Ronald W. Busuttil, MD, PhD: William P. Longmire, Jr, Chair of Surgery, Chief of Liver and Pancreas Transplantation, Director, UCLA-Dumont Transplant & Liver Cancer Center.

Abstract

You celebrated 6000 liver transplants at UCLA in 2016. How does one build the largest liver transplant program in the world?FigureRWB: The building of our Liver Transplantation Program at UCLA, was a complex undertaking stimulated by a 20-year-old patient whom I had performed a distal splenorenal shunt for variceal bleeding. Unexpectedly, he developed liver failure 7 days postoperatively and died, before I could transfer him to Dr. Starzl in Pittsburgh for consideration of liver transplantation. As I walked out of the ICU that day, I turned to my friend and hepatology colleague, Dr. Leonard Goldstein and stated “Leonard, we need to start doing liver transplants at UCLA.” In late 1982, I told Dr. William P. Longmire, Jr., a renowned liver surgeon and Chairman at UCLA, that I would like to start a liver transplant program. He was supportive, and I assembled a team and initiated a program of porcine orthotopic liver transplantation. We performed over 50 transplants using venous-venous bypass, with excellent success. I then visited Dr. Starzl in Pittsburgh to observe clinical liver transplantation and participated in about 6 cases. Over the next several months, we put together our multidisciplinary team at UCLA despite some skepticism from hospital administration. On February 1, 1984, we performed our first liver transplant on a recipient with a hepatic schwannoma and used venous venous bypass. The patient required 17 units of blood and was discharged on postoperative day 17. We performed our 100th liver transplant at UCLA in November 1986, and reported our experience the following year at the American Surgical Association. In my closing remarks, I recognized Dr. Starzl’s contributions: “how well I remember the multiple phone conversations on our first few transplants, in which I sought your advice, encouragement and leadership and I am very grateful for that.” After our first 100 liver transplants, our program continued to grow rapidly since we were one of the first programs in the western part of the United States, and encompassed the entire spectrum of pediatric and adult liver transplantation including the sickest patients. Our team performed our 5000th liver transplant on September 9, 2010, and our 6000th on June 30, 2016, making our program one of the largest worldwide. None of this could have happened without the unfailing support of our totally dedicated multidisciplinary team of surgical and medical specialists, nurse coordinators, hospital leadership, administrators, organ procurement agency, and the supportive generosity of donor families. More than 6000 liver transplants would not go by without remembering very special cases. What is your most memorable surgery and patient? RWB: To be honest, all of my patients are memorable. Certainly, those who did not survive have influenced me in ways that resulted in improving our patient and donor selection, operative techniques and postoperative management. If we look for instance at our pediatric patients there has been a significant improvement in 15 year graft survival from 51% from 1984 to 2000 to 72% from 2001 to 2017. Although all of my patients are memorable, there is a very special 1-year-old child, who I transplanted on August 8, 1984, our fifth transplant, with a giant hepatic hemangioendothelioma who is now 34 years old, married, and living a wonderful life. She is one of over 1000 children that we have transplanted in our program. In addition to excellent clinical outcomes, you have a unique collection of clinical data. How did you built your database and what have you learnt and brought back to clinical application? RWB: From the inception of our program, each patient evaluated for liver transplantation has been registered into an IRB sanctioned transplant database, with a comprehensive list of recipient, donor, and perioperative variables maintained prospectively. Over the years, our transplant surgeons have played the leading role in extracting additional clinical, laboratory, radiologic, and pathologic information from the medical records, resulting in the continuous growth and enrichment of the database which is updated regularly. This robust research database has been integral to our research productivity over the years. With greater than 800 publications in peer-reviewed journals, the UCLA transplant program has made significant contributions to the field of liver transplantation, with leading roles in numerous randomized-controlled trials that led to the current standard of care in immunosuppression (tacrolimus), and fungal, viral, and PCP prophylaxis following LT. Furthermore, we have contributed important innovations in surgical techniques such as in situ split-liver transplantation, as well as innumerable reports of clinical outcomes examining salient issues pertaining to donor allocation, use of extended-criteria donor