Impact of Pre-Liver Transplant Treatments on the Imaging Accuracy of HCC Staging and Their Influence on Outcomes.

The outcome of liver transplantation (LT) for hepatocarcinoma (HCC) is strongly influenced by HCC staging, which is based on radiological examinations in a pre-LT setting; concordance between pre-LT radiological and definitive pathological staging remains controversial. To address this issue, we retrospectively analyzed our LT series to assess concordance between radiology and pathology and to explore the factors associated with poor concordance and outcomes. We included all LTs with an HCC diagnosis performed between 2013 and 2018. Concordance (Co group) was defined as a comparable tumor burden in preoperative imaging and post-transplant pathology; otherwise, non-concordance was diagnosed (nCo group). Concordance between radiology and pathology was observed in 32/134 patients (Co group, 24%). The number and diameter of the nodules were higher when nCo was diagnosed, as was the number of pre-LT treatments. Although concordance did not affect survival, more than three pre-LT treatments led to a lower disease-free survival. Patients who met the Milan Criteria (Milan-in patients) were more likely to receive ≥three prior treatments, leading to a lower survival in multi-treated Milan-in patients than in other Milan-in patients. In conclusion, the concordance rate between the pre-LT imaging and histopathological results was low in patients with a high number of nodules. Multiple bridging therapies reduce the accuracy of pre-LT imaging in predicting HCC stages and negatively affect outcomes after LT.

Recent outcomes of liver transplantation for Budd-Chiari syndrome: A study of the European Liver Transplant Registry (ELTR) and affiliated centers.

BACKGROUND AND AIMS: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplantant (post-LT) outcomes in Europe. APPROACH AND RESULTS: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). CONCLUSIONS: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.

Perfusion fluid-related infections in liver transplant recipients: A 5-year, single-center, retrospective study.

BACKGROUND: Perfusion fluid (PRF) is employed in liver transplantation (LTx) to maintain graft viability. Still, it represents a new potential way of infection transmission in LTx recipients (LTRs). Currently, no systematic research has investigated this topic. METHODS: Five-year single-center retrospective study conducted on LTRs from January 2017 to December 2021. We analyzed the incidence of positive PRF culture (PRF+) and perfusion fluid-related infections (PRF-RI) and their associated factors. We also assessed 1-year mortality, both overall and infection-related. RESULTS: Overall, 234 LTx were included. PRF+ were found in 31/234 (13.2%) LTx for a total of 37 isolates, with >1 isolate identified in 5 (2.1%) cases. High-risk microorganisms (Enterobacterales 13/37, Enterococcus spp. 4/37, S. aureus 3/37, P. aeruginosa 2/37) were isolated in 25/37 (67.6%) LTRs, the remaining being coagulase-negative staphylococci (12/37, 32.4%). Antimicrobial prophylaxis was administered to all LTRs, always active against the isolate even if suboptimal in 19 cases (61.3%). PRF-RI developed in 4/234 LTx (1.7%), and prophylaxis was considered suboptimal in 2/4 of them. The isolation of >1 microorganism in PRF culture was associated with an increased risk of developing PRF-RI (OR 37.5 [95%CI 2.6-548.4], p = .01). PRF-RI were associated with longer ICU stays (p = .005) and higher 1-year mortality, both overall and related to infections (p = .001). CONCLUSION: Despite PRF+ being infrequent, only a minority of patients develops PRF-RI. Nonetheless, once occurred, PRF-RI seems to increase morbidity and mortality rates.

Induced myocardial ischemia in candidates to liver transplantation without evidence of heart disease.

