Quality of life and functional outcome for individuals who underwent very early colectomy for familial adenomatous polyposis.

BACKGROUND: The major manifestation of familial adenomatous polyposis is colorectal adenomas, which, if untreated, lead to colorectal cancer. The impact of IPAA on quality of life in adolescents with familial adenomatous polyposis is favorable. There is a group of children who develop polyps at a younger age requiring earlier colectomy. Little is known about this very young subgroup in relation to bowel function or quality of life. OBJECTIVE: The aim of this study was to investigate the outcome in patients with familial adenomatous polyposis who had colectomy at ≤14 years. DESIGN: A cross-sectional quantitative survey was designed to assess outcome. Standardized validated instruments included bowel/psychosocial functioning and quality of life. RESULTS: Among 1337 patients with familial adenomatous polyposis from 409 kindreds, 4% (n = 59) of patients underwent colectomy at ≤14 years of age. Response rate was 84% (n = 32). The mean age at colectomy was 12 years (SD 2), with a current mean age of 24 years (SD 8.5). Fifty-seven percent of patients reported continence. Of the 43% reporting daytime or nighttime incontinence, the majority are <18 years (86%). Younger participants (currently less than 18 years of age) report more restrictions. Mental health is significantly lower among participants with incontinence. They report higher depression and anxiety symptoms, higher levels of intrusion and avoidance, and inferior mental health. The percentage of those worrying about risk of cancer is significantly higher in the younger group (71% vs 24%). Most patients (n = 24, 75%) have had surveillance endoscopy within the past 2 years. LIMITATIONS: This study is limited by study generalizability, selection bias, and small sample size. CONCLUSIONS: Twelve years after colectomy more than half of the patients have favorable bowel function. The rate of incontinence is high, especially among younger patients who have had a shorter time since surgery. Patients with incontinence reported lower psychosocial functioning, are very concerned about their cancer risk, and experience greater distress. This subgroup would benefit from added psychological interventions to enhance coping with familial adenomatous polyposis and surgery.

Mismatch repair deficiency in phenotypically normal human cells.

Tumor cells in patients with hereditary nonpolyposis colorectal cancer (HNPCC) are characterized by a genetic hypermutability caused by defects in DNA mismatch repair. A subset of HNPCC patients was found to have widespread mutations not only in their tumors, but also in their non-neoplastic cells. Although these patients had numerous mutations in all tissues examined, they had very few tumors. The hypermutability was associated with a profound defect in mismatch repair at the biochemical level. These results have implications for the relation between mutagenesis and carcinogenesis, and they suggest that mismatch repair deficiency is compatible with normal human development.

Pathological features of colorectal carcinomas in MYH-associated polyposis.

AIMS: MYH is a DNA glycosylase in the base excision repair pathway. Germ-line biallelic mutations in the MYH gene are associated with the development of multiple colorectal adenomas and colorectal carcinoma (CRC). A slightly increased risk of CRC is suggested in monoallelic MYH mutation carriers. The aim was to characterize the histopathological features of carcinomas from biallelics and monoallelics. METHODS AND RESULTS: Clinicopathological features of 57 colorectal carcinomas from 50 patients identified in familial CRC registries were recorded. These included 16 cancers from 14 MYH biallelics; 25 cancers from 22 MYH monoallelics; and 16 cancers from 14 controls. Carcinomas in biallelics demonstrated tubular, papillary or cribriform patterns as the predominant histological subtype, and main histological groups differed according to mutation status (P = 0.0053). All biallelic cancers were low grade, with high-grade tumours more common in monoallelics and controls (P = 0.002). Synchronous polyps were observed in 75% of biallelics, 33% of monoallelics and 43% of controls (P = 0.035). Serrated carcinoma was the predominant type in 12% (3/25) of the monoallelics but in none of the biallelics or controls. MYH immunohistochemistry failed to distinguish between groups. CONCLUSIONS: Neither pathological features nor immunohistochemistry could predict the MYH mutation status of CRCs in this study.

Inhibition of vascular endothelial growth factor-induced retinal neovascularization by retinoic acid in experimental retinopathy of prematurity.

