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AimPatients with synchronous colon cancer metastases have highly variable overall survival (OS), making accurate predictive models challenging to build. We aim to use machine learning to more accurately predict OS in these patients and to present this predictive model in the form of nomograms for patients and clinicians.MethodsUsing the National Cancer Database (2010-2014), we identified right colon (RC) and left colon (LC) cancer patients with synchronous metastases. Each primary site was split into training and testing datasets. Nomograms predicting 3- year OS were created for each site using Cox proportional hazard regression with lasso regression. Each model was evaluated by both calibration (comparison of predicted vs observed OS) and validation (degree of concordance as measured by the c-index) methodologies.ResultsA total of 11 018 RC and 8346 LC patients were used to construct and validate the nomograms. After stratifying each model into five risk groups, the predicted OS was within the 95% CI of the observed OS in four out of five risk groups for both the RC and LC models. Externally validated c-indexes at 3 years for the RC and LC models were 0.794 and 0.761, respectively.ConclusionsUtilization of machine learning can result in more accurate predictive models for patients with metastatic colon cancer. Nomograms built from these models can assist clinicians and patients in the shared decision-making process of their cancer care.

Purpose: The transarterial radioembolization (TARE) dose is traditionally calculated using the single-compartment Medical Internal Radiation Dose (MIRD) formula. This study utilized voxel-based dosimetry to correlate tumor dose with explant pathology in order to identify dose thresholds that predicted response., Methods: All patients with HCC treated with TARE using yttrium-90 [ 90 Y] glass microspheres at a single institution between January 2015 - June 2023 who underwent liver transplantation were eligible. The [ 90 Y] distribution and dose-volume histograms were determined using Simplicity 90 (Mirada Medical, Oxford UK) with a Bremsstrahlung SPECT/CT. A complete response was assigned if explant pathology showed complete necrosis and the patient had not undergone additional treatments to the same tumor after TARE. Logistic regression and receiver operator characteristic (ROC) curves were constructed to evaluate dose thresholds correlated with response., Results: Forty-one patients were included. Twenty-six (63%) met criteria for complete response. Dose to 95% (D95), 70% (D70), and 50% (D50) of the tumor volume were associated with likelihood of complete response by logistic regression (all p < 0.05). For lesions with complete response versus without, the median D95 was 813 versus 232 Gy, D70 was 1052 versus 315 Gy, and D50 was 1181 versus 369 Gy (all p < 0.01). A D95 > 719 Gy had the highest accuracy at 68% (58% sensitivity, 87% specificity) for predicting complete response. Median percent of tumor volume receiving at least 100 Gy (V100), 200 Gy (V200), 300 Gy (V300), and 400 Gy (V400) also differed by pathologic response: the median V100, V200, V300, and V400 was 100% versus 99%, 100% versus 97%, 100% versus 74%, and 100% versus 43% in the complete response versus non-complete response groups, respectively (all p < 0.05)., Conclusion: Voxel-based dosimetry was well-correlated with explant pathology. The D95 threshold had the highest accuracy, suggesting the D95 may be a relevant target for multi-compartment dosimetry., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background & Aims: The use of immune checkpoint inhibitors (ICIs) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention-to-treat (ITT) outcomes in the peri-transplant setting are currently based on small and heterogenous single-center reports., Methods: This first multiregional US study (2016-2023) included 117 consecutive patients with HCC assessed for liver transplantation (LT) and treated preoperatively with ICIs. ITT and survival analyses were conducted with evaluation of post-LT rejection rates., Results: In total, 86 (73.5%) patients exceeded Milan criteria (MC) and 65 (75.6%) were successfully downstaged within a median of 5.6 months; 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) who were initially beyond but were downstaged. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included being beyond MC (p <0.001), alpha-fetoprotein doubling from baseline (p = 0.014) and radiographic responses (p <0.001). The 3-year ITT survival rate was 71.1% (73.5% within MC vs. 69.7% beyond MC, p = 0.329), with a 3-year post-LT survival rate of 85%. Post-LT rejection occurred in seven patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss., Conclusions: The first multicenter evaluation of patients with HCC receiving ICIs pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of alpha-fetoprotein levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes., Impact and Implications: Herein, we report results from the first multicenter evaluation of pretransplant immune checkpoint inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune checkpoint inhibitors, either alone or combined with locoregional therapy, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated alpha-fetoprotein levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pretransplant use of immune checkpoint inhibitors, pending results from ongoing trials., (Copyright © 2024. Published by Elsevier B.V.)

Importance: Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR)., Objective: To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery., Design, Setting, and Participants: This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers., Exposures: cDCD livers were recovered by either NRP or SRR., Main Outcomes and Measures: The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival., Results: A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P < .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts., Conclusion and Relevance: There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

Competing Interests: The authors declare no conflicts of interest.