BACKGROUND: Coronary artery disease (CAD) is associated with perioperative liver transplantation (LT) mortality. In absence of a defined risk algorithm, we aimed to test whether stress echocardiography and coronary computed tomography angiography (CCTA) could detect CAD in end-stage liver disease (ESLD) patients without previous evidence of heart disease. METHODS: LT candidates ≥30 years underwent a cardiovascular (CV) assessment through stress echocardiography. CCTA was performed in patients ≥50 years with two or more CV risk factors (e.g. diabetes, CAD family history, dyslipidaemia). Coronary angiography (CAG) was scheduled when stress echocardiography and/or CCTA were positive. Sensibility, specificity, positive and negative predictive values of stress echocardiography and CCTA were assessed by numbers of coronary revascularization (true positives) and lack of acute coronary events over a mean follow-up of 3 years (true negatives). RESULTS: Stress echocardiography was performed in 273 patients, CCTA in 34 and CAG in 41. Eight patients had critical coronary lesions, and 19 not-critical lesions. Sensitivity, specificity, positive and negative predictive values were 50.0%, 90.2%, 13.3% and 98.4% for stress echocardiography and 100%, 76.7%, 36.4% and 100% for CCTA. Among 163 patients who underwent LT (57.6%), 16 died and 5 had major adverse CV events over a mean follow-up of 3 years. CONCLUSIONS: A very low prevalence of CAD in a selected population of ESLD at intermediate to high CV risk was found. A screening based on stress echocardiography and CCTA resulted in low incidence of post-LT acute coronary events in ELSD patients. CAD has no impact on mid-term survival.

Central retinal thickness fluctuations in patients treated with anti-VEGF for neovascular age related macular degeneration.

PURPOSE: This is a retrospective, single-center, non randomized interventional real life study, investigating the correlation between variability of central retinal thickness (CRT) and functional outcomes during 2 years of anti-VEGF therapy in patients treated for neovascular age related macular degeneration (nAMD). BACKGROUND: CRT fluctuations can depend on various factors such as the correct timing of injections, the therapeutic algorithm, and the number of injections (NI) performed; it is important to understand if CRT fluctuations are responsible for worse visual outcomes and consequently to identify the correct ways to avoid or reduce them. METHODS: Forty-one patients were treated for nAMD with aflibercept: 0.5 mg intravitreal aflibercept was administered every 4 weeks during the first 3 months, then bimonthly over the first year, and after the first year adopting a PRN regimen. Standard deviation of CRT (CRT/SD), BCVA, and NI were recorded. Correlation studies were performed by Pearson's test, Ancova, and Principal Component Analysis. RESULTS: A negative correlation was found between CRT/SD and final BCVA. In patients who lost more than 15 letters, CRT/SD mean was significantly higher in comparison with patients who lost less than 15 letters. Patients with final BCVA >65 letters showed lower CRT/SD values compared to patients with final BCVA ⩽65 letters. Multivariate analysis confirmed that in patients with higher baseline BCVA, improvement of BCVA was correlated to NI, and lower values of CRT fluctuations were observed. CONCLUSIONS: CRT fluctuations, even after an appropriate NI given per year, significantly influence BCVA; a proactive treatment algorithm appears crucial when treating patients with nAMD.

The Role of Ex Situ Hypothermic Oxygenated Machine Perfusion and Cold Preservation Time in Extended Criteria Donation After Circulatory Death and Donation After Brain Death.

Hypothermic oxygenated machine perfusion (HOPE) has the potential to counterbalance the detrimental consequences of cold and warm ischemia time (WIT) in both donation after brain death (DBD) and donation after circulatory death (DCD). Herein we investigated the protective effects of HOPE in extended criteria donor (ECD) DBD and overextended WIT DCD grafts. The present retrospective case series included 50 livers subjected to end-ischemic HOPE or dual DHOPE in 2 liver transplantation (LT) centers from January 2018 to December 2019. All DCD donors were subjected to normothermic regional perfusion before organ procurement. Results are expressed as median (interquartile range [IQR]). In the study period, 21 grafts were derived from overextended WIT DCD donors (total WIT 54 [IQR, 40-60] minutes and 75% classified as futile), whereas 29 were from ECD DBD. A total of 3 biliary complications and 1 case of ischemia-type biliary lesion were diagnosed. The rate of early allograft dysfunction (EAD) was 20%, and those patients had higher Comprehensive Complication Index scores. Through a changing point analysis, cold preservation time >9 hours was associated with prolonged hospital stays (P = 0.02), higher rates of EAD (P = 0.009), and worst post-LT complications (P = 0.02). Logistic regression analyses indicated a significant relationship between cold preservation time and EAD. No differences were shown in terms of the early post-LT results between LTs performed with DCD and DBD. Overall, our data are fully comparable with benchmark criteria in LT. In conclusion, the application of DHOPE obtained satisfactory and promising results using ECD-DBD and overextended DCD grafts. Our findings indicate the need to reduce cold preservation time also in the setting of DHOPE, particularly for grafts showing poor quality.

