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BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVE(S): The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHOD(S): We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (+/-20 kb) for a total of 412 SNPs. RESULT(S): The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSION(S): Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.Copyright Published by Oxford University Press on behalf of the American Society for Nutrition 2021.

BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.

Background and Aims: Hepatocellular carcinoma (HCC) is a worldwide public health problem, accounting for increasing mortality and high costs. Aim of our study was to identify and test outcome indicators (OIs) in HCC, in light of their potential use in policy decision models. Methods: A panel of experts identified a list of OIs using a modified Delphi method; three of these OIs with the highest RAND/UCLA scores were tested in a prospective multicenter observational study (Value Based Medicine in Hepatology, VBMH). During 18 months, 711 HCC patients were enrolled and prospectively followed. Median follow-up time was 14 months. Results: The first OI was survival after 1–3–5 years stratified for BCLC stage or treatment (OI#1). One-year survival for BCLC stage 0/A, B, C, D was 93%, 86%, 50%, 26% respectively. One-year survival of 288 patients who had the first treatment during the study time was 88% for liver transplantation, 97% surgical resection, 100% ablation and 89% for TACE. The remaining two OIs meant to evaluate the appropriateness of treatments. Worsening of BCLC and/or CPT score after loco-regional therapy or surgical resection recorded at three months (OI#2), occurred in 16% of cases (76% after TACE). Very early HCC recurrence (within 6 months) after curative treatments (OI#3) happened in 15% of patients treated (20% after ablation). Conclusions: This set of outcome indicators proved their feasibility in a large cohort of patients and could serve as a benchmark for healthcare providers to move towards a value-based approach in the management of HCC.

Background and Aims: Liver Cirrhosis (LC) is responsible for high morbidity, mortality and increasing costs. Aim of our study was to identify outcome indicators (OIs) able to measure quality and value of care in compensated (CC) and decompensated (DC) cirrhosis. Methods: A panel of experts identified a list of OIs using a modified Delphi method; seven of these OIs with the highest RAND/UCLA scores were then tested in a prospective multicenter observational study (Value Based Medicine in Hepatology, VBMH). During 18 months, 1751 patients with LC were enrolled (1004 CC, 747 DC). Results: Annual rate of decompensation (OI#1), annual incidence of first variceal bleeding (OI#2) and annual incidence of HCC (OI#3) in CC were 12%, 2% for low- and 3% for high-risk varices, and 4.3% (81% diagnosed in BCLC-A stage) respectively. One-year survival for CPT score A, B, C was 96%, 81% and 59% (OI#4) respectively, and 94%, 56% when stratified for MELD cut-off of 15 (OI#5). Among DC patients, 4% of them had an episode of variceal bleeding (6 weeks survival 90%, 32% recurrence) (OI#6), 3% had spontaneous bacterial peritonitis (6 weeks survival 86%, 13% recurrence) (OI#7). Conclusions: The seven outcome indicators identified in our study performed well when tested in a large cohort of patients and represent a reference tool to implement a value-based approach to liver diseases.

Background and Aims: Liver disease (LD) is a major cause of morbidity and mortality worldwide. Development of outcome indicators (OIs) provides health care policy makers with objective criteria that can be used to generate a virtuous competition to improve value of care. Aim of our study was to generate and test a set of health care OIs for the major LDs. Methods: Using a modified Delphi method, 7 expert panels identified a set of OIs according to experience and scientific evidence (as of 2010). Each OI was rated in a two-step process using the RAND 9-point agreement scale. Median scores were computed for each OI. After the second rating, a disagreement index (DI) was calculated to identify and accept (if DI≤1) OIs with median rating ≥7. The final set of selected OIs was tested through an ongoing prospective multicenter observational study involving three tertiary centers in Lombardy, Italy. Results: A total of 51 OIs were identified by the focus groups. We recruited 3213 consecutive liver patients, of whom 91% had at least one follow-up visit after a median follow-up time of 15 months. Among these patients, 1752 were cirrhotic and 711 were affected by HCC. During observation time, 156 patients were transplanted and 210 patients died. All the identified OIs were successfully tested in the clinical setting showing excellent performance and correlation with natural history information. Conclusions: This study provides a set of validated outcomes indicators that can be used to monitor the performance of referral centers and improve the value and sustainability of care.

Introduction: The management of hepatocellular carcinoma (HCC) is a well-known public health problem, accounting for increasing mortality and high costs. Quality parameters able to measure clinical outcomes are still lacking. Aim of our study (Value Based Medicine in Hepatology, VBMH)was to identify and test outcome indicators (OIs) in HCC, in light of their potential use in policy decision models. Methods: A panel of experts identified a list of OIs using a modified Delphi method, according to experience and published evidence; four OIs with the highest RAND/UCLA score were tested in a prospective multicenter observational study. During 18 months, 711 HCC patients were enrolled and prospectively followed. 677 patients (95%) had at least one follow-up consultation. Median follow-up time was 14 months. Results: The first OI was 1–3–5 years survival stratified for BCLC stage or treatment (OI#1). One-year survival for BCLC stage 0/A–D was 93%, 86%, 50%, 26% respectively. One-year survival of 288 patients treated for the first time during the study was 88% for liver transplantation, 97% surgical resection, 100% ablation and 89% for TACE. The other three OIs evaluated the appropriateness of treatments: worsening of BCLC and/or CPT score after three months from a loco-regional therapy or surgical resection (OI#2), occurred in 16% of cases (76% after TACE). Recurrence of HCC within 6 months after curative treatments (OI#3) happened in 15% of patients treated, mainly after ablation (20%). Presence of severe morbidity three months after loco-regional procedure or resection, evaluated as grade≥3 according to Clavien-Dindo classification (OI#3), was found in 3% of patients treated. Conclusions: The outcome indicators identified in the VBMH study proved their feasibility in a large cohort of patients and could stand as a benchmark for healthcare providers to move towards a value-based approach in the management of HCC.

