Tumour-educated circulating monocytes are powerful candidate biomarkers for diagnosis and disease follow-up of colorectal cancer.

OBJECTIVE: Cancer immunology is a growing field of research whose aim is to develop innovative therapies and diagnostic tests. Starting from the hypothesis that immune cells promptly respond to harmful stimuli, we used peripheral blood monocytes in order to characterise a distinct gene expression profile and to evaluate its potential as a candidate diagnostic biomarker in patients with colorectal cancer (CRC), a still unmet clinical need. DESIGN: We performed a case-control study including 360 peripheral blood monocyte samples from four European oncological centres and defined a gene expression profile specific to CRC. The robustness of the genetic profile and disease specificity were assessed in an independent setting. RESULTS: This screen returned 43 putative diagnostic markers, which we refined and validated in the confirmative multicentric analysis to 23 genes with outstanding diagnostic accuracy (area under the curve (AUC)=0.99 (0.99 to 1.00), Se=100.0% (100.0% to 100.0%), Sp=92.9% (78.6% to 100.0%) in multiple-gene receiver operating characteristic analysis). The diagnostic accuracy was robustly maintained in prospectively collected independent samples (AUC=0.95 (0.85 to 1.00), Se=92.6% (81.5% to 100.0%), Sp=92.3% (76.9% to 100.0%). This monocyte signature was expressed at early disease onset, remained robust over the course of disease progression, and was specific for the monocytic fraction of mononuclear cells. The gene modulation was induced specifically by soluble factors derived from transformed colon epithelium in comparison to normal colon or other cancer histotypes. Moreover, expression changes were plastic and reversible, as they were abrogated upon withdrawal of these tumour-released factors. Consistently, the modified set of genes reverted to normal expression upon curative treatment and was specific for CRC. CONCLUSIONS: Our study is the first to demonstrate monocyte plasticity in response to tumour-released soluble factors. The identified distinct signature in tumour-educated monocytes might be used as a candidate biomarker in CRC diagnosis and harbours the potential for disease follow-up and therapeutic monitoring.

Predicting mortality in non-variceal upper gastrointestinal bleeders: validation of the Italian PNED Score and Prospective Comparison with the Rockall Score.

OBJECTIVES: We sought (i) to validate a new prediction rule of mortality (Progetto Nazionale Emorragia Digestiva (PNED) score) on an independent population with non-variceal upper gastrointestinal bleeding (UGIB) and (ii) to compare the accuracy of the Italian PNED score vs. the Rockall score in predicting the risk of death. METHODS: We conducted prospective validation of analysis of consecutive patients with UGIB at 21 hospitals from 2007 to 2008. Outcome measure was 30-day mortality. All the variables used to calculate the Rockall score as well as those identified in the Italian predictive model were considered. Calibration of the model was tested using the chi2 goodness-of-fit and performance characteristics with receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) was used to quantify the diagnostic accuracy of the two predictive models. RESULTS: Over a 16-month period, data on 1,360 patients were entered in a national database and analyzed. Peptic ulcer bleeding was recorded in 60.7% of cases. One or more comorbidities were present in 66% of patients. Endoscopic treatment was delivered in all high-risk patients followed by high-dose intravenous proton pump inhibitor in 95% of them. Sixty-six patients died (mortality 4.85%; 3.54-5.75). The PNED score showed a high discriminant capability and was significantly superior to the Rockall score in predicting the risk of death (AUC 0.81 (0.72-0.90) vs. 0.66 (0.60-0.72), P<0.000). Positive likelihood ratio for mortality in patients with a PNED risk score >8 was 16.05. CONCLUSIONS: The Italian 10-point score for the prediction of death was successfully validated in this independent population of patients with non-variceal gastrointestinal bleeding. The PNED score is accurate and superior to the Rockall score. Further external validation at the international level is needed.

Predictive factors of mortality from nonvariceal upper gastrointestinal hemorrhage: a multicenter study.

