Research

Liver surgery

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 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:

  • Minimally invasive liver surgery (including robotic) and laparoscopic/thoracoscopic thermal ablation
  • Ex-situ and ante situ liver surgery
  • Two-staged hepatectomy
  • RAPID technique

1. Minimally invasive liver surgery (including robotic) and laparoscopic/thoracoscopic  thermal ablation

In the last two decades, minimally invasive liver surgery (MILS) has become a standard indication for the surgical treatment of both malignant and benign liver lesions. Specialized centers with solid background on hepatic and laparoscopic surgery are increasingly interested in this research area. Our institution is  particularly involved in an Italian MILS project: IgoMILS (Italian group of Minimally Invasive Liver Surgery) with the objective to share research and clinical protocols. Another special issue is represented by the use of heat for the treatment of small primary and secondary liver malignancies. Laparoscopic thermal ablation is standardized based in well codified guidelines. 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 is also participating at the LIVACOR project (Minimally invasive liver and simuoltaneous colorectal resection - trial GOV  NCT05138094) that is a European wide, randomized controlled, open-label, multicenter trial for patients with synchronous CRLMs and primary colorectal tumor. In 2018 the Da Vinci Robotic platform was introduced in our center: different cases of benign and malignant liver lesions were resected with this innovative technique: our group published a pioneer case series of robotic hepatectomy and biliary riconstruction for perhilar cholangiocarcinoma.

Publications:

1: Aldrighetti L, Ratti F, Cillo U, Ferrero A, Ettorre GM, Guglielmi A, Giuliante F, Calise F; Italian Group of Minimally Invasive Liver Surgery (I GO MILS).Diffusion, outcomes and implementation of minimally invasive liver surgery: a snapshot from the I Go MILS (Italian Group of Minimally Invasive Liver Surgery).Registry. Updates Surg. 2017 Sep;69(3):271-283.

2: Gringeri E, Boetto R, Bassi D, D'Amico FE, Polacco M, Romano M, Barbieri S,Feltracco P, Spampinato M, Zanus G, Cillo U. Totally laparoscopic caudate lobe resection: technical aspects and literature review. Surg Laparosc Endosc Percutan Tech. 2014 Dec;24(6):e233-6.

3: Cillo U, Vitale A, Dupuis D, Corso S, Neri D, D'Amico F, Gringeri E, Farinati F, Vincenzi V, Zanus G. Laparoscopic ablation of hepatocellular carcinoma in cirrhotic patients unsuitable for liver resection or percutaneous treatment: a cohort study. PLoS One. 2013;8(2):e57249. doi: 10.1371/journal.pone.0057249. Epub 2013 Feb 21.

4: Cillo U, Noaro G, Vitale A, Neri D, D'Amico F, Gringeri E, Farinati F,Vincenzi V, Vigo M, Zanus G; HePaTIC Study Group. Laparoscopic microwave ablationin patients with hepatocellular carcinoma: a prospective cohort study. HPB(Oxford). 2014 Nov;16(11):979-86. doi: 10.1111/hpb.12264. Epub 2014 Apr 18.

5: Aldrighetti L, Belli G, Boni L, Cillo U, Ettorre G, De Carlis L, Pinna A,Casciola L, Calise F; Italian Group of Minimally Invasive Liver Surgery (I GOMILS). Italian experience in minimally invasive liver surgery: a national survey.Updates Surg. 2015 Jun;67(2):129-40.

6: 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.

7: Levi Sandri GB, Ettorre GM, Aldrighetti L, Cillo U, Dalla Valle R, Guglielmi A, Mazzaferro V, Ferrero A, Di Benedetto F, Gruttadauria S, De Carlis L, Vennarecci G; I Go MILS Group on HCC. Laparoscopic liver resection of hepatocellular carcinoma located in unfavorable segments: a propensity score- matched analysis from the I Go MILS (Italian Group of Minimally Invasive Liver Surgery) Registry. Surg Endosc. 2019 May;33(5):1451-1458. doi: 10.1007/s00464-018-6426-3. Epub 2018 Sep 10. PMID: 30203200.