Background: United States transplant centers have low rates of liver allograft utilization from donation after circulatory death (DCD) donors. Prolonged functional donor warm ischemic time (f-DWIT) is associated with worse outcomes; however, center practices regarding f-DWIT are unclear. As emerging technologies are changing the landscape of DCD liver transplantation, this study aims to gain insights into the practices of US centers around DCD liver allograft utilization., Methods: An electronic survey was distributed to transplant surgeons at US transplant centers from May to July 2022., Results: Responses were received from 108 transplant surgeons, of which, 44.4% reported their center's annual DCD liver transplant volume as <10%, and 40.7% reported volumes of 10% to 30%. Warm ischemic time (WIT) was the principal donor variable considered by accepting surgeons (72.2%). Center definition of f-DWIT varied widely, with at least 14 definitions being used. Nearly half of the surgeons (48.6%) defined f-DWIT as time from systolic blood pressure (SBP) <80 mm Hg or oxygen saturation (Sp0 2 ) <80% to flush; 21.5% defined f-DWIT as ≤30 minutes from withdrawal of life-sustaining therapy to flush. Nearly 13% of centers use normothermic machine perfusion for most of their DCD liver allografts. More than half of surgeons transplanted at least 1 DCD liver allograft recovered after normothermic regional perfusion., Conclusions: Differences in the definition of f-DWIT and acceptance patterns of DCD liver allografts limit the ability to evaluate patient and allograft outcomes. As the DCD landscape is evolving, consensus definitions and granular databases can improve the transplant community's ability to evaluate outcome data and utilization from DCD liver allografts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Donation after circulatory death (DCD) liver allografts are associated with higher rates of primary non-function (PNF) and ischemic cholangiopathy (IC). Advanced recovery techniques, including thoracoabdominal normothermic regional perfusion (TA-NRP), may improve organ utilization and patient and allograft outcomes. Given the increasing US experience with TA-NRP DCD recovery, we evaluated outcomes of DCD liver allografts transplanted after TA-NRP., Methods: Liver allografts transplanted from DCD donors after TA-NRP were identified from 5/1/2021 to 1/31/2022 across 8 centers. Donor data included demographics, functional warm ischemic time (fWIT), total warm ischemia time (tWIT) and total time on TA-NRP. Recipient data included demographics, model of end stage liver disease (MELD) score, etiology of liver disease, PNF, cold ischemic time (CIT), liver function tests, intensive care unit (ICU) and hospital length of stay (LOS), post-operative transplant related complications., Results: The donors' median age was 32 years old and median BMI was 27.4. Median fWIT was 20.5 min; fWIT exceeded 30 min in two donors. Median time to initiation of TA-NRP was 4 min and median time on bypass was 66 min. The median recipient listed MELD and MELD at transplant were 22 and 21, respectively. Median allograft CIT was 292 min. The median length of follow up was 257 days. Median ICU and hospital LOS were 2 and 7 days, respectively. Three recipients required management of anastomotic biliary strictures. No patients demonstrated IC, PNF or required re-transplantation., Conclusion: Liver allografts from TA-NRP DCD donors demonstrated good early allograft and recipient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author (JW) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Brubaker, Taj, Jackson, Lee, Tsai, Berumen, Parekh, Mekeel, Gupta, Gardner, Chaly, Mathur, Jadlowiec, Reddy, Nunez, Bellingham, Thomas, Wellen, Pan, Kearns, Pretorius and Schnickel.)

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., (Copyright © 2023 American Association for the Study of Liver Diseases.)

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients., (Copyright © 2022 American Association for the Study of Liver Diseases.)

Limited case series describe conflicting results regarding the safety of checkpoint inhibitors (CPI) prior to liver transplantation (LT). We reviewed single-center data on all consecutive patients who underwent LT for hepatocellular carcinoma treated with CPI between January 1, 2018, and January 30, 2021. Time from CPI to LT, immunosuppression, biopsy-proven acute cellular rejection (BPACR), graft loss and death were evaluated. Five patients with a mean age 65 (range 61-71) years underwent LT after CPI with nivolumab. Time from last CPI to LT ranged from 0.3 to 11 months. Two patients with <3 months from the last dose of CPI to LT developed BPACR and severe hepatic necrosis, one of whom required retransplantation with recurrent BPACR but without recurrent graft loss over 38 months of follow up. None of the patients who underwent LT >3 months from the last dose of CPI had BPACR. In conclusion, pretransplant use of CPIs, particularly within 90 days of LT, was associated with BPACR and immune-mediated hepatic necrosis. Future multicenter studies should consider a sufficient interval from the last dose of CPI to LT to mitigate the risk for adverse immune-mediated outcomes and graft loss., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Immune checkpoint inhibitors (ICI) have been used to treat hepatocellular carcinoma (HCC) since 2017. The safety of ICIs in the setting of solid organ transplantation remains controversial. When used in the post-transplant setting, ICIs have been associated with high allograft rejection rates, but there are few published reports on the use of ICIs prior to transplant. We present the first reported case of rescue liver re-transplantation after loss of the first allograft due to severe acute rejection with extensive hepatic necrosis in the setting of pre-transplant ICI therapy with the PD-1 inhibitor nivolumab. It is likely that the durable immune response triggered by nivolumab contributes to graft rejection, therefore extreme caution should be taken when using ICIs before transplant until further investigation has been conducted on their safety in the pre-transplant setting., (© 2021. The Author(s).)