An Italian survey on the use of T-tube in liver transplantation: old habits die hard!

There is enough clinical evidence that a T-tube use in biliary reconstruction at adult liver transplantation (LT) does not significantly modify the risk of biliary stricture/leak, and it may even sustain infective and metabolic complications. Thus, the policy on T-tube use has been globally changing, with progressive application of more restrictive selection criteria. However, there are no currently standardized indications in such change, and many LT Centers rely only on own experience and routine. A nation-wide survey was conducted among all the 20 Italian adult LT Centers to investigate the current policy on T-tube use. It was found that 20% of Centers completely discontinued the T-tube use, while 25% Centers used it routinely in all LT cases. The remaining 55% of Centers applied a selective policy, based on criteria of technical complexity of biliary reconstruction (72.7%), followed by low-quality graft (63.6%) and high-risk recipient (36.4%). A T-tube use > 50% of annual caseload was not associated with high-volume Center status (> 70 LT per year), an active pediatric or living-donor transplant program, or use of DCD grafts. Only 10/20 (50%) Centers identified T-tube as a potential risk factor for complications other than biliary stricture/leak. In these cases, the suspected pathogenic mechanism comprised bacterial colonization (70%), malabsorption (70%), interruption of the entero-hepatic bile-acid cycle (50%), biliary inflammation due to an indwelling catheter (40%) and gut microbiota changes (40%). In conclusion, the prevalence of T-tube use among the Italian LT Centers is still relatively high, compared to the European trend (33%), and the potential detrimental effect of T-tube, beyond biliary stricture/leak, seems to be somehow underestimated.

Concurrent Thoracic Endovascular Aortic Repair and Liver Transplant: Multidisciplinary Management of Multiple Posttraumatic Lesions.

Association of thoracic and abdominal injuries in patients with major trauma is common. Under emergency conditions, it is often difficult to promptly perform a certain diagnosis and identify treatment priorities of life-threatening lesions. We present the case of a young man with combined thoracic and abdominal injuries after a motorcycle accident. Primary evaluation through echography and X-ray showed fluid within the hepatorenal recess and an enlarged mediastinum. Volume load, blood transfusions, and vasoactive agents were initiated to sustain circulation. Despite hemodynamic instability, we decided to perform computed tomographic angiography (CTA) scan that revealed a high-grade traumatic aortic pseudoaneurysm, multiple and severe areas of liver contusion, and a small amount of hemoperitoneum, without active bleeding spots. The patient was successfully submitted to thoracic endovascular aortic repair (TEVAR). Immediately after the end of the successful TEVAR, signs of massive abdominal bleeding revealed. Immediate explorative laparotomy was performed showing massive hepatic hemorrhage. After liver packing and Pringle's maneuver, control of bleeding was lastly obtained with hemostatic devices and selective cross-clamping of the right hepatic artery. The patient was then transferred to intensive care unit where, despite absence of further hemorrhage, hemodynamic instability, anuria, severe lactic acidosis together with liver necrosis indices appeared. A new CTA demonstrated massive parenchymal disruption within the right lobe of the liver and multiple hematomas in the left lobe. Considering the high-grade lesions of the hepatic vascular tree and liver failure, patient was listed for emergency liver transplantation (LT). LT occurred few hours later, and patient's clinical conditions rapidly improved even if the subsequent clinical course was characterized by a severe fungal infection because of immunosuppression. Evaluation of life-threatening lesions and treatment priorities, availability of different excellence skills, and multidisciplinary collaboration have a key role to achieve clinical success in such severe cases.

Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial.

BACKGROUND: Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. METHODS: We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18-65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503. FINDINGS: Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4-11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60-85). 5-year tumour event-free survival was 76·8% (95% CI 60·8-96·9) in the transplantation group versus 18·3% (7·1-47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07-0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9-97·1) in the transplantation group versus 31·2% (16·6-58·5) in the control group (HR 0·32, 95% CI 0·11-0·92; p=0·035). The most common registered grade 3-4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). INTERPRETATION: Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. FUNDING: Italian Ministry of Health.

Experience With Early Sorafenib Treatment With mTOR Inhibitors in Hepatocellular Carcinoma Recurring After Liver Transplantation.

