Familial Adenomatosis Research Articles

Abstract 4374: Plant stanols induce the formation of intestinal adenomas and activate ERK1 signaling in the ApcMin/+ mouse

Abstract Introduction The incidence of colorectal cancer (CRC) has been increasing in many Western countries for several decades. Diet rich in plant foods is known to decrease CRC risk, whereas high intake of fat and cholesterol is associated with an increased risk. Plant sterols have been shown to inhibit colon cancer cell growth in vitro (Awad et al. 1996, Choi et al. 2003). The ApcMin/+ mouse carries a heterozygous germ line mutation in the Apc tumour suppressor gene. The homologous gene is mutated in patients with hereditary colon cancer (FAP, familial adenomatosis polyposis). In the ApcMin/+ mouse, the loss of heterozygosity in Apc allele activates the Wnt/Tcf-pathway which leads to accumulation of β-catenin in the cytosol and its translocation to the cell nucleus. β-Catenin acts as a transcription factor for several genes (e.g. cyclin D1, c-myc) and enhances cell proliferation. ApcMin/+ mice develop dozens of adenomas in the small intestine. The aim of this study was to investigate the effect of plant stanol feeding on adenoma formation and cell signaling in ApcMin/+ mice. The sterol composition of the intestinal mucosa was also analyzed. Materials and methods ApcMin/+ mice were fed either a 0.8% (w/w) plant stanol diet (n=14) or a control diet without plant stanols (n=14). Plant stanols were added to the experimental diet in the form of freeze-dried products with plant stanol ester enrichment. The level of cyclin D1, phosphorylated and total ERK1/2 (extracellular signal regulated kinase) were analyzed from the normal appearing intestinal mucosa by Western blot. Cholesterol, plant sterols (sitosterol, campesterol) and stanols (sitostanol, campestanol) were isolated from the intestinal mucosa by direct saponification method and analyzed by gas chromatography. Results The number of small intestinal adenomas was significantly increased by plant stanol feeding (p=0.002). Plant stanols induced adenoma formation by over 60% compared to the control group. No difference in the size of intestinal adenomas was seen. Plant stanol feeding increased the level of activated ERK1 (the ratio of phosphorylated p44 to total p44) and nuclear cyclin D1 in the intestinal mucosa (p=0.024 and p=0.038, respectively). The level of mucosal cholesterol was not affected by plant stanol feeding; however, the level of sitosterol and campesterol were decreased (p<0.001 for both) and sitostanol and campestanol increased (p<0.001 for both) in the intestinal mucosa of plant stanol fed ApcMin/+ mice. The number of intestinal adenomas and the level of mucosal plant sterols appear to have a negative correlation (rs=-0.517; p=0.007). References Awad et al. Anticancer Res 1996;16:2797-2804. Choi et al. Int J Oncol 2003;23:1657-62. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4374.

Ileostomy adenocarcinoma associated with familial adenomatous polyposis (FAP): new problem in old disease

