Criteria For Transplantation Research Articles

Low Toxicity and Disease Responses in Systemic AL-Amyloidosis Using an Yttrium-90 Labelled Anti-CD66 Monoclonal Antibody TLX66 As the Only Conditioning Prior to Autologous Stem Cell Transplantation

Despite the introduction of new therapies Systemic AL-amyloidosis (AL) remains incurable and the majority of patients will relapse. Autologous stem cell transplantation (ASCT) remains an important treatment option with improvement of organ function and survival in responding patients, however the toxicity of ASCT using conventional chemotherapy results in high morbidity and mortality limiting the application in this vulnerable patient group. We tested the use of a monoclonal anti-CD66 radiolabelled with yttrium-90, TLX66 (90Y-besilesomab) as the sole conditioning agent prior to ASCT in a phase I study in patients with AL. The study had full ethical and regulatory approvals (EudraCT 2015-002231-18; ISRCTN 13400668). The study consisted of three radiation activity levels, 30, 40 and 45 Mega Becquerels (MBq) per kg body weight with 3 patients treated at each activity level. Patients entered the study after fulfilling entry requirements and with informed consent. Prior to receiving the 90Y-besilesomab organ dosimetry and biodistribution were determined using the same anti-CD66 radiolabelled with indium-111 (111In-anti-CD66) with sequential gamma camera imaging. Estimated absorbed radiation to critical organs was determined from an established dosimetry model, organ radiation dose expressed in Gray (Gy). Radiation dose limits of 45Gy for the bone marrow and 15Gy for the liver were used as safety measures. Table 1 summarises patient details. The median previous lines of treatment were 2 (range 1-5) including three who had previous ASCT using high dose melphalan. The primary end-point was treatment related toxicity as determined using CTCAE v4.0. Haematological toxicities (cytopenia) were excluded as adverse events (AEs) unless considered life-threatening. Secondary end-points: Disease response determined by changes in clonal free light chain assay (FLCa), malignant plasma cell percentage in BM as determined by multi-colour flow cytometry; cardiac toxicity from NT-proBNP assay; overall survival and time to disease progression; biodistribution and dosimetry SPECT-CT imaging; engraftment using the European Blood and Marrow Transplant (EBMT) criteria for neutrophil and platelet engraftment. Results: Ten patients underwent dosimetry with 111In-anti-CD66, 9 received the 90Y-besilesomabwith infused activity determined by study cohort and patient body weight; one patient failed dosimetry with excessive hepatic uptake, two received reduced activity to keep the marrow dose within the 45Gy limit. There were no serious adverse events (SAE's) in the trial. There were 3 grade 4 AE's (mainly cytopenias during transplantation) and no SUSAR's were reported. A total of 41 grade 1-4 AE's were recorded. There were no transplant related deaths. All patients became profoundly cytopenic consistent with bone marrow suppression due to the targeted radiation. All patients engrafted with median neutrophils recovery by D+13 and platelets by D+11. Importantly, no patients experienced any mucositis or therapy related diarrhoea. All maintained oral nutrition. Only two patients experienced a fever post-transplant, neither were life-threatening. Table 2 summarises the estimated absorbed radiation dose to critical organs and disease responses. Of the 9 patients treated with 90Y-besilesomaband ASCT 7 had haematologic responses with 2 complete responses (CR), 5 partial responses (PR), 1 stable disease (SD) and 1 progressive disease (PD) as determined. Six of 8 evaluable patients showed a reduction in percentage of malignant plasma cells in the BM. The study collected data up to D+100 post-transplant but 2 patients showed continuing slow reduction in clonal FLCa beyond D+100 with 1 achieving a CR 5 months post-transplant. No radiation dose limiting toxicity was seen. No consistent changes were seen in NT-proBNP. Importantly no cardiac AEs were recorded. All patients are alive. The long term follow up data will be presented. Acknowledgement: The native anti CD66 MAb (Besilesomab) was provided by Telix Pharmaceuticals. TLX66 (90Y-besilesomab) was acquired by Telix Pharmaceuticals in 2021. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mosunetuzumab with Polatuzumab Vedotin Is Effective and Has a Manageable Safety Profile in Patients Aged

