Laparoscopic colon surgery: unreliability of end-tidal CO2 monitoring.

BACKGROUND: The relatively good haemodynamic and respiratory tolerance to abdominal CO(2) insufflation has mostly been observed in healthy patients during short-lasting laparoscopic procedures. End-tidal CO(2) pressure (PetCO(2)) has been shown to be a reliable method to assess arterial CO(2) (PaCO(2)) in the absence of cardio-respiratory disease in this setting. However, no study has investigated whether PetCO(2) is accurately related to PaCO(2) during laparoscopic colon surgery. Indeed, these procedures last longer, prolonging the pneumoperitoneum and requiring a Trendelenburg position. The aim of the present study was to measure the PaCO(2)-PetCO(2) difference over time in patients undergoing laparoscopic colon surgery and to determine whether PaCO(2) is reliably assessed by PetCO(2). METHODS: Forty consecutive patients (ASA I and II) scheduled for laparoscopic colon surgery were anaesthetized and ventilated to obtain a PetCO(2) between 4.0 and 5.5 kPa. After initiation of CO(2) insufflation, PaCO(2) and PetCO(2) were recorded every 30 min during surgery. RESULTS: No complication was observed during anaesthesia. The mean arterial pressure increased significantly after CO(2) insufflation and remained steady up to the end of pneumoperitoneum. The heart rate remained stable over time. The relation between PaCO(2) and PetCO(2) was not constant among patients and increased over time within the same patients. The R(2) values fluctuated and did not show a constant correlation between PaCO(2) and PetCO(2). CONCLUSION: The correlation between PaCO(2) and PetCO(2) during laparoscopic colon surgery is inconsistent mainly due to inter- and intra-individual variability.

Low-dose oral microemulsion ciclosporin for severe, refractory ulcerative colitis.

BACKGROUND: The optimal modalities of treatment with oral microemulsion ciclosporin in patients with severe, steroid-refractory ulcerative colitis are uncertain. AIM: To assess the applicability, in terms of efficacy and tolerability, of a standard oral microemulsion ciclosporin treatment protocol targeting relatively low blood ciclosporin concentrations, in patients with severe, steroid-resistant ulcerative colitis. PATIENTS AND METHODS: Patients with a severe attack of ulcerative colitis and no satisfactory response to intravenous corticosteroids were started on oral microemulsion ciclosporin. Dosages were adapted according to a standard protocol, targeting a blood predose ciclosporin concentration (C0) of 100-200 ng/mL. Patients without a clinical response on day 8 were scheduled for colectomy. RESULTS: Sixteen patients were enrolled. A clinical response was observed in 14/16 (88%). The mean clinical activity index scores and concentrations of C-reactive protein on days 0, 4 and 8 were 11.8, 6.7 and 4.1, and 50.3, 19.3 and 9.7 mg/L respectively. The mean C0 (days 0-8) was 149 pg/mL. The mean creatinine clearance rates on days 0 and 8 were 88 and 96 mL/min. One patient had an acute elevation of transaminases that resulted in discontinuing ciclosporin. CONCLUSIONS: Even when dosed for a target C0 of 100-200 ng/mL, oral microemulsion ciclosporin for severe, steroid-refractory ulcerative colitis achieves an efficacy similar to that attained with higher, potentially more toxic levels. The oral route should replace intravenous treatment in this clinical setting.

[Intestinal stoma: preoperative and postoperative management]. / Les stomies digestives: indications, complications, prise en charge pré et postopératoire.

The aim of this review is to present the management and indications of intestinal stomas. A stoma induces a body image alteration with important familial and social consequences. A preoperative visit to the stoma nurse prevents technical and/or psychological complications. Stoma nurses, surgeons and general practionners work together to help the patient in his/her new life. New stoma devices have also contributed to improve quality of life. Social and sexual activity can be maintain despite intestinal stoma with appropriate education.

Randomized clinical trial of mechanical bowel preparation versus no preparation before elective left-sided colorectal surgery.