Dear Editor: Familial adenomatosis polyposis (FAP) is an autosomal dominant disease caused by germline mutations in the adenomatosis polyposis coli (APC) gene, which is located in chromosome 5. FAP occurs in approximately one in 5,000 to one in 10,000 live births and accounts for less than 1% of the total colorectal cancers in the USA. This disease is manifested by numerous adenomatous polyps of the large bowel and to a lesser extent in the gastric fundus, duodenal, periampullary, and small bowel. These colonic polyps invariably progress to adenocarcinoma, the risk of which approaches 100% by the fourth decade of life. With advancements made in the surgical techniques, prophylactic restorative proctocolectomy with ileoanal pouch anastomosis (IPAA) is currently the procedure of choice in younger, continent patients. Prior to the introduction of the restorative proctocolectomy with ileoanal pouch, total proctocolectomy with end ileostomy was the procedure most routinely performed in patients with FAP to completely abolish the colorectal mucosa and hence reduce the risk of colorectal malignancies. However, as these patients live longer and with functioning ileostomies of greater than 15–20 years, late development of adenocarcinoma has been reported in the literature. We describe another patient with FAP, who underwent total proctocolectomy and end ileostomy decades earlier, presented with a parastomal hernia and adenocarcinoma arising within a tubulovillous adenoma. To our knowledge, 11 cases including ours have been reported in English language journals. A 60-year-old white male patient with history of FAP, Gardner’s syndrome, underwent total proctocolectomy with end ileostomy in 1984. The final pathology then did not reveal any malignancy. He presented to surgical services in the year 2008 with complaints of a parastomal hernia, chronic skin irritation, and difficulty with proper placement of the stoma appliance. Examination revealed a reducible parastomal hernia in the right lower abdomen and multiple polypoidal projections of the mucosal surface of the ileostomy. A biopsy of the polyp was carried out, and the pathology revealed dilated adenomatous glands with severe dysplasia and dissecting pool of mucin diagnostic of adenocarcinoma. A staging workup was carried with a CT scan of the chest, abdomen, and pelvis which did not reveal any metastatic disease. Serum carcinoembryonic antigen (CEA) marker was within the normal range. An upper endoscopy did not reveal any abnormality, and an ileoscopy up to 80 cm through the ileostomy stoma did not reveal any other small bowel lesions. The patient underwent exploratory laparotomy and en bloc resection of the ileostomy with the surrounding skin, subcutaneous tissue, and distal 10 cm of the intraabdominal portion of the terminal ileum with its mesentery; repair of the hernial defect with a bioabsorbable mesh; and creation of a new ileostomy in the left lower quadrant. Postoperatively, he recovered well and was discharged without any complications. Int J Colorectal Dis (2009) 24:1475–1476 DOI 10.1007/s00384-009-0739-6

Gastric mucosal polyps--an irrelevant finding? Studies on the incidence and clinical significance

Among about 20.000 patients who had a gastroscopy in a period of 6 years, 92 had gastric mucosal polyposis, diagnosed by endoscopy and histology, an incidence of 0.46%. Eight patients with an age average of 38 years had familial gastrointestinal adenomatosis, in six of them the criteria of Gardner's disease were fulfilled. The remaining 84 patients had an average age of 62 years. In patients with more than ten polyps the sex ratio (female to male) was 3.9:1. In 56 patients without familial gastrointestinal adenomatosis, coloscopy and(or) proctosigmoidoscopy was performed. In 18 there were polyps in the colon, in three an invasive carcinoma in an adenoma. In three further patients extensive carcinoma of the colon (in two with stenosis) was found. These observations suggest that patients with gastric mucosal polyposis have a higher incidence of colon polyps and carcinoma.

Normal high resolution karyotypes in patients with adenomatosis of the colon and rectum.

Chromosome analysis by means of high resolution banding technique was performed on lymphocyte cultures from 15 patients with familial adenomatosis of the colon and rectum (four patients with the Gardner syndrome and 11 with non-Gardner polyposis coli). Special emphasis was given to the possible presence of a heteromorphism, tentatively interpreted as an interstitial deletion, previously reported on the long arm of chromosome 2. No such deletion could be detected: all analyzed karyotypes were found to be normal.