allografts, and transplantation for malignancies. Our clinical research program is integrated with our robust basic science and translational program focusing on hepatic ischemia/reperfusion injury, leading to several clinical trials in human liver transplantation. You have mentored many transplant surgeons who went on to take very successful leadership roles. What is the secret of your mentoring style? RWB: I truly believe that one of the most important components of my career has been my commitment to training and mentoring future leaders in transplantation. This is a multifaceted commitment, and as stated by Gary Burnison, CEO of Korn Ferry International, “to lead is to be all in, transparent and accessible, calm in the face of upset and even crisis, and always mindful that you are a steward of something bigger than yourself.” Transplantation is certainly a discipline which demands all of the above. Additionally, to be successful in training our future leaders, you must demonstrate vision, self-direction, courage to take on complex cases, and most importantly to always embody honesty and integrity. Finally, genuine, personal interaction is essential. Despite my administrative role as Chairman of our Department, I always set time aside for personal interaction and the mentoring of medical students, residents and fellows, which includes clinical rounding, one-on-one meetings, and hosting a monthly Journal Club at my house for the last 30 years. The LA Times had an interview, now almost 2 decades back in which they featured you and your efforts in finding novel ways to keep up with the demand for liver transplantation. All those attempts, at the time seemed unable to keep up with havoc caused by hepatitis C. Today, new and effective antivirals have changed the game. How have the new antivirals changed liver transplantation? RWB: Hepatitis C was clearly the most common indication for liver transplantation in most centers in the United States until the advent of effective antiviral agents over the past couple of years. However, even patients who have cleared the virus may still require liver replacement due to failing liver function. In these cases, the results of liver transplant are vastly improved due to the lack of HCV recurrence. HCV is diminishing as an indication for liver transplant, and we now have a new leader in the queue, which is nonalcoholic steatohepatitis (NASH). In many cases, these patients are more complex, more technically demanding and have additional co-morbidity. We are pushing to establish a trial to determine if sleeve gastrectomy performed with liver transplantation will improve the outcomes of these difficult patients. There has been a long debate on the timing for patients with end-stage alcohol toxic liver disease. Is it safe to transplant those patients without a minimum time of documented abstinence? RWB: Liver transplantation for alcoholic hepatitis is a very controversial topic, due to the high rate of recidivism and the limited donor pool. However, there is more data coming out which shows that early liver transplantation for severe alcoholic hepatitis in selected patients can provide very good short-term survival and equivalent rates of relapse as seen in patients who have 6 months of abstinence pretransplant. One of my former fellows, Dr. Andrew Cameron, Chief of Liver Transplantation at Johns Hopkins University, recently published the results of a 3-year pilot program comparing patients with alcoholic hepatitis after first liver decompensation versus those with the same condition that had 6 months of abstinence. The survival and incidence of alcohol relapse was the same in both groups. In an editorial that I authored for this article, I concluded that the dramatic improvement in survival in those transplanted early and the equivalent recidivism rates compared to those transplanted after 6 months sobriety justifies this approach and careful consideration should be given to implementing this policy with close scrutiny. You list more than 700 publications in PubMed. What do you consider your most important scientific contribution? Together with Dr. Jerzy Kupiec-Weglinski you have explored many novel mechanistic and therapeutic avenues addressing ischemia/reperfusion injury. What of those efforts have been or about to be translated into clinical application? RWB: I have been intensively involved in both clinical and basic science research since I was a medical student at Tulane, where I obtained my MD and MS degrees. My masters degree thesis was “The Cytological Localization of Erythropoietin Using the Fluorescent Antibody Technique”. Upon obtaining my PhD in 1975, I published one of the first articles demonstrating that steroid therapy was successful in blocking ischemia reperfusion injury in ischemic hearts. Since founding the liver transplant program in 1984, my basic research program has been focused on the prevention of ischemia reperfusion injury (IRI) of the liver. I have been continually funded from the NIH and other peer-reviewed