chung mau lo 2
TRANSCRIPT
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Living Donor Liver Transplantation
for Hepatocellular Carcinoma
Chung-Mau Lo
Chin Lan Hong Professor of Hepatobiliary Surgery
Department of Surgery
The University of Hong Kong Medical Center
Queen Mary Hospital
Hong Kong, China
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Pros:
Widest resection
Removes multicentric tumor/intrahepatic metastasis
Prevents metachronous disease
Cures underling liver disease
Prevents liver failure
Most accurate pathologic staging
Cons:
Transplant-related morbidity
Need for immunosuppression
Recurrence under immunosuppression
Cost
Limited organ supply
HEPATOCELLULAR CARCINOMA
Liver Transplantation
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HEPATOCELLULAR CARCINOMA
Selection Criteria for Transplantation
Criteria n long-term survival
Milan solitary 5 cm 48 75%
(NEJM 1996) 1-3 lesions, 3 cm
USCF solitary 6.5 cm 70 72.4%
(Hepatology 2001) 1-3 lesions, 4.5 cm
total diameter 8 cm
Expected 5-year survival >70%
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Limited availability
restricted candidacy
Prolonged waiting timetumor progression and dissemination
Unpredictable timingimpossible to plan neoadjuvant treatmentinaccurate assessment of tumor status
HEPATOCELLULAR CARCINOMA
Liver Transplantation: Deceased Donor Graft
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HEPATOCELLULAR CARCINOMA
Liver Transplantation: Intention-to-treat Analysis
Survival(%)no. of patients drop out 1 years 3 years 5 years
Llovet et al 1999
Partial hepatectomy 77 / 85 62 51
Liver transplant 87 8 (9%) 82 69 69
Yao et al 2002
Liver transplant 46 11 (23%) 92 73 /
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HEPATOCELLULAR CARCINOMA
Liver Transplantation
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HEPATOCELLULAR CARCINOMA
Living Donor Liver Transplantation
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Deceased donor Living donor
Availability
Source Limited Unlimited
Candidacy Maximal benefit Risk/benefit analysis
Allocation Objective criteria Dedicated gift
Waiting time Long Short
Timing Unpredictable Planned
HEPATOCELLULAR CARCINOMA
Liver Transplantation: Deceased Vs Living Donor
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0 12 24 36 48 60
Months
0
10
20
30
40
50
60
70
80
90
100
Patie
ntsurvival(%)
LDLTCDLT
no transplant
HEPATOCELLULAR CARCINOMA
Deceased Donor Vs Living Donor- Decision Analysis
Cheng et al, Transplantation 2001
86%
71%
63%
8%
42%
68%
Hypothetical cohort of patients:
unresectable HCC of 3.5 cm with cirrhosis
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Ignores the risks of living donors
Wrong assumptions Living donor readily available
Comparable outcome between deceased and living donor transplants
HEPATOCELLULAR CARCINOMA
Limitation of Decision Analysis
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Ignores the risks of living donors
Wrong assumptions Living donor readily available
Comparable outcome between deceased and living donor transplants
HEPATOCELLULAR CARCINOMA
Limitation of Decision Analysis (I)
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Location Number Total
Asia Japan 1 5
Hong Kong 1
Singapore 1
India 2
Europe Germany 2 4
France 1
Unknown 1N. America USA 3 3
S. America Brazil 1 1
Africa Egypt 1 1
Total 14
LIVING DONOR LIVER TRANSPLANTATIONDonor Deaths
Search in medical and lay literature
Trotter, Adam and Lo Liver Transplantation 2006
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Ignores the risks of living donors
Wrong assumptions
Living donor readily available
donor voluntarism
donor selection criteria
Comparable outcome between deceased and living donor transplants
HEPATOCELLULAR CARCINOMA
Limitation of Decision Analysis (II)
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Selection Criteria
Recipients (n=51)
65 years old
unresectable HCC, Milan/UCSF criteria Donors
voluntarism and informed consent
60 years old
ABO compatibility
negative hepatitis serology and normal liver function
no extra operative risk
graft size >40% of recipients standard liver weight
liver remnant >30% of donors standard liver weight
HEPATOCELLULAR CARCINOMA
Are Living Donors Readily Available?