Background: Treatment decision-making for elderly DLBCL patients (pts) is challenging. Advancing age is associated with an increase in the incidence of comorbidity and vulnerability to treatment-related toxicities (Thieblemont & Coiffier. J Clin Oncol 2007). Mosunetuzumab (M) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Ab) that redirects T cells to eliminate malignant B cells. The Phase Ib/II GO40516 study (NCT03671018) is evaluating M in combination with the anti-CD79b antibody-drug conjugate polatuzumab vedotin (Pola; M-Pola) in pts with B-cell non-Hodgkin lymphoma (B-NHL). In the ongoing Phase II part of the study, M-Pola showed an acceptable safety profile with promising activity in pts with R/R B-NHL (Budde et al. ASH 2021). Here, we present a subgroup analysis of the efficacy and safety of M-Pola in pts aged <65 and ≥65 years with R/R aggressive B-NHL from the Phase Ib dose-escalation and Phase II dose-expansion cohorts. Methods: All pts in this analysis had DLBCL (including transformed follicular lymphoma and follicular lymphoma grade [Gr] IIIB), an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and ≥1 prior line of therapy, including an anti-CD20 Ab. Treatment cycles were 21 days. Pola (1.8mg/kg intravenous [IV] infusion) was given on Day (D)1 of Cycle (C)1-6. M (IV infusion) was given with step-up dosing during C1 to mitigate cytokine release syndrome (CRS), and the recommended Phase II dose was used in the Phase II dose-expansion cohort (1mg on C1D1, 2mg on C1D8, 60mg on C1D15 and C2D1, and 30mg on D1 of C3-8). Pts with stable disease or a partial response at the end of C8 could continue M for a total of 17 cycles, while pts with a complete response (CR) discontinued M after C8. In the Phase II expansion cohort, mandatory hospitalization was not required for M administration. Response was assessed by investigators using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). CRS events were reported using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of March 15, 2021, with a median follow-up of 5.3 months (range: 0.7-23.7 months), 60 pts with R/R DLBCL had received M-Pola: 24 (40%) were aged <65 years and 36 (60%) were aged ≥65 years. At study entry, for pts aged ≥65 years, the median age was 73 years (range: 65-83), 53% had ECOG PS 1 and 8% had PS 2, 50% had International Prognostic Index 3-5, 81% had Ann Arbor stage III/IV disease, and 81% and 72% were refractory to a prior anti-CD20 Ab and to last prior therapy, respectively. There were more pts <65 years than pts ≥65 years with high lactate dehydrogenase (LDH; 63% vs 44%, respectively), with ≥3 prior lines of therapy (67% vs 56%), and refractory to CAR T-cell therapy (38% vs 25%; Table). Compared with younger pts, those aged ≥65 years had a numerically higher ORR (72% [95% CI: 55-86] vs 54% [95% CI: 33-75]) and CR rate (56% [95% CI: 38-72] vs 38% [95% CI: 19-59]). The rate of Gr 3-4 adverse events (AEs) was lower in pts ≥65 years than in those <65 years (39% vs 58%, respectively), with fewer neutropenia events occurring (14% vs 33%); the rate of serious AEs of any Gr was similar (39% vs 33%). Five pts ≥65 years discontinued M and/or Pola due to treatment-related AEs compared with one pt <65 years. The rate of CRS was comparable in pts aged ≥65 and <65 years (17% vs 21%), all CRS events were low-Gr (≥65 vs <65 years: Gr 1, 14% vs 21%; Gr 2, 3% vs 0%), and all CRS events resolved. Rates of serious AEs of infection were comparable in pts aged ≥65 and <65 years (11% vs 17%, respectively). Rates of peripheral neuropathy were 42% in pts aged ≥65 years vs 21% in pts aged <65 years, with most events Gr1-2 (≥65 vs <65 years: 1 vs 2 Gr 3 events). After the first M-Pola dose, pharmacodynamic changes in interferon-α and T-cell activation in peripheral blood were similar across age groups. Conclusions: M-Pola is effective and has a manageable safety profile in pts with heavily pretreated DLBCL, including older pts who may have more comorbidities and fewer treatment options, such as those who are poor candidates for CAR T-cell therapy. Numerically higher ORR and CR rates were seen in pts aged ≥65 years, although longer follow-up is required. Comparable rates of CRS and serious AEs were observed across age groups. Enrollment in the Phase II study with no mandatory hospitalization is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Liver Health in Patients with Hemophilia: Residual Risk Factors of Liver-Related Complications after HCV Clearance

Background and Aim: Hepatitis C virus (HCV) is highly prevalent in patients with hemophilia, but today almost all patients achieve a sustained virological response (SVR) to therapy. Unfortunately, other risk factors (e.g. metabolic and/or alcohol) can make chronic hepatitis continue even after SVR and, potentially, evolve to cirrhosis. We herein report data from a prospective hepatological screening program aimed at evaluating any relevant risk factor of liver-related complications after SVR in patients with hemophilia. Methods: We enrolled 75 HCV-patients (median age: 54; range: 36-80): 68/7 hemophilia A/B, 63% suffering from a severe inherited bleeding disorder. At time of inclusion, 22 patients (29%) had achieved a SVR after successful interferon-based therapies, 48 (64%) after third generation antiviral agents, 5 (7%) had obtained a spontaneous virus clearance. All patients were screened for active etiologic factors of chronic hepatitis, biochemistry, liver stiffness measurement (LSM) and ultrasound-exploration (US) to rule in/out cirrhosis. Invasive diagnostic tests were adopted when appropriate. Data before SVR were available in 44 patients for pre/post-SVR analysis to explore their potential diagnostic accuracy to rule out an advanced chronic liver disease at time of the screening. Results: Thirty-one patients (41%) presented at least one active risk factor of potential chronic liver damage, metabolic syndrome being the most prevalent (36%). Twenty-nine patients (39%) had also HIV/HBV infection although adequately treated at time of the screening. Steatosis was detected by US in 37 patients (48%). Based on clinical, biochemical and/or morphological criteria 21 patients (28%) had signs cirrhosis. Among them, 4 patients (5%) had esophageal varices needing treatment, 3 (4%) hepatocellular carcinoma (HCC). One HCC was detected in a non-cirrhotic liver but was associated with metabolic comorbidities, 2 were HCC out of transplantation criteria and were addressed to a multi-disciplinary down-staging approach (e.g. surgery, chemoembolization, chemotherapy). Finally 2 of HCC were transplanted. All the non-invasive tests for cirrhosis (e.g. LSM, APRI, Fib4, Forns score) were sensibly reduced after virus clearance (p<0.05). On the contrary typical US-signs of cirrhosis did not significantly change after SVR. Eleven patients had LSM between 6-9 KPa. Interestingly, 3 of them had irregular liver surface, 1 caudate hypertrophic liver lobe, 6 splenomegaly, suggesting that non-invasive tests may not accurately rule out an advanced chronic liver disease after HCV clearance even for low levels of LSM. Conclusions: A residual risk of chronic liver damage after HCV-clearance is frequently observed. Non-invasive tests of fibrosis dramatically change after SVR and could be inaccurate to rule out cirrhosis. A specific diagnostic work-up is mandatory to preserve liver-health in this clinical setting.