Fundic Gland Polyp Dysplasia Is Common in Familial Adenomatous Polyposis

Fundic gland polyps (FGPs) are common in familial adenomatous polyposis (FAP) but have been considered nonneoplastic. Gastric carcinoma arises from FGPs in FAP presumably from a dysplasia-carcinoma pathway. Our study examined the prevalence of FGPs and FGP dysplasia in FAP and identified endoscopic or demographic features associated with FGPs and dysplasia. Demographic and endoscopic information were obtained prospectively from 75 consecutive subjects undergoing upper-endoscopic surveillance for FAP. Systematic biopsy specimens of FGPs, normal-appearing fundic mucosa, and antral mucosa for Helicobacter pylori were obtained. Multivariable analysis assessed the association of demographic or endoscopic factors with the presence of FGP or FGP dysplasia. FGPs were detected in 88% of subjects and were dysplastic in 41% (38% low grade, 3% high grade). H pylori infection was rare in subjects with vs without FGPs (1.5% vs 33.3%, P = .005). In the multivariable analysis larger FGP size (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.1-14.4), higher stage of duodenal polyposis (OR, 2.3; 95% CI, 1.2-4.5), and antral gastritis (OR, 11.2; 95% CI, 1.2-103.9) were associated with FGP dysplasia. Exposure to acid-suppressive medications was associated with a marked decrease in dysplastic FGPs (OR, 0.14; 95% CI, 0.03-0.64). The majority of FAP patients have FGPs and nearly half will have dysplastic FGPs. There is an inverse relationship between H pylori and FGPs. FGP dysplasia is associated with larger polyp size, increased severity of duodenal polyposis, and antral gastritis. Acid-suppressive therapy use appears protective against dysplasia in FGPs.

Further upregulation of β-catenin/Tcf transcription is involved in the development of macroscopic tumors in the colon of ApcMin/+ mice

Apc(Min/+) mouse, a mouse model for human familial adenomatosis polyposis, contains a truncating mutation in the Apc gene and spontaneously develops intestinal tumors. Our previous study revealed two distinct stages of tumorigenesis in the colon of Apc(Min/+) mouse: microadenomas and macroscopic tumors. Microadenomas already have lost their remaining allele of the Apc and all microadenomas show accumulation of beta-catenin, indicating that activation of the canonical Wnt pathway is an initiating event in the tumorigenesis. This study shows that expression of nuclear beta-catenin in macroscopic tumors is further upregulated in comparison with that in microadenomas. Furthermore, transcriptional activity of beta-catenin/T-cell factor (Tcf) signaling, assessed using beta-catenin/Tcf reporter transgenic mice, is higher in the macroscopic tumors than that in microadenomas. In addition, the expression level of Dickkopf-1, which is known to be a negative modifier of the canonical Wnt pathway, was reduced only in colon tumors. These results suggest that activation of beta-catenin/Tcf transcription plays a role not only in the initiation stage but also in the promotion stage of colon carcinogenesis in Apc(Min/+) mice.

Association of CYP1B1 Germ Line Mutations with Hepatocyte Nuclear Factor 1α–Mutated Hepatocellular Adenoma

Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1alpha (HNF1alpha) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1alpha germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1alpha-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1alpha-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1alpha-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1alpha mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line-inactivating mutations might increase the incidence of HCA in women with HNF1alpha mutations.

Ethical Issues Related to Genetic Testing of Families with Hereditary Non-Polyposis Colorectal Cancer and Familial Adenomatosis Polyposis Syndrome.

Ethical Issues Related to Genetic Testing of Families with Hereditary Non-Polyposis Colorectal Cancer and Familial Adenomatosis Polyposis Syndrome.

Incidence of dysplasia in the anorectal mucosa in patients having restorative proctocolectomy

The incidence of dysplasia in the mucosal strippings from the anorectal stump was studied in 132 patients treated by restorative proctocolectomy with ileal reservoir for ulcerative colitis and familial adenomatosis. The anorectal mucosa was stripped from the level of division of the gut tube to the dentate line. Of 118 patients with ulcerative colitis, 12 (10.2 per cent) had dysplasia in some part of the large bowel. Mucosal strippings were examined histologically in 118 cases, of which only three (2.5 per cent) showed dysplasia. There was a correlation between dysplasia and the presence of carcinoma and the duration of the disease in the operative specimen of colon and rectum and also in the anorectal mucosal specimen although the number of patients with carcinoma (eight cases) in this analysis was small. All 14 patients with familial adenomatous polyposis showed large bowel mucosal dysplasia in the operative specimen which was severe in six cases. Anorectal mucosal strippings were examined in these patients and 12 showed dysplasia which was severe in three.

Gardner's stigmas in patients with familial adenomatosis coli.

