Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.

Learning from multiple annotators for medical image segmentation.

Supervised machine learning methods have been widely developed for segmentation tasks in recent years. However, the quality of labels has high impact on the predictive performance of these algorithms. This issue is particularly acute in the medical image domain, where both the cost of annotation and the inter-observer variability are high. Different human experts contribute estimates of the "actual" segmentation labels in a typical label acquisition process, influenced by their personal biases and competency levels. The performance of automatic segmentation algorithms is limited when these noisy labels are used as the expert consensus label. In this work, we use two coupled CNNs to jointly learn, from purely noisy observations alone, the reliability of individual annotators and the expert consensus label distributions. The separation of the two is achieved by maximally describing the annotator's "unreliable behavior" (we call it "maximally unreliable") while achieving high fidelity with the noisy training data. We first create a toy segmentation dataset using MNIST and investigate the properties of the proposed algorithm. We then use three public medical imaging segmentation datasets to demonstrate our method's efficacy, including both simulated (where necessary) and real-world annotations: 1) ISBI2015 (multiple-sclerosis lesions); 2) BraTS (brain tumors); 3) LIDC-IDRI (lung abnormalities). Finally, we create a real-world multiple sclerosis lesion dataset (QSMSC at UCL: Queen Square Multiple Sclerosis Center at UCL, UK) with manual segmentations from 4 different annotators (3 radiologists with different level skills and 1 expert to generate the expert consensus label). In all datasets, our method consistently outperforms competing methods and relevant baselines, especially when the number of annotations is small and the amount of disagreement is large. The studies also reveal that the system is capable of capturing the complicated spatial characteristics of annotators' mistakes.

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

HLA-DRB1*1501 influences long-term disability progression and tissue damage on MRI in relapse-onset multiple sclerosis.

BACKGROUND: Whether genetic factors influence the long-term course of multiple sclerosis (MS) is unresolved. OBJECTIVE: To determine the influence of HLA-DRB1*1501 on long-term disease course in a homogeneous cohort of clinically isolated syndrome (CIS) patients. METHODS: One hundred seven patients underwent clinical and MRI assessment at the time of CIS and after 1, 3, 5 and 15 years. HLA-DRB1*1501 status was determined using Sanger sequencing and tagging of the rs3135388 polymorphism. Linear/Poisson mixed-effects models were used to investigate rates of change in EDSS and MRI measures based on HLA-DRB1*1501 status. RESULTS: HLA-DRB1*1501 -positive (n = 52) patients showed a faster rate of disability worsening compared with the HLA-DRB1*1501 -negative (n = 55) patients (annualised change in EDSS 0.14/year vs. 0.08/year, p < 0.025), and a greater annualised change in T2 lesion volume (adjusted difference 0.45 mL/year, p < 0.025), a higher number of gadolinium-enhancing lesions, and a faster rate of brain (adjusted difference -0.12%/year, p < 0.05) and spinal cord atrophy (adjusted difference -0.22 mm2/year, p < 0.05). INTERPRETATION: These findings provide evidence that the HLA-DRB1*1501 allele plays a role in MS severity, as measured by long-term disability worsening and a greater extent of inflammatory disease activity and tissue loss. HLA-DRB1*1501 may provide useful information when considering prognosis and treatment decisions in early relapse-onset MS.

Novel Benchmark Values for Redo Liver Transplantation: Does the Outcome Justify the Effort?