8: Rocca A, Cipriani F, Belli G, Berti S, Boggi U, Bottino V, Cillo U, Cescon M, Cimino M, Corcione F, De Carlis L, Degiuli M, De Paolis P, De Rose AM, D'Ugo D, Di Benedetto F, Elmore U, Ercolani G, Ettorre GM, Ferrero A, Filauro M, Giuliante F, Gruttadauria S, Guglielmi A, Izzo F, Jovine E, Laurenzi A, Marchegiani F, Marini P, Massani M, Mazzaferro V, Mineccia M, Minni F, Muratore A, Nicosia S, Pellicci R, Rosati R, Russolillo N, Spinelli A, Spolverato G, Torzilli G, Vennarecci G, Viganò L, Vincenti L, Delrio P, Calise F, Aldrighetti L. The Italian Consensus on minimally invasive simultaneous resections for synchronous liver metastasis and primary colorectal cancer: A Delphi methodology. Updates Surg. 2021 Aug;73(4):1247-1265. doi: 10.1007/s13304-021-01100-9. Epub 2021 Jun 5. PMID: 34089501.

9: Görgec B, Benedetti Cacciaguerra A, Lanari J, Russolillo N, Cipriani F, Aghayan D, Zimmitti G, Efanov M, Alseidi A, Mocchegiani F, Giuliante F, Ruzzenente A, Rotellar F, Fuks D, D'Hondt M, Vivarelli M, Edwin B, Aldrighetti LA, Ferrero A, Cillo U, Besselink MG, Abu Hilal M. Assessment of Textbook Outcome in Laparoscopic and Open Liver Surgery. JAMA Surg. 2021 Aug 1;156(8):e212064. doi: 10.1001/jamasurg.2021.2064. Epub 2021 Aug 11. PMID: 34076671; PMCID: PMC8173471.

10: Cillo U, Finotti M, Di Renzo C, Vitale A, Zanus G, Gringeri E, Bertacco A, Polacco M, D'Amico F. Thoracoscopic Ablation of Critically Located Liver Tumors: A Safety and Efficacy Cohort Study. Front Surg. 2021 Mar 17;8:626297. doi: 10.3389/fsurg.2021.626297. PMID: 33816545; PMCID: PMC8010311.

11: Bertacco A, D'Amico F, Romano M, Finotti M, Vitale A, Cillo U. Liver radiofrequency ablation as emergency treatment for a ruptured hepatocellular carcinoma: a case report. J Med Case Rep. 2017 Mar 1;11(1):54. doi: 10.1186/s13256-017-1199-1. PMID: 28245861; PMCID: PMC5331708.

12: 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.

13: Russolillo N, Aldrighetti L, Cillo U, Guglielmi A, Ettorre GM, Giuliante F, Mazzaferro V, Dalla Valle R, De Carlis L, Jovine E, Ferrero A; I Go MILS Group. Risk-adjusted benchmarks in laparoscopic liver surgery in a national cohort. Br J Surg. 2020 Jun;107(7):845-853. doi: 10.1002/bjs.11404. Epub 2020 Jan 10. PMID:31925777.

14: Ardito F, Aldrighetti L, Guglielmi A, Jovine E, Cillo U, Ferrero A, De Carlis L, Belli G, Dalla Valle R, Slim A, Mazzaferro V, Navarra G, Ettorre GM, Calise F, Pinna AD, Giuliante F; Italian Group of Minimally Invasive Liver Surgery (I Go MILS). Surgical Management of Hepatic Benign Disease: Have the Number of Liver Resections Increased in the Era of Minimally Invasive Approach? Analysis from the I Go MILS (Italian Group of Minimally Invasive Liver Surgery) Registry. J Gastrointest Surg. 2020 Oct;24(10):2233-2243. doi: 10.1007/s11605-019-04260-7. Epub 2019 Sep 10. PMID: 31506894.

15: Russolillo N, Aldrighetti L, Cillo U, Guglielmi A, Ettorre GM, Giuliante F, Mazzaferro V, Dalla Valle R, De Carlis L, Jovine E, Ferrero A; I Go MILS Group. Risk-adjusted benchmarks in laparoscopic liver surgery in a national cohort. Br J Surg. 2020 Jun;107(7):845-853. doi: 10.1002/bjs.11404. Epub 2020 Jan 10. PMID:31925777.

16: Sposito C, Monteleone M, Aldrighetti L, Cillo U, Dalla Valle R, Guglielmi A, Ettorre GM, Ferrero A, Di Benedetto F, Rossi GE, De Carlis L, Giuliante F, Mazzaferro V. Preoperative predictors of liver decompensation after mini- invasive liver resection. Surg Endosc. 2021 Feb;35(2):718-727. doi: 10.1007/s00464-020-07438-2. Epub 2020 Mar 2. PMID: 32124061.

17: 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.

