Early-onset colorectal cancer: a sporadic or inherited disease?

Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a "sporadic" subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the "sporadic" subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this "sporadic" early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.

Early-onset colorectal cancer patients without family history are "at very low risk" for lynch syndrome.

INTRODUCTION: Several studies evaluated the prevalence of Lynch Syndrome (LS) in young onset colorectal cancer (CRC) patients and the results were extremely variable (5%-20%). Immunohistochemistry (IHC) for MMR proteins and/or MSI analysis are screening tests that are done, either by themselves or in conjunction, on colon cancer tissue to identify individuals at risk for LS. The primary aim of our study was to evaluate the prevalence of LS in a large series of early-onset CRC without family history compared with those with family history. The secondary aim was to assess the diagnostic accuracy of IHC and MSI analysis as pre-screening tools for LS. METHODS: Early-onset CRC patients (≤ 50 years) were prospectively recruited in the study. IHC and MSI analysis were performed in all the patients. Germ-line mutation analysis (GMA) was carried out in all MMR deficient tumors. A logistic regression model was performed to identify clinical features predictive of MSI-H. RESULTS: 117 early onset CRC cases were categorized in three groups (A, B, C) according with family history of CRC. IHC and MSI analysis showed MMR deficiency in 6/70 patients (8.6%) of group A, 24/40 patients (60%) of group B and none of group C. GMA showed a deleterious mutation in 19 (47.5%) patients of group B. MSI analysis had a diagnostic accuracy of 95.7% (CI 92.1-99.4) and IHC of 83.8% (CI 77.1-90.4). The logistic regression model revealed that by using a combination of the two features "No Amsterdam Criteria" and "left sided CRC" to exclude MSI-H, accuracy was 89.7% (84.2-95.2). CONCLUSIONS: Early-onset CRC patients, with left sided CRC and without family history are "at very low risk" for Lynch syndrome. The two simple criteria of family history and CRC site could be used as a pre-screening tool to evaluate whether or not patients should undergo tissue molecular screening. In the few cases of suspected LS (right sided CRC and/or Amsterdam Criteria), a reasonable approach could be to perform MSI analysis first and IHC afterwards only in MSI-H patients.

Upper GI endoscopy in elderly patients: predictive factors of relevant endoscopic findings.

Elderly patients are at increased risk for peptic ulcer and cancer. Predictive factors of relevant endoscopic findings at upper endoscopy in the elderly are unknown. This was a post hoc analysis of a nationwide, endoscopic study. A total of 3,147 elderly patients were selected. Demographic, clinical, and endoscopic data were systematically collected. Relevant findings and new diagnoses of peptic ulcer and malignancy were computed. Both univariate and multivariate analyses were performed. A total of 1,559 (49.5%), 213 (6.8%), 93 (3%) relevant findings, peptic ulcers, and malignancies were detected. Peptic ulcers and malignancies were more frequent in >85-year-old patients (OR 3.1, 95% CI = 2.0-4.7, p = 0.001). The presence of dysphagia (OR = 5.15), weight loss (OR = 4.77), persistent vomiting (OR = 3.68), anaemia (OR = 1.83), and male gender (OR = 1.9) were significantly associated with a malignancy, whilst overt bleeding (OR = 6.66), NSAIDs use (OR = 2.23), and epigastric pain (OR = 1.90) were associated with the presence of peptic ulcer. Peptic ulcer or malignancies were detected in 10% of elderly patients, supporting the use of endoscopy in this age group. Very elderly patients appear to be at higher risk of such lesions.

Direct mailing of faecal occult blood tests for colorectal cancer screening: a randomized population study from Central Italy.

