Liver Transplantation and Hepatobiliary Surgery: Interplay of Technical and Theoretical Aspects [1st ed. 2020] 978-3-030-19761-2, 978-3-030-19762-9

Table of contents :
Front Matter ....Pages i-xiv
Cross Training and Didactic Interplay in Liver Transplantation and Hepatobiliary Surgery (Quirino Lai, Massimo Rossi)....Pages 1-8
Preoperative Assessment of Comorbidities in Liver Transplantation and Hepatobiliary Surgery (Duilio Pagano, Salvatore Gruttadauria)....Pages 9-20
Liver Resection and Total Vascular Exclusion (Andrea Lauterio, Riccardo De Carlis, Stefano Di Sandro, Luciano De Carlis)....Pages 21-27
Cooling Techniques and Ex Situ Liver Surgery (Umberto Cillo, Enrico Gringeri)....Pages 29-39
Machine Perfusion in Liver Transplantation (Riccardo De Carlis, Vincenzo Buscemi, Andrea Lauterio, Stefano Di Sandro, Luciano De Carlis)....Pages 41-52
Liver Vascular Reconstructions (Umberto Cillo, Alessandra Bertacco)....Pages 53-60
Biliary Reconstruction Techniques: From Biliary Tumors to Transplantation (Leonardo Centonze, Stefano Di Sandro, Iacopo Mangoni, Luciano De Carlis)....Pages 61-73
The Interplay Between Living Donor Liver Transplantation and Liver Surgery (Andrea Lauterio, Riccardo De Carlis, Stefano Di Sandro, Luciano De Carlis)....Pages 75-84
Pediatric Living Donor Liver Transplantation (Roberta Angelico, Chiara Grimaldi, Maria Cristina Saffioti, Alessandro Coppola, Marco Spada)....Pages 85-95
Left Split Liver (Umberto Cillo, Riccardo Boetto)....Pages 97-106
Extended Right Split Liver Graft (Giuliano Bottino, Enzo Andorno)....Pages 107-113
Full-Left Full-Right Split Liver Transplantation (Stefania Camagni, Michele Colledan)....Pages 115-122
Small-for-Size Syndrome (Umberto Cillo, Francesco Enrico D’Amico)....Pages 123-137
Regeneration Techniques: TSH and ALPPS (Matteo Serenari, Elio Jovine)....Pages 139-143
Combined Cardiothoracic and Abdominal Approach (Fabio Ferla, Vincenzo Buscemi, Riccardo De Carlis, Luciano De Carlis)....Pages 145-155
Portal Vein Thrombosis in Liver Transplantation and in Non-transplant Treatment (Umberto Cillo, Domenico Bassi)....Pages 157-166
APOLT and RAPID Techniques (Umberto Cillo)....Pages 167-174
Robotic Surgery in Liver Transplantation and Resection (Fabrizio Di Benedetto, Giuseppe Tarantino, Gian Piero Guerrini, Roberto Ballarin, Paolo Magistri)....Pages 175-182
Other “Bridge” Therapies for Liver Transplantation: RFA, TACE, and TARE (Giuseppe Maria Ettorre, Andrea Laurenzi)....Pages 183-191
Interplay Between General Surgery and Liver Transplantation (Alfonso W. Avolio, Marco M. Pascale, Salvatore Agnes)....Pages 193-201
Liver Transplantation as a Challenge for the Anesthesiologist: Preoperative Cardiac Assessment to Orient the Perioperative Period (Andrea De Gasperi, Gianni Biancofiore, Ernestina Mazza, Pietro Molinari)....Pages 203-219
Liver Resection and Transplantation for Metastases from Gastroenteropancreatic Neuroendocrine Tumors (Michele Droz dit Busset, Matteo Virdis, Christian Cotsoglou, Jorgelina Coppa, Roberta Rossi, Vincenzo Mazzaferro)....Pages 221-233

Citation preview

Updates in Surgery

Umberto Cillo Luciano De Carlis Editors

Liver Transplantation and Hepatobiliary Surgery Interplay of Technical and Theoretical Aspects

Updates in Surgery

The aim of this series is to provide informative updates on hot topics in the areas of breast, endocrine, and abdominal surgery, surgical oncology, and coloproctology, and on new surgical techniques such as robotic surgery, laparoscopy, and minimally invasive surgery. Readers will find detailed guidance on patient selection, performance of surgical procedures, and avoidance of complications. In addition, a range of other important aspects are covered, from the role of new imaging tools to the use of combined treatments and postoperative care. The topics addressed by volumes in the series Updates in Surgery have been selected for their broad significance in collaboration with the Italian Society of Surgery. Each volume will assist surgical residents and fellows and practicing surgeons in reaching appropriate treatment decisions and achieving optimal outcomes. The series will also be highly relevant for surgical researchers.

More information about this series at http://www.springer.com/series/8147

Umberto Cillo  •  Luciano De Carlis Editors

Liver Transplantation and Hepatobiliary Surgery Interplay of Technical and Theoretical Aspects Foreword by Paolo De Paolis

Editors Umberto Cillo Department of Surgery, Oncology and Gastroenterology University of Padua Hepatobiliary Surgery and Liver Transplant Unit Padua University Hospital Padua Italy

Luciano De Carlis Department of General Surgery and Transplantation Niguarda Hospital School of Medicine and Surgery University of Milano-Bicocca Milan Italy

The publication and the distribution of this volume have been supported by the Italian Society of Surgery ISSN 2280-9848     ISSN 2281-0854 (electronic) Updates in Surgery ISBN 978-3-030-19761-2    ISBN 978-3-030-19762-9 (eBook) https://doi.org/10.1007/978-3-030-19762-9 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Revision and editing: R. M. Martorelli, Scienzaperta (Novate Milanese, Italy) This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

It’s really a pleasure for me to introduce this important work by Umberto Cillo, Luciano De Carlis, and coworkers, focusing on the interplay of technical and theoretical aspects of liver transplantation and hepatobiliary surgery. Umberto and Luciano, leaders of the Italian surgical school and community, engaged distinguished experts in the field; the significant experience and scientific excellence of the contributors have produced a high-quality monograph. This volume highlights all the important aspects of liver transplantation and hepatobiliary surgery, providing updates on hot topics in this area and regarding new techniques, not only related to surgery but also to liver and graft preservation from ischemic injury, and parenchymal regeneration. Many chapters describe the split liver technique, in its various forms, but always highlighting the deep interplay between transplant surgery and hepatobiliary surgery. Particular attention is paid to young surgeons trained in a setting of liver and split liver transplantation; they’ll certainly acquire relevant expertise to proceed in their learning path toward more complex liver resection procedures. The high scientific level and the updating of the techniques make this volume valuable for the experienced surgeon and helpful for the less experienced surgeon, in order to understand the evolution of surgery in this field. On behalf of the Italian Society of Surgery, I’d like to thank all the eminent authors who collaborated in producing this useful monograph. Turin, Italy Paolo De Paolis President September 2019 Italian Society of Surgery

v

Preface

The pages of this book are dedicated to all those young surgeons or experienced specialists who believe that surgery is a complex patchwork of different mental engrams originating from our multiform previous experiences, from our wide multidisciplinary knowledge, from the small details “captured” in the observations of others, from the psychologic attitude to approach difficulties, attitude that we derive from our personal character, strength, background, and history. The Niguarda Hepatobiliary and Transplant Unit and the Padua Hepatobiliary and Liver Transplant Center have developed from a similar surgical matrix and history. In Padua a great tradition of general surgery descending from Ceccarelli and Cevese prompted Davide D’Amico to decide to embark on the liver transplantation enterprise. Belli in Milan put his extraordinary general surgery knowledge in the hands of young surgeons who, after attending the Galmarini and Fassati liver transplant experience, built the current Niguarda program. Vittorio Staudacher represented a relevant liaison between our two realities. After graduating at the University of Padua in 1938, he developed there his first studies on lung and liver transplantation before following Guido Oselladore to Milan in 1950. He has been recently acknowledged in the American Journal of Transplantation (2012) as the first surgeon to report on an experimental orthotopic liver transplant in Western history in 1952. In both our experiences at Niguarda and in Padua, transplant techniques remained deeply anchored to the concepts of general surgery, fully contaminated by the procedures of vascular and oncologic surgery, of massive organ debulking and abdominal reconstructive surgery typical of the 1970s and 1980s. In those years, hepatobiliary resective surgery, starting from few embryonic procedures, became increasingly practiced in our settings. Our frequent travels abroad (in the pre videoexchange era) allowed us to be deeply contaminated by the refined French, Japanese, and Korean liver transection techniques, which were (already at that time) totally devoted to the concepts of strict anatomical research of surgical planes and to the biodynamic study of the hepatic parenchyma in normal and diseased conditions. The Niguarda and Padua Centers were among the very first to be involved in the extraordinary experience represented by the Italian split liver program in the context of the North Italy Transplant program (NITp), where ourselves and all our young surgeons had the extraordinary chance to be exposed to a complex resective surgery in the absence of preoperative anatomical planning. vii

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Preface

Both centers were also the first in Italy to perform living donor-related liver transplantations, in a pediatric case in Padua in 1996 and in an adult case at Niguarda immediately after. The advent of minimally invasive surgery from the 1990s onward was again among the areas of interest our two centers embraced early on, first in general surgery operations and then in the more complex videolaparoscopic and robotic liver resections. As a result, since the early 2000s surgical activities both in Niguarda and in Padua have been widely “blended,” including liver transplant as well as high volumes of open and minimally invasive hepatobiliary intervention mostly, but not exclusively, oriented to the oncologic area. All these polyhedral surgical experiences have been crucial in developing an extremely flexible technical attitude enabling us to proceed in transplantation and hepatobiliary surgery with a myriad of overlapping concepts and practices. The extensive overlap between these two (only initially distant) surgical worlds is the topic of the following pages. Close to 70  years after the first described hepatic lobectomy by Lortat-Jacob in 1952, the continuous and rapid evolution of the surgical technique has improved the hemostatic control of the resected liver surface, and innovative methods of parenchymal dissection have allowed an enormous expansion of the number of indications and candidates. In the beginning, liver resection and liver transplantation were performed by different surgical teams with poor interplay with each other. However, the evolution of both liver resection and transplantation toward a more complex operation called for increasingly intense interaction between these surgical techniques. Therefore, split liver and living donor liver transplantation became popular in the transplant community that utilized the Couinaud segmental anatomy in a very sophisticated way. Portal and arterial resection and reconstruction became indispensable techniques to treat Klatskin tumor infiltrating the hepatic hilum. Ex-situ techniques for resection of tumor at the suprahepatic confluence with or without venous reconstruction and total vascular exclusion of the liver with the use of a venovenous bypass arose from the experimental area before transferring to clinical practice. The development of minimally invasive liver surgery changed the treatment options for HCC patients on a waiting list for liver transplantation, allowing for a lower degree of decompensation in cirrhotic patients after surgery and extending the surgical indications. The aim of this book, under the auspices of the Italian Society of Surgery, is to offer a complete survey of the interplay between liver transplantation and hepatobiliary surgery through the contribution of many Italian and international experts. This work also owes a tribute to all the pioneers and masters of hepatobiliary and liver transplantation surgery with particular reference to Henri Bismuth, Rudolf Pichlmayr, Roy Calne Koichi Tanaka, and, above all, Thomas Earl Starzl. They launched a clear message by indicating pathophysiology, deep anatomic awareness, and interdisciplinary cross-fertilization as crucial and indispensable tools for any sophisticated technical skill. We aim to proceed along their path well aware that, day after day, this field of surgery astonishes our eyes, challenges our minds, and gratifies our hearts. Padua, Italy Milan, Italy September 2019

Umberto Cillo Luciano De Carlis

Contents

1 Cross Training and Didactic Interplay in Liver Transplantation and Hepatobiliary Surgery ������������������������������������������   1 Quirino Lai and Massimo Rossi 2 Preoperative Assessment of Comorbidities in Liver Transplantation and Hepatobiliary Surgery ������������������������������������������   9 Duilio Pagano and Salvatore Gruttadauria 3 Liver Resection and Total Vascular Exclusion����������������������������������������  21 Andrea Lauterio, Riccardo De Carlis, Stefano Di Sandro, and Luciano De Carlis 4 Cooling Techniques and Ex Situ Liver Surgery��������������������������������������  29 Umberto Cillo and Enrico Gringeri 5 Machine Perfusion in Liver Transplantation������������������������������������������  41 Riccardo De Carlis, Vincenzo Buscemi, Andrea Lauterio, Stefano Di Sandro, and Luciano De Carlis 6 Liver Vascular Reconstructions����������������������������������������������������������������  53 Umberto Cillo and Alessandra Bertacco 7 Biliary Reconstruction Techniques: From Biliary Tumors to Transplantation������������������������������������������������������������������������������������������  61 Leonardo Centonze, Stefano Di Sandro, Iacopo Mangoni, and Luciano De Carlis 8 The Interplay Between Living Donor Liver Transplantation and Liver Surgery����������������������������������������������������������  75 Andrea Lauterio, Riccardo De Carlis, Stefano Di Sandro, and Luciano De Carlis 9 Pediatric Living Donor Liver Transplantation ��������������������������������������  85 Roberta Angelico, Chiara Grimaldi, Maria Cristina Saffioti, Alessandro Coppola, and Marco Spada 10 Left Split Liver ������������������������������������������������������������������������������������������  97 Umberto Cillo and Riccardo Boetto ix

x

Contents

11 Extended Right Split Liver Graft ������������������������������������������������������������ 107 Giuliano Bottino and Enzo Andorno 12 Full-Left Full-Right Split Liver Transplantation������������������������������������ 115 Stefania Camagni and Michele Colledan 13 Small-for-Size Syndrome�������������������������������������������������������������������������� 123 Umberto Cillo and Francesco Enrico D’Amico 14 Regeneration Techniques: TSH and ALPPS ������������������������������������������ 139 Matteo Serenari and Elio Jovine 15 Combined Cardiothoracic and Abdominal Approach���������������������������� 145 Fabio Ferla, Vincenzo Buscemi, Riccardo De Carlis, and Luciano De Carlis 16 Portal Vein Thrombosis in Liver Transplantation and in Non-transplant Treatment�������������������������������������������������������������������� 157 Umberto Cillo and Domenico Bassi 17 APOLT and RAPID Techniques �������������������������������������������������������������� 167 Umberto Cillo 18 Robotic Surgery in Liver Transplantation and Resection���������������������� 175 Fabrizio Di Benedetto, Giuseppe Tarantino, Gian Piero Guerrini, Roberto Ballarin, and Paolo Magistri 19 Other “Bridge” Therapies for Liver Transplantation: RFA, TACE, and TARE ���������������������������������������������������������������������������� 183 Giuseppe Maria Ettorre and Andrea Laurenzi 20 Interplay Between General Surgery and Liver Transplantation������������������������������������������������������������������������������������������ 193 Alfonso W. Avolio, Marco M. Pascale, and Salvatore Agnes 21 Liver Transplantation as a Challenge for the Anesthesiologist: Preoperative Cardiac Assessment to Orient the Perioperative Period���������������������������������������������������������������������������������� 203 Andrea De Gasperi, Gianni Biancofiore, Ernestina Mazza, and Pietro Molinari 22 Liver Resection and Transplantation for Metastases from Gastroenteropancreatic Neuroendocrine Tumors���������������������������������� 221 Michele Droz dit Busset, Matteo Virdis, Christian Cotsoglou, Jorgelina Coppa, Roberta Rossi, and Vincenzo Mazzaferro

Contributors

Salvatore Agnes  Catholic University of the Sacred Heart, Rome, Italy Division of General Surgery and Liver Transplantation, Department of Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Enzo  Andorno  Hepatobiliary Pancreatic Surgery and Transplantation Unit, Policlinico San Martino Hospital, Genoa, Italy Roberta  Angelico  Division of Abdominal Transplantation and Hepatobilio­ pancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy Alfonso W. Avolio  Catholic University of the Sacred Heart, Rome, Italy Division of General Surgery and Liver Transplantation, Department of Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Roberto  Ballarin  Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Policlinico University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy Domenico  Bassi  Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy Alessandra  Bertacco  Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy Gianni Biancofiore  Unit of Anesthesia and Critical Care for General, Vascular and Transplantation Surgery, Pisa University Hospital, Pisa, Italy Riccardo  Boetto  Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy Giuliano  Bottino  Hepatobiliary Pancreatic Surgery and Transplantation Unit, Policlinico San Martino Hospital, Genoa, Italy Vincenzo Buscemi  Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy xi

xii

Contributors

Stefania Camagni  Department of Organ Failure and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy Leonardo  Centonze  Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy Umberto Cillo  Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy Michele Colledan  Department of Organ Failure and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy Jorgelina  Coppa  Hepatopancreatobiliary Surgery, Gastroenterology, and Liver Transplantation, Istituto Nazionale dei Tumori, Milan, Italy Alessandro  Coppola  Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy Christian  Cotsoglou  Hepatopancreatobiliary Surgery, Gastroenterology, and Liver Transplantation, Istituto Nazionale dei Tumori, Milan, Italy Francesco  Enrico  D’Amico  Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy Luciano De Carlis  Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy Riccardo De Carlis  Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy Department of Surgical Sciences, University of Pavia, Pavia, Italy Andrea  De Gasperi  Division of Anesthesia and Intensive Care 2, Niguarda Hospital, Milan, Italy Fabrizio  Di Benedetto  Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Policlinico University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy Stefano Di Sandro  Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy Michele Droz dit Busset  Hepatopancreatobiliary Surgery, Gastroenterology, and Liver Transplantation, Istituto Nazionale dei Tumori, Milan, Italy Giuseppe  Maria  Ettorre  Transplantation Department, S.  Camillo-Forlanini Hospital, Rome, Italy National Institute of Infectious Disease L. Spallanzani, Rome, Italy

