Survival After Liver Transplantation: An International Comparison Between the United States and the United Kingdom in the Years 2008–2016
Tommy IvanicsDavid WallacePhillipe AbreuMarco P. A. W. ClaasenChris CallaghanThomas E. CowlingKate WalkerNigel HeatonNeil MehtaGonzalo SapisochínJan van der Meulen
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Background. Compared with the United States, risk-adjusted mortality in the United Kingdom has historically been worse in the first 90 d following liver transplantation (LT) and better thereafter. In the last decade, there has been considerable change in the practice of LT internationally, but no contemporary large-scale international comparison of posttransplant outcomes has been conducted. This study aimed to determine disease-specific short- and long-term mortality of LT recipients in the United States and the United Kingdom. Methods. This retrospective international multicenter cohort study analyzed adult (≥18 y) first-time LT recipients between January 2, 2008, and December 31, 2016, using the Organ Procurement and Transplantation Network/United Network for Organ Sharing and the UK Transplant Registry databases. Time-dependent Cox regression estimated hazard ratios (HRs) comparing disease-specific risk-adjusted mortality in the first 90 d post-LT, between 90 d and 1 y, and between 1 and 5 y. Results. Forty-two thousand eight hundred seventy-four US and 4950 UK LT recipients were included. The main LT indications in the United States and the United Kingdom were hepatocellular carcinoma (25.4% and 24.9%, respectively) and alcohol-related liver disease (20.3% and 27.1%, respectively). There were no differences in mortality during the first 90 d post-LT (reference: United States; HR, 0.96; 95% confidence interval [CI], 0.82–1.12). However, between 90 d and 1 y (HR, 0.71; 95% CI, 0.59–0.85) and 1 and 5 y (HR, 0.71; 95% CI, 0.63–0.81]) the United Kingdom had lower mortality. The mortality differences between 1 and 5 y were most marked in hepatocellular carcinoma (HR, 0.71; 95% CI, 0.58–0.88) and alcohol-related liver disease patients (HR, 0.64; 95% CI, 0.45–0.89). Conclusions. Risk-adjusted mortality in the United States and the United Kingdom was similar in the first 90 d post-LT but better in the United Kingdom thereafter. International comparisons of LT may highlight differences in healthcare delivery and help benchmarking by identifying modifiable factors that can facilitate improved global outcomes in LT.Keywords:
Liver disease
Key Points 1 How do physicians decide which patients with pulmonary vascular disease will benefit from liver transplantation? 2 Studies on patients with pulmonary vascular disease are limited and the findings and recommendations may not apply to all practice sites. 3 All patients with hypoxemia, liver disease, and pulmonary vasodilation do not have hepatopulmonary syndrome (HPS). 4 Not all patients with hepatopulmonary syndrome will benefit from liver transplantation. 5 The mean pulmonary artery pressure (mPAP) may not be an accurate predictor of mortality in patients with portopulmonary hypertension. 6 The effects of pulmonary vasodilators on the outcome of patients with portopulmonary hypertension (PPHTN) is still unconfirmed but promising. (Liver Transpl 2004;10:S54–S58.)
Portopulmonary hypertension
Hepatopulmonary syndrome
Liver disease
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Liver transplantation (LT) is in theory, the best treatment for hepatocellular carcinoma (HCC) in cirrhotic patients since it is a treatment that simultaneously deals with the malignancy and its causes [1Adam R. McMaster P. O’Grady J.G. Castaing D. Klempnauer J.L. Jamieson N. et al.Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry.Liver Transpl. 2003; 9: 1231-1243Crossref PubMed Scopus (491) Google Scholar, 2Yoo H.Y. Patt C.H. Geschwind J.F. Thuluvath P.J. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time.J Clin Oncol. 2003; 21: 4329-4335Crossref PubMed Scopus (214) Google Scholar, 3El-Serag H.B. Siegel A.B. Davila J.A. Shaib Y.H. Cayton-Woody M. McBride R. et al.Treatment and outcomes of treating of hepatocellular carcinoma among medicare recipients in the United States: a population-based study.J Hepatol. 2006; 44: 158-166Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar]. However, the prognosis is directly related to the risk of HCC recurrence post-transplantation. The aim of preoperative assessment in LT for HCC is therefore to detect existing extra-hepatic metastases and predict extra-hepatic micro-metastases that are responsible for recurrence, graft loss and often, death of the patient.Following the retrospective study by Bismuth et al. [[4]Bismuth H. Chiche L. Adam R. Castaing D. Diamond T. Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients.Ann Surg. 1993; 218: 145-151Crossref PubMed Scopus (823) Google Scholar], Mazzaferro et al. prospectively showed that careful selection of patients with a single lesion of <5 cm or three lesions each <3 cm, known as Milan criteria, has resulted in a satisfactory balance between survival (75%) at four years and recurrence rates (8%) [[5]Mazzaferro V. Chun Y.S. Poon R.T. Schwartz M.E. Yao F.Y. Marsh J.W. et al.Liver transplantation for hepatocellular carcinoma.Ann Surg Oncol. 2008; 15: 1001-1007Crossref PubMed Scopus (227) Google Scholar]. The validity of these criteria to predict recurrence-free survival after transplantation has been largely confirmed by several studies, which have demonstrated an overall 10-year survival ranging from 60% to 62% [6Jonas S. Bechstein W.O. Steinmuller T. Herrmann M. Radke C. Berg T. et al.Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.Hepatology. 2001; 33: 1080-1086Crossref PubMed Scopus (805) Google Scholar, 7Zavaglia C. De Carlis L. Alberti A.B. Minola E. Belli L.S. Slim A.O. et al.Predictors of long-term survival after liver transplantation for hepatocellular carcinoma.Am J Gastroenterol. 