Germline Alterations in Patients With IBD-associated Colorectal Cancer.

BACKGROUND: Patients with inflammatory bowel diseases (IBD), both ulcerative colitis (UC) and Crohn's disease (CD), are at risk of developing a colorectal cancer (CRC). No information is available on the contribution of patients' genetic background to CRC occurrence. This study investigates germline alterations in patients with IBD-associated CRC. METHODS: We profiled a panel of 39 genes potentially involved in cancer predisposition and searched for germline variants in IBD patients with CRC or high-grade dysplasia. RESULTS: After clinical exclusion of genetic cancer syndromes, 25 IBD patients (4 CD and 21 UC) with CRC or high-grade dysplasia were studied. After excluding variants with low likelihood of pathogenicity (classes 1 or 2 according the International Agency for Research on Cancer [IARC]), the panel identified pathogenic variants, likely pathogenic, or variants with unknown significance in 18 patients (72%). Six patients (24%) carried pathogenic or likely variants (IARC class 5 or 4). Of the identified variants, 4 encompassed the APC region, 3 the MLH1 gene, and the remaining ones the MSH2, MSH3, monoallelic MUTYH, EPCAM, BRCA1, CHEK2, POLD1, POLE, CDKN2A, and PDGFRA genes. Four patients carried at least 2 variants in different genes. Duration of IBD was significantly shorter in carriers of 4 or 5 IARC variants (7 years; range 0-21; P = .002) and in those with variants with unknown significance (12 years; range 0-22; P = .005) compared with patients without or with only benign variations (23.5 years; range 15-34). CONCLUSIONS: In silico analysis and sequence-based testing of germline DNA from IBD patients with CRC or high-grade dysplasia detected 24% of variants positioned in pathogenic classes. In patients with type 3, 4, and 5 variants, the onset of high-grade dysplasia or CRC was significantly earlier than in patients with benign or unidentified variants. The screening for these genes could identify IBD patients requiring a more intensive endoscopic surveillance for earlier detection of dysplastic changes.

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

Inverted colonic diverticulum (ICD): report of two cases and literature review of a not that unusual endoscopic challenge.

Inverted colonic diverticulum (ICD) is a rare intraluminal lesion occurring in about 0.7-1.7% of people, often endoscopically indistinguishable from polyps. Some unspecific endoscopic features may assist to distinguish polypoid ICD from true polyps. This differentiation bears relevance for the therapeutic approach, as colonic polyps require snare polypectomy, a practice which may be associated with colonic perforation in case of true ICD. The endoscopist, therefore, should be aware of the likelihood of detecting these lesions during colonoscopy. A close inspection and a gentle probing could assist in a correct diagnosis and avoid risky procedures such as biopsy or polypectomy. Rarely, a neoplasm arising over an ICD and its treatment has been described. We reported two cases, one of which with dysplasia, and their treatment, and reviewed all the ICD endoscopic cases so far reported in the literature, remarking the possibility of finding pedunculated ICDs or neoplasm arising over an ICD.

Accuracy and inter-observer agreement of the nice and kudo classifications of superficial colonic lesions: a comparative study.

PURPOSE: For superficial colonic lesions, the NICE and Kudo classifications are used in the in vivo prediction of histology and as guide to therapy. The NICE system derives information from unmagnified NBI endoscopic images. The Kudo one necessitates a magnification, but, as this tool is not commonly available, it is applied also to characterize unmagnified pictures to compare their diagnostic performances. METHODS: We conducted a prospective comparison of the NICE versus the Kudo classification for the differential diagnosis of colonic polyps taking histology as the gold standard. The inter-observer agreement for both classifications among 11 colonoscopists was also evaluated. Short unmagnified NBI videoclips of 64 colonic polyps were sent twice to the participants. In the first round, they classified the lesions according to the NICE classification; 4 months later, the same videos were assessed with the Kudo system. The diagnosis provided by the participants was grouped in non-neoplastic, non-invasive neoplasia, invasive neoplasia. RESULTS: Overall, the diagnostic accuracy was 82% (95%CI: 79-85) with the NICE system and 81% (95%CI: 78-84) with the Kudo one (ρ = 0.78). The accuracy of the NICE classification for non-neoplastic lesions was greater compared with the Kudo's (ρ = 0.03). Sensitivity sub-analyses revealed a higher ability of the NICE in distinguishing between neoplastic vs. non-neoplastic lesions (ρ = 0.01). The overall inter-rater agreement did not differ when the classifications were compared. CONCLUSION: The NICE and the Kudo classifications might be considered comparable. Our data could allow the use of the NBI Kudo classification even in those centers where magnification is not available.

