Publications by authors named "Raffaele Pezzilli"

248 Publications

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk.

Front Genet 2021 30;12:693933. Epub 2021 Aug 30.

Blood Transfusion Service, Azienda Ospedaliero-Universitaria Meyer, Children's Hospital, Florence, Italy.

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, = 3.03 × 10 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of , a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.
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http://dx.doi.org/10.3389/fgene.2021.693933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435735PMC
August 2021

Genetic polymorphisms involved in mitochondrial metabolism and pancreatic cancer risk.

Cancer Epidemiol Biomarkers Prev 2021 Sep 15. Epub 2021 Sep 15.

Division of Gastroenterology and Research Laboratory, Casa Sollievo della Sofferenza, IRCCS Casa Sollievo della Sofferenza.

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC aetiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNPs) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported.

Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analysed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using MAGMA software.

Results: In the discovery phase we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P <0.05). In the second phase none of the findings were replicated. In the gene-level analysiswe observed that three genes (TERT, SUGCT and SURF1) involved in the mitochondrial metabolismshowed an association below the Bonferroni-corrected threshold of statistical significance (P=0.05/1588=3.1 x10-5).

Conclusions: Even though the mitochondrial metabolism might be involved in PDAC aetiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk.

Impact: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0353DOI Listing
September 2021

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

Carcinogenesis 2021 Aug;42(8):1037-1045

Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.

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.
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http://dx.doi.org/10.1093/carcin/bgab057DOI Listing
August 2021

Patients With Coronavirus Disease 2019 Interstitial Pneumonia Exhibit Pancreatic Hyperenzymemia and Not Acute Pancreatitis.

Pancreas 2021 May-Jun 01;50(5):732-735

Department of Health Sciences, Università degli Studi di Milano.

Objectives: Gastrointestinal manifestations of coronavirus disease 19 (COVID-19) have been well established, but pancreatic involvement is under debate. Our aims were to evaluate the presence of acute pancreatitis in COVID-19 patients and to assess the frequency of pancreatic hyperenzymemia.

Methods: From April 1, 2020, to April 30, 2020, 110 consecutive patients (69 males, 41 females; mean age, 63.0 years; range, 24-93 years) met these criteria and were enrolled in the study. The clinical data and serum activity of pancreatic amylase and lipase were assayed in all patients using commercially available kits.

Results: None of the patients studied developed clinical signs or morphological alterations compatible with acute pancreatitis. However, it was found that 24.5% of the patients had amylase values above 53 IU/L and 16.4% had lipase values above 300 IU/L. Only 1 patient (0.9%) had both amylase and lipase values in excess of 3-fold the upper normal limit without clinical signs of pancreatitis.

Conclusions: The presence of pancreatic hyperenzymemia in a patient with COVID-19 requires the management of these patients be guided by clinical evaluation and not merely by evaluation of the biochemical results.
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http://dx.doi.org/10.1097/MPA.0000000000001824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202102PMC
June 2021

Editorial for "Does Training in LI-RADS Version 2018 Improve Readers' Agreement With the Expert Consensus and Inter-Reader Agreement in MRI Interpretation?"

J Magn Reson Imaging 2021 May 6. Epub 2021 May 6.

Potenza County Medical Association, Potenza, Italy.

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http://dx.doi.org/10.1002/jmri.27687DOI Listing
May 2021

Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival.

Sci Rep 2021 Apr 7;11(1):7570. Epub 2021 Apr 7.

Department of Biology, University of Pisa, Via Derna 1, 56126, Pisa, Italy.

Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients' response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58-15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.
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http://dx.doi.org/10.1038/s41598-021-87130-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027406PMC
April 2021

Pancreatic cancer in patients with autoimmune pancreatitis: A scoping review.

Pancreatology 2021 Aug 18;21(5):928-937. Epub 2021 Mar 18.

CLINTEC, Karolinska Institute, Stockholm, Sweden; Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.

Background: Chronic pancreatitis is a known risk factor of pancreatic cancer (PDAC). A similar association has been suggested but not demonstrated for autoimmune pancreatitis (AIP).