OBJECTIVE: To define benchmark cutoffs for redo liver transplantation (redo-LT). BACKGROUND: In the era of organ shortage, redo-LT is frequently discussed in terms of expected poor outcome and wasteful resources. However, there is a lack of benchmark data to reliably evaluate outcomes after redo-LT. METHODS: We collected data on redo-LT between January 2010 and December 2018 from 22 high-volume transplant centers. Benchmark cases were defined as recipients with model of end stage liver disease (MELD) score ≤25, absence of portal vein thrombosis, no mechanical ventilation at the time of surgery, receiving a graft from a donor after brain death. Also, high-urgent priority and early redo-LT including those for primary nonfunction (PNF) or hepatic artery thrombosis were excluded. Benchmark cutoffs were derived from the 75th percentile of the medians of all benchmark centers. RESULTS: Of 1110 redo-LT, 373 (34%) cases qualified as benchmark cases. Among these cases, the rate of postoperative complications until discharge was 76%, and increased up to 87% at 1-year, respectively. One-year overall survival rate was excellent with 90%. Benchmark cutoffs included Comprehensive Complication Index CCI ® at 1-year of ≤72, and in-hospital and 1-year mortality rates of ≤13% and ≤15%, respectively. In contrast, patients who received a redo-LT for PNF showed worse outcomes with some values dramatically outside the redo-LT benchmarks. CONCLUSION: This study shows that redo-LT achieves good outcome when looking at benchmark scenarios. However, this figure changes in high-risk redo-LT, as for example in PNF. This analysis objectifies for the first-time results and efforts for redo-LT and can serve as a basis for discussion about the use of scarce resources.

Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: A Real-world Case Series.

OBJECTIVE: To examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting. METHODS: This was a retrospective cohort study of PwMS treated with AHSCT at 2 centers in London, UK, consecutively between 2012 and 2019 who had ≥6 months of follow-up or died at any time. Primary outcomes were survival free of multiple sclerosis (MS) relapses, MRI new lesions, and worsening of Expanded Disability Status Scale (EDSS) score. Adverse events rates were also examined. RESULTS: The cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS. At baseline, the median EDSS score was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85 months). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of participants at 2 years and in 85% at 4 years. EDSS score progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. Epstein-Barr virus reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplantation-related deaths within 100 days (2.5%), all after fluid overload and cardiac or respiratory failure. CONCLUSIONS: Efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher. CLASSIFICATION OF EVIDENCE: This study is rated Class IV because of the uncontrolled, open-label design.

Sequential Liver-Kidney Transplantation for Recurrent Liver Cysts Infection in a Patient With Autosomal Dominant Polycystic Kidney Disease: A Case Report.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disorder. Liver cysts are the most common extrarenal manifestation of the disease and usually remain asymptomatic. Liver cyst infection is rare, and its treatment is challenging. Liver transplantation (LT) is the only curative therapeutic option in symptomatic polycystic liver disease associated with ADPKD. Only a few cases of LT for recurrent liver cyst infection have been published. To our knowledge, we report the first case of sequential liver-kidney transplantation for recurrent liver cysts infection in a patient with ADPKD. A 55-year-old woman with ADPKD who had a kidney transplantation (KT) presented with multiple liver cysts infection 9 months after her KT. These episodes started after biliary tract complications due to an ampullary adenoma necessitating multiple endoscopic interventions. Her general status gradually degraded because antibiotic treatment was not effective, and she underwent LT for recurrent liver cysts infection 1 year and 9 months after her KT. LT in this setting turned out to be challenging but was possible. We think that better biliary tract workup before KT may prompt better care in these patients.

The role of the comprehensive complication index for the prediction of survival after liver transplantation.

In the last years, several scoring systems based on pre- and post-transplant parameters have been developed to predict early post-LT graft function. However, some of them showed poor diagnostic abilities. This study aims to evaluate the role of the comprehensive complication index (CCI) as a useful scoring system for accurately predicting 90-day and 1-year graft loss after liver transplantation. A training set (n = 1262) and a validation set (n = 520) were obtained. The study was registered at https://www.ClinicalTrials.gov (ID: NCT03723317). CCI exhibited the best diagnostic performance for 90 days in the training (AUC = 0.94; p < 0.001) and Validation Sets (AUC = 0.77; p < 0.001) when compared to the BAR, D-MELD, MELD, and EAD scores. The cut-off value of 47.3 (third quartile) showed a diagnostic odds ratio of 48.3 and 7.0 in the two sets, respectively. As for 1-year graft loss, CCI showed good performances in the training (AUC = 0.88; p < 0.001) and validation sets (AUC = 0.75; p < 0.001). The threshold of 47.3 showed a diagnostic odds ratio of 21.0 and 5.4 in the two sets, respectively. All the other tested scores always showed AUCs < 0.70 in both the sets. CCI showed a good stratification ability in terms of graft loss rates in both the sets (log-rank p < 0.001). In the patients exceeding the CCI ninth decile, 1-year graft survival rates were only 0.7% and 23.1% in training and validation sets, respectively. CCI shows a very good diagnostic power for 90-day and 1-year graft loss in different sets of patients, indicating better accuracy with respect to other pre- and post-LT scores.Clinical Trial Notification: NCT03723317.

