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to predict patient survival following liver transplantation. Am JTransplant 2008;8:2537e2546.

26. Petrowsky H, Busuttil RW. Evolving surgical approaches inliver transplantation. Semin Liver Dis 2009;29:121e133.

Discussion

DR YUMAN FONG (New York, NY): A few months ago, I ran

a national congress on gene therapy for rare childhood diseases,where we thought that we had announced the first approvedwestern gene therapies for genetic diseases in humans. However,when this paper was sent to me for review, it was very clear that

our transplantation surgeons have been doing this for decades.The results showing that 77% of the pediatric patients are alive20 years after such transplantation tell us that the results are

good, and that this is one of the ways of tackling these diseases.I have 4 questions for the authors. First of all, the authors state

that there’s a 9.2% in-hospital mortality for this group of patients.

That’s rather high. I was just wondering what the reasons were, andwas it related to the metabolic syndromes that we’re seeing in thesepatients?

Second question: in patients who had lethal extrahepatic geneticdefects that resulted in cirrhosis in the liver, were any of thesepatients transplanted both with a liver and with a bone marrowtransplant?

Third, in cases in which the genetic defect was in the liver butthe target organs were outside the liver, how does our organ alloca-tion system currently work in the United States for such patients

since they do not have cirrhosis?Last, at UCLA there is a great department in pediatric genetic

medicine. Were any of these explanted organs used by those inves-

tigators in their genetics department to study any of the diseasesthat were treated by the surgeons?

DR WILLIAM C CHAPMAN (St Louis, MO): Liver transplanta-tion is an important and largely successful modality of treatment

for liver-related inherited genetic syndromes. In this manuscript,the authors report their center’s experience over 29 years withsuch therapies in 152 patients, and showed that the long-term

survival in adults is comparable for transplantation for all indica-tions, and is superior in children.

The UCLA program, under Dr Busuttil’s leadership now foralmost 3 decades, has demonstrated excellent outcomes with liver

transplantation in high-risk, end-stage liver disease patients. Thereare few areas in surgery where 20-year results are reported, andwhat we’ve heard today shows just how outstanding the long-

term results can be.I’m a little confused about the use of the terms gene therapy and

personalized medicine to describe the use of transplantation for these

indications, although perhaps I need to rethink my ideas on this.Although these concepts are currently the focus of the future, theiruse in this situation is not one with which we’ve traditionally asso-ciated liver transplantation. For most of the disorders presented

today, if you have the condition, you are likely to be recommendedfor liver transplantation at some stage of the disease. For example,

with OTC deficiency, although some patients may have a lesssevere form, there is no genetic test that I’m aware of that stratifies

patients into those who might need a transplant or might not.I tend to think of personalized medicine, for example, in the case

of hepatocellular carcinoma; in some patients you might use trans-

plantation and in others you’d use hepatic resection based on theinvestigation. And, by the way, we don’t have that technologyyet today.

Similarly, transplantation has not been typically thought of asa form of gene therapy. And the FDA, as far as I know, currentlyconsiders all forms of gene therapy as experimental. And, clearly,liver transplantation is not. I have 3 questions for the authors.

The authors show that over time, more genetic testing has beenused in their center. Could you comment on how this genetictesting has affected patient management? Does genetic testing repre-

sent just a more accurate and convenient diagnostic tool but notnecessarily provide additional information over biochemical testing?

Second, you presented data pertaining to patients requiring

simultaneous multiple organ transplants. Can you tell us if anyof the diseases in this group needed more simultaneous transplantsthan others?

Finally, do any of the diagnoses presented here, for example,

hepatic artery thrombosis or primary nonfunction, have dispropor-tionately poor outcomes?

DR ALAN LIVINGSTONE (Miami, FL): There are not very manypapers that follow out liver transplants for 20 years, and I am inter-ested in knowing how many of these people are off immunosup-pression. Teenagers sometimes rebel about taking long-term

medications, and will discontinue drugs of their own volition.