Objective: The aim of our study was to identify and analyse all published cases of AIP and PDAC co-occurrence, focusing on the interval between the diagnoses and the cancer site within the pancreas.

Methods: Relevant studies were identified through automatic searches of the MEDLINE, EMBASE, Scopus, and Web of Science databases, and supplemented by manual checks of reference lists in all retrieved articles. Missing/unpublished data were obtained from the authors of relevant publications in the form of pre-prepared questionnaires.

Results: A total of 45 cases of PDAC in AIP patients were identified, of which 12 were excluded from the analysis due to suspicions of duplicity or lack of sufficient data. Thirty-one patients (94%) had type 1 AIP. Synchronous occurrence of PDAC and AIP was reported in 11 patients (33%), metachronous in 22 patients (67%). In the metachronous group, the median period between diagnoses was 66.5 months (2-186) and a majority of cancers (86%) occurred more than two years after AIP diagnosis. In most patients (70%), the cancer originated in the part of the pancreas affected by AIP.

Conclusions: In the literature, there are reports on numerous cases of PDAC in AIP patients. PDAC is more frequent in AIP type 1 patients, typically metachronous in character, and generally found in the part of the pancreas affected by AIP.
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http://dx.doi.org/10.1016/j.pan.2021.03.007DOI Listing
August 2021

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

Int J Cancer 2021 06 3;148(11):2779-2788. Epub 2021 Feb 3.

Department of General Surgery, University of Heidelberg, Heidelberg, Germany.

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 ). 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.
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http://dx.doi.org/10.1002/ijc.33475DOI Listing
June 2021

Premedication with simethicone and N-acetylcysteine for improving mucosal visibility during upper gastrointestinal endoscopy in a Western population.

Endosc Int Open 2021 Feb 25;9(2):E190-E194. Epub 2021 Jan 25.

Gastroenterology and Endoscopy Department, ASST Crema Maggiore Hospital, Crema, Italy.

 Pre-endoscopic use of a preparation with tensioactive and mucolytic agents improved gastric mucosa visualization in Eastern studies. Data on Western population are scanty.  This prospective, endoscopist-blinded, randomized study enrolled patients who underwent esophagogastroduodenoscopy in a single center. Before endoscopy patients, were randomized to receive or not receive an oral preparation with simethicone and N-acetylcysteine in water. A pretested score (Crema Stomach Cleaning Score [CSCS]) for gastric mucosa cleaning evaluation was used. In detail, the stomach was divided into the antrum, body, and fundus and a score of 1 to 3 was assigned to each part (the higher the score, the better the preparation), and a total value ≤ 5 was considered as insufficient. Time between endoscope insertion and clean achievement (mouth to clean time) or the end of examination (mouth to mouth time) was recorded.  A total of 197 patients were enrolled. The mean overall CSCS value and mucosal cleaning in all parts was better in treated patients than in controls. Prevalence total score ≤ 5 was significantly lower in patients treated before endoscopy. Need for water flush occurred less frequently in treated patients (  < 0.0001). The mouth to clean time was lower in the treated than in the control group (2.3 ± 1.6 vs 3.8 ± 1.6 min;  < 0.001), whereas no significant difference in mouth to mouth time emerged.  Data from this study show that premedication with simethicone and N-acetylcysteine results in significantly better endoscopic visualization of gastric mucosa, and the proposed CSCS could be useful for standardizing this evaluation.
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http://dx.doi.org/10.1055/a-1315-0114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834924PMC
February 2021

[Screening protocols for pancreatic cancer.]

Recenti Prog Med 2021 Jan;112(1):58-67

Unità Operativa Complessa di Medicina Interna, Ospedale San Carlo, Potenza.