Interobserver agreement of the Paris and simplified classifications of superficial colonic lesions: a Western study.

Background and study aims The Paris classification of superficial colonic lesions has been widely adopted, but a simplified description that subgroups the shape into pedunculated, sessile/flat and depressed lesions has been proposed recently. The aim of this study was to evaluate the accuracy and inter-rater agreement among 13 Western endoscopists for the two classification systems. Methods Seventy video clips of superficial colonic lesions were classified according to the two classifications, and their size estimated. The interobserver agreement for each classification was assessed using both Cohen k and AC1 statistics. Accuracy was taken as the concordance between the standard morphology definition and that made by participants. Sensitivity analyses investigated agreement between trainees (T) and staff members (SM), simple or mixed lesions, distinct lesion phenotypes, and for laterally spreading tumors (LSTs). Results Overall, the interobserver agreement for the Paris classification was substantial (κ = 0.61; AC1 = 0.66), with 79.3 % accuracy. Between SM and T, the values were superimposable. For size estimation, the agreement was 0.48 by the κ-value, and 0.50 by AC1. For single or mixed lesions, κ-values were 0.60 and 0.43, respectively; corresponding AC1 values were 0.68 and 0.57. Evaluating the several different polyp subtypes separately, agreement differed significantly when analyzed by the k-statistics (0.08-0.12) or the AC1 statistics (0.59-0.71). Analyses of LSTs provided a κ-value of 0.50 and an AC1 score of 0.62, with 77.6 % accuracy. The simplified classification outperformed the Paris classification: κ = 0.68, AC1 = 0.82, accuracy = 91.6 %. Conclusions Agreement is often measured with Cohen's κ, but we documented higher levels of agreement when analyzed with the AC1 statistic. The level of agreement was substantial for the Paris classification, and almost perfect for the simplified system.

Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.

Transabdominal ultrasound-guided pancreatic biopsy: a neglected but safe, effective and inexpensive procedure that needs to be re-juvinalized.

BACKGROUND: For solid pancreatic masses, ultrasound endoscopic fine-needle biopsy is suggested as the front-line investigation for tissue achievement, notwithstanding the optimal performance of transabdominal ultrasound (TUS)-guided biopsy. PURPOSE: To reassess the efficacy and effectiveness of TUS-guided sampling and to determine the factors predictive of accurate histology. METHODS: In total, 142 patients with an indication for a TUS-guided biopsy of a pancreatic mass were analyzed. A single pass of an 18-gauge Biomol needle was carried out by the Menghini technique. The accuracy, sensitivity, and specificity of the procedure in terms of correctly diagnosing an inflammatory or neoplastic lesion were determined. The patients' characteristics, the size and location of the mass, and the sonographers' experience in performing TUS were recorded. RESULTS: The sampling was unsuccessful in 24 cases, owing to the deep localization of lesions (57%), bloating (33%), or low patient compliance (10%). The accuracy, sensitivity, and specificity of the 118 successful biopsies were 81%, 79%, and 100%, respectively. A biopsy core was obtained in 90 of the 118 patients (76%) in whom the procedure was attempted. In the multivariate analysis, lesion size (≤ 20 mm vs. > 20 mm) (OR = 5.3 [1.7-17.0]) and operator experience (OR = 4.4 [1.6-12.1]) predicted the acquisition of adequate samples. With an expert sonographer, the accuracy, sensitivity, and specificity were 87%, 85%, and 100%, respectively. Two adverse events were registered: mild abdominal pain and a hypotensive crisis. CONCLUSIONS: The present investigation highlights the optimal performance of a TUS-guided biopsy of a pancreatic mass. Because of its simplicity and safety, the procedure needs to be included among the recommended investigative options.