DR HENRIK PETROWSKY (Los Angeles, CA): Dr Fong’s firstquestion addresses the in-hospital mortality rate of 9%. The in-hospital mortality rate was related to the advanced liver disease in

our geographic region. In 2011, approximately 30% of our recipi-ents at UCLA had a Model for End-Stage Liver Disease (MELD)score of 40 or higher at time of liver transplantation. Second, the

overall in-hospital mortality reflects the outcomes of the entire seriessince the start of the UCLA program in 1984. When we broke itdown, the in-hospital mortality of the most recent era was signifi-

cantly lower compared with the early period of the pioneer time.The second question addresses combined liver and bone marrow

transplantation in patients with extrahepatic expression of the

genetic defect. We presented 2 patients with recurrent geneticdiseases, in whom the genetic defect was corrected in the liverbut not in bone marrow-derived blood cells. It has been suggestedthat genetic diseases of both recurrent conditions should be treated

by combined liver and bone marrow transplantation. We did notdo this because both patients received transplants in the earlyperiod, between the 1980s and 1990s.

Third question: How is allocation done in patients with noncir-rhotic livers? The severity of genetic diseases, especially in noncir-rhotic conditions, is not reflected by the MELD systems.

Therefore, these patients receive extra points to increase theirpriority on the waiting list.

Last question: Did we use explanted organs for genetic testing or

further investigations? We did routine testing of these organs

544 Petrowsky et al Discussion J Am Coll Surg

including histology, immunohistochemistry, and even electronmicroscopy, but we did not use these explanted organs for specific

genetic tests. We just started whole exome sequencing in our patientswith lethal genetic syndromes. In patients who have died and fromwhom we have no chance to get blood, we will attempt to extract

DNA from embedded tissue for whole exome sequencing.Dr Chapman’s first question addressed whether genetic testing

affects management; in some patients, yes; in others, no. However,

genetic testing will identify the disease including the specific type ofthe mutation. One example is hemochromatosis, which can behereditary or secondary. The clinical picture of both conditionscan be pretty similar. Genetic testing for this disease will clarify

if hemochromatosis is a genetic disease or a secondary condition.Genetic testing also offers testing of family members, which mightguide treatment of positively tested individuals. In summary,

genetic testing has effects on patient management in many lethalgenetic syndromes but other genetic diseases, such as OTC defi-ciency, can be diagnosed by biochemical tests only.

His second question asked for some more information aboutsimultaneous transplantation. We had 2 patients with recurrentdisease, in whom we could correct the extrahepatic genetic defect.Both genetic diseases have 2 things in common: the genetic defect

is expressed in the liver as well as in extrahepatic tissue. Both condi-tions would probably benefit more from combined liver and bonemarrow transplantation. We also showed the case of a patient with

simultaneous liver-lung transplantation for cystic fibrosis. This isa nice example in which a genetic disease affects the liver and the

lung. Other genetic diseases with primary hepatic expression ofthe genetic defect, like OTC deficiency, will be cured by liver trans-

plantation only.The last question asked whether any genetic diseases have

disproportionately poor outcomes in terms of hepatic artery throm-

bosis or primary nonfunction. The answer to this question is no.Complications and adverse outcomes were mainly related to thetype of grafts, such as partial or pediatric, instead of this having

anything to do with the underlying disease.I would like to make a brief comment because there was some

confusion about considering liver transplantation as gene therapy.I agree with Dr Chapman that the FDA definition considers

only experimental therapies as gene therapy. If we would presenttoday molecular gene therapy approaches for these lethal geneticsyndromes, everybody would probably agree that this represents

gene therapy or personalized medicine. However, molecular genetherapy, stem cell therapy, and liver transplantation have thesame goal: to correct the genetic defect. Therefore, from the scien-

tific point of view, liver transplantation represents personalizedmedicine or gene therapy for lethal genetic syndromes.

The last question, from Dr Livingstone, was related to immuno-suppression withdrawal. I believe that none of the patients were off

of immunosuppression. Many patients who had retransplantationwere children or young adults with chronic rejection as the leadingindication. Because these patients are relatively healthy with an

intact immune system, I advise to be very cautious about with-drawing immunosuppression.