Eric VIBERTCentre Hépato-Biliaire, INSERM U1193, DHU HepatinnovHopital Paul Brousse, APHP, Villejuif

Les alternatives à la Transplantation Hépatique Cadavérique

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La transplantation hépatique classique

Prélèvement Cœur Battant Foie entier

23%

78%

Type of Liver Graft in Europe according to the Date of Transplantation

100

80

60

40

20

0

%

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012

Others : 14967 Cadaveric Full size : 94895

ELTR

Alternatives to the Use of the Full SizeCadaveric Liver Grafts in Europe

100

80

60

40

20

0

%

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012

Reduced liver : 2292NHB : 1318

Living donor : 6349

25%

50%

10%

Split liver : 6255Domino : 881

ELTR

Transplantation d’un foie cadavérique partagée

Foie droit + Seg 4/1 Lobe Gauche Foie droit Foie Gauche

Split Adulte / Enfant Split pour 2 adultes

Transplantation d’un foie issu d’un donneur vivant

Foie droit Foie gauche

L’intérêt du Donneur Vivant dans le CHC ?

12% de Drop-out

Optimisation de l’attribution des greffons

Délai d’attente de 6 mois à 1 an

At Listing Actually Received Transplant

Candidates forCDLT (n=147)

Candidates for LDLT (n=36) P Value Transplanted with

CDLT (n=120)Transplated with

LDLT (n=36) P value

Sex, men/women 125/22 32/4 0.55 100/20 32/4 0.41

Age, years 56 ± 8 55 ± 7 0.51 56 ± 8 54 ± 7 0.45

Ethiologiy of cirrhosis, n (%)- Viral- Alcoholic- Other

99 (67)38 (26)10 (7)

28 (77)6 (16)2 (6)

0.2788

26 (21)6 (7)

28 (77)6 (16)2 (6)

0.58

HIV coinfection, n (%) 20 (13) 2 (6) 0.18 15 (12) 2 (5) 0.24

MELD score 13.5 ± 5.6 14.5 ± 6.0 0.35 14.5 ± 5.9 13.5 ± 5.9 0.35

AFP, ug/L 309 ± 2,052 207 ± 779 0.77 77.0 ± 360 207 ± 779 0.16

No. of nodules 2.0 ± 2.1 2.1 ± 1.7 0.81 1.9 ± 2.1 2.1 ± 1.7 0.68

Maximum tumor diameter, mm 29 ± 21 29 ± 11 0.95 30 ± 23 29 ± 11 0.73

Beyond Milan criteria, n (%) 33 (22) 10 (27) 0.49 26 (21) 10 (27) 0.44

Outside UCSF criteria, n (%) 20 (13) 5 (13) 0.96 16 (13) 5 (13) 0.93

Pretransplant ablation therapy, n (%) 68 (40) 13 (36) 0.80 45 (38) 12 (33) 0.73

Transarterial chemoembolization, n (%) 65 (96) 12 (92) 0.57 42 (93) 11 (92) 0.87

Radiofrequency ablation, n (%) 3 (4) 1 (8) 0.57 3 (7) 1 (8) 0.87

Survie identique après listing et transplantation

100

80

60

40

20

00 12 24 36 48 60

% o

f su

rviv

al

Patients at risk (N.)

CDLTLDLT

14736

12930

8326

6419

Months

Log rank; p=0.68

73%

71%

80%

77%

89%

86%

89%

86%

100

80

60

40

20

00 12 24 36 48 60

% o

f su

rviv

al

Patients at risk (N.)

CDLTLDLT

12036

10530

6925

4718

Months

Log rank; p=0.36

73%

82%

80%

82%

86%

90%

Les conséquences de la précipitation…

100%

80%

60%

40%

20%

0%0 12 24 36 48 60

Patients at risk (N.)

CDLTLDLT

11426

10022

7019

4412

Months

Log rank; p=0.14

84%

70%

84%

77%

88%

88%

100%

80%

60%

40%

20%

0%0 12 24 36 48 60

CDLTLDLT

3310

288

227

152

Months

Log rank; p=0.0642%

74%

70%

78%

80%

85%

Dans Milan Hors Milan

At the End of Year

1 2 3 4 5 6

DDLT 5 9 11 15 19 20

LDLT 8 10 12 14 16 16

100

80

60

40

20

00 65

Years from Transplant4321

Survie Sans Récidive

Number of Recurrencesor Deaths

At the End of Year

1 2 3 4 5 6

DDLT 64 52 43 29 18 10

LDLT 36 29 21 14 7 4

Number at Risk

DDLT

LDLT

2012

1998-2009 : 229 patients avec HCC évalués pour un potentiel DV100 Tranplantés en DV (LDLT), 97 en DC (CDLT) et 32 Non TH