Vascular endothelial growth factor (VEGF) has an important role in the pathogenesis of retinopathy of prematurity (ROP) and inhibition of VEGF expression in the neovascular phase might prevent destructive neovascularization in ROP. It is suggested that retinoids exert a highly potent antiangiogenic activity by inhibiting VEGF expression. The aim of this study was to demonstrate the preventive effect of retinoic acid (RA) on the VEGF-induced retinal neovascularization in a rat model of ROP. Wistar albino rats were placed into incubators at birth and exposed to an atmosphere alternating between 50 % and 10 % O(2) every 24 hours. After 14 days, the animals were removed to room air and received either an intraperitoneal injection of RA (5 mg/kg/day) (n=9) or saline (n=4) daily for six days, and sacrificed at 21 days. Other rats (n=4) were raised in room air and served as age-matched controls. The globe of each eye was cut through the cornea and embedded in paraffin. Serial sections were stained with hematoxylin-eosin for quantification of neovascular nuclei. The avidin-biotin peroxidase method was performed for evaluation of VEGF expression. The average number of neovascular nuclei was significantly lower in the control group compared to that in the ROP groups. In addition, it significantly decreased in the RA-treated ROP group compared to that of the saline-administrated ROP group. VEGF immunostaining was overall negative in room air-exposed rats. The VEGF immunostaining score significantly decreased in the RA-treated ROP group compared to that in the saline-administered ROP group. RA treatment might be beneficial in preventing neovascularization resulting from oxygen-induced retinopathy by downregulation of VEGF expression.

A truncated hMSH2 transcript occurs as a common variant in the population: implications for genetic diagnosis.

Germline mutations of the hMSH2 gene are responsible for many cases of hereditary nonpolyposis colorectal cancer. While screening for hMSH2 gene mutations in hereditary nonpolyposis colorectal cancer kindreds, we observed that a previously reported germline mutation is in fact a common, alternatively spliced variant in the population. Using RT-PCR and the protein truncation test, the hMSH2 exon 13 deletion variant was found in more than 90% of individuals. The exon 13 deletion transcript was only present in lymphocyte RNA, no abnormalities were detected in genomic DNA flanking exon 13, and the deletion transcript is apparently not translated. These findings highlight further that caution should be exercised in providing genetic risk assessment on the basis of currently used germline mutation detection strategies.

Somatic APC and K-ras codon 12 mutations in periampullary adenomas and carcinomas from familial adenomatous polyposis patients.

Periampullary adenomas in the duodenum of Familial Adenomatous Polyposis (FAP) patients are among the most frequent and clinically important extracolonic neoplasms in FAP. The purpose of this study was to characterize the frequency and nature of somatic adenomatous polyposis coli (APC) gene and K-ras codon 12 mutations in periampullary adenomas and carcinomas in FAP. These molecular changes have been shown to be important during the early stages of colorectal carcinogenesis. DNA was prepared from endoscopic periampullary biopsies and paraffin blocks from 49 FAP patients. Of 143 samples, 77 were histologically normal, 29 were biopsies from small periampullary adenomas, 29 biopsies were from 19 large adenomas and eight samples were from periampullary cancers. APC mutations in the mutation cluster region and K-ras codon 12 mutations were detected by polymerase chain reaction based techniques. Somatic APC mutations consisting of deletions at codons 1464 and 1465 were detected in one small and two large periampullary adenomas. Loss of heterozygosity was seen in one periampullary carcinoma. K-ras codon 12 mutations were detected in seven of 19 large periampullary adenomas and in one of eight periampullary carcinomas. These data suggest that K-ras codon 12 mutations may be important during periampullary tumorigenesis in FAP but somatic APC mutations in the mutation cluster region are infrequent. Local environmental factors in the duodenum may contribute to differences in the molecular changes which occur during the adenoma-to-carcinoma sequence in periampullary compared to colonic tumorigenesis.

Intraductal papillary mucinous neoplasm of the pancreas in a patient with attenuated familial adenomatous polyposis.