Pancreatic cancer is one of the most aggressive malignancies and represents the seventh leading cause of cancer deaths in industrialized countries; in the United States, it is the third leading cause of death from cancer while in Italy it is the fourth. It is expected to become the second cancer death by 2030. The five-year survival rate is 9%, as patients with pancreatic cancer rarely exhibit symptoms until they reach an advanced stage of the disease. Therefore, despite advances in imaging techniques, over 80% of patients receive a diagnosis in the advanced stage of the disease and survival is not high at 5 years from the diagnosis despite the progress of chemotherapy and supportive therapies. An early diagnosis in people at risk is the main objective of clinical research on pancreatic cancer. The purpose of this review is to evaluate the current literature on the possibility and presence of screening programs to prevent, diagnose and treat this silent killer neoplasm.
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http://dx.doi.org/10.1701/3525.35125DOI Listing
January 2021

Vitamin D in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients with non-invasive ventilation support.

Panminerva Med 2021 Jan 25. Epub 2021 Jan 25.

Respiratory Unit, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy -

Background: Vitamin D (VitD) deficiency has been reported to be associated with respiratory tract infection. In this work we evaluated the concentration of VitD in COVID-19 patients experiencing acute respiratory infections of different levels of severity excluding those who underwent invasive respiratory support.

Methods: The levels of serum VitD and C-reactive protein (CRP) were analyzed in 118 consecutive hospitalized COVID-19 patients (74M, 44F), confirmed with rRT-PCR. Of these patients with ventilation support 52 (44.1%) received oxygen via nasal cannula, oxygen mask or an oxygen mask with a reservoir, 48 (40.7%) were on a continuous positive airway pressure device (CPAP) and 18 (15,3%) on non-invasive mechanical ventilation (NIMV).

Results: The median values (range) of VitD and of CRP were 15.1 ng/mL (1.3-73.3) and 14.2 mg/L (5.0-151.2), respectively. A negative correlation from VitD levels and those of CRP (correlation coefficient - 0.259: P=0.005) was observed. VitD levels in O2 support patients were significantly higher than in both CPAP and NIMV patients. No statistical differences were found for CRP levels (P=0.834) among the three type of oxygen support. Fewer patients with O2 support had VitD <30 ng/mL and <20 ng/mL than CPAP and NIMV patients. There were no relationships between VitD and the three classes of IgM (P=0.419) and of IgG (P=0.862) SARS-CoV-2 antibodies values. The behavior was the same for CRP.

Conclusions: Our study shows that a significant proportion of COVID-19 patients have a VitD deficiency and that this condition is more frequent in CPAP and in NIMV patients.
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http://dx.doi.org/10.23736/S0031-0808.21.04277-4DOI Listing
January 2021

Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up of Exocrine Pancreatic Ductal Adenocarcinoma: Evidence Evaluation and Recommendations by the Italian Association of Medical Oncology (AIOM).

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Department of Medical Oncology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in women (7%) and the sixth in men (5%) in Italy, with a life expectancy of around 5% at 5 years. From 2010, the Italian Association of Medical Oncology (AIOM) developed national guidelines for several cancers. In this report, we report a summary of clinical recommendations of diagnosis, treatment and follow-up of PDAC, which may guide physicians in their current practice. A panel of AIOM experts in upper gastrointestinal cancer malignancies discussed the available scientific evidence supporting the clinical recommendations.
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http://dx.doi.org/10.3390/cancers12061681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352458PMC
June 2020

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction.

J Med Genet 2021 Jun 26;58(6):369-377. Epub 2020 Jun 26.

Cancer Center Amsterdam, Amsterdam, The Netherlands.

Background: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.

Objective: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.

Methods: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.

Results: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10, highest vs lowest quintile of the weighted multifactorial score).

Conclusion: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.
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http://dx.doi.org/10.1136/jmedgenet-2020-106961DOI Listing
June 2021

The Applicability of a Checklist for the Diagnosis and Treatment of Exocrine Pancreatic Insufficiency: Results of the Italian Exocrine Pancreatic Insufficiency Registry.

Pancreas 2020 07;49(6):793-798

Pancreatic Surgery, Humanitas Hospital, Milan, Italy.

Objective: To evaluate a rapid checklist capable of identifying exocrine pancreatic insufficiency in outpatients.

Methods: Prospective observational study of a multicenter cohort.