BACKGROUND: Mechanical bowel preparation (MBP) is performed routinely before colorectal surgery to reduce the risk of postoperative infectious complications. The aim of this randomized clinical trial was to compare the outcome of patients who underwent elective left-sided colorectal surgery with or without MBP. METHODS: Patients scheduled for elective left-sided colorectal resection with primary anastomosis were randomized to preoperative MBP (3 litres of polyethylene glycol) (group 1) or surgery without MBP (group 2). Postoperative abdominal infectious complications and extra-abdominal morbidity were recorded prospectively. RESULTS: One hundred and fifty-three patients were included in the study, 78 in group 1 and 75 in group 2. Demographic, clinical and treatment characteristics did not differ significantly between the two groups. The overall rate of abdominal infectious complications (anastomotic leak, intra-abdominal abscess, peritonitis and wound infection) was 22 per cent in group 1 and 8 per cent in group 2 (P = 0.028). Anastomotic leak occurred in five patients (6 per cent) in group 1 and one (1 per cent) in group 2 (P = 0.210) [corrected] Extra-abdominal morbidity rates were 24 and 11 per cent respectively (P = 0.034). Hospital stay was longer for patients who had MBP (mean(s.d.) 14.9(13.1) versus 9.9(3.8) days; P = 0.024). CONCLUSION: Elective left-sided colorectal surgery without MBP is safe and is associated with reduced postoperative morbidity.

Long-term expression of fibrogenic cytokines in radiation-induced damage to the internal anal sphincter.

BACKGROUND: There is accumulating evidence, both quantitative and qualitative, that pelvic irradiation affects anorectal function. However, the molecular mechanisms responsible for radiation-induced damage to the anal sphincter remain unclear. AIM: To determine the expression of transforming growth factor-beta 1 (TGF-beta 1) and its downstream effector connective tissue growth factor (CTGF) in the anal sphincter of a patient irradiated for prostate cancer. PATIENT: A 82 year-old patient developed a rectal adenocarcinoma and underwent an abdomino-perineal resection (APR), four years after receiving pelvic irradiation for prostate carcinoma. METHODS: Tissue sections of the anal sphincter were processed for histology. Immunostaining for TGF-beta 1 and CTGF were performed. RESULTS: CTGF and TGF-beta 1 immunoreactivity was detected in the irradiated anal sphincter, and was absent in controls. Immunoreactivity for both cytokines predominated in the internal sphincter. CTGF and TGF-beta 1 were preferentially detected in endothelial cells, myofibroblasts and fibroblasts; in addition, there was strong immunoreactivity for TGF-beta 1, but not for CTGF in smooth muscle cells of the anal canal. CONCLUSION: Four years after pelvic irradiation, radiation-induced damage appeared to affect predominantly the smooth muscle layer of the anal canal. The molecular mechanisms responsible for radiation-induced fibrosis to these tissues involve prolonged activation of TGF-beta 1 and its downstream effector CTGF.

[Bilateral adrenal gland hemorrhage after anterior deep rectum resection. Case report with review of the literature]. / Bilaterale Nebennierenhämorrhagie nach vorderer tiefer Rektumresektion. Fallbericht mit Literaturübersicht.

UNLABELLED: Adrenal insufficiency due to bilateral adrenal hemorrhage is a rare but potentially life-threatening postoperative complication. The difficulty lies in making a timely diagnosis, as the symptoms are often unspecific and similar to those presented by other, more common postoperative complications. We report the case of a 71-year-old patient presenting bilateral adrenal hemorrhage following an otherwise uncomplicated low anterior rectum resection for a villous adenoma of the middle rectum. CONCLUSION: In cases of unexplained postoperative deterioration, surgeons should be aware of acute adrenal insufficiency due to bilateral adrenal hemorrhage. With a high index of suspicion the diagnosis is made easily by CT scan and serum-cortisol measurements and prompt steroid replacement can help to avoid a deleterious outcome.

Long-term follow-up after first acute episode of sigmoid diverticulitis: is surgery mandatory?: a prospective study of 118 patients.