The real incidence of biliary tract complications after adult liver transplantation: the role of the prospective routine use of cholangiography during post-transplant follow-up.

Biliary tract complications (BTCs) still burden liver transplantation (LT). The wide reporting variability highlights the absence of systematic screening. From 2000 to 2009, simultaneous liver biopsy and direct biliary visualization were prospectively performed in 242 recipients at 3 and 6 months (n = 212, 87.6%) or earlier when indicated (n = 30, 12.4%). Median follow-up was 148 (107-182) months. Seven patients (2.9%) experienced postprocedural morbidity. BTCs were initially diagnosed in 76 (31.4%) patients; 32 (42.1%) had neither clinical nor biological abnormalities. Acute cellular rejection (ACR) was present in 27 (11.2%) patients and in 6 (22.2%) BTC patients. Nine (3.7%) patients with normal initial cholangiography developed BTCs after 60 (30-135) months post-LT. BTCs directly lead to 7 (2.9%) re-transplantations and 14 (5.8%) deaths resulting in 18 (7.4%) allograft losses. Bile duct proliferation at 12-month biopsy proved an independent risk factor for graft loss (P = 0.005). Systematic biliary tract and allograft evaluation allows the incidence and extent of biliary lesions to be documented more precisely and to avoid erroneous treatment of ACR. The combination 'abnormal biliary tract-canalicular proliferation' is an indicator of worse graft outcome. BTCs are responsible for important delayed allograft and patient losses. These results underline the importance of life-long follow-up and appropriate timing for re-transplantation.

Pathologic correlates of the magnetization transfer ratio in multiple sclerosis.

OBJECTIVE: To identify pathologic correlates of magnetization transfer ratio (MTR) in multiple sclerosis (MS) in an MRI-pathology study. METHODS: We acquired MTR maps at 3T from 16 fixed MS brains and 4 controls, and immunostained 100 tissue blocks for neuronal neurofilaments, myelin (SMI94), tissue macrophages (CD68), microglia (IBA1), B-lymphocytes, T-lymphocytes, cytotoxic T-lymphocytes, astrocytes (glial fibrillary acidic protein), and mitochondrial damage (COX4, VDAC). We defined regions of interest in lesions, normal-appearing white matter (NAWM), and cortical normal-appearing gray matter (NAGM). Associations between MTR and immunostaining intensities were explored using linear mixed-effects models (with cassettes nested within patients) and interaction terms (for differences between regions of interest and between cases and controls); a multivariate linear mixed-effects model identified the best pathologic correlates of MTR. RESULTS: MTR was the lowest in white matter (WM) lesions (23.4 ± 9.4%) and the highest in NAWM (38.1 ± 8.7%). In MS brains, lower MTR was associated with lower immunostaining intensity for myelin (coefficient 0.31; 95% confidence interval [CI] 0.07-0.55), macrophages (coefficient 0.03; 95% CI 0.01-0.07), and astrocytes (coefficient 0.51; 95% CI 0.02-1.00), and with greater mitochondrial damage (coefficient 0.31; 95% CI 0.07-0.55). Based on interaction terms, MTR was more strongly associated with myelin in WM (coefficient 1.58; 95% CI 1.09-2.08) and gray matter (GM) lesions (coefficient 0.66; 95% CI 0.13-1.20), and with macrophages (coefficient 1.40; 95% CI 0.56-2.25), astrocytes (coefficient 2.66; 95% CI 1.31-4.01), and mitochondrial damage (coefficient -12.59; 95% CI -23.16 to -2.02) in MS brains than controls. In the multivariate model, myelin immunostaining intensity was the best correlate of MTR (coefficient 0.31; 95% CI 0.09-0.52; p = 0.004). CONCLUSIONS: Myelin was the strongest correlate of MTR, especially in WM and cortical GM lesions, but additional correlates should be kept in mind when designing and interpreting MTR observational and experimental studies in MS.