Impact of the COVID-19 outbreak and the serum prevalence of SARS-CoV-2 antibodies in patients with inflammatory bowel disease treated with biologic drugs.

BACKGROUND: Patients receiving biologic therapies are at risk for viral infections. This study investigated the impact of the SARS-CoV-2 infection and the serum prevalence of SARS-CoV-2 antibodies in patients with inflammatory bowel disease (IBD) treated with biologic drugs. METHODS: Information on demography, co-morbidities, clinical data regarding IBD, symptoms suggestive of the SARS-CoV-2 infection, close contacts with SARS-CoV-2 positive patients, hospitalization, and therapies administered for COVID-19 was collected for all patients who were being treated with biologic drugs. All patients underwent SARS-CoV-2 antibody testing. RESULTS: Two hundred and fifty-nine patients (27 children) with a mean age of 42.2 ±â€¯16.7 years (range 9 - 88) and a mean duration of disease of 13.4 ±â€¯10 years (range 0.2 - 49) were enrolled. One hundred four patients (40.2%) had ulcerative colitis, and 155 (59.8%) had Crohn's disease. About the therapy: 62 patients were receiving infliximab, 89 adalimumab, 20 golimumab, 57 vedolizumab, 27 ustekinumab, 1 thalidomide, and 3 an experimental compound. The mean Charlson Comorbidity Index was 2. Thirty-two patients (12.3%) reported respiratory symptoms, and 2 of them were hospitalized (0.77%). Two patients resulted positive for IgG against SARS-CoV-2 (0.77%). CONCLUSIONS: In patients with IBD, treatment with biologic drug does not represent a risk factor for the SARS-CoV-2 infection.

Early-Onset Diabetes as Risk Factor for Pancreatic Cancer: miRNA Expression Profiling in Plasma Uncovers a Role for miR-20b-5p, miR-29a, and miR-18a-5p in Diabetes of Recent Diagnosis.

The high prevalence of early-diabetes in patients with pancreatic cancer (PanC) implies that its recognition could help identify people at high risk of developing PanC. Candidate microRNAs (miRNAs) associated with recent diabetes were screened from our previous miRNA expression profiling on 10 pools of plasma from PanC patients and non-PanC controls, both including also subjects with early- and late-diabetes. The droplet digital PCR (ddPCR) was used to re-test candidate miRNAs in a new independent cohort of 69 subjects (40 PanC, 29 non-PanC) with early- (17 PanC, 13 non-PanC) or late-diabetes (23 PanC, 16 non-PanC), and in 100 non-diabetic healthy subjects (HS). miRNA levels were evaluated for differences between subjects enrolled into the study and for their diagnostic performance, also compared to the CA 19-9 determinations. MiR-20b-5p, miR-29a, and miR-18a-5p were selected from the previous miRNA expression profiling. The ddPCR confirmed the increase of miR-20b-5p and miR-29a levels in PanC with early- compared to those with late-diabetes. Conversely, miR-20b-5p, miR-29a, and miR-18a-5p were over-expressed in both PanC and non-PanC with recent diabetes compared to HS, and each miRNA achieved a similar diagnostic performance in distinguishing either PanC or non-PanC with early-diabetes from HS (miR-20b-5p: AUC = 0.877 vs. AUC = 0.873; miR-29a: AUC = 0.838 vs. AUC = 0.810; miR-18a-5p: AUC = 0.824 vs. AUC = 0.875). Despite miR-20b-5p and miR-29a expressions were also higher both in PanC and non-PanC with late-diabetes with respect to HS, the diagnostic accuracy in PanC with late-diabetes vs. HS reached by each miRNA (miR-20b-5p: AUC = 0.760; miR-29a: AUC = 0.630) was lower than the ones achieved in PanC with early-diabetes vs. HS. Furthermore, miR-20b-5p achieved a higher diagnostic accuracy to discriminate non-PanC with early-diabetes from HS (AUC = 0.868; SP = 81%; PPV = 32.1%) compared to the CA 19-9 (AUC = 0.700; SP = 40.0%; PPV = 15.5%), and the joint (miR-20b-5p and CA 19-9) discrimination ability was higher than the one achieved by the CA 19-9 tested alone (AUC = 0.900, p = 0.003). Our data highlighted the association between miR-18a-5p and early-diabetes, and suggested for miR-20b-5p and miR-29 a role in identifying early diabetes in PanC, albeit not as an early manifestation of cancer. MiR-20b-5p as more informative marker than CA 19-9 in distinguishing non-PanC with recent diabetes from HS was also uncovered.