Log-rank p=0.4973

100

80

60

40

20

00 65

Years from Transplant4321

Survie Global

At the End of Year

1 2 3 4 5 6

DDLT 5 6 8 11 16 17

LDLT 4 9 10 12 12 13

Number of Deaths

At the End of Year

1 2 3 4 5 6

DDLT 64 55 46 31 18 10

LDLT 41 31 24 16 11 6

Number at Risk

DDLT

LDLTLog-rank p=0.2969

At the End of Year

1 2 3 4 5 6

Non-LDLT 75 66 54 35 24 16

LDLT 40 31 24 16 11 6

Number at Risk

100

80

60

40

20

0

0 65

Years from Donor Evaluation

HR=0.90 p=0.8271

4321

Non-LDLT

LDLT

Salvage Transplantation for HCC on cirrhotic liverOverall Survival in Paul Brousse Hospital

100

Log rank p= 0.038

100%

81%

Living donor : 11

Cadaveric donor : 22

80

60

40

20

0

50 4321

100%

56%

78%

41%

Activité de greffe hépatique à partir d’un donneur vivant (sauf domino) adulte + enfants

Remerciement C. Antoine

60

50

40

30

20

10

01992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

8 équipes autorisées pour le prélèvement de foie sur donneur vivant

44 des 46 prélèvements réalisés sur 2 sites

Foie droit

Foie gauche

14 5

10 11

18 1813 15 15

512

10

19 21

95

914 11

3

12 12

1 410

37 33

40 3039

30

15

9

53

33

6

1

Living related LT in Europe - Donor Operative Mortality6 / 3263 (0.18%) Oct. 1991 – June 2009

Early mortality < 2 months

Relation Type of graft Mortality Cause of death

Mother LLB 2 days Pulmonary embolism

Brother RLV 11 days Sepsis – MOF

Spouse RLV 21 days Sepsis – MOF

Mother RLV 32 days Heart failure

Son RLV 49 days MOF

Brother RLV 56 daysMOF associated

to myeloma

ELTR

19 (0.16%) Décès en rapport avec le don dont 2 suicides

136 (1.2%) Hépatectomies finalement non réalisées (Arrêt de Procédure - AH)

126 (1.1%) Evènements « Near Miss » (Evénements qui aurait pu être fatal)

4 (0.03%) Transplantation Hépatique et 1 (0.008%) Transplantation Rénale

71 Services (48% des centres mondiaux) 11 553 Donneurs dans 21 pays

2000-2009n=90

DV1 - DV45n=45

DV45 - DV90n=45

Transfusion 22(24%) 16(35%) 6(13%) <0.01

Durée Hosp 13 +/- 5 12 +/- 3 14 +/- 6 0.08

Réhosp. 19 (21%) 13 (28%) 6 (13%) 0.08

Morbidité 43 (47%) 22 (48%) 21 (46%) ns

Morbidité MineureMorbidité Majeure

32 (35%)20 (22%)

13 (28%)14 (31%)

19(42%)6 (13%)

0.04

Fistule Biliaire 7 (14%) 7 (15%) 6 (15%) ns

Pulmonaire 4 (10%) 4 (9%) 5 (11%)

Insuffisance Hep 7 (8%) 6 (13%) 1 (2%) 0.05

Short- and long-term donor morbidityin right lobe living donor liver transplantation:91 consecutive cases in european center

Azoulay et al. Am J Transpl 2011

Operative morbidity of living donors in Japan1989 – 2002 : 1853 donneurs sur 46 Centres – Pas de mortalité

Graft type n Mortality Morbidity (%)

Monosegment (segment 3) 8 0 0 (0)

Lateral segment 753 0 62 (8.2)*

Posterior segment 13 0 2 (15.4)

Left lobe 484 0 58 (12)†

Left lobe and caudate lobe 140 0 22 (15.7)

Right lobe 443 0 84 (19)

Total 1841 0 228 (12.4)

*p=0.038 compared with left lobe; p=0.011 compared with left lobe and caudale lobe; and p<0.0001 compared with right lobe. † p=0.0035 compared with right lobe

Graft type n

Complication

Biliary fistulaGastroduodenal

complication

Segment 3 8 0 (0-0%) 0 (0-0)

