Risk of desmoid tumours after open and laparoscopic colectomy in patients with familial adenomatous polyposis.

BACKGROUND: Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP. METHODS: The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed. RESULTS: A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0-516) months in the open group and 60 (12-108) months in the laparoscopic group, 98 patients (16·3 per cent) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13·0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0·042). In multivariable analysis, female sex (hazard ratio (HR) 2·18, 95 per cent confidence interval 1·40 to 3·39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3·85, 1·90 to 7·80), proctocolectomy (HR 1·67, 1·06 to 2·61), open colectomy (HR 6·84, 1·96 to 23·98) and year of surgery (HR 1·04, 1·01 to 1·07) were independent risk factors for the diagnosis of DT after prophylactic surgery. CONCLUSION: Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP.

Peutz-Jeghers syndrome: a systematic review and recommendations for management.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Recommendations to improve identification of hereditary and familial colorectal cancer in Europe.

Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.

PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients.

BACKGROUND: It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear. PATIENTS AND METHODS: We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing. RESULTS: Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs. CONCLUSION: These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.

Quantitative and qualitative characterization of plasma DNA identifies primary and recurrent colorectal cancer.

Because plasma DNA may be a useful tool for cancer detection, we screened primary tumors and related multiple plasma samples at the time of surgery and during the follow-up period for plasma DNA level as well as for K-Ras mutations and p16INK4a promoter hypermethylation in colorectal cancer patients. At the time of surgery, DNA levels were higher in tumor patients than in healthy donors, and K-Ras and p16INK4a alterations were detected in 7 and 11 cancers respectively, and in all related plasma samples. During the follow-up, plasma DNA levels decrease progressively but rapidly increased when a relapse occurred, whereas K-Ras and p16INK4a alterations were detected only in relapsed patients. Therefore, combined quantitative and qualitative analyses of plasma DNA confirm the presence of colorectal cancer, define disease-free status and indicate the presence of relapse.

Guidelines for the clinical management of familial adenomatous polyposis (FAP).

BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.

Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer).

Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.

Putative common origin of two MLH1 mutations in Italian-Quebec hereditary non-polyposis colorectal cancer families.

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.

Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis.

PURPOSE: Familial adenomatous polyposis (FAP), caused by a mutation in the APC gene, is a colorectal cancer predisposition syndrome associated with several other clinical conditions. The severity of the FAP is related to the position of the inherited mutation in the APC gene. We analyzed a large series of FAP patients to identify associations among major clinical manifestations and to correlate the mutation site with specific disease manifestations. MATERIALS AND METHODS: APC mutations were identified in 953 FAP patients from 187 families. We used unconditional logistic regression models and a method involving generalized estimating equations to investigate the association between genotype and phenotype. We used multiple correspondence analysis to represent the interrelationships of a multiway contingency table of the considered variables. RESULTS: APC germline mutations were located between codons 156 and 2011 of the APC gene. Mutations spanning the region between codons 543 and 1309 were variable, but strongly associated with congenital hypertrophy of retinal pigment epithelium. Mutations between codons 1310 and 2011 were associated with a six-fold risk of desmoid tumors relative to the low-risk reference region (159 to 495). Mutations at codon 1309 were associated with early development of colorectal cancer. Mutations between codons 976 and 1067 were associated with a three- to four-fold increased risk of duodenal adenomas. The cumulative frequency of extracolonic manifestations was highest for mutations between codons 976 and 1067, followed by mutations between 1310 and 2011. CONCLUSION: Analysis of the relation between APC mutation site and phenotype identifies subgroups of FAP patients at high risk for major extracolonic disease, which is useful for surveillance and prevention.

Tissue localization of TGFalpha and apoptosis are inversely related in colorectal tumors.

Expression of TGFalpha and the EGF receptor was studied in relation to apoptosis in human colorectal mucosa and premalignant and malignant tumors. In normal mucosa the proteins colocalized both in the proliferation compartment and at the luminal pole of the crypts in cells committed to undergo apoptosis. While staining for the EGF receptor was increased in premalignant and malignant lesions, TGFalpha was undetectable in aberrant crypt foci as well as large areas of adenomas. Incidence of apoptosis (AI) was high in these areas ranging from 8.83-24.59. Adenomas did, however, contain islands of high TGFalpha expression where AI was decreased to a range of 0.76-4.00 (decreased at P=0.0027). In carcinomas TGFalpha expression was increased above both normal and adenoma levels corresponding to the decrease in apoptosis in the malignant tumors. Tissue localization of TGFalpha and AI were still inversely related ( P=0.022), but interpatient variability was much larger than for adenomas. The data indicate that TGFalpha is the main survival factor in premalignant tumor cells of the colon, while additional factors moderate its effect in carcinomas. This suggests the possibility of targeting the EGF receptor pathway not only for treatment but also for the reversal of adenoma growth and the prevention of malignant colorectal tumors.