2005; 100: 2708-2716Crossref PubMed Scopus (214) Google Scholar]. Hence, survival of carefully selected patients is not different from survival of patients transplanted for non-malignant indications [[8]Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5580) Google Scholar]. Survival analysis by ITT clearly suggested that resection or ablation in patients with compensated cirrhosis are the only alternatives to liver transplantation on the wait list. Moreover there is growing evidence that by limiting OLT only to patients falling within the Milan criteria might represent an unjust penalty for selected patients beyond the Milan criteria who could still have a favourable outcome with OLT.In the United States, around 70% of cirrhotic patients diagnosed with a HCC fall beyond the Milan criteria [[3]El-Serag H.B. Siegel A.B. Davila J.A. Shaib Y.H. Cayton-Woody M. McBride R. et al.Treatment and outcomes of treating of hepatocellular carcinoma among medicare recipients in the United States: a population-based study.J Hepatol. 2006; 44: 158-166Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar]. Survival analysis by ITT clearly suggested that regular ultrasound screening of cirrhotic patients has permitted detection of small unique nodule in Child-Pugh A cirrhotic patients in whom alternatives to transplantation are possible. Second, liver transplantation will provide a major survival gain in some patients with a HCC who fall beyond the Milan criteria. Therefore, several expansions of the Milan criteria have been proposed, with the University of California, San Francisco (UCSF) criteria described by Yao et al. being the most investigated [9Yao F.Y. Ferrell L. Bass N.M. Watson J.J. Bacchetti P. Venook A. et al.Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.Hepatology. 2001; 33: 1394-1403Crossref PubMed Scopus (1732) Google Scholar, 10Yao F.Y. Xiao L. Bass N.M. Kerlan R. Ascher N.L. Roberts J.P. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging.Am J Transplant. 2007; 7: 2587-2596Crossref PubMed Scopus (407) Google Scholar]. The UCSF criteria include a solitary tumor of 6.5 cm or less, no more than three lesions with the largest being 4.5 cm or less, and a total tumor diameter 8 cm or less, without gross vascular invasion. Unfortunately, the 5-year survival of patients beyond Milan and within UCSF criteria ranges from 46% to 93% [9Yao F.Y. Ferrell L. Bass N.M. Watson J.J. Bacchetti P. Venook A. et al.Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.Hepatology. 2001; 33: 1394-1403Crossref PubMed Scopus (1732) Google Scholar, 10Yao F.Y. Xiao L. Bass N.M. Kerlan R. Ascher N.L. Roberts J.P. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging.Am J Transplant. 2007; 7: 2587-2596Crossref PubMed Scopus (407) Google Scholar, 11Decaens T. Roudot-Thoraval F. Hadni-Bresson S. Meyer C. Gugenheim J. Durand F. et al.Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time.Liver Transpl. 2006; 12: 1761-1769Crossref PubMed Scopus (160) Google Scholar, 12Duffy J.P. Vardanian A. Benjamin E. Watson M. Farmer D.G. Ghobrial R.M. et al.Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA.Ann Surg. 2007; 246: 502-509Crossref PubMed Scopus (2) Google Scholar]. The resulting discrepancies between studies which used UCSF criteria are related to the time of application of the criteria (preoperative/radiological and postoperative/pathological). Interestingly, a French multicentric study of 479 patients demonstrated a higher rate of understaging (48%) if UCSF criteria is used to list patients for LT as compared to the understaging rate of 34% when the Milan criteria is used [[11]Decaens T. Roudot-Thoraval F. Hadni-Bresson S. Meyer C. Gugenheim J. Durand F. et al.Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time.Liver Transpl. 2006; 12: 1761-1769Crossref PubMed Scopus (160) Google Scholar]. Indeed, the 5-year survival of UCSF excluding Milan patients was 45% compared to 60% in Milan patients [[11]Decaens T. Roudot-Thoraval F. Hadni-Bresson S. Meyer C. Gugenheim J. Durand F. et al.Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time.Liver Transpl. 2006; 12: 1761-1769Crossref PubMed Scopus (160) Google Scholar]. Heterogeneous survival results in studies using UCSF criteria emphasized that macroscopic parameters like size and number would probably lose their efficacy as surrogate criteria to accurately predict the risk of tumor recurrence in comparison to tumoral volume exceeding the Milan criteria.Several studies have identified vascular invasion as the strongest independent predictor factor of recurrence, a pathological parameter also associated with other poor prognostic factors like a poor differentiation of the tumor, the presence of satellite nodules and a high level of α-fetoprotein [6Jonas S. Bechstein W.O. Steinmuller T. Herrmann M. Radke C. Berg T. et al.Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.Hepatology. 2001; 33: 1080-1086Crossref PubMed Scopus (805) Google Scholar, 13Pawlik T.M. Delman K.A. Vauthey J.N. Nagorney D.M. Ng I.O. Ikai I. et al.Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma.Liver Transpl. 2005; 11: 1086-1092Crossref PubMed Scopus (489) Google Scholar, 14Parfitt J.R. Marotta P. Alghamdi M. Wall W. Khakhar A. Suskin N.G. et al.Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence.Liver Transpl. 2007; 13: 543-551Crossref PubMed Scopus (132) Google Scholar]. Unfortunately, except for the latter, all these parameters are not easily available in the preoperative setting and particularly at listing.In 2003, based on the knowledge that HCC display molecular alterations Marsh et al., classified HCC according to the level of gene damage [[15]Marsh J.W. Finkelstein S.D. Demetris A.J. Swalsky P.A. Sasatomi E. Bandos A. et al.Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival.Liver Transpl. 