Transcriptome and Gene Fusion Analysis of Synchronous Lesions Reveals lncMRPS31P5 as a Novel Transcript Involved in Colorectal Cancer.

Fusion genes and epigenetic regulators (i.e., miRNAs and long non-coding RNAs) constitute essential pieces of the puzzle of the tumor genomic landscape, in particular in mechanisms behind the adenoma-to-carcinoma progression of colorectal cancer (CRC). In this work, we aimed to identify molecular signatures of the different steps of sporadic CRC development in eleven patients, of which synchronous samples of adenomas, tumors, and normal tissues were analyzed by RNA-Seq. At a functional level, tumors and adenomas were all characterized by increased activity of the cell cycle, cell development, cell growth, and biological proliferation functions. In contrast, organic survival and apoptosis-related functions were inhibited both in tumors and adenomas at different levels. At a molecular level, we found that three individuals shared a tumor-specific fusion named MRPS31-SUGT1, generated through an intra-chromosomal translocation on chromosome 13, whose sequence resulted in being 100% identical to the long non-coding RNA (lncRNA) MRPS31P5. Our analyses suggest that MRPS31P5 could take part to a competitive endogenous (ce)RNA network by acting as a miRNA sponge or/and as an interactor of other mRNAs, and thus it may be an important gene expression regulatory factor and could be used as a potential biomarker for the detection of early CRC events.

Landmarks for dual biological therapy in inflammatory bowel disease: lesson from two case reports of vedolizumab in combination with ustekinumab.

Inflammatory bowel disease (IBD) is a chronic and disabling disorder. Severity of IBD is prominent among refractory with patients with concomitant immune-mediated disorders. Among those patients, dual biological therapy (DBT) has been suggested as an alternative approach to spare steroids and avoid surgery. However, pieces of evidence on clinical outcomes among patients receiving DBT are still limited. We present two cases of IBD patients, with dermatological comorbidity, treated with a combination of vedolizumab and ustekinumab, identifying possible landmarks to address therapeutic choice. No patient experienced adverse events in the follow-up period and both obtained complete clinical remission. DBT may be an effective approach to consider in selected patients with refractory IBD with concomitant severe immune-mediated diseases taking into account medical history of the patient, presence, and type of concomitant extraintestinal manifestations, safety profile of selected DBT, licensed therapeutic indications, and costs.

Endoscopic stenting for colorectal cancer obstruction as a bridge-to-surgery strategy.

