肝移植的进展-ppt课件.ppt

1、肝移植的进展肝移植的进展1PPT课件肝移植的发展现状 肝移植的历史 肝移植的现状； 肝移植适应症的变迁； 肝癌肝移植 肝移植外科技术的发展； 肝移植的问题和展望；2PPT课件精品资料 你怎么称呼老师？ 如果老师最后没有总结一节课的重点的难点，你是否会认为老师的教学方法需要改进？ 你所经历的课堂，是讲座式还是讨论式？ 教师的教鞭 “不怕太阳晒，也不怕那风雨狂，只怕先生骂我笨，没有学问无颜见爹娘 ” “太阳当空照，花儿对我笑，小鸟说早早早”First orthotopic experimental liver replacement Transplant bulletin 3:7, 1956Jac

2、k A. Cannon5PPT课件Orthotopic Liver Transplantation 1st orthotopic liver transplantation 1963. Approximately 5,000 orthotopic liver transplantations annually for 17,000 in need.6PPT课件 7PPT课件8PPT课件9PPT课件10PPT课件11PPT课件12PPT课件13PPT课件肝移植的发展现状 肝移植的历史 肝移植的现状； 肝移植适应症的变迁； 肝癌肝移植 肝移植外科技术的发展； 肝移植的问题和展望；14PPT课件肝移

3、植目前的现状（美国） 1-年 生存率达: 85% to 90%； 3-年生存率达: 75% to 80%; 8-年生存率: 60% to 70% 近 3 年中每年6000 例肝移植 110 中心； 近 3 年中每年17,000 例病人在等待肝移植； 近 3 年中每年有1800 例在等待中死亡； 供受体的不匹配大大制约的了肝移植的发展；15PPT课件16PPT课件17PPT课件18PPT课件19PPT课件20PPT课件21PPT课件22PPT课件Survival After LT UNOS registry 1990-96 (N = 17,044)1 Average survival: 83.0

4、% at 1 yr, 70.2% at 5 yrs, and 61.9% at 8 yrs 1-yr survival improved over time: 74.8% in 1990 to 86.2% in 1996 (P .001) Survival higher in women and patients 80% mortality, 20% survived Intensive medical management often futile Liver transplantation only “cure” 5.7% OLT for FLF Shortage of donor org

5、an Death or complications often interveneLiver Transplantation Fulminant Liver Failure44PPT课件Recurrence of Disease After LT Increasing problem as patients live longer after LT Some recurrent disease inconsequential, whereas other recurrence a cause of death or re-LT Potential requirement for re-LT a

6、n added burden to already limited resources for LT Results of re-LT inferior to initial LT (survival: 62% vs 87% at 1 yr and 54% vs 77% at 3 yrs, respectively)11. UNOS Update: UNOS Scientific Registry. 1996; p. 11-32.45PPT课件Diseases That May Recur After LT Hepatitis B Hepatitis C Primary biliary cir

7、rhosis Primary sclerosing cholangitis Autoimmune hepatitis Malignant tumors Hemochromatosis Alcoholic liver disease Nonalcoholicsteatohepatitis Budd-Chiari syndrome46PPT课件Liver transplantation is indicated for appropriately selected patients with decompensated cirrhosis secondary to chronic hepatiti

8、s BContinuous administration of HBIg after liver transplantation Diminishes reinfection rate Improves short-term survival compared with that of patients who underwent transplantation for other conditionsHowever, HBIg is costly and must be administered for the lifetime of the patientOther strategies

9、using nucleoside analogues or vaccines for hepatitis B being explored by many transplant centersLiver Transplantation for HBV47PPT课件1957Interferon discovered1991Interferon alfa-2b approved for HBV 1998Lamivudine (3TC) approved as first nucleoside analogue for HBV 1991 3TC anti-HBV and anti-HIV activ

10、ity discovered1990 PMEA anti-HBV activity discovered2002Adefovir dipivoxil (PMEA prodrug) approved for HBV 1998 Entecavir anti-HBV activity discovered2005Entecavir and peginterferon alfa-2a approved for HBV 2006Telbivudine approved for HBV 2001 Telbivudine anti-HBV activity discoveredHBV Treatment i

11、n the United States: 200748PPT课件High-dose HBIgLamivudine Lamivudine + HBIgLAM +/- Adefovir plus HBIgInterferonLamivudineFamciclovirAdefovirTenofovirEntecavirNucleos/tide Analogue(s) + plus HBIgTherapeutic Advances in Management of HBV Infection49PPT课件TransplantationClinical StabilizationReversal of

12、DecompensationReduced HBV DNA levelsLamivudineAdefovirEntecavirPrevent recurrent infectionProphylacticTherapies =HBIG +Nucleos/tideAnaloguesPrevent cirrhosisand graft failureListedGraft lossRecurrent DiseaseLamivudineAdefovirEntecavir(Tenofovir)Treatment of Chronic HBV Pre- and Post-Transplantation