2003; 9: 664-671Crossref PubMed Scopus (120) Google Scholar]. The goal of this paper was to determine whether a panel of tumor suppressor gene markers could be useful to predict recurrence after LT for HCC. By microdissection, non-neoplastic and neoplastic tissue samples for each patient transplanted with a minimum of 5 years follow-up were evaluated for informative status of 18 genes located on microsatellite. Absence of microsatellites or loss of heterozygoty (LOH) corresponded to the loss of specific tumor suppressor genes such as APC, CDKN2A, p53, and p34. Among 18 microsatellites tested, 9 were significantly correlated with the post-transplant recurrence-free survival but none achieved perfect discrimination alone. As a test, two types of simplified panel of LOH that were the most accurate to predict recurrence were defined. Thanks to this method and with the help of an artificial neural network, an accurate response was obtained in 91 of the 103 patients tested (88%). The prediction of recurrence was accurate in 89% of cases.Very recently, the same team has performed a similar analysis on a larger cohort of patients transplanted for HCC with more than 5 years of follow-up (183 patients from Mount Sinai and University of Pittsburgh Medical Center) [[16]Dvorchik I. Schwartz M. Fiel M.I. Finkelstein S.D. Marsh J.W. Fractional allelic imbalance could allow for the development of an equitable transplant selection policy for patients with hepatocellular carcinoma.Liver Transpl. 2008; 14: 443-450Crossref PubMed Scopus (41) Google Scholar]. In this study, a fractional allelic imbalance (FAI) rate was calculated for each patient. This index was defined as the number of mutated markers divided by the total number of informative markers. These markers corresponded to the 9 microsatellites retrieved as correlated with the post-transplant recurrence free survival in their initial work [[15]Marsh J.W. Finkelstein S.D. Demetris A.J. Swalsky P.A. Sasatomi E. Bandos A. et al.Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival.Liver Transpl. 2003; 9: 664-671Crossref PubMed Scopus (120) Google Scholar]. Of note, all these 9 markers were not always informative, i.e present, in each patient. The rate of mutation, i.e. FAI, was then dependent on the number of informative markers. Hence, the FAI represents a rough estimate of cumulative mutational damage in tumor compared to non-neoplastic tissue. FAI in the 9-gene panel ranged from 0% to 89% (mean 31%). Among the patients tested, FAI and vascular invasion were the most important independent factors of tumor-free survival. Patients with FAI > 40% compared to those with FAI ⩽ 20% have an increased risk of recurrence by a factor of 19.5. Comparatively, patients with macrovascular invasion compared with those without vascular invasion have an increased risk of recurrence of 5.9. This difference emphasized the power of the FAI even comparatively with the more predictive pathological factor, vascular invasion [6Jonas S. Bechstein W.O. Steinmuller T. Herrmann M. Radke C. Berg T. et al.Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.Hepatology. 2001; 33: 1080-1086Crossref PubMed Scopus (805) Google Scholar, 13Pawlik T.M. Delman K.A. Vauthey J.N. Nagorney D.M. Ng I.O. Ikai I. et al.Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma.Liver Transpl. 2005; 11: 1086-1092Crossref PubMed Scopus (489) Google Scholar, 14Parfitt J.R. Marotta P. Alghamdi M. Wall W. Khakhar A. Suskin N.G. et al.Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence.Liver Transpl. 2007; 13: 543-551Crossref PubMed Scopus (132) Google Scholar]. Interestingly, a correlation with the Milan, UCSF criteria and FAI has been described in this paper. For patients outside the Milan criteria, the risk of recurrence increased 4.5-fold compared to patients within, while a FAI > 40% increased this risk 14-fold compared to FAI ⩽ 20%. For patients beyond UCSF criteria, the risk of recurrence increased 6.0-fold compared to patients within, while a FAI > 40% increased this risk 17.4-fold compared to FAI ⩽ 20%. In summary, this second paper has demonstrated the much more powerful correlation with recurrence of FAI compared with pathological data and macroscopic usual classification.Hence, the paper by Schwartz et al. which appears in this issue of the Journal of Hepatology [[17]Schwartz M. Dvorchik I. Roayaie S. Fiel M.I. Finkelstein S. Marsh J.W. et al.Liver transplantation for hepatocellular carcinoma: Extension of indications based on molecular markers.J Hepatol. 2008; 49: 581-588Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar] focused on the potential applicability of the FAI score in patients beyond the Milan criteria with a favourable outcome of LT. With the same methods of allelic imbalance analysis of HCC in transplanted patients, they have compared tumoral and non-tumoral liver tissue for 18 genes markers to determine the FAI score. Statistically, a FAI score of 0.27 was determined as the more reliable cut-off value to predict recurrence or not. Univariate and multivariate analysis of prognostic factors of recurrence were performed with 70 patients transplanted for HCC with at least 5 years of follow-up. The FAI score and macroscopic vascular invasion were the 2 independent factors associated with recurrence. Interestingly, FAI predicted recurrence in 86% compared to 76% using Milan criteria. Unfortunately, the statistical significance if any of this difference was not reported in the paper. Besides, it was probably due to the low rate of recurrence in Milan criteria (3/35) patients that this paper focused on patients beyond Milan criteria. In the subgroup of patients beyond Milan criteria, the same predictive factors of recurrence were confirmed but, in this group, a FAI ⩾ 0.27 was predictive of recurrence with a sensitivity of 83%, a specificity of 91% and overall accuracy of 89%. Thus, this paper emphasized the utility of FAI analysis only in patients beyond the Milan criteria. Besides, among the 35 patients within the Milan criteria, 4 of 6 of those who were predicted to have recurrence according to FAI did not.Even if it was useful in patients beyond Milan criteria, the major drawback of this technique was the necessity of full pathological examination. To date, all papers that explored evaluation of FAI have used surgical specimens to predict recurrence. As underlined by Marsh et al. in 2003 [[15]Marsh J.W. Finkelstein S.D. Demetris A.J. Swalsky P.A. Sasatomi E. Bandos A. et al.Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival.Liver Transpl. 