Cancer Risk in Inflammatory Bowel Disease: A 6-Year Prospective Multicenter Nested Case-Control IG-IBD Study.

BACKGROUND: In a 6-year, multicenter, prospective nested case-control study, we aimed to evaluate risk factors for incident cancer in inflammatory bowel disease (IBD), when considering clinical characteristics of IBD and immunomodulator use. The secondary end point was to provide characterization of incident cancer types. METHODS: All incident cases of cancer occurring in IBD patients from December 2011-2017 were prospectively recorded in 16 Italian Group for the Study of Inflammatory Bowel Disease units. Each of the IBD patients with a new diagnosis of cancer was matched with 2 IBD patients without cancer, according to IBD phenotype (ulcerative colitis [UC] vs Crohn's disease [CD]), age (±5 years), sex. Risk factors were assessed by multivariate logistic regression analysis. RESULTS: Cancer occurred in 403 IBD patients: 204 CD (CD cases), 199 UC (UC cases). The study population included 1209 patients (403 IBD cases, 806 IBD controls). Cancer (n = 403) more frequently involved the digestive system (DS; 32%), followed by skin (14.9%), urinary tract (9.7%), lung (6.9%), genital tract (6.5%), breast (5.5%), thyroid (1.9%), lymphoma (2.7%, only in CD), adenocarcinoma of the small bowel (SBA; 3.9%, 15 CD, 1 pouch in UC), other cancers (15.9%). Among cancers of the DS, colorectal cancer (CRC) more frequently occurred in UC (29% vs 17%; P < 0.005), whereas SBA more frequently occurred in CD (13% vs 6.3% P = 0.039). In CD, perforating (B3) vs non-stricturing non-perforating (B1) behavior represented the only risk factor for any cancer (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.33-4.11). In CD, risk factors for extracolonic cancer (ECC) were a B3 vs B1 and a stricturing (B2) vs B1 behavior (OR, 2.95; 95% CI, 1.62-5.43; OR, 1.79; 95% CI, 1.09-2.98). In UC, risk factors for ECC and for overall cancer were abdominal surgery for UC (OR, 4.63; 95% CI, 2.62-8.42; OR, 3.34; 95% CI, 1.88-5.92) and extensive vs distal UC (OR, 1.73; 95% CI, 1.10-2.75; OR, 1.99; 95% CI, 1.16-3.47). Another risk factor for ECC was left-sided vs distal UC (OR, 1.68; 95% CI, 1.00-2.86). Inflammatory bowel disease duration was a risk factor for skin and urinary tract cancers. CONCLUSIONS: Perforating CD, extensive UC, and abdominal surgery for UC were identified as risk factors for overall incident cancer and for ECC. The clinical characteristics associated with severe IBD may increase cancer risk.

Inflammatory Bowel Disease Phenotype as Risk Factor for Cancer in a Prospective Multicentre Nested Case-Control IG-IBD Study.

BACKGROUND AND AIMS: Cancer risk in inflammatory bowel disease [IBD] is still debated. In a prospective, multicentre, nested case-control study, we aimed to characterise incident cases of cancer in IBD. The role of immunomodulators vs clinical characteristics of IBD as risk factors for cancer was also investigated. MATERIALS AND METHODS: From January 2012 to December 2014, each IBD patient with incident cancer was matched with two IBD patients without cancer for: IBD type, gender, and age. Risk factors were assessed by multivariate regression analysis. RESULTS: IBD patients considered numbered 44619: 21953 Crohn's disease [CD], 22666 ulcerative colitis [UC]. Cancer occurred in 174 patients: 99 CD [CD-K], 75 UC [UC-K]. Controls included 198 CD [CD-C], 150 UC [UC-C]. Cancer incidence in IBD was 3.9/1000, higher in CD (4.5/1000 [99/21,953]) than in UC (3.3/1000 [75/22,666]; p = 0.042). Cancers involved: digestive system [36.8%], skin [13.2%], urinary tract [12.1%], lung [8.6%], breast [8%], genital tract [6.9%], thyroid [4.6%], lymphoma [3.5%], others [6.3%]. In CD, penetrating behaviour and combined thiopurines and tumour necrosis factor alpha [TNFα] antagonists were risk factors for cancer overall: odds ratio [OR] (95% confidence interval [CI] 2.33 [1.01-5.47]); 1.97 [1.1-3.5]; and for extracolonic cancers 3.9 [1.56-10.1]; 2.15 [1.17-4.1], respectively. In UC, risk factors were pancolitis and disease-related surgery for cancer overall (OR: 2.52 [1.26-5.1]; 5.09 [1.73-17.1]); disease-related surgery for colorectal cancer [CRC] (OR 3.6 [1.0-12]); and extensive and left-sided vs distal UC for extracolonic cancers (OR: 2.55 [1.15-5.9]; 2.6 [1.04-6.6]), respectively. CONCLUSIONS: In a multicentre study, penetrating CD and extensive UC were risk factors for cancer overall. Cancer incidence was higher in CD than in UC.