Lateral segment 753 14 (1-9%) 20 (2-7)

Posterior segment 13 0 (0-0%) 0 (0-0)

Left lobe 484 9 (1-9%) 20 (4-1)*

Left lobe and caudate lobe 140 5 (5-6%) 4 (2-9)

Right lobe 443 45 (10-2%)† 5 (1-1)

Total 1841 73 (4-0%) 49 (2-7)

*p=0.007 compared with right lobe; † p<0.0001 compared with lateral segment and left lobe p=0.015 compared with left lobe and caudale lobe

Plus de complication Biliaire après Hépatectomie DrtMorbidité supérieur après Hépatectomie Drt

FactorsLeft lobe(n=200)

Right lobe(n=112)

P-value

Complications (%)

SFSS 19.5 7.1 0.0063

HAT 2 1.7 NS

PVT 2 0.9 NS

ACR 16 17 NS

Bile leak 6.5 5.4 NS

Bile duct stictures 20 17 NS

Relaparotomy 15 8.9 NS

In-Hospital mortality 12 8 NSYears posttransplant

0

20

40

60

80

100

2 4 6 10 12 14

Survie du Greffon Identique

0 8

Right lobe (n=112)

Left lobe (n=200)

P=NS

Cu

mu

lati

ve s

urv

iva

l (%

)

Left Lobe

Left lobeMELD <30 ; *GV/SLV >35%

Right lobeRemnant liver volume >35%

Yes No

RLG selection HPCS (-)

GRWR = Poids du Greffon / Poids du Receveur

LLG selection

GRWR <0.6% GRWR >1%0.6% < GRWR < 1%

PVP >20mmHg PVP <20mmHg

HPCS (-)HCPS (+)

2013

Splenectomy si PP > 20 mm Hg

Firts author Year Surgical techniques or therapies Case no.

Nishizaki 2001 Adult-to-adult cases, predicted GV/SLV > 30% 1

Ikegami 2001 Left-lobe graft with the caudale lobe 17

Shimada 2004 Splenic artery ligation 37

Hiroshige 2003 Three-dimensional CT-based graft volumetry 39

Suehiro 2005 Graft venoplasty and recipient cavoplasty 50

Soejima 2012 Predicted GV/SLV >35% 102

Ikegami 2009 Splenectomy for portal venous pressure control 122

Refinements of surgical techniques and therapies forLeft-lobe living donor liver transplantation

GV: Graft Volume; SLV: Strandard Liver Volume

0

10

20

30

Laparotomy

Po

rta

l ven

ou

s p

ress

ure

(mm

Hg

)

End of surgery

p<0.01

0

10

15

20

ERA-In=121

Tota

l bili

rub

in (

mg

/dl)

p=0.02

5

ERA-IIn=129

0

1

1.5

2

ERA-In=121

Asc

ites

ou

tpu

t (L/

da

y)

p<0.01

0.5

ERA-IIn=129

In conclusion, the outcomes of left-lobe LDLT were ignificantly improved by accumulated experience and technical developments including wide veno-canal anastomosis and splenectomy

Post-transplant years0

20

40

60

80

100

1 2 3 5

Cumulative graft survival rate in Era-I and ERA-II

0 4

ERA-I (n=121)

ERA-II (n=129)

P<0.01

Cu

mu

lati

ve g

raft

su

rviv

al r

ate

(%

)

DV1-DV121 DV121-DV250 p

MELD 15.7 +/- 7.4 16.4 +/- 7.3 ns

Donor 35 +/- 11 35 +/- 10 ns

Male 91 (75%) 41 (46%) 0.05

GRWR 0.84 +/- 0.25 0.71 +/- 0.13 0.01

Splenectomy 9(7.4%) 89 (69%) 0.01

Dysfunct 18 (15%) 9 (7%) 0.04

Survie 1 an 82% 91% 0.01

Open (n=20) Full Laparoscopic (n=22) p

Lenght of stay (mean ±SD), days 5.95 ± 1.5 4.27 ± 1.5 0.001

Back to work (mean ±SD), days 63.07 ± 38.2 33.66 ± 7.0 0.01

Blood loss (mean ±SD), cc 375.3 ± 190.9 177.3 ± 100.6 0.001

Surgery duration(mean ±SD) 6 hours 38 minutes± 42 minutes

7 hours 58 minutes± 1 hour 0.001

Hernia, n(%) 3 (15) 1 (4.5) 0.25

Bile leak, n(%) 2 (10) 1 (4.5) 0.49

Reoperation, n(%) 4 (20) 1 (4.5) 0.12

Donor Outcomes

103 (100%) FDutilisé localement

13/21 (61%) FGutilisé localement

8 FG prélevés pour pédiatrie

Type d’hépatectomie pour DV à PB sur 15 ans

Coelio Pur 4/21 (19%)