Effect of lifestyle, smoking, and diet on development of intestinal metaplasia in H. pylori-positive subjects.

OBJECTIVES: This study aimed to evaluate the influence of environmental and sociodemographic factors and the effect of smoking, alcohol, and dietary habits on the risk of gastric intestinal metaplasia (IM) in Helicobacter pylori-infected subjects. METHODS: The investigation was based on 2598 consecutive volunteer blood donors tested for the presence of antibodies against H. pylori from March 1995 to March 1997. Endoscopy with multiple biopsies was offered to all H. pylori-positive, symptomatic subjects. The presence or absence of IM was diagnosed by gastric biopsies. A serologically H. pylori-positive subject with gastric IM was defined as a case, whereas serologically H. pylori-positive subjects without IM were used as controls. All patients answered a detailed questionnaire collecting sociodemographic characteristics and smoking, alcohol drinking, and dietary habits. Odds ratios (ORs) and their 95% CIs were estimated by unconditional logistic regression, including terms for age and sex, to assess the association between the data collected and IM. RESULTS: Three hundred forty-four subjects with serological H. pylori infection and upper-GI symptoms underwent GI endoscopy, during which biopsies were taken for histological diagnosis. Histology revealed metaplasia in 74 subjects (21.5%). Incomplete IM was found in 37.8% of these cases. No significant associations were found between IM and anthropometric or sociodemographic factors. There was a significant association between age and IM (chi2 for trend, 6.67; p value, 0.009). Current smokers of over 20 cigarettes per day had a 4-fold risk of IM (OR, 4.75, 95% CI, 1.33-16.99). A 2-fold increased risk was found for high butter consumers (OR, 2.17; 95% CI, 1.14-4.11). No significant specific associations were found between the variables studied and complete or incomplete IM. CONCLUSIONS: This study found that smoking and high butter consumption may increase the risk of having gastric IM in H. pylori-positive subjects.

Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.

Desmoids represent the most important cause of death, after colorectal cancer, in patients affected with familial adenomatous polyposis (FAP), an inherited disease due to mutations in the APC gene. The aims of our study were to estimate the risk of developing desmoids in FAP patients and to evaluate the association between desmoids and different risk factors. The occurrence of desmoids, colorectal cancer and other extra-colonic manifestations were assessed in 897 FAP patients, 653 of whom were also investigated for APC mutations. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using an unconditional multiple logistic regression model. Desmoids developed in 107 patients (11.9%), with a cumulative risk of 20.6%. Females had a significantly higher risk than males (OR = 2.1; 95% CI 1.4-3.1). Family history of desmoids (OR = 8.75; 95% CI 5.66-13.51), osteomas (OR = 2.9; 95% CI 1.8-4.8) and epidermoid cysts (OR = 1.8; 95% CI 1.1-3.2) was also significantly associated with the occurrence of disease. Subjects with APC mutations beyond codon 1444 had a 12-fold increased risk, compared with patients with mutations located upstream. Mutations beyond codon 1309 conferred a 17-fold higher risk, compared with mutations upstream codon 452. Multivariate analysis identified as independent predictors mutation beyond codon 1444 (OR = 6.2; 95% CI 2.5-15.8), family history of desmoids (OR = 5.8; 95% CI 3.1-10.6), female gender (OR = 2.1; 95% CI 1.1-3.8) and the presence of osteomas (OR = 1.9; 95% CI 1.1-3.4). Our results indicate that integrating genetic and clinical data is helpful in defining subgroups of patients at higher risk for desmoids, who may benefit from specific prevention programs.

Double-contrast barium enema and computerised tomography in the pre-operative evaluation of rectal carcinoma: are they still useful diagnostic procedures?

PURPOSE: In modern management of rectal carcinoma, the preoperative evaluation of disease parameters is important for selection of therapeutic options. Such parameters are currently defined through endorectal ultrasonography or endoscopic ultrasonography. A retrospective analysis of the parameters obtained with double-contrast barium enema (DCBE) and endorectal balloon computed tomography (CT) was conducted to verify the diagnostic reliability of the radiological techniques and to establish whether there is still an indication for their use. METHODS: 53 consecutive patients with adenocarcinoma of the distal half of the rectal ampulla underwent double contrast barium enema examination and CT of the pelvis with endorectal balloon. On the basis of the DCBE and CT assessment we evaluated: 1) the distance between the cranial extremity of the anal canal and the distal margin of the neoplasm; 2) the radial diffusion of the tumor; 3) the metastatic involvement of the perirectal and inferior mesenteric lymph nodes. RESULTS: 1) CT and DBCE measurements of the distal margin tended to coincide, but both tended to overestimate the measurement when compared to the pathologic examination; 2) in the identification of neoplastic infiltration of perirectal fat (T3) CT had 100% sensitivity, 78.7% specificity and 86.8% accuracy; 3) the CT sensitivity for detecting lymph node metastasis was 52.6%, specificity 85.3% and accuracy 73.6%. CONCLUSIONS: The diagnostic information provided by the radiological examinations is comparable to that of clinical and instrumental methods currently employed for staging of rectal carcinoma, although the latter are preferred because they are more readily accessible and less costly. DCBE and CT can therefore be usefully employed for staging of cancer of the rectum in those cases in which there are limitations of the current standard methods.