Extracolonic lesions compatible with Gardner's syndrome were studied in 34 patients from 17 unrelated families with established familial adenomatosis coli. Thirteen patients (38 per cent) had the complete syndrome and 12 patients (35 per cent) a bisymptomatic syndrome. Bone lesions were found in 79 per cent of the patients examined, epidermoid cysts in 35 per cent, desmoid tumours in 18 per cent and dental changes in 18 per cent. One extracolonic manifestation of the triad in at least one affected family member was detected in 14 families (82 per cent). The findings provide additional evidence for the view that all cases of familial adenomatosis coli belong to a single genetic entity. The usually innocent extracolonic signs of Gardner's syndrome severe as valuable markers for early detection of asymptomatic family members at risk. Panoramic X-ray of the jaws seems to be especially suitable for this purpose.

Improvements in the treatment and prognosis of colorectal carcinoma.

In a survey of the surgical results in 709 patients with colorectal carcinoma (CRC) treated between 1976 and 1985 a favourable shift of stage distribution was observed. The tumour was localized (Dukes' classification A or B) in 61 per cent of patients, as compared with 47 per cent in the previous 10-year period. This change was, in part, due to different interpretation of stage definitions. Clear improvements of the results were, however, also noted. Radical surgery was possible in 76 per cent of patients and the primary tumour was removed in 93 per cent. Surgical mortality was 4.4 per cent and complication rate 15 per cent, significantly less than earlier (6.5 and 38 per cent, respectively). Increasing numbers of sphincter-saving operations were performed in rectal cancers (47 per cent as compared with 24 per cent in the previous 10-year period). The overall 5-year survival rate improved from 40.5 to 52.5 per cent. Premalignant conditions were identified in 12.6 per cent of patients: previous CRC 4.8 per cent, cancer family syndrome 4.1 per cent, ulcerative colitis 1.7 per cent and familial adenomatosis 0.6 per cent. In order to sustain the favourable trend of improving survival prospects, more emphasis must be directed to the detection of early stage cancers.

Intra‐abdominal desmoid tumor after successful treatment for Hodgkin disease

The risk of second malignancies after successful treatment for Hodgkin disease can be considerable. The most common malignancies are solid tumors arising in irradiated sites, such as the breast and thyroid gland after mantle field radiation. Sarcomas and other musculoskeletal tumors are also seen. We describe a young woman who developed an intra-abdominal desmoid tumor more than 4 years after completing therapy for Stage IIB Hodgkin disease, treated with combination chemotherapy (ABVD) and mantle irradiation. The tumor did not occur at either a surgical site or within a radiation field. She did not carry a mutation for familial adenomatosis polypoli.