Growing research supports an increased survival benefit of combined heart and kidney transplantation in patients with both heart and renal failure. As a result, the frequency of these combined transplants continues to increase. Despite this trend, little has been done to quantify the impact of chronic illness in this population. We identified adult recipients of combined heart-kidney transplant from the Scientific Registry of Transplant Recipients (SRTR) database between 2005 and 2018. We focused on renal disease secondary to diabetes and duration of dialysis as markers of chronic illness. The primary outcome was post-transplant mortality. Our final multivariable Cox proportional hazard model found that diabetes-associated renal disease (HR 1.57, 95% CI 1.14-2.15, p = .01) and dialysis duration (HR 1.08, 95% CI 1.01-1.15, p = .02) were significant predictors of post-transplant mortality. Given the significant impact of dialysis duration and renal disease secondary to diabetes mellitus, these chronically ill patients should be closely examined for conditions such as peripheral vascular disease and frailty, which have been shown to affect mortality in heart transplant recipients and are prevalent in the chronic dialysis population., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The incidence of hepatocellular carcinoma (HCC) is growing in the United States, especially among the elderly. Older patients are increasingly receiving transplants as a result of HCC, but the impact of advancing age on long-term posttransplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium of 4980 patients. We divided the patients into 4 groups by age at transplantation: 18 to 64 years (n = 4001), 65 to 69 years (n = 683), 70 to 74 years (n = 252), and ≥75 years (n = 44). There were no differences in HCC tumor stage, type of bridging locoregional therapy, or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic, and cancer-related factors on multivariable analysis. A dose-response effect of age on survival was observed, with every 5-year increase in age older than 50 years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non-HCC-related mortality (P = 0.004), and not HCC-related death (P = 0.24). To delineate the precise cause of death, we further analyzed a single-center cohort of patients who received a transplant as a result of HCC (n = 302). Patients older than 65 years had a higher incidence of de novo cancer (18.1% versus 7.6%; P = 0.006) after transplantation and higher overall cancer-related mortality (14.3% versus 6.6%; P = 0.03). Even carefully selected elderly patients with HCC have significantly worse posttransplant survival rates, which are mostly driven by non-HCC-related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve the outcomes in elderly patients who received a transplant as a result of HCC., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Despite an increasing demand for liver transplantation in older patients, our understanding of posttransplant outcomes in older recipients is limited to basic recipient and graft survival. Using National Surgical Quality Improvement Program Transplant, we tracked early outcomes after liver transplantation for patients >65., Methods: We conducted a retrospective analysis of patients in National Surgical Quality Improvement Program Transplant between March 1, 2017 and March 31, 2019. Recipients were followed for 1 y after transplant with follow-up at 30, 90, and 365 d. Data were prospectively gathered using standard definitions across all sites., Results: One thousand seven hundred thirty-one adult liver transplants were enrolled; 387 (22.4%) were >65 y old. The majority of older recipients were transplanted for hepatocellular carcinoma. The older cohort had a lower lab Model for End-Stage Liver Disease and was less likely to be hospitalized at time of transplant. Overall, older recipients had higher rates of pneumonia but no difference in intensive care unit length of stay (LOS), total LOS, surgical site infection, or 30-d readmission. Subgroup analysis of patients with poor functional status revealed a significant difference in intensive care unit and total LOS. Pneumonia was even more common in older patients and had a significant impact on overall survival., Conclusions: By targeting patients with hepatocellular carcinoma and lower Model for End-Stage Liver Diseases, transplant centers can achieve nearly equivalent outcomes in older recipients. However, older recipients with poor functional status require greater resources and are more likely to develop pneumonia. Pneumonia was strongly associated with posttransplant survival and represents an opportunity for improvement. By truly understanding the outcomes of elderly and frail recipients, transplant centers can improve outcomes for these higher-risk recipients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: The role of laterality for patients with synchronous metastatic colon cancer (SMCC) is not well-defined., Methods: Using the National Cancer Database (2010-2015), we compared patients with metastatic right- (RCC) versus left-sided colon cancer (LCC). We performed Kaplan-Meier analysis to compare overall survival (OS) for each metastatic site and utilized adjusted Cox proportional hazard analysis to identify predictors of OS., Results: Patients with RCCs were more likely to be older, female, and have more comorbidities. LCCs were more likely to metastasize to liver and lung, whereas RCCs were more likely to metastasize to peritoneum and brain. There was equal likelihood to metastasize to bone. OS was significantly longer for LCCs for all metastatic sites. After controlling for multiple variables, RCC (HR 1.426, p < 0.001) remained an independent predictor of worse OS compared to LCC., Conclusions: Laterality of the primary tumor plays an important role in outcomes for patients with SMCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Appropriate graft regeneration after living donor liver transplantation (LDLT) is crucial to avoid small-for-size syndrome. We enrolled 44 recipients who underwent ABO-identical/compatible LDLT from December 2007 to August 2016 and determined possible factors associated with low graft regeneration after LDLT. Liver regeneration was calculated by the ratio of the graft size on postoperative day (POD) 7 ± 1 day (calculated by CT volumetry) to the size of the donated liver at implant. Postoperative outcomes were compared between the low and high regeneration groups. Median regeneration rate was 1.65-fold. Regeneration rate was negatively correlated with graft-to-recipient weight ratio. Postoperative morbidity rates on POD 14-90 were significantly higher in the low group compared with the high group (63% vs 18%, P = .03). Graft and patient survival in the low group were significantly worse than the high group (1-year graft survival 73% vs 100%, P = .002; patient survival 82% vs 100%, P = .01). Cold ischemia time (CIT; per 10 minute; odds ratio [OR] =1.37) and platelet count <60 000/μL on POD 5 (OR = 14.32) were independently associated with low regeneration. In conclusion, longer CIT and postoperative thrombocytopenia were associated with low graft regeneration in the early phase after LDLT, which could consequently lead to poor graft and patient survival., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Biliary stricture is a common cause of morbidity after liver transplantation (LT). This study aimed to determine the risk factors for post-transplant biliary anastomotic strictures (BAS), focusing on perioperative platelet counts. We enrolled 771 consecutive recipients who underwent ABO-identical/compatible deceased donor LT with duct-to-duct biliary reconstruction from January 2000 to June 2012. BAS was identified in 142 cases. The median time for stricture development was 176 days. Preoperative and postoperative platelet counts within 5 days after LT were significantly lower in patients with BAS than those without BAS. Using cutoff values acquired by the receiver operating characteristic curve analysis, persistent postoperative thrombocytopenia was defined as platelet counts <41 × 1000/μl and <53 × 1000/μl on postoperative day (POD) 3 and POD 5, respectively. Multivariate analysis indicated persistent postoperative thrombocytopenia (OR = 2.38) was the only independent risk factor for BAS. No significant associations were observed in terms of donor and surgical factors. Multivariate analysis demonstrated estimated blood loss (OR = 1.01, per 100 ml) was an independent contributing factor for persistent postoperative thrombocytopenia. We demonstrated low platelet count was associated with progression of post-transplant BAS. Minimizing intraoperative blood loss potentially contributes to maintain post-transplant platelet count, which may reduce incidence of BAS., (© 2017 Steunstichting ESOT.)