COVID-19 in an international European liver transplant recipient cohort.

OBJECTIVE: Knowledge on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in liver transplant recipients is lacking, particularly in terms of severity of the disease. The aim of this study was to describe the demographic, baseline clinical characteristics and early outcomes of a European cohort of liver transplant recipients with SARS-CoV-2 infection. DESIGN: We conducted an international prospective study across Europe on liver transplant recipients with SARS-CoV-2 infection confirmed by microbiological assay during the first outbreak of COVID-19 pandemic. Baseline characteristics, clinical presentation, management of immunosuppressive therapy and outcomes were collected. RESULTS: 57 patients were included (70% male, median (IQR) age at diagnosis 65 (57-70) years). 21 (37%), 32 (56%) and 21 (37%) patients had one cardiovascular disease, arterial hypertension and diabetes mellitus, respectively. The most common symptoms were fever (79%), cough (55%), dyspnoea (46%), fatigue or myalgia (56%) and GI symptoms (33%). Immunosuppression was reduced in 22 recipients (37%) and discontinued in 4 (7%). With this regard, no impact on outcome was observed. Forty-one (72%) subjects were hospitalised and 11 (19%) developed acute respiratory distress syndrome. Overall, we estimated a case fatality rate of 12% (95% CI 5% to 24%), which increased to 17% (95% CI 7% to 32%) among hospitalised patients. Five out of the seven patients who died had a history of cancer. CONCLUSION: In this European multicentre prospective study of liver transplant recipients, COVID-19 was associated with an overall and in-hospital fatality rate of 12% (95% CI 5% to 24%) and 17% (95% CI 7% to 32%), respectively. A history of cancer was more frequent in patients with poorer outcome.

Ocrelizumab for Treating Patients with Primary Progressive Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Ocrelizumab is indicated for relapsing remitting and primary progressive multiple sclerosis (RRMS and PPMS, respectively). In an appraisal undertaken by the National Institute for Health and Care Excellence (NICE), the company Roche presented the evidence for ocrelizumab used in patients with PPMS, which came from one single randomised controlled trial (RCT) comparing ocrelizumab versus placebo. Based on results from this trial, the licensed indication was restricted to patients with early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity. Overall, the Evidence Review Group (ERG) found that the RCT had a low risk of bias. In the post-hoc defined magnetic resonance imaging (MRI) active subgroup, matching the label indication, the risk of confirmed disability progression sustained for 12 weeks (CDP-12) was significantly delayed in the ocrelizumab group compared to placebo. However, considering the same risk with progression sustained for 24 weeks (CDP-24), which was deemed the most clinically relevant, the benefit from ocrelizumab did not reach statistical significance. In the same MRI active subgroup, benefits from ocrelizumab on functional outcomes and on health-related quality of life were not clearly demonstrated. A de novo Markov model was used to estimate the cost-effectiveness of ocrelizumab versus best supportive care (BSC) for treating patients with PPMS. Health states were defined by the Expanded Disability Status Scale (EDSS), ranging from 0 to 9. Disability progression was based on the MSBase natural history cohort that exhibited disease progression in the absence of disease-modifying therapy. Treatment with ocrelizumab delayed disability progression, with evidence of its clinical effectiveness obtained from the RCT. The economic analysis was undertaken from the National Health Service and Personal Social Services perspective, and the outcomes were reported in terms of life years gained and quality-adjusted life years (QALYs), with the overall results reported in terms of an incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained over a 50-year time horizon. Both costs and effects were discounted at 3.5% per annum. The company undertook deterministic one-way sensitivity analyses and scenario analyses, including probabilistic sensitivity analysis (PSA). The ERG raised several concerns, which were discussed at the appraisal committee meetings, resulting in the committee's preferences being applied and a revised economic analysis from the company. Under an approved patient access scheme with appraisal committee preferences applied, analyses yielded an ICER of approximately £78,300 per QALY. Sensitivity analysis results indicated that the treatment effect on CDP-12 had the greatest impact. Results for the PSA showed that at a willingness-to-pay threshold of £30,000 per QALY gained, ocrelizumab versus BSC had a zero probability of being cost-effective. Following new analyses submitted by the company, with a revised confidential patient access scheme, NICE recommended ocrelizumab in the treatment of early PPMS in adults with imaging features characteristic of inflammatory activity.

