Liver Transplantation: An Update

Mahmoud El-Meteini, MDGeneral Secretary of PALTS

Professor of HPB & Liver Transplant Surgery, Ain Shams University. Director of Ain-Shams Center for Organ Transplant (ASCOT)

Ain Shams University, Cairo - Egypt

History of Orthotopic Liver Transplantation (OLTx)

• 1963: 1st Unsuccessful attempt (Denver)• 1967: 1st Long term survivor• 1970’s: 1 year pt Survival: 35%• 1980’s: 5 year pt Survival: 70%• 1984: Reduced Liver Tx• 1989: Split Liver Tx • 1989/1990: 1st successful LDLT (Brazil/ Australia)• 1994: 1st AALDLT (Japan)• 1993: 1st Unsuccessful LDLT (Egypt)• 1996: Undisciplined trial OLT (Egypt)• 2001: 1st Real LDLT Program (Egypt)

3

Patient survival after liver transplantation has shown continued improvement

• The last 10 yrs have seen steady improvements in pt survival in Europe, the US, Australia & New Zealand1–3

– 1-year post-transplant survival of ≈ 90%

– These improvements are due to advances in peri-operative care, perfection of surgical technique, introduction of potent immunosuppressants, antibiotics & antiviral drugs4

1. European Liver Transplant Registry, ELTR. 2010. Available at: http://www.eltr.org/spip.php?article152, accessed 28 October 2011. 2. US Organ Procurement and Transplantation Network, OPTN. 2008. Available at: http://optn.transplant.hrsa.gov/ar2008/Preface_Contributors.htm?cp=1, accessed 28 October 2011; 3. Lynch SV, Balderson GA. ANZLTR Registry Report. Australia and New Zealand Liver Transplant Registry. Available at: http://www.anzltr.org/thisYear/report.pdf, 28 October 2011.4. Braun F et al. Transplant Proc 2009;41:2564-66

European patient survival (%) following liver transplantation has improved over the past 25 years1

0 1 2 3 4 5 6 7 8 9 100

20

40

60

80

100

18

465661

66

79

2234

64

818586

52

65

1995–99: 18162<1985: 519 1985–89: 4129 1990–94: 12007

2000–2004: 22945 >2004: 18786

Time Post-transplant (years)

Perc

enta

ge S

urvi

val (

%)

Indications/ Contraindications for LTX

Indications: East versus West

8

In Egypt: HCV & HCC are the main indications

65%

30%

5%

HCVHCCOther

200 Million People Infected With HCV Worldwide

2.5%–10%

>10%

1%–2.5%

Prevalence of infection

Global Burden of HCV Working Group. J Clin Pharmacol. 2004;4420-4429.WHO. Wkly Epidemiol Rec. 2002;77:41-48.

Not available

• HCC is the 3rd cancer related mortalitiy worldwide.³• Its the 5th common malignancey in males, the 9th among females.²• Main cause of mortalitiy in cirrhotic patients.4

• Its annual incidence is 560,000, and annual mortality of 550,000.5

1. Perz JF, et al. J Hepatol. 2006;45:529-38. 2. Jelic S. Ann Oncol. 2009;Suppl 4:iv41-5. 3. Garcia M, et al. American Cancer Society. 2007. www.cancer.org. Accessed Jan 2010.4. Llovet J, J Hepatol. 2000;33:423-9. 5. Marrero CR, Marrero JA. Arch Med Res. 2007;38:612-20.

Survival of the 3 Leading Indications for LTx (01/1988 - 06/2002)

Cirrhosis : 24227Cancers : 4608

Acute hepatic failure : 4026

6366

7175

82

414449

58

74

5556596165

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10

(%)

Yrs

Total Log Rank test p = 0.0001

p Log Rank :Acute Hepatic Failure vs Cirrhosis : 0.0001Cancers vs Cirrhosis : 0.0001Acute Hepatic Failure vs Cancers : 0.0001 (Wilcoxon test)

12

Brazil Germany Italy Spain UK USA0

1000

2000

3000

4000

5000

6000

1197 1018 984 1070638

5124

121 14 29 23 192

Whole liver (deceased donor) Liver (living donor)

Nu

mb

er

of

live

r tr

an

sp

lan

tati

on

s

More than 20,000 liver transplants are now performed annually worldwide

1. US Organ Procurement and Transplantation Network, OPTN. 2008. Available at: http://srtr.org/annual_reports/current/905_li.htm, accessed 28 October 2011; 2. European Liver Transplant Registry, ELTR. 2010. Available at: http://eltr.org, accessed 28 October 2011; 3. Van Gelder F et al. Organs,Tissues & Cells 2010;13:5-8.