A 67 year old man with a clinical diagnosis of attenuated familial adenomatous polyposis (AFAP) and a past history of synchronous colon cancers in the transverse colon was also found to have an intraductal papillary mucinous neoplasm (IPMN) of the pancreas. In addition, several foci of heterotopic gastric oxyntic mucosa were noted in the duodenum, interspersed with flat and polypoid adenomas. The duodenal adenomas showed low grade dysplasia, loss of adenomatous polyposis coli (APC) protein expression, but retention of beta catenin staining, localised to the nucleus and cytoplasm. The IPMN in the pancreas showed an identical immunohistochemical profile to the duodenal adenomas. The heterotopic gastric foci in the duodenum were negative for the APC protein, and beta catenin staining was membranous in location. Although the patient did not show germline truncating APC mutations or mutations in the MYH gene, the past history, clinical features, and immunohistochemical profile of the various lesions suggest strongly that the IPMN is part of the spectrum of lesions encountered in AFAP. Whether the heterotopic oxyntic gastric mucosa in the duodenum is also related is unclear, but it may represent a forme fruste of fundic gland polyps.

Management of advanced duodenal polyposis in familial adenomatous polyposis.

Patients with familial adenomatous polyposis (FAP) are at increased risk for the development of periampullary cancer. The aim of this study was to evaluate the roles of endoscopic and surgical therapy in the management of advanced duodenal polyposis in FAP. From 1990 to 1995, seventy-four FAP patients were enrolled in a prospective endoscopic surveillance protocol. Among these, 11 (14.8%) developed advanced duodenal polyposis and one had duodenal adenocarcinoma. Six patients underwent endoscopic resection of duodenal (n=5) or ampullary adenomas (n=1). The following operations were performed in the remaining six patients: ampullectomy in four, open polypectomy in one, and a Whipple procedure in one. There was one patient who died of acute pancreatitis following endoscopic ampullectomy. The patient with invasive duodenal cancer died of local recurrence. Small polyps were observed at the site of previous resection in all (9 of 9) patients undergoing repeat endoscopy during a mean follow-up of 18 months (range 4 to 34 months). An endoscopic and local surgical resectional approach to advanced duodenal polyposis in FAP is fraught with high recurrence rates, although recurrent polyps are small and may be amenable to retreatment in the future. Long-term follow-up is necessary to prove that deaths from duodenal or ampullary cancer are prevented with this strategy.

Coping styles, psychopathology and intellectual performance in patients with familial adenomatous polyposis.

Thirty-eight patients with familial adenomatous polyposis (FAP) were compared with 19 patients with ulcerative colitis (UC) for differences in illness-related variables, coping styles, psychiatric symptomatology, and intellectual performance. Patients with FAP had significantly less education, longer time since recent surgery, less psychiatric illness, and evidence of less preoccupation with their illness, as compared with UC patients. FAP patients with a positive family history (N = 28) scored significantly lower on both verbal and performance intellectual tests, even when taking education into account, compared with FAP patients without a family history (N = 9). The relevance of these findings to the ongoing monitoring and surveillance of patients with FAP is discussed.

Familial segregation in the occurrence and severity of periampullary neoplasms in familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) patients often develop periampullary adenomas that may progress to periampullary cancer, a common cause of death in this population. The risk of periampullary cancer in FAP is unclear, and variables that predict the occurrence and severity of periampullary tumors are not well understood. The specific aim of this study was to determine whether the risk of periampullary neoplasia segregates in specific FAP families. MATERIALS AND METHODS: A total of 144 FAP patients from 74 families were either screened by gastroduodenoscopy (n = 132) or information was obtained from surgical or autopsy reports (n = 12). The severity of periampullary neoplasia was recorded for each patient and graded based on maximum polyp size and histology. Linear regression was used to determine the significance of a number of variables with respect to periampullary neoplasia. A blood sample was available from at least one member of 50 unrelated families and used to detect germline mutations in codons 686 through 1693 of the adenomatous polyposis coli (APC) gene. RESULTS: Statistically significant familial segregation was found for the incidence and severity of periampullary neoplasia (P < 0.02). Age was also a statistically significant variable (P < 0.01). No correlation was observed between specific APC germline mutations and periampullary polyp frequency and severity. CONCLUSIONS: The occurrence and severity of periampullary neoplasms in patients with FAP segregates in families. This familial association may be related to as yet unidentified modifier genes or perhaps common environmental factors. These results should prove useful in developing upper gastrointestinal screening protocols for FAP patients at risk for periampullary neoplasia.