Secondary non-resectable liver tumors: A single-center living-donor and deceased-donor liver transplantation case series.

BACKGROUND: During the last decades, deceased-donor liver transplantation (DDLT) has gained a place in the therapeutic algorithm of well-selected patients harbouring non-resectable secondary liver tumors. Living-donor LT (LDLT) might represent a valuable means to further expand this indication for LT. METHODS: Between 1985 and 2016, twenty-two adults were transplanted because of neuroendocrine (n = 18, 82%) and colorectal metastases (n = 4, 18%); 50% received DDLT and 50% LDLT. In LDLT, 4 (36%) right and 7 (64%) left grafts were used; the median graft-to-recipient-weight ratios (GRWR) were 1.03% (IQR 0.86%-1.30%) and 0.59% (IQR 0.51%-0.91%), respectively. Median post-LT follow-up was 64 months (IQR 17-107) in the DDLT group and 40 months (IQR 35-116) in the LDLT group. DDLT and LDLT recipients were compared in terms of overall survival, graft survival, postoperative complications and recurrence. RESULTS: The 1- and 5-year actuarial patient survivals were 82% and 55% after DDLT, 100% and 100% after LDLT, respectively (P < 0.01). One- and 5-year actuarial graft survivals were 73% and 36% after DDLT, 91% and 91% after LDLT (P < 0.01). The outcomes of right or left LDLT were comparable. Donor hepatectomy proved safe, and one donor experienced a Clavien IIIb complication. Bilirubin peak was significantly lower after left hepatectomy compared with that after right hepatectomy [1.3 (IQR 1.2-2.2) vs. 3.3 (IQR 2.3-5.2) mg/dL; P = 0.02]. CONCLUSIONS: The more recent LDLT series compared favorably to our DDLT series in the treatment of secondary liver malignancies. The absence of portal hypertension and the use of smaller left grafts make recipient and donor surgeries safe. The safety of the procedures and lack of interference with the scarce allograft pool are expected to lead to a more frequent use of LDLT in the field of transplant oncology.

The Intention-to-Treat Effect of Bridging Treatments in the Setting of Milan Criteria-In Patients Waiting for Liver Transplantation.