Results: One hundred and two patients were enrolled; 61.8% of the patients had medically-treated benign or malignant pancreatic disease, and 38.2% had a pancreatic resection. Visual examination of the feces was evaluated in 84 patients and it was related to steatorrhea in 51 patients (50.0%). Receiver operating characteristic curves were evaluated for each symptom or clinical sign and four of them (ie, increase in daily bowel movements, number of bowel movements, fatty stools, >10% weight loss) had a satisfactory area under the curve. At multivariate analysis, fatty stools and >10% weight loss entered into this analysis having an area under the curve of 0.916 (95% confidence interval, 0.851-0.981). At 1 month and at one year of follow-up, the pancreatic enzyme replacement therapy administered showed that pancreatic extracts were able to significantly improve the increase in daily bowel movements, the number of bowel movements, fatty and bulky stools and >10% weight loss.

Conclusion: Both fatty stools and >10% weight loss were able to clinically evaluate steatorrhea, and their improvement was sufficient to evaluate substitution therapy.
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http://dx.doi.org/10.1097/MPA.0000000000001575DOI Listing
July 2020

Multicentric Italian survey on daily practice for autoimmune pancreatitis: Clinical data, diagnosis, treatment, and evolution toward pancreatic insufficiency.

United European Gastroenterol J 2020 07 12;8(6):705-715. Epub 2020 May 12.

Pancreas Unit, Department of Gastroenterology, Sant'Orsola Polyclinic, Bologna, Italy.

Background: Autoimmune pancreatitis (AIP) is a rare, and relatively new, form of chronic pancreatitis. The management of AIP can vary considerably among different centres in daily clinical practice.

Objectives: The aim of this study is to present a picture of epidemiological, clinical characteristics, outcomes, and the real-life practice in terms of management in several academic and non-academic centres in Italy.

Methods: Data on the clinical presentation, diagnostic work-up, treatments, frequency of relapses, and long-term outcomes were retrospectively collected in a cohort of AIP patients diagnosed at 14 centres in Italy.

Results: One hundred and six patients were classified as type 1 AIP, 48 as type 2 AIP, and 19 as not otherwise specified. Epidemiological, clinical, radiological, and serological characteristics, and relapses were similar to those previously reported for different types of AIP. Endoscopic cytohistology was available in 46.2% of cases, and diagnostic for AIP in only 35.2%. Steroid trial to aid diagnosis was administered in 43.3% cases, and effective in 93.3%. Steroid therapy was used in 70.5% of cases, and effective in 92.6% of patients. Maintenance therapy with low dose of steroid (MST) was prescribed in 25.4% of cases at a mean dose of 5 (±1.4) mg/die, and median time of MST was 60 days. Immunosuppressive drugs were rarely used (10.9%), and rituximab in 1.7%. Faecal elastase-1 was evaluated in only 31.2% of patients, and was pathological in 59.2%.

Conclusions: In this cohort of AIP patients, diagnosis and classification for subtype was frequently possible, confirming the different characteristics of AIP1 and AIP2 previously reported. Nevertheless, we observed a low use of histology and steroid trial for a diagnosis of AIP. Steroid treatment was the most used therapy in our cohort. Immunosuppressants and rituximab were rarely used. The evaluation of exocrine pancreatic insufficiency is underemployed considering its high prevalence.
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http://dx.doi.org/10.1177/2050640620924302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437084PMC
July 2020

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

Int J Cancer 2020 10 1;147(8):2065-2074. Epub 2020 May 1.

Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.

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 ). 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 ). 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.
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http://dx.doi.org/10.1002/ijc.33004DOI Listing
October 2020

Epidemiology, clinical features and diagnostic work-up of cystic neoplasms of the pancreas: Interim analysis of the prospective PANCY survey.

Dig Liver Dis 2020 05 29;52(5):547-554. Epub 2020 Feb 29.

IRCCS Hospital, Reggio Emilia, Italy.

Introduction: A prospective survey to evaluate the diagnostic workup of cystic pancreatic neoplasms (CPNs) according to the Italian guidelines.

Methods: An online data sheet was built.

