Research

Liver cancer

Clinical oncology

The General Surgery 2, Hepato-bilio-pancreatic and Liver Transplantation Unit of Padova University Hospital is a Regional Referral Centre for liver cancer and has a proven expertise in surgical treatment for primitive and metastatic liver cancer. It represents the center with the highest volume of oncological interventions for liver tumors in Italy according to last reports AGENAS. The clinical activity is based on solid contributions in basic, translational and clinical research. The continuous collaboration with other research groups is based on a strong commitment to innovation and guarantees the sharing of clinical and research protocols useful for training fellows and for providing care for patients with oncological liver diseases.

Overview of the research lines: 

  • Primary liver cancer
  • Metastatic liver cancer
  • Liver transplantation for oncologic indications
  • Biobanking and cell biology Prognostic tools and Molecular signature

Primary liver cancer 

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of cancer-related death worldwide. The treatment of HCC is based on liver transplantation, liver resection, thermal ablation, locoregional therapies and pharmacological treatment. The center provided a relevant contribution in the most recent national clinical guideline production. Our group has always been involved in several Italian multi-center studies to define the prognostic stratification, therapeutic management and response to surgical treatment of patients with HCC with the aim to offer personalized treatment. Our group collaborates with the multi-center group ITA.LI.CA (Italian Liver Cancer) in the production of scientific evidence on the epidemiology, diagnosis and therapy of hepatocellular carcinoma. In particular, within the ITA.LI.CA group, the aim is to define the best therapeutic strategies in cirrhotic patients (even at high risk), and to define new prognostic systems in the scenario of treatments for HCC. In particular, the indication for surgical treatment of HCC was expanded through minimally invasive laparoscopic access with good clinical response and adequate oncological outcome. The prospective HEPATIC study will evaluate the response to treatment with laparoscopic thermal ablation of patients with early and intermediate stage hepatocarcinoma compared to alternative loco-regional therapies. The participation in the HE.RC.O.LE.S project, on the other hand, is evaluating at an international level the prognosis and therapeutic efficacy of hepatic resection (open and laparoscopic) for hepatocellular carcinoma. Our group also participates in the Italian registry of minimally invasive hepatic surgery IGOMILS.

Cholangiocarcinoma (CCA) is a rare malignancy of the biliary duct system that may originate within the liver or in extrahepatic bile ducts, which terminate at the ampulla of Vater. Three different kinds of tumor are described: intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA) with different clinical presentation, diagnosis, treatment and prognosis. Our center represents one of the Italian reference centers for CCA surgery through major resection and vascular reconstruction operations. A study is also currently underway on the application of minimally invasive surgery with robots for CCA.

Publications:

1: Vitale A, Trevisani F, Farinati F, Cillo U. Treatment of Hepatocellular Carcinoma in the Precision Medicine Era: From Treatment Stage Migration to Therapeutic Hierarchy. Hepatology. 2020 Dec;72(6):2206-2218. doi: 10.1002/hep.31187. Epub 2020 Oct 26.

2: Vitale A, Farinati F, Pawlik TM, et al. The concept of therapeutic hierarchy for patients with hepatocellular carcinoma: A multicenter cohort study. Liver Int. 2019 Aug;39(8):1478-1489. doi: 10.1111/liv.14154.

3: Cillo U, Bertacco A, Fasolo E, et al. Videolaparoscopic microwave ablation in patients with HCC at a European high-volume center: Results of 815 procedures. J Surg Oncol. 2019 Nov;120(6):956-965. doi: 10.1002/jso.25651.

4: Cillo U, Fondevila C, Donadon M, et al. Surgery for cholangiocarcinoma. Liver Int. 2019 May;39 Suppl 1(Suppl Suppl 1):143-155. doi: 10.1111/liv.14089.

5: Cillo U, D'Amico FE, Furlanetto A, Perin L, Gringeri E. Robotic hepatectomy and biliary reconstruction for perihilar cholangiocarcinoma: a pioneer western case series. Updates Surg. 2021 Jun;73(3):999-1006. doi: 10.1007/s13304-021-01041-3.

6: Moustafa M, Fasolo E, Bassi D, D'amico FE, Gringeri E, Pawlik TM, Cillo U. The impact of liver resection on survival for locally advanced intrahepatic cholangiocarcinoma tumors: A propensity score analysis. Eur J Surg Oncol. 2020 Apr;46(4 Pt A):632-637. doi: 10.1016/j.ejso.2019.11.502.