NA

In the US, the incidence of liver transplantation was 21.6 ppm in 20071

In Europe, there were 6120 transplants during 2007, compared with only 531 in 19862

IRODaT 2009 preliminary data3

Cadaveric Donors/ million population

WL: Problems/ Management

• OLTx is the only treatment that improves Survival rate in pts. with ESLD.• OLTx is the only treatment with potential for cure in pts. with HCC in Cirrhotic

liver. • Globally, 1.4 million deaths occur annually as a result of chronic liver diseases. • UNOS Waiting List: as of April 27th,2011

Liver 16,171<30 days

85430 to < 90 days 1,43990 to 6 months 1,539Total

3832

(23.6%)>75% of ESLD pts has been listed for > 6 month

Liver Tx Waiting List is growing& Waiting times are now longer

0

2,000

4,000

6,000

8,000

10,000

12,000

The liver waiting list has grown by 23% since 1998

20052006

20072008

20092010

0

2

4

6

8

10

12

14

Time on the liver transplant wait-ing list has increased by 54%

since 2005

Med

ian

mon

ths

to tr

ansp

lant

Nu

mb

er o

f p

atie

nts

US Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients Annual Report 2011, Available at: http://srtr.transplant.hrsa.gov/annual_reports/2011/default.aspx. Accessed February 2013.

Gap between supply and demand

2007 2008 2009 2010 20111000

1500

2000

2500

3000 Number of donors Patients active on waiting list

Num

ber o

f pati

ents

In the UK, about 14% of all waiting list patients die or become too sick to undergo the transplant procedure2

Eurotransplant International Foundation Annual Report 2012, Figure 6.5, Available at: http://statistics.eurotransplant.org/.Accessed April 2013; 2. van der Meulen JH, et al. Transplantation 2007;84:572–579.

19

In the face of donor organ shortage, Organ Allocation is determined by MELD score

• MELD scale provides a predictive measure of short-term mortality risk & prognosis in patients with ESLD1,2

– MELD score is based on laboratory indicators of renal dysfunction (serum creatinine), liver disease (serum bilirubin) and bleeding risk (INR for prothrombin time)

• The higher the MELD score, the higher the priority for a liver transplant

• In the MELD era, patients with ESLD and poor renal function have become increasingly common candidates for liver transplantation3

• Allocation of donor livers is based on MELD scores in most countries

ESLD, end stage liver disease; MELD, Model for End-stage Liver Disease; INR, international normalized ratio1. Malinchoc M et al. Hepatology 2000;31:864-871;2. Kamath PS et al. Hepatology 2001;33:464-470;3. Sharma P et al. Liver Tranpl 2009;15:1142-48

MELD score: 6- 40• Serum Bilirubin, serum Creatinine & INR to predict survival

• Patients dialyzed twice within the last 7 days, value for serum creatinine should be 4.0

Hepatology, 2001

Benefit Benefit Benefit Benefit

Benefit

Benefit

• T1 no extra MELD points

• T2 (within Milan) MELD 22

Freeman RB, et al. Am J Transplant. 2006;6:1416-21.Freeman RB, et al. Liver Transpl. 2004;10:7-15.

The 2004 MELD for HCC in USA

Extended Criteria Donors (ECD)Marginal Donors

• Ideal Donor: Age<40, trauma as cause of death, donation after brain death (DBD), haemodynamic stability at time of procurement, no steatosis or any underlying liver disease & no transmissible diseases (infectious/ malignant).

• ECD: Any donor who does not fit these criteriaSRTR Data: increased utilization of elderly donors, DCD &

donors with positive markers of HBV & HCV

• Implications: 1ry graft nonfunctioning Early graft poor function

Transmission of donor derived disease

Death or need for re-transplantation

Donor after Cardiac Death (DCD)

• Def. Organ procurement after a standoff period of 5 min. after death is certified

• Implications: variable period of warm ischemia time that may result in early poor function, non-function of the graft or diffuse cholangiopathy

• Measures to halt deleterious effects on graft function: judicious donor selection (age<40, no steatosis), use of heparinized perfusate, use of extracorporeal oxygenation, short WIT (<15 min) & short CIT (<10 hrs)

Deshpande R, Heaton N: J.Hepatology 2006; 45: 499

Donor Assessment

• Age 18-50• BMI < 30• No Co-morbid disease• Phase I: ABO blood group compatibility & Blood

chemistry (CBC, Liver and Kidney function)• Phase II: Virology markers (e.g. Anti HCV antibodies,

Anti HBV antibodies, etc)• Phase III: CT scan anatomy & Volumetry.• Phase IV: Liver biopsy, Medical consultation (e.g.