2003; 9: 664-671Crossref PubMed Scopus (120) Google Scholar], the two principal limitations in extrapolating this work to the preoperative area were: (1) All tumors are not recognized preoperatively. (2) It is not practical or feasible to biopsy all detected tumors multiple times in the preoperative setting. Indeed, Pawlik et al. have analyzed the concordance between histological data using preoperative needle core biopsy (14–18 gauges) of HCC and final pathological analysis [[18]Pawlik T.M. Gleisner A.L. Anders R.A. Assumpcao L. Maley W. Choti M.A. Preoperative assessment of hepatocellular carcinoma tumor grade using needle biopsy. Implications for transplant eligibility.Ann Surg. 2007; 245: 435-442Crossref PubMed Scopus (168) Google Scholar]. In this study that included 120 patients, preoperative biopsy misclassified tumor grade in 55% of cases. The poor diagnostic accuracy of preoperative biopsy was related to the very heterogeneous pathological and molecular alteration of HCC, even in small tumors. Incidence of grading heterogeneity was reported in 18–46% [19Kenmochi K. Sugihara S. Kojiro M. Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC.Liver. 1987; 7: 18-26Crossref PubMed Scopus (232) Google Scholar, 20Nakashima O. Sugihara S. Kage M. Kojiro M. Pathomorphologic characteristics of small hepatocellular carcinoma: a special reference to small hepatocellular carcinoma with indistinct margins.Hepatology. 1995; 22: 101-105PubMed Google Scholar, 21An F.Q. Matsuda M. Fujii H. Tang R.F. Amemiya H. Dai Y.M. et al.Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 and beta-catenin.Int J Cancer. 2001; 93: 468-474Crossref PubMed Scopus (61) Google Scholar] of HCC smaller than 2 cm and 36–43% in 2–3 cm nodules [19Kenmochi K. Sugihara S. Kojiro M. Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC.Liver. 1987; 7: 18-26Crossref PubMed Scopus (232) Google Scholar, 21An F.Q. Matsuda M. Fujii H. Tang R.F. Amemiya H. Dai Y.M. et al.Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 and beta-catenin.Int J Cancer. 2001; 93: 468-474Crossref PubMed Scopus (61) Google Scholar]. This heterogeneity was due to sequential development of HCC often displaying the nodule-in-nodule pattern where a subpopulation with a more malignant potential develops in a pre-existing nodule. Interestingly, as grading heterogeneity, molecular alterations, notably mutation of p53 and β-catenin, were also retrieved inside small HCCs [[21]An F.Q. Matsuda M. Fujii H. Tang R.F. Amemiya H. Dai Y.M. et al.Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 and beta-catenin.Int J Cancer. 2001; 93: 468-474Crossref PubMed Scopus (61) Google Scholar].As reported in the paper by Schwartz et al. [[17]Schwartz M. Dvorchik I. Roayaie S. Fiel M.I. Finkelstein S. Marsh J.W. et al.Liver transplantation for hepatocellular carcinoma: Extension of indications based on molecular markers.J Hepatol. 2008; 49: 581-588Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar], the value of FAI was dependent on the number of mutated genes to the total number of informative genes. It was the variability of informative gene numbers that has imposed the calculation of an index. Indeed, a recent paper has focused on the genetic diversity of human HCC [[22]Boyault S. Rickman D.S. de Reynies A. Balabaud C. Rebouissou S. Jeannot E. et al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52Crossref PubMed Scopus (842) Google Scholar]. In this work, a transcriptome analysis with genotype and phenotype correlation has been performed in a surgical series of 120 HCCs and 3 hepatocellular adenomas. The transcriptome analysis identified 6 subgroups (G1–G6) of HCCs associated with clinical and genetic characteristics. HCC of G1 and G2 group were associated with HBV infection. G3 HCC mainly included p53 mutation but without HBV infection. G4 HCC was a heterogeneous group of HCCs.G5 and G6 were highly related to β-catenin activation. Interestingly, HCC groups G1 to G3 were associated with a high rate of chromosomal instability in contrast to G5 and G6 where no chromosome deletion, then no LOH was identified. Hence, claims that FAI, largely correlated with LOH, in these subgroups of HCC is questionable and emphasized the fact that the FAI ratio is only a rough measure of cumulative mutational damage. It should be emphasized that the correlation of FAI and viral hepatitis was not assessed in the paper by Schwartz and colleagues.Despite these limitations, FAI represents a promising new tool to predict recurrence after LT, even if it is only of benefit postoperatively in patients falling beyond the Milan criteria. In the post-transplant setting, FAI could provide useful information to adapt immunosuppressive therapy and adjuvant chemotherapy thus attenuating the risk of recurrence [[23]Zimmerman M.A. Trotter J.F. Wachs M. Bak T. Campsen J. Skibba A. et al.Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma.Liver Transpl. 2008; 14: 633-638Crossref PubMed Scopus (171) Google Scholar]. In the pre-transplant setting, the application of molecular markers needs further evaluation before being used as selection criteria for liver transplantation. Liver transplantation (LT) is in theory, the best treatment for hepatocellular carcinoma (HCC) in cirrhotic patients since it is a treatment that simultaneously deals with the malignancy and its causes [1Adam R. McMaster P. O’Grady J.G. Castaing D. Klempnauer J.L. Jamieson N. et al.Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry.Liver Transpl. 2003; 9: 1231-1243Crossref PubMed Scopus (491) Google Scholar, 2Yoo H.Y. Patt C.H. Geschwind J.F. Thuluvath P.J. The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time.J Clin Oncol. 2003; 21: 4329-4335Crossref PubMed Scopus (214) Google Scholar, 3El-Serag H.B. Siegel A.B. Davila J.A. Shaib Y.H. Cayton-Woody M. McBride R. et al.Treatment and outcomes of treating of hepatocellular carcinoma among medicare recipients in the United States: a population-based study.J Hepatol. 2006; 44: 158-166Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar]. However, the prognosis is directly related to the risk of HCC recurrence post-transplantation. The aim of preoperative assessment in LT for HCC is therefore to detect existing extra-hepatic metastases and predict extra-hepatic micro-metastases that are responsible for recurrence, graft loss and often, death of the patient. Following the retrospective study by Bismuth et al. [[4]Bismuth H. Chiche L. Adam R. Castaing D. Diamond T. Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients.Ann Surg. 1993; 218: 145-151Crossref PubMed Scopus (823) Google Scholar], Mazzaferro et al. prospectively showed that careful selection of patients with a single lesion of <5 cm or three lesions each <3 cm, known as Milan criteria, has resulted in a satisfactory balance between survival (75%) at four years and recurrence rates (8%) [[5]Mazzaferro V. Chun Y.S. Poon R.T. Schwartz M.E. Yao F.Y. Marsh J.W. et al.Liver transplantation for hepatocellular carcinoma.Ann Surg Oncol. 2008; 15: 1001-1007Crossref PubMed Scopus (227) Google Scholar]. The validity of these criteria to predict recurrence-free survival after transplantation has been largely confirmed by several studies, which have demonstrated an overall 10-year survival ranging from 60% to 62% [6Jonas S. Bechstein W.O. Steinmuller T. Herrmann M. Radke C. Berg T. et al.Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.Hepatology. 2001; 33: 1080-1086Crossref PubMed Scopus (805) Google Scholar, 7Zavaglia C. De Carlis L. Alberti A.B. Minola E. Belli L.S. Slim A.O. et al.Predictors of long-term survival after liver transplantation for hepatocellular carcinoma.Am J Gastroenterol. 2005; 100: 2708-2716Crossref PubMed Scopus (214) Google Scholar]. Hence, survival of carefully selected patients is not different from survival of patients transplanted for non-malignant indications [[8]Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5580) Google Scholar]. Survival analysis by ITT clearly suggested that resection or ablation in patients with compensated cirrhosis are the only alternatives to liver transplantation on the wait list. Moreover there is growing evidence that by limiting OLT only to patients falling within the Milan criteria might represent an unjust penalty for selected patients beyond the Milan criteria who could still have a favourable outcome with OLT. In the United States, around 70% of cirrhotic patients diagnosed with a HCC fall beyond the Milan criteria [[3]El-Serag H.B. Siegel A.B. Davila J.A. Shaib Y.H. Cayton-Woody M. McBride R. et al.Treatment and outcomes of treating of hepatocellular carcinoma among medicare recipients in the United States: a population-based study.J Hepatol. 2006; 44: 158-166Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar]. Survival analysis by ITT clearly suggested that regular ultrasound screening of cirrhotic patients has permitted detection of small unique nodule in Child-Pugh A cirrhotic patients in whom alternatives to transplantation are possible. Second, liver transplantation will provide a major survival gain in some patients with a HCC who fall beyond the Milan criteria. Therefore, several expansions of the Milan criteria have been proposed, with the University of California, San Francisco (UCSF) criteria described by Yao et al. being the most investigated [9Yao F.Y. Ferrell L. Bass N.M. Watson J.J. Bacchetti P. Venook A. et al.Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.Hepatology. 2001; 33: 1394-1403Crossref PubMed Scopus (1732) Google Scholar, 10Yao F.Y. Xiao L. Bass N.M. Kerlan R. Ascher N.L. Roberts J.P. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging.Am J Transplant. 2007; 7: 2587-2596Crossref PubMed Scopus (407) Google Scholar]. The UCSF criteria include a solitary tumor of 6.5 cm or less, no more than three lesions with the largest being 4.5 cm or less, and a total tumor diameter 8 cm or less, without gross vascular invasion. Unfortunately, the 5-year survival of patients beyond Milan and within UCSF criteria ranges from 46% to 93% [9Yao F.Y. Ferrell L. Bass N.M. Watson J.J. Bacchetti P. Venook A. et al.Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.Hepatology. 2001; 33: 1394-1403Crossref PubMed Scopus (1732) Google Scholar, 10Yao F.Y. Xiao L. Bass N.M. Kerlan R. Ascher N.L. Roberts J.P. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging.Am J Transplant. 2007; 7: 2587-2596Crossref PubMed Scopus (407) Google Scholar, 11Decaens T. Roudot-Thoraval F. Hadni-Bresson S. Meyer C. Gugenheim J. Durand F. et al.Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time.Liver Transpl. 2006; 12: 1761-1769Crossref PubMed Scopus (160) Google Scholar, 12Duffy J.P. Vardanian A. Benjamin E. Watson M. Farmer D.G. Ghobrial R.M. et al.Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA.Ann Surg. 2007; 246: 502-509Crossref PubMed Scopus (2) Google Scholar]. The resulting discrepancies between studies which used UCSF criteria are related to the time of application of the criteria (preoperative/radiological and postoperative/pathological). Interestingly, a French multicentric study of 479 patients demonstrated a higher rate of understaging (48%) if UCSF criteria is used to list patients for LT as compared to the understaging rate of 34% when the Milan criteria is used [[11]Decaens T. Roudot-Thoraval F. Hadni-Bresson S. Meyer C. Gugenheim J. Durand F. et al.Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time.Liver Transpl. 2006; 12: 1761-1769Crossref PubMed Scopus (160) Google Scholar]. Indeed, the 5-year survival of UCSF excluding Milan patients was 45% compared to 60% in Milan patients [[11]Decaens T. Roudot-Thoraval F. Hadni-Bresson S. Meyer C. Gugenheim J. Durand F. et al.Impact of UCSF criteria according to pre- and post-OLT tumor features: analysis of 479 patients listed for HCC with a short waiting time.Liver Transpl. 2006; 12: 1761-1769Crossref PubMed Scopus (160) Google Scholar]. Heterogeneous survival results in studies using UCSF criteria emphasized that macroscopic parameters like size and number would probably lose their efficacy as surrogate criteria to accurately predict the risk of tumor recurrence in comparison to tumoral volume exceeding the Milan criteria. Several studies have identified vascular invasion as the strongest independent predictor factor of recurrence, a pathological parameter also associated with other poor prognostic factors like a poor differentiation of the tumor, the presence of satellite nodules and a high level of α-fetoprotein [6Jonas S. Bechstein W.O. Steinmuller T. Herrmann M. Radke C. Berg T. et al.Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.Hepatology. 2001; 33: 1080-1086Crossref PubMed Scopus (805) Google Scholar, 13Pawlik T.M. Delman K.A. Vauthey J.N. Nagorney D.M. Ng I.O. Ikai I. et al.Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma.Liver Transpl. 