Background: The positive impact of platelets has been recently implicated in liver transplantation (LT). The aim of this study was to determine the risk factors for graft loss and mortality after LT, focusing on perioperative platelet counts., Methods: We reviewed all deceased donor LT from 2000 to 2012 and enrolled 975 consecutive recipients. The risk factors for graft loss and mortality were analyzed by multivariate analysis, using Cox's regression model., Results: Using cutoff values acquired by receiver operating characteristics curve analysis, multivariate analyses determined that viral hepatitis C (hazard ratio [HR]=1.32), donor age >40 (HR=1.33), higher peak serum alanine aminotransferase (HR=1.01), reoperation within 30 days (HR=1.51), and platelet count <72 500/μL on postoperative day (POD) 5 (HR=1.30) were independent risk factors for graft loss. Viral hepatitis C (HR=1.33), reoperation within 30 days (HR=1.35), and platelet count <72 500/μL on POD 5 (HR=1.38) were independent risk factors for mortality., Conclusion: A low platelet count on POD 5 was associated with graft loss and mortality after LT. Platelet count <72 500/μL on POD 5 can be a predictor of poor graft and overall survival. Maintaining higher postoperative platelet counts could potentially improve graft and overall survival rates., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The aim of this study was to evaluate the outcome of patients with intrahepatic cholangiocarcinoma (ICCA) incidentally found in the explanted liver after liver transplantation., Material and Methods: We retrospectively reviewed 1188 recipients undergoing liver transplantation from August 2003 to August 2014; 13 patients were found to have ICCA (1.1%). Recurrence-free survival (RFS) rate was compared between ICCA patients and the matched cohort of 39 patients with hepatocellular carcinoma (HCC). We also investigate the relevance of clinical and pathological parameters in recurrence of ICCA., Results: ICCA patients showed significantly higher recurrence rate with lower 1-year and 3-year RFS rates than HCC patients (recurrence rate, 12.8% vs. 54.8%; 1-year and 3-year RFS rates, 94% and 84% vs. 67% and 42%). Of the 13 ICCA patients, 4 were diagnosed with a well-differentiated ICCA and 9 with a moderately-differentiated ICCA. There was no recurrence among those with a well-differentiated ICCA, whereas 78% recurred in the moderately-differentiated group. The median RFS time for the moderately-differentiated group was 13.0 months, yielding RFS rates of 56% at 1 year and 22% at 3 years., Conclusions: Liver transplantation in patients with a well-differentiated ICCA yielded excellent outcomes as compared to patients with a moderately-differentiated ICCA. This may allow consideration of transplantation in the setting of a well-differentiated ICCA, and obviate the need for adjuvant systemic treatment. Conversely, a moderately-differentiated ICCA carries a poor prognosis with a prohibitively high recurrence rate and poor survival. Liver transplantation should remain a contraindication in this group.