Contributors

xiii

Fabio  Ferla  Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy Chiara Grimaldi  Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy Enrico  Gringeri  Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy Salvatore Gruttadauria  Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, ISMETT - Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione IRCCS / UPMC Italy, Palermo, Italy Department of Surgery, University of Catania, Catania, Italy Gian Piero Guerrini  Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Policlinico University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy Elio Jovine  Department of General Surgery, Maggiore Hospital, AUSL Bologna, Bologna, Italy Quirino Lai  Liver Transplantation and Hepatobiliary Surgery Unit, Department of General Surgery and Surgical Specialties, Umberto I University Hospital, Sapienza University of Rome, Rome, Italy Andrea  Laurenzi  Transplantation Department, S.  Camillo-Forlanini Hospital, Rome, Italy National Institute of Infectious Disease L. Spallanzani, Rome, Italy Andrea Lauterio  Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy Paolo Magistri  Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Policlinico University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy Iacopo  Mangoni  Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy Ernestina Mazza  Division of Anesthesia and Intensive Care 2, Niguarda Hospital, Milan, Italy Vincenzo  Mazzaferro  Hepatopancreatobiliary Surgery, Gastroenterology, and Liver Transplantation, Istituto Nazionale dei Tumori, Milan, Italy University of Milan, Milan, Italy Pietro Molinari  Division of Anesthesia and Intensive Care 2, Niguarda Hospital, Milan, Italy Duilio Pagano  Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, ISMETT - Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione IRCCS / UPMC Italy, Palermo, Italy

xiv

Contributors

Marco  M.  Pascale  Fondazione Policlinico Universitario A.  Gemelli IRCCS, Rome, Italy Massimo Rossi  Liver Transplantation and Hepatobiliary Surgery Unit, Department of General Surgery and Surgical Specialties, Umberto I University Hospital, Sapienza University of Rome, Rome, Italy Roberta  Rossi  Hepatopancreatobiliary Surgery, Gastroenterology, and Liver Transplantation, Istituto Nazionale dei Tumori, Milan, Italy Maria  Cristina  Saffioti  Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy Matteo  Serenari  Department of Surgical and Medical Sciences, University of Bologna, Sant’Orsola-Malpighi Hospital, Bologna, Italy Marco Spada  Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy Giuseppe Tarantino  Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Policlinico University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy Matteo  Virdis  Hepatopancreatobiliary Surgery, Gastroenterology, and Liver Transplantation, Istituto Nazionale dei Tumori, Milan, Italy

1

Cross Training and Didactic Interplay in Liver Transplantation and Hepatobiliary Surgery Quirino Lai and Massimo Rossi

1.1

Introduction

We need a system, and we shall surely have it, which will produce not only surgeons, but surgeons of the highest type, men who will stimulate the first youths of our country to study surgery and to devote their energies and their lives to raising the standard of surgical science—William Stewart Halsted (1904)

William Halsted’s paradigm for surgical residency training is recognized as the most appropriate educational system to become a competent general surgeon. The length of training largely varies from a minimum of 4 years in countries such as West Africa and Brazil to 5 years in Italy, and at least 8 years in the UK and Hong Kong [1]. Hepatopancreatobiliary (HPB) and liver transplantation (LT) surgery are the cornerstones of general surgery training, because of their high prevalence and complexity. However, the recent evolution observed in these fields has transformed modern HPB surgery into a technically complex and technology-dependent procedure. Moreover, a rising number of HPB cases can be routinely performed using minimally invasive surgery (MIS), which has forced to move a number of cases out of residents’ hands, placing them in the domain of specialist fellows or staff surgeons. This is particularly true in consideration of the increasing number of “disappearing” HPB procedures, such as open cholecystectomy, and explains why the new generations of resident graduates are concerned about their being unprepared for independence. Unfortunately, such a condition gives rise to a perverse mechanism in which many highly specialized surgeons finish their training and find a position either going back to general surgery or moving on to other specialization branches.

Q. Lai (*) · M. Rossi Liver Transplantation and Hepatobiliary Surgery Unit, Department of General Surgery and Surgical Specialties, Umberto I University Hospital, Sapienza University of Rome, Rome, Italy e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 U. Cillo, L. De Carlis (eds.), Liver Transplantation and Hepatobiliary Surgery, Updates in Surgery, https://doi.org/10.1007/978-3-030-19762-9_1

1

2

Q. Lai and M. Rossi

The present chapter reports on the importance and criticisms of cross training HPB/LT surgery, with special reference to the possible implementation of the models used worldwide. It will discuss detailed aspects concerning residency and fellowship in HPB and LT centers, as well as the special role of organ procurement as a unique opportunity to teach specific open surgical skills. Further topics include the growing role of MIS with the conflicting need to perform difficult procedures while allowing young surgeons to acquire technical skills, and, lastly, the peculiar role of women in a male-dominated branch of surgery.

1.2

Surgical Training in Hepatopancreatobiliary Surgery

A survey published in 2014 showed that HPB surgery presents many training routes and practice patterns in the United States. The investigated surgeons were residents/ fellows in surgical oncology units in 28% of cases, followed by LT (24.8%), HPB (24.2%), HPB/Complex gastrointestinal (16%) and HPB/MIS (4%) [2]. These data are confirmed by another study from the US, in which the general surgical residency programs presenting higher rates of HPB procedures typically have dedicated LT or HPB units [3]. Therefore, this condition should represent a shortcoming for residents trained in hospitals without LT or HPB surgeons, limiting the possibility of performing HPB surgery in their future practice, especially if located in remote areas. Starting from the assumption that it is essential that a general surgeon practicing in a remote area should be capable of performing HPB surgery, since there may not be an HPB surgeon in the region, a question arises on the adequacy of the residency lengths needed to acquire the necessary technical skills for performing HPB surgery. A recent study from the US investigated the number of complex HPB (i.e., pancreatectomies, major hepatectomies) performed by general surgery end-of-term residents during a 16-year-long period. In general, although the numbers increased over the years, the reported numbers were low, typically less than five per end-of-­ term resident [4]. Another study confirmed this result, showing that residents approaching an HPB fellowship felt poorly comfortable in performing advanced HPB or laparoscopy, citing a combination of inadequate case volume and lack of autonomy during residency as the main reasons. In many cases, extra-rotations in transplant, vascular surgery or MIS were believed to be most helpful in preparing general surgery residents for HPB fellowships [5]. The difficulties of the residents starting an HPB fellowship were also confirmed by the HPB program directors. According to the results of a survey from the US, only 50% of program directors felt residents were competent [6]. The best way to solve the limited opportunities a resident has for acquiring enough competence in HPB surgery is planning a fellowship trainee period after the residency. A study investigating the number of HPB cases performed during a 2-year-long fellowship in the US reported a median number of 26 biliary cases, 19 major liver cases (hemi-­livers), 28 other liver cases, 40 pancreaticoduodenectomies, 18 distal pancreatectomies, and 9 other pancreas cases. The programs providing LT experience offered 10 cases for each fellow [7].

1  Cross Training and Didactic Interplay in Liver Transplantation and Hepatobiliary…

3

However, some doubts have arisen about the possibility that an HPB fellowship incorporated into an established surgical residency program might diminish the surgical residents’ exposure to complex HPB procedures. As a consequence, only high-volume centers should incorporate an HPB fellowship program into clinical training programs without detracting from the residents’ HPB experience [8]. However, although a fellowship program allows young surgeons to perform high-­ complexity procedures in high-volume centers, prolonging their training period by at least 2 years, also the HPB surgery fellowship training has some limitations. A large survey reported MILS and ultrasound as the most commonly identified areas of training deficiencies [9].

1.3

Surgical Training in Liver Transplantation

The same problems observed for HPB training exist in transplant programs. The main limitation is represented by the idea that complex LT procedures performed by a resident/fellow can cause higher and unacceptable complication rates. A study from Germany investigated 155 consecutive LT, correlating the results with the degree of surgical experience of a surgeon operating for the first time. No significant differences were reported among the cases transplanted by an experienced surgeon versus a fellow in terms of complication rate, overall patient survival, blood loss, intraoperative transfusion requirements and operating time [10]. The so-called “July effect”, namely the increased number of complications in US academic institutions following the influx of new resident physicians, has been also investigated in LT centers. Of a total of 108,666 LT, those performed in the month of April showed significantly improved outcomes while in the month of December significantly decreased outcomes were observed. Therefore, no correlation with the arrival of new trainees was observed in the setting of LT [11]. Another problem in the LT setting is the progressive drop in the number of surgeons sufficiently motivated to sacrifice long years of their lives in the LT training process. This is due to the fact that LT surgical training often ends in non-­competitive salaries and dead-end academic careers. As an example, US transplant surgeons reported working approximately 70  h per week, with a median of 195 operative cases per year [12]. This huge activity, entirely done in public healthcare hospitals and often performed afterhours, does not represent a great attraction for young surgeons. This is particularly true at a time when an overall reduction of surgeons’ work hours is typically observed. A study from Germany observed that a long-term commitment of surgeons to transplantation is rare. The median time passed in LT was typically short (median  =  3.5  years). Surgeons completing their training remained in the field for 7 years. The individual total caseloads of transplant surgeons were relatively low [13]. Unfortunately, half a century after its introduction by Prof. Starzl, LT has become a “routine” surgery for many, thereby losing “attractivity” and “prestige” within the medical community. A survey realized by the European Society of Organ Transplantation (ESOT) in relation to burnout and career planning of transplant surgeons reported the

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following as the main reasons for abandoning a LT career: better appeal of other surgical specialties within (65%) or outside the hospital (35%), personal or familial reasons (52%), financial reasons (21%), lack of career planning (21%), and too demanding job (6%). When asked how to make transplant surgery more attractive as a profession, the respondents answered: financial upgrading (100%), career planning (64%), widening of surgical spectrum leading to a better mental rest (56%), improving administrative help (54%), introducing flexible working time (36%), reduced workload (33%), adapted duty Scheme (33%), and finally team building (24%) [14].

1.4

 he Peculiar Importance of the Organ Procurement T Procedure in General Surgeons’ Training

The growing impact of MIS is progressively limiting the evolution of surgical resident experience regarding open surgical procedures. MIS has replaced many open procedures as the current standard of care. As MIS progresses, the access of surgical residents to open techniques is becoming significantly limited by the lack of exposure to common open operations. In the near future, new surgeons, well-versed in MIS, may suffer from inexperience with the basic principles of open surgery. As an example, a study reporting the number of surgical procedures performed by the residents in a US center during the period 2000–2009 confirmed a marked increase in the number of laparoscopic procedures performed and a concomitant decrease of open and trauma surgery [15]. A possible solution for the lack of open surgical experience can be enhancing residents’ participation in organ procurement. An anonymous national survey was performed in the US with the intention of evaluating the organ-procurement experiences and attitudes of general surgical residents. Interestingly, over 85% of the residents agree that organ procurement is a good educational and operative experience, with 73% of them believing that it will benefit their future surgical career. About 68% of the residents agree that organ procurement provides better knowledge of anatomy and exposures [16]. Organ procurement allows trainee surgeons to perform several maneuvers and open procedures linked not only to general surgery but also to vascular surgery, urology, and trauma [17–19]. As an example, a significant improvement in the operative exposure and control of great vessels of the abdomen and chest was reported in senior residents after their rotation in a Transplant Center [17]. Another study from Canada investigated the utility of performing organ procurement by urology residents, allowing them to obtain some expertise in open nephrectomy [18]. Organ procurement offers an almost unique lesson in overall thoraco-abdominal anatomy and operative technique, providing the opportunity for a fundamental understanding of complex vascular, hepatopancreatobiliary, renal, and thoracic structures in a semi-elective scenario. All of these conditions give the trainees a tremendous advantage before trying to achieve control over a massively bleeding

1  Cross Training and Didactic Interplay in Liver Transplantation and Hepatobiliary…

5

patient, thus representing a great advantage in trauma surgery as well [19]. As a consequence, working in a Transplant Center should be mandatory in the professional education of residents and fellows, which means that every residency program and several fellowships should incorporate a rotation in a Transplant Unit.

1.5

Minimally Invasive Liver Surgery and Training

After the First International Consensus Conference on Laparoscopic Liver Surgery in Louisville in 2008, the number of laparoscopic liver resections performed worldwide has exponentially increased, including not only minor resections but also major resections, robotic hepatectomies, and living donor hepatectomies. The growing impact of MIS, mainly in liver surgery, has been obviously connected with important implications concerning the trainee period. The Second International Consensus of Morioka 2015 investigated this aspect very well and made the following statement: “Major laparoscopic liver surgery requires a high level of technical skill and has a steep learning curve. How skills should be acquired by trainees and surgeons already in practice should be the subject of an urgent focused effort by the leaders in this field. The future of laparoscopic liver surgery is dependent on this issue. (STRONG recommendation)” [20]. This problem is clearly elucidated in an International survey in which the perceived adequacy of HPB/MIS training was investigated among 250 surgeons. Almost surprisingly, 50% and 80% of non-HPB surgeons do not consider themselves adequately trained to perform a laparoscopic common bile duct exploration and a laparoscopic staging of upper gastrointestinal malignancy, respectively [21]. The high complexity of laparoscopic liver surgery requires longer learning curves, and a higher rate of capacities and surgical skills. As a consequence, specific training models and teaching courses have been implemented worldwide. As an example, a simulated-bleeding continuously perfused training model has been created with the intention of obtaining a suture training model for laparoscopic liver resection [22]. Another example is represented by the use of a dedicated cadaver laparoscopic training facility, where individuals can be safely trained and also certified within this growing technique [23]. The need to start with laparoscopic training from the beginning of a surgeon’s career is another important aspect. A study investigating if a single-incision laparoscopic cholecystectomy could be efficaciously and safely incorporated into resident education reported excellent results. All the single-incision laparoscopic cholecystectomy conversions to standard laparoscopic cholecystectomy were reported at the beginning of the learning curve, with a progressive decline in the operative times [24]. Lastly, internationally recognized courses and web databases of laparoscopic interventions represent a further tool to be used in the learning process. The advanced IRCAD/EITS courses organized in Strasbourg, France, and the “online university” WebSurg (available at: https://www.websurg.com) represent the two most famous examples.

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Women in Hepatopancreatobiliary and Transplant Surgery

Particular consideration should be given to the training of women in surgery. An increasing portion of students entering the medical profession are women. Before 1970, women represented 6% or less of the medical student population. In drastic contrast, nearly half of first-time applicants to medical schools in 2011 were women [25]. However, residents in general surgery continues to experience attrition, mainly if they are women. A survey from the US showed an incredibly high percentage of residents (58.0%) seriously considering the idea of leaving training. The most frequent reasons for this were sleep deprivation (50.0%), an undesirable future lifestyle (47.0%), and excessive work hours (41.4%). After correcting for several confounders, only women were significantly associated with serious thoughts of leaving residency, with a 20% increased risk of leaving the residency training [26]. One of the main reasons for withdrawing from residency is pregnancy. A Canadian survey investigated residents and program directors’ attitudes toward pregnancy during residency. The lack of adequate policies for maternity/parenting, major obstacles to breast-feeding, and the increased workload for fellow resident colleagues were reported [27]. Interestingly enough, men and women have a completely different perception of the effects of marriage and childbirth during surgery residency. A prospective, longitudinal study of general surgery residents performed in the US during the period 2008–2010 reported that women at the end of residency were less likely to be married (47.3 vs. 67.6%) or have children (18.0% vs. 45.8%) (p 30% or >40%), prolonged cold ischemia (>12 h), a very high donor age (>80 years), or additional warm ischemia as in the case of donation after circulatory death (DCD) [5, 6]. These grafts are more vulnerable to cold ischemia and therefore need optimization before implantation, especially when transplanted into high-risk recipients—retransplantation, high MELD (model for end-stage liver disease) score. MP offers three main advantages over SCS: a high-quality and prolonged preservation, the ability to optimize graft function (reconditioning), and the possibility of testing the graft’s viability prior to implantation [7].