BACKGROUND: Sending faecal occult blood tests (FOBT) by mail has been proposed both as a method to increase participation and a way to reduce staff costs in colorectal cancer screening. METHODS: Two multicentre randomized controlled trials (ISRCTN10351276) were performed: one randomly assigned 3196 individuals who had previously participated in colorectal screening to receive a FOBT kit at home or a standard invitation; in the second, 4219 people aged 50-69 years who did not respond to a screening invitation were either sent a FOBT or a standard recall letter. The cost per returned kit was calculated in each arm. RESULTS: Participation was higher with direct FOBT mailing in both trials: relative risk 1.11 (95% CI 1.06-1.17) and 1.36 (95% CI 1.16-1.60) for previous responders and non-responders, respectively. The cost per returned kit for previous responders ranged from 4.24€ to 16.10€, and from 3.29€ to 7.36€ with FOBT mailing and standard invitation, respectively, not including staff costs; for non-responders it ranged from 17.13€ to 46.80€, and from 7.36€ to 18.30€ with FOBT mailing and standard recall, respectively. CONCLUSIONS: The FOBT mailing strategy modestly increased participation. This method can be used on a population of previous responders to reduce personnel costs and workload. When used as a reminder to non-responders, this method increases costs.

Obscure-occult bleeding: resolution of unexplained chronic sideropenic anaemia by colonoscopic removal of a colonic leiomyoma.

Although leiomyomas of the stomach or small intestine are relatively common, those of the colon or rectum are rare. Several cases of endoscopic resection of colorectal leiomyomas have been described. However, conventional polypectomy of leiomyomas can result in perforation. To reduce the risk of perforation, submucosal injection can be performed before removal. We report a case of chronic sideropenic anaemia in a patient affected by leiomyoma of the sigmoid colon in which after complete endoscopic enucleation of the lesion we obtained the stable resolution of anaemia.

Down-regulation of serum/glucocorticoid regulated kinase 1 in colorectal tumours is largely independent of promoter hypermethylation.

BACKGROUND: We have previously shown that serum/glucocorticoid regulated kinase 1 (SGK1) is down-regulated in colorectal cancers (CRC) with respect to normal tissue. As hyper-methylation of promoter regions is a well-known mechanism of gene silencing in cancer, we tested whether the SGK1 promoter region was methylated in colonic tumour samples. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the methylation profile of the two CpG islands present in the promoter region of SGK1 in a panel of 5 colorectal cancer cell lines by sequencing clones of bisulphite-treated DNA samples. We further confirmed our findings in a panel of 10 normal and 10 tumour colonic tissue samples of human origin. We observed CpG methylation only in the smaller and more distal CpG island in the promoter region of SGK1 in both normal and tumour samples of colonic origin. We further identified a single nucleotide polymorphism (SNP, rs1743963) which affects methylation of the corresponding CpG. CONCLUSIONS/SIGNIFICANCE: Our results show that even though partial methylation of the promoter region of SGK1 is present, this does not account for the different expression levels seen between normal and tumour tissue.

Appropriateness guidelines and predictive rules to select patients for upper endoscopy: a nationwide multicenter study.

OBJECTIVES: Selecting patients appropriately for upper endoscopy (EGD) is crucial for efficient use of endoscopy. The objective of this study was to compare different clinical strategies and statistical methods to select patients for EGD, namely appropriateness guidelines, age and/or alarm features, and multivariate and artificial neural network (ANN) models. METHODS: A nationwide, multicenter, prospective study was undertaken in which consecutive patients referred for EGD during a 1-month period were enrolled. Before EGD, the endoscopist assessed referral appropriateness according to the American Society for Gastrointestinal Endoscopy (ASGE) guidelines, also collecting clinical and demographic variables. Outcomes of the study were detection of relevant findings and new diagnosis of malignancy at EGD. The accuracy of the following clinical strategies and predictive rules was compared: (i) ASGE appropriateness guidelines (indicated vs. not indicated), (ii) simplified rule (>or=45 years or alarm features vs. <45 years without alarm features), (iii) logistic regression model, and (iv) ANN models. RESULTS: A total of 8,252 patients were enrolled in 57 centers. Overall, 3,803 (46%) relevant findings and 132 (1.6%) new malignancies were detected. Sensitivity, specificity, and area under the receiver-operating characteristic curve (AUC) of the simplified rule were similar to that of the ASGE guidelines for both relevant findings (82%/26%/0.55 vs. 88%/27%/0.52) and cancer (97%/22%/0.58 vs. 98%/20%/0.58). Both logistic regression and ANN models seemed to be substantially more accurate in predicting new cases of malignancy, with an AUC of 0.82 and 0.87, respectively. CONCLUSIONS: A simple predictive rule based on age and alarm features is similarly effective to the more complex ASGE guidelines in selecting patients for EGD. Regression and ANN models may be useful in identifying a relatively small subgroup of patients at higher risk of cancer.