Hybride 12/21 (57%)

Laparo 5/21 (24%)

63

28

12

3

18

0

10

20

30

40

50

60

70

2000-2005 2005-2010 2010-2015

Co

un

t

RightLeft

Comparaison Donneur Foie droit – Foie Gauche

TH FD DV (n=103) TH FG DV (n=21) p

Age Donneur 39±12 40±7 0.4

Homme 35% 75% 0.002

Voie d’abordLaparoHybrideCoelio pur

97.1%2.9%0%

23.8%57.1%19%

0.0001

Graft Weight Ratio (%) 0.78±0.17 1.34±0.18 < 0.0001

Perte Sanguine 708±585 478±405 0.1

Fistule Biliaire 15.5% 4.8% 0.1

Collection Post-Opératoire 3% 9.50% 0.4

Encephalopathie Hépatique 1.90% 0 0.7592

Pneumopathie 2.90% 4.80% 0.8

Durée Hospitalisation 12.9±5 7.3±2.5 0.0001

Biologie Post-opératoire Donneur FD vs FG

Time after hepatectomy

-40

20

40

60

80

100

Day 1 Day 5Day 3

Right

Left

Bili

rub

in le

vel (

mm

ol/

l)

0

-20

Time after hepatectomy

-40

20

40

60

80

100

Day 1 Day 5Day 3

Right

Left

Bili

rub

in le

vel (

mm

ol/

l)

0

-20

Résultat Transplantation Hep. Adulte FD vs FG

TH FD DV (n=108) TH FG DV (n=13) p

Age Receveur 46±13 45±19 0,8531

IndicationCancerEnd Stage Liver DiseaseMaladie MétaboliqueHepatite Fulminante

55 (51%)35 (32%)14 (13%)

4 (4%)

8 (61%)4 (31%)1 (7%)0 (%)

ns

Graft Weight Ratio (%) 1,15±0.3 0,72±0.2 < 0.0001

Durée Hospitalisation (Jours) 29±15 28±17 0,973

Sténose Biliaire N (%) 21 (19%) 1 (7%) 0,511

Thrombose AH N (%) 6 (5.6%) 2 (16%) 0,3932

Dysfonction Greffon / Small For Size N (%) 24 (20%) 9 (75%) 0,0004

ReTH N (%) 5 (4.6%) 3 (25%) 0,7237

Survie à 1 an 72% 69% 0,9

Early Recurrence

Into the HCC

Preemptive LT

CI à la TH

?Test of time…

Swiss Watch

Late Recurrence

Into the parenchyma

Scatton et al. Liver Transpl. Fuks et al. Hepatology

Bridge LT If recurrence

Salvage LT

2015

0.6

0.4

0.0

0

p=0.587

0.2

0.8

9624 48 72 12012 36 60 84 108

1.0

13465

11157

10652

5124

8739

106

Intention-to-treat Transplanted patients

6332

0.6

0.4

0.0

0

p=0.044

0.2O

vera

llSu

rviv

al(%

)

0.8

9624 48 72 12012 36 60 84 108

1.0

17271

13267

12158

10250

147

PHNo PH

Months

p=0.01

Months

p=0.04p=0.02

38%

22% 22%

16%

7%8%

Globaldrop out

Tumorprogression

Drop outdue to TP

No PHPH

Uncontroled NHBD Maastrich 2 Controled NHBD Maastrich 3

Transplantation d’un foie issu d’un donneur en arrêt cardio-circulatoire

5 à 8%

> 60%

IF < 8h

0 60 120 840660540420300180 780

Minutes

<15 min.

Car

dia

car

rest

CPR < 150 min.