OBJECTIVES: From an Italian Registry of patients with upper gastrointestinal hemorrhage (UGIH), we assessed the clinical outcomes and explored the roles of clinical, endoscopic, and therapeutic factors on 30-day mortality in a real life setting. METHODS: Prospective analysis of consecutive patients endoscoped for UGIH at 23 community and tertiary care institutions from 2003 to 2004. Covariates and outcomes were defined a priori and 30-day follow-up obtained. Logistic regression analysis identified predictors of mortality. RESULTS: One thousand and twenty patients were included. A total of 46 patients died for an overall 4.5% mortality rate. In all, 85% of deaths were associated with one or more major comorbidity. Sixteen of 46 patients (35%) died within the first 24 h of the onset of bleeding. Of these, eight had been categorized as ASA class 1 or 2 and none of them was operated upon, despite a failure of endoscopic intention to treatment in four. Regression analysis showed advanced age, presence of severe comorbidity, low hemoglobin levels at presentation, and worsening health status as the only independent predictors of 30-day mortality (P < 0.001). The acute use of a PPI exerted a protective effect (OR 0.23, 95% CI 0.09-0.73). Recurrent bleeding was low (3.2%). Rebleeders accounted for only 11% of the total patients deceased (OR 3.27, 95% CI 1.5-11.2). CONCLUSIONS: These results indicate that 30-day mortality for nonvariceal bleeding is low. Deaths occurred predominantly in elderly patients with severe comorbidities or those with failure of endoscopic intention to treatment.

[Diverticular disease: towards 2020. An evidence-based approach]. / La malattia diverticolare verso il 2020. Un approccio evidence-based.

Diverticular disease (DD) of the colon has an increasing burden on health service resources, in terms of hospital admissions, mortality and surgery rate. We present an overview of the clinical history of DD, and of the ways that gastroenterologists have to modify it. Prevalence of the disease increases with aging. Most of diverticulosis are occasionally identified on colonscopy, and most of them remain asymptomatic for all life. Only 4% of these subjects develop diverticulitis. However, 4-25% of these patients are expected to present a second episode of diverticulitis, and 15% of them develop complications. Hospitalizations for diverticulitis and relapses of diverticulitis show strong growth (+21% 2013 vs 2003 in USA). The total annual costs for hospitalization for DD in USA are over 2,2 billion of dollars, and in Italy exceed 63 million of euros. In-hospital mortality can reach 0,5%. Diagnosis of diverticulitis is based on clinical history, lab tests and imaging (ultrasonography, CAT). Clinical diagnosis has a sensitivity of 68% and specificity around 98%. According to a meta-analysis, the performance of ultrasonograhy and CAT results very high ("pooled" sensitivity 92-94%, and specificity 90-99%; "pooled" Likelihood Ratio positive 9.6 for ultrasonography and 78.4 for CAT. Likelihood Rato negative 0.09 and 0.06 respectively). Evidences for preventing relapse are poor. Anyway, a very recent meta-analysis on 6 RCTs suggests no role for mesalazine (GRADE SCALE for evidence 3). Non absorbable antibiotics (rifaximin) have been used in two studies (one RCT, one retrospective observational). Data from the two studies suggest some evidence in favour of its use (GRADE SCALE 1). The number of admitted patients is 291. Considering a base-line risk of 19 relapses every 100 patients (5-year observation period), the absolute risk difference is minus 9 patients with relapse (CI 95% -14 a + 3) in the RCT and minus 14 patients (CI 95% -17 a -5) in the observational study. A 2020 preview suggests an exploding interest in assessing the risk factors for relapse (including aspirin and NSAIDs) and identifying the better strategy to reduce it. Further trials are requested, including the use of probiotics alone.

Platelet count/spleen diameter ratio for non-invasive diagnosis of oesophageal varices: is it useful in compensated cirrhosis?

AIM: To assess the diagnostic accuracy of the platelet count/spleen diameter ratio for identification of oesophageal varices and/or hypertensive gastropathy in patients with compensated cirrhosis. METHODS: Platelet count/spleen diameter ratio was calculated in 87 consecutive patients with compensated cirrhosis. A new cut-off with the highest sensitivity and specificity for the presence/absence of oesophageal varices and/or hypertensive gastropathy was identified. Performance of the platelet count/spleen diameter ratio considering previously reported cut-off values were then tested in our population. RESULTS: A platelet count/spleen diameter ratio <936.4 had the best sensitivity and specificity for the diagnosis of oesophageal varices and for all endoscopic findings of portal hypertension. A value lower than 936.4 allowed identification of 64.5% of patients with oesophageal varices and 66.7% of patients with any sign of portal hypertension; a value higher than 936.4 excluded oesophageal varices in 64.3% of patients and any sign of portal hypertension in 68.6% of patients. CONCLUSIONS: In patients with compensated cirrhosis, the platelet count/spleen diameter ratio is not a useful parameter to avoid unnecessary upper endoscopy, independently of the cut-off.