Results: Fifteen of the 1385 patients (1.1%) had non cystic neoplastic lesions. Forty percent (518/1295) had at least one 1st degree relative affected by a solid tumor of the digestive and extra-digestive organs. Symptoms/signs associated with the cystic lesion were present in 24.5% of the patients. The cysts were localized in the head of the pancreas in 38.5% of patients. Of the 2370 examinations (1.7 examinations per patient) which were carried out for the diagnosis, magnetic resonance imaging was performed as a single test in 48.4% of patients and in combination with endoscopic ultrasound in 27% of the cases. Of the 1370 patients having CPNs, 89.9% had an intraductal papillary mucinous neoplasm (IPMN) (70.1% a branch duct IPMN, 6.2% a mixed type IPMN and 4.6% a main duct IPMN), 12.7% had a serous cystadenoma, 2.8% a mucinous cystadenoma, 1.5% a non-functioning cystic neuroendocrine neoplasm, 0.7% a solid-pseudopapillary cystic neoplasm, 0.3% a cystic adenocarcinoma, and 1.2% an undetermined cystic neoplasm. Seventy-eight (5.7%) patients were operated upon after the initial work-up.

Conclusions: This prospective study offers a reliable real-life picture of the diagnostic work-up CPN.
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http://dx.doi.org/10.1016/j.dld.2020.02.003DOI Listing
May 2020

Pancreatic Enzyme Replacement Therapy in Pancreatic Cancer.

Cancers (Basel) 2020 Jan 22;12(2). Epub 2020 Jan 22.

Pancreatic Surgery, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy.

Pancreatic cancer is an aggressive malignancy and the seventh leading cause of global cancer deaths in industrialised countries. More than 80% of patients suffer from significant weight loss at diagnosis and over time tend to develop severe cachexia. A major cause of weight loss is malnutrition. Patients may experience pancreatic exocrine insufficiency (PEI) before diagnosis, during nonsurgical treatment, and/or following surgery. PEI is difficult to diagnose because testing is cumbersome. Consequently, PEI is often detected clinically, especially in non-specialised centres, and treated empirically. In this position paper, we review the current literature on nutritional support and pancreatic enzyme replacement therapy (PERT) in patients with operable and non-operable pancreatic cancer. To increase awareness on the importance of PERT in pancreatic patients, we provide recommendations based on literature evidence, and when data were lacking, based on our own clinical experience.
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http://dx.doi.org/10.3390/cancers12020275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073203PMC
January 2020

Acute Pancreatitis Associated With Myotonic Dystrophy Type I.

Pancreas 2019 09;48(8):e63-e64

Department of Gastroenterology Sant'Orsola Polyclinic Bologna, Italy

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http://dx.doi.org/10.1097/MPA.0000000000001366DOI Listing
September 2019

Gossypibomas as a rare cause of common bile duct dilation.

Hepatobiliary Pancreat Dis Int 2019 Oct 25;18(5):498-500. Epub 2019 Jul 25.

Department of Gastroenterology, Sant'Orsola Hospital, 40138 Bologna, Italy.

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http://dx.doi.org/10.1016/j.hbpd.2019.07.009DOI Listing
October 2019

A rare cause of melena in lung cancer.

Dig Liver Dis 2019 08 22;51(8):1196. Epub 2019 Apr 22.

Department of Emergency, Sant'Orsola Hospital, Bologna, Italy; Department of Pathology, Sant'Orsola Hospital, Bologna, Italy.

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http://dx.doi.org/10.1016/j.dld.2019.03.029DOI Listing
August 2019

The Clinical Impact of Splanchnic Ischemia on Patients Affected by Thoracoabdominal Aortic Aneurysms Treated with Fenestrated and Branched Endografts.

Ann Vasc Surg 2019 Aug 19;59:102-109. Epub 2019 Apr 19.

Vascular Surgery, Department of Experimental, Diagnostic and Speciality Medicine, University of Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy.

Background: Fenestrated/branched endografts for aortic repair (FB-EVAR) are valid options to treat thoracoabdominal aortic aneurysms (TAAAs). Successful repair requires manipulation of target visceral vessels (TVVs) with possible splanchnic ischemia. The aim of the study was to evaluate the clinical impact of splanchnic ischemia occurring in FB-EVAR for TAAA.