Cardiac , Chest & Psychiatric consultation)

Donor Assessment

Volume of harvested lobe should be ≥ 1% of the recipient weight:

GRWR ≥ 0.8%

Recipient Assessment

• History – Etiology of liver disease– Previous liver transplantation– GIT hemorrhage– Ascites– History of SBP– History of encephalopathy– Surgical history– Medical history eg, diabetes, hypertension, ischemic

heart disease• Child-Pugh & MELD score

Recipient Assessment

CVS assessment:› Clinical examination› ECG› Echocardiography (pulmonary hypertension; cardiomyopathy, etc)› Dobutamine Stress echo

Respiratory assessment› Clinical examination› Chest x-ray› Pulmonary function tests

Renal assessment› Urea and serum creatinine &Creatinine clearance

ENT and dental examination› Exclude septic foci

Imaging and laboratory investigation

Surgical Team

Technique

• Cadaveric full size• Split

Split liver transplantation

• Partial liver graft Tx was initially suggested by Smith in 1969.

•Reduced liver graft was reported by Bismuth & Houssin 1984.

•Pichlamyr & Bismuth reported successful split liver transplant 1989

Technical Aspects of LDLT

Interrelationship for Technically Successful LDLT

Surgical procedures

• The two surgical techniques are performed simultaneously; the donor procedure last 6-8 hrs while the recipient procedure 10-12 hrs

• The donor spend the first 24- 48 hrs post-op in the ICU & an 6- 10 days in hospital

• The two half-livers (both in donor and recipient) grow back to 80% of their size in 3-4 weeks

Kidney-CD Kidney-LD Pancreas SPK Liver Heart0

10

20

30

40

50

60

70

80

90

1001 year 5 years 10 years

% G

raft

su

rviv

al

Excellent short-term but poor long-term survival

CD, cadaver donor; LD, living donor; SPK, simultaneous pancreas and kidney transplant.Levy, GA, Lake, JR, Holt, DW, Wallemacq P. Current Trends in Transplantation: Drug Therapy and Monitoring, Abbott Laboratories, Abbott Park, USA, 1–157 (2009). Published in July 2009 37

Organ type

Infections, malignancies and CVD are leading causes of death among liver transplant patients

CVD, cardiovascular diseaseUS Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients Annual Report 2008; Available at: http://optn.transplant.hrsa.gov/ar2008/Preface_Contributors.htm?cp=1, accessed 28 September 2012 38

4 12 20 28 36 44 52 60 68 76 84 920

50

100

150

200 Infection

Malignancy

CVD

Other

Unknown

Dea

ths

per

100

pat

ien

t-ye

ars

wit

h

a fu

nct

ion

ing

gra

ft

Time posttransplant, months

39

LTx pts had the 2nd-highest Cumulative Incidence of “chronic renal failure” at 5 yrs

Ojo AO et al. N Engl J Med 2003;349:931-40

Incidence of CRF in a study of >60,000 non-renal organ transplant recipients

0 12 24 36 48 60 72 84 96 108 1200.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Cum

ulati

ve in

cide

nce

of

chro

nic

rena

l fai

lure

Months since Transplantation

IntestineLiverLungHeartHeart-lung

40

Liver transplant recipients are becoming; Older with Higher MELD scores

MELD, Model for End-stage Liver Disease ;CRF, chronic renal failure 1. US Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients Annual Report 2008; Available at: http://optn.transplant.hrsa.gov/ar2008/Preface_Contributors.htm?cp=1, accessed 28 October 2011;2. Sharma P et al. Liver Transpl 2009;15:1142-8

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

0

2

4

6

8

10

12Deceased donor transplant

Living donor transplant

Patie

nts

(%)

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

0

5

10

15

20

25

30Deceased donor transplant

Living donor transplant

Age >65 years1 MELD score 21–301

US data show that 24% of recipients of deceased donor transplants have MELD score >20, compared with 9% of recipients of living donor transplants1