Introduction: Liver Cirrhosis (LC) is responsible for high morbidity, mortality and costs, with increasing need to improve quality of care. Aim of our study (Value Based Medicine in Hepatology Study, VBMH) was to identify outcome indicators (OIs) able to measure quality in liver diseases, including compensated (CC) and decompensated (DC) LC. Methods: A panel of hepatologists identified a list of 7 OIs for LC according to experience and published evidence, using a modified Delphi method and a standard 9-pointRANDappropriateness scale. Then, these 7 OIs were tested in clinical practice in a prospective multicenter observational study involving three tertiary centers in Italy, using a web-based electronic medical record. 1751 LC patients were enrolled in 18 months: 1004 CC and 747 DC. 92% of patients had at least two consultations in 17 months median follow-up. Results: Annual rate of decompensation in CC was 12% (OI#1). Annual incidence of 1st variceal bleeding (VB) was 2% for low-risk and 3% for high-risk varices (OI#2) indicating a significant success of primary profilaxis. Annual incidence of HCC in CC was 4.3%, with 81% patients found at early stage (OI#3), underlining the accuracy of oncologic surveillance. One-year survival after the first decompensation episode (ascites in 74% of cases) was 96%, 81% and 59% stratified for CPT score A, B, C respectively (OI#4), and 94%, 56% stratified for MELD below or above 15 (OI#5). 4% of DC patients had an episode of VB with 90% survival after 6 weeks, and 33% recurrence (OI#6). Similarly, 3% ofDCpatients had spontaneous bacterial peritonitis with 6 weeks survival of 86% and 13% recurrence (OI#7). Conclusions: The value-based OIs generated in this study performed well in a large cohort of consecutive patients, and could represent a reference tool for healthcare providers to improve care in LC.

Liver Cirrhosis (LC) is responsible for high morbidity, mortality and raising costs. Current guidelines set the standard of care for management of cirrhosis in clinical practice, but explicit outcome indicators (OIs) are lacking. If available, OIs could guide clinical care and decision making, so that efforts and resources can be properly allocated. Aim of our study was to generate and test a set of health care OIs for compensated (CC) and decompensated (DC) LC. This study is part of a larger effort (the V.B.M.H. study) to generate OIs for several liver diseases. An expert panel of hepatologists identified a set of OIs for LC according to experience and scientific evidence (as of 2010), and used a modified Delphi method to rate them through a RAND 9-point agreement scale. A final list of 7 indicators with median rating ≥7 and with disagreement index ≤1 was selected. Three OIs were designed for CC and 4 for DC. In the second phase of the study, the selected OIs were tested in clinical practice through a prospective multicenter observational study, involving three tertiary centers in Lombardy, Italy. A web-based EMR was used to collect data. 1732 LC patients were enrolled in 18 months: 984 CC (57%) and 748 DC (43%). 91% of these LC patients had at least two consultations in a 13 months median follow-up. The annual rate of decompensation in CC (OI#1) was 12%, decompensation being more frequent in HCV-related CC. The annual incidence of 1st variceal bleeding (VB) for low-risk varices was 2% and was null for high risk varices, indicating effective primary profilaxis (OI#2). Annual incidence of HCC was 4%, while the percentage of CC patients diagnosed at early stage HCC (BCLC 0/A) was 74%, reflecting the accuracy of oncologic surveillance (OI#3). In DC patients, survival at 1 year after the first episode of decompensation (ascites in 78% of cases) was 99% for CPT A, 87% for CPT B and 73% for CPT C (OI#4). 3% of DC patients had an episode of VB, with survival of 88% after

Liver diseases (LDs) have a high impact on morbidity, mortality and health-related quality of life (HRQoL). Different LDs may have different effects on patients’ HRQoL. The aim of our study was to assess the reliability and benefit of using a generic HRQoL questionnaire to evaluate the health status of patients with the major liver conditions: hepatitis B (HBV), hepatitis C (HCV), cirrhosis, hepatocellular carcinoma (HCC), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), NAFLD/NASH and patients in the liver transplant list. A naturalistic, prospective, multicenter study has been conducted to generate and validate a set of health care outcomes indicators for the major liver conditions. LDs patients (age>18 years) were enrolled in 3 major Italian medical centers and are still being followed up (median f-up: 13 months). Within this study, socio-demographic, clinical and HRQoL were collected using the EQ-5D-3L, a generic instrument that enables HRQoL to compared within and between clinical conditions and with the general population. It generates a health profile made up of 5 domains (mobility, self care, anxiety/depression, usual activities and pain/discomfort), each one with three levels of severity. It also consists of a visual analogue scale (EQ-5D VAS) which measures overall HRQoL in a range from 0 (worst imaginable health state) to 100 (best imaginable health state). The baseline HRQoL data was analyzed dividing the patients in sub-groups according to the most recently diagnosed and most severe condition. The results reported below focus on the mean VAS. We enrolled 3,217 patients, 64.8% male, aged 19-91 (median=61) years; 95.0% of them filled in the EQ-5D at baseline. Patients in the HCC group were 22.6%, those with compensated cirrhosis were 21.2%, HCV 20.9%, decompensated cirrhosis 10.3%, HBV 9.5%. The HBV group reported the best HRQoL with a mean EQ-5D VAS of 77.8. NAFLD/NASH, HCV and PSC patients had a similar