Methods: Between 2010 and 2015, patients with TAAAs undergoing FB-EVAR were prospectively enrolled. Clinical, morphological, procedural, and 30-day data were evaluated. Splanchnic ischemia was defined as the presence of splanchnic ischemic lesions (SILs) visible at perioperative computed tomography angiography. Preoperative, postoperative, and 30-day hepatic/pancreatic/renal laboratory functions were analyzed. End points were incidence of SILs, laboratory splanchnic functions worsening (≥25% of baseline), and presence of related clinical/morphological and procedural risk factors.

Results: Thirty-six patients (male: 78%; age: 73 ± 7 years) with 27 (75%) type I-III and 9 (25%) type IV TAAA who underwent FB-EVAR for a total of 127 TVV (branches: 47-60%; fenestrations: 53-67%). Fourteen SILs occurred in 12 (33%) patients: 4 (29%) in pancreas, 3 (21%) in spleen, 2 (14%) in bowel, 5 (36%) in kidney. The cause was embolic in 79% and thrombotic in 21%. No preoperative clinical/morphological data or procedural data were correlated with SIL. Pancreatic, hepatic, or renal function worsening occurred at 24 hr in 16 (44%), 16 (44%), and 9 (25%) cases, respectively. Overall, SILs were associated with increased values of C-reactive protein (CRP) (17.9 ± 0.4 vs. 9.9 ± 9.0 mg/dL; P = 0.03) and bilirubin (1.2 ± 2.3 vs. 1.0 ± 0.5 mg/dL; P = 0.02) at 24 hr. Specifically, SIL of the celiac trunk and superior mesenteric and renal arteries' parenchyma were associated with the significant laboratory function changes 24 hr. SIL of the superior mesenteric artery was associated with increased 30-day mortality (50% vs. 7 %; P = 0.002). Pancreatic, hepatic, or renal function worsening occurred at 30 days in 2 (6%), 0 (0%), and 4 (12%) cases, with similar laboratory tests in patients with and without SIL.

Conclusions: SIL can be frequently detected after FB-EVAR for TAAA and appears mainly of embolic origin. No clinical, morphological, or procedural predictors could be identified in our series. Postoperative laboratory changes of CRP, bilirubin, activated partial thromboplastin time, and amylases are associated with SIL but disappear without clinical consequences within 30 days. However, SIL occurring in the superior mesenteric artery are associated with an increased 30-day mortality.
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http://dx.doi.org/10.1016/j.avsg.2019.01.026DOI Listing
August 2019

Alcohol-related chronic exocrine pancreatic insufficiency: diagnosis and therapeutic management. A proposal for treatment by the Italian Association for the Study of the Pancreas (AISP) and the Italian Society of Alcohology (SIA).

Minerva Med 2019 Oct 1;110(5):425-438. Epub 2019 Apr 1.

National Observatory on Alcohol, National Institute of Health, Rome, Italy.

Current estimates of the prevalence of chronic pancreatitis, one of the most common causes of exocrine pancreatic insufficiency, are in the range of 3-10 per 100,000 people in many parts of the world. Alcohol consumption is a very important risk factor for exocrine pancreatic insufficiency and is involved in nearly half of all cases. The main hypothesis regarding the role of chronic alcohol consumption in pancreatitis is that there must be additional environmental or genetic risk factors involved for ongoing damage to occur. Treatment of patients with alcohol-related exocrine pancreatic insufficiency is complex, as the patient has two concomitant pathologies, alcohol-use disorder (AUD) and exocrine pancreatic insufficiency/chronic pancreatitis. Alcohol abstinence is the starting point for treatment, although even this along with the most advanced therapies allow only a slowdown in progression rather than restoration of function. This position paper of the Italian Association for the Study of the Pancreas and the Italian Society of Alcohology provides an overview of the pathogenesis of alcohol-related pancreatitis and discuss diagnostic issues. Treatment options for both exocrine pancreatic insufficiency/chronic pancreatitis (with a focus on pancreatic enzyme replacement therapy) and AUD (acamprosate, disulfiram, oral naltrexone, long-acting injectable naltrexone, sodium oxybate, nalmefene, baclofen, and psychosocial interventions) are also reviewed.
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http://dx.doi.org/10.23736/S0026-4806.19.06043-9DOI Listing
October 2019

Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients.