18: Zimmitti G, Sijberden JP, Osei-Bordom D, Russolillo N, Aghayan D, Lanari J, Cipriani F, López-Ben S, Rotellar F, Fuks D, D'Hondt M, Primrose JN, Görgec B, Cacciaguerra AB, Marudanayagam R, Langella S, Vivarelli M, Ruzzenente A, Besselink MG, Alseidi A, Efanov M, Giuliante F, Dagher I, Jovine E, di Benedetto F, Aldrighetti LA, Cillo U, Edwin B, Ferrero A, Sutcliffe RP, Hilal MA. Indications, trends, and perioperative outcomes of minimally invasive and open liver surgery in non-obese and obese patients: An international multicentre propensity score matched retrospective cohort study of 9963 patients. Int J Surg. 2022 Oct 14:106957. doi: 10.1016/j.ijsu.2022.106957. Epub ahead of print. PMID: 36252942.

19: Görgec B, Cacciaguerra AB, Aldrighetti LA, Ferrero A, Cillo U, Edwin B, Vivarelli M, Lopez-Ben S, Besselink MG, Abu Hilal M; International Study Group of Bile Leakage after Liver Surgery. Incidence and Clinical Impact of Bile Leakage after Laparoscopic and Open Liver Resection: An International Multicenter Propensity Score-Matched Study of 13,379 Patients. J Am Coll Surg. 2022 Feb 1;234(2):99-112. doi: 10.1097/XCS.0000000000000039. PMID: 35213428.

20: Levi Sandri GB, Colasanti M, Aldrighetti L, Guglielmi A, Cillo U, Mazzaferro V, Dalla Valle R, De Carlis L, Gruttadauria S, Di Benedetto F, Ferrero A, Ettorre GM; I Go MILS Group on HCC. Correction to: Is minimally invasive liver surgery a reasonable option in recurrent HCC? A snapshot from the I Go MILS registry. Updates Surg. 2022 Apr;74(2):799. doi: 10.1007/s13304-021-01200-6. Erratum for: Updates Surg. 2022 Feb;74(1):87-96. PMID: 34714536.

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

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



2. Ex-situ and ante-situ liver surgery

Ex-situ liver resection is a complex technique for the treatment of liver malignancies critically localized within the liver and unresectable with conventional liver surgery. Ex-situ liver resection consists in the removal of the liver, liver resection outside the abdomen and implantation of the liver in the original position. During these phases the liver is continuously perfused using specific hypothermic preservation solutions. This particular surgical technique requests both liver surgery and liver transplantation expertise. The initial experience was described in the 80s by Pichlmayr but this technique was progressively abandoned due to his high morbidity and mortality rate. We recently are focusing our research in this specific area and a clinical protocol was approved by local ethical committee. Ante situ liver surgery is an other complex technique of total vascular exclusion considered for selected patients with unresecable liver lesions. Over the years we integrated this procedure with in situ hypotermic oxygenated perfusion (HOPE).

Publications:

1: Gringeri E, Polacco M, D'Amico FE, Bassi D, Boetto R, Tuci F, Bonsignore P,Noaro G, D'Amico F, Vitale A, Feltracco P, Barbieri S, Neri D, Zanus G, Cillo U. Liver autotransplantation for the treatment of unresectable hepatic metastasis:an uncommon indication-a case report. Transplant Proc. 2012 Sep;44(7):1930-3.

2: Gringeri E, Polacco M, D'Amico FE, Scopelliti M, Bassi D, Bonsignore P,Luisetto R, Lodo E, Carraro A, Zanus G, Cillo U. A new liver autotransplantation technique using subnormothermic machine perfusion for organ preservation in aporcine model. Transplant Proc. 2011 May;43(4):997-1000.

3: Gringeri E, Auricchio P, Perin L, D'Amico FE, Bassi D, Boetto R, Polacco M, Di Giunta M, Luisetto R, Cillo U.A Translational Approach to Standardization of Machine Perfusion Adoption in Ex Vivo Liver Resection. Ann Surg Oncol. 2020 Jun;27(6):1919. doi: 10.1245/s10434-019-08163-4. Epub 2020 Jan 3.PMID: 31900807

4: 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

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

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



3. Two-staged hepatectomy

The liver is the unique organ of our organism with a particular characteristic: to regenerate itself. The liver is able to regenerate itself after a specific stimulus. Liver resection represent a proved stimulus to liver regeneration. This pathophysiological feature was used to increase the liver volume in order to avoid the fatal post-surgical liver failure. The first reports have been described by Adam for the surgical treatment of bilateral liver metastases. More recently new staged hepatectomies procedures are described: ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy). Our group for the first time described a new staged liver technique: LAPS (Laparoscopic Ablation and Portal vein ligation for staged hepatectomy).