PURPOSE: This study was designed to evaluate the long-term natural history of sigmoid diverticulitis in patients treated nonoperatively after a first acute episode and to assess the role of elective colectomy. METHODS: Between 1986 and 1991, 144 patients were admitted for acute diverticulitis diagnosed by abdominal computed tomography and had a successful nonoperative treatment. Remote complications (persisting or recurring diverticulitis) were also diagnosed by computed tomography. Patients had a poor outcome if they had one of these complications. Diverticulitis was graded mild or severe on computed tomography according to Ambrosetti's criteria. We determined statistically whether young age (< or =50 years old) and severe diverticulitis were risk factors for a poor outcome. RESULTS: One hundred eighteen patients with a contributive computed tomographic scan at admission were followed up. Median age was 63 (range, 23-93) years, with a median follow-up of 9.5 (range, 0.2-13.8) years. Eighty patients had no complications, and 38 had remote complications. The incidence of remote complications was the highest (54 percent at 5 years) for young patients with severe diverticulitis on computed tomography and the lowest (19 percent at 5 years) for older patients with mild disease. Young age and severe diverticulitis taken separately were both statistically significant factors of poor outcome (P = 0.007 and P = 0.003, respectively), although age was no longer significant after stratification for disease severity on computed tomography (P = 0.07). Twenty-four patients died. The cause of death was unrelated to diverticulitis in 21 cases and unknown in the remaining 3. CONCLUSIONS: We propose that after a first acute episode of diverticulitis treated nonoperatively, elective colectomy should be offered to young patients (< or =50 years old) with severe diverticulitis on computed tomography.

Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis.

Germ-line mutations in the 5' half of the Adenomatous Polyposis Coli (APC) gene are found in about 80% of the patients affected with familial adenomatous polyposis (FAP). The vast majority of these are nonsense or frameshift mutations which result in the loss of the carboxyl terminus of the APC protein. Using an in vivo assay in yeast, we have identified pathogenic germ-line mutations in 26 of 32 (81%) unrelated Swiss families affected with FAP. Nine mutations were novel and eight families were shown to harbor two recurrent mutations. Correlations were attempted between the location of APC germ-line mutations and clinical manifestations of the disease.

[Multidisciplinary management of hereditary colorectal cancer]. / Prise en charge multidisciplinaire du cancer colorectal héréditaire.

AIM: The aim of this study was to assess the feasibility and success of multidisciplinary approach for the management of hereditary colorectal cancer. MATERIAL AND METHODS: From November 1998 to November 2000, 32 individuals with putative familial/hereditary predisposition to colorectal cancer were investigated for adenomatous polyposis (attenuated or classical familial adenomatous polyposis coli, FAP) or for hereditary nonpolyposis colorectal cancer (HNPCC). Amsterdam criteria (I and II) and Bethesda guidelines were used to select putative HNPCC kindreds. Clinical data including endoscopy, pathological and operative reports as well as family history were collected. Pre- and post-test genetic counseling was offered to at-risk individuals. Genetic testing included microsatellite instability (MSI) and search for germline mutations in the APC, hMSH2 and hMLH1 genes. Immunohistochemistry (IHC) of hMSH2 and hMLH1 protein expression in tumour samples was also performed. RESULTS: 11 APC mutations were characterized, whereas four mutations in HNPCC genes were found in hMSH2 (2) and in hMLH1 (2). MSI and IHC correlated completely for cases with identified pathogenic mutation (100%). CONCLUSION: A thorough evaluation and management of hereditary colorectal requires a multidisciplinary approach. Thus, more mutation carriers can be identified and benefit from appropriate genetic counselling, while non-carrier individuals are relieved from unnecessary surveillance.

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.

Desmoid disease in patients with familial adenomatous polyposis.