Funding:

Ordinary department funding.

People involved: 

  • Umberto Cillo, Full Professor
  • Enrico Gringeri, Associate Professor
  • Alessandro Vitale, Associate Professor
  • Francesco Enrico D’Amico, Associate Professor
  • Jacopo Lanari, RTA
  • Fabio Farinati, Full Professor
  • Luca Fabris, Associate Professor

Group members:
Domenico Bassi, Riccardo Boetto, Francesco D’Amico, Marina Polacco, Alessandra Bertacco, Annalisa Dolcet (Hepatobiliary Surgeons), Silvia Caregari (Hepatobiliary Surgery Fellows)



Metastatic liver cancer 

A liver metastasis is a tumor that has spread to the liver from a cancer that started in another place in the body. The liver is commonly involved when the tumor arises from gastrointestinal tract (colon, rectum, stomach, esophagus), pancreas, breast, lung, uterus. The best treatment is based on surgical resection. Unfortunately, only 10-20% of the patients are really resectable at diagnosis and the only possible treatment is based on systemic therapy. Our fields of interest are represented by minimally invasive liver surgery, ex situ-liver resection, new biomarkers identification, research on circulating tumor cells.

Our Group has always been involved in several Italian and international multi-center studies to define the prognostic stratification, therapeutic management and response to surgical treatment of patients with liver metastases (in particular from colorectal and mammary neoplasms) with the aim of offering personalized treatment. Our center works in close collaboration with the Veneto Oncology Institute for the surgical treatment of these neoplasms. In this regard, our center collaborates with the international “Met Survey (LIVERMET”), with the Italian multi-center registry on minimally invasive hepatic surgery IGOMILS.

Our center has also devised, registered and initiated two multicentre randomized protocols on liver transplantation for colorectal metastases. In addition, a prospective study on laparoscopic treatment with microwaves of colorectal and breast cancer metastases is underway.

Publications:

1: Masetti M, Fallani G, Ratti F, Ferrero A, Giuliante F, Cillo U, Guglielmi A, Ettorre GM, Torzilli G, Vincenti L, Ercolani G, Cipressi C, Lombardi R, Aldrighetti L, Jovine E. Minimally invasive treatment of colorectal liver metastases: does robotic surgery provide any technical advantages over laparoscopy? A multicenter analysis from the IGoMILS (Italian Group of Minimally Invasive Liver Surgery) registry. Updates Surg. 2022 Apr;74(2):535-545. doi: 10.1007/s13304-022-01245-1.

2: Loupakis F, Sharma S, Derouazi M, Murgioni S, Biason P, Rizzato MD, Rasola C, Renner D, Shchegrova S, Koyen Malashevich A, Malhotra M, Sethi H, Zimmermann BG, Aleshin A, Moshkevich S, Billings PR, Sedgwick JD, Schirripa M, Munari G, Cillo U, Pilati P, Dei Tos AP, Zagonel V, Lonardi S, Fassan M. Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases. JCO Precis Oncol. 2021 Jul 21;5:PO.21.00101. doi: 10.1200/PO.21.00101.

3: Cillo U, Furlanetto A, Nieddu E, Polacco M, Boetto R, Bassi D, Gringeri E. Ante situm liver surgery using machine perfusion liver preservation: pilot human experience. Br J Surg. 2021 Jul 23;108(7):e235-e236. doi: 10.1093/bjs/znab095. PMID: 33824957

4: Cremolini C, Casagrande M, Loupakis F, Aprile G, Bergamo F, Masi G, Moretto R R, Pietrantonio F, Marmorino F, Zucchelli G, Tomasello G, Tonini G, Allegrini G, Granetto C, Ferrari L, Urbani L, Cillo U, Pilati P, Sensi E, Pellegrinelli A,Milione M, Fontanini G, Falcone A. Efficacy of FOLFOXIRI plus bevacizumab inliver-limited metastatic colorectal cancer: A pooled analysis of clinical studiesby Gruppo Oncologico del Nord Ovest. Eur J Cancer. 2017 Mar;73:74-84.

5: Spolverato G, Vitale A, Ejaz A, Cosgrove D, Cowzer D, Cillo U, Pawlik TM. Hepatic Resection for Disappearing Liver Metastasis: a Cost-Utility Analysis. J Gastrointest Surg. 2015 Sep;19(9):1668-75

6: Romano M, DE Francesco F, Zarantonello L, Ruffolo C, Ferraro GA, Zanus G,Giordano A, Bassi N, Cillo U. From Inflammation to Cancer in Inflammatory Bowel Disease: Molecular Perspectives. Anticancer Res. 2016 Apr;36(4):1447-60. Review.

