis coli (APC), is characterized by hundreds to thousands of adenomatous polyps. A previously reported family had colon cancer associated with a low average but highly heterogenous number of colonic polyps, this phenotype mapped to the APC locus on 5q. Four new families have been ascertained in which the phenotypic pattern was different from classical polyposis but similar to that of the "prototype" kindred reported earlier. By multilocus linkage analysis, the gene responsible for the disease phenotype was mapped, with a high level of confidence, to the APC locus in two of the four families with the attenuated or variant form of polyposis (AAPC); the results for the two remaining kindreds were inconclusive. A combined maximum LOD score of approximately 7.6 at a recombination fraction of 0 was obtained when the results were summed over the four pedigrees with markers closest to the APC locus. The establishment of genetic linkage in such families may point to the APC locus as having a more significant role in inherited predispositions to colorectal cancer than was previously thought.
Natural history of at-risk Lynch syndrome family members with respect to adenomas.
UNLABELLED: Our goal is to determine colon cancer surveillance strategy in patients at risk for Lynch's syndrome. Asymptomatic persons at 50% risk of having Lynch syndrome (age 25-70 years) were enrolled in colonoscopic screening. Those without adenomas were asked to return in one year. Those with adenomas were asked to return in six months because of concern for rapid malignant degeneration. RESULTS: Twenty-five males and thirty females participated. On initial exam, eight of fifty-five patients (14.5%) had adenomas. Logistic regression showed a significant effect of age on the probability of finding adenomas at initial examination (p < 0.02). Followup was available in 27 patients (mean 35.5 months). Kaplan-Meier estimation of time to finding new or previously missed adenomas was 58 months for patients clear on first colonoscopy and 16 months for patients who had adenomas on first exam (p < 0.01). One adenocarcinoma has been found arising in a tubulovillous adenoma. CONCLUSION: The short-term risk of colorectal cancer in Lynch syndrome relatives without adenomas is low, as is the risk in those who have had all visualized adenomas removed.
Upper gastrointestinal bleeding in acute pancreatitis.
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Ciprostene and indomethacin partially reverse the mechanisms of distal end necrosis in the rat random skin flap.
Survival of random skin flap distal end depends on hemodynamic, cellular, and coagulation mechanisms. This study was designed to evaluate whether administration of ciprostene, a stable prostaglandin I2 analogue, and indomethacin, a cyclooxygenase-hydroperoxydase enzyme inhibitor, would improve the survival rate of random skin flaps. Forty-five male rats were divided into nine groups and injected with sesame oil (control), ciprostene (20 micrograms/kg/day), and/or indomethacin (2 mg/kg/day). Injections were done before (pretreatment for 4 days), after (posttreatment for 6 days), and before/after (pre/posttreatment for 4 and 6 days, respectively) the elevation of random dorsal skin flaps. In the pretreatment and pre/posttreatment studies, the flap survival rate of all drug-injected groups was significantly higher than that of the control group (p less than 0.02). In addition administration of ciprostene alone yielded a trend of better flap survival rate, which, however, was not statistically significant (p less than 0.12). Of interest in the posttreatment study, only the simultaneous administration of ciprostene and indomethacin significantly increased skin flap viability compared with the other groups (p less than 0.02). Therefore, the results demonstrated that administration of ciprostene and indomethacin either alone or together partially reversed the pathophysiological mechanisms that cause necrosis of random skin flap distal end. These pharmacological changes significantly improved random skin flap survival rate.
Familial breast-ovarian cancer locus on chromosome 17q12-q23.
Familial breast cancer has been linked to the D17S74 locus on chromosome 17q. To confirm this finding and to investigate whether ovarian cancer is also linked to this locus, five large families with a hereditary predisposition to cancer of the breast and ovary were investigated. Three families were positive for linkage. For the largest family the lod score was 2.72. These findings suggest that the chromosomal region 17q12-q23, previously shown to contain a gene for early-onset breast cancer, is also associated with a proportion of hereditary ovarian cancers.
Hereditary ovarian cancer. Heterogeneity in age at diagnosis.
An unknown fraction of the ovarian cancer burden occurs in women with a family history indicative of a putative autosomal dominantly inherited cancer susceptibility syndrome. The results from a five-generation, extended, hereditary breast-ovarian cancer kindred are described 10 years after it was initially ascertained. Significantly more cancers were observed in high-risk family members during this decade than were expected (P less than 0.001). The age of ovarian cancer diagnosis was studied in additional ovarian cancer-prone families of three types: site-specific ovarian cancer syndrome, the breast-ovarian cancer syndrome, and Lynch syndrome II. The age of onset in each of the three sets was significantly (P less than 0.001) earlier than the general population mean of 59, and there were significant differences in the age of onset (P = 0.050) among these three cohorts. Ovarian cancer histology was similar to that of patients with negative family histories. There may be clinically significant heterogeneity in the age at diagnosis of ovarian cancer among these ovarian cancer-prone syndromes. This has important implications for understanding its natural history and targeting surveillance-management strategies.
Managing spinal cord compression in small cell lung cancer.
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