13、50PPT课件Experimental Vaccine in Liver Transplant Patients Nonrandomized vaccine trial of adjuvant HBsAg/AS04 Vaccine results in high rates of protective (anti-HBs) titers Anti-HBs titers 500 IU/mL after 12 mos achieved in 53% Vaccine had favorable safety profile No clinical HBV recurrence No reported

14、 rejections No occurrence of HBsAg positivity Vaccine allowed discontinuation of HBIg in large proportion of patientsStarkel P, et al. AASLD 2004. Abstract 61.51PPT课件Recurrent Hepatitis C Recurrent HCV universal and immediate after LT Recurrence of HCV associated with reduced QOL and worse graft and

15、 patient survival Risk factors for histologic recurrence: donor (age, steatosis, ischemic time, LDLT), recipient (age), and viral (HCV RNA level and quasispecies) 20% to 40% of recipients progress to cirrhosis within 5 yrs (vs 5% of non-LT patients) Rate of progression from compensated to decompensa

16、tion cirrhosis to death acceleratedCharlton M. Liver Transpl. 2005;11(suppl 1):S57-S62.52PPT课件Recurrent Hepatitis C (contd) HCV therapy in ESLD promising, but difficult Heavy immunosuppressive regimens associated with greater viral replication and graft damage Preemptive therapy only modestly effect

17、ive Standard therapy (IFN + RBV) limited by immunocompromise, renal impairment, and risk of rejection, but has SVR of 20% PegIFN + RBV has SVR of 30% to 45% More potent drugs with fewer toxicities neededTerrault NA. Clin Gastroenterol Hepatol. 2005;3(suppl 2):S125-S131.53PPT课件肝移植的发展现状 肝移植的历史 肝移植的现状；

18、 肝移植适应症的变迁； 肝癌肝移植 肝移植外科技术的发展； 肝移植的问题和展望；54PPT课件55PPT课件Mazzaferro, NEJM 199656PPT课件Yao, Hepatology 200157PPT课件58PPT课件 肝癌肝移植术后生存率肝癌肝移植术后生存率Single HCC 5 cm, or 2-3 3 cm (n=48)Mazzaferro et al. NEJM, 1996Survival %02040608010001224364875%59PPT课件肝癌肝移植严格选择病例的结果 * 4-yr survivalAuthors N Selection criteria

19、Rec5-yr Survival Mazzaferro, NEJM 1996 48Single 5cm 8% 74%*3 nodules 3cmBismuth, Semin Liver Dis 1999 45Single 3cm 11% 74%3 nodules 3cmLlovet, Hepatology 1999 79Single 5cm 4% 75%Jonas, Hepatology 2001120Single 5cm 16% 71%3 nodules 3cm60PPT课件 liver Transplantation61PPT课件Hepatocellular carcinomaLong-t

20、erm survival rate5-year survival ratePartial hepatectomy49%TOCE23%Radiofrequency ablation33%Transplantation80%Alcohol injection20%62PPT课件 Liver transplantation for HCC dual role eradication of main cancer and all microscopic foci provision of good liver function63PPT课件China Liver Transplant Registry

21、Comparison of cumulative survivals of liver transplant recipients with benign and malignant liver diseases in China (1993 2009.5)Benign (n=6429, 51.8%) 76.7 %83.8 %78.8%76.1%71.6 %55.8 %49.2 %Malignant (n=5992, 48.2%)Cumulative survival (%)Survival time (month)Benign diseases vs. Malignant diseases:

22、 P Log rank 5cm or 3, 3cm)No transplantCurrent management schemeCurrent management scheme66PPT课件 Accurate prediction of HCC recurrence for allocation of scarce organs ? Patients with tumor status beyond Milan criteria not worthy of liver transplantation67PPT课件Imaging studies60 years old gentlemanNo

23、family history of HCCIncidentally finding occupying leision in liver 2 years ago, occasionally RUQ ache; weight loss,Past medical historyEpididymal tuberculosis 40 years ago. Simons syndrome 5 years. hypertension 5 years. No hepatitis. No liver cirrhosisIncidentally finding occupying leision in live

24、r 2 years ago, occasionally RUQ ache; weight loss,68PPT课件69PPT课件HCC 20 nodules, extensive venous permeation, moderate differentiationNo recurrence since the transplant in September 200370PPT课件3cm HCC, portal vein branch invasionNo recurrence since the transplant in September 200071PPT课件2.9cm moderat