5.4

Timing and Temperature

There are different types of MP, which differ according to timing and temperature. SCS and MP are not mutually exclusive and can be used in combination. If used for the entire preservation time, MP requires a transportable device or a donor local to the transplant center. In this modality, a short period of SCS is still required in the last phase of organ procurement, throughout back-table preparation, and during implantation to avoid warm ischemia when anastomoses are performed. Therefore, MP is most frequently used in the recipient hospital after the organ is maintained in SCS during initial transportation (Fig.  5.1). Three temperature ranges have been reported for MP in animal and clinical studies [7]: • 0–12 °C for hypothermic MP (HMP) • 13–34 °C (usually 20–22 °C) for subnormothermic MP (SNMP) • 35–38 °C for normothermic MP (NMP). The main differences between SCS and MP at different temperatures are summarized in Table 5.1.

5  Machine Perfusion in Liver Transplantation Procurement

43 Transport

Implantation

In situ MP

SCS

SCS

MP

MP

MP

SCS

Fig. 5.1  Timing of machine perfusion (MP). In situ MP refers to graft perfusion within the donor before organ procurement. Ex situ MP is most frequently used in the recipient hospital after the organ is maintained in static cold storage (SCS) during initial transportation. If used for the entire preservation time, MP requires a transportable device or a donor local to the transplant center. MP before SCS has also been reported

Table 5.1  Characteristics of different preservation methods SCS 4 °C No

HMP 0–12 °C Single/dual

SNMP 20–22 °C Dual

NMP 35–38 °C Dual

Perfusion solution/oxygen carrier Yes

Metabolism Energy recovery

Low No

Decreased Yes

Yes Yes

Bile production Viability testing

No No

Decreased Yes

Yes Yes

Reperfusion injury

Yes

Perfusion solution No/(yes for HOPE) Low No/(yes for HOPE) No No (ongoing research) Low

Oxygen carrier

Oxygen

Perfusion solution No

Decreased

Yes

Characteristic Temperature Vessel cannulation Perfusate

Yes

HMP hypothermic machine perfusion, HOPE hypothermic oxygenated perfusion, NMP normothermic machine perfusion, SCS static cold storage, SNMP subnormothermic machine perfusion

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5.5

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Hypothermic Machine Perfusion

After Brettschneider’s early attempts, there were no clinical applications of HMP until Guarrera et  al. showed in 2010 that HMP of standard livers was associated with lesser ischemic injury than SCS [8]. Subsequently, Dutkowski et al. explored the possibility of delivering oxygen during HMP at a higher pressure than atmospheric oxygen partial pressure (PO2), an approach called hypothermic oxygenated perfusion (HOPE). They first used this approach in human livers from DCD [9]. An example of an HMP circuit is shown in (Fig. 5.2).

5.5.1 Physiological Mechanisms The rate of most enzymatic reactions decreases with decreasing temperature, according to the van’t Hoff equation [10]. Under hypothermic conditions, metabolism is reduced but not entirely halted, leading to the depletion of energy stores and accumulation of metabolites. The continuous flow of preservation solution through the graft, which permits sinusoidal cleaning and repair of the glycocalyx, makes HMP more advantageous than SCS [11, 12]. Additional advantages are linked to HOPE. Delivery of gaseous oxygen directly through the hepatic veins before reperfusion (oxygen persufflation) has been reported to improve early aerobic metabolism and primary graft function after liver transplantation [13, 14]. Several studies have demonstrated that only 1–2 h of HOPE promote adenine triphosphate (ATP) resynthesis and, notably improves mitochondrial activity by promoting forward instead of reverse electron flow, as observed in animals during hibernation or winter rest. Consequently, reperfusion of ischemic livers that have undergone HOPE significantly reduces the release of reactive oxygen species and inflammatory mediators, thereby reducing reperfusion injury (Fig. 5.3) [6, 11, 12]. Fig. 5.2  Example of a hypothermic machine perfusion circuit. The perfusion solution is pumped through the hepatic artery and portal vein (dual perfusion), then drains passively into a reservoir over which the liver is suspended. In single portal perfusion, only the portal vein is cannulated. Cannulation is always performed far away from the anastomotic sites

5  Machine Perfusion in Liver Transplantation

45 Electron leakage ROS

Kupffer cell

e– O2 e–

I II III

DAMPS

IV

Endothelial cell Reduces ROS release

Stellate cell

Sinusoidal cleaning glycocalyx repair

ROS

HOPE Allow ATP resynthesis

Mitochondrion

hepatocyte

Fig. 5.3  Mechanisms of hypothermic oxygenated perfusion (HOPE). HOPE promotes adenine triphosphate resynthesis and reduces the release of reactive oxygen species (ROS) and damage-­ associated molecular pattern signaling (DAMPS) proteins, which activate Kupffer cells after reperfusion. Sinusoidal cleaning and glycocalyx repair do not depend on oxygenation

5.5.2 Hypothermic Oxygenated Perfusion in Clinical Practice According to the HOPE protocol, liver grafts are perfused through the portal vein with cooled (10 °C) and oxygenated (40–60 kPa) UW gluconate solution, with a perfusion pressure of no more than 3 mmHg to limit shear stress. Schlegel et al. demonstrated that HOPE spreads to the entire biliary tree, exclusively via the portal vein, within the first 5 min of perfusion, which eliminates the need for arterial perfusion [15]. Perfusion is maintained for 1–2 h until the recipient hepatectomy is completed [9]. This approach has been reported to reduce preservation injury and ischemic cholangiopathy, thus prolonging graft survival in DCD livers [16]. Our group first reported the sequential use of NRP and HOPE in human DCD livers to overcome the legal no-touch period of 20 min for death declaration in Italy [17]. The resulting protocol has proven effective in salvaging DCD livers that would otherwise be discarded because of their prolonged warm ischemia [18, 19].

5.5.3 Limitations and Future Perspectives Although successful liver transplantation has been reported even after 72 h of HMP [3, 20], it remains unclear how long a liver graft can be safely maintained with this method. Indeed, a time-dependent increase in vascular resistance has been observed when HMP extends beyond 18  h, which has been attributed to prolonged shear

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stress on the sinusoids [11, 21]. However, we have recently demonstrated that a limited period of HOPE after SCS can be used when necessary, to safely prolong the total cold ischemia time for up to 20 h [22]. The main limitation of HMP is the current shortage of methods to assess graft function during perfusion. As a result, liver selection during HMP is difficult to perform in clinical practice. Indeed, no active bile production can be observed during hypothermia [6]. Although vascular resistance is currently used as a marker of graft function for kidneys, this parameter is insensitive for the liver [23]. Only one recent study suggested a potential role of arterial resistance in liver evaluation [24]. We await the results of various ongoing studies to clarify whether analysis of perfusate during HMP will permit reliable graft selection.

5.6

Normothermic Machine Perfusion

The rationale for NMP is to reproduce physiologic circulation outside the body using warm oxygenated blood or a surrogate solution. This would promote ATP resynthesis and enable the transplant surgeon to make an assessment of liver function prior to transplantation, with appropriate predictive tools [25]. At least three commercial devices have been used in clinical trials to date. All function on similar principles but differ in terms of portability, degree of automation, substrate type and delivery, pressure, and flow targets. NMP devices use a normothermic suspension of red blood cells in a colloid to perfuse the liver in a fully cannulated system or an open system. The perfusate is pumped out of the inferior vena cava using a centrifugal pump or allowed to drain passively, and then heated and oxygenated. This is followed by diversion of the perfusion either to the hepatic artery via a high-­pressure, low-flow system or to the portal vein via a high-flow, low-pressure system. Continuous blood gas analysis enables monitoring and control of PO2 and PCO2 levels, which facilitates the maintenance of acid-base homeostasis. Continuous infusions ensure sufficient vasodilation, protection against coagulation, and provision of an environment that enables near-physiologic, metabolic, and synthetic liver function [26].

5.6.1 A  dvantages of Normothermic Machine Perfusion and Clinical Practice NMP may help overcome complications, such as primary graft non-function or early graft dysfunction, by allowing liver function assessment prior to implantation. The benefits of NMP have been tested in several studies, which suggest that the viability of donor organs can be predicted by a combination of synthetic, hemodynamic, and metabolic parameters during the perfusion phase. This provides a functional assessment of the donor liver that is not possible with SCS or HMP [27]. These parameters include bile production, stability of hepatic artery and portal vein blood flow and/or pressure, and lactate and transaminase levels. Mergental et  al.

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47

suggested criteria that included perfusate lactate 7.3, hepatic artery flow >150 mL/min, portal vein flow >500 mL/min, and homogenous graft perfusion with soft parenchymal consistency achieved within 3 h of initiating NMP [28]. Friend et al. were the first to describe NMP and its benefits by measuring alanine aminotransferase levels and Factor V production during perfusion [29]. The first human NMP trial in 2013 confirmed the safety of this technology. In 20 patients transplanted with livers after NMP, graft survival and patient survival were both at 100% at 6 months [30]. A similarly structured trial in Canada reported one graft loss over 10 cases because of technical failure and noted a prolonged hospital stay for patients that underwent this procedure [31]. A recent randomized clinical trial of 220 liver transplantations reported that NMP was associated with a 50% lower level of graft injury than conventional SCS, as measured by hepatocellular enzyme release; this occurred despite a 54% longer mean preservation time. Early allograft dysfunction was 72% lower in the NMP group than in the SCS group, and post-reperfusion syndrome was more common with SCS. Interestingly, the number of discarded organs was over 50% lesser in the NMP group than the SCS group, which resulted in 20% more transplanted livers. A 20% increase in the number of transplantable donor livers would hugely impact the mortality or dropout rates of patients on transplantation waiting lists around the world. However, this trial failed to demonstrate a significant difference in bile duct complications, graft survival, or overall survival with NMP compared with SCS [32]. As summarized in Table 5.2, similar beneficial results of NMP have been reported in few other clinical trials published to date [30, 31, 33].

5.6.2 Limitations and Remaining Questions NMP technology does not eliminate reperfusion injury, but rather brings the process ex situ. Few studies have compared NMP with HMP with respect to reperfusion injury. In a study of rodent DCD livers, Schlegel et  al. demonstrated that NMP reduced ischemic injury compared with SCS but was not as effective as HOPE in decreasing hepatocyte injury and inflammation because the full cascade of reperfusion injury was initiated with NMP [34]. In theory, NMP could indefinitely prolong total preservation time. In a study conducted by Ravikumar et al., one liver was perfused for 18.5 h before successful transplantation [30]. Similarly, Bral et al. reported maintaining a DCD liver with NMP for 22.5 h before successful transplantation [31]. Nevertheless, NMP requires high expertise for correct use and strict surveillance throughout the entire perfusion period. Unrecognized vascular occlusion or system failure during NMP could produce irreversible graft damage because of warm ischemia, whereas HMP does not face such challenges. Bral et al. reported one case of discarded liver after NMP caused by an unrecognized twist in the donor portal vein, which was hidden above the tissues of the hilar plate [31]. Watson et al. described

NMP:SCS 20:40 10:30 137:133

TIT nsd NMP NMP

Peak AST NMP nsd NMP

EAD nsd nsd NMP

Discard rate na na NPM PNF nsd nsd nsd

30-Day mortality nsd nsd nsd

6-Month GS nsd nsd nsd

6-Month biliary complications nsd nsd nsd

1-Year OS nsd nsd nsd

AST aspartate aminotransferase, EAD early graft dysfunction, GS graft survival, na not available, NMP normothermic machine perfusion, nsd not significantly different, OS overall survival, PNF primary non-function, SCS static cold storage, TIT total ischemic time

Authors Ravikumar et al. [30] Bral et al. [31] Nasralla et al. [32]

Table 5.2  Outcomes following NMP or SCS in clinical trials

48 R. De Carlis et al.

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two types of technical problems during NMP: occlusion of the biliary catheter, which prevented the assessment of bile production (but without long-term biliary sequelae), and occlusion of the hepatic vein catheter shortly after initiating perfusion [35]. Current widespread use of NMP for liver transplantation is limited by high cost and shortage of clinical trial evidence. Further research is necessary to evaluate the full potential of NMP and its advantages.

5.7

Subnormothermic Machine Perfusion

SNMP combines the benefits of lower metabolic demands at a subphysiological temperature with the benefits of maintaining sufficient metabolism for viability testing and improved graft function [36, 37]. Therefore, it can serve an intermediate role between HMP and NMP. Gradual rewarming during SNMP possibly reduces reperfusion injury by employing stepwise normalization of temperature and metabolic demands [38, 39]. Recently, Tolboom et al. reported that oxygen carriers were unnecessary with SNMP preservation for 5 h [40]. Berendsen et al. also demonstrated successful preservation of rat DCD livers using temperature-uncontrolled SNMP without oxygen carriers for 3 h, and subsequent transplantation, with good survival outcomes [36]. Data from animal experiments and human discarded livers [41] using SNMP appear promising for introducing this technology into clinical practice. Future studies should assess the potential advantages of SNMP over the gold standard SCS, and over HMP and NMP.

5.8

I nterplay Between Machine Perfusion and Hepatobiliary Surgery

5.8.1 Liver Splitting During Machine Perfusion Split-liver transplantation involves the division of one liver graft into two hemigrafts. It is used to overcome the shortage of donor organs, especially pediatric donors. There are two main techniques of liver partition: the ex situ method and the in situ method. The in situ technique involves parenchymal transection in the donor prior to aortic cross-clamping. It reduces cold ischemia time and simplifies the identification of biliary and vascular structures, but requires a longer operative time [42]. Conversely, the ex situ technique has been associated with a higher incidence of postoperative hemorrhage [43]. The use of MP in liver splitting has the potential to combine the advantages of both liver partition techniques. Throughout splitting, the cut surface can be inspected and vessels ligated to ensure hemostasis. NMP permits continuous viability assessment. This may contribute to recipient selection, aid with informed decision-­making, and facilitate the logistics of transplanting two grafts by preventing a long cold ischemia time. Barney et al. described a case of ex situ liver splitting using NMP in a liver

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that was unsuitable for transplantation [44]. A similar case was described by Brockmann et al. using a discarded DCD liver, which emphasized that splitting can be performed in the context of a fully anticoagulated perfusion system without loss of perfusion, thereby minimizing ischemic injury [26].

5.8.2 Machine Perfusion in Liver Resections A large liver tumor, with or without vascular infiltration, is a challenge even for an expert liver surgeon. The need for extended liver resection and vascular reconstruction often requires prolonged vascular clamping and multiple blood transfusions because of major blood loss. Intermittent hilar clamping or total vascular exclusion (TVE) are frequently used by most liver surgeons, but are generally limited to short periods to avoid ischemic liver injury [45–47]. When longer durations are required, other techniques, such as in situ hypothermic perfusion, venovenous bypass, portacaval temporary shunt, or an ex situ technique, are required to reduce the risk of postoperative liver failure [48–50]. The ex situ technique allows vascular reconstruction or complex hepatectomies to be performed at a comfortable bench table for a prolonged time, which limits bleeding and the need for transfusions. However, it requires vascular anastomosis for liver autotransplantation, which increases morbidity and mortality [50–52]. For prolonged and complex ex situ resection and vascular reconstruction, Gringeri et al. have proposed using MP, which could prevent cold ischemic injury and may be suitable in livers with chronic disease [53]. Currently, MP use during complex hepatectomies is limited by costs, a prolonged anhepatic phase, and restricted liver mobilization during perfusion. Further studies are necessary to evaluate the advantages of using MP in ex situ liver resections.

References 1. Fondevila C, Hessheimer AJ, Ruiz A, et  al. Liver transplant using donors after unexpected cardiac death: novel preservation protocol and acceptance criteria. Am J Transplant. 2007;7:1849–55. 2. Brettschneider L, Daloze PM, Huguet C, et al. The use of combined preservation techniques for extended storage of orthotopic liver homografts. Surg Gynecol Obstet. 1968;126:263–74. 3. Starzl TE.  The puzzle people. 10th ed. Pittsburg, PA: University of Pittsburg Press; 2003. p. 145–54. 4. Jamieson NV, Sundberg R, Lindell S, et al. Preservation of the canine liver for 24-48 hours using simple cold storage with UW solution. Transplantation. 1988;46:517–22. 5. Burra P, Burroughs A, Graziadei I, et al. EASL clinical practice guidelines: liver transplantation. J Hepatol. 2016;64:433–85. 6. Schlegel A, Muller X, Dutkowski P. Hypothermic machine preservation of the liver: state of the art. Curr Transplant Rep. 2018;5:93–102. 7. Karangwa SA, Dutkowski P, Fontes P, et al. Machine perfusion of donor livers for transplantation: a proposal for standardized nomenclature and reporting guidelines. Am J Transplant. 2016;1967:2932–42. 8. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation in human liver transplantation: the first clinical series. Am J Transplant. 2010;10:372–81.