Improving Transplant-free Survival With Low-volume Plasma Exchange to Treat Children With Rodenticide Induced Hepatotoxicity

In a prior report, no patient with rodenticidal hepatotoxicity who met Kochi criteria (MELD score ≥36 or baseline INR ≥6 with hepatic encephalopathy) (PMID: 26310868) for urgent liver transplantation survived with medical management alone. Plasma exchange (PLEX) may improve survival in these patients. We describe our experience with low-volume PLEX (PLEX-LV) in treating rodenticide ingestion induced hepatotoxicity in children. From prospectively collected database of rodenticidal hepatotoxicity patients managed as in-patient with department of Hepatology from December 2017 to August 2021, we retrospectively studied outcomes in children (≤18 years). Hepatotoxicity was categorized as acute liver injury (ALI, coagulopathy alone) or acute liver failure (ALF, coagulopathy and encephalopathy). Kochi criteria was used to assess need for urgent liver transplantation. The primary study outcome was one-month survival. Of the 110 rodenticidal hepatotoxicity patients, 32 children (females: 56%; age: 16 [4.7-18] years; median, range) constituted the study patients. The study patients presented 4 (1-8) days after poison consumption (impulsive suicidal intent:31, accidental:1). Twenty children (62%) had ALI [MELD: 18 (8-36)] and 12 (38%) had ALF [MELD: 37 (24-45)].All children received standard medical care, including N-acetyl cysteine; ALF patients also received anti-cerebral edema measures. None of the patient families opted for liver transplantation. Seventeen children (ALI: 6, ALF: 11) were treated with PLEX-LV (3 [1-5] sessions, volume of plasma exchanged per session: 26 [13-38] ml/kg body weight) and peri-procedure low dose prednisolone.At 1 month, 28 of the 32 children (87.5%) were alive (4 ALF patients died). Of 10 children who met Kochi listing criteria for urgent liver transplantation, two children were ineligible for PLEX-LV (due to hemodynamic instability) and of the remaining 8 children treated by PLEX-LV, 6 (75%) survived. PLEX-LV shows promise as an effective non-liver transplant treatment in children with rodenticidal hepatotoxicity.

Improved Outcomes in Severe Primary Graft Dysfunction After Heart Transplantation Following Donation After Circulatory Death Compared With Donation After Brain Death

Primary graft dysfunction (PGD), the leading cause of early mortality after heart transplantation, is more common following donation after circulatory death (DCD) than donation after brain death (DBD). We conducted a single-center, retrospective cohort study to compare the incidence, severity and outcomes of patients experiencing PGD after DCD compared to DBD heart transplantation. Medical records were reviewed for all adult heart transplant recipients at our institution between March 2016 and December 2021. PGD was diagnosed within 24 hours after transplant according to modified International Society for Heart and Lung Transplant criteria. A total of 459 patients underwent isolated heart transplantation during the study period, 65 (14%) following DCD and 394 (86%) following DBD. The incidence of moderate or severe PGD in DCD and DBD recipients was 34% and 23%, respectively (P = 0.070). DCD recipients were more likely to experience severe biventricular PGD than DBD recipients (19% vs 7.4%; P = 0.004). Among patients with severe PGD, DCD recipients experienced shorter median (Q1, Q3) duration of post-transplant mechanical circulatory support (6 [4, 7] vs 9 [5, 14] days; P = 0.039), shorter median post-transplant hospital length of stay (17 [15, 29] vs 52 [26, 83] days; P = 0.004), and similar 60-day survival rates (100% [95% CI: 76.8%-100%] vs 80.0% [63.1%-91.6%]; P = 0.17) and overall survival (log-rank; P = 0.078) compared with DBD recipients. DCD heart transplant recipients were more likely to experience severe, biventricular PGD than DBD recipients. Despite this, DCD recipients with severe PGD spent fewer days on mechanical circulatory support and in the hospital than similar DBD patients. These findings suggest that patterns of graft dysfunction and recovery may differ between donor types, and they support the expansion of the heart-donor pool with DCD.