41

HCV recurrence post-transplant is a key unmet need in HCV patients

HCV, hepatitis C virus; CNI, calcineurin inhibitor1. Berenguer M et al. Hepatology 2002;36:202-10; 2. Prieto M et al. Hepatology 1999;29:250-256; 3. Berenguer M et al. J Hepatol 2001;35:666-78; 4. Berenguer M et al. J Hepatol 2000;32:673-684. 5. Firpi RJ et al. Liver Transpl 2009;15:1063-71; 6. Bhat I, Mukherjee S. Panminerva Med 2009;51:235-47

Liver transplant

Recurrence of infection: >98%

Acute hepatitis: 25–45%

• HCV-related chronic hepatitis: 80–100%• HCV-related graft cirrhosis: 8–30%• Cholestatic hepatitis: 2–8%

Follow-up: 3.5 months (1–13 months)

Follow-up: 5 years

• HCV reinfection is “Universal”1–5

• Early & aggressive HCV recurrence significantly accelerates the progression of the disease, compared with HCV in the non-transplant population1–5

• HCV Recurrence after LTx is associated with

– Accelerated fibrosis progression– Accelerated graft cirrhosis– Reduced graft survival– Reduced pt survival

• Reducing the use of CNIs & Steroids appears to slow the progression of HCV6

42

HCV recurrence is associated with Reduced Patient Survival

HCV, hepatitis C virus.Berenguer M et al. Hepatology. 2002;36:202-10

Log-rank p=0.0001

HCV–

HCV+

0.0

Time post-transplant (years)

1 2 3 4 5 6 7 8 9

20

40

60

80

100

0

Patie

nt s

urvi

val

(%)

HCV+

77

65

61

55

HCV–

87

83

76

70

Year

1

3

5

7

Patient survival (%)

Prospective, single-centre study of 522 pts who underwent liver transplant between 1991 and 2000

Portal pressure/bilirubin

HCC

PEI/RFA Sorafenib

Stage 0PST 0, Child–Pugh A

Very early stage (0) 1 HCC < 2 cm

Carcinoma in situ

Early stage (A)1 HCC or 3 nodules

< 3 cm, PST 0

End stage (D)

Liver transplantation TACEResection Symptomatictreatment (20%)

Survival < 3 monthsCurative treatments (30%)5-year survival (40–70%)

Palliative treatments (50%)Median survival 11–20 months

Associated diseases

YesNo

3 nodules ≤ 3 cm

Increased

Normal

1 HCC

Stage DPST > 2, Child–Pugh C

Intermediate stage (B)Multinodular,

PST 0

Advanced stage (C) Portal invasion, N1, M1, PST 1–2

Stage A–CPST 0–2, Child–Pugh A–B

Adapted from Bruix J, Sherman M. Hepatology. 2010.

AASLD = American Association for the Study of Liver Diseases;PEI = percutaneous ethanol injection; PST = Performance Status test; RFA = radiofrequency ablation;TACE = transarterial chemoembolization.

BCLC Staging System Treatment Strategy (AASLD guidelines updated 2010)

Treatment options in Intermediate HCC

Bhoori S, et al. Transplant International. 2010;23:712-22.

Proposals of Expansion of Conventional Criteria in Liver Tx for HCC

Author (year), centre Expanded criteria5-yr specific survival for exceeding Milan criteria

Yao et al. (2001), San Francisco 1 HCC 6.5 cm or 3 HCC 4.5 cm with cumulated diameter 8 cm

73%

Herrero et al. (2001), Pamplona 1 HCC 6 cm or 3 HCC 5 cm 73%

Onaca et al. (2007), Dallas 1 HCC 6 cm or 4 HCC 5 cm N/A

*Kwon (2007), Seoul HCC 5 cm, no number restriction AFP 400 ng/mL

80% (including Milan)

*Jonas et al. (2007), Berlin Any number, each 6 cm with cumulated diameter 15 cm

62% at 3 years

*Takada et al. (2007), Kyoto 10 HCC, each 5 cm PIVKA-II < 400 mAU/mL

67%

*Soejima et al. (2007), Fukuoka Any number, each 5 cm 74%

*Sugawara et al. (2007), Tokyo 5 HCC 5cm 70% (at 3 years)

Zheng et al. (2008), Hangzhou Total tumor diameter 8cm or HCC grade I/II and AFP 400 ng/mL

72.3%

*Lee et al. (2008), Asan 6 HCC 5 cm 76.3%

Silva et al. (2008), Valencia 3 HCC 5 cm with cumulated diameter 10 cm

67%

Toso et al. (2008), Edmonton TTV 115 cm3 72%

Mazzaferro et al. (2009), Milan Number of HCC nodules maximum diameter (cm) 7

71% (if microvascular invasion absent)

*LDLT = living donor liver transplantation.