Carcinogenesis 2019 06;40(4):544-550

Department of Biology, University of Pisa, Pisa, Italy.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients.
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http://dx.doi.org/10.1093/carcin/bgz006DOI Listing
June 2019

Results of First-Round of Surveillance in Individuals at High-Risk of Pancreatic Cancer from the AISP (Italian Association for the Study of the Pancreas) Registry.

Am J Gastroenterol 2019 04;114(4):665-670

Pancreatic Surgery Unit, Humanitas Clinical and Research Center, Milano, Italy.

Introduction: Surveillance programs on high-risk individuals (HRIs) can detect pre-malignant lesions or early pancreatic cancer (PC). We report the results of the first screening round of the Italian multicenter program supported by the Italian Association for the study of the Pancreas (AISP).

Methods: The multicenter surveillance program included asymptomatic HRIs with familial (FPC) or genetic frailty (GS: BRCA1/2, p16/CDKN2A, STK11/LKB1or PRSS1, mutated genes) predisposition to PC. The surveillance program included at least an annual magnetic resonance cholangio pancreatography (MRCP). Endoscopic ultrasound (EUS) was proposed to patients who refused or could not be submitted to MRCP.

Results: One-hundreds eighty-seven HRIs underwent a first-round screening examination with MRCP (174; 93.1%) or EUS (13; 6.9%) from September 2015 to March 2018.The mean age was 51 years (range 21-80).One-hundreds sixty-five (88.2%) FPC and 22 (11.8%) GF HRIs were included. MRCP detected 28 (14.9%) presumed branch-duct intraductal papillary mucinous neoplasms (IPMN), 1 invasive carcinoma/IPMN and one low-grade mixed-type IPMN, respectively. EUS detected 4 PC (2.1%): 1 was resected, 1 was found locally advanced intraoperatively, and 2 were metastatic. Age > 50 (OR 3.3, 95%CI 1.4-8), smoking habit (OR 2.8, 95%CI 1.1-7.5), and having > 2 relatives with PC (OR 2.7, 95%CI 1.1-6.4) were independently associated with detection of pre-malignant and malignant lesions. The diagnostic yield for MRCP/EUS was 24% for cystic lesions. The overall rate of surgery was 2.6% with nil mortality.

Discussion: The rate of malignancies found in this cohort was high (2.6%). According to the International Cancer of the Pancreas Screening Consortium the screening goal achievement was high (1%).
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http://dx.doi.org/10.1038/s41395-018-0414-zDOI Listing
April 2019

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

Int J Cancer 2019 03 12;144(6):1275-1283. Epub 2018 Nov 12.

Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University, Rome, Italy.

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 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10 , p = 3.27 × 10 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10 for highest vs. lowest quintile; p = 1.82 × 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.
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http://dx.doi.org/10.1002/ijc.31928DOI Listing
March 2019

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

Nat Commun 2018 02 8;9(1):556. Epub 2018 Feb 8.

Digestive and Liver Disease Unit, 'Sapienza' University of Rome, 00185, Rome, Italy.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
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http://dx.doi.org/10.1038/s41467-018-02942-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805680PMC
February 2018

Identification of Small Proteins and Peptides in the Differentiation of Patients with Intraductal Mucinous Neoplasms of the Pancreas, Chronic Pancreatitis and Pancreatic Adenocarcinoma.

Dig Dis Sci 2018 04 8;63(4):920-933. Epub 2018 Feb 8.

Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy.

Background: There are a limited number of studies investigating the type of serum proteins capable of differentiating intraductal papillary mucinous neoplasms from benign or malignant diseases of the pancreas.

Aims: To select proteins able to differentiate intraductal papillary mucinous neoplasms from benign and malignant pancreatic disease using semiquantitative proteomics.