2005; 11: 1086-1092Crossref PubMed Scopus (489) Google Scholar, 14Parfitt J.R. Marotta P. Alghamdi M. Wall W. Khakhar A. Suskin N.G. et al.Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence.Liver Transpl. 2007; 13: 543-551Crossref PubMed Scopus (132) Google Scholar]. Unfortunately, except for the latter, all these parameters are not easily available in the preoperative setting and particularly at listing. In 2003, based on the knowledge that HCC display molecular alterations Marsh et al., classified HCC according to the level of gene damage [[15]Marsh J.W. Finkelstein S.D. Demetris A.J. Swalsky P.A. Sasatomi E. Bandos A. et al.Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival.Liver Transpl. 2003; 9: 664-671Crossref PubMed Scopus (120) Google Scholar]. The goal of this paper was to determine whether a panel of tumor suppressor gene markers could be useful to predict recurrence after LT for HCC. By microdissection, non-neoplastic and neoplastic tissue samples for each patient transplanted with a minimum of 5 years follow-up were evaluated for informative status of 18 genes located on microsatellite. Absence of microsatellites or loss of heterozygoty (LOH) corresponded to the loss of specific tumor suppressor genes such as APC, CDKN2A, p53, and p34. Among 18 microsatellites tested, 9 were significantly correlated with the post-transplant recurrence-free survival but none achieved perfect discrimination alone. As a test, two types of simplified panel of LOH that were the most accurate to predict recurrence were defined. Thanks to this method and with the help of an artificial neural network, an accurate response was obtained in 91 of the 103 patients tested (88%). The prediction of recurrence was accurate in 89% of cases. Very recently, the same team has performed a similar analysis on a larger cohort of patients transplanted for HCC with more than 5 years of follow-up (183 patients from Mount Sinai and University of Pittsburgh Medical Center) [[16]Dvorchik I. Schwartz M. Fiel M.I. Finkelstein S.D. Marsh J.W. Fractional allelic imbalance could allow for the development of an equitable transplant selection policy for patients with hepatocellular carcinoma.Liver Transpl. 2008; 14: 443-450Crossref PubMed Scopus (41) Google Scholar]. In this study, a fractional allelic imbalance (FAI) rate was calculated for each patient. This index was defined as the number of mutated markers divided by the total number of informative markers. These markers corresponded to the 9 microsatellites retrieved as correlated with the post-transplant recurrence free survival in their initial work [[15]Marsh J.W. Finkelstein S.D. Demetris A.J. Swalsky P.A. Sasatomi E. Bandos A. et al.Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival.Liver Transpl. 2003; 9: 664-671Crossref PubMed Scopus (120) Google Scholar]. Of note, all these 9 markers were not always informative, i.e present, in each patient. The rate of mutation, i.e. FAI, was then dependent on the number of informative markers. Hence, the FAI represents a rough estimate of cumulative mutational damage in tumor compared to non-neoplastic tissue. FAI in the 9-gene panel ranged from 0% to 89% (mean 31%). Among the patients tested, FAI and vascular invasion were the most important independent factors of tumor-free survival. Patients with FAI > 40% compared to those with FAI ⩽ 20% have an increased risk of recurrence by a factor of 19.5. Comparatively, patients with macrovascular invasion compared with those without vascular invasion have an increased risk of recurrence of 5.9. This difference emphasized the power of the FAI even comparatively with the more predictive pathological factor, vascular invasion [6Jonas S. Bechstein W.O. Steinmuller T. Herrmann M. Radke C. Berg T. et al.Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.Hepatology. 2001; 33: 1080-1086Crossref PubMed Scopus (805) Google Scholar, 13Pawlik T.M. Delman K.A. Vauthey J.N. Nagorney D.M. Ng I.O. Ikai I. et al.Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma.Liver Transpl. 2005; 11: 1086-1092Crossref PubMed Scopus (489) Google Scholar, 14Parfitt J.R. Marotta P. Alghamdi M. Wall W. Khakhar A. Suskin N.G. et al.Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence.Liver Transpl. 2007; 13: 543-551Crossref PubMed Scopus (132) Google Scholar]. Interestingly, a correlation with the Milan, UCSF criteria and FAI has been described in this paper. For patients outside the Milan criteria, the risk of recurrence increased 4.5-fold compared to patients within, while a FAI > 40% increased this risk 14-fold compared to FAI ⩽ 20%. For patients beyond UCSF criteria, the risk of recurrence increased 6.0-fold compared to patients within, while a FAI > 40% increased this risk 17.4-fold compared to FAI ⩽ 20%. In summary, this second paper has demonstrated the much more powerful correlation with recurrence of FAI compared with pathological data and macroscopic usual classification. Hence, the paper by Schwartz et al. which appears in this issue of the Journal of Hepatology [[17]Schwartz M. Dvorchik I. Roayaie S. Fiel M.I. Finkelstein S. Marsh J.W. et al.Liver transplantation for hepatocellular carcinoma: Extension of indications based on molecular markers.J Hepatol. 2008; 49: 581-588Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar] focused on the potential applicability of the FAI score in patients beyond the Milan criteria with a favourable outcome of LT. With the same methods of allelic imbalance analysis of HCC in transplanted patients, they have compared tumoral and non-tumoral liver tissue for 18 genes markers to determine the FAI score. Statistically, a FAI score of 0.27 was determined as the more reliable cut-off value to predict recurrence or not. Univariate and multivariate analysis of prognostic factors of recurrence were performed with 70 patients transplanted for HCC with at least 5 years of follow-up. The FAI score and macroscopic vascular invasion were the 2 independent factors associated with recurrence. Interestingly, FAI predicted recurrence in 86% compared to 76% using Milan criteria. Unfortunately, the statistical significance if any of this difference was not reported in the paper. Besides, it was probably due to the low rate of recurrence in Milan criteria (3/35) patients that this paper