BACKGROUND: Acute obstructive colorectal cancer requires prompt decompression commonly by emergency surgery (ES). However, self-expanding metal stents (SEMS) have been increasingly used as a bridge-to-surgery (BTS) strategy. MATERIALS AND METHODS: In an 8-year period, consecutive patients with acute left-sided colonic obstruction, due to locally advanced colorectal cancer, underwent ES or SEMS implantation. We evaluated technical/clinical success of SEMS, adverse events, and overall (OS) and disease-free survival (DFS) of the two therapeutic options. RESULTS: Forty-five patients underwent ES (n = 23) or SEMS (n = 22). The two groups were comparable for sex, age, ASA score and cancer site/stage. Technical and clinical successes of SEMS were 100% and 72.7%, respectively. Clinical success correlated with neutrophil-lymphocyte ratio (NLR) at baseline (OR = 0.65, 95% CI 0.43-0.98, P = .04). SEMS allowed primary anastomosis in the 45.5% of cases (0% in ES). SEMS implantation allowed a higher rate of surgery carried out by a laparoscopic approach: 36.4% vs 13.0% in ES. Performance of a definitive stoma and complications were similar. Median OS (34 in SEMS; 45 in ES, P = .33) and DFS (36 in SEMS; 35 in ES, P = .35) did not differ between the two groups. At univariate analysis, DFS was positively associated with primary anastomosis (HR = 2.44, 95% CI 1.4-16.6, P = .04) and laparoscopic surgery (HR = 8.33, 95% CI 1.08-50, P = .04), and inversely associated with a NLR > 3.6 (HR = 0.59, 95% CI 0.16-0.92, P = .03). At multivariate analysis, no feature retained an independent predictive power. CONCLUSION: SEMS is an effective and safe procedure, equivalent to emergency surgery in terms of complications, OS and DFS, providing the chance of a primary anastomosis in the majority of patients.

Genome-wide association study identifies an early onset pancreatic cancer risk locus.

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore, we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1 × 10-4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset ≤50, and 4142 controls from the PANDoRA consortium while in the in silico data, we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15 × 10-4 ). In conclusion, we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature.

Clinical Significance of Circulating miR-1273g-3p and miR-122-5p in Pancreatic Cancer.

The burden of pancreatic cancer (PanC) requires innovation in the current diagnostic approach. This study aimed to uncover new circulating microRNAs (miRNAs) that would distinguish patients with PanC from healthy subjects (HS) compared with the cancer antigen 19-9 (CA 19-9), and predict patients' clinical phenotypes and outcomes. MiRNA expression profiles in plasma were investigated by using a two-stage process. In a discovery phase, miRNAs levels were analyzed using the GeneChip™ miRNA 4.0 Affymetrix assay in 10 pools of plasma samples from PanC patients and HS; in a validation phase, significantly altered miRNAs were re-tested in independent cohorts of cancer patients and controls by droplet digital PCR (ddPCR). The diagnostic performance of the resulting miRNAs was compared to CA 19-9 determinations, and the associations of miRNAs plasma levels with patients' clinical phenotypes and outcomes were also taken into account. Bioinformatics selection of miRNAs differentially expressed in plasma uncovered miR-18a-5p, miR-122-5p, miR-1273g-3p, and miR-6126 as candidate oncogenic miRNAs in PanC. The ddPCR technology confirmed the significant over-expression of miR-122-5p, miR-1273g-3p, and miR-6126 in PanC compared to HS, in line with the trend of the CA 19-9 levels. Plasma levels of miR-1273g-3p, in combination with CA 19-9, showed higher power in distinguishing PanC patients from HS compared to the CA 19-9 tested alone, with a gain in both sensitivity and negative predictive value indicating a low false-negative rate (SE = 90.2% and NPV = 92.3% vs. SE = 82.1% and NPV = 87.9%). None of the oncogenic miRNAs were able to distinguish between a neoplastic and a proliferative/inflammatory disease of the pancreas, and were not able to stratify subjects according to the clinical risk for the disease. The only valuable association in PanC patients was found between miR-1273g-3p and tumor stage, and increased miR-122-5p levels emerged as independent negative prognostic factor for PanC patients (HR = 1.58, 95% CI = 1.03-2.43, p = 0.037). Our data highlighted a role for circulating miR-1273g-3p and miR-122-5p as new diagnostic and prognostic biomarkers for PanC.

Real-Life Effectiveness and Safety of Golimumab and Its Predictors of Response in Patients with Ulcerative Colitis.