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria (MC), the benefit of locoregional therapies (LRTs) in the context of liver transplantation (LT) is still debated. Initial biases in the selection between treated and untreated patients have yielded conflicting reported results. The study aimed to identify, using a competing risk analysis, risk factors for HCC-dependent LT failure, defined as pretransplant tumor-related delisting or posttransplant recurrence. The study was registered at www.clinicaltrials.gov (identification number NCT03723304). In order to offset the initial limitations of the investigated population, an inverse probability of treatment weighting (IPTW) analysis was used: 1083 MC-in patients (no LRT = 182; LRT = 901) were balanced using 8 variables: age, sex, Model for End-Stage Liver Disease (MELD) value, hepatitis C virus status, hepatitis B virus status, largest lesion diameter, number of nodules, and alpha-fetoprotein (AFP). All the covariates were available at the first referral. After the IPTW, a pseudo-population of 2019 patients listed for LT was analyzed, comparing 2 homogeneous groups of untreated (n = 1077) and LRT-treated (n = 942) patients. Tumor progression after LRT was the most important independent risk factor for HCC-dependent failure (subhazard ratio [SHR], 5.62; P < 0.001). Other independent risk factors were major tumor diameter, AFP, MELD, patient age, male sex, and period of wait-list registration. One single LRT was protective compared with no treatment (SHR, 0.51; P < 0.001). The positive effect was still observed when 2-3 treatments were performed (SHR, 0.66; P = 0.02), but it was lost in the case of ≥4 LRTs (SHR, 0.80; P = 0.27). In conclusion, for MC-in patients, up to 3 LRTs are beneficial for success in intention-to-treat LT patients, with a 49% to 34% reduction in failure risk compared with untreated patients. This benefit is lost if more LRTs are required. A poor response to LRT is associated with a higher risk for HCC-dependent transplant failure.

Adult-to-adult living-donor liver transplantation: The experience of the Université catholique de Louvain.

BACKGROUND: Liver transplantation is the treatment for end-stage liver diseases and well-selected malignancies. The allograft shortage may be alleviated with living donation. The initial UCLouvain experience of adult living-donor liver transplantation (LDLT) is presented. METHODS: A retrospective analysis of 64 adult-to-adult LDLTs performed at our institution between 1998 and 2016 was conducted. The median age of 29 (45.3%) females and 35 (54.7%) males was 50.2 years (interquartile range, IQR 32.9-57.5). Twenty-two (34.4%) recipients had no portal hypertension. Three (4.7%) patients had a benign and 33 (51.6%) a malignant tumor [19 (29.7%) hepatocellular cancer, 11 (17.2%) secondary cancer and one (1.6%) each hemangioendothelioma, hepatoblastoma and embryonal liver sarcoma]. Median donor and recipient follow-ups were 93 months (IQR 41-159) and 39 months (22-91), respectively. RESULTS: Right and left hemi-livers were implanted in 39 (60.9%) and 25 (39.1%) cases, respectively. Median weights of right- and left-liver were 810 g (IQR 730-940) and 454 g (IQR 394-534), respectively. Graft-to-recipient weight ratios (GRWRs) were 1.17% (right, IQR 0.98%-1.4%) and 0.77% (left, 0.59%-0.95%). One- and five-year patient survivals were 85% and 71% (right) vs. 84% and 58% (left), respectively. One- and five-year graft survivals were 74% and 61% (right) vs. 76% and 53% (left), respectively. The patient and graft survival of right and left grafts and of very small (<0.6%), small (0.6%-0.79%) and large (≥0.8%) GRWR were similar. Survival of very small grafts was 86% and 86% at 3- and 12-month. No donor died while five (7.8%) developed a Clavien-Dindo complication IIIa, IIIb or IV. Recipient morbidity consisted mainly of biliary and vascular complications; three (4.7%) recipients developed a small-for-size syndrome according to the Kyushu criteria. CONCLUSIONS: Adult-to-adult LDLT is a demanding procedure that widens therapeutic possibilities of many hepatobiliary diseases. The donor procedure can be done safely with low morbidity. The recipient operation carries a major morbidity indicating an important learning curve. Shifting the risk from the donor to the recipient, by moving from the larger right-liver to the smaller left-liver grafts, should be further explored as this policy makes donor hepatectomy safer and may stimulate the development of transplant oncology.

Tumoral response and tumoral phenotypic changes in a rat model of diethylnitrosamine-induced hepatocellular carcinoma after salirasib and sorafenib administration.