Optimizing Survival for Hepatocellular Carcinoma After Liver Transplantation: A Single-Center Report and Current Perspectives

Hepatocellular carcinoma (HCC) is the leading primary liver tumor and a main indication for transplant. Transplant criteria are based on clinicopathologic features, meanwhile adequate downstaging and molecular mechanisms are getting more attention in evolving therapeutic algorithm of HCC. The aim of our study was to overview the results of the Hungarian Liver Transplant Program in the field of HCC and introduce new aspects of personalized treatment options. We performed retrospective analysis of survival and tumor recurrence of HCC-associated liver transplant recipients between October 2013 and December 2020. Patients were categorized in Milan criteria (MC), beyond MC but within University of California, San Francisco (UCSF), and beyond UCSF criteria groups after pathologic examination of the explanted liver. Demographic data and preoperative locoregional treatments were assessed. A total of 529 primer liver transplants were performed, 88 because of HCC. A total of 87 patients had underlying cirrhosis because of hepatitis C (54%), alcohol-related liver disease (33.7%), hepatitis B (4.5%), or unknown etiology. A total of 55.6% of the patients had at least one locoregional treatment. A total of 67.4% of the patients were within MC, 5.6% were within UCSF criteria, and 27% were beyond UCSF criteria. The 1-, 3-, and 5-year survival rates were 80%, 79%, and 75%. The outcome was better in early-stage tumors, but the difference was not significant (P=.745) CONCLUSIONS: The favorable survival in our department legitimates the strict transplant criteria of HCC. Adequate locoregional therapy as downstaging can expand recipient pool. Molecular tumor profiling may lead to personalized treatment of HCC.

Successful Unilateral Dual-Kidney Transplant of Discarded Kidneys From Two Expanded Criteria Donors

In recent years, dual-kidney transplant has become an established method to overcome the inferior quality of donor organs and to allow the recovery of discarded human kidneys. However, in some cases, 1 of the 2 donor kidneys is unsuitable for transplant because of severe pathological changes, and the remaining marginal kidney is often discarded regardless of whether it meets criteria for dual-kidney transplant. Here, we report the use of marginal kidneys from 2 different donors, both of whom had missed kidney donation as a result of the serious pathological changes in their contralateral kidney. We combined the 2 donors' marginal kidneys for dual-kidney transplant, which were implanted into the right iliac fossa of the recipient after cold ischemia times of 13 hours 40 minutes and 30 hours 30 minutes, respectively. The recipient had fully recovered and showed favorable renal function without complications at discharge and at the 1.5-year follow-up. To the best of our knowledge, this is the first case report of successful unilateral dual-kidney transplant of discarded kidneys from 2 expanded criteria donors.

Impact of COVID-19 on Organ Donation and Transplantation in the UK

The COVID-19 pandemic has placed considerable strain on the allocation of healthcare resources. In this research, we explored the views of healthcare professionals in the UK on the countrywide management of organ donation and transplantation during the first COVID-19 surge in the spring of 2020.&#x0D; Methods: An internet-based survey was developed and distributed over a 2-week period in May/June 2020.&#x0D; Results: Three hundred and fourteen professionals responded, covering all organ donation and transplant regions across the UK. Data suggest a considerable degree of scaling back of activity in all but one region (Northern Ireland). A range of absolute criteria for organ donation and transplantation were highlighted that have since been implemented in practice.&#x0D; Notable strengths of the countrywide response included the donation and transplant community acting responsibly and proportionately (51.6%), providing access to up-to-date information and data (43.9%,) and communicating risk (40.8%). Mixed views were expressed on equity in resource allocation, with 32% aligning with inequity, 28% with equity and 17% of respondents stating that equity issues are not relevant in a crisis.&#x0D; Conclusion: Findings highlight that managing scarcity is complex during a pandemic. Embedding ethical values in recovery and future threats preparedness should be prioritised.

Survival Outcomes of Lung Transplant Recipients From Donors With Abnormal Kidney Function

BackgroundRecovering lungs with pulmonary edema due to abnormal kidney function is considered one of the expanded selection criteria for lung transplant. The aim of this study is to assess lung transplant recipients’ survival from donors with abnormal kidney function and to determine differences in lung recovery rates from donors with and donors without abnormal kidney function. MethodsWe reviewed the United Network for Organ Sharing registry for first-time adult lung transplant donors and recipients from June 2005 to March 2017. Donor kidney function was categorized into three groups based on estimated glomerular filtration rate: group I, greater than 60 mL/min; group II, 15 to 59 mL/min; and group III, less than 15 mL/min. Recipient survival was stratified based on estimated glomerular filtration rate using Kaplan-Meier. A multivariate Cox Regression model with known risk factors that affect survival was used to compare survival among groups. Comparison of lung recovery among the three groups was also performed. ResultsLung recovery rates were 29.7% (15,670 of 52,747), 19.4% (3879 of 20,040), and 18.1% (704 of 3898) for groups I, II, and III, respectively. The 1-, 3-, and 5-year recipient survival rates were 86.2%, 69.2%, and 55.7% for group I; 84.9%, 66.9%, and 53.8% for group II; and 85.5%, 65.3%, and 50.3% for group III, respectively (adjusted P = .25; multivariate Cox regression method). When group I was used as reference, the adjusted hazard ratio for group II was 1.04 (95% CI, 0.98-1.10) and for group III, it was 1.08 (95% CI, 0.96-1.23), after adjusting with the multivariate Cox regression model. ConclusionsThere was no significant difference in lung recipient survival. The lung recovery rate from donors with abnormal kidney function was lower compared with that of donors with normal kidney function.