PURPOSE: The aim of this retrospective study was to review the clinical features, and surgical and medical management of patients with familial adenomatous polyposis-associated desmoid tumors. METHODS: From 1980 to 1997, 97 of 780 patients with familial adenomatous polyposis developed desmoid disease. Clinical and demographic data; operative notes; and histologic, radiologic, and follow-up reports were retrieved from patients' medical records. Risk factors for desmoid disease, such as prior surgery, age at desmoid tumor diagnosis, pregnancy, and family history were sought. The outcome after noncytotoxic and cytotoxic therapy was evaluated with respect to improvement of symptoms. RESULTS: There were 38 males with a mean age of 32.1 years and 59 females with a mean age of 29.1 years. A family history of desmoid tumors was found in 41 patients (42 percent), and a history of pregnancy was documented in 33 females (56 percent). The most common clinical presentation was small-bowel obstruction (58 percent). One-half of the desmoids were located in the mesentery, and 32 percent were located in the mesentery and the abdominal wall. Desmoids developed after colectomy in 77 cases (80 percent), after a mean time of 4.6 years. Partial resection of desmoid tumor was performed in 46 patients (47 percent), resection of extra-abdominal desmoid tumors was performed in 17 cases (17 percent), and biopsy only was performed in 34 patients (35 percent). Postoperative morbidity was 23 percent after desmoid tumor resection. Eight patients (8 percent) died of their intra-abdominal desmoid. Mean follow-up time was 5.3 years. Sulindac, tamoxifen, or toremifene therapy was able to alleviate symptoms in only 4 of 31 patients. Symptomatic improvement was noted after chemotherapy in six of ten patients with extremely complex desmoids. CONCLUSION: Desmoid disease was found in 12.4 percent of our patients with familial adenomatous polyposis. In view of the high rate of morbidity, indication for surgery should be limited mainly to acute or chronic small-bowel obstruction, because resection triggers a high recurrence rate. Noncytotoxic therapy was not effective for progressive desmoid tumors, whereas chemotherapy was effective in aggressive cases of intra-abdominal desmoid tumors.

Early prediction in acute pancreatitis: the contribution of amylase and lipase levels in peritoneal fluid.

CONTEXT: Predicting the severity of acute pancreatitis early in the course of the disease is still difficult. OBJECTIVE: The value of amylase and lipase levels in serum and peritoneal fluid might be of value in predicting the course of acute pancreatitis. DESIGN: Prospective study. PATIENTS: One-hundred and sixty-seven patients with acute pancreatitis as confirmed by computed tomography scan within 24 hours of admission were studied. MAIN OUTCOME MEASURES: Each patient was given an enzymatic score which reflected the predominance of serum or peritoneal levels of amylase and/or lipase. Enzymatic score was 0 if neither enzyme was predominant in the peritoneal fluid, 1 if amylase or lipase alone were predominant and 2 if both enzymes were predominant. The predictive value of the enzymatic score or computed tomography scan for a severe attack was determined. RESULTS: One-hundred and thirty-three attacks were graded as mild (79.6%) and 34 were considered as severe (20.4%). The frequency of severe acute pancreatitis significantly increased as the enzymatic score increased (5.4%, 12.5%, and 31.7% in 0, 1, and 2 enzymatic score patients, respectively; P<0.001). An enzymatic score greater than 0 predicted a severe outcome in 32 of 34 patients (sensitivity 94.1%, specificity 26.3%), whereas an enzymatic score of 2 predicted a severe attack in 26 of 34 patients (sensitivity 76.5%, specificity 57.9%). Edema on computed tomography scan was found in 97 of 129 mild attacks (specificity 75.2%) and necrosis in 25 of 33 severe attacks (sensitivity 75.8%), whereas all patients with severe attacks exhibited extrapancreatic acute fluid collection (sensitivity 100%, specificity 34.9%). CONCLUSIONS: Peritoneal dialysis is less predictive and more cumbersome than a computed tomography scan in the early prediction of acute pancreatitis.

Comparison of ileal pouch-anal anastomosis and ileorectal anastomosis in patients with familial adenomatous polyposis.