Lactational amenorrhea for family planning.

BACKGROUND: 50 % of pregnancies are unwanted. For several reasons including difficulty in obtaining contraceptives, no or ineffective contraception is used to prevent these unwanted pregnancies. The Lactational Amenorrhoea Method(LAM) however is a contraceptive method available and accessible for many women. OBJECTIVES: To assess in fully breastfeeding women, staying amenorrheic, the efficacy of the Lactational Amenorrhoea Method as a contraceptive method. The efficacy of LAM, as defined in 1988 in Bellagio, was compared with alternative definitions of LAM; the outcomes were measured using pregnancy and menstruation life tables. DATA SOURCES: MEDLINE searches from 1966 until 2002 and EMBASE from 1988 until 2002; reference lists of studies and review articles; books related to LAM; published abstracts from breastfeeding, reproductive health, contraceptive conferences; and e-mail communication with coordinators of such studies. SELECTION CRITERIA: From 454 potentially relevant studies 154 investigated the risk of pregnancy during LAM or lactational amenorrhea. Two reviewers applied the following inclusion criteria: prospective study, cases and -if available- controls had to be sexually active, pregnancy had to be confirmed by physical examination or a pregnancy test. Life table menstruation rates and life table pregnancy rates were taken as endpoints. Thirteen publications, reporting on 9 intervention groups and 2 control groups, met the inclusion criteria and were included in this systematic review. Their quality was assessed. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data, disagreements were resolved through discussion. Because of the heterogeneity of the included studies, the studies were analyzed using narrative methods. MAIN RESULTS: For the outcome two controlled studies of LAM users reported life table pregnancy rates at 6 months of 0.45 and 2.45 percent and 5 uncontrolled studies of LAM users reported 0-7.5 percent. Life table pregnancy rates of women fully breastfeeding and amenorrheic but not using any contraceptive method were 0.88 in one study and 0.9-1.2 percent (95% CI 0. 0-2.4 ) in a second study, depending on the definition of menstruation used. The life table menstruation rate at 6 months in all studies varied between 11.1-39.4 percent. REVIEWER'S CONCLUSIONS: No clear difference in life table pregnancy rates was found between women using LAM and supported in doing so, and fully breastfeeding, amenorroic women not using any method. Because the length of lactation amenorrhoea of women using LAM is too different between populations studied, and population specific, it is uncertain whether LAM extends lactational amenorrhoea.

Amelogenesis imperfecta with growth hormone deficiency in a 12 year-old boy.

Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders that are characterized by a defect in the formation of the tooth enamel and a high degree of clinical diversity. X-linked, autosomal dominant and recessive inheritance have been demonstrated. Growth hormone (GH) has an effect on bone and soft tissue development. Dental and facial abnormalities associated with pituitary dwarfism have been reported, but GH deficiency with AI is very rare. We describe a 12 year-old pre-pubertal boy who was referred to our hospital with teeth deformities and growth retardation. His teeth had brown-yellow pigmented surfaces, and dental examination showed extensive enamel deficiency in his permanent teeth. He also had severe growth retardation; height SDS was -3.6. Laboratory examinations showed reduced GH levels, and he was diagnosed as having idiopathic isolated GH deficiency and AI.

Familial variation in retinal pigmentation in adenomatous polyposis.