Methods: Serum samples were obtained from 74 patients (19 with type II intraductal papillary mucinous neoplasms, 8 with type I/III intraductal papillary mucinous neoplasms, 24 with chronic pancreatitis, 23 with pancreatic ductal adenocarcinomas) and 21 healthy subjects. Small proteins and peptides were assayed by matrix-assisted laser desorption/ionization for the detection of differentially abundant species possibly related to tumor onset. Serum pancreatic amylase, lipase, carcinoembryonic antigen and carbohydrate antigen 19-9 (CA 19-9) were also assayed.

Results: Twenty-six of 84 peaks detected were dysregulated (7 more abundant and 19 less abundant in the type II intraductal papillary mucinous neoplasms, p < 0.05). Of the differentially abundant peaks, 17 were commonly dysregulated (3 peaks more abundant and 13 less abundant in type II intraductal papillary mucinous neoplasms, and one at  m/z = 9961 at variance), indicating a protein fingerprint shared by types I/III and type II intraductal papillary mucinous neoplasms and pancreatic ductal adenocarcinomas.

Conclusions: These results suggest that our approach can be used to differentiate type II intraductal papillary mucinous neoplasms from type I/III neoplasms, and type II intraductal papillary mucinous neoplasms from pancreatic ductal adenocarcinomas.
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http://dx.doi.org/10.1007/s10620-018-4944-4DOI Listing
April 2018

Levels of uric acid in erectile dysfunction of different aetiology.

Aging Male 2018 Sep 12;21(3):200-205. Epub 2018 Jan 12.

a Dipartimento di Scienze della Salute , Università degli Studi di Milano , Milano , Italy.

Erectile dysfunction is a common disease characterized by endothelial dysfunction. The aetiology of ED is often multifactorial but evidence is being accumulated in favor of the proper function of the vascular endothelium that is essential to achieving and maintaining penile erection. Uric acid itself causes endothelial dysfunction via decreased nitric oxide production. This study aims to evaluate the serum uric acid (SUA) levels in 180 ED patients, diagnosed with the International Index of Erectile Function-5 (IIEF-5) and 30 non-ED control. Serum uric acid was analyzed with a commercially available kit using ModularEVO (Roche, Monza, Italy). Within-assay and between-assay variations were 3.0% and 6.0%, respectively. Out of the ED patients, 85 were classified as arteriogenic (A-ED) and 95 as non-arteriogenic (NA-ED) with penile-echo-color-Doppler. Uric acid levels (median and range in mg/dL) in A-ED patients (5.8, 4.3-7.5) were significantly higher (p < .001) than in NA-ED patients (4.4, 2.6-5.9) and in control group (4.6, 3.1-7.2). There was a significant difference (p < .001) between uric acid levels in patients with mild A-ED (IIEF-5 16-20) and severe/complete A-ED (IIEF-5 ≤ 10) that were 5.4 (range 4.3-6.5) mg/dL and 6.8 (range 6.4-7.2) mg/dL, respectively. There was no difference between the levels of uric acid in patients with different degree of NA-ED. Our findings reveal that SUA is a marker of ED but only of ED of arteriogenic aetiology.
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http://dx.doi.org/10.1080/13685538.2017.1420158DOI Listing
September 2018

Pancreatic enzyme replacement therapy after gastric resection: An update.

Dig Liver Dis 2018 Jan 10;50(1):1-5. Epub 2017 Nov 10.

Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy.

Exocrine pancreatic insufficiency (EPI) is one of the possible mechanisms of fat maldigestion following gastric surgery, together with reduced food intake, loss of gastric reservoir, small bowel bacterial overgrowth and rapid small bowel transit. Oral pancreatic enzyme replacement therapy (PERT) is the mainstay of treatment for EPI. The efficacy and safety of pancreatic enzyme substitution in patients following gastric resection remains unclear. This review article summarizes relevant studies addressing PERT after gastric resection.
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http://dx.doi.org/10.1016/j.dld.2017.10.025DOI Listing
January 2018
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