Surgical treatment of gastric cancer invading the oesophagus.

INTRODUCTION: There is controversy regarding which type of surgical treatment is most appropriate for upper gastric cancer invading the oesophagus. METHODS: A review of the pertinent literature was carried out regarding oesophageal involvement in gastric cancer. RESULTS: Invasion of the oesophagus occurred in 26-63% of Western surgical series. It was more frequent in Borrmann IV type, linitis plastica, pT3-pT4, diffuse type by Lauren, N+ or tumours exceeding 5 cm in diameter. Lymphatic tumour spread was caudad (coeliac nodes, hepatoduodenal nodes, paraortic nodes) but mediastinal nodes were also involved if tumour growth in the oesophagus exceeded 3 cm or if there was transmural oesophageal infiltration. In Western countries there was less than 30% 5-year survival and no long-term survivors when hepatoduodenal or mediastinal nodes were metastatic. Mediastinal dissection through thoracotomy did not provide any benefit. CONCLUSIONS: A rational approach involves total gastrectomy plus partial oesophagectomy. Abdominal transhiatal resection may be performed in the case of a localized, non-infiltrating tumour and oesophageal involvement <2 cm. However, infiltrating, poorly differentiated or Borrmann III-IV tumours require a right thoracotomy to achieve a longer margin of clearance. When oesophageal involvement is >3 cm, or hepatoduodenal or mediastinal nodes are positive, no surgical procedure is curative and the literature demonstrates that extended aggressive surgery has no benefits.

Colorectal cancer: how does it start? How does it metastasize?

Colorectal carcinogenesis is a multistep process with an apparently orderly progression from benign tissue to invasive malignancy and metastases. Yet at the genome level, a considerably more chaotic situation exists, with order arising through the process of natural selection in the midst of genomic instability. Major pathways for colorectal carcinogenesis begin with suppressor loss or acquisition of a mutator phenotype, but there are other pathways known and yet to be described. These pathways result in the natural selection of cells with unstable genomes leading to malignancy and metastases.

A prospective multicenter evaluation of new fecal occult blood tests in patients undergoing colonoscopy.

OBJECTIVE: Guaiac-based fecal occult blood (FOB) tests, in particular, Hemoccult II (HO), are commonly used to detect colorectal neoplasia. Because the sensitivity and specificity of these tests are critical to cost-effective screening programs, we aimed to investigate the improved performance characteristics of new FOB tests for known colonic lesions. METHODS: Nine centers worldwide performed FOB testing with guaiac-based tests (Hemoccult II [HO] and Hemoccult II SENSA [SENSA]) and immunochemical tests (HemeSelect [HS] and FlexSure OBT [FS]) on 554 patients referred for colonoscopy for predetermined indications. A combination testing strategy consisting of SENSA followed by HS or FS (which was considered positive only when both tests were positive) was also evaluated. Results of FOB tests were compared to findings on colonoscopy. RESULTS: Cancers were identified in 2.9% of subjects, whereas adenomas > or =10 mm were found in 39 patients. Small adenomas, colitis, and other lesions were identified in 141 patients. The positivity rate of HO for adenomas > or =10 mm was less than for SENSA (20.5% vs 35.9%, p < 0.05), whereas the positivity rate of HO, SENSA, FS, HS, or the combination tests for cancers was not statistically different. The overall positivity rates were significantly greater for FS (15.9%, p = 0.0002) and significantly lower using the combination tests (SENSA/FS 6.0%, p = 0.01; SENSA/HS 6.2%, p = 0.02) compared to HO (9.4%). In this study population, the relative specificity (i.e., true-negative tests/true-negatives + false-positives in patients without adenomas > or =10 mm or cancers) of HO (93.9%; 95% CI, 91.7-96.1) was similar to that of SENSA (92.8%; 95% CI, 90.4-95.2) and HS (90.1%; 95% CI, 87.4-92.8), and greater than FS (88.0%; 95% CI, 85.1-90.9, p < 0.001). When considering adenomas > or =10 mm, cancers alone or cancers and adenomas combined, the combination test using SENSA/FS was associated with significantly fewer false-positive tests than any of the individual tests. CONCLUSIONS: Compared to single tests, the combination test with the highly sensitive SENSA and an immunochemical test had slightly reduced sensitivity but significantly fewer false-positive tests than any single test. These data raise the possibility that a combination test (i.e., highly sensitive guaiac plus immunochemical) could reduce the costs of screening for colon cancer, and suggest that further study of combination test strategies is warranted.