Unlabelled: Deep vein thrombosis (DVT) and pulmonary embolism (PE) are surgical complications estimated to occur in 5% to 10% of patients. There are limited data regarding DVT/PE in the early postoperative period in liver transplant patients. The aim of this study is to determine risk factors that influence the incidence of DVT/PE and the effectiveness of prophylaxis., Methods: We reviewed the records of 999 patients who underwent initial liver transplant between January 2000 and June 2012 at Henry Ford Hospital. In 2011, a standardized prophylactic regimen using subcutaneous (SQ) heparin was initiated. All patients that developed either upper/lower extremity DVT or PE within the first 30 days of transplant formed the cohort of this study., Results: On multivariate analysis, only peripherally inserted central catheter (PICC) placement and SQ heparin were associated with DVT/PE. In patients receiving heparin, 3 (1.0%) had DVT/PE versus 25 (3.5%) who did not receive heparin (P = 0.03). Sixteen (6.9%) patients that had a PICC developed DVT/PE compared with 12 (1.6%) patients without a PICC (P < 0.001). In the heparin group, DVT/PE with PICC was reduced to 3 (3.0%) versus 13 (9.9%) in those with a PICC and did not receive heparin (P = 0.03). Mean time from transplant to DVT/PE diagnosis was 12.3 days. Length of hospitalization was significantly longer in patients who developed DVT/PE (18.5 vs 10.0 days, P < 0.001)., Conclusions: In this study, we demonstrated that PICC placement significantly increases the likelihood of DVT/PE in liver transplant recipients. Prophylactic SQ heparin effectively reduced DVT/PE events in this patient population.

An accurate clinical assessment of hepatic steatosis before transplantation is critical for successful outcomes after liver transplantation, especially if a pathologist is not available at the time of procurement. This prospective study investigated the surgeon's accuracy in predicting hepatic steatosis and organ quality in 201 adult donor livers. A steatosis assessment by a blinded expert pathologist served as the reference gold standard. The surgeon's steatosis estimate correlated more strongly with large-droplet macrovesicular steatosis [ld-MaS; nonparametric Spearman correlation coefficient (rS ) = 0.504] versus small-droplet macrovesicular steatosis (sd-MaS; rS  = 0.398). True microvesicular steatosis was present in only 2 donors (1%). Liver texture criteria (yellowness, absence of scratch marks, and round edges) were mainly associated with ld-MaS (variance = 0.619) and were less associated with sd-MaS (variance = 0.264). The prediction of ≥30% ld-MaS versus <30% ld-MaS was excellent when liver texture criteria were used (accuracy = 86.2%), but it was less accurate when the surgeon's direct estimation of the steatosis percentage was used (accuracy = 75.5%). The surgeon's quality grading correlated with the degree of ld-MaS and the surgeon's steatosis estimate as well as the incidence of poor initial function and primary nonfunction. In conclusion, the precise estimation of steatosis remains challenging even in experienced hands. Liver texture characteristics are more helpful in identifying macrosteatotic organs than the surgeon's actual perception of steatosis. These findings are especially important when histological assessment is not available at the donor's hospital., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Graft thrombosis and infectious complications are the main early causes of pancreatic allograft loss in recipients of whole vascularized pancreas transplants, resulting in loss rates up to 10 per cent in the first post transplant week. In this study we sought to determine if initiation of a standardized selection criteria and posttransplant chemoprophylaxis regimen could reduce the rate of early allograft loss; we compared the rate of early allograft loss after introduction of these changes. Of the 61 diabetic recipients who underwent these protocols, 50.8 per cent were female. Average age was 42.9 ± 7.4 years of age, average length of stay was 12.7 ± 8.7 days, with all transplants performed heterotopic to the right lower quadrant with venous drainage to the proximal external or common iliac vein. Organ donors were 21.4 ± 4.8 years of age, body mass index was 23.9 ± 2.8 kg/m(2), with a length of stay of 3.7 ± 1.6 days. One-week pancreatic allograft survival for the protocolized versus nonprotocolized patients was 100 per cent versus 96.7 per cent, 1 month was 98.4 per cent versus 93.4 per cent, and 1 year was 96.7 per cent versus 88.5 per cent, respectively. In the protocolized group there were two graft losses due to infectious complications and none due to thrombosis. Before initiation of the protocols patient survival at 1 year was 91.8 per cent and after was 100 per cent. Pancreas transplantation is arguably the most technically demanding organ transplant from a complication and loss standpoint. However, highly successful outcomes can be obtained with standardized protocols beginning pretransplant to reduce the incidence of posttransplant complications.