granting agencies since 1981. In 1997, I recruited Jerzy Kupiec-Weglinski, MD, PhD, from Harvard University to lead the basic science thrust of our laboratory. I have worked very closely with Dr. Kupiec-Weglinski to specifically identify the mechanisms of (IRI) and to develop treatment modalities to prevent the injury. Indeed, our “bench-to-bedside” collaborative research on the innate—adaptive immune interface in liver transplant recipients has been recently awarded a 5-year Program Project Grant from the NIH. As there are less than 10 program project grants in the country funded by the NIH that are related to organ transplantation, this is quite an achievement. The focus of the research on liver ischemia reperfusion injury (IRI) is both basic and translational since IRI contributes to poor graft function after transplantation. Minimizing the adverse effects of IRI could increase the number of patients that may successfully undergo liver transplantation. Our research has involved studying the platelet leukocyte endothelial cell interactions which play a central role in IRI. We were the first group to document that inhibition of P-Selectin activation by blocking P-Selectin glycoprotein ligand-1 was highly successful in increasing survival in marginal liver grafts after transplantation. I have been the principal investigator of these studies since they were initiated in the mid-1990s and currently these have been expanded to the clinical arena with Phase II clinical trials utilizing P-Selectin/PSGL-1 blockade in both kidney and liver transplantation. In 2012, I was the lead author of a randomized placebo controlled phase II clinical trial comparing placebo versus selectin blockade in a series of 47 patients undergoing liver transplantation. Selectin blockade proved to be nontoxic and improved graft survival, liver function tests and biomarkers of inhibition of IRI. This study is the stimulus for a multicenter trial investigating selectin blockade as a mechanism to improve liver graft function and has applicability to other organ transplants. In addition to this basic science research, I have been the senior author on numerous seminal clinical articles which have served as benchmarks in the treatment of liver transplant patients in many areas of clinical focus including: immunosuppression, perioperative viral and fungal prophylaxis, technical modifications, use of extended criteria donors, management of infants undergoing liver transplantation, hepatocellular carcinoma, living donor organ donation, split liver transplantation, combined kidney - liver transplants, multivisceral transplants, and transplantation of patients with the highest Model for End-stage Liver Disease score, which is used to allocate organs. Many of these accomplishments were supported by NIH and other peer-reviewed funding. Looking into the future: what do you see as the main challenges for liver transplantation in the 10 years? RWB: There are indeed numerous challenges for liver transplantation that we will encounter over the next 10 years. Today, liver transplantation is considered the gold standard for treatment of patients with end-stage liver disease. However, new improved treatment strategies, as we now have for HCV and HBV, and in the possible near future for hepatocellular carcinoma will surely decrease the need for liver replacement. In certain metabolic diseases, cellular transplantation may become very effective as the preferred treatment over whole organs. Life-long immunosuppression definitely has its drawbacks. However, once our ability to induce tolerance improves, immunosuppressive drug therapy will be minimized. Furthermore, the new avenues of research such as blockade of ischemia reperfusion injury and the resuscitation of marginal grafts with novel preservation concepts will significantly increase the organ donor pool. Your energy does not seem to stop outside of the hospital walls. There are rumors that a unique collection of Italian sport cars share your home address. Moreover, you are an avid runner and have finished the new your city marathon twice. What do you enjoy outside the operating room? RWB: My career would not have developed were it not for the incredible, selfless, and loving support of my family: my wife of 50 years, JoAnn, our 2 daughters, Amber and Ashley, and my 4 grandsons. One of my passions is indeed automobiles, perhaps a genetic trait inherited from my father, who was a car dealer when I was growing up. I worked in his dealership as a teenager and attended many races including the 12 hours of Sebring, the Monte Carlo Grand Prix, and the Indianapolis 500. I personally raced in the Mille Miglia 1000-mile race in Italy 3 times. I have been playing tennis since I was a medical student, and still exercise daily with a morning or evening run depending on my OR and administrative schedule. My wife, JoAnn is an art enthusiast, collector, and docent for the Los Angeles Museum of Art, and I have enjoyed and benefited from her expertise and passion in this area for many years.