Lo et al, Liver Transplantation 2004
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Patients with HCC on
list
51
On list for CDLT
30
Voluntary donor available
25
No voluntary donor
26
Died before CDLT 19
Alive, off list 2Alive, waiting 1
CDLT oversea 2
CDLT performed
6(12%)
LDLT performed
21 (41%)
Donor not suitable 4HBsAg positive 2ABO incompatible 1Liver dysfunction 1
HEPATOCELLULAR CARCINOMA
Results
Lo et al, Liver Transplantation 2004
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0 6 12 18 24 30 36 42 48
Time (months)
0
10
20
30
40
50
60
70
80
90
100
Probabilityofpatientsurvival(%)
No. at riskWith donor 25 24 23 16 13 9 7 3 3Without donor 26 22 18 14 8 7 6 5 4
HEPATOCELLULAR CARCINOMA
Intention-to-treat Patient Survival
Lo et al, Liver Transplantation 2004
66%
31%
P=0.029
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Ignores the risks of living donors
Wrong assumptions
Living donor readily available
donor voluntarism
donor selection criteria
Comparable outcome between deceased and living donor transplants
Lower graft survival
Higher risk of biliary complications
Other complications and learning curve effect
?Higher recurrence rate
Lack of waiting period for drop-out of poor risk tumors
acute-phase injury of small-for size graft with regeneration and angiogenesis
promotes recurrence
HEPATOCELLULAR CARCINOMA
Limitation of Decision Analysis (III)
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LIVING DONOR LIVER TRANSPLANTATION
Graft Survival in Adults (US Data)
LDLT
Donor younger shorter ischemic time
Recipient
fewer retransplant lower MELD score fewer status 1 or 2a
Abt et al, Am J Transplantation 2004
A Marginal Graft!?
Adjusted HR for graft failure requiringretransplantation = 1.66 (1.30-2.11)
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0 6 12 18 24 30 36 42Time (months)
0
0.2
0.4
0.6
0.8
1
Probabilityofsurvival
RIGHT LOBE LIVER TRANSPLANTATION
Graft Survival
96%100%
74%
First 50 cases
Second 50 cases
74%78%
P=0.0015
Lo et al, Ann Surg 2004
Relative risk (95% CI) P-valueSecond 50 cases 0.13 (0.03-0.66) 0.014 Child C 2.28 (0.28-18.87) 0.443MELD >30 1.96 (0.35-11.10) 0.446ICU-bound 0.30 (0.05-1.88) 0.200Hepatorenal syndrome 0.95 (0.22-4.05) 0.947
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Kyoto (Kaihara, 2003) Mount Sinai (Gondolesi, 2004)
Number of patients 56 36
Byond Milan criteria 25 (45%) 19 (53%)
Median follow up (mths) 11 (1-39) 15.7 (
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LDLT (n=43) DDLT (n=17)
Age (yrs) 52 (11-64) 49 (38-61)
Male gender 39 (91%) 15 (88%)
MELD score 15 (6-59) 16 (12-33)
Incidental tumour in explant 3 (7%) 5 (29%)*
Recurrence after hepatectomy/RFA 10 (23%) 1 (6%)TOCE after on list 1 (2%) 4 (50%)*
AFP (ng/ml) 30 (1-15084) 19 (4-902)
* p
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LDLT (n=43) DDLT (n=17)
Waiting time (days) 27 (1-341) 110 (7-1359)*
Graft weight (gm) 570 (330-1120) 1105 (830-1845)*
Graft weight/recipient SLW 0.45 (0.31-0.79) 0.85 (0.62-1.87)*
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LDLT (n=43) DDLT (n=17)
Tumor no. 1 (1- >9) 1 (1- >9)
Tumor size 2.5 (1.0-7.0) 2.5 (1.2-6.5)
Vascular permeation 15 (35%) 3 (18%)
Differentiation (well/moderate/poor) 17/18/8 5//9/3
Beyond Milan criteria 11 (26%) 5 (29%)
Beyond UCSF criteria 7 (16%) 2 (12%)
HEPATOCELLULAR CARCINOMA
Deceased Donor Vs Living Donor-Histology
Lo et al, BJS in press
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LIVER TRANSPLANTATION FOR HCC
Patient Survival
0 6 12 18 24 30 36 42 48 54 60
Time (months)
0
20
40
60
80
100
Overallpatientsurv
ival(%)
Cause of death LDLT DDLT
recurrent HCC 6 0
recurrent HCV 1 0
recurrent HBV 0 1
Others 3 0
No. at risk
Living donor graft 43 35 30 26 20 15 11 7 5 3 2