Funding:

Ordinary department funding.

People involved: 

  • Umberto Cillo, Full Professor
  • Enrico Gringeri, Associate Professor
  • Alessandro Vitale, Associate Professor
  • Francesco Enrico D’Amico, Associate Professor
  • Jacopo Lanari, RTA
  • Fabio Farinati, Full Professor
  • Luca Fabris, Associate Professor

Group members:
Domenico Bassi, Riccardo Boetto, Francesco D’Amico, Marina Polacco, Alessandra Bertacco, Annalisa Dolcet (Hepatobiliary Surgeons), Silvia Caregari (Hepatobiliary Surgery Fellows)



Liver transplantation for oncologic indications

The efficacy of Direct-Acting Antiviral (DAA) for the eradication of hepatitis C infection (HCV) is significantly changing the scenario of liver transplantation. In the immediate future more and more donors will be available for new oncological indications. Liver transplantation for Hepatocarcinoma (HCC) represents one of the most frequent indication for liver transplantation. Recently, in Italy, well selected cases of patients with oncological diagnosis are considered for liver transplantation: colo-rectal liver metastases, perihilar cholangiocarcinoma (pCCA), hepitelioid hemangioendotelioma and neuroendocrine tumor liver metastases. We are focusing our research area in the improvement of liver transplantation protocol for oncological indication and surveillance after transplantation.

Our center has also devised, registered and initiated two multi-center protocols on liver transplantation for colorectal metastases: MELODIC (Colorectal metastases and liver transplantation with organs from deceased donors: an inductive Padova center protocol – trial GOV NCT04870879 and RAPID (Resection and partial liver segment transplantation with delayed total hepatectomy as treatment for selected patients with unresecable liver metastases from colorectal cancer – trial GOV NCT04865471). We also partecipated at the TRANSMET study (trial GOV  NCT02597348): an european multicenter, randomized study on liver transplantation for colorectal metastases.

Publications:

1:Cillo U, Vitale A, Volk ML, et al. Liver Transplantation for T2 Hepatocellular Carcinoma during the COVID-19 Pandemic: A Novel Model Balancing Individual Benefit against Healthcare Resources. Cancers (Basel). 2021 Mar 19;13(6):1416. doi: 10.3390/cancers13061416.

2: Vitale A, Scolari F, Bertacco A, Gringeri E, D'Amico F, Bassi D, D'Amico FE, Angeli P, Burra P, Lai Q, Cillo U. Sustained Complete Response after Biological Downstaging in Patients with Hepatocellular Carcinoma: XXL-Like Prioritization for Liver Transplantation or "Wait and See" Strategy? Cancers (Basel). 2021 May 17;13(10):2406. doi: 10.3390/cancers13102406.

3: Finotti M, Vitale A, Volk M, Cillo U. A 2020 update on liver transplant for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol. 2020 Oct;14(10):885-900. doi:10.1080/17474124.2020.1791704.

4: Gringeri E, Gambato M, Sapisochin G, Ivanics T, Lynch EN, Mescoli C, Burra P, Cillo U, Russo FP. Cholangiocarcinoma as an Indication for Liver Transplantation in the Era of Transplant Oncology. J Clin Med. 2020 May 5;9(5):1353. doi: 10.3390/jcm9051353.

5: Finotti M, Vitale A, Gringeri E, D'Amico FE, Boetto R, Bertacco A, Lonardi S, Bergamo F, Feltracco P, Cillo U. Colon Rectal Liver Metastases: The Role of the Liver Transplantation in the Era of the Transplant Oncology and Precision Medicine. Front Surg. 2021 Jul 20;8:693387. doi: 10.3389/fsurg.2021.693387.

6: Fodor M, Zoller H, Oberhuber R, Sucher R, Seehofer D, Cillo U, Line PD, Tilg H, Schneeberger S. The Need to Update Endpoints and Outcome Analysis in the Rapidly Changing Field of Liver Transplantation. Transplantation. 2022 May 1;106(5):938-949. doi: 10.1097/TP.0000000000003973.