BACKGROUND: Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence. METHODS: All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (January 2008 to June 2018). Baseline and on-treatment data were collected. RESULTS: Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor [mTORi], 54% HCC-treated at baseline) were enrolled. During 7.3 (0.3-88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3-4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% confidence Interval [CI], 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18 months (95% CI, 8-27); 5-year OS was 18% (95% CI, 4%-32%). Baseline predictors of OS were SOR+mTORi (hazard ratio [HR], 0.4; 95% CI, 0.2-0.9; P = 0.04), previous curative treatments (HR, 0.3; 95% CI, 0.2-0.7; P = 0.003) and alpha-fetoprotein > 100 ng/mL (HR, 2.5; 95% CI, 1.1-5.0, P = 0.02). At multivariate analysis, HCC curative treatment was the only independent predictor (HR, 0.4; 95% CI 0.2-1.0; P = 0.04). CONCLUSIONS: Early and combined treatment with SOR and mTORi resulted in a favorable safety profile, while its effectiveness should be confirmed by meta-analysis of previous studies or by larger studies. Curative treatment for HCC resulted the only independent predictor of OS.

Hepatitis C virus-induced glomerular disease and posterior reversible encephalopathy syndrome after liver transplant: Case report and literature review.

Chronic hepatitis C virus (HCV) infection is associated with numerous extra-hepatic complications, including neurological and renal manifestations. We describe the case of a 67-year-old Caucasian man with HCV-associated cryoglobulinemic glomerulonephritis, cirrhosis, and hepatocellular carcinoma. The early posttransplant course was complicated by fibrosing cholestatic hepatitis due to recurrent HCV in the graft (HCV RNA up to 44,944,438 IU/mL). Proliferative glomerulonephritis (nephritic and nephrotic syndrome) with mixed cryoglobulinemia (purpura) was also recorded. Seventy-two days after surgery, the patient presented with seizures and arterial hypertension; brain magnetic resonance imaging indicated the diagnosis of posterior reversible encephalopathy syndrome (PRES). PRES responded well to medical treatment with complete resolution of neurological changes. Antiviral therapy (sofosbuvir and ribavirin, six months) gave a sustained viral response with the improvement of cryoglobulinemic symptoms (including glomerular disease). Repeat liver biopsy revealed the regression of cholestatic damage and perisinusoidal fibrosis. The current follow-up shows stable chronic renal failure (serum creatinine: 1.4 mg/dL) and mild nephritic syndrome. The impact of extrahepatic manifestations of HCV on patient outcomes is highlighted from novel observational studies reporting a relationship between HCV cure (as expressed by the sustained viral response) and a decrease in both liver-related and renal complications. Clinical trials evaluating the efficacy and tolerance of novel direct-acting antiviral agents for the management of HCV-associated glomerular diseases are underway.

Environmental Health in Perinatal and Early Childhood: Awareness, Representation, Knowledge and Practice of Southern France Perinatal Health Professionals.

The exposure of adults of reproductive age as well as pregnant women and children to environmental contaminants is of particular concern, as it can impact fertility, in utero development, pregnancy outcomes and child health. Consequently, the World Health Organisation (WHO) and international societies advocate including Environmental Health (EH) in perinatal care, yet perinatal health professionals (HPs) hardly put these recommendations into practice. In 2017, a cross-sectional study was performed in a large panel of perinatal HPs in south-eastern France with the aim of painting a picture of their current attitudes, representation, knowledge, and training expectations. Quantitative and qualitative information was collected via auto-questionnaire. Questionnaires were completed by 962 participants, mainly midwives (41.1%), physicians (25.6%) and nursery nurses (11%). Indoor/outdoor air quality and endocrine disruptors were the best-mastered topics, whereas electromagnetic fields and diet gave rise to unsure responses. Overall, perinatal HPs were ill-trained and -informed about the reproductive risks linked to daily environmental exposure. HPs reported scarce knowledge, fear of patient reaction and lack of solutions as the main barriers to providing information regarding EH to the public. Our findings highlight the need to set up EH training programmes focused on scientific knowledge and to provide simple messages and tips to help perinatal HPs deliver advice to populations to mitigate exposure to environmental toxicants.