Deceased donor graft 17 15 13 13 11 10 8 7 7 6 6
LDLT (n=43)
DDLT (n=17) 94%
58%
P=0.187
Median follow-up 33 (4-120) months
Lo et al, BJS in press
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LIVER TRANSPLANTATION FOR HCC
Recurrence Rate
No. at risk
Living donor graft 43 41 33 27 22 17 14 10 6 5 4
Deceased donor graft 17 16 16 13 13 13 10 8 7 7 6
LDLT (n=43)
DDLT (n=17)
29%
0%
P=0.029
Median time to recurrence 15 (6-26) months
0 6 12 18 24 30 36 42 48 54 60
Time (months)
0
20
40
Cumulativerecurrencerate(%)
Lo et al, BJS in press
All patients fulfilled radiologic UCSF criteria
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5-yr survival p-value 5-yr recurrence p-value
Incidental tumor (yes/no) 100%/64% 0.102 0%/23% 0.160
Salvage transplant (yes/no) 63%/81% 0.053 45%/14% 0.002
Graft type (LDLT/DDLT) 58%/94% 0.187 29%/0% 0.029
Graft weight/SLW ( 0.6/>0.6) 53%/96% 0.078 32%/0% 0.009
Tumor no. ( 3/> 3) 72%/67% 0.152 16%/52% 0.032
Vascular permeation (yes/no) 69%/74% 0.206 29%/16% 0.034
Beyond Milan criteria (yes/no) 71%/71% 0.412 38%/14% 0.028
Beyond UCSF criteria (yes/no) 67%/72% 0.180 50%/16% 0.047
LIVER TRANSPLANTATION FOR HCC
Results-Prognostic Variables
Lo et al, BJS in press
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Time to Recurrence by Donor Type
Free
domfromR
ecurrence
(%)
100
75
25
0
50
Years from Transplant
0 1 2 3
DDLT
LDLT
Unadjusted P=0.0024
A2ALL, AASLD San Francisco 2006
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Recurrences by Stage at Explant
17/870/3117/56Total
5/240/85/16T4a or T4b
7/240/57/19T3
4/300/134/17T1 or T2
1/90/51/4No HCC
TotalDDLTLDLTStage at Explant
A2ALL, AASLD San Francisco 2006
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Orthotopic rat liver transplantation modelMale Buffalo rats (300g) as donors and recipients
Whole graft Small (50-60%) graft
Sampling at day 1, 3, 7, 14 and 21 after liver transplantation
Acute phase injury
Tumor cell (CRL1601, 2105) injection
via portal vein after reperfusion
Tumor progression
and invasion
AngiogenesisCell adhesion
and invasion
Histology
Protein expression IHC and Western blot
Gene expression - cDNA microarray
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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Whole graft
Small graft
Day 14 Day 21
Larger tumor in small liver graft
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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Invasive growth pattern in small liver graft (day14)
Whole graft
Small graft
Tumor Non-tumor
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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Whole graft
Small graft
Venous invasion in small liver graft (day21)
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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010
20
30
40
50
60
70
80
90
100
Day 14 Day 21
Whole graft
Small graft
Percent of liver occupied by tumor
*
*
0.061
0.015
4/6 (66.7%)
6/6 (100%)
0/6 (0%)
1/6 (16.7%)
Tumor growth
at day 7
by macroscopy
by microscopy
0.01210/12 (83.3%)3/12 (25%)Tumor thrombus
0.00311/12 (91.7%)3/12 (25%)Venous invasion
PSmall graftWhole graft
Tumor Invasiveness
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size- Tumor Growth and Invasiveness
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Day 14 Day 21
Whole graft
Small graft
Significant tumor proliferation (Ki67) in small liver graft
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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Whole graft
Small graft
Significant stellate cell activation (-SMA) in small liver graft
Da 14 Da 21
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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CAKRac1