Routine Reflux Testing Guides Timely Antireflux Treatment to Reduce Acute and Chronic Rejection After Lung Transplantation.

Gastroesophageal reflux has been associated with poorer lung transplantation outcomes, although no standard approach to evaluation/management has been adopted. We aimed to evaluate the effect of timely antireflux treatment as guided by routine reflux testing on postlung transplant rejection outcomes. This was a retrospective cohort study of lung transplant recipients at a tertiary center. All patients underwent pretransplant ambulatory pH monitoring. Timely antireflux treatment was defined as proton pump inhibitor initiation or antireflux surgery within 6 months of transplantation. Patients were separated into 3 groups: normal pH monitoring (-pH), increased reflux (+pH) with timely treatment, and +pH with delayed treatment. Rejection outcomes included acute rejection, bronchiolitis obliterans syndrome, and chronic lung allograft dysfunction per International Society for Heart and Lung Transplantation criteria. Time-to-event analyses using Cox proportional hazard models were applied. Patients not meeting outcomes were censored at death or last clinic visit. One hundred seventy-five patients (59% men/mean 56.3 yr/follow-up: 496 person-years) were included. On multivariable analyses, +pH/delayed treatment patients had higher risks of acute rejection (adjust hazard ratio [aHR]:3.81 [95% confidence interval [CI]: 1.90-7.64], P = 0.0002), bronchiolitis obliterans syndrome (aHR: 2.22 [95% CI: 1.07-4.58], P = 0.03), and chronic lung allograft dysfunction (aHR: 2.97 [95% CI: 1.40-6.32], P = 0.005) than +pH/timely treatment patients. Similarly, rejection risks were increased among +pH/delayed treatment patients vs -pH patients (all P < 0.05). No significant differences in rejection risks were noted between +pH/timely treatment patients and -pH patients. Failure/complications of antireflux treatment were rare and similar among groups. Timely antireflux treatment, as directed by pretransplant reflux testing, was associated with reduced allograft rejection risks and demonstrated noninferiority to patients without reflux. A standardized peri-transplant test-and-treat algorithm may guide timely reflux management to improve lung transplant outcomes.

Predictors of renal recovery in recipients of liver transplant alone who met 2017 simultaneous liver-kidney transplant criteria.

Severe renal dysfunction is common among liver transplant (LT) candidates and often prompts simultaneous liver-kidney transplantation (SLKT) consideration. In view of 2017 United Network of Organ Sharing (UNOS) criteria for SLKT, we investigated the likelihood and predictors of renal recovery among patients who met the aforementioned criteria yet received liver transplant alone (LTA). We retrospectively analyzed relative renal recovery (RRR; increase in eGFR to >30ml/min) in adult LTA recipients between 1/2009 and 1/2019. Of 1165 LT recipients, 54 met 2017 UNOS criteria, with 37 receiving LTA. RRR occurred in 84% of LTA recipients, none of whom had pre-LT eGFR <20ml/min. Sustained RRR (>180 days) occurred in 43% of patients. While prolonged pre-LT severe renal impairment (eGFR <30 ml/min) predicted failure to have sustained RRR (HR .19 per 90-day, CI .04-.87, p<.005), having an eGFR measurement of >30ml/min within 90 days pre-LT (HR 5.52, CI 1.23-24.79, p .01) associated with achieving sustained RRR. Sustained RRR was protective againstthe composite outcome of renal replacement therapy, kidney transplant, and death (HR .21, p .01). LT candidates who meet 2017 UNOS criteria for SLKT yet undergo LTA can still have relative renal recovery post-LT, exceeding 80% on short-term follow-up and 40% on long-term follow-up. eGFR trends within 90 days pre-LT can predict sustained renal recovery, which appears protective of adverse outcomes. These recovery rates advocate for applying the more restrictive criteria for SLKT outlined in this article and increasing utilization of the safety net (SN) policy for those who do not meet the proposed criteria.

Local-Regional Treatment of Hepatocellular Carcinoma: A Primer for Radiologists.

The treatment planning for patients with hepatocellular carcinoma (HCC) relies predominantly on tumor burden, clinical performance, and liver function test results. Curative treatments such as resection, liver transplantation, and ablative therapies of small lesions should be considered for all patients with HCC. However, many patients are ineligible for these treatments owing to advanced disease stage and comorbidities. Despite efforts to increase screening, early-stage HCC remains difficult to diagnose, which decreases the possibility of curative therapies. In this context, local-regional treatment of HCC is accepted as a form of curative therapy in selected patients with early-stage disease, as a therapeutic option in patients who are not eligible to undergo curative therapies, as a downstaging approach to decrease tumor size toward meeting the criteria for liver transplantation, and as a bridging therapy to avoid tumor growth while the patient is on the waiting list for liver transplantation. The authors review the indications, types, mechanism of action, and possible complications of local-regional treatment, as well as the expected postprocedural imaging features of HCC. Furthermore, they discuss the role of imaging in pre- and postprocedural settings, provide guidance on how to assess treatment response, and review the current limitations of imaging assessment. Finally, the authors summarize the potential future directions with imaging tools that may add value to contemporary practice at response assessment and imaging biomarkers for patient selection, treatment response, and prognosis. ©RSNA, 2022.