BACKGROUND.: Recruitment of recipient mononuclear cells to the donor heart is a central event in the development of cardiac allograft vasculopathy (CAV). The role of individual chemokine receptors in this process is incompletely defined. TAK-779 (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetra-hydro-2H-pyran-4-aminium chloride) is a synthetic nonpeptide antagonist of CCR5 and CXCR3. The purpose of this study is to determine if combined CCR5 and CXCR3 blockade by TAK-779 would attenuate CAV in an experimental model. METHODS.: We used a previously characterized murine model of CAV. Recipient mice were treated with TAK-779 or vehicle control. Donor hearts were harvested on day 24 posttransplantation and analyzed for intimal thickening and cellular infiltration. Recipient splenocytes were analyzed for proliferative response and interferon (IFN)-gamma production by enzyme-linked immunosorbent spot assay. The donor hearts were also examined for heme oxygenase-1 (HO-1) gene induction. RESULTS.: CCR5 and CXCR3 blockade by TAK-779 reduced the severity of intimal lesions (53+/-10% vs. 16+/-2%; P<0.05) and decreased the number of graft infiltrating CCR5 and CXCR3 CD4 and CD8 lymphocytes. Moreover, treatment with TAK-779 (a) decreased alloantigen-specific T-lymphocyte proliferation and number of IFN-gamma producing cells and (b) increased HO-1 gene transcript level in the allografts. CONCLUSIONS.: Antagonism of CCR5 and CXCR3 by TAK-779 is effective in controlling CAV. The beneficial effects of TAK-779 may be because of (a) reduction in CCR5 and CXCR3 T-lymphocyte subset infiltration into the graft, (b) attenuation of alloantigen-specific T-lymphocyte proliferative response and IFN-gamma production, and (c) induction of HO-1 gene. This compound may offer a novel approach in clinical management of CAV.

Chemokine-chemokine receptor interactions orchestrate mononuclear cells recruitment to the allograft, leading to acute and chronic rejection. Despite biologic redundancy, several experimental studies have demonstrated the importance of CXCR3 and CCR5 in acute rejection of allografts. In these studies, deficiency or blockade of CXCR3 or CCR5 led to prolongation of allograft survival, yet allografts were ultimately lost to acute rejection. Given the above findings and the specificity of mononuclear cells bearing CXCR3 and CCR5, we hypothesized that combined blockade of CXCR3 and CCR5 will lead to indefinite (>100 days) graft survival in a full MHC-mismatched murine cardiac allograft model. The donor hearts in the control group were rejected in 6 +/- 1 days after transplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival >15-fold vs the control group; all allografts survived for >100 days. More importantly, the donor hearts did not display any intimal lesions characteristic of chronic rejection. Further analysis of the donor hearts in the CXCR3/CCR5 blockade group demonstrated graft infiltration with CD4(+)CD25(+) T cells expressing the Foxp3 gene. Depletion of CD25(+) cells in the combined CXCR3 and CCR5 blockade group resulted in acute rejection of the allografts in 22 +/- 2 days. Combined CXCR3 and CCR5 blockade also reduced alloantigen-specific T lymphocyte proliferation. Combined CXCR3 and CCR5 blockade is effective in preventing acute and chronic rejection in a robust murine model. This effect is mediated, in part, by CD25(+) regulatory T cell recruitment and control of T lymphocyte proliferation.

Objective: Age 65 years and older is generally considered a contraindication to lung transplantation. Our group has offered lung transplantation to select patients 65 years of age and older who lack other comorbid conditions. We sought to define the short- and medium-term outcome of lung transplantation in patients aged 65 years and older., Methods: We reviewed the records of our lung transplant recipients from March 2000 to September 2006. During this interval, 50 patients were 65 years or older at the time of transplantation. Fifty patients younger than 65 years were matched to the older cohort by means of propensity analysis. The demographics and perioperative and postoperative characteristics and survival of the 2 groups were compared., Results: Older patients were more likely to receive single-lung transplantation (older group: 76% vs younger group: 16%, P < .05) and nonstandard donor lungs (older group: 46% vs younger group: 28%, P = .06). The composite in-hospital morbidity rate was similar in the older and younger groups. There was no significant difference in the early oxygenation parameters, incidence of acute cellular rejection, or incidence of bronchiolitis obliterans syndrome between the 2 groups. The early survival of the older patients was 95.7% compared with 95.9% in the younger cohort (P = .73). The 1-year survival of the 2 groups was also similar (older group: 79.7% vs younger group: 91.2%, P = .16). The 3-year survival of the older and younger recipients was 73.6% and 74.2%, respectively (P = .64). There were 8 deaths in the older recipient group during the 1-month to 1-year posttransplantation interval, predominantly because of infections., Conclusions: Lung transplantation can be performed in patients older than 65 years with acceptable clinical outcomes. The "increased" mortality of older patients between 1 month and 1 year after transplantation, predominantly from infectious causes, might be due to immunosenescence of older patients. This finding warrants adjustments in the immunosuppression protocol of older patients undergoing lung transplantation. The effect of offering lung transplantation to older patients on donor lung availability deserves further investigation.