Whole graft
Small graft
Significant activation of cell invasion signals in small liver graft
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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Up-regulation of ROCK and VEGF in small liver graft
T NT T NT T NT T NT
Whole graft Small graft
Actin
VEGF
ROCK I
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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Distinct gene signature linking to acute phase injury and proliferation in
small liver graft - by cDNA microarray screening (day 1)
Gene names (selected)Gene names (selected) Fold ratio (S/W)Fold ratio (S/W)Wnt 4 24.25Ki67 6.06
Cell division cycle control protein (Cdc2a) 3.73
G protein coupled receptor 19 (GRP19) 3.48
IP10 2.14
IL1b 2.14IL1r2 2.14
MMP2 1.87
HSP70 0.18
Insulin-like growth factor binding protein 3 (IGFBP3) 0.41
LIVER TRANSPLANTATION FOR HCC
Effect of Graft Size-Animal Model
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Acute phase injury and late phase tumor recurrenceAcute phase injury and late phase tumor recurrence
Liver transplantation using small liver graft
Portal hyperperfusion-
Shear stress
Inflammatory cascades
Angiogenesis
(VEGF , HSC activation )
Favorable environmentfor tumor growth and
metastasis
Liver regeneration
Hepatic sinusoidal injury
Microvascular barrier dysfunctionIncreased vascular permeability
Cell adhesion, migration
and invasion
(ROCK , RAC , CAK )
Tumor cell proliferation
(Ki67 )
Invasive tumor growth in small liver graft
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The benefits of LDLT over DDLT for early HCCderived from decision analysis should be interpretedwith caution
There is a risk of waiting list mortality both for organallocation in DDLT and for donor voluntarism/selectionin LDLT
Difference in selection of patients and graft size mayresult in a higher recurrence rate after LDLT for earlyHCC
The role of LDLT for HCC remains to be defined by
more clinical studies
LIVING DONOR LIVER TRANSPLANTATION
Summary
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Figure 1
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1-a 2-a
1-b 2-b
Day 14 Day21
0
10
20
30
40
50
60
70
80
90
100
Day 14 Day 21
Whole graft
Small graft
% of liver occupied by tumor
*
*
1-a 2-a
1-b 2-b
0
200
400
600
800
1000
1200
Week 4 Week 6
Liver tumor from whole graft
Liver tumor from small graft
*
*
Tumor volume (mm3)
Week 4 Week 6
A B
3 3
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Distinct gene signature linking to tumor invasiveness in small liver graft
- by cDNA microarray screening (day21)
Gene names (selected)Gene names (selected) Fold ratio (S/W)Fold ratio (S/W)
Laminin 5 beta3 chain 4.29S100 calcium binding protein A8 (S100A8) 4.29
S100 calcium binding protein A9 (S100A9) 3.03
IL6 2.46
HSP70 3.03
MMP2 2.83
MAPK13 2.14Tissue factor 2.14
Foslike antigen1 (FOSL1) 2
Insulin-like growth factor binding protein 2 (IGFBP2) 0.38
Serine protease inhibitor (Spin2b) 0.31
Claudin-7 0.27
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Poor expected outcome
Advanced malignancy
Sickest complicated cirrhosis
Psychosocial problems e.g. alcoholism
Relative contraindications e.g. HIV positive
Minimum outcome limit
1-yr survival=50%
5-yr survival=30%
LIVING DONOR LIVER TRANSPLANTATION
Extended Indications
Malago et al, Liver Transplantation 2001
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HEPATOCELLULAR CARCINOMA
Liver Transplantation: Extended Indication
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LIVING DONOR LIVER TRANSPLANTATIONHepatocellular Carcinoma: Extended Indications
Multi-center study on 316 patients with HCC
49 transplant centers- one-third adopt Milan criteria
, n=137, n=172 , n=137, n=172