Selected treatments for duodenal perforation after ERCP. A report of three cases.

Perforation is one of the most serious complications of endoscopic sphincterotomy. In the last decade, the management has shifted towards a more selective approach. Three cases are reported here involving three different treatments. In one case, the patient was submitted to a surgical procedure, while a conservative strategy was preferred in the other two, consisting in a naso-biliary drain and endoscopic clip placement, respectively. In this way, the safety of surgical and nonsurgical management of ERCP-related duodenal perforations was tested.

Appropriateness of upper-GI endoscopy: an Italian survey on behalf of the Italian Society of Digestive Endoscopy.

BACKGROUND AND OBJECTIVE: Open-access endoscopy allows physicians to directly schedule endoscopic procedures for their patients without prior consultation. An evaluation of both appropriateness and diagnostic yield of endoscopic procedures is critical when assessing the costs and benefits of endoscopy in an open-access setting. The aim of this Italian multicenter study was to assess the appropriate use of upper endoscopy (EGD) in an open-access system and to establish the yield of diagnostic information relevant to patient care. DESIGN AND SETTING: Cross-sectional, prospective, multicenter study. PATIENTS: A total of 6270 patients referred to 44 Italian centers for open-access EGD during 1 month were prospectively enrolled. INTERVENTIONS: The American Society for Gastrointestinal Endoscopy (ASGE) guidelines were used to assess the relation between the appropriate use of EGD and the presence of relevant endoscopic findings. MAIN OUTCOME MEASUREMENTS AND RESULTS: The rate for "generally not indicated" EGDs was 22.9%: 29.4% for primary care physicians and 12.9% for specialists (P < .01). A relevant endoscopic finding was detected in 2929 examinations (46.7%). The diagnostic yield was significantly higher for "generally indicated" EGDs compared with "generally not indicated" procedures (52% vs 29%; odds ratio [OR] 2.65, 99% confidence interval [CI] 2.23-3.20; P < .01). Of the 133 malignant lesions diagnosed, all but 1 were diagnosed in patients with an appropriate indication (OR >20, 99% CI 3 to >100; P < .01). CONCLUSIONS: Open-access EGD is an useful procedure for clinical practice. Because most of the relevant findings were detected during examinations performed for appropriate indications, the use of ASGE guidelines emerges as crucial to the cost-effectiveness of an open-access system.

The Intestinal Wnt/TCF Signature.

BACKGROUND & AIMS: In colorectal cancer, activating mutations in the Wnt pathway transform epithelial cells through the inappropriate expression of a TCF4 target gene program, which is physiologically expressed in intestinal crypts. METHODS: We have now performed an exhaustive array-based analysis of this target gene program in colorectal cancer cell lines carrying an inducible block of the Wnt cascade. Independently, differential gene-expression profiles of human adenomas and adenocarcinomas vs normal colonic epithelium were obtained. RESULTS: Expression analyses of approximately 80 genes common between these data sets were performed in a murine adenoma model. The combined data sets describe a core target gene program, the intestinal Wnt/TCF signature gene set, which is responsible for the transformation of human intestinal epithelial cells. CONCLUSIONS: The genes were invariably expressed in adenomas, yet could be subdivided into 3 modules, based on expression in distinct crypt compartments. A module of 17 genes was specifically expressed at the position of the crypt stem cell.

Transcriptome profile of human colorectal adenomas.

Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the beta-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation.

Effects of mineral-water supplementation on gastric emptying of solids in patients with functional dyspepsia assessed with the 13C-octanoic-acid breath test.