Endoscopic Snare Papillectomy a Large Single Center Series

Aims: To review the efficacy, safety, and outcome of Endoscopic Snare Papillectomy (ESP) compared to Surgical Resection (SR) for papillary adenomas (PA) at a single center. Methods: Between 1996 and 2003, a total of 64 patients were evaluated for possible ESP of which 43 (27 male, 16 females, mean age 46±12) with localized PA underwent ESP. 21 patients with large tumor size (> 3 cm) and/or high-grade dysplasia or carcinoma underwent SR. ESP was performed using a stiff polypectomy snare and electrocautery. Biliary sphincterotomy and stent placement were performed if ERCP revealed insufficient drainage. A pancreatic stent was placed in cases of delayed pancreatic drainage. All patients were admitted for 24 hours post-ESP. Complications were classified by the consensus criteria on ERCP complications. Follow-up ERCP was performed at 3-6 months and thereafter in cases of residual adenoma, symptoms, or elevated LFTs. Results: The presenting symptoms included jaundice in 20 patients(31%), anemia in 7(10.9%), non-specific abdominal pain in 11(17.3%), pancreatic symptoms in 1(1.6%). History of familial adenomatosis polyposis (FAP) was present in 10 patients (15.6%), leading to detection of PA via surveillance EGD. The mean tumor size in the ESP group was 1.7±0.44 cm and 4.1±2.5 cm in the SR group. ESP was assisted by submucosal saline injection in 36 cases (56%) and performed en bloc in 33 cases (52%). A pancreatic stent was inserted in 21/43 patients (48.8%) and a biliary stent was inserted in 4/43 patients (9.3%). The only 30-day complication in the ESP group was hemorrhage in one patient who subsequently died. There were 7 complications in the SR group. There were no cases of pancreatitis in either group. Neither age, presenting symptoms nor tumor size were associated with development of complications. In the ESP group, if patients had a history of FAP, their risk of minor bleeding was 44% vs. 15% for those without FAP (RR=3.02, 95% CI 1.01-8.99, p=0.073). SR patients had significantly longer hospital stays than ESP(mean 10.6±8.6 days vs. 1 day, p<0.0001). At follow-up, 3 ESP patients had recurrence, all benign FAP-associated PA (mean interval 5.4 months) and were treated endoscopically. Conclusion: Endoscopic resection of localized PA by experienced endoscopists is a good alternative to surgical resection. The recurrence rate post ESP is small and can be treated endoscopically. Patients with FAP must be enrolled in a long-term endoscopic surveillance program. Aims: To review the efficacy, safety, and outcome of Endoscopic Snare Papillectomy (ESP) compared to Surgical Resection (SR) for papillary adenomas (PA) at a single center. Methods: Between 1996 and 2003, a total of 64 patients were evaluated for possible ESP of which 43 (27 male, 16 females, mean age 46±12) with localized PA underwent ESP. 21 patients with large tumor size (> 3 cm) and/or high-grade dysplasia or carcinoma underwent SR. ESP was performed using a stiff polypectomy snare and electrocautery. Biliary sphincterotomy and stent placement were performed if ERCP revealed insufficient drainage. A pancreatic stent was placed in cases of delayed pancreatic drainage. All patients were admitted for 24 hours post-ESP. Complications were classified by the consensus criteria on ERCP complications. Follow-up ERCP was performed at 3-6 months and thereafter in cases of residual adenoma, symptoms, or elevated LFTs. Results: The presenting symptoms included jaundice in 20 patients(31%), anemia in 7(10.9%), non-specific abdominal pain in 11(17.3%), pancreatic symptoms in 1(1.6%). History of familial adenomatosis polyposis (FAP) was present in 10 patients (15.6%), leading to detection of PA via surveillance EGD. The mean tumor size in the ESP group was 1.7±0.44 cm and 4.1±2.5 cm in the SR group. ESP was assisted by submucosal saline injection in 36 cases (56%) and performed en bloc in 33 cases (52%). A pancreatic stent was inserted in 21/43 patients (48.8%) and a biliary stent was inserted in 4/43 patients (9.3%). The only 30-day complication in the ESP group was hemorrhage in one patient who subsequently died. There were 7 complications in the SR group. There were no cases of pancreatitis in either group. Neither age, presenting symptoms nor tumor size were associated with development of complications. In the ESP group, if patients had a history of FAP, their risk of minor bleeding was 44% vs. 15% for those without FAP (RR=3.02, 95% CI 1.01-8.99, p=0.073). SR patients had significantly longer hospital stays than ESP(mean 10.6±8.6 days vs. 1 day, p<0.0001). At follow-up, 3 ESP patients had recurrence, all benign FAP-associated PA (mean interval 5.4 months) and were treated endoscopically. Conclusion: Endoscopic resection of localized PA by experienced endoscopists is a good alternative to surgical resection. The recurrence rate post ESP is small and can be treated endoscopically. Patients with FAP must be enrolled in a long-term endoscopic surveillance program.