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9. Dutkowski P, Schlegel A, De Oliveira M, et al. HOPE for human liver grafts obtained from donors after cardiac death. J Hepatol. 2014;60:765–72. 10. Petrowsky H, Clavien P-A.  Principles of liver preservation. In: Busuttil RW, Klintmalm GBG, editors. Transplantation of the liver. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2015. p. 582–99. 11. Schlegel A, de Rougemont O, Graf R, et  al. Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts. J Hepatol. 2013;58:278–86. 12. Selten J, Schlegel A, de Jonge J, Dutkowski P. Hypo- and normothermic perfusion of the liver: which way to go? Best Pract Res Clin Gastroenterol. 2017;31:171–9. 13. Treckmann J, Minor T, Saad S, et al. Retrograde oxygen persufflation preservation of human livers: a pilot study. Liver Transpl. 2008;14:358–64. 14. Suszynski TM, Rizzari MD, Scott WE, et al. Persufflation (or gaseous oxygen perfusion) as a method of organ preservation. Cryobiology. 2012;64:125–43. 15. Schlegel A, Kron P, De Oliveira ML, et al. Is single portal vein approach sufficient for hypothermic machine perfusion of DCD liver grafts? J Hepatol. 2016;64:239–41. 16. Dutkowski P, Polak WG, Muiesan P, et al. First comparison of hypothermic oxygenated perfusion versus static cold storage of human donation after cardiac death liver transplants: an international-matched case analysis. Ann Surg. 2015;262:764–71. 17. De Carlis L, De Carlis R, Lauterio A, et al. Sequential use of normothermic regional perfusion and hypothermic machine perfusion in donation after cardiac death liver transplantation with extended warm ischemia time. Transplantation. 2016;100:e101–2. 18. De Carlis R, Di Sandro S, Lauterio A, et  al. Successful donation after cardiac death liver transplants with prolonged warm ischemia time using normothermic regional perfusion. Liver Transpl. 2017;23:166–73. 19. De Carlis R, Di Sandro S, Lauterio A, et  al. Liver grafts from donors after cardiac death on regional perfusion with extended warm ischemia compared with donors after brain death. Liver Transpl. 2018;24:1523–35. 20. Pienaar BH, Lindell SL, Van Gulik T, et al. Seventy-two-hour preservation of the canine liver by machine perfusion. Transplantation. 1990;49:258–60. 21. Minor T, Manekeller S, Sioutis M, Dombrowski F.  Endoplasmic and vascular surface activation during organ preservation: refining upon the benefits of machine perfusion. Am J Transplant. 2006;6:1355–66. 22. De Carlis R, Lauterio A, Ferla F, et  al. Hypothermic machine perfusion of liver grafts can safely extend cold ischemia for up to 20 hours in cases of necessity. Transplantation. 2017;101:e223–4. 23. Derveaux K, Monbaliu D, Crabbé T, et al. Does ex vivo vascular resistance reflect viability of non-heart-beating donor livers? Transplant Proc. 2005;37:338–9. 24. Liu Q, Vekemans K, Iania L, et al. Assessing warm ischemic injury of pig livers at hypothermic machine perfusion. J Surg Res. 2014;186:379–89. 25. Monbaliu D, Brassil J.  Machine perfusion of the liver: past, present and future. Curr Opin Organ Transplant. 2010;15:160–6. 26. Brockmann JG, Vogel T, Coussios C, Friend PJ. Liver splitting during normothermic organ preservation. Liver Transpl. 2017;23:701–6. 27. Jayant K, Reccia I, Virdis F, Shapiro AMJ.  The role of normothermic perfusion in liver transplantation (TRaNsIT study): a systematic review of preliminary studies. HPB Surg. 2018;2018:6360423. https://doi.org/10.1155/2018/6360423. 28. Mergental H, Roll GR.  Normothermic machine perfusion of the liver. Clin Liver Dis. 2017;10:97–9. 29. Friend PJ, Imber C, St Peter S, et al. Normothermic perfusion of the isolated liver. Transplant Proc. 2001;33:3436–8. 30. Ravikumar R, Jassem W, Mergental H, et al. Liver transplantation after ex vivo normothermic machine preservation: a phase 1 (first-in-man) clinical trial. Am J Transplant. 2016;16:1779–87. 31. Bral M, Gala-Lopez B, Bigam D, et  al. Preliminary single-center Canadian experience of human normothermic ex  vivo liver perfusion: results of a clinical trial. Am J Transplant. 2017;17:1071–80.

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32. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature. 2018;557:50–6. 33. Selzner M, Goldaracena N, Echeverri J, et  al. Normothermic ex  vivo liver perfusion using steen solution as perfusate for human liver transplantation: first north American results. Liver Transpl. 2016;22:1501–8. 34. Schlegel A, Kron P, Graf R, et al. Warm vs. cold perfusion techniques to rescue rodent liver grafts. J Hepatol. 2014;61:1267–75. 35. Watson CJE, Kosmoliaptsis V, Randle LV, et al. Normothermic perfusion in the assessment and preservation of declined livers before transplantation. Transplantation. 2017;101:1084–98. 36. Berendsen TA, Bruinsma BG, Lee J, et al. A simplified subnormothermic machine perfusion system restores ischemically damaged liver grafts in a rat model of orthotopic liver transplantation. Transplant Res. 2012;1:6. https://doi.org/10.1186/2047-1440-1-6. 37. Morito N, Obara H, Matsuno N, et  al. Oxygen consumption during hypothermic and subnormothermic machine perfusions of porcine liver grafts after cardiac death. J Artif Organs. 2018;21:450–7. 38. Minor T, Efferz P, Fox M, et  al. Controlled oxygenated rewarming of cold stored liver grafts by thermally graduated machine perfusion prior to reperfusion. Am J Transplant. 2013;13:1450–60. 39. Shigeta T, Matsuno N, Obara H, et al. Impact of rewarming preservation by continuous machine perfusion: improved post-transplant recovery in pigs. Transplant Proc. 2013;45:1684–9. 40. Tolboom H, Izamis M-L, Sharma N, et  al. Subnormothermic machine perfusion at both 20°C and 30°C recovers ischemic rat livers for successful transplantation. J Surg Res. 2012;175:149–56. 41. Bruinsma BG, Yeh H, Özer S, et al. Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation. Am J Transplant. 2014;14:1400–9. 42. Lauterio A, Di Sandro S, Concone G, et al. Current status and perspectives in split liver transplantation. World J Gastroenterol. 2015;21:11003–15. 43. Renz JF, Emond JC, Yersiz H, et al. Split-liver transplantation in the United States: outcomes of a national survey. Ann Surg. 2004;239:172–81. 44. Stephenson BTF, Bonney GK, Laing RW, et al. Proof of concept: liver splitting during normothermic machine perfusion. J Surg Case Rep. 2018;2018:rjx218. https://doi.org/10.1093/jscr/ rjx218. 45. Bismuth H, Castaing DJ, Garden O. Major hepatic resection under total vascular exclusion. Ann Surg. 1989;210:13–9. 46. Heaney JP, Stanton WK, Halbert DS, et al. An improved technic for vascular isolation of the liver: experimental study and case reports. Ann Surg. 1966;163:237–41. 47. Huguet C, Gavelli A, Chieco PA, et al. Liver ischemia for hepatic resection: where is the limit? Surgery. 1992;111:251–9. 48. Cauchy F, Brustia R, Perdigao F, et al. In situ hypothermic perfusion of the liver for complex hepatic resection: surgical refinements. World J Surg. 2016;40:1448–53. 49. Azoulay D, Eshkenazy R, Andreani P, et al. In situ hypothermic perfusion of the liver versus standard total vascular exclusion for complex liver resection. Ann Surg. 2005;241:277–85. 50. Pichlmayr R, Grosse H, Hauss J, et  al. Technique and preliminary results of extracorporeal liver surgery (bench procedure) and of surgery on the in situ perfused liver. Br J Surg. 1990;77:21–6. 51. Lei P, Liu X, Liu S, Lv Y.  Ex situ liver resection for unresectable tumors. Dig Surg. 2012;29:140–8. 52. Aji T, Dong J-H, Shao Y-M, et  al. Ex vivo liver resection and autotransplantation as alternative to allotransplantation for end-stage hepatic alveolar echinococcosis. J Hepatol. 2018;69:1037–46. 53. Gringeri E, Polacco M, D’Amico FE, et al. A new liver autotransplantation technique using subnormothermic machine perfusion for organ preservation in a porcine model. Transplant Proc. 2011;43:997–1000.

6

Liver Vascular Reconstructions Umberto Cillo and Alessandra Bertacco

6.1

Introduction

Liver resection, with R0 margins, is associated with improved survival over non-­ operative treatments for both primary and secondary liver malignancies. In the past, liver tumors with vascular involvement were considered unresectable and with a poor outcome. These patients were directed to alternative non-curative therapies. In recent years, there has been an evolution in surgical attitude and many centers perform vascular resections and reconstructions in order to achieve R0 resection with a potential for an improved oncological outcome and a consequent survival benefit. Experience in the liver transplant field, improvements in surgical techniques (i.e., ex vivo resection, in situ cold perfusion), the use of microvascular surgeries, careful preoperative assessment and intraoperative anesthesiological support are the main features representing the backbone of this new tendency. Evolution in the management of liver malignancies has led to extend long-term survival in part by means of an increased rate of resectability with curative intent. If portal vein resection (PVR) is currently routinely performed, experiences with the hepatic artery, hepatic veins and inferior vena cava (IVC) are increasing; at the same time the mortality and morbidity related to this complex surgery are decreasing in high-­ volume centers. The lack of alternative therapies and the poor outcome of non-­ operative management seem to justify this aggressive approach. In the particular setting of perihilar cholangiocarcinoma (pCCA), the “no touch” technique was introduced in 1999 by Neuhaus et al. [1]. They observed an improved middle-long-term postoperative survival when an extended hepatic resection was combined with an en bloc resection of the portal confluence, carefully avoiding any

U. Cillo (*) · A. Bertacco Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 U. Cillo, L. De Carlis (eds.), Liver Transplantation and Hepatobiliary Surgery, Updates in Surgery, https://doi.org/10.1007/978-3-030-19762-9_6

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dissection close to the tumor. The rationale for such an en bloc resection is to avoid the risk of cancer cells dissemination during portal vein dissection in the hilar region. In 2012 the same group [2] confirmed the oncological superiority of the “no touch” resection compared to classic major hepatectomy for hilar cholangiocarcinoma (5-year survival, 58% vs. 29%, p = 0.021). Since then, this technique has represented one the core concepts in hepatobiliary cancer surgery.

6.2

Inferior Vena Cava and Hepatic Veins

Major vascular involvement is one of the most common reasons for unresectability. Tumor location in tight adhesion to the IVC may represent a tough challenge; nevertheless, skills acquired in the liver transplant field and in living donor liver transplantation (LDLT) have played a relevant role in no longer considering it a prohibitive region to approach. Resection of the vena cava is now diffusely accepted for all hepatic tumors, including human hepatocellular carcinoma, cholangiocarcinoma, and colorectal liver metastases; it has become reasonably safe, but it is still limited and with heterogenous applications among different centers. Over the last 2 decades, advances in surgical techniques, perioperative care and interdisciplinary teamwork have represented a paradigm shift for patients undergoing complex liver reconstruction after vascular resections. Liver resection extended to the IVC is mandatory to achieve R0 resection when major vascular invasion is detected pre- or intraoperatively. In the case of involvement of the hepatic veins (HVs) a combined liver-HVs resection is required not only to obtain a clear margin but also to avoid major hepatectomies in cases of insufficient/borderline future remnant livers. A “parenchymal-sparing” approach with HVs reconstruction can be an alternative to major hepatectomies especially in patients that have received intensive chemotherapy before surgery. An Italian group has recently produced the results of a vascular detachment series. In the case of liver metastases from colorectal cancer the long-term results were similar to those achieved with R0 resection. A further approach allows the sacrifice of one major invaded HV after confirming the presence of venous collaterals draining into the contralateral HVs. We believe that when approaching a tumor with potential vascular involvement the team has to guarantee the ability to manage the case by both detachment or vascular reconstruction with or without total vascular exclusion (TVE) with the same degree of confidence. Surgical procedure has to be carefully planned; grafts of adequate diameter and length need to be available and advanced techniques—such as TVE, venovenous bypass (VVB), ante situm resection—need to be in the armamentarium of the team facing hepatic vascular invading tumors. TVE consists of clamping the portal triad and IVC above and below the liver and results in various degrees of ischemic damage that could be attenuated by using in situ hypothermic portal perfusion under a VVB [3] or a venovenous extracorporeal membrane oxygenation (VV-ECMO) [4]. VVB is used in the case of hemodynamic

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intolerance to caval clamping but concomitant liver and IVC resection is reported to be safe also without using VVB [5]. Worldwide experiences with IVC or HVs reconstructions have reported perioperative mortality rates ranging from 0% to 16.7%; the most common causes of death were sepsis, multiorgan failure, small-for-size syndrome, and bleeding. Overall morbidity ranged from 16.7% to 50% while overall 5-year survival was around 40% [6]. However, reports are mainly from single-center experiences and include only limited data with variable tumor histopathology types and length of follow-up. The type of resection and repair are based on tumor location and IVC involvement. When involvement is minimal, the IVC can be reconstructed by primary suture or with a patch graft (49.2% of cases); when the defect is larger a patch graft or a complete IVC replacement is necessary (50.8%) [6]. Li et al. [7] proposed that if IVC involvement is less than 30% of the IVC circumference and 2  cm of the length, the defect can be sutured transversely after removing the invaded IVC wall. If IVC involvement is 30% to 50% of IVC circumference and longer than 2 cm, an autologous vein such as great saphenous vein patches or expanded polytetrafluoroethylene (ePTFE; Gore-Tex, Flagstaff, AZ, USA) patches have to be used for IVC repair or replacement. According to Azoulay et al. [8], if less than 50% of the circumference of the IVC wall is involved, a transverse suture is recommended to prevent stenosis; if 50% or more of IVC is resected, a 20-mm diameter PTFE graft should be used [7, 8]. In the case of involvement of the HVs, the remaining stump of hepatic vein after the resection has to be reimplanted directly into the vena cava, or with an interposed reinforced ePTFE graft or a venous graft. Reconstruction is necessary to preserve outflow and to avoid liver congestion. Clearly, the use of a conduit to reach the vena cava has potential for postoperative complication, namely kinking, thrombosis and in turn outflow obstruction. Therefore, an accurate design and realization of the implant has to be undertaken. Long-term transplant and particularly LDLT experience is of great help. For the patch different materials reported in the literature are nowadays available: • Artificial/synthetic vascular graft (Dacron, ring-reinforced PTFE) (Fig.  6.1). Dacron was the option of choice in the past, but it was associated with high thrombosis and stenosis rate. PTFE graft is an inert and biocompatible material: it is widely used [8] but requires concomitant anticoagulant therapy over a long period. Bleeding requiring reoperation was reported in 4.7% of cases [8]. For these reasons and for the concretely increased possibility of serious postoperative infections some authors [9, 10] prefer the use of autologous grafts. • Biological grafts (bovine-horse pericardium) or cold-storage cadaveric venous grafts (Fig. 6.2). Probably among the most effective and easy to use, these types of grafts are available only at transplant centers (cold-storage cadaveric venous grafts). Furthermore, some regulatory issues have been raised related to the quality of storage and donor data traceability. Since cadaveric venous grafts have been diffusely used in Italy, a national effort has to be undertaken to provide regulation patterns and promote sharing among transplant and non-transplant high-specialty hepatobiliary centers.

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Fig. 6.1  Female, 62 years with colorectal liver metastases; previous extended right hepatectomy. Computed tomography scan: 30  mm lesion with left hepatic vein infiltration (left). Segment 2 hepatic resection and left hepatic vein reconstruction with Gore-Tex patch (right)

Fig. 6.2  Female, 65 years with colorectal liver metastases. Magnetic resonance imaging: 25 mm lesion of segment 7 with right hepatic vein involvement (left). Hepatic resection and right hepatic vein reconstruction with cadaveric graft (right)

• Autologous grafts. Autologous vein grafts are widely used but have some limitations. External iliac vein grafts are most suitable for reconstructing the major HV because of its length and caliber; however, grafting the external iliac vein requires an extensive surgical dissection and causes edema of the extremities on the ipsilateral side. Left renal vein grafts are easy to use and of adequate caliber but are often limited in length. Saphenous vein grafts are usually about 3 cm in length and 8 Fr in caliber, which may be sufficient for interposing one of the major HVs in the absence of alternatives; however, it is a preferred option for segmental HV interposition. Grafting the great saphenous vein reaching up to 12 cm in length may take 20 to 30 min. Other experiences reported the use of the umbilical vein,

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portal vein and ovarian vein. The use of autologous grafts is associated with longer surgical times and the need for a second incision. • Cryopreserved homologous grafts. Yamamoto et al. (2017) [11] reported the largest experience in HVs reconstruction using cryopreserved grafts, reporting no difference in patency compared to autologous grafts. Cost, need to electively program the interventions and the fact that many biobanks do not accept the return of unused grafts fully charging for costs are among some of the limitations reported. • Parietal peritoneum can be used for patches [12] or tubularized [13] for cava replacement; preliminary series suggest this option in cases of infected surgical sites, complex abdominal trauma or malignancies requiring the resection of involved adjacent digestive structures. Our group routinely use parietal peritoneum for the reconstruction of portal defects when needed in major hepatectomies associated with PVR. Standard perioperative anticoagulant therapy is necessary, but standardized protocols are absent.