BACKGROUND: Golimumab is a new anti-TNF-alpha monoclonal antibody for patients with ulcerative colitis. AIMS: To assess the short- and long-term effectiveness and safety of golimumab in daily clinical practice and to identify predictors of response. METHODS: Consecutive patients treated with golimumab in 22 Italian centers were enrolled. Clinical, laboratory, and endoscopic data were prospectively collected before and during treatment. A subgroup of patients completed a questionnaire to assess personal satisfaction with a golimumab autoinjector system. RESULTS: A total of 196 patients were included. After 3 months, 130 patients were responders (66.3%) and showed significant reductions in mean partial, total, and endoscopic Mayo scores and in mean ESR, C-reactive protein, and fecal calprotectin levels (p < 0.001). Multivariate analysis revealed that a higher total Mayo score (p < 0.001, OR 1.5, 95% CI 1.2-1.8) and naïve status to anti-TNF-alpha (p = 0.015, OR 3.0, 95% CI 1.2-7.5) were predictive of a favorable response. Seventy-seven (39.3%) of the 130 responders maintained a response at month 12 of therapy. There were 17 adverse events, 28 patients needed hospitalization, and 15 patients underwent surgery. Self-administration of the drug was appreciated by most patients. CONCLUSIONS: The efficacy and safety of golimumab in daily clinical practice were confirmed for the short- and long-term treatment of patients with active ulcerative colitis. Patients naïve to the anti-TNF-alpha monoclonal antibody and those with a higher total Mayo score were more likely to respond to golimumab.

Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study.

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

Droplet digital PCR quantification of miR-1290 as a circulating biomarker for pancreatic cancer.

Droplet digital PCR was used to validate miR-1290 as circulating biomarker for pancreatic cancer (PC). The diagnostic performance of miR-1290 was evaluate in 167 PC patients and 267 healthy subjects at clinical risk of developing the disease (HS). MiR-1290 plasma levels were compared to CA 19-9 determinations, and the combination of the two biomarkers was also taken into account. Plasma levels of miR-1290 were higher in PC patients compared to HS (p = 2.55 × 10-16). A similar trend was observed for CA 19-9 determinations (p = 1.03 × 10-47). ROC curve analysis revealed that miR-1290 in combination with CA 19-9 was effective for discriminating between PC patients and HS (AUC = 0.956, 95% CI = 0.933-0.979) than the two biomarkers tested alone (miR-1290: AUC = 0.734, 0.678-0.789; CA 19-9: AUC = 0.914, 0.877-0.951). The discriminating ability was higher when only PC patients with low or slightly increased CA 19-9 levels were compared with HS. MiR-1290 concentrations were not able to differentiate between PC patients with single or multiple risk factors for developing PC. Our data suggest that the absolute quantification of circulating miR-1290 levels does not allow to select patients at clinical risk of PC for entry into a surveillance program, and underline the methodological challenges still existing in utilizing circulating miRNAs as new promising biomarkers for PC.

Forecasting Hepatitis C liver disease burden on real-life data. Does the hidden iceberg matter to reach the elimination goals?

BACKGROUND & AIMS: Advances in direct-acting antiviral treatment of HCV have reinvigorated public health initiatives aimed at identifying affected individuals. We evaluated the possible impact of only diagnosed and linked-to-care individuals on overall HCV burden estimates and identified a possible strategy to achieve the WHO targets by 2030. METHODS: Using a modelling approach grounded in Italian real-life data of diagnosed and treated patients, different linkage-to-care scenarios were built to evaluate potential strategies in achieving the HCV elimination goals. RESULTS: Under the 40% linked-to-care scenario, viraemic burden would decline (60%); however, eligible patients to treat will be depleted by 2025. Increased case finding through a targeted screening strategy in 1948-1978 birth cohorts could supplement the pool of diagnosed patients by finding 75% of F0-F3 cases. Under the 60% linked-to-care scenario, viraemic infections would decline by 70% by 2030 but the patients eligible for treatment will run out by 2028. If treatment is to be maintained, a screening strategy focusing on 1958-1978 birth cohorts could capture 55% of F0-F3 individuals. Under the 80% linked-to-care scenario, screening limited in 1968-1978 birth cohorts could sustain treatment at levels required to achieve the HCV elimination goals. CONCLUSION: In Italy, which is an HCV endemic country, the eligible pool of patients to treat will run out between 2025 and 2028. To maintain the treatment rate and achieve the HCV elimination goals, increased case finding in targeted, high prevalence groups is required.