25、ely differentiated HCC with venous permeation0.9cm well differentiated HCC without venous permeationLiver and lung recurrences 7 months after transplant72PPT课件Expanded selection criteria of HCC for transplantationCriteriaYearAdditional patients benefitedUCSF, USA200130%Kyoto, Japan200711%Tokyo, Japa

26、n20076%Seoul, Korea200810%Hangzhou, China200837.5%73PPT课件RadiologicalfeaturesPathologicalfeaturesBiological behavior of HCCProblem of current tumor assessmentAggressive tumor growth and tendency to recurrence are the ultimate determinants of survival74PPT课件Biological behaviour of HCC Clinical respon

27、se to non-surgical treatment Tumor differentiationBiomarkers of HCC Disseminating cancer cells in bloodPrediction75PPT课件Transarterial chemoembolization (TACE)Chemotherapeutic agentsEmbolic agents76PPT课件Cumulative disease-free survival after liver transplantation for HCC Effect of TACE and tumor necr

28、osisMajno PE et al, Ann Surg, 199795%87%87%74%66%60%72%54%47%TACE tumor necrosis + (n=15)No TACE (n=57)TACE tumor necrosis (n=39)Survival time (years)1.9.8.7.6.5.4.3.2.10012345Cumulative percent surviving disease-free77PPT课件Complete tumor necrosis in liver explant and correlation with post-transplan

29、t survival 10 patients with 100% tumor necrosis in explant No recurrence after transplant (median follow-up of 19 months)Sotivopoulos GC et al, Eur J Med Res, 200578PPT课件Incomplete tumor necrosis treated by TACE79PPT课件Failure of treatment of HCC by TACE Molecular basisTACE Hypoxic tumor Tumor necros

30、is Activation of hepatic stellate cellsHypoxia inducible factor 1 alphaPDGF-B VEGF Yang ZF et al, Cancer Research, 2004 Lau CK et al, 200880PPT课件Clinical response to TACE (not long-lasting) Prediction of biological behavior of HCC 81PPT课件62% at 3 yWell- to moderately Differentiated HCC (n=8) Poorly

31、differentiated HCC (n=6)1.00.80.60.40.20050010001500200025003000Follow-up, dProportion survivalPoorly differentiated HCC ( 5cm) patients had poor survival rateTamura S et al, Arch Surg, 200182PPT课件HCC biomarkersHepatocarcinogensisMarkersProliferationp53, PTEN, c-met, c-myc, PCNA, Ki-67, granulinAvoi

32、dance of apoptosisp53, Bcl-2, survivinLimitless replicative potentialTelomerase, TERTSustained angiogenesisMVD, VEGF, angiopoietinTissue invasion and metastasisCadherin/catenin complex MMPs Genomic instabilityChromosomal instability, microsatellite instabilityMann CD et al, Eur J Cancer, 200783PPT课件

33、Transcript AA454543 expression in tumor predicts HCC prognosisCheung ST et al, Neoplasia, 2005Cumulative overall survivalCumulative overall survivalCumulative overall survivalLate TNM stage patientsEarly TNM stage patientsP=0.001P=0.014P=0.01484PPT课件Prognostic role of markers of HCCStudies on prolif

34、eration markersYearMarkerRole% positive in tumorOsada et al2004p53Yes41.7Ng et al1995p53No31Matsuda et al2003p16Yes70Li et al2004p16No58Jing et al2005p27Yes40.4Wang et al2006Ki-67No22.7Watanabe et al2004Ki-67Yes66.6Sun et al2007PyK2Yes59Cheung et al2004GranulinYes7285PPT课件Mas VR et al, Transplantati

35、on, 200754 probe sets differentiate HCC progression in patients waiting for liver transplantation98 probe sets were associated with post transplant survival (n=10)86PPT课件Risk of tumor biopsy87PPT课件88PPT课件Circulating cancer cellDistant metastasisImplantation in liver graftLiver cancerHypothesis of HC

36、C recurrence after liver transplantation89PPT课件Pantel K et alhttp:/educationbook.aacrjournals.orgQuantitative RT-PCRFree nucleic acidmRNADNAmRNASecreted protein by viable cellsImmunocyto-chemistryEPISPOT assayMethods and targets to detect circulating cancer cells90PPT课件Detection of AFP mRNA-expressi

37、ng cells in peripheral blood predicts HCC recurrence after LDLTPositive detection in pre-op bloodPositive detection in intra-op bloodSensitivity33%44%Specificity100%74%Accuracy81%66%Marubashi S et al, Transpl Int, 200691PPT课件Cheung ST et al, Transplantation, 2008Plasma albumin mRNA levels before tra

38、nsplant predicts HCC recurrence ratesUniversity of HKSensitivity 73%Specificity 70%Accuracy 71%(14.6)(14.6)P = 0.001(n=28)(n=44)92PPT课件Cheung ST et al, Transplantation, 2008Comparison of plasma albumin mRNA levels in healthy individuals, cirrhosis patients with and without HCCCirrhosis patientsHealt