PURPOSE: The aim of this study was to evaluate the surgical complications and long-term outcome and assess the functional results and quality of life after ileorectal anastomosis and ileal pouch-anal anastomosis in patients with familial adenomatous polyposis. METHODS: From 1980 to 1997, 131 patients with familial adenomatous polyposis were operated on or were followed up or both at the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital. Demographic and operative data were prospectively collected in the ileal pouch-anal anastomosis group, and retrospectively in the ileorectal anastomosis group. A questionnaire or telephone interview or both were undertaken to evaluate functional outcome and quality of life. RESULTS: The ileorectal anastomosis group consisted of 60 patients (mean age, 31 years; mean follow-up, 7.7 years). In the ileal pouch-anal anastomosis group there were 50 patients (mean age, 35 years; mean follow-up, 6 years). There were no statistically significant differences with respect to anastomotic leak rate in ileal pouch-anal anastomosis vs. ileorectal anastomosis (12 vs. 3 percent; P = 0.21), risk of small-bowel obstruction (24 vs. 15 percent; P = 0.58), and risk of intra-abdominal sepsis (3 vs. 2 percent; P = 0.86). Reoperation rate was similar in the two groups (14 vs. 16 percent; P = 0.94). Twenty-one patients (37 percent) with ileorectal anastomosis were converted to ileal pouch-anal anastomosis (12 patients) or proctocolectomy (9 patients), because of rectal cancer (5 patients), dysplasia (1 patient), or uncontrollable rectal polyps (15 patients). Two pelvic pouches were excised, and another one was defunctioned. Information regarding functional results and quality of life was obtained in 40 patients (66.6 percent) in the ileorectal anastomosis group and in 43 patients (86 percent) in the ileal pouch-anal anastomosis group. Patients with ileorectal anastomosis had a significantly better functional outcome with regard to nighttime continence and perineal skin irritation. But otherwise, functional results and quality of life were similar. CONCLUSIONS: Although ileorectal anastomosis has a better functional outcome, ileal pouch-anal anastomosis may be preferable because of the lower long-term failure rate. Ileorectal anastomosis is still an option in patients with familial adenomatous polyposis with rectal polyp sparing and good compliance for follow-up.

Functional outcome of conversion of ileorectal anastomosis to ileal pouch-anal anastomosis in patients with familial adenomatous polyposis and ulcerative colitis.

PURPOSE: The aim of this study was to review the functional outcome in 20 patients with familial adenomatous polyposis and ulcerative colitis who were converted from ileorectal anastomosis to ileal pouch-anal anastomosis. METHODS: From 1985 to 1997, 12 patients with familial adenomatous polyposis (5 males; mean age, 39.1 years) and 8 patients with ulcerative colitis (5 males; mean age, 36.7 years) underwent conversion from ileorectal anastomosis to ileal pouch-anal anastomosis. Clinical and operative data were analyzed retrospectively. Functional results were obtained by telephone interview in 16 patients (94 percent) after pouch construction. Four patients were not interviewed (2 were deceased, 1 was lost to follow-up, and 1 was not reachable). RESULTS: Indications for conversion were uncontrollable rectal polyps (10 patients) and colonic cancer found in the pathology specimen after ileorectal anastomosis in patients with familial adenomatous polyposis (2 patients), intractable proctitis (5 patients), colonic cancer found in the pathology specimen of patients with ulcerative colitis after ileorectal anastomosis (2 patients), and rectal dysplasia (1 patients). Mean follow-up time was 5 (range, 1-11) years. Ileal pouch-anal anastomosis was handsewn in 14 patients, and the remaining cases were double-stapled in 4 patients with ulcerative colitis. No intraoperative difficulties were reported in 13 cases; technical problems were related to adhesions (3 cases), difficult rectal dissection (2 cases), and stapler-related difficulties (2 cases). Postoperative complications after ileal pouch-anal anastomosis included small-bowel obstruction (4 patients) and ileal pouch-anal anastomosis leak (1 patient). Patients with ileorectal anastomosis vs. those with ileal pouch-anal anastomosis had a better functional outcome with regard to nighttime continence (14 (88 percent) vs. 6 (38 percent) patients) and average bowel movements (<6/day; 12 (75 percent) vs. 4 (25 percent) patients). Complete daytime continence, 15 (94 percent) vs. 10 (62 percent) patients, was similar in the two groups. Physical and emotional well-being were similarly rated as very good to excellent. CONCLUSIONS: In patients with familial adenomatous polyposis and ulcerative colitis with ileorectal anastomosis, conversion to ileal pouch-anal anastomosis may be required. In view of the risk of rectal cancer or intractable proctitis, patients seem to accept the conversion in spite of poorer bowel function.

Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer.