ADENOMYOMATOSIS OF THE AMPULLA OF VATER IN CHRONIC HEPATITIS C

Adenomyomatosis of the ampulla of vater is a rare condition with only a few case reports in the literature. It is a benign tumor originating from connective tissue of the ampulla of vater. The etilogy is unknown. Benign neoplasms involving the extrahepatic biliary tree are extremely rare. Adenomyomatosis has been reported as the cause of bile duct obstruction, recurrent acute pancreatitis, and jaundice. An increased frequency of adenomyomatosis of ampulla is seen in patients with familial adenomatosis polyposis syndrome. The major importance of the lesion is the possibility that it may be confused with carcinoma which would lead to unnecessary extensive surgical resection. We are reporting two patients with Chronic hepatitis C and adenomyomatosis of the ampulla seen in our institution(see table).Table: Case summariesIn light of these findings, chronic hepatitis C patients with lesions in the periampullary region presenting with all or some of the following findings: (1) abdominal pain, (2) weight loss, (3) worsening liver function tests, (4) pancreatic duct or CBD dilatation, should have diagnostic intervention to evaluate the presence of adenomyomatosis of the ampulla of Vater. This evaluation may be best accomplished by performing ERCP with biopsies of the periampullary lesion that can undergo histopathological evaluation and grading of dysplasia if present. This should be performed before major surgical intervention to avoid unnecessary major surgical resection. We hereby report two case of Chronic hepatitis C and adenomyomatosis of ampulla of vater and we think there might be a causal relationship. This relationship should be confirmed by a large observational study

Cribriform-Morular Variant of Papillary Carcinoma: Association with Familial Adenomatous Polyposis - Report of Three Cases and Review of Literature

We describe a rare variant of papillary thyroid carcinoma (PTC), the Cribriform-Morular Variant (C-MV). A handful of cases have been described in the literature of this entity. They exhibit the morphologic features of a distinctive papillary neoplasm along with solid, cribriform, and squamoid-morular areas. The cribriform and morular features make this a separate entity which could be mistaken for a high grade aggressive thyroid neoplasm. These lesions are usually associated with familial adenomatosis polyposis (FAP) but rarely may be sporadic. We report three cases that we have encountered.

Familia liver adenomatosis associated with hepatocyte nuclear factor 1α inactivation

Background & Aims: Germline mutations in hepatocyte nuclear factor 1α (TCF1/HNF-1α) are associated with maturity-onset diabetes of the young type 3 (MODY3), and somatic biallelic inactivations of the gene are found in hepatocellular adenomas and liver adenomatosis. This study investigated cosegregation of HNF-1α germline mutations with diabetes and liver adenomatosis in 2 families. Methods: Two unrelated patients with liver adenomatosis and harboring HNF-1α germline and somatic mutations were studied. Subsequently, we screened 9 relatives in the 2 independent families for diabetes, hepatocellular adenomas, and HNF-1α germline mutations. Results: In family A, a father and his son presented with an intraperitoneal hemorrhagic rupture of a liver adenomatosis without diabetes. A heterozygous R229X germline mutation was identified in HNF-1α in the father and his son and also in his second 27-year-old son without hepatocellular adenomas. In family B, a diagnosis of liver adenomatosis was made fortuitously in a 14-year-old girl. A heterozygous G55fsX57 germline mutation in HNF-1α was identified in this patient, her diabetic father, and her 2 sisters. Systematic exploration showed liver adenomatosis in the 2 sisters. Somatic inactivation of the second HNF-1α allele was found in liver tumors in both families. Conclusions: This study describes familial liver adenomatosis and shows the association with germline HNF-1α mutations in adults and children. It also highlights the importance of screening for hepatocellular adenomas, diabetes, and HNF-1α germline mutations in relatives of patients with liver adenomatosis. Finally, prevalence of liver adenomatosis remains to be evaluated in MODY3 subjects.

Role of cyclooxygenase-2 in the angiogenesis of colorectal cancer.

Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of prostaglandins. It exists in two isoforms: COX-1 which is constitutively expressed and COX-2 which is an inducible form activated by a variety of cytokines during inflammation. Interest in this enzyme arose in the early 1990s when, following epidemiological studies, aspirin (which is a COX inhibitor) was found to reduce the risk of colorectal cancer. Since then various studies to decipher the mechanisms by which COX reduces the development of colorectal cancer have been undertaken. One of the mechanisms being studied is its role in the angiogenesis of colorectal cancer. Angiogenesis of its own has been well established as a key factor in the development of tumours. Agents that specifically inhibit COX-2 are now in clinical development and have been licensed to be used in patients with familial adenomatosis polyposis. What needs to be determined is whether the antiangiogenic effects of COX-2 inhibitors can be used in the prevention and/or treatment of colorectal cancer and its metastases.

Nesidioblastosis in adults: a challenging cause of organic hyperinsulinism

Nesidioblastosis in adults has been reintroduced into the differential diagnosis of organic hyperinsulinism by the description of 'noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS)'. Pathologic specimens of all adult patients (n = 66) operated on for organic hyperinsulinism were re-examined. Five patients fulfilled the histomorphological criteria of nesidioblastosis. Retrospective review of clinical presentation, results of 72-h fasts, intravenous tolbutamide tolerance tests, pre- and intraoperative localization studies and surgical therapy was performed. In contrast to NIPHS, fasting tests became positive after 8-14 h. Tolbutamide tests were positive and preoperative imaging showed negative results in all patients. At first operation distal pancreatic resections were performed in three patients, resection of the pancreatic body in one patient and biopsy of the pancreatic tail in one patient. Two of three patients with recurrent disease had to be reoperated. One patient showed a coexistence of nesidioblastosis and multiple small insulinomas and is part of a kindred with autosomal dominantly inherited 'familial islet-cell adenomatosis'. Surgical exploration is indicated only after thorough biochemical diagnosis. An aggressive strategy for preoperative localization including selective arterial calcium stimulation testing seems justified. There may be a combination of nesidioblastosis and islet cell tumours. A link between beta-cell hyperplasia and progression to insulinoma based on not yet known genetic causes can be suspected.

Family history of colorectal cancer in a Sweden county.

Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatosis polyposis (FAP) are well-known high-risk cancer syndromes. Hereditary colorectal cancer (HCRC) with at least three relatives with colorectal cancer and a dominant pattern of inheritance but with no specifications for age at onset and two close relatives with colorectal cancer (TCR) are other forms of familial clustering known to carry an increased risk of the disease. The frequency of the total burden of familial colorectal cancer is not well known. We therefore investigated the family history of 400/411 (97%) eligible patients with recently diagnosed colorectal cancer in Västmanland county, Sweden, during a 3-year period. Records or death certificates confirmed the diagnoses of relatives. Five patients (1.2%, 95% CI 0.15-2.2) were diagnosed as having HNPCC, eight (1.9%, 95% CI 0.6-3.2) as having HCRC and thirty-four (8.3%, 95% CI 5.6-11.0) were identified as having TCR. In total, 47 patients (11.4%, 95% CI 8.3-14.5) were found to have a contributing familial background. The implication is thus that every ninth patient with colorectal cancer represents a highly or intermediately increased risk of the disease among relatives. We conclude that the low frequency of individuals identified by family history alone makes the establishment of surveillance programs feasible.

Molecular screening for colon cancer in inflammatory bowel disease

Prophylactic colectomy is an established method of bowel cancer prevention in high-risk patients such as familial adenomatosis polyposis coli (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in patients with longstanding ulcerative colitis or Crohn's disease. The decision to perform such a major procedure cannot be made lightly, and issues of timing are important. In inflammatory bowel disease (IBD), the trigger to carry out colectomy usually relates to detection of dysplasia, well recognized to be a premalignant lesion. Screening methods are aimed at detection of precursor lesions or clinically occult malignancies. In current clinical practice, such screening methods are either resource intensive (e.g. colonoscopy and biopsy) or of low sensitivity and specificity (e.g. faecal occult blood testing). We discuss the development of screening techniques based upon molecular technologies and the limitations engendered by our incomplete understanding of the natural history and molecular biology of colorectal neoplasia in IBD.