Publications:

1: Cillo U, Gringeri E, Feltracco P, Bassi D, D'Amico FE, Polacco M, Boetto R.Totally Laparoscopic Microwave Ablation and Portal Vein Ligation for StagedHepatectomy : A New Minimally Invasive Two-Stage Hepatectomy. Ann Surg Oncol.2015 Aug;22(8):2787-8.

2: Gringeri E, Boetto R, DʼAmico FE, Bassi D, Cillo U. Laparoscopic microwave ablation and portal vein ligation for staged hepatectomy (LAPS): a minimally invasive first-step approach. Ann Surg. 2015 Feb;261(2):e42-3.

3: Serenari M, Zanello M, Schadde E, Toschi E, Ratti F, Gringeri E, Masetti M,Cillo U, Aldrighetti L, Jovine E; ALPPS Italian Registry Group. Importance of primary indication and liver function between stages: results of a multicenter Italian audit of ALPPS 2012-2014. HPB (Oxford). 2016 May;18(5):419-27.

4: Aldrighetti L, Ratti F, Cillo U, Ferrero A, Ettorre GM, Guglielmi A, Giuliante F, Calise F; Italian Group of Minimally Invasive Liver Surgery (I GO MILS).Diffusion, outcomes and implementation of minimally invasive liver surgery: a snapshot from the I Go MILS (Italian Group of Minimally Invasive Liver Surgery)Registry. Updates Surg. 2017 Sep;69(3):271-283. doi: 10.1007/s13304-017-0489-x.

5: Li J, Moustafa M, Linecker M, Lurje G, Capobianco I, Baumgart J, Ratti F, Rauchfuss F, Balci D, Fernandes E, Montalti R, Robles-Campos R, Bjornsson B, Topp SA, Fronek J, Liu C, Wahba R, Bruns C, Brunner SM, Schlitt HJ, Heumann A, Stüben BO, Izbicki JR, Bednarsch J, Gringeri E, Fasolo E, Rolinger J, Kristek J, Hernandez-Alejandro R, Schnitzbauer A, Nuessler N, Schön MR, Voskanyan S, Petrou AS, Hahn O, Soejima Y, Vicente E, Castro-Benitez C, Adam R, Tomassini F, Troisi RI, Kantas A, Oldhafer KJ, Ardiles V, de Santibanes E, Malago M, Clavien PA, Vivarelli M, Settmacher U, Aldrighetti L, Neumann U, Petrowsky H, Cillo U, Lang H, Nadalin S. ALPPS for Locally Advanced Intrahepatic Cholangiocarcinoma: Did Aggressive Surgery Lead to the Oncological Benefit? An International Multi- center Study. Ann Surg Oncol. 2020 May;27(5):1372-1384. doi: 10.1245/s10434-019-08192-z. Epub 2020 Jan 30. PMID: 32002719; PMCID: PMC7138775.

6: Torzilli G, Serenari M, Viganò L, Cimino M, Benini C, Massani M, Ettorre GM, Cescon M, Ferrero A, Cillo U, Aldrighetti L, Jovine E. Outcomes of enhanced one- stage ultrasound-guided hepatectomy for bilobar colorectal liver metastases compared to those of ALPPS: a multicenter case-match analysis. HPB (Oxford). 2019 Oct;21(10):1411-1418. doi: 10.1016/j.hpb.2019.04.001. Epub 2019 May 9. PMID: 31078424.

7: Cillo U, Lonati C; Bertacco A, Battistin C, Borsetto L, Dondossola D. Implementation of an advanced perfusion system for rat liver normothermic machine perfusion based on a mesenchymal stem cell bioreactor, Journal of Hepatology . IN PRESS

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

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



4. RAPID technique

According to Line et al. the acronimus for RAPID is: Resection And Partial Liver Segment 2/3 Transplantation With Delayed Total Hepatectomy.  RAPID is the results of various surgical technique and physiopathological knowledge: the concept includes conceptual elements deriving on one side from the classic Auxiliary partial orthotopic liver transplantation (APOLT) and on the other from the two staged hepatectomy. Our group performed the first case of liver transplantation with RAPID technique in Italy in December 2018. It was the sixth RAPID procedure ever, the second case worldwide using a living donor and the first case with a minimally invasive approach for the second-stage hepatectomy. To date four cases were performed in our center.

The General Surgery 2, Hepato-bilio-pancreatic and Liver Transplantation Unit of Padova University Hospital is the principal investigator and coordinator of the Italian multicentric protocol 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).

Publications:

1: 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

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