Post-operative recurrence of Crohn's disease: A prospective study at 5 years.

BACKGROUND: We aimed to prospectively assess whether endoscopic recurrence severity at 1 year in Crohn's disease is predictive of clinical recurrence within 5 years. METHODS: Clinical recurrence (Crohn's Disease Activity Index>150) was assessed yearly for 5 years in Crohn's disease patients undergoing ileo-colonic resection. At 1 year, recurrence was assessed by colonoscopy (Rutgeerts' score ≥i1 or ≥2i) and small intestine contrast ultrasonography. RESULTS: 40 patients were included (23 males, median age 39 [16-69] years). Clinical recurrence occurred within 5 years in 16 (40%) patients (years 1, 2, 3, 4, 5: 2 [5%]; 10 [25%]; 4 [10%]; 2 [5%]; 4 [10%], respectively). At 1 year, endoscopic recurrence (score≥i1) occurred in 39 (97.5%) patients (score≥i2: 33 [82.5%]). Ultrasound detected lesions compatible with recurrence in 39/40 (97.5%) patients. Endoscopic score at 1 year was correlated with clinical score at 2 years (p=0.007; r=0.41). Endoscopic score at 1 year was higher in patients with (n=10) vs without (n=30) clinical recurrence at 2 years (3 [2-4] vs 2 [0-4]; p=0.003). Higher endoscopic score (>i2) at 1 year was a risk factor for clinical recurrence within 5 years (OR=0.18; 95% CI 0.04-0.71; p=0.008). CONCLUSIONS: In Crohn's disease, severity of endoscopic recurrence at 1 year remains a predictive marker of clinical recurrence within 5 years. Small intestine contrast ultrasonography is useful for assessing 1-year recurrence.

Autophagy and inflammatory bowel disease: Association between variants of the autophagy-related IRGM gene and susceptibility to Crohn's disease.

BACKGROUND: Crohn's disease and ulcerative colitis are inflammatory bowel diseases involving a genetically determined inappropriate mucosal immune response towards luminal antigens, including resident bacterial flora. Recent studies identified susceptibility genes involved in autophagy. AIMS: We analyzed known autophagic loci (IRGM, ULK1 and AMBRA1) previously described as associated with inflammatory bowel diseases or with other autoimmune and/or inflammatory disorders in a sample of Italian inflammatory bowel diseases patients in order to confirm their possible involvement and relative contribution in the disease. METHODS: We performed a case-control association study, a sub-phenotype correlation and a haplotype analysis. The analysis included 263 Crohn's disease, 206 ulcerative colitis patients and 245 matched healthy controls. Five polymorphisms were genotyped by allelic discrimination assays. RESULTS: IRGM was the most strongly associated with Crohn's disease susceptibility [rs13361189: P=0.011, OR=1.66 [95% CI: (1.12-2.45)]; rs4958847: P=0.05, OR=1.43 [95% CI: (1-2.03)]. The SNP rs13361189 was also found to increase the risk of Crohn's disease clinical sub-phenotype (fibrostricturing behaviour, ileal disease, perianal disease, intestinal resection). These findings suggest that IRGM variants may modulate clinical characteristics of Crohn's disease. CONCLUSIONS: Our study confirms IRGM rs13361189 and rs4958847 polymorphisms to be important for Crohn's disease susceptibility and phenotype modulation, in accordance with previous findings.