Background: Chronic rejection in transplanted hearts or cardiac allograft vasculopathy (CAV) is the leading cause of late death among heart transplant recipients. Strategies to control CAV traditionally have focused on lymphocyte functions. We hypothesized that D-4F, an apoA-I mimetic peptide with potent anti-inflammatory/antioxidant properties, will attenuate CAV., Methods: We used a previously characterized murine model of CAV. B6.C-H2 hearts were heterotopically transplanted into C57BL/6 mice. Recipient mice were treated with either 20 microg of D-4F or carrier daily. Donor hearts were harvested on day 24 after transplantation., Results: Treatment of recipients with D-4F reduced the severity of intimal lesions (62.5+/-3.4% vs. 31.1+/-8.7%, P<0.009). Treatment also resulted in a decrease in the number of graft-infiltrating CD4 and CD8 lymphocytes and CXCR3+ T-lymphocyte subsets. Heme oxygenase-1 (HO-1) gene transcript in the donor hearts was up-regulated with D-4F treatment, and HO-1 blockade partially reversed the beneficial effects of D-4F. In vitro studies showed that D-4F reduced allogeneic T-lymphocyte proliferation and effector cytokine production. These processes were HO-1 independent., Conclusion: This study suggests that D-4F, a prototypical apoA-I mimetic peptide, is effective in controlling CAV via induction of HO-1 in the graft and a direct effect on T-lymphocyte function. This class of peptides with anti-inflammatory/antioxidant properties provides a novel strategy in the treatment of CAV.

Chronic rejection in transplanted hearts or cardiac allograft vasculopathy (CAV) is the leading cause of late death among heart transplant recipients. We hypothesized that induction of HO-1 by D4-F, an apoA-I mimetic peptide with potent antiinflammatory/antioxidant properties, attenuated CAV. We utilized a previously characterized murine model of CAV. B6.C-H2(bml2) hearts were heterotopically transplanted into C57BL/6 mice. In the control group, recipient mice were treated with 20 microg of saline daily. In experimental group I, mice were treated daily with 20 microg of D4-F. In experimental group II, mice were treated daily with 20 microg of D4-F daily, plus CuPP, which does not have any effect on HO-1 activity. In experimental group III, recipient mice were treated with 20 mug of D4-F daily, plus SnPP, which is a competitive inhibitor of HO-1. Donor hearts were harvested on day 24 after transplantation. The donor hearts in the control group developed severe intimal lesions. In experimental group I, treatment with D4-F was associated with upregulation of HO-1 and a marked reduction in intimal lesions, which was consistent in experimental group II. In experimental group III, inhibition of HO-1 was associated with partial restoration of intimal lesions. Induction of HO-1 by an apoA-1 mimetic peptide was effective to control CAV. This class of antiinflammatory peptides, which show an ability to induce HO-1, provides a novel strategy for the treatment of CAV.

Unlabelled: Chemokines are known to participate in allograft rejection by mediating leukocyte trafficking. Despite redundancy in chemokine family, several chemokine-chemokine receptor interactions have proven critical in alloimmune responses. We sought to determine the effect of combined blockade of CXCR3 and CCR5, two critical chemokine receptors, in acute rejection., Methods: Heterotopic heart transplantation was performed using BALB/c to B6/129 mice deficient in CCR5. Following transplantation these mice were treated with goat anti-CXCR3 serum every other day. In the control group, BALB/c hearts were transplanted in wild type B6/129 recipients and treated with goat serum alone. No immunosuppression was given to either group. Recipient mice were then assessed daily for allograft function by abdominal palpation, and graft survival was confirmed by laparotomy., Results: The donor hearts in the control group were rejected at 6 +/- 1 days posttransplantation. Combined blockade of CXCR3 and CCR5 prolonged allograft survival versus control; all allografts survived to 24 days. In addition, there was a decrease in graft infiltrating CD4 and CD8 lymphocytes in the experimental group at 24 days., Conclusion: Combined CXCR3 and CCR5 blockade is effective in prolonging allograft survival in a fully MHC mismatched murine model. Combined chemokine blockade holds promise in control of acute rejection in organ transplantation.