AFP = alpha-fetoprotein; PIVKA-II = protein-induced by vitamin K antagonist II; TTV = total tumor volume.

Contour plot of 5-yr survival according to size & number of tumors

Mazzaferro V, et al. Lancet Oncology. 2009;10:35-43.

Size of largest tumor in mm

*1,112 patients exceed Milan criteria.

Liver Transplantation: 5-yr survival in an Exploratory Analysis of 1,556* HCC pts

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mo

rs

Mazzaferro V, et al. Lancet Oncology. 2009;10:35-43.

Patients beyond Milan criteria & exceeding “up-to-7”criteria have a poor overall survival of < 50%

Liver Transplantation: Overall Survival in an Exploratory Analysis of 1,556 HCC patients

• 444 patients within Milan criteria .• 283 patients beyond Milan criteria and within “up-to-7” criteria. • 829 patients beyond Milan criteria and exceeding “up-to-7” criteria

• More HCC pts could be candidates for transplant if precise survival estimation using individual tumor characteristics and “up-to-7” criteria is employed

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60 72Months

Su

rviv

al

pro

ba

bil

ity

1.0

Exceeding “up-to-7” criteria (N = 829)

Beyond Milan – “up-to-7” criteria (N = 283)

Milano IN (N = 444)

73%

71%

48%

Are Neo-Adjuvant Locoregional Treatment Indicated in pts listed for LT ?

• Bridge Therapy: No recommendation could be made on bridging therapy in pts with UNOS T1 HCC .

• A cost-effective analysis based on Markov

model & the review of cohort studies indicate a benefit for bridging therapies if the waiting time is expected to be > 6 months to avoid TP.

Definitions of Down-staging before transplantation

Toso C, et al. J Hepatology. 2010;52:930-6.

Neo-adjuvanttreatment

Down-staging

To decrease tumor progression

and hence dropout from the

waiting list

To improve long-term results To select pts with good

long-term outcomes among

poor risks pts.

(Response to ttt & observation time

used as a surrogate markers for

favorable biology)

To bring patient whose tumor

burden is outside accepted

criteria for Tx to within acceptable

criteria.

Before transplantation

Which is the best neo-adjuvant treatment in Pts considered for LT?

Locoregional therapy Indications Risks Benefits

RFA Small HCC (usually 3 cm), away from the liver surface,

away from major vessels

HCC seeding (1–2%) liver rupture (small)

• OK even in case of decreased liver function

• Only one session usually required

• Complete necrosis in 90% of cases

TACE Any HCC size preserved liver function (Child–Pugh A-B)

uptake of contrast

Liver failure arterial injury (2%)

• OK even for large HCCs

TARE Any HCC preserved liver function (Child–Pugh A-B),

absence of intra-hepatic shunt, uptake of contrast

Off-target embolization arterial injury

• OK even for large HCCs (up to 10 cm?)

• OK even in case of portal vein thrombosis more efficient than TACE (to be confirmed)

• Shorter time to response (to be confirmed)

Toso C, et al. J Hepatology. 2010;52:930-6.

Response to therapy is a potentially effective tool for prioritizing HCC patients for liver transplantation

Vitale A, et al. Ann Surg Oncol. 2010;17:2290-302.Siegel AB, et al. Hepatology. 2010;52:360-9.

Response to therapy as a criterion for awarding priority to patients with HCC awaiting liver transplantation

Months post-liver transplantation

Intention-to-treat survival

1.0

0.8

0.6

0.4

0.2

0 12 24 36 48 60

Responder (n = 85)

Non-responder (n = 62)

p < 0.01

Months

Free

dom

from

recu

rren

ce

Increased HCC recurrence & lower survival are linked to Several Factors

Higher exposure to CNIs1

Portal vein thrombus3 Pretransplant AFP levels1,3

Vascular invasion1

TNM staging3Tumor biology1,2

AFP, alpha fetoprotein; CNI, calcineurin inhibitor; HCC, hepatocellular carcinoma; TNM, tumor node metastasis. 1. Vivarelli M, et al. Ann Surg. 2008;248:857862; 2. Vakili K, et al. Liver Transpl. 2009;15:18611866; 3. Wang ZX, et al. Clin Transplant. 2010;24:752757. 53