BACKGROUND: Several intracellular signaling pathways that are deregulated during hepatocarcinogenesis might constitute potential targets for hepatocellular carcinoma (HCC) therapy. The aim of this study was to test the potential synergic antitumor effect of salirasib and sorafenib in a diethylnitrosamine (DEN)-induced HCC model in rat. The hypothesis of tumor phenotype changes during treatment was also analyzed. MATERIALS AND METHODS: DEN was administered to Wistar rats during 9 weeks to induce cirrhosis and liver cancer. After tumor development, rats were treated with intraperitoneal injections of dimethyl sulfoxide (DMSO), or salirasib, and/or with oral sorafenib 5 days/week, during 4 weeks. At sacrifice, number and size of liver tumors as well as tumor burden were recorded, and all liver tumors were processed for histological and immunohistological analyses. RESULTS: Mortality rate was significantly higher in rats treated with salirasib and/or sorafenib than in the control group (P=0.001). Tumor burden was smaller in the treated group compared with the DMSO control group (P=0.044), but a synergistic effect of the two chemotherapies could not be observed. In 62.5% of rats (10/16) treated with salirasib and/or sorafenib, a cytokeratin-7 and -19-positive hepatocholangiocellular carcinoma (HCC/CHC) was found vs 20% (5/25) developing such phenotype in the DMSO control group (P=0.018). Ki67 immunostaining showed significantly reduced tumor cell proliferation in treated rats (P=0.001), whereas apoptosis as assessed by caspase-3 activity in cell lysate was similar in all groups. CONCLUSIONS: The addition of sorafenib to salirasib did not seem to provide any synergistic therapeutic effect in this study. Both chemotherapeutic agents, administered alone or in combination, induced tumoral phenotypic changes in the majority of rats, a finding not associated with an increased tumor cell proliferation or decreased apoptosis. The rat model described in this work constitutes the first experimental tool generating putatively more aggressive combined HCC/CHC tumors following chemotherapy. Further work is required to better characterize this clinically relevant phenomenon.

Tacrolimus and Single Intraoperative High-dose of Anti-T-lymphocyte Globulins Versus Tacrolimus Monotherapy in Adult Liver Transplantation: One-year Results of an Investigator-driven Randomized Controlled Trial.

OBJECTIVE: The aim of the study is to evaluate whether intra-operative induction with anti-lymphocytic serum (ALS) is superior to no induction in adult liver transplantation (LT). BACKGROUND: The efficacy of ALS induction remains inconclusive in LT, because of poorly designed trials. METHODS: A randomized controlled trial was conducted, including 206 adults (>15 years) and comparing tacrolimus monotherapy (TAC, n = 109) and tacrolimus plus a single, intraoperative, high-dose (9 mg/kg), rabbit anti-T-lymphocyte globulins (ATLG; n = 97). All patients had similar follow-up, including Banff-scored biopsies. Rejection was considered clinically relevant and treated if pathologic and biochemical changes were concordant. The primary endpoint was immunosuppression minimization to monotherapy; secondary endpoints were biopsy-proven rejection, clinical rejection, patient (PS) and graft (GS) survival. RESULTS: At 1 year, 79/81 (96.3%) ATLG and 101/102 (99.0%) TAC patients were steroid-free (P = 0.585); 28 (34.6%) ATLG, and 31 (30.4%) TAC patients were on double-drug immunosuppression (P = 0.633). One-year PS and GS of ATLG and TAC patients were 84% and 92% (P = 0.260) and 76% and 90% (P = 0.054).Despite significantly a fewer day-7 moderate-to-severe acute cellular rejections (ACR) in ATLG group (10.0% vs 24.0% in TAC group, P = 0.019), cumulative proportion of patients experiencing steroid-sensitive (11.3% ATLG vs 14.7% TAC, P = 0.539), steroid-resistant (2.1% ATLG vs 3.7% TAC, P = 0.686) and chronic rejection (1.0% ATLG vs 0.9% TAC, P = 1.000) were similar. ATLG administration brought about greater hemodynamic instability and blood products use (P = 0.001). CONCLUSIONS: At 1 year from LT, ATLG induction did not significantly affect immunosuppressive load, treated rejection, patient, and graft survival. The observed adverse events justify a modification of dosing and timing of ATLG infusion. Long-term results are required to judge the ATLG possible benefits on immunosuppressive load and tolerance induction.