OBJECTIVE: To examine the relationship between familial adenomatous polyposis and retinal pigment epithelial (RPE) pigmentation in affected patients and their first-degree relatives. DESIGN: Retrospective study. SETTING: Affected families across Canada registered in the Steve Atanas Stavro Familial Gastrointestinal Cancer Registry. SUBJECTS: A total of 134 subjects aged 10 to 35 years (at high risk for the disease) who had undergone examination of the gut by sigmoidoscopy, colonoscopy with biopsy or resection with biopsy and indirect ophthalmoscopy. MAIN OUTCOME MEASURES: Weighted eye score for large and small retinal lesions; family eye pigmentation index (FEPI), calculated from the weighted eye scores for individual affected family members. RESULTS: Families differed in the number and type of RPE lesions manifest, but affected family members showed similar pigmentation. An FEPI below 3 was uninformative, but with a medium or high FEPI the sensitivity and specificity of the index approached 100%. CONCLUSIONS: A positive retinal examination signifies a high risk for adenomatous polyposis, whereas a negative retinal examination is uninformative. Current molecular analysis is informative in 95% of families. However, in cases of spontaneous mutation and in patients with no first-degree relatives available or with unknown parenthood, RPE lesions are the most valuable extracolonic manifestation of adenomatous polyposis.

Histopathological features of congenital fundus lesions in familial adenomatous polyposis.

We report the light and electron microscopic findings for two lesions from two patients who died of complications of familial adenomatous polyposis. In the first case microscopy of a small (100 to 200 mu), uniformly dark lesion (the commonest type seen in this condition) showed enlarged retinal pigment epithelial cells with an increased number of pigment granules. This is consistent with the term "hypertrophy of the retinal pigment epithelium", currently used to describe these lesions. In the second case we sectioned a larger (1000 to 1500 mu), oval, grey lesion from the posterior pole. The pigment epithelium was normal, but between it and outer retina was an unusual choristoma consisting largely of myelinated axons and astrocytes.

Underlying pathologies in secondary strabismus.

PURPOSE: In this prospective cross-sectional observational study, the distribution of organic pathologies in patients initially presenting with strabismus was evaluated. METHODS: Thirty-one of 243 patients examined between May 1997 and May 1998 had strabismus due to organic causes and 28 patients had posterior segment abnormalities. RESULTS: Toxoplasma chorioretinitis, morning glory anomaly, toxocara retinopathy, retinopathy of prematurity and Coats' disease were the most common diagnoses. Eighteen patients (58%) had esotropia and 13 (42%) had exotropia. The mean age of onset of deviation was significantly lower in the esotropic patients. There was no correlation between the degree of visual impairment and direction of deviation. CONCLUSIONS: Our study strongly underlines the importance of fundus examination in each strabismic patient.

Treatment and follow-up of affected family members with familial polyposis.

In conclusion, it is the intention of our Familial Polyposis Registry to ensure that members of an affected family are aware of the reasons for ongoing surveillance and of the potential for developing extracolonic manifestations or malignancies. A second and equally important aim is to make available to the medical community-at-large reliable and progressive resource data, not only to stimulate discussion about the total management of familial polyposis, but to encourage cooperation in our common goal of cancer prevention.

Genetic testing and surgical decision making in hereditary colorectal cancer.

Hereditary colorectal cancer results from specific genetic alterations. The causative genes for familial adenomatous polyposis, juvenile polyposis, Peutz-Jeghers syndrome, and hereditary nonpolyposis colorectal cancer have been cloned and characterized within the past decade. Genetic testing has therefore become more widely used to confirm the clinical diagnosis of each of those syndromes, to provide adequate surveillance, to allow screening of at-risk family members, and to help the surgeon in surgical decision making. The aim of this review is to analyze the importance of genetic testing in view of the clinical and surgical management of those gene-carriers individuals, and to discuss how should the surgeon integrate genetic testing in the evaluation of such patients.

Gastric antral vascular ectasia associated with gastric carcinoma.

Gastric antral vascular ectasia (GAVE), or watermelon stomach, is an uncommon cause of chronic gastrointestinal blood loss and iron deficiency anemia. Although GAVE has not previously been reported in association with gastric cancer, it is often associated with atrophic gastritis and pernicious anemia, which are known risk factors for gastric malignancy. We report a 72-yr-old woman with pernicious anemia who was found to have GAVE associated with adenosquamous carcinoma of the gastric cardia and adenocarcinoma in situ of the pylorus. In view of recent reports of the use of endoscopic modalities rather than surgical resection to treat GAVE, our case alerts endoscopists to the possibility of coexisting carcinoma.