focused on patients beyond Milan criteria. In the subgroup of patients beyond Milan criteria, the same predictive factors of recurrence were confirmed but, in this group, a FAI ⩾ 0.27 was predictive of recurrence with a sensitivity of 83%, a specificity of 91% and overall accuracy of 89%. Thus, this paper emphasized the utility of FAI analysis only in patients beyond the Milan criteria. Besides, among the 35 patients within the Milan criteria, 4 of 6 of those who were predicted to have recurrence according to FAI did not. Even if it was useful in patients beyond Milan criteria, the major drawback of this technique was the necessity of full pathological examination. To date, all papers that explored evaluation of FAI have used surgical specimens to predict recurrence. As underlined by Marsh et al. in 2003 [[15]Marsh J.W. Finkelstein S.D. Demetris A.J. Swalsky P.A. Sasatomi E. Bandos A. et al.Genotyping of hepatocellular carcinoma in liver transplant recipients adds predictive power for determining recurrence-free survival.Liver Transpl. 2003; 9: 664-671Crossref PubMed Scopus (120) Google Scholar], the two principal limitations in extrapolating this work to the preoperative area were: (1) All tumors are not recognized preoperatively. (2) It is not practical or feasible to biopsy all detected tumors multiple times in the preoperative setting. Indeed, Pawlik et al. have analyzed the concordance between histological data using preoperative needle core biopsy (14–18 gauges) of HCC and final pathological analysis [[18]Pawlik T.M. Gleisner A.L. Anders R.A. Assumpcao L. Maley W. Choti M.A. Preoperative assessment of hepatocellular carcinoma tumor grade using needle biopsy. Implications for transplant eligibility.Ann Surg. 2007; 245: 435-442Crossref PubMed Scopus (168) Google Scholar]. In this study that included 120 patients, preoperative biopsy misclassified tumor grade in 55% of cases. The poor diagnostic accuracy of preoperative biopsy was related to the very heterogeneous pathological and molecular alteration of HCC, even in small tumors. Incidence of grading heterogeneity was reported in 18–46% [19Kenmochi K. Sugihara S. Kojiro M. Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC.Liver. 1987; 7: 18-26Crossref PubMed Scopus (232) Google Scholar, 20Nakashima O. Sugihara S. Kage M. Kojiro M. Pathomorphologic characteristics of small hepatocellular carcinoma: a special reference to small hepatocellular carcinoma with indistinct margins.Hepatology. 1995; 22: 101-105PubMed Google Scholar, 21An F.Q. Matsuda M. Fujii H. Tang R.F. Amemiya H. Dai Y.M. et al.Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 and beta-catenin.Int J Cancer. 2001; 93: 468-474Crossref PubMed Scopus (61) Google Scholar] of HCC smaller than 2 cm and 36–43% in 2–3 cm nodules [19Kenmochi K. Sugihara S. Kojiro M. Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC.Liver. 1987; 7: 18-26Crossref PubMed Scopus (232) Google Scholar, 21An F.Q. Matsuda M. Fujii H. Tang R.F. Amemiya H. Dai Y.M. et al.Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 and beta-catenin.Int J Cancer. 2001; 93: 468-474Crossref PubMed Scopus (61) Google Scholar]. This heterogeneity was due to sequential development of HCC often displaying the nodule-in-nodule pattern where a subpopulation with a more malignant potential develops in a pre-existing nodule. Interestingly, as grading heterogeneity, molecular alterations, notably mutation of p53 and β-catenin, were also retrieved inside small HCCs [[21]An F.Q. Matsuda M. Fujii H. Tang R.F. Amemiya H. Dai Y.M. et al.Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 and beta-catenin.Int J Cancer. 2001; 93: 468-474Crossref PubMed Scopus (61) Google Scholar]. As reported in the paper by Schwartz et al. [[17]Schwartz M. Dvorchik I. Roayaie S. Fiel M.I. Finkelstein S. Marsh J.W. et al.Liver transplantation for hepatocellular carcinoma: Extension of indications based on molecular markers.J Hepatol. 2008; 49: 581-588Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar], the value of FAI was dependent on the number of mutated genes to the total number of informative genes. It was the variability of informative gene numbers that has imposed the calculation of an index. Indeed, a recent paper has focused on the genetic diversity of human HCC [[22]Boyault S. Rickman D.S. de Reynies A. Balabaud C. Rebouissou S. Jeannot E. et al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52Crossref PubMed Scopus (842) Google Scholar]. In this work, a transcriptome analysis with genotype and phenotype correlation has been performed in a surgical series of 120 HCCs and 3 hepatocellular adenomas. The transcriptome analysis identified 6 subgroups (G1–G6) of HCCs associated with clinical and genetic characteristics. HCC of G1 and G2 group were associated with HBV infection. G3 HCC mainly included p53 mutation but without HBV infection. G4 HCC was a heterogeneous group of HCCs.G5 and G6 were highly related to β-catenin activation. Interestingly, HCC groups G1 to G3 were associated with a high rate of chromosomal instability in contrast to G5 and G6 where no chromosome deletion, then no LOH was identified. Hence, claims that FAI, largely correlated with LOH, in these subgroups of HCC is questionable and emphasized the fact that the FAI ratio is only a rough measure of cumulative mutational damage. It should be emphasized that the correlation of FAI and viral hepatitis was not assessed in the paper by Schwartz and colleagues. Despite these limitations, FAI represents a promising new tool to predict recurrence after LT, even if it is only of benefit postoperatively in patients falling beyond the Milan criteria. In the post-transplant setting, FAI could provide useful information to adapt immunosuppressive therapy and adjuvant chemotherapy thus attenuating the risk of recurrence [[23]Zimmerman M.A. Trotter J.F. Wachs M. Bak T. Campsen J. Skibba A. et al.Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma.Liver Transpl. 2008; 14: 633-638Crossref PubMed Scopus (171) Google Scholar]. In the pre-transplant setting, the application of molecular markers needs further evaluation before being used as selection criteria for liver transplantation. The authors thank Dr. Emir Hoti for reading the manuscript.