Does cirrhotic cardiomyopathy exist? 50 years of uncertainty.

Subtle abnormalities of cardiac structure or function are often identified in patients with liver cirrhosis and have been termed cirrhotic cardiomyopathy. However, in the absence of a precise definition, its diagnosis remains a challenge. Cardiac dysfunction in patients with cirrhosis can often be attributed to concomitant diseases such as hypertension, ischaemic heart disease or excess alcohol consumption in many patients. Further research is required to identify the existence, origin and importance of abnormal cardiac function due specifically to liver disease. Cardiac dysfunction may be masked by treatments given to cirrhotic patients, such as mineral-corticoid receptor antagonists, or by co-existing conditions, such as anaemia. New imaging tests or plasma biomarkers might be able to detect abnormal cardiac function at an early stage of its development.

High expression of the "A Disintegrin And Metalloprotease" 19 (ADAM19), a sheddase for TNF-α in the mucosa of patients with inflammatory bowel diseases.

BACKGROUND: Tumor necrosis factor α (TNF-α) plays a major role in the tissue-damaging immune response in inflammatory bowel diseases (IBDs). The tissue concentration of TNF-α is related to the activity of "A Disintegrin And Metalloprotease" (ADAMs), enzymes that process membrane-bound TNF-α and liberate the TNF-α trimer into the extracellular environment. Although IBD-related inflammation is associated with high ADAM17 levels, the contribution of other members of the ADAMs family is not known. In this study, we characterized the expression of other TNF-α convertases (i.e., ADAM9, ADAM10, and ADAM19) in IBD. METHODS: Normal and IBD biopsies were examined for the content of ADAMs by real-time polymerase chain reaction, Western blotting and immunohistochemistry. ADAM19 was also analyzed in intestinal epithelial cells and normal colonic explants stimulated with inflammatory cytokines and in ex vivo biopsies taken from IBD patients before and after a successful infliximab treatment. RESULTS: ADAM19 RNA transcripts and protein were upregulated in patients with ulcerative colitis and, to a lesser extent, in patients with Crohn's disease compared with normal controls. In contrast, ADAM9 and ADAM10 expression did not differ between patients with IBD and controls. Immunohistochemical analysis showed that epithelial cells were the major source of ADAM19 in IBD. ADAM19 expression was increased in colonic epithelial cell lines and normal colonic explants by TNF-α, interleukin 21 and interleukin 6, and was downregulated in IBD tissue by infliximab. CONCLUSIONS: These findings suggest the existence of a positive feedback mechanism involving cytokines and ADAM19 that can amplify cytokine production in IBD.

Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease.

BACKGROUND: Cirrhotic cardiomiopathy is described as the presence of cardiac dysfunction in cirrhotic patients. The aim of the study was to investigate factors associated with cardiac dysfunction in cirrhotic patients. PATIENTS AND METHODS: Seventy-four cirrhotic patients and twenty-six controls performed a conventional echocardiography and Tissue Doppler Imaging (TDI) for systolic and diastolic function. Results were analyzed by using the Guidelines of American Society of Echocardiography. RESULTS: In patients with cirrhosis, left ventricular end-diastolic diameter was increased (p<0.001) , peak systolic velocities were decreased (11.3±2.7 vs 13.9±1.4cm/s; p<0.001) and left atrial volumes were increased (32.7±8.3 vs 24±8.5ml, p<0.001) as well as cardiac mass (90.6±23 vs 70.5±22g/m(2), p<0.001). Forty-seven cirrhotic patients (64%) showed diastolic dysfunction at rest: grade I in 37 and grade II in 10 patients. Systolic and/or diastolic dysfunction were not influenced by a more severe liver impairment. Diastolic dysfunction was more prevalent in patients with ascites vs those without (77% vs 56%; p=0.04). CONCLUSION: A mild diastolic dysfunction at rest is frequent in cirrhotic patients but cardiac load conditions are confounding factors in this diagnosis. We did not identify an association between severity of liver disease and cardiac dysfunction.