Recent characterization of the molecular genetic basis of hereditary nonpolyposis colorectal cancer provides an important opportunity for identification of individuals and their families with germline mutations in mismatch repair genes. Cancer family history criteria that accurately define hereditary colorectal cancer are necessary for cost-effective testing for germline mutations in mismatch repair genes. The present report describes the results of analysis of 33 colorectal cancer cases/families that satisfy our modified family history criteria (Mount Sinai criteria) for colorectal cancer. Fourteen of these families met the more stringent Amsterdam criteria. Germline MSH2 and MLH1 mutations were identified by the reverse transcription-polymerase chain reaction and the protein truncation test, and confirmed by sequencing. Microsatellite instability analysis was performed on available tumors from affected patients. MSH2 or MLH1 mutations were detected in 8 of 14 Amsterdam criteria families and in 5 of the remaining 19 cases/families that only satisfied the Mount Sinai criteria. Three of the latter families had features of the Muir-Torre syndrome. A high level of microsatellite instability (MSI-H) was detected in almost all (16/18) colorectal cancers from individuals with MSH2 and MLH1 mutations, and infrequently (1/21) in colorectal cancer specimens from cases without detectable mutations. Families with germline MSH2 and MLH1 mutations tended to have individuals affected at younger ages and with multiple tumors. The Amsterdam criteria are useful, but not sufficient, for detecting hereditary colorectal cancer families with germline MSH2 and MLH1 mutations, since a proportion of cases and families with mutations in mismatch repair genes will be missed. Further development of cancer family history criteria are needed, using unbiased prospectively collected cases, to define more accurately those who will benefit from MSH2 and MLH1 mutation analysis.

Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.

We report two familial adenomatous polyposis (FAP) kindreds with thyroid cancer, harboring two apparently novel germlineAPC mutations. The clinical phenotype in the first kindred was typical of classical adenomatous polyposis, whereas the second kindred exhibited an attenuated adenomatous polyposis phenotype. There was a female predominance with a mean age of 34 years (range, 23-49) at cancer diagnosis. Multiple sections of four thyroid tumors from three FAP patients were analyzed in detail. Histological examination of thyroid tumors showed a range of morphological features. Some tumors exhibited typical papillary architecture and were associated with multifocal carcinoma; in others, there were unusual areas of cribriform morphology, and spindle-cell components with whorled architecture. Immunoreactivity for thyroglobulin and high molecular weight keratins was strong. Somatic APC mutation analysis revealed an insertion of a novel long interspersed nuclear element-1-like sequence in one tumor sample, suggesting disruption of APC. In three FAP patients, ret/PTC-1 and ret/PTC-3 were expressed in thyroid cancers. No positivity was observed for ret/ PTC-2. p53 immunohistochemistry was positive in only one section of a recurrent thyroid tumor sample. Our data suggest that genetic alterations in FAP-associated thyroid cancer involve loss of function of APC along with the gain of function of ret/PTC, while alterations of p53 do not appear to be an early event in thyroid tumorigenesis.

[Hereditary colorectal cancer without associated polyadenomatosis]. / Le cancer colo-rectal héréditaire sans polyadénomatose associée.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition in which affected individuals develop colorectal cancer or extracolonic cancer, most commonly endometrial, at an early age. Recent advances in molecular genetics have led to the identification of a germline mutation of DNA mismatch-repair genes to be responsible for the majority of HNPPC cases. Since clinical screening of gene carriers can help to prevent cancer, it is important to devise strategies applicable to this syndrome. Recommendations for current management, especially screening and surgical treatment are under study, as they have not yet been clearly established. This paper reviews the clinical presentation, the molecular genetic diagnosis and therapeutic approaches of this syndrome including the controversies concerning prophylactic colectomy for cancer or gene carriers.

[Hereditary colorectal cancer associated with polyposis syndromes]. / Le cancer colo-rectal héréditaire associé aux syndromes polyposiques.