Thrombophilia in Budd-Chiari syndrome patient

A 27-years old female patient presented with a severe general condition of generalized edema and hypotension. Two months earlier computed tomography imaged thrombosis of the inferior vena cava and the three hepatic veins, or Budd-Chiari syndrome (BCS). Additional findings were thrombosis of the right common iliac vein and thrombosis of the renal veins bilaterally. Genetic testing proved congenital thrombophilia. Anticoagulation therapy did not affect thrombotic occlusions. In another cardiovascular center, an unsuccessful attempt for interventional treatment of the inferior vena cava with a jugular approach was made. The patient was admitted to our hospital for further evaluation and decision on treatment strategy. Laboratory and non-invasive imaging at admission rejected hepatic cirrhosis. An abdominal ultrasound scan demonstrated complete occlusion of the three hepatic veins and post hepatic portal hypertension. When thrombosis of all hepatic veins was detected transjugular intrahepatic portosystemic shunt (TIPS) was an option. An endovascular strategy for inferior vena cava was undertaken and complete revascularization was achieved with the right femoral approach as a bridge to TIPS shunt procedure, since the patient didn&amp;rsquo;t meet the criteria for liver transplantation. In diagnosing disease, the main contributors were the gastroenterologist, diagnostic imaging specialist, and hematologist, while the multidisciplinary team included also cardiologist, interventional cardiologist, and angiologist. In this case the multidisciplinary decisions played a major role in diagnosing and building an appropriate therapeutic strategy for systemic illnesses and conditions for which medical guidance does not yet have clear guidelines.

The benefit of liver transplant beyond Milan criteria: An analysis using the National Cancer Database

BackgroundPublished studies examining the efficacy of liver transplantation in patients presenting with hepatocellular cancer beyond the traditional Milan criteria for liver transplantation have primarily been single institution series with limited ability to compare outcomes to alternative methods of management. MethodsWe queried the National Cancer Database to identify patients presenting between 2004 and 2016 with histologically confirmed clinical stage III and IVA hepatocellular cancer. Multivariable regression was used to identify factors associated with liver transplantation. Patients undergoing liver transplantation were 1:1 propensity score-matched for age, demographics, comorbid disease, clinical stage, and histologic resection margin to those undergoing surgical resection. The Kaplan-Meier method was used to compare overall survival profiles for matched cohorts. ResultsSeven hundred and ninety-two patients met inclusion criteria—590 (74.5%) underwent surgical resection and 202 (25.5%) liver transplantation. On adjusted analysis, patients undergoing liver transplantation were less likely to have advanced age (>60 years; odds ratio 0.39, 95% confidence interval [0.21–0.71]) and to be of Black race (odds ratio 0.42, 95% confidence interval [0.23–0.73]) or Asian (odds ratio 0.25, 95% confidence interval [0.11–0.53]) ethnicity but were more likely to have advanced (Charlson score >2) comorbidity scores, (odds ratio 2.48, 95% confidence interval [1.58–3.90]) and more likely to have private health insurance (odds ratio 4.17, 95% confidence interval [1.31–18.66]) than those undergoing surgical resection. On Kaplan-Meier analysis of matched cohorts, patients undergoing liver transplantation demonstrated significantly better rates of 5-year overall survival (65.3% vs 26.3%, P < .0001) and longer median overall survival times than those undergoing resection (53.1 ± 2.78 vs 26.9 ± 1.20 months, P < .0001). ConclusionLiver transplantation offers the potential to be an effective treatment modality in select patients presenting with stage III and IVA hepatocellular cancer.

Pediatric acute liver failure: An experience of a pediatric intensive care unit from resource limited settings.

IntroductionPediatric acute liver failure is a rare and serious disease. Though liver transplantation is considered as the established treatment option for patients who are unlikely to recover with medical management, however, with the advancement of medical care there has been an increase in spontaneous regeneration of liver, obviating the need for liver transplantation. We identified the etiologies, outcome and prognostic factors of acute liver failure and the validity of the existing liver transplantation criteria to predict the outcome of pediatric acute liver failure.Materials and methodsThis was a retrospective study done from January 2014 to December 2019 in a tertiary pediatric critical care unit in South India. All children aged between 1 month to 18 years admitted with acute liver failure were enrolled.ResultsOf 125 children with acute liver failure, the main etiologies were infections (32%), indeterminate (23%), paracetamol toxicity (21%), metabolic (13%) and others (11%). Dengue was the most common infection (55%). The median pediatric logistic organ dysfunction score at admission was 12 (4–27). Of 125 patients, 63.2% (n = 79) had spontaneous regeneration which was higher in paracetamol induced (92.3%) compared to non-paracetamol induced acute liver failure (55.5%). Only two patients underwent liver transplantation and 35% died. Peak alanine transaminase and use of inotropes significantly predicted the outcome of disease. Of 38 children meeting King's College Hospital criteria for liver transplantation, 57.9% had spontaneous regeneration and 36.8% died. Of 74 children meeting INR > 4 criteria, 54% (n = 40) had spontaneous regeneration and 43.2% died. INR >4 criteria was more sensitive than King's College Hospital criteria for predicting the need for liver transplantation.ConclusionPediatric acute liver failure is caused by varied etiologies and infections were the commonest cause. Despite having a seriously ill cohort of patients, medical management resulted in spontaneous regeneration in the majority of children with acute liver failure. The use of inotropes, advanced hepatic encephalopathy, and peak alanine transaminase were predictors of poor outcome in children with acute liver failure and these patients could be considered for liver transplantation as available. Therefore, we may need to develop better predictors of pediatric acute liver failure in resource limited settings.