6.3

Portal Vein

Until the late 1990s portal vein thrombosis was considered a contraindication to resection for pCCA. Klempnauer et al. [14] described for the first time a combined extended right hepatectomy and PVR. This concept was then adapted by Neuhaus et al. [1] who in 1999 introduced the “no touch technique” reporting a benefit in survival for hilar cancer after PVR.  Since then many studies have confirmed the increased curative effect of PVR, which has nowadays become diffusely practiced and strongly recommended for biliary hilar tumors. Unfortunately, despite the improvements in preoperative imaging and staging, often the involvement of the portal vein is discovered intraoperatively. Mortality rates reported in the literature for PVR ranged from 0% to 5% while complications ranged from 43% to 100% [15]. Three-year survival after PVR and reconstruction for pCCA is reported between 19% and 58%. The adoption of aggressive surgical techniques (major resection, vascular reconstruction) demonstrated an increased 2-year survival from 33% (1993–1998) to 60% (1998–2003) [16]. In the particular subset of patients with hepatocellular carcinoma, neoplastic portal thrombosis is considered a formal contraindication to liver resection. According to recent EASL guidelines a certain degree of stage migration is allowed based on the very low adherence of clinicians to previous guidelines. In the context of a multidisciplinary decision-making setting, a major resection associated with PVR may be a therapeutic option. PVR and reconstruction can be performed either before or after the liver parenchymal transection. Anastomosis follows the classic roles of liver transplantation and can be completed by means of a primary end-to-end suture or with a graft interposition. A wide liver transplant experience may be of relevant help in reducing the postoperative complications and prevalence of portal thrombosis.

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Hepatic Artery

Hepatic artery resection (HAR) may be necessary to achieve R0 especially for hilar malignancies: the involvement of hilar structures may require concomitant multivascular resections (PVR, HAR) and reconstructions. Currently, while PVR is more diffusely applied, HAR adoption remains controversial. Recent series report the use of different arterial reconstruction techniques to obtain negative margins. Before the seminal paper of Nagino et al. in 2010 [17], previous reported experiences of arterial resection/reconstruction for biliary cancer were numerically scarce (5 cm, serum carcinoembryonic antigen (CEA) level greater than 200 ng/ mL, three or more metastases in the FRL, progression during preoperative chemotherapy, and presence of extrahepatic disease were demonstrated to be all significant factors predicting failure to achieve completion of hepatectomy [9]. It is not clear whether the use of chemotherapy between the first and second stage can lower tumor progression and dropout rates. What is more likely is that liver regeneration can be impaired or altered by use of some chemotherapy agents, thus increasing the risk of posthepatectomy liver failure (PHLF) and overall morbidity.

14.3 A  ssociating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) ALPPS is a novel technique which combines PVL and in situ splitting of the liver (Fig. 14.1), in order to achieve a more rapid liver hypertrophy than classical TSH, with almost 100% of completion rate [10]. The ALPPS approach is considered for patients with an insufficient FLR volume regardless of tumor origin and at least one of the following [11]: • • • •

a tumor margin close to the FLR or its vascular pedicles; a bilobar disease with contraindication for PVE; a failure of PVE/PVL; an unexpected tumor extension during surgical exploration with a larger than planned surgical resection; • the need for a large hypertrophy in an extremely small FLR.

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Fig. 14.1  77-year-old patient affected by intrahepatic cholangiocarcinoma. ALPPS was considered due to a preoperative sFLR (segment 2–3) of 20%. After 10 days the FLR increased from 297 cc to 595 cc (100%) and the patient was subjected to a right trisectionectomy. ALPPS associating liver partition and portal vein ligation for staged hepatectomy, FLR future liver remnant, sFLR standardized FLR

In the first stage, besides PVO and in situ splitting, colorectal resection or biliodigestive anastomosis can be performed. During parenchymal transection, ligation of the small arteries directed to segment 4 should be avoided to prevent necrosis and consequent biliary leak. For this reason, a partial liver split (3–5  cm) has been recently advocated [11]. A partial split together with PVE, in place of PVL, namely “mini-ALPPS”, has been demonstrated to enable a good hypertrophy rate, minimizing at the same time the impact of stage 1 [12]. PVE is particularly useful in cases of Klatskin tumor where a no-touch technique has to be preferred to limit potential tumor spread due to manipulation. Moreover, PVE and partial split can both be performed laparoscopically, thus reducing even more the impact of stage 1 [13]. In fact, these modifications were introduced after the first publication of the original ALPSS technique, as a result of the high morbidity and mortality rates reported [14]. In particular, the first results from the ALPPS International Registry showed that 93% of deaths occurred after stage 2 and PHLF was the most important cause of death. Hyperbilirubinemia or more in general liver dysfunction between stages in ALPPS has been shown to be associated with higher 90-day mortality after stage 2 [15]. The biological basis for such a dramatic increase in liver volume, registered already one week after stage 1, is thought to be related to hepatocyte enlargement without a corresponding increase in liver function. In other words, volumes in ALPPS overestimate liver function [16], as reported by studies on liver regeneration and function performed in ALPPS patients. Molecular nuclear imaging techniques as 99mTc-mebrofenin hepatobiliary scintigraphy and single photon-emission computed tomography (Fig. 14.2) have been used to estimate FLR function and to predict PHLF and liver-related mortality before the second stage of ALPPS [17]. The HIBA (Hospital Italiano de Buenos Aires) index described by Serenari et al. seems to be a promising tool to assess the right timing of the second stage, bearing in mind

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Fig. 14.2  SPECT image before completion of ALPPS, showing the distribution of function within the deportalized liver and the future liver remnant. SPECT single photon-emission computed tomography, ALPPS associating liver partition and portal vein ligation for staged hepatectomy

that other well-known risk factors such as the patient’s age, tumor type, occurrence of liver failure and/or surgical complications between stages should also be taken into account to guide decision-making in ALPPS. ALPPS is not intended to supplant conventional TSH, but rather to expand the armamentarium for hepatic resection. The first results from randomized control trials comparing ALPPS versus TSH have shown a comparable rate of complications (43%) between the two techniques. However, the oncological results are still awaited.

References 1. Yang C, Rahbari NN, Mees ST, et al. Staged resection of bilobar colorectal liver metastases: surgical strategies. Langenbeck’s Arch Surg. 2015;400:633–40. 2. Vauthey JN, Chaoui A, Do KA, et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery. 2000;127:512–9. 3. Truant S, Oberlin O, Sergent G, et al. Remnant liver volume to body weight ratio ≥ 0.5%: a new cut-off to estimate postoperative risks after extended resection in noncirrhotic liver. J Am Coll Surg. 2007;204:22–33. 4. Guglielmi A, Ruzzenente A, Conci S, et al. How much remnant is enough in liver resection? Dig Surg. 2012;29:6–17. 5. Madoff DC, Abdalla EK, Gupta S, et al. Transhepatic ipsilateral right portal vein embolization extended to segment IV: improving hypertrophy and resection outcomes with spherical particles and coils. J Vasc Interv Radiol. 2005;16:215–25. 6. Broering DC, Hillert C, Krupski G, et al. Portal vein embolization vs. portal vein ligation for induction of hypertrophy of the future liver remnant. J Gastrointest Surg. 2002;6:905–13. 7. Abulkhir A, Limongelli P, Healey AJ, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg. 2008;247:49–57. 8. Lam VWT, Laurence JM, Johnston E, et al. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB (Oxford). 2013;15:483–91.

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9. Giuliante F, Ardito F, Ferrero A, et al. Tumor progression during preoperative chemotherapy predicts failure to complete 2-stage hepatectomy for colorectal liver metastases: results of an Italian multicenter analysis of 130 patients. J Am Coll Surg. 2014;219:285–94. 10. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg. 2012;255:405–14. 11. Alvarez FA, Ardiles V, de Santibañes M, et al. Associating liver partition and portal vein ligation for staged hepatectomy offers high oncological feasibility with adequate patient safety: a prospective study at a single center. Ann Surg. 2015;261:723–32. 12. de Santibañes E, Alvarez FA, Ardiles V, et al. Inverting the ALPPS paradigm by minimizing first stage impact: the mini-ALPPS technique. Langenbeck's Arch Surg. 2016;401:557–63. 13. Pekolj J, Alvarez FA, Biagiola D, et  al. Totally laparoscopic mini-ALPPS using a novel approach of laparoscopic-assisted transmesenteric portal vein embolization. J Laparoendosc Adv Surg Tech A. 2018;28:1229–33. 14. Schadde E, Raptis DA, Schnitzbauer AA, et al. Prediction of mortality after ALPPS stage-1: an analysis of 320 patients from the International ALPPS Registry. Ann Surg. 2015;262:780–5; discussion 785–6. 15. Serenari M, Zanello M, Schadde E, et al. Importance of primary indication and liver function between stages: Results of a multicenter Italian audit of ALPPS 2012-2014. HPB (Oxford). 2016;18:419–27. 16. Olthof PB, Tomassini F, Huespe PE, et al. Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: liver volume overestimates liver function. Surgery. 2017;162:775–83. 17. Serenari M, Collaud C, Alvarez FA, et al. Interstage assessment of remnant liver function in ALPPS using hepatobiliary scintigraphy: prediction of posthepatectomy liver failure and introduction of the HIBA index. Ann Surg. 2017;267:1141–7.

Combined Cardiothoracic and Abdominal Approach

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Fabio Ferla, Vincenzo Buscemi, Riccardo De Carlis, and Luciano De Carlis

15.1 Introduction Hepatobiliary procedures are generally performed by laparotomy or laparoscopy, although in a few patients, a combined cardiothoracic and abdominal approach is necessary. Most of these cases are technically challenging and require a high degree of expertise in both liver and cardiothoracic surgery. The aims of the present chapter are: • To identify the main indications for the combined approach in liver resection surgery and liver transplantation (LT) • To describe the operative technique adopted during combined cardiothoracic-­ abdominal procedures • To analyze the short-term and long-term results of such procedures

Electronic supplementary material  The online version of this chapter (https://doi.org/10.1007/ 978-3-030-19762-9_15) contains supplementary material, which is available to authorized users. F. Ferla (*) · V. Buscemi Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy e-mail: [email protected]; [email protected] R. De Carlis Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy Department of Surgical Sciences, University of Pavia, Pavia, Italy e-mail: [email protected] L. De Carlis Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 U. Cillo, L. De Carlis (eds.), Liver Transplantation and Hepatobiliary Surgery, Updates in Surgery, https://doi.org/10.1007/978-3-030-19762-9_15

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15.2 Indications The indications for opening the chest as well as the abdomen are different in liver resection surgery and LT.

15.2.1 Liver Resection Surgery In liver resection surgery, the combined cardiothoracic and abdominal approach may be needed in three circumstances, namely, when: • The liver tumor extends into the hepatic veins. • The tumor invades the diaphragm. • A huge tumor requires extensive mobilization of the liver from the inferior vena cava (IVC) at the hepatocaval confluence.

15.2.1.1 Tumor Extending into the Hepatic Veins Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) tend to invade and occlude blood vessels with tumor thrombus (TT). HCC with extension into the IVC or right atrium (RA) is rare and occurs in approximately 3.8% and 2.0% of patients, respectively [1, 2]; clear data for CCA are not available, but it seems that CCA is less likely to invade the hepatic veins and to go up to the RA. In 2013 Li et al. [3] proposed a classification of HCC with TT invading the vena cava or RA; this classification was intended to guide the surgical approach to extended HCC but seems to fit with CCA too. Clinically, TT was classified into three types according to its anatomic location relative to the heart: the inferior hepatic type (type I), where the TT is in the IVC below the diaphragm; the superior hepatic type (type II), where the TT is in the IVC above the diaphragm, but still outside the RA; and the intracardiac type (type III), where the TT is above the diaphragm and has entered the RA (Fig. 15.1). To properly identify the tumor extension in the hepatic veins, vena cava, and RA, a diagnostic workup should include a contrast-enhanced computed tomography scan and cardiac ultrasonography. In type I TT, there is no need for a combined cardiothoracic and abdominal approach: liver surgery can be safely performed by a standard abdominal approach and total hepatic vascular exclusion (THVE). In type II TT, it is necessary to control the intrathoracic vena cava: that can be done safely by dividing the diaphragm from the abdomen; in type II TT, THVE and liver surgery do not require sternotomy or thoracotomy. In type III TT, complete access to the heart is mandatory since the RA has to be incised: to perform a combined cardiac and liver surgery, a cardiopulmonary bypass (CPB) [1] with or without deep hypothermia and circulatory arrest (DHCA) [4, 5] is needed. 15.2.1.2 Tumor Invading the Diaphragm When the diaphragm is invaded by liver tumor, the muscle should be resected en bloc with the tumor itself. In such circumstances three approaches are possible:

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Fig. 15.1  Hepatocellular carcinoma (HCC) with tumor thrombus (TT) is classified into three types according to its anatomic location relative to the heart: inferior hepatic type (Type I), where the TT is in the inferior vena cava below the diaphragm; superior hepatic type (Type II), where the TT is in the inferior vena cava above the diaphragm, but still outside the right atrium; intracardiac type (Type III), where the TT is above the diaphragm and has entered the right atrium

Fig. 15.2  Tumor invading the diaphragm: for invasion less than 2 cm, the diaphragm can be clamped above the neoplastic invasion to allow en bloc resection without opening the chest

• For invasion less than 2 cm, the diaphragm can be clamped above the neoplastic invasion to allow en bloc resection without opening the chest (Fig. 15.2). • For invasion between 2 and 4 cm, the opening of the diaphragm (and of the chest) is required to remove the tumor. The subsequent defect in the continuity of the muscle can be repaired by direct suture [6]. • For invasions greater than 4  cm, the removal of the tumor creates defects that should be repaired by the interposition of a mesh (when the surgical field is not contaminated) [6] or a muscle flap (when the field is contaminated) [7].

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The greater the diaphragm invasion, the higher the chance to see it at preoperative radiology, so the need for a mesh (needed for big diaphragm defects) can be generally predicted before surgery.

15.2.1.3 H  uge Tumor Requiring Extensive Mobilization of the Liver from IVC at the Hepatocaval Confluence Although not universally accepted, the use of a thoraco-phreno-abdominal access has been proposed as standard approach for huge tumors located in segments 1, 4 superior, 7, and 8 close to the hepatic vein confluence into the IVC [8]. This approach may allow a better exposure of the hepatocaval confluence, increasing the safety of the surgery involving this area. Another indication for the thoraco-phreno-­abdominal approach is the patient with severe adhesions because of previous liver surgery or the patient with a long and narrow thoracic cage. In both circumstances, opening of the chest enlarges the field to safely operate while minimizing the risk of iatrogenic injury and providing the chance to repair it, if needed.

15.2.2 Liver Transplantation In LT, the combined cardiothoracic and abdominal approach may be needed in four circumstances, namely, when: • The LT is performed in combination with heart transplantation. • The LT is performed in combination with lung transplantation. • Coronary bypass or aortic valve replacement is to be performed in combination with the LT. • The upper caval anastomosis is to be performed directly on the RA.

15.2.2.1 Combined Heart and Liver Transplantation Progressive cardiac dysfunction can cause hypoxic hepatic injury because of congestive hepatopathy leading to hepatic fibrosis [9] and to the need for combined heart-liver transplantation (CHLT). The most common indication for CHLT is familial amyloid polyneuropathy (FAP) with associated cardiac cirrhosis [10]. Other indications are familial hypercholesterolemia, β-thalassemia, hemochromatosis, alcoholic cardiomyopathy, cryptogenic cirrhosis with underlying cardiomyopathy, and glycogen storage disease. Cardiac-specific causes include hypertrophic cardiomyopathy, systemic lupus erythematous, and dilated cardiomyopathy. According the database of OPTN/UNOS (Organ Procurement and Transplantation Network/United Network for Organ Sharing), 278 CHLTs have been performed in the United States from 1992 to 2018 [11]. 15.2.2.2 Combined Lung and Liver Transplantation Similar to CHLT, lung disease is the primary driver for combined lung-liver transplantation (CLLT). The most common indication is cystic fibrosis (CF). Hepatic manifestations associated with CF include liver steatosis and cirrhosis. Other indications for CLLT include pulmonary hypertension (which is a contraindication for LT alone) and α1-antitrypsin deficiency. The majority of CLLT recipients without

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CF have undergone transplantation for concurrent liver and lung diseases with distinct causes. According the database of OPTN/UNOS, 106 CHLTs have been performed in the United States from 1994 to 2018 [12].