BACKGROUND/AIMS: Functional dyspepsia is a major problem in terms of prevalence and drug-therapy expenditures. In dyspeptic patients the symptoms are frequently caused by delayed gastric emptying. Conventional treatment is often inefficient. Mineral-water supplementation is prescribed for the treatment of this condition, but there is no concrete proof of its actual efficacy. The aim of this study was to evaluate the effect of supplementation with mineral waters with high mineral salt contents (Acqua Tettuccio, Acqua Regina, Montecatini Terme) on gastric emptying of solids and symptoms in patients with functional dyspepsia. METHODOLOGY: Eight patients with functional dyspepsia and two healthy (non-dyspeptic) controls were placed on high-mineral-content water supplementation (500 cc/day) for eight days. Before and after completion of the supplementation treatment, patient symptoms were scored and the 13C-octanoic-acid breath test was administered to assess gastric emptying. RESULTS: After the treatment, the dyspeptic subjects presented clear decreases in parameters of gastric emptying (half time and lag time) as well as an improvement in symptom scores. CONCLUSIONS: Health spa treatments based on consumption of waters with a high content of mineral salts seem to be capable of improving gastric emptying of solids in dyspeptics. Longer and longitudinal studies are needed to verify the persistence of this effect.

Fine needle biopsy of focal liver lesions: the hepatologist's point of view.

Guided biopsy of hepatocellular carcinoma has been recently discussed again due to the progress of imaging techniques and the risk of malignant seeding after the procedure. Ultrasound is probably still the most accurate imaging modality for early detection of nodules arising on cirrhosis, even when compared with more advanced imaging techniques. It can be easily employed in the surveillance of high-risk cirrhotic patients. Ultrasound-guided biopsy has very high sensitivity and almost absolute specificity, which allows the appropriate treatment to start after a positive diagnosis. It also allows correct diagnosis of lymphomatous nodules, the incidence of which is increased in hepatitis C virus-related cirrhosis. The risk of seeding appears limited according to the currently available epidemiological data; this should be considered against the risk of false-positive diagnosis of malignancy based on imaging studies alone. Ultrasound-guided biopsy is a valuable tool also for the diagnosis of small nodules (less than 10 mm in diameter). The best accuracy in the sampling of hepatocellular carcinoma nodules is obtained by combining smear cytology and microhistology. This can be achieved by a single biopsy with a fine cutting needle that furnishes pathologic material suitable for both examinations, reducing risks and costs.

The stool antigen test for detection of Helicobacter pylori after eradication therapy.

BACKGROUND: Current noninvasive tests to confirm the eradication of Helicobacter pylori must be performed 4 weeks or more after eradication therapy is completed. OBJECTIVE: To determine whether the stool antigen test, a relatively new noninvasive test for H. pylori, administered at various times after eradication therapy correctly identifies persons with persistent H. pylori infection. DESIGN: Prospective blinded study. SETTING: Six clinical centers in the United States and Europe. PATIENTS: 84 H. pylori --infected patients undergoing endoscopy for upper abdominal symptoms. MEASUREMENTS: At baseline and on day 35 after the completion of triple eradication therapy, all patients underwent endoscopy with histologic examination, rapid urease test and culture, urea breath test, and a stool antigen test. The stool antigen test was also performed on days 3, 7, 15, 21, 28, and 35 after completion of therapy. RESULTS: Compared with the gold-standard endoscopic tests on day 35 after antimicrobial therapy, the urea breath test had a sensitivity of 94% (95% CI, 71% to 100%) and a specificity of 100% (CI, 94% to 100%). The stool antigen test had a sensitivity of 94% (CI, 71% to 100%) and a specificity of 97% (CI, 89% to 100%). On day 7 after treatment, the stool antigen test was predictive of eradication (positive predictive value, 100% [CI, 69% to 100%]; negative predictive value, 91% [CI, 82% to 97%]). CONCLUSION: A positive result on the stool antigen test 7 days after completion of therapy identifies patients in whom eradication of H. pylori was unsuccessful.