340.6: Variability in Workup and Eligibility Criteria for Adult Kidney Transplantation Among Canadian Transplant Centres

Introduction: All potential kidney transplant recipients undergo rigorous evaluation to rule out or ensure appropriate treatment of conditions that may increase risk of post-transplant complications, but specific recommendations regarding workup and kidney transplant candidacy vary across published guidelines. We assessed current pre-transplant evaluation practices and eligibility criteria for adult kidney transplantation across Canada to elucidate differences in guideline interpretation and identify areas of most uncertainty. Methods: We compared published guidelines on kidney transplant workup and eligibility in order to create a focused digital survey that included both undisputed and controversial domains. The survey was divided into: referral process, history/physical exam, multidisciplinary assessments, laboratory/imaging, and contraindications. Given the many cancers and different staging for each, malignancy-related inquiries were simplified. The medical directors of all 18 Canadian adult kidney transplant programs were invited to complete the survey. We defined consensus and uncertainty, respectively, as >90% and <65% agreement between centers. Results: Survey completion rate was 78% (14/18). There was consensus on mandatory pre-transplant viral serology testing, tuberculosis screening, and dental evaluation, while cardiac evaluation protocols varied considerably. Of 28 questioned conditions, 6 were considered absolute contraindications by >90% of centers (active bacterial infection/malignancy, non-healing ulcer, COVID-19, severe lung/liver disease). Moderate uncertainty existed for: medication non-adherence (57%), symptomatic heart failure (50%), recent myocardial infarction (57%), and frailty (35%). Other parameters demonstrating wide variability included latent tuberculosis treatment protocols, and exclusion thresholds for parathyroid hormone, body mass index, left ventricular ejection fraction, and blood pressure. Centers used several guidelines to determine eligibility for patients with treated cancer. Conclusion: There is marked variability in evaluation requirements and eligibility criteria for kidney transplantation across Canada. National harmonization of evaluation processes and eligibility criteria may help to ensure more equitable and transparent access to kidney transplantation for Canadian patients with end-stage kidney disease.

342.1: Comparable Kidney Transplant Outcomes in Selected Patients With a BMI ≥40: A Personalized Medicine Approach To Recipient Selection

Introduction: Kidney transplantation confers a survival benefit compared with dialysis in most studies of obese patients. Yet, many transplant centers decline patients with a body mass index (BMI) ≥40 kg/m2. Our practice relies on computed tomography imaging to evaluate iliac depth and pelvic angle to assess candidacy (see Figure 1). Our aim was to evaluate post-transplant outcomes including survival in patients according to recipient BMI. Methods: We performed a single-center retrospective review of adult kidney transplant alone recipients comparing BMI ≥40 patients (n=84, BMI =42±2 kg/m2) to a matched BMI <40 cohort (n=84, BMI =28±5 kg/m2). Patients were matched for recipient age, gender, race, presence of diabetes, and donor type (living vs. deceased). Results: BMI ≥40 patients were on dialysis longer pre-transplant (5.2±3.2 years vs. 4.1±3.5 years, p=0.03) and received lower kidney donor profile index (KDPI) kidneys (40±25% vs. 53±26%, p=0.003) compared to lower BMI patients. There were no significant differences in prevalence of delayed graft function, reoperations, readmissions, wound complications, patient survival, or renal function at 1 year according to serum creatinine and eGFR. Long-term graft survival was higher for BMI ≥40 patients, including after adjusting for KDPI (BMI ≥40: aHR=1.79, 95% CI=1.09-2.9) (see Figure 2). BMI ≥40 patients had similar weight gain and BMI change in the first year post-transplant (delta weight: BMI ≥40 + 2.5±9.1 kg vs. BMI <40 + 3.0±8.0 kg, p=0.74; delta BMI: BMI ≥40 + 0.9±3.3 vs. BMI <40 + 1.1±3.2, p=0.59). BMI ≥40 patients had a higher mean HbA1c level (6.9±1.7% vs. 5.9±1.4%, p=0.003) at one year post-transplant. Conclusions: Overall patient survival and complications after kidney transplantation were comparable in BMI ≥40 patients compared to a matched cohort with lower BMI with improved long-term graft survival in the obese patients. BMI-based exclusion criteria for kidney transplantation should be reexamined in favor of a more individualized approach.