15.2.2.3 L  iver Transplantation and Coronary Bypass or Aortic Valve Replacement Patients with end-stage liver disease (ESLD) and coronary artery disease (CAD) or severe valvular heart disease have been reported with simultaneous LT and coronary artery bypass grafting or aortic valve replacement (AVR) [13, 14]. The need for a simultaneous heart-liver procedure resides in the high risk the heart or transplantation surgery would carry if performed alone. Liver transplantation is precluded to patients with known CAD since the 3-year mortality after the transplantation varies between 26% and 50% [15, 16]; at the same time coronary artery bypass is precluded to Child-Pugh class C patients owing to the high perioperative mortality. Similarly, LT is precluded to patients with aortic valvulopathies, and AVR is precluded to Child-Pugh class C patients. In patients in whom severe heart disease and ESLD are concomitant, the only possible treatment is simultaneous heart and liver surgery. 15.2.2.4 L  iver Transplantation with Upper Caval Anastomosis on the Right Atrium As for liver resection surgery, all the conditions in which complete control of the RA is needed for the upper caval anastomosis should be managed by a combined cardiothoracic and abdominal approach. In particular, Budd-Chiari syndrome requiring LT, some cases of polycystic liver disease, and some cases of re-­ transplantation are just a few of the circumstances in which sternotomy may be required to perform a safe surgery.

15.3 Surgical Technique As done for the indications, we will address separately the surgical techniques used in: • Liver resection surgery requiring a combined approach • LT requiring a combined approach

15.3.1 Liver Resection Surgery Requiring a Combined Approach 15.3.1.1 Tumor Extending into the Hepatic Veins As mentioned above, only type III TT requires complete access to the heart (see Video 15.1 from the authors’ series). In type III TT, an intraoperative transesophageal echocardiography is advised [17] (Fig. 15.3a). Surgery starts with a groin incision and preparation for cannulation of the right common femoral vein. Laparotomy is that performed through an L-shaped right subcostal incision. Abdominal exploration is performed. The hepatic pedicle is prepared for a Pringle maneuver, and liver disease extension is confirmed

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a

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Fig. 15.3  Intraoperative images of a case from the authors’ series: (a) intraoperative transesophageal echocardiography; (b) the diaphragm is partially divided from the abdomen; (c) a complete median sternotomy is performed; (d) the superior vena cava is encircled

by intraoperative ultrasound. The diaphragm may be partially dived from the abdomen (Fig. 15.3b). Liver parenchyma transection may start at this time or may be postponed after CPB preparation. A complete median sternotomy is then performed (Fig.  15.3c). The pericardium is opened, the superior vena cava encircled (Fig. 15.3d), and the diaphragm division is completed (Fig. 15.4a). The ascending aorta is cannulated. The superior vena cava and common femoral vein are cannulated to ensure venous drainage of the upper half and lower half of the body (Fig. 15.4b). The suprarenal vena cava is clamped as well as the hepatic pedicle, and CPB can be started. When the suprarenal IVC and hepatic pedicle are clamped, the liver is under THVE. CPB is generally conducted in mild (32–35 °C) to moderate hypothermia (28–32 °C), although some authors add DHCA to CPB when performing this kind of surgery [5]. When DHCA is applied, the patient body temperature is progressively dropped below 28  °C; at 18–20  °C the brain’s electrical activity stops, and the CPB flow can be reduced to 1–1.5 L/min [4] or stopped [5]. When DHCA is applied, the hepatic pedicle should not be clamped to ensure hepatic cooling [5]. The reported advantages of DHCA are a bloodless surgical field and a reduced risk of warm hepatic ischemia. On the other hand, DHCA may be burdened by postoperative bleeding and coagulopathy. If CPB is applied without DHCA, the THVE should not last more than 60 min to avoid postoperative liver failure [18, 19]. If DHCA is performed, it should not last more than 30 min to avoid brain damage [4]. When CPB (with or without DHCA) starts, the RA is opened, and the resection surgery can be completed by en bloc removal of the tumor from the heart and from the abdomen (Fig. 15.4c). Cava-atrium continuity has to be re-established (a bovine pericardium patch may be useful in this setting) before the CPB can be stopped (Fig. 15.4d). Once the CPB

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Fig. 15.4  Intraoperative images of a case from the authors’ series: (a) the diaphragm division is completed; (b) the femoral vein is cannulated; (c) the right atrium is cut and the tumor is removed from the heart; (d) cava-atrium continuity is re-established with a bovine pericardium patch

stops, the cardiothoracic and liver surgeons proceed with a standard technique to complete the operation.

15.3.1.2 Tumor Invading the Diaphragm A huge hepatic neoplasm (especially HCC) may invade the diaphragm and require a large en bloc diaphragm excision. In these cases, the anterior approach is generally advised to perform the hepatectomy, as described by other authors [20]. When the removal of the tumor determines a diaphragm defect wider than 3–4 cm, muscle reconstruction with a mesh is advised because the diaphragm cannot be pulled to its original position with too much tension. In our experience a 2-mm Gore-Tex prosthetic mesh can be inserted in the area of the diaphragmatic defect and sutured with a 1/0 or 2/0 polypropylene running suture with good results. When the surgical field is contaminated or the patient is at high risk for postoperative collection, a latissimus dorsi flap (LDF) can be used for the reconstruction. Other authors have described the technique, which is performed in three steps [7]: the LDF is dissected and the thoracodorsal pedicle is identified and preserved; the flap is brought into the chest through the lateral segment of the third intercostal space; and the LDF is fixed with separate sutures in order to isolate the pleural and abdominal cavities. 15.3.1.3 H  uge Tumor Requiring Extensive Mobilization of the Liver from IVC at the Hepatocaval Confluence The so-called thoraco-phreno-abdominal approach is characterized by an incision that is first made from the xiphoid process to approximately 4–5 cm above the umbilicus and then curves laterally to the right hypochondrium along the ninth intercostal space up to the posterior axillary line. In all patients the xiphoid process is fully

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exposed and removed to gain about 3–5 cm of exposure just above the hepatocaval confluence. The insertions of the external oblique muscle and of the internal oblique muscle upon the costal arch are carefully detached in order to expose the costal arch around the ninth intercostal space and enter the thorax. The bone cartilage of the costal arch is removed, and the intercostal muscles are resected along the superior border of the tenth rib to avoid injuries of the neurovascular bundle. Such resection of the intercostal muscles is prolonged posteriorly into the thoracic cavity to prevent rib fractures and bleeding during retractor pulling. The diaphragm is divided for 10 cm following a line directed to the hepatocaval confluence. Careful dissection should be carried out to prevent injuries to the phrenic nerve, which usually runs posteriorly and medially, and to the phrenic veins, which run in the direction of the right hepatic vein confluence. At this point, the liver can be pushed out by the left hand of the surgeon. Closure of the thoraco-phreno-abdominal access starts from the thoracic wall. After placement of a thoracic drain, single large absorbable sutures are placed between the two adjacent costal margins. Then, the diaphragm is closed with a running suture that is placed starting from the internal and medial side up to the costal margin. At this time the single sutures in the thoracic wall are closed. Finally, the laparotomy is closed using standard techniques.

15.3.2 Liver Transplantation Requiring a Combined Approach 15.3.2.1 Combined Heart and Liver Transplantation For CHLT, most surgeons follow a standard bicaval technique although on CPB for heart transplantation. The chest is left open, and the liver is transplanted with selective use of venovenous bypass. The chest and abdomen are then closed. For FAP, the domino technique can be used. A piggyback (Belghiti) or standard bicaval technique is used for whole orthotopic LT. Alternatively, en bloc CHLT has been described for pediatric cases: donor hilar and retroperitoneal dissections are performed prior to cross-clamping to minimize heart ischemia. The diaphragm is split at the level of the IVC, and phrenic veins are ligated. Following cross-clamping, venous venting is performed through the right atrial appendage and infrarenal vena cava. In the recipient, the liver is mobilized, and the recipient diaphragm is split. The heart is mobilized toward the end of the hepatectomy. En bloc organs are then simultaneously implanted on bypass, and the organs are simultaneously reperfused. 15.3.2.2 Combined Lung and Liver Transplantation For CLLT, a bilateral thoracosternotomy or bilateral anterolateral thoracotomy is performed. Venovenous bypass is employed to support hemodynamic instability and reduce portal or retroperitoneal venous hypertension. Use of CPB is also possible during lung implant; it is followed by heparinization antagonization and LT. Ceulemans et al. [21] describe a CLLT in which the liver was transplanted first. The aim is to prevent coagulopathy, reduce lung edema, and reduce the risk of posttransplantation biliary strictures. The authors conclude the “sicker organ” should be transplanted first.

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15.3.2.3 L  iver Transplantation and Coronary Bypass or Aortic Valve Replacement Coronary bypass or aortic valve replacement are performed just before the LT. The techniques adopted for both heart and liver surgery are the same as for a standard “single” procedure; the only difference is that the chest is closed before the abdomen after the LT is complete. 15.3.2.4 L  iver Transplantation with Upper Caval Anastomosis on the Right Atrium When the LT requires full access to the RA, the technique is the same as adopted during liver resection with RA TT previously described.

15.4 Postoperative Outcomes Liver resection surgery requiring a combined cardiothoracic and abdominal approach is generally burdened by high postoperative morbidity (40%) and mortality [22]. Although patients undergoing this kind of surgery have advanced disease for which the oncologic outlook is dismal at diagnosis, surgery could prolong survival, which would be very poor otherwise (especially in the case of atrial occlusion, death for cardiac arrest or a rapidly progressive cava syndrome could occur suddenly). For HCC patients undergoing HCC and TT resection, Wang et al. and Wakayama et al. reported a median overall survival of 19.0 and 30.8 months, respectively [23, 24]. Kokudo et al. reported a survival of 16.4 months [25]. A clear prospective on survival for CCA with TT in IVC or RA is missing, but it could possibly be worse than that of HCC. For huge HCC tumors invading the diaphragm, the postoperative morbidity is 20.7% (Clavien grade >2), and the mortality is 1.9% [20]. Long-term survival depends on the histology and stage of the tumor; for huge HCC involving the diaphragm, the reported overall survival at 1, 3, and 5  years is 71.7%, 39.6%, and 27.6%, respectively [20]. Analysis of the 2016 OPTN/UNOS data for adult patients undergoing CHLT demonstrates 1-, 3-, and 5-year patient survival rates of 87.2%, 83.1%, and 82.0%, respectively, which is comparable to survival outcomes for liver or heart transplantation alone [26]. Analysis of the 2016 OPTN/UNOS data for adult patients undergoing CLLT demonstrates a 79% 1-year graft survival, which is comparable to the 81.3% reported for isolated lung transplantation [26]. Data on combined LT and coronary bypass or aortic valve replacement are poor. In a report from Giakoustidis et al. [27], perioperative mortality occurred in 1 case out of 16 (6%) during LT and coronary bypass and in 2 cases out of 8 (25%) during LT and AVR. Organized data on LT requiring cardiac access are missing as well; in our experience (four cases) both short-term and long-term results seem to be similar to those of patients transplanted without the need for sternotomy.

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References 1. Georgen M, Regimbeau JM, Kianmanesh R, et  al. Removal of hepatocellular carcinoma extending in the right atrium without extracorporal bypass. J Am Coll Surg. 2002;195:892–4. 2. Lee IJ, Chung JW, Kim HC, et al. Extrahepatic collateral artery supply to the tumor thrombi of hepatocellular carcinoma invading inferior vena cava: the prevalence and determinant factors. J Vasc Interv Radiol. 2009;20:22–9. 3. Li AJ, Zhou WP, Lin C, et al. Surgical treatment of hepatocellular carcinoma with inferior vena cava tumor thrombus: a new classification for surgical guidance. Hepatobiliary Pancreat Dis Int. 2013;12:263–9. 4. Azoulay D, Lim C, Salloum C, editors. Surgery of the inferior vena cava. A multidisciplinary approach: Springer; 2017. 5. Leo F, Rapisarda F, Stefano PL, Batignani G. Cavo-atrial thrombectomy combined with left hemi-hepatectomy for vascular invasion from hepatocellular carcinoma on diseased liver under hypothermic cardio-circulatory arrest. Interact Cardiovasc Thorac Surg. 2010;10:473–5. 6. Kuwahara H, Salo J, Tukiainen E.  Diaphragm reconstruction combined with thoraco-­ abdominal wall reconstruction after tumor resection. J Plast Surg Hand Surg. 2018;52:172–7. 7. Kanso F, Nahon P, Blaison D, et  al. Diaphragmatic necrosis after radiofrequency ablation of hepatocellular carcinoma: a successful surgical repair. Clin Res Hepatol Gastroenterol. 2013;37:e59–63. 8. Donadon M, Costa G, Gatti A, Torzilli G. Thoracoabdominal approach in liver surgery: how, when, and why. Updat Surg. 2014;66:121–5. 9. Atluri P, Gaffey A, Howard J, et al. Combined heart and liver transplantation can be safely performed with excellent short- and long-term results. Ann Thorac Surg. 2014;98:858–62. 10. Cannon RM, Hughes MG, Jones CM, et  al. A review of the United States experience with combined heart-liver transplantation. Transpl Int. 2012;25:1223–8. 11. Organ Procurement and Transplantation Network/United Network for Organ Sharing. Multiorgan transplants by center. U.S. Multiorgan transplants performed 1 January 1988–31 December 2018. Liver-Heart. https://optn.transplant.hrsa.gov/data/view-data-reports/nationaldata. Accessed 30 January 2019. 12. Organ Procurement and Transplantation Network/United Network for Organ Sharing. Multiorgan transplants by center. U.S. Multiorgan transplants performed 1 January 1988–31 December 2018. Liver-Lung. https://optn.transplant.hrsa.gov/data/view-data-reports/nationaldata. Accessed 30 January 2019. 13. Kniepeiss D, Iberer F, Grasser B, et al. Combined coronary artery bypass grafting and orthotopic liver transplantation: a case report. Transplant Proc. 2003;35:817–8. 14. Parker BM, Mayes JT, Henderson JM, Savage RM. Combined aortic valve replacement and orthotopic liver transplantation. J Cardiothorac Vasc Anesth. 2001;15:474–6. 15. Plotkin JS, Scott VL, Pinna A, et al. Morbidity and mortality in patients with coronary artery disease undergoing orthotopic liver transplantation. Liver Transpl Surg. 1996;2:426–30. 16. Diedrich DA, Findlay JY, Harrison BA, Rosen CB. Influence of coronary artery disease on outcomes after liver transplantation. Transplant Proc. 2008;40:3554–7. 17. Koide Y, Mizoguchi T, Ishii K, Okumura F. Intraoperative management for removal of tumor thrombus in the inferior vena cava or the right atrium with multiplane transesophageal echocardiography. J Cardiovasc Surg. 1998;39:641–7. 18. Emond JC, Kelley SD, Heffron TG, et al. Surgical and anesthetic management of patients undergoing major hepatectomy using total vascular exclusion. Liver Transpl Surg. 1996;2:91–8. 19. Azoulay D, Lim C, Salloum C, et al. Complex liver resection using standard total vascular exclusion, venovenous bypass, and in situ hypothermic portal perfusion: an audit of 77 consecutive cases. Ann Surg. 2015;262:93–104. 20. Zheng J, Shen S, Jiang L, et al. Outcomes of anterior approach major hepatectomy with diaphragmatic resection for single huge right lobe HCC with diaphragmatic invasion. Medicine (Baltimore). 2018;97:e12194. https://doi.org/10.1097/MD.0000000000012194.

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21. Ceulemans LJ, Monbaliu D, Verslype C, et al. Combined liver and lung transplantation with extended normothermic lung preservation in a patient with end-stage emphysema complicated by drug-induced acute liver failure. Am J Transplant. 2014;14:2412–6. 22. Sakamoto K, Hiroaki N. Outcomes of surgery for hepatocellular carcinoma with tumor thrombus in the inferior vena cava or right atrium. Surg Today. 2018;48:819–24. 23. Wang Y, Yuan L, Ge RL, et al. Survival benefit of surgical treatment for hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombus: results of a retrospective cohort study. Ann Surg Oncol. 2013;20:914–22. 24. Wakayama K, Kamiyama T, Yokoo H, et al. Surgical management of hepatocellular carcinoma with tumor thrombi in the inferior vena cava or right atrium. World J Surg Oncol. 2013;11:259. https://doi.org/10.1186/1477-7819-11-259. 25. Kokudo T, Hasegawa K, Matsuyama Y, et al. Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: a Japanese nationwide survey. Hepatology. 2017;66:510–7. 26. Yi SG, Lunsford KE, Bruce C, Ghobrial RM. Conquering combined thoracic organ and liver transplantation: indications and outcomes for heart-liver and lung-liver transplantation. Curr Opin Organ Transplant. 2018;23:180–6. 27. Giakoustidis A, Cherian T, Antoniadis N, Giakoustidis D. Combined cardiac surgery and liver transplantation: three decades of worldwide results. J Gastrointestin Liver Dis. 2011;20:415–21.