Dea

th

Operating roomCold ischemia

<480 min. (liver)ANOR<240 min

(1) (2) (3)

AS/AL < 200 UI/ml

0

20

40

60

80

100

Kidneytransplanted

Liver transplanted

Reins sur machine

NS

BDD

Type 2 DCD

0.2

Surv

ival

(%)

0.4

0.6

0.8

1.0

0.0480 12 24 36

Months

69%

p=0.031

0.0

0.2

Surv

ival

(%)

0.4

0.6

0.8

1.0 BDD

Type 2 DCD

480 12 24 36

Months

Patients Grafts

Liver Transplatation 21:631-643, 2015

13 transplantations

3 PNF (23%) → 3 reTH → 1 Décès 1 Décès post-op par Sepsis 2 Sténose Biliaires (20%)

2010200920082007200620052004

80

90

70

60

50

40

30

20

10

020032002*

132

26

11

29

18

41429

21025

71631

41735

42045

81659

Transplants (n=34)

Organ Donors (n=111)

Potential Donors (N=255)

-110 excluded during CRS

-145 excluded during NECMO

-111 excluded at organ recovery

400 protocol activations

290 canulations

145 organ donors

34 OLT 8,5%

< 15 min asystolie ≤150 min de planche à masser ≤240 min de NECMO

8/34 (12%) cplc. BiliairesDont 3 responsables de ReTH

Survie du malade et du greffon

DCDDBD

6207

9254

14315

17390

24463

34538

0

20

Pati

ent

surv

ival

(%)

40

60

80

100 DBD

p=0.141

DCD

60480 12 24 24

Time (months)

DCDDBD

4193

6242

10304

12375

19444

34538

DBD

p=0.011

DCD

20

gRA

FTsu

rviv

al(%

)

40

60

80

100

060480 12 24 24

Time (months)

Phase d’arrêt Circulatoire

Prise en charge

Décision de Limitation ou

Arrêt Thérapeutique

Foie < 30 minPoum. < 90 minRein < 120 min

Le Maastricht 3 à la Française….

Perfusion des organes CRN

Admission ExtubationConstat de décès

Asystolie

PAM < 45 mmHg

Phase agonique

< 30 min !!!

Ischémie chaudefonctionnelle

NHBD Maastrich 3 (n=8 pts) Résultats à Court Terme

Grafttype

Donor

Functional warm ischemia*

Age(yr)

AST(IU/L)

Total DWIT (min)

MAP<50 mmHg

to flush (min)

Syst P<50 mmHg

to flush (min)

AsyslWIT

(min)

DCD (n=8)

1 40 183 26 25 22 20

2 38 246 41 30 26 18

3 54 33 39 34 30 17

4 62 40 32 29 25 15

5 37 26 42 31 28 17

6 55 120 36 22 20 16

7 53 62 36 34 29 21

8 64 273 43 41 36 17

Median 54 91 38 31 27 18

*No. of HCC in cohort - †1 x intrahepatic lymphoma, 1x lung cancer

DBD (n=8) DCD (n=8)

Primary non-function 0/8 0/8

Delayed graft function 0/8 0/8

Acute Kidney failure requiring

intermediate dialysis/

hemofiltration

3/8 2/8

Arterial thrombosis 0/8 0/8

Extrahepatic biliary

complications (strictures, leaks)2/8 2/8

Intrahepatic biliary

cholangiopathy0/8 0/8

Rejection (biopsy proven within

6 mo after transplantation)5/8 1/8

Infection

Sepsis (+SIRS)

1/8

0/8

1/8

1/8

Secondary tumor 0/8 2/8*

Tumor (HCC) recurrence 0/1* 0/6*

Re-listing 0/8 0/8

Re-transplantation 0/8 0/8

6 month graft survival 100% (8/8) 100% (8/8)

1 à 2h de Perfusion Portale Hypothermique Oxygénée

Belzer / p02 70 kPa

Graft loss

Results within 1 year after OLT

Dutkowski et al. ESA 2015.Accepted in

Annals of Surgery

0

75

0

Time after OLT (days)

Gra

ftsu

rviv

al(%

)

DBD

255050

Number at risk

HOPE treated DCDUnperfused DCD

DBD

80

85

90

95

100

60 120 180 240 300 360

254449

234149

213949

183347

203549

143047

HOPE treated DCD

Un-perfused DCD69%

96%

90%

First 6 months after OLT

Dans le domaine du CHC, la TH DV ne modifie pas la survie des patients. C’est un greffon supplémentaire pour l’ensemble des malades sur liste

L’utilisation du foie gauche de donneur vivant chez des malades avec peu ou pas d’hypertension portale (en absence de modulation de flux portale) est raisonnable

Les résultats de la TH à cœur arrêté Maastricht 3 « à la Française » seront liés aux machines des perfusions

Conclusions

Etude de Phase I/II : Faisabilité de la Modulation