Evolution of liver donation in Moscow. Movement towards expanded donor selection criteria

The objective of the study was to investigate the evolution and trends in liver donation in the city of Moscow, with special focus on the expansion of liver donor selection criteria for transplantation. Materials and methods. The study included 1,548 effective donors (EDs) in the period from January 1, 2012 to December 31, 2020. Their basic characteristics – age and cause of death – are presented. The dynamics of changes in the age groups of donors and the dynamics of the number of ≥60-year-old liver donors were studied. The influence of expanded liver donor selection criteria over the dynamics of the number of transplant surgeries and patient flow on the waiting list was assessed. Results. During the study period, the number of effective liver donors (ELDs) in Moscow increased 4.7-fold. The average age of ELDs increased from 37.1 in 2012 to 48.8 in 2020. There was an absolute prevalence of donors who died from cerebrovascular accident compared with donors who died from traumatic causes, 83.4% vs 16.6%, respectively. Since 2016, there has been a progressive increase in ≥60-year-old liver donors; the number of such donors in 2020 reached 39, accounting for 13.6% of the total pool of EDs. The progressive growth in the number of liver transplants has significantly influenced patient movement on the waiting list. In 2012, there was a 25.2% increase in the number of liver transplants per 100 patients on the waiting list; by 2020, it had reached 86.6%. Conclusion. The results reasonably indicate an increase in liver donation and liver transplantation (LTx) in Moscow. Comparison of Russian data with those of leading foreign donor programs shows that the trends in the donor pool in the context of older age, including ≥60-year-old donors, and shifting causes of donor death towards cerebrovascular diseases are similar. An overall increase in donor activity and expansion of liver donor criteria contributed to an increase in the number of transplants performed per 100 patients on the waiting list, which, in turn, reduced the waiting time for a donor organ and increased the intensity of patient flow on the waiting list.

Malignancies in adult kidney transplant candidates and recipients: current status.

Posttransplant malignancies, particularly recurrent and de novo, in solid organs including kidney transplant recipients (KTRs) are a significant complication associated with substantial mortality, largely attributed to the long-term immunosuppression necessary to maintain allograft tolerance. Older age at transplantation and oncogenic virus infection along with pretransplant malignancies are among the main factors contributing to the risk of cancer in this population. As the mean age of transplant candidates rises, the rate of transplant recipients with pretransplant malignancies also increases. The eligibility criteria for transplantation in patients with prior cancer have recently changed. The overall risk of posttransplant malignancies is at least double after transplantation, including KTRs, relative to the general population, and is most pronounced for skin cancers associated with UV radiation and virally mediated tumors. The risk of renal cell carcinoma is specifically increased in the kidney transplant population. The therapy for cancer in transplant patients is associated with risk of higher toxicity, and graft rejection and/or impairment, which poses a unique challenge in its management. Reduction of immunosuppression and the use of mammalian target of rapamycin inhibitors are common after cancer diagnosis, although optimal immunosuppression for transplant recipients with cancer remains undefined. Suboptimal cancer treatment contributing to a worse prognosis has been reported for malignancies in this population. In this article, we focus on the prevalence and outcomes of posttransplant malignancies, cancer therapy including a short overview of immunotherapy, cancer screening and prevention strategies, and immunosuppression as a cancer risk factor. The 2020/2021 recommendations of the Kidney Disease: Improving Global Outcomes and the American Society of Transplantation for transplant candidates with a history of cancer are presented.

Non-transplantable recurrence after percutaneous thermal ablation of ≤3-cm HCC: Predictors and implications for treatment allocation.

Percutaneous thermal ablation (PTA), resection, and liver transplantation are the standard curative options for hepatocellular carcinoma (HCC). Liver transplantation yields the best long‐term outcomes but is limited by graft shortage. Thus, patients with ≤3‐cm HCC are primarily treated by PTA even though recurrence is frequent and may occur outside transplant criteria. Data on non‐transplantable recurrence (NTR) following PTA are lacking, however. We therefore investigated the incidence and predictors of NTR among 213 potentially transplantable patients (cirrhosis, 93%; Child‐Pugh A, 98.6%; alcohol‐related disease, 62%) with ≤3‐cm HCC(s) treated by PTA, to stratify them according to their NTR risk and to improve treatment allocation. During follow‐up (median: 41.2 months), NTR occurred in 18.3% (alpha‐fetoprotein [AFP] model) and 23% (Milan) patients. NTR prediction with competing‐risk analysis and internal validation revealed AFP > 100 ng/ml (subdistribution hazard ratio: 7.28; p < 0.001) and prior HCC (subdistribution hazard ratio: 3.77; p = 0.002) as independent predictors (Harrell's C: 0.76). Based on this model using the AFP score (equally predictive within Milan criteria), patients were stratified into three NTR risk categories: HCC‐naïve with AFP < 100 ng/ml (low risk, n = 108 of 213), non‐HCC naïve with AFP < 100 ng/ml (intermediate risk, n = 92 of 213), AFP ≥ 100 ng/ml (high risk, n = 13 of 213), among whom 9.3% (3.7% [Milan]), 22.8% (25% [Milan]), and 61.5% (38/5% [Milan]) presented NTR (p < 0.001). Median recurrence‐free survival was 4.6, 14.5, and 43.4 months, respectively, in high‐risk, intermediate‐risk, and low‐risk categories (p < 0.001). Median overall survival, which was 19.1 months in high‐risk patients, was not reached otherwise (p < 0.001). Conclusion: Overall, PTA of ≤3‐cm HCC incurs a low NTR risk. Simple and noninvasive predictors (HCC naivety, AFP) accurately stratified patients' risk of NTR, and should help to improve treatment allocation. Patients with AFP ≥ 100 ng/ml have a high risk of NTR, poor recurrence‐free survival, and overall survival. Further studies evaluating preemptive transplantation or adjuvant/neoadjuvant strategies are highly needed in this small patient subset.