7: Settmacher U, Ali-Deeb A, Coubeau L, Cillo U, Line PD, Guba M, Nadalin S, Rauchfuß F. Auxilliary Liver Transplantation According to the RAPID Procedure in Non-cirrhotic Patients - Technical Aspects and Early Outcomes. Ann Surg. 2022 Oct 13. doi: 10.1097/SLA.0000000000005726.

Funding:

Ordinary department funding.

People involved: 

  • Umberto Cillo, Full Professor
  • Enrico Gringeri, Associate Professor
  • Alessandro Vitale, Associate Professor
  • Francesco Enrico D’Amico, Associate Professor
  • Jacopo Lanari, RTA
  • Fabio Farinati, Full Professor
  • Luca Fabris, Associate Professor

Group members:
Domenico Bassi, Riccardo Boetto, Francesco D’Amico, Marina Polacco, Alessandra Bertacco, Annalisa Dolcet (Hepatobiliary Surgeons), Silvia Caregari (Hepatobiliary Surgery Fellows)



Biobanking and cell biology - Molecular signature 

A biobank is essentially a collection of biospecimens that have been ethically collected, well-annotated, and stored using standard operating procedures (SOPs). The field of biobanking has grown tremendously in size and complexity over the last couple of decades, and is now considered an essential part of the healthcare infrastructure. In this era of precision (sometimes termed “personalized”) oncology, biobanks represent a highly valuable resource for biomarker translational research and cancer drug discovery. We are particularly interested in this new and promising research area. Our department has recently submitted a research program regarding the preparation of a biobank. A methodological and logistical implementation project of a regional cancer biobanking and its computerization is underway. The goal will be to regionally standardize the collection of biomaterials with high quality standards both in elective and urgent conditions but above all to computerize all the stored material in a telematic platform so that it can be used by each professional for the execution of studies for clinical and research purposes.

Publications:

1: Pelizzaro F, Cardin R, Penzo B, Pinto E, Vitale A, Cillo U, Russo FP, Farinati F.  Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now? Cancers (Basel). 2021 May 10;13(9):2274. doi: 10.3390/cancers13092274.

2: Fasolato S, Trevellin E, Ruvoletto M, Granzotto M, Zanus G, Boscaro E, Babetto E, Terrin L, Battocchio MA, Ciscato F, Turato C, Quarta S, Cillo U, Pontisso P,Vettor R. SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma. Life Sci. 2018 May 1;200:134-141.

3: Turato C, Cannito S, Simonato D, Villano G, Morello E, Terrin L, Quarta S, Biasiolo A, Ruvoletto M, Martini A, Fasolato S, Zanus G, Cillo U, Gatta A, Parola M, Pontisso P. SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity. Sci Rep. 2015 Dec 4;5:17701.

4: Pozzan C, Cardin R, Piciocchi M, Cazzagon N, Maddalo G, Vanin V, Giacomin A,Pontisso P, Cillo U, Farinati F. Diagnostic and prognostic role of SCCA-IgM serumlevels in hepatocellular carcinoma (HCC). J Gastroenterol Hepatol. 2014 Aug;29(8):1637-44.

5: Piciocchi M, Cardin R, Vitale A, Vanin V, Giacomin A, Pozzan C, Maddalo G,Cillo U, Guido M, Farinati F. Circulating free DNA in the progression of liver damage to hepatocellular carcinoma. Hepatol Int. 2013 Oct;7(4):1050-7. doi:10.1007/s12072-013-9481-9. Epub 2013 Nov 2.

6: Romano M, De Francesco F, Pirozzi G, Gringeri E, Boetto R, Di Domenico M,Zavan B, Ferraro GA, Cillo U. Expression of cancer stem cell biomarkers as a tool for a correct therapeutic approach to hepatocellular carcinoma. Oncoscience. 2015 May 15;2(5):443-456. eCollection 2015. Review.

Funding:

Ordinary department funding.

People involved: 

  • Umberto Cillo, Full Professor
  • Enrico Gringeri, Associate Professor
  • Alessandro Vitale, Associate Professor
  • Francesco Enrico D’Amico, Associate Professor
  • Jacopo Lanari, RTA
  • Fabio Farinati, Full Professor
  • Luca Fabris, Associate Professor

Group members:
Domenico Bassi, Riccardo Boetto, Francesco D’Amico, Marina Polacco, Alessandra Bertacco, Annalisa Dolcet (Hepatobiliary Surgeons), Silvia Caregari (Hepatobiliary Surgery Fellows)