54

100

75

50

25

0

HCC Recurrence post transplantation is a key unmet need in HCC pts

HCC, hepatocellular carcinoma; OLT, orthotopic liver transplant1. Valdivieso A et al. Transplant Proc 2010;42:660-2; 2. Lee KK et al. J Surg Oncol. 2010;101:47-53

Cumulative post-transplant survival for patients with and without HCC recurrence1

Surv

ival

aft

er O

LT (%

)

0 1 2 5 10

No HCC recurrence (n=159)HCC recurrence (n=23)

Years

p<0.001

3 4

HCC recurrence following transplantation ranges from 10–35%1,2

Pts with HCC recurrence have a poorer prognosis

Drinking coffee cuts liver cancer risk ??

Drinking three cups of coffee daily can reduce the risk of developing liver cancer by more than 50 per cent, a new study has claimed.

EVEROLIMUS in LTx

The incidence of acute transplant rejection is declining. . .

19921993

19941995

19961997

19981999

20002001

20022003

0%

10%

20%

30%

40%

50%

60%

US Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients Annual Reports 2003 & 2005, Available at: http://www.srtr.org/annual_Reports/default.aspx. Accessed March 2013.

Acu

te r

ejec

tio

n [

%]

Percentage of liver transplant patients who received antirejection medication by 1-year posttransplant from 1992–2003

CNI minimization in liver transplant patients

…… but High level exposure to CNIs is a well-recognized risk factor for chronic kidney disease in liver transplant recipients1

Attempts to withdraw CNI have lead to increased risk of

acute rejection2,3

CNI minimization can help tip the balance between adequate

immunosuppression and exposure to CNIs2

CNI, calcineurin inhibitor.1. Kong Y, et al. PLoS One. 2011;6:e24387; 2. De Simone P, et al. Am J Transplant. 2012;12:3008–3020; 3. Schlitt HJ, et al. Lancet. 2001;357:587591. 58

59

Everolimus + low Tac demonstrated a Comparable Safety profile with standard Tac

aThe incidence of clinically relevant proteinuria above 3 g/day in the everolimus + low Tac group was comparable to that in the standard Tac group. Patients with proteinuria ≥0.5 g/24 hrs at one month post-transplant had no progression to more severe proteinuria with everolimus + low Tac.

Incidence rates of selected adverse events

Everolimus + low Tac (n=245)

Standard Tac (n=241)

Hyperlipidemia 23.7% 9.5%

Hypertension 17.1% 15.8%

New Onset DM 19.6% 16.6%

Proteinuriaa 17.6% 0.8%

Peripheral edema 2.9% 10.8%

Stomatitis, Mouth Ulceration 9.4% 1.2%

Tremor 9.4% 12.0%

Wound Healing Complications 11% 7.9%

Tac, Tac, tacrolimusDeSimone P et al. Am J Transpl. 2012

Both Sirolimus (P≤ 0.05) & Anti-CD25 Antibody induction (P≤ 0.01) demonstrated significantly improved survivals after LTx for HCC.

HR (95% CI) to compare Risk of Mortality after LTx using diff. immunosuppress. protocols. Results corrected for MELD, Tx year, Primary Liver Disease (non-HCC), Age at Tx & when applicable: TTV, AFP & PreTx HCC ttt.

*Significant variables

Use of Everolimus as a Rescue Immunosuppressive therapy in Liver Transplant Patients with Neoplasms

Gomez-Camarero J et al, Transplantation 2007;84: 786–791

Father of Modern Transplantation

Thomas StarzlFirst successful human liver transplant in 1967 (Denver, U.S.A.)

No sense of accomplishment can exceed that of seeing a robust LT recipient who, a few weeks earlier, was seemingly near death from ESLD.

Summary

• Successful LTx requires optimal patient selection and timing of Tx.• Indications across most centers are similar, however, a regional

difference exists with HCC & metabolic reasons being on the rise. • To date, MELD score is the most accurate to predict early outcome of

LTx & to prioritize organ allocation including that for HCC patients.• Organ shortage is currently tackled by: ECD & Surgical innovation. • Current unmet needs following LTx include: minimizing CNI toxicity,

CKD, HCV & HCC recurrence.• Introduction of new immunosuppressant with less severe AEs and

equivalent anti-rejection efficacy are urgently needed with mTORi emerging as a new player in this context.