39、hy personsHCC patients with transplantP = 0.001P = 0.04393PPT课件Liver cancerImplantation in liver graft or extrahepatic organsApotopsisCirculating Cancer stem cellCirculating cancer cellHypothesis of HCC recurrence after liver transplantation94PPT课件Detection of HCC cancer stem cell in blood% of CD45-

40、CD90+CD44+ cellsNormal persons0%Cirrhotic patients0%Liver cancer patients0.015% (0 4.02)Yang ZF et al, Cancer Cell, 2008University of HK95PPT课件Single CD90- cellBlue: DAPI (nucleus)Single CD90+ cellBlue: DAPI (nucleus)Red: CD90 (cytoplasm and membrane)HCC cancer stem cell96PPT课件Correlation between th

41、e number of circulating CD45-CD90+ cells and tumor sizeTumor sizeNNo. of circulating CD45-CD90+ cells 5cm211.47 2.46*Yang ZF et al, Cancer Cell, 2008* P = 0.04797PPT课件Molecular biology screening(tumor, blood)Listed for DDLT/LDLTHCC progressionDDLT/LDLTDe-listedDisease-free SurvivedHCC recurrenceDied

42、Complications of transplant Died Child B/C HCC patientsRadiological screeningTOCE, RFATarget therapyTarget therapyFuture management scheme98PPT课件99PPT课件100PPT课件101PPT课件102PPT课件103PPT课件肝移植的发展现状肝移植的发展现状 肝移植的历史 肝移植的现状；肝移植的现状； 肝移植适应症的变迁；肝移植适应症的变迁； 肝癌肝移植 肝移植外科技术的发展肝移植外科技术的发展； 肝移植的问题和展望；肝移植的问题和展望；104PPT课件

43、Deceased Donor Classifications Standard criteria donors (SCD) Donor who is neither ECD or DCD Expanded criteria donors (ECD) Donor characteristics with higher relative risk of graft failure* Donation after cardiac death (DCD) Donation from a patient whose heart has irreversibly stopped beating*Defin

44、ition in evolution (?RR of graft failure 1.7 x expected); potential factors include advanced donor age, steatosis, DCD, split liver, positive hepatitis serologies, some donor causes of death, pressor use, significant down time105PPT课件Expansion of Donor Pool Living donors: donor risk, higher rate of

45、complications, adult to child, adult to adult Older donor: higher PNF, higher recurrence rate of HCV Split liver: higher complication rate, labor intensive, disadvantage to primary recipient Marginal livers: increased risk of PNF High-risk livers: some long-term risk Domino transplant: amyloid donor

46、106PPT课件LDLT in the United StatesUnited Network for Organ Sharing. Available at: http:/www.unos.org. Accessed August 9, 2006.05010015020025030035040045019911993199519971999200120032005AdultPeds107PPT课件108PPT课件109PPT课件110PPT课件111PPT课件Advantages of LDLT Decreased waiting time Extensive donor testing R

47、educed cold ischemic time Elective procedure Increased number of cadaver organs for others waiting for LT112PPT课件Disadvantages of LDLTDonor risk Mortality: 0.2% to 0.5% Morbidity: median 15% to 30%, primarily biliary complications and infections ? Economic, physical, psychological sequelaeRecipient

48、risk New procedure (track record?) Smaller liver mass Increased biliary complications Other (? higher HCV and HCC recurrence)Middleton PF, et al. Liver Transpl. 2006;12:24-30. Nadalin S, et al. HPB. 2006;8:10-21.113PPT课件114PPT课件Split Liver Transplantationfor Pediatric and Adult Recipient115PPT课件116P

49、PT课件活体肝移植移植物类型 A）左外侧叶（第2和第3段） B）肝左叶（2，3，4段）+/-尾状叶（1段） 包括MHV 不包括MHV C）肝右叶（5，6，7，8） 不包括MHV（肝中静脉） 5/8段重建 包括MHV D） 右后段（6，7段）117PPT课件Living Donor Liver Transplantationusing left lobe 118PPT课件肝右静脉重建Adult to Adult Living Donor Liver Transplantation119PPT课件Anterior Segment Congestion of Right Lobe in Recipi

50、ent 肝静脉重建的技巧Adult to Adult Living Donor Liver Transplantation120PPT课件肝静脉重建的技巧n首先采用肝中静脉架桥技术nLee SG, Transplantation 2002; 74: 54.Adult to Adult Living Donor Liver Transplantation121PPT课件肝静脉重建的技巧nLee SG, Transplantation 2002; 74: 54.Adult to Adult Living Donor Liver Transplantation122PPT课件RHVRHV与与MHVM