Portal Vein Thrombosis in Liver Transplantation and in Non-transplant Treatment

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Umberto Cillo and Domenico Bassi

16.1 Introduction The presence of portal vein thrombosis (PVT) represents one of the most relevant challenges in liver transplantation as well as in the non-transplant treatment of portal hypertension and in some oncologic hepatobiliary operative approaches. A wide interplay of pathophysiologic, clinical and technical pieces of information among the different hepatobiliary and transplant disciplines is fundamental to improve clinical results. PVT is defined as a partial or complete occlusion of the blood flow within the portal vein (PV) by an intraluminal thrombus. Cirrhosis represents the most common etiologic factor, accounting for up to 24–32% of cases [1]. Other common causes include cancer, inflammation, infection and thrombophilic disorders. The incidence of PVT in cirrhotic patients usually correlates with the severity of the underlying liver disease and thus it is a common finding in decompensated cirrhotic patients that are waiting for a liver transplantation (LT) [2]. The prevalence reported in the literature is up to 28% in LT candidates [3]. Cirrhosis itself is now recognized as a hypercoagulable disease that, combined with a low portal venous flow in the setting of portal hypertension, is one of the main risks relating to the onset of PVT [4]. PVT can be described and categorized in different ways: it can be intrahepatic or extrahepatic, non-occlusive or occlusive, acute or chronic. Although advancements in knowledge, understanding and treatment of this disease, the clinical impact of PVT, especially in LT patients, remains still significant. In a retrospective analysis of 21,673 LT recipients in the United Network for Organ Sharing (UNOS) registry,

U. Cillo (*) · D. Bassi Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2020 U. Cillo, L. De Carlis (eds.), Liver Transplantation and Hepatobiliary Surgery, Updates in Surgery, https://doi.org/10.1007/978-3-030-19762-9_16

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the presence of PVT was identified as an independent risk factor for post-­ transplantation mortality [5]. Technical skills to manage the extremely relevant portal hypertension associated with PVT in the transplantation setting prove to be very useful also in non-­transplant scenarios. Viceversa, a huge amount of pathophysiologic and technical details arising from the experience in portal hypertension surgery represents the backbone of prophylaxis of the small-for-size syndrome in modern living donor LT [6].

16.2 Classification and Diagnosis of Portal Vein Thrombosis PVT usually arises within the liver and extends downwards into the extrahepatic portion of the PV. In some cases, the thrombosis further extends to the mesenteric branches resulting in a splanchnic venous thrombosis. Following this scheme, Yerdel et al. classified PVT from grade 1 (50% of the lumen, including total occlusion), with or without minimal extension into the SMV. (c) Grade 3: complete thrombosis of both PV and proximal SMV. (d) Grade 4: complete thrombosis of both PV and proximal and distal SMV. PV portal vein, SMV superior mesenteric vein, SV splenic vein

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The diagnosis of PVT is fundamental in tracing the correct clinical pathway in transplant evaluation and pretransplant management, and it is critical in the operative planning of the LT. Similar considerations can be applied in the non-transplant setting where the location of the neoplastic thrombus has relevant clinical drawbacks. Doppler ultrasonography (DUS) has become the most common initial diagnostic tool for PVT, with a sensitivity and specificity ranging from 60% to 100% [10, 11]. Computed tomography and magnetic resonance imaging with contrast are used to define the extent of the thrombosis and the nature of the thrombus especially in patients with hepatocellular carcinoma (HCC), and help in the preoperative assessment for transplantation [12]. Less frequently a fine-needle aspiration cytology may be indicated in the workup of a suspected unclear neoplastic portal thrombus [13].

16.3 Preoperative Management of Portal Vein Thrombosis PVT is in the majority of cases asymptomatic and often only routine DUS guides in the diagnosis. In other cases, the appearance of decompensation symptoms will alert to a possible PVT. The correct management of PVT in a pretransplant setting has the goal of reducing complications and mortality: in fact, PVT has been shown to be independently associated with a higher risk of variceal bleeding, failure of endoscopic treatment during bleeding and rebleeding, leading to an increased 6-week mortality (36% in PVT vs. 16% in non-PVT patients) [14, 15]. In general, in cirrhotic patients listed for transplantation there is an increased mortality in the presence of occlusive PVT, independently from transplantation [16]. Again, complete PVT is related to a significant increase in 30-day and 1-year mortality after LT when compared to patients transplanted without PVT [17]. Medical treatment for PVT is based on anticoagulant therapy that must always be started after implementing an adequate prophylaxis for gastrointestinal bleeding [18]. Progression of the thrombosis in patients without treatment is evident in 48–70% of individuals at 2-year follow-up [19, 20]. In patients treated with anticoagulants, the rate of re-permeabilization is around 55–75% with a mean interval time of about 6 months. The most important factor able to predict the probability of response to anticoagulant therapy is a time interval less than 6 months between the diagnosis of PVT and the start of treatment [20]. The recurrence rate of PVT in patients with re-permeabilization of the vein after withdrawal of anticoagulation therapy (38%) [21] suggests prolonging the treatment to prevent re-thrombosis especially in patients waiting for a LT. In LT candidates, who have progressive PVT not responding to anticoagulation, it is possible, in specific situations, to consider a percutaneous approach with transjugular intrahepatic portosystemic shunt (TIPSS) [18]. In the non-transplant setting, when a surgical treatment of portal hypertension has to be scheduled, as in the presence of idiopathic portal thrombosis, a complete

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thrombophilia screening has to be undertaken including protein S, protein C, and antithrombin levels, Factor V Leiden mutation, prothrombin G20210A gene variant and antiphospholipid antibodies (APA). Moreover, the workup consists of diagnosis of inherited and acquired thrombophilia factors, myeloproliferative neoplasms (JAK2V617F mutation), paroxysmal nocturnal hemoglobinuria and autoimmune disorders [18]. At the same time, patients need an accurate vascular morphology (angioCT scan or angioMRI) particularly focused on caliber and distance of the splenic vein (SV) and left renal vein (RV), if a splenorenal shunt has to be planned, or mesenteric vein and cava in the case of a mesocaval shunt. Site and caliber of spontaneous portosystemic shunts, if present, have to be carefully studied to better design the intervention. Such an accurate morphologic preoperative study is even more relevant in planning a transplantation in the presence of PVT and spontaneous portosystemic shunts which represent the most relevant cause of portal re-thrombosis after transplantation. A similar morphologic workup is also needed when scheduling a major resection for HCC with portal neoplastic thrombosis, since the involvement of portal bifurcation may represent an oncologic contraindication to the resective plan. Such an attitude to an accurate and detailed preoperative study and knowledge of venous splanchnic circulation widely overlaps between transplantation and hepatobiliary surgical scenarios.

16.4 Surgical Approaches to Portal Vein Thrombosis Surgery of portal hypertension, including cases of PVT, preceded LT, starting in the 1950s and developing until the introduction of TIPSS. Nowadays its role is limited to the few cases in which endoscopic and/or radiologic approaches have failed. The technical contents of shunt surgery, however, remain extremely current in that they represent key background knowledge to be retrieved, for example, in the presence of portal overflow and a risk of endothelial shear stress after partial LT.  In such cases, it may be useful to perform a portocaval shunt in order to reduce portal pressure to less than 20 mmHg to avoid a small-for-size syndrome, provided, however, that portal flow remains in normal ranges. A splenorenal shunt is a technically demanding peripheral shunt to be adopted to decrease portal hypertension in the specific district of gastroesophageal varices. Nowadays, even though rarely adopted, it is performed according the Orozco and Mercado description including a side-to-side rather than end-to-side anastomosis between the SV and RV [22]. Technical knowledge of this intervention may prove extremely useful when preparing SV and RV to find spontaneous shunts to be ligated after portal thrombectomy during LT in order to increase portal flow and prevent post-transplantation portal re-thrombosis. In the pediatric population, the occurrence of a PVT in the presence of a healthy liver may require a mesoRex shunt connecting the mesenteric vein to the left patent

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PV in the Rex recessus in order to reperfuse the intrahepatic portal system [23]. Such a shunt needs an iliac venous graft interposition. Clearly, knowledge of LT reconstruction techniques is of fundamental help. The goals of surgical PVT management during LT are: to establish adequate blood flow into the graft PV; to decompress the splanchnic circulation; to deliver portal trophic factors to the allograft. The first successful LT in a patient with PVT was reported in 1985 by the Pittsburgh group, who described the technique of extensive dissection of the PV to the confluence of the splenic and mesenteric veins with the use of a free iliac vein allograft [8]. Since that initial experience, several new techniques have been proposed to solve this problem and provide acceptable results. Adequate preoperative imaging is critical for correct surgical planning; for instance, it may help in avoiding wasting time in portal dissection in the presence of cavernomatous transformation and extensive thrombosis. However, detection of PVT not infrequently occurs during surgery.

16.4.1 Management of Grade 1–2 The management of grade 1–2 PVT starts with a careful dissection of the porta hepatis in order to assess the presence and extension of the thrombosis taking care to avoid injury to the large collateral vessels that often are present. The PV needs to be dissected to the confluence of SMV and SV behind the head of the pancreas till a soft patent vessel is encountered at the confluence. The majority of PVT grade 1–2 are managed with the removal of the thrombus. In cases of a soft and acute thrombus, this may be removed with a Fogarthy catheter. Care must be taken during balloon inflation not to lacerate the posterior wall of the confluence, which is difficult to repair due to its retropancreatic position. Most cases of PVT are chronic, and in these situations the thrombus is teased out with the innermost layer of the vessel (thromboendovenectomy) [2]. This is accomplished using an endarterectomy spatula under direct vision everting the vessel wall [24, 25]. Blind extraction of the thrombus is not recommended as it can rip the vessel causing uncontrollable bleeding. Part of the thrombus especially when it extends into the SV or SMV may remain adherent to the vessel wall with a thrombogenic potential. The residual part of the thrombus can be fixed to the vessel wall. Once the thrombus is removed, the portal flow must be checked and if it is considered inadequate, a Fogarty catheter can be passed in the SMV and SV, inflated gently and pulled. Another possibility is to check for spontaneous portosystemic shunts that have to be ligated in order to reduce the “steal phenomenon”. Thrombectomy and thromboendovenectomy are the most frequent techniques used in presence of PVT and in a large review of 1957 LT recipients with PVT [26] they were used in 75% of cases with a very low risk of PVT recurrence and complications.

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16.4.2 Management of Grade 3–4 In those situations, in which the thrombus extends beyond the SMV and SV confluence in the presence of a patent proximal SMV (grade 3 PVT) and thrombectomy is not feasible, a jump graft bypass may be performed. The SMV is exposed below the transverse mesocolon at the root of the small bowel mesentery and here the proximal anastomosis is completed in an end-to-side fashion. The vein graft is tunneled through the mesentery of the transverse colon and passed anteriorly to the pancreas in order to avoid disruption of the pancreatic capsule and its associated risks [27]. In the case of extensive portomesenteric thrombosis in the absence of patent proximal SMV (grade 4 PVT), the only possibility to revascularized the graft is to connect an alternative inflow to the porta vein. When possible, a coronary vein or an unnamed collateral vessel can be anastomosed to the donor PV [28]. These vessels must have a proper diameter (2 cm or more) and adequate flow; sometimes an interposition vein graft in used. Great care must be taken when suturing these variceal structures to the graft PV because these vessels are extremely delicate and will tear easily and may not hold suture. This is probably the best and more physiological approach in cases of grade 4 PVT since the blood from the collateral vessel anastomosed to the PV comes directly from the splanchnic system. Other alternative inflow sources can be the hepatic artery, the gastroduodenal artery or the aorta with the interposition of a free graft [29]. This technique, called PV arterialization, is simple but not at all physiological, and the systemic arterial pressure in the PV bed causes hemorrhage, right heart failure, aneurysmal dilatation of intrahepatic portal branches, acute and secondary PVT. Moreover, the chronic elevated pressure in the graft portal system and the consequent modification of the microcirculation develops graft fibrosis [30, 31]. These complications suggest that PV arterialization should be used only in exceptional cases. When an effective portal thrombectomy is impossible, cavoportal hemitransposition is a further option to restore the inflow to the donor PV. Tsakis et al. in 1998 [32] first described this technique in LT with diffuse PVT consisting of anastomosing the infrahepatic vena cava to the PV in an end-to-end or end-to-side fashion (Fig.  16.2). In this way al the IVC flow is directed to the PV.  In the end-to-side anastomosis, the IVC is best ligated in order to redirect the systemic vein flow to the donor PV. In 2007 the same group published their series of 23 patients with long follow-up [33]: the 1- and 5-year survival rates were 60% and 38%. Postoperative gastrointestinal variceal bleeding occurred in 30.4%, while ascites and edema of the bilateral lower extremities were observed in 91% of patients, and usually resolved with medical therapy in 6–12 weeks. Transitory renal dysfunction is seen in many patients, and it is usually self-resolving by 3 months postoperatively. Renoportal anastomosis (RPA) has been proposed as an alternative strategy to establish a portal inflow to the allograft [34]. This is best done in the presence of splenorenal shunts that are seen in up to 50% of patients with SVP. This suggests that almost half of grade 4 thromboses may be suitable for an RPA. After isolation

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Fig. 16.2 (a) Computed tomography scan of cavoportal hemitransposition. (b) Scheme of cavoportal hemitransposition. C-P thick arrow cavoportal anastomosis, IVC inferior vena cava, PV portal vein, G iliac vein graft, thin arrow ligation of the IVC

and control of the left RV, it is anastomosed directly or with the interposition of a vein graft to the PV in an end-to-end fashion. An RPA ensures adequate flow to the liver, optimal coaxiality, congruence of the anastomosed vessels and preservation of the retrohepatic inferior vena cava flow. In particular, the left RV flow in cirrhotic patients with significant splenorenal shunts is more than 1000 mL/min (55 F). In the systematic review published by D’Amico et al. in 2018 [35], the all-cause mortality was reported to be 19.6% (13 patients) and the overall patient and graft survival were each 80%, with a mean follow-up of 35.2 ± 29.7 months. Overall, 71% of patients developed postoperative complications, the more common being ascites, transient renal dysfunction, infection, and variceal hemorrhage. All cases of postoperative ascites and transient renal dysfunction resolved within 3 months of LT. The extreme surgical option in grade 4 PVT is the hepatointestinal or multivisceral transplantation. These techniques allow replacement of the recipients’ entire splanchnic venous system, but the scarcity of donors causes a very high waiting-list mortality, up to 50%. Moreover, these techniques are burdened by a high risk of rejection, infection and surgical complications with a 5-year survival of 49% [36]. Again, the intraoperative management of splanchnic-systemic shunts is a critical point during transplantation of patients with PVT. They can be left in place during portions of the hepatectomy to continue to decompress the portal system and then taken down to improve portal flow if causing PV steal. In cases of splenorenal shunts, in the presence of a “steal phenomenon” and despite interruption of collaterals, ligation of the left RV can augment portal flow by eliminating the steal from the splenorenal shunt. This is accomplished initially by clamping temporarily the RV vein and then, when the portal flow is confirmed to be improved, with its ligation [37].

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16.4.3 Surgical Management in Hepatocellular Carcinoma Neoplastic Portal Vein Thrombosis HCC neoplastic PVT represents in the majority of cases a contraindication for resective surgery. These patients in fact have often a decompensated liver function and if not, they are best candidates for systemic oncological therapy. In a small group of patients with compensated liver function and good clinical conditions a liver resection with PV thrombectomy may be offered with acceptable risks [38]. According to the Liver Cancer Study Group of Japan classification system, PV invasion (Vp) can be classified into four groups [39]: • • • •

Vp1 as an invasion or tumor thrombus distal to the second branch of the PV; Vp2 as an invasion or tumor thrombus in the second branch of the PV; Vp3 as an invasion or tumor thrombus in the first branch of the PV; Vp4 as an invasion or tumor thrombus in the portal trunk or extending to a branch on the contralateral side.

In the first two groups anatomical or atypical liver resections may be used to achieve R0 resections. In cases of Vp3 and Vp4 a PV resection is necessary to ensure radicality and often a reconstruction of part of the vessel wall with a peritoneal patch or the complete resection of the bifurcation and an end-to-end anastomosis is necessary to allow an adequate portal flow.

16.5 Conclusions Management of PVT both in the setting of LT and in the hepatobiliary surgical patient requires knowledge of the diseases and their pathophysiology as well as technical skills that overlap in the field of LT and hepatobiliary oncological surgery. In both situations a careful selection of candidates for surgery and preoperative assessment are critical.