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Milan criteria
Risk Stratification
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Background Although most people with relapsing onset multiple sclerosis (R-MS) eventually transition to secondary progressive multiple sclerosis (SPMS), little is known about disability progression in SPMS. Methods All R-MS patients in the Cardiff MS registry were included. Cox proportional hazards regression was used to examine a) hazard of converting to SPMS and b) hazard of attaining EDSS 6.0 and 8.0 in SPMS. Results 1611 R-MS patients were included. Older age at MS onset (hazard ratio [HR] 1.02, 95%CI 1.01–1.03), male sex (HR 1.71, 95%CI 1.41–2.08), and residual disability after onset (HR 1.38, 95%CI 1.11–1.71) were asso- ciated with increased hazard of SPMS. Male sex (EDSS 6.0 HR 1.41 [1.04–1.90], EDSS 8.0 HR 1.75 [1.14–2.69]) and higher EDSS at SPMS onset (EDSS 6.0 HR 1.31 [1.17–1.46]; EDSS 8.0 HR 1.38 [1.19–1.61]) were associated with increased hazard of reaching disability milestones, while older age at SPMS was associated with a lower hazard of progression (EDSS 6.0 HR 0.94 [0.92–0.96]; EDSS 8.0: HR 0.92 [0.90–0.95]). Conclusions Different factors are associated with hazard of SPMS compared to hazard of disability progres- sion after SPMS onset. These data may be used to plan services, and provide a baseline for comparison for future interventional studies and has relevance for new treatments for SPMS RobertsonNP@cardiff.ac.uk
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Patients listed for liver transplantation and hepatocellular carcinoma are considered priority on the waiting list, and this could overly favor them.This study aimed to evaluate the impact of this prioritization.We analyzed the liver transplants performed in adults from 2011 to 2020 and divided into three groups: adjusted Model of End-Stage Liver Disease (MELD) score for hepatocellular carcinoma, other adjusted Model of End-Stage Liver Disease situations, and no adjusted Model of End-Stage Liver Disease.A total of 1,706 patients were included in the study, of which 70.2% were male. Alcoholism was the main etiology of cirrhosis (29.6%). Of the total, 305 patients were with hepatocellular carcinoma, 86 with other adjusted Model of End-Stage Liver Disease situations, and 1,315 with no adjusted Model of End-Stage Liver Disease. Patients with hepatocellular carcinoma were older (58.9 vs. 53.5 years). The predominant etiology of cirrhosis was viral hepatitis (60%). The findings showed that group with adjusted Model of End-Stage Liver Disease had lower physiological Model of End-Stage Liver Disease (10.9), higher adjusted Model of End-Stage Liver Disease (22.6), and longer waiting list time (131 vs. 110 days), as compared to the group with no adjusted Model of End-Stage Liver Disease. The total number of transplants and the proportion of patients transplanted for hepatocellular carcinoma increased from 2011 to 2020. There was a reduction in the proportion of patients with hepatocellular carcinoma and adjusted Model of End-Stage Liver Disease of 20 and there was an increase on waiting list time in this group. There was an increase in the proportion of those with adjusted Model of End-Stage Liver Disease of 24 and 29, but the waiting list time remained stable.Over the past decade, prioritization of hepatocellular carcinoma resulted in an increased proportion of transplanted patients in relation to those with no priority. It also increased waiting list time, requiring higher adjusted Model of End-Stage Liver Disease to transplant an organ.
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The classical form of alpha-1-antitrypsin deficiency (A1ATD) is known to cause liver disease in children and adults, but there is relatively little information about the risk of severe, progressive liver disease and the need for liver transplantation. To better understand how newly evolving pharmacological, genetic, and cellular therapies may be targeted according to risk for progressive liver disease, we sought to determine the age distribution of A1ATD as a cause of severe liver disease, as defined by the need for liver transplantation. Using 3 US liver transplantation databases for the period 1991-2012, we found 77.2% of 1677 liver transplants with a reported diagnosis of A1ATD were adults. The peak age range was 50-64 years. Using 2 of the databases which included specific A1AT phenotypes, we found that many of these adults who undergo liver transplantation with A1ATD as the diagnosis are heterozygotes and have other potential causes of liver disease, most notably obesity and ethanol abuse. However, even when these cases are excluded and only ZZ and SZ phenotypes are considered, severe liver disease requiring transplantation is more than 2.5 times as likely in adults. The analysis also showed a markedly increased risk for males. In the pediatric group, almost all of the transplants are done in children less than 5 years of age. In conclusion, A1ATD causes progressive liver disease most commonly in adults with males in the highest risk category. In the pediatric group, children less than 5 years of age are highest in risk. These results suggest that A1ATD most commonly causes liver disease by mechanisms similar to age-dependent degenerative diseases and more rarely in children by powerful modifiers. Liver Transplantation 22 886-894 2016 AASLD.
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The model for end-stage liver disease (MELD) is considered to be a good predictor of disease status in patients with end-stage liver disease and has been used for organ distribution in liver transplantation. This article briefly describes the relationship between MELD, MELD-Na score and the mortality of patients waiting for liver transplantation, the intraoperative blood transfusion, the survival, complications, and re-transplantation after liver transplantation.
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End stage liver disease; Liver transplantation; MELD-Na score; Postoperative complications
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The hazard ratio and median survival time are the routine indicators in survival analysis. We briefly introduced the relationship between hazard ratio and median survival time and the role of proportional hazard assumption. We compared 110 pairs of hazard ratio and median survival time ratio in 58 articles and demonstrated the reasons for the difference by examples. The results showed that the hazard ratio estimated by the Cox regression model is unreasonable and not equivalent to median survival time ratio when the proportional hazard assumption is not met. Therefore, before performing the Cox regression model, the proportional hazard assumption should be tested first. If proportional hazard assumption is met, Cox regression model can be used; if proportional hazard assumption is not met, restricted mean survival times is suggested.风险比（hazard ratio，HR）和中位生存时间是生存分析时的常规分析和报告指标。本文简要介绍了HR和中位生存时间的关系以及比例风险假定在这两者之间的作用，分析了检索出的58篇文献中的110对风险比和中位生存时间比的差异，并通过实例阐明了产生这种差异的原因。结果表明，在不满足比例风险假定时，Cox回归模型计算得到的风险比是不合理的，且与中位生存时间之比不等价。因此，在使用Cox回归模型前，应先进行比例风险假定的检验，只有符合比例风险假定时才能使用该模型；当不符合比例风险假定时，建议使用限制性平均生存时间。.
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Background data: Liver transplantation is the best therapeutic option for patients with end- stage liver disease due to its excellent long term survival results. The demand for deceased donor liver transplantation vastly exceeds the supply. In the U.S. the Model for End Stage Liver Disease (MELD) score is now used for allocation in liver transplantation waiting lists, replacing the Child- Turcotte- Pugh (CTP) score. The MELD system is based on the risk of death without transplantation and was originally developed for survival estimation in patients after TIPS. The majority of the European countries still use the CTP score for liver organ allocation. However, there is a debate whether the MELD score is superior CTP to predict mortality in patients with cirrhosis on waiting list and after liver transplantation.
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