This study reviews different aspects of hereditary colorectal cancer associated with three polyposis syndromes: familial adenomatous polyposis, juvenile polyposis coli and Peutz-Jeghers syndrome. All these syndromes share some similarities: low incidence, autosomal dominant inheritance, genetic predisposition to colorectal cancer and/or other extracolonic cancers. Classical familial adenomatous polyposis is clinically defined by the presence of hundreds of adenomatous polyps in the colon and rectum, whereas less than 100 polyps are found in attenuated familial adenomatous polyposis. Without prophylactic colectomy, colorectal cancer develops inevitably by the age of 40. Restorative proctocolectomy with ileal anal-pouch anastomosis is the operation of choice in familial adenomatous polyposis. In juvenile polyposis coli, 50-200 hamartomatous polyps are found in the colon, rectum, stomach and small bowel. Life-time cumulative risk for colorectal cancer is estimated to be 50%. Prophylactic colectomy is required only in cases in which endoscopic surveillance is not able to control polyp development. Hereditary mixed polyposis syndrome is a variant form of juvenile polyposis coli, consisting of multiple mixed adenomatous, hyperplastic and hamartomatous polyps. Peutz-Jeghers syndrome is characterized by multiple hamartomatous polyps located in the small bowel, colon and stomach. Small bowel follow through and colonoscopy is advised for surveillance. Surgery is warranted only in cases of polyps larger than 1 cm. The causative genes of these syndromes have been cloned. Molecular genetic testing of affected and at-risk individuals is proposed in order to advise surveillance and management.

Genotype-phenotype correlations in attenuated adenomatous polyposis coli.

Germ-line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli (AAPC), a variant of familial adenomatous polyposis (FAP). AAPC is recognized by the occurrence of <100 colonic adenomas and a later onset of colorectal cancer (age >40 years). The aim of this study was to assess genotype-phenotype correlations in AAPC families. By protein-truncation test (PTT) assay, the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds, and their phenotypic differences were examined. Five novel germ-line APC mutations were identified in seven kindreds. Mutations were located in three different regions of the APC gene: (1) at the 5' end spanning exons 4 and 5, (2) within exon 9, and (3) at the 3' distal end of the gene. Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1, and upper-gastrointestinal manifestations were more severe in them. In individuals with mutations in either region 2 or region 3, the average number of adenomas tended to be lower than those in individuals with mutations in region 1, although age at diagnosis was similar. In all AAPC kindreds, a predominance of right-sided colorectal adenomas and rectal polyp sparing was observed. No desmoid tumors were found in these kindreds. Our data suggest that, in AAPC families, the location of the APC mutation may partially predict specific phenotypic expression. This should help in the design of tailored clinical-management protocols in this subset of FAP patients.

Overexpression of the nonpancreatic secretory group II PLA2 messenger RNA and protein in colorectal adenomas from familial adenomatous polyposis patients.

The synovial fluid or group II secretory phospholipase A2 (sPLA2) has been implicated in various inflammatory processes and has been shown to release arachidonic acid for prostaglandin biosynthesis. In human colorectal cancer, both arachidonic acid and eicosanoid levels are elevated. Recently, sPLA2 has been identified as a candidate gene that modifies the Apc gene in the Min mouse, a murine model for familial adenomatous polyposis (FAP). Loss of sPLA2 gene function results in susceptibility to the Min phenotype and the formation of multiple intestinal polyps, whereas mice expressing an active sPLA2 gene are resistant to polyp formation. Therefore, there are two potentially contrasting roles for sPLA2 in colon cancer; one is protection against polyp formation, and the other, the release of arachidonic acid for prostaglandin production and subsequent tumor promotion. To investigate these contrasting dual roles of sPLA2, we have examined the expression and sequence of the sPLA2 mRNA in normal mucosa and duodenal and colorectal polyps from FAP patients. In 11 of 14 patients, there was a significant increase in sPLA2 mRNA levels in the adenoma over the normal tissue. In some cases, there was over 100-fold increase in mRNA levels in the adenoma compared with normal tissue. Analysis of multiple adenomatous polyps from individual patients revealed that not all polyps contained elevated levels of sPLA2 mRNA. Immunoblot analysis also showed that sPLA2 protein expression was elevated in adenoma over normal tissue in five of six FAP patients analyzed. Furthermore, sequence analysis of sPLA2 mRNA present in these samples did not reveal mutations in the coding region. The implications of the up-regulation of sPLA2 in FAP is not clear, but unlike the Min mouse model, it does not seem to have a significant effect on polyp formation. In contrast, the high level of sPLA2 expression is more likely contributing to the elevated levels of arachidonic acid found in colorectal cancer and, in conjunction with the elevated expression of cyclooxygenase-2, could be another factor in tumor formation.