References 1. Cohen J, Edelman RR, Chopra S. Portal vein thrombosis: a review. Am J Med. 1992;92:173–82. 2. Yerdel MA, Gunson B, Mirza D, et  al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation. 2000;69:1873–81. 3. Nonami T, Yokoyama I, Iwatsuki S, Starzl TE. The incidence of portal vein thrombosis at liver transplantation. Hepatology. 1992;16:1195–8. 4. Senzolo M, Burra P, Cholongitas E, Burroughs AK.  New insights into the coagulopathy of liver disease and liver transplantation. World J Gastroenterol. 2006;12:7725–36. 5. Rana A, Hardy MA, Halazun KJ, et  al. Survival outcomes following liver transplantation (SOFT) score: a novel method to predict patient survival following liver transplantation. Am J Transplant. 2008;8:2537–46. 6. Tucker ON, Heaton N. The ‘small for size’ liver syndrome. Curr Opin Crit Care. 2005;11:150–5.

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7. Seu P, Shackleton CR, Shaked A, et al. Improved results of liver transplantation in patients with portal vein thrombosis. Arch Surg. 1996;131:840–4. discussion 844–5 8. Shaw BW Jr, Iwatsuki S, Bron K, Starzl TE. Portal vein grafts in hepatic transplantation. Surg Gynecol Obstet. 1985;161:66–8. 9. Shaked A, Busuttil RW. Liver transplantation in patients with portal vein thrombosis and central portacaval shunts. Ann Surg. 1991;214:696–702. 10. Subramanyam BR, Balthazar EJ, Lefleur RS, et al. Portal venous thrombosis: correlative analysis of sonography, CT and angiography. Am J Gastroenterol. 1984;79:773–6. 11. Kreft B, Strunk H, Flacke S, et al. Detection of thrombosis in the portal venous system: comparison of contrast-enhanced MR angiography with intraarterial digital subtraction angiography. Radiology. 2000;216:86–92. 12. DeLeve LD, Valla DC, Garcia-Tsao G.  Vascular disorders of the liver. Hepatology. 2009;49:1729–64. 13. Yang L, Lin LW, Lin XY, et al. Ultrasound-guided fine needle aspiration biopsy in differential diagnosis of portal vein tumor thrombosis. Hepatobiliary Pancreat Dis Int. 2005;4:234–8. 14. Amitrano L, Guardascione MA, Scaglione M, et al. Splanchnic vein thrombosis and variceal rebleeding in patients with cirrhosis. Eur J Gastroenterol Hepatol. 2012;24:1381–5. 15. D’Amico G, de Franchis R, Cooperative Study Group. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology. 2003;38:599–612. 16. Englesbe MJ, Kubus J, Muhammad W, et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl. 2010;16:83–90. 17. Rodriguez-Castro KI, Porte RJ, Nadal E, et  al. Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review. Transplantation. 2012;94:1145–53. 18. European Association for the Study of the Liver. EASL clinical practice guidelines: vascular diseases of the liver. J Hepatol. 2016;64:179–202. 19. Luca A, Caruso S, Milazzo M, et al. Natural course of extrahepatic nonmalignant partial portal vein thrombosis in patients with cirrhosis. Radiology. 2012;265:124–32. 20. Senzolo M, Sartori M, Rossetto V, et al. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis. Liver Int. 2012;32:919–27. 21. Delgado MG, Seijo S, Yepes I, et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol. 2012;10:776–83. 22. Orozco H, Mercado MA.  The evolution of portal hypertension surgery: lessons from 1000 operations and 50 years’ experience. Arch Surg. 2000;135:1389–93. discussion 1394 23. Bertocchini A, Falappa P, Grimaldi C, et al. Intrahepatic portal venous systems in children with noncirrhotic prehepatic portal hypertension: anatomy and clinical relevance. J Pediatr Surg. 2014;49:1268–75. 24. Stieber AC, Zetti G, Todo S, et al. The spectrum of portal vein thrombosis in liver transplantation. Ann Surg. 1991;213:199–206. 25. Lerut JP, Mazza D, van Leeuw V, et  al. Adult liver transplantation and abnormalities of splanchnic veins: experience in 53 patients. Transpl Int. 1997;10:125–32. 26. Rodríguez-Castro KI, Porte RJ, Nadal E, et  al. Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review. Transplantation. 2012;94:1145–53. 27. Tzakis A, Todo S, Stieber A, Starzl TE. Venous jump grafts for liver transplantation in patients with portal vein thrombosis. Transplantation. 1989;48:530–1. 28. Lerut J, Tzakis AG, Bron K, et al. Complications of venous reconstruction in human orthotopic liver transplantation. Ann Surg. 1987;205:404–14. 29. Bonnet S, Sauvanet A, Bruno O, et  al. Long-term survival after portal vein arterialization for portal vein thrombosis in orthotopic liver transplantation. Gastroenterol Clin Biol. 2010;34:23–8. 30. Ott R, Böhner C, Müller S, et al. Outcome of patients with pre-existing portal vein thrombosis undergoing arterialization of the portal vein during liver transplantation. Transpl Int. 2003;16:15–20.

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31. Charco R, Margarit C, López-Talavera JC, et al. Outcome and hepatic hemodynamics in liver transplant patients with portal vein arterialization. Am J Transplant. 2001;1:146–51. 32. Tzakis AG, Kirkegaard P, Pinna AD, et al. Liver transplantation with cavoportal hemitransposition in the presence of diffuse portal vein thrombosis. Transplantation. 1998;65:619–24. 33. Selvaggi G, Weppler D, Nishida S, et  al. Ten-year experience in porto-caval hemitransposition for liver transplantation in the presence of portal vein thrombosis. Am J Transplant. 2007;7:454–60. 34. Sheil AG, Stephen MS, Chui AK, et al. A liver transplantation technique in a patient with a thrombosed portal vein and a functioning renal-lieno shunt. Clin Transpl. 1997;11:71–3. 35. D’Amico G, Hassan A, Diago Uso T, et al. Renoportal anastomosis in liver transplantation and its impact on patient outcomes: a systematic literature review. Transpl Int. 2019;32:117–27. 36. Tzakis AG, Kato T, Levi DM, et al. 100 multivisceral transplants at a single center. Ann Surg. 2005;242:480–90. discussion 491–3. 37. Slater RR, Jabbour N, Abbass AA, et  al. Left renal vein ligation: a technique to mitigate low portal flow from splenic vein siphon during liver transplantation. Am J Transplant. 2011;11:1743–7. 38. Ban D, Shimada K, Yamamoto Y, et  al. Efficacy of a hepatectomy and a tumor thrombectomy for hepatocellular carcinoma with tumor thrombus extending to the main portal vein. J Gastrointest Surg. 2009;13:1921–8. 39. Liver Cancer Study Group of Japan. General rules for the clinical and pathological study of primary liver cancer . 2nd English edition. Tokyo: Kanehara; 2003. p. 13–28.

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17.1 Introduction The auxiliary partial orthotopic liver transplantation (APOLT) and resection and partial liver segment 2–3 transplantation with delayed total hepatectomy (RAPID) techniques are two of the most relevant paradigms of the interplay between liver transplantation and hepatobiliary surgery. In both techniques, the complex concepts of liver partition are merged with the articulated issues related to graft implantation. In both, the key factors implied in liver regeneration and the clinician’s ability to modulate and influence it are of paramount importance for the postoperative results. Owing to the complexity of the techniques and the large number of variables involved in the clinical outcomes, realizing an APOLT or a RAPID technique is a major achievement for a hepatobiliary and liver transplant surgeon. Such an achievement is the result of a full technical and conceptual maturity reached through massive exposure to both live resection and liver transplantation surgery. The Padua center performed both the first APOLT in Italy in 2007 (and is still the only Italian center to perform APOLT) and the first Italian RAPID technique in 2018.

Electronic supplementary material  The online version of this chapter (https://doi.org/10.1007/ 978-3-030-19762-9_17) contains supplementary material, which is available to authorized users. U. Cillo (*) Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospital, Padua, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2020 U. Cillo, L. De Carlis (eds.), Liver Transplantation and Hepatobiliary Surgery, Updates in Surgery, https://doi.org/10.1007/978-3-030-19762-9_17

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17.2 APOLT Technique Auxiliary partial orthotopic liver transplantation (APOLT) is a particularly complex technique that includes a major hepatectomy realized to create enough room to implant a partial liver graft in the orthotopic position. The procedure never gained wide diffusion in the transplant community due to extreme technical complexity and a somewhat problematic reproducibility. The concept, however, represents one of the most fascinating in surgery. On one hand, it maintains the native liver in place allowing a future reversal in the event of a full recovery from the underlying disease and, on the other, it enables the “addition” of functioning liver parenchyma to support metabolic processes in the recipient. The orthotopic position of the graft guarantees a perfectly physiologic inflow and outflow. APOLT was initially offered to children with metabolic liver disease without cirrhosis, as a sort of gene therapy. Even small amounts of liver parenchyma can efficiently correct single enzyme-related metabolic disorders. Additionally, in the event that a future gene therapy becomes available, the APOLT can be removed with withdrawal of immunosuppression [1]. It is extremely interesting that even very small parts of liver, namely a left lateral segment (LLS) graft, can be enough to support the metabolic deficit. This can be provided by a standard LLS split graft in a deceased donor liver transplantation setting or a left lateral segmentectomy in a living donor setting. Moreover, in the living donor liver transplantation (LDLT) setting donor safety is much better preserved with APOLT than with a classical transplantation procedure due to the much smaller amount of liver parenchyma needed. A further important indication for APOLT has historically been fulminant hepatic failure. In particular, in the pediatric population, the idea was to support the native liver recovery during a phase of acute life-threatening insufficiency by means of an “extra metabolically functioning parenchyma”. Such an extra parenchyma could have been subsequently removed (or just let undergo atrophy without immunosuppression) once native liver function had recovered fully [2]. Recently, both conditions—non-cirrhotic metabolic disease and acute liver failure—are gaining acceptance as standard indications for the adoption of APOLT in selected cases. In particular, in the case of acute liver failure the concept of a potential bridge to native liver function recovery gives the patient the possibility of an immunosuppression-free survival. Among the most important technical issues presented by APOLT is the potential for a portal steal. After transplantation the graft implanted in the orthotopic position is almost invariably associated with inflammatory events that may increase intraparenchymal resistance to blood flow. This generates a difference in resistance to portal flow between the graft and the native liver where resistances are classically normal. In turn, this may result in a diversion of portal flow in the direction of the native liver where resistances are low. As a result, the graft may undergo a relative ischemia leading to progressive atrophy. In addition, potential rejection episodes may further increase intragraft resistance to portal flow thereby worsening the relative ischemia. Some techniques have been developed to overcome the problem. Portal modulation consists in reducing the caliber of the portal branch going to the native liver.

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A complete portal diversion may be needed in some cases (complete ligation of the native liver portal vein) [3]. This decision, however, is irreversible since the native liver function cannot recover after complete portal ligation. Broering et  al. suggested inducing venous congestion in part of the native remnant by ligating the middle hepatic vein close to its outflow in the vena cava in order to prevent portal flow competition between both livers [4]. If portal steal is detected or suspected in the postoperative phase a radiological segmental portal embolization can be performed to increase native portal vein resistance and rebalance portal flow.

17.3 RAPID Technique According to Line et al., the acronym RAPID stands for “resection and partial liver segment 2–3 transplantation with delayed total hepatectomy” [5]. The concept includes elements deriving from classical APOLT, on the one hand, and, on the other, from two-stage hepatectomy. It is indeed an auxiliary liver transplantation where a small partial liver graft (namely an LLS graft) is implanted orthotopically after a left hepatectomy of the native liver. Subsequently, in order to promote a fast regeneration of the transplanted segments, a portal flow diversion is operated in the direction of the future remnant as in the ALPSS (associating liver partitioning and portal vein ligation for staged hepatectomy) technique. Once a fast regeneration of the auxiliary future remnant has been obtained, the native liver hepatectomy is completed as in a two-stage hepatectomy. The RAPID technique meets some major clinical and pathophysiologic demands: 1. It provides “extra donor resources” to allow transplantation for “unconventional indications” for transplantation: LLSs are easily obtainable either by means of a cadaveric split (once served the pediatric population) or by LDLT with an extremely low risk for the donor; 2. It overcomes the problem of an insufficient metabolic mass typical of LLSs (with the aim of supporting life); 3. It prevents the shear stress on the portal endothelium associated with an excess of portal pressure related to the small vascular bed of a small graft; 4. It promotes a fast future remnant regeneration allowing completion of the native hepatectomy in the context of a safe two-stage hepatectomy.

17.3.1 The Technique According to the Description of the First Italian Case in Padua We performed the first case of RAPID technique in Italy in December 2018. It was the sixth RAPID procedure ever, the second case worldwide using a living donor [6], and the first case with a minimally invasive approach for the second stage hepatectomy (Videos 17.1, 17.2 and Figs. 17.1, 17.2 and 17.3).

170 Fig. 17.1 RAPID technique: diagram of step 1

Fig. 17.2 RAPID technique: diagram of step 2

Fig. 17.3 RAPID technique: intraoperative picture (personal experience)

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A 47-year-old patient affected by more than 20 colorectal liver metastases (CRLM) was considered not resectable by the Padua multidisciplinary oncologic meeting. The unresectability was subsequently confirmed by an international multidisciplinary board. The patient had undergone a full course of Folfox evacizumab therapy with a partial response. After ethics committee approval, two potential donors were evaluated. The patient’s brother-in-law agreed to provide his LLSs, for a total liver weight of 400 g. The donor operation was totally uneventful and the donor was discharged on the sixth postoperative day after a regular postoperative course. The recipient operation started with a full left hepatectomy (segments 1–4) extended to the left hepatic vein. Subsequently, the donor LLSs were implanted orthotopically. The graft left hepatic vein was anastomosed on the stump of the middle and left hepatic veins. The graft left portal vein was then anastomosed end-­ to-­end with the recipient’s left portal vein. Similarly, the left hepatic artery was anastomosed end-to-end with the recipient’s stump of a replaced left hepatic artery from left gastric artery by means of a microsurgical technique and the use of operative microscope. Portal pressure and flows were repeatedly measured. After right portal vein ligation, left portal vein pressure remained stable below 20 mmHg. The left biliary stump was anastomosed on a Roux-en-Y loop. The postoperative increase in graft volume was tightly monitored. After 15 days, the volume reached a graft-to-body weight ratio (GRWR) of 1. A hepatobiliary iminodiacetic acid (HIDA) scan was also completed. We then decided to proceed with the second stage hepatectomy. The native right hepatectomy was performed laparoscopically and the native liver was extracted through a 10-cm incision. The patient is well and disease-free 2 months after the procedure.

17.3.2 Providing Extra Donor Resources Even after the introduction of direct antiviral agents for the treatment of HCV infection leading to a dramatic drop in the demand for liver transplantation for these patients, the waiting list pressure for liver transplantation remains severe. Furthermore, new indications have arisen in recent years with particular reference to CRLM. The incidence of colorectal cancer (CRC) is about 700 cases per million population. Among the new cases, about 50% will develop metastases in the liver, which represent the major cause of morbidity and mortality in these patients. Systemic chemotherapy associated with radical surgical resection is the milestone of treatment in these patients. However, only 20% of patients are resectable in the course of the disease. The Oslo group has shown how liver transplantation in selected patients with CRLM is associated with good survivals rates in the middle and long term (well above 50% at 5 years). These survival rates are significantly greater if compared with similar patients undergoing only systemic chemotherapy (less than 20% at 5 years). Even though recurrence-free survival is relatively low (10 months median recurrence-free survival), recurrences are more frequently in the lung and are

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associated with a relatively mild outcome only marginally impacting survival. It has been shown that lung metastases are slow-growing and that their growth rate is not significantly influenced by immunosuppressants. When patients with partial response or stable disease after chemotherapy, CEA 2 mg/dL   – Creatinine clearance 180 mg/dL) •  Smoke (>15 cigarettes/day) •  Cardiac hypertrophy •  Prolonged drug abuse (>2 years) •  Familiarity with CAD (family history of ischemic heart disease in first degree relatives) TIA transient ischemic attack, EKG electrocardiography, NASH non-alcoholic steatohepatitis, LVH left ventricular hypertrophy, LBBB left bundle branch block, LDL low-density lipoprotein Table 21.2  Two-dimensional transthoracic echocardiographic (2D TTE) evaluation • Morphology •  Valvular heart disease and severity   – mild   – moderate   – severe •  Atrial dilatation •  Left ventricular ejection fraction (LVEF)    –  contraindication with resting LVEF  38 mmHg). The combination of main pulmonary artery diameter at CT and TTE might improve the diagnostic accuracy [38]. Interestingly enough, TTE false positive results (estimated PASP >45 mmHg) even in case of normal values at RHC are possible. PoPH is classified according to mPAP at RHC as mild (25–35 mmHg), moderate (35–45 mmHg), and severe (>45  mmHg). According to very recent guidelines, while mild PoPH does not constitute a contraindication to LT, patients with moderate PoPH should be temporarily delisted, treated (pulmonary vasodilators; prostacyclin analogs, phosphodiesterase inhibitors, endothelin receptor antagonists), reassessed (RHC and TTE) to evaluate the hemodynamic improvement (mPAP