Objective: Severe primary graft dysfunction occurs in 10% to 20% of lung transplant recipients and is the leading cause of early death after lung transplantation. We hypothesized that altering the content of the initial reperfusate and maintaining a low reperfusion pressure after surgical implantation would lead to a low incidence of primary graft dysfunction., Methods: We analyzed the records of all patients who underwent lung transplantation at our institution from March 1, 2000, to August 30, 2004. The modified reperfusion technique involved the insertion of a catheter into the main or individual pulmonary artery after implantation. The recipient blood was depleted of leukocytes; supplemented with nitroglycerin; adjusted for pH and calcium level; enriched with aspartate, glutamate, and dextrose; and then administered into the pulmonary arteries of the newly transplanted lung(s) for the first 10 minutes of reperfusion. Severe primary graft dysfunction was defined as a PaO2/inspired oxygen fraction of less than 150 with diffuse infiltrate on the radiograph in absence of other causes., Results: During this interval, 100 patients underwent lung transplantation with the modified reperfusion technique. Forty-two patients underwent single-lung transplantation, of which 5 patients required cardiopulmonary bypass for the procedure. Fifty-eight patients underwent double-lung transplantation; all double-lung transplantation procedures were performed with patients on cardiopulmonary bypass. There were no technical complications associated with the modified reperfusion. The mean PaO2/inspired oxygen fraction at 6 hours in this cohort was 252 +/- 123 mm Hg. The median number of days on the ventilator was 2. More importantly, the incidence of severe primary graft dysfunction in this cohort was 2.0%. The early survival (30-day or in-hospital mortality) of this group of patients was 97%., Conclusions: The technique of modified reperfusion in human lung transplantation is associated with a low incidence of severe primary graft dysfunction and favorable short-term outcomes.

Background: The role of CD8 lymphocytes, in chronic rejection or cardiac allograft vasculopathy (CAV), is incompletely understood. The purposes of this study were to determine whether CD8 lymphocytes, in the absence of CD4 lymphocytes, are capable of causing the intimal lesions of CAV; and if so, to define the effector mechanism(s) of CD8 lymphocytes., Methods: We modified a previously characterized major histocompatibility complex class II mismatched murine model of CAV. Wild-type CD8 lymphocytes were transferred to nude mice followed by heterotopic heart transplantation. Recipient mice were then treated with a CD40 activating antibody, which is known to provide help for CD8 lymphocyte activation, in the absence of CD4 lymphocytes. Donor hearts were harvested on day 40 posttransplantation and analyzed for cellular infiltrates and intimal thickening. In separate experiments, isolated perforin -/-, Fas ligand (FasL) -/-, and interferon (IFN)-gamma -/- CD8 lymphocytes were transferred to nude mice followed by identical experimented protocol., Results: With adaptive transfer of wild-type CD8 lymphocytes, the donor hearts were infiltrated with activated CD8 lymphocytes and displayed significant intimal lesions. Adoptive transfer of perforin -/- and FasL -/- CD8 lymphocytes to nude mice resulted in similar patterns of CD8 lymphocyte infiltration and similar severity of intimal lesions. The donor hearts from IFN-gamma -/- CD8 lymphocyte reconstituted recipients displayed minimal intimal lesions, although CD8 lymphocytes were present in the allografts., Conclusions: Unprimed CD8 lymphocytes in the absence of CD4 lymphocytes can cause intimal lesions of CAV. CD8 lymphocytes production of IFN-gamma, but not the perforin or the FasL-mediated cytotoxicity, is the critical step in the development of intimal lesions.

Purpose: We undertook this study to document the functional natural history of patients undergoing major amputation in an academic vascular surgery and rehabilitation medicine practice., Methods: A retrospective review was conducted of consecutive patients undergoing major lower extremity amputation and rehabilitation in a university and Department of Veterans Affairs hospital. Main outcome variables included operative mortality, follow-up, survival, median time to incision healing, secondary operative procedures for wound management, and conversion from below-knee amputation (BKA) to above-knee amputation (AKA). For surviving patients, quality of life was determined by degree of ambulation, eg, outdoors, indoors only, or no ambulation; use of a prosthesis; and independence, eg, community housing or nursing facility., Results: From August 1997 through March 2002, 154 patients (130 men; median age, 62 years) underwent 172 major amputations, 78 AKA and 94 BKA, because of either critical limb ischemia (87%) or diabetic neuropathy (13%). Thirty-day operative mortality was 10%. Mean follow-up was 14 months. Healing at 100 and 200 days, as determined with the Kaplan-Meier method, was 55% and 83%, respectively, for BKA, and 76% and 85%, respectively, for AKA. Twenty-three BKA and 16 AKA required additional operative revision, and 18 BKA ultimately were converted to AKA. Survival was 78% at 1 year and 55% at 3 years. Function in surviving patients at 10 and 17 months, respectively, was as follows: 21% and 29% of patients ambulated outdoors, 28% and 25% ambulated indoors only, and 51% and 46% of patients were nonambulatory; 32% and 42% of patients used prosthetic limbs; and 17% and 8% of patients who lived in the community before amputation required care in a nursing facility., Conclusions: We were surprised to find that vascular patients in a contemporary setting who require major lower extremity amputation and rehabilitation often remain independent despite infrequent prosthesis use and outdoor ambulation. Although any hope for postoperative ambulation in this population requires salvaging the knee joint, because of the morbidity incurred in both wound healing and rehabilitation efforts, aggressive effort should be reserved for selected patients at good risk. Ability to predict ambulation after BKA in the vascular population is poor.