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

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

Acute Kidney Injury in Deceased Organ Donors and Kidney Transplant Outcomes: A National Cohort Study Using a Novel Data Source.

OBJECTIVE: The aim of this study was to determine graft function and survival for kidney transplants from deceased donors with acute kidney injury (AKI) that persists at the time of organ procurement. BACKGROUND: Kidneys from donors with AKI are often discarded and may provide an opportunity to selectively expand the donor pool. METHODS: Using Organ Procurement and Transplantation Network and DonorNet data, we studied adult kidney-only recipients between May 1, 2007 and December 31, 2016. DonorNet was used to characterize longitudinal creatinine trends and urine output. Donor AKI was defined using KDIGO guidelines and terminal creatinine ≥1.5 mg/dL. We compared outcomes between AKI kidneys versus "ideal comparator" kidneys from donors with no or resolved AKI stage 1 plus terminal creatinine <1.5mg/dL. We fit proportional hazards models and hierarchical linear regression models for the primary outcomes of all-cause graft failure (ACGF) and 12-month estimated glomerular filtration rate (eGFR), respectively. RESULTS: We identified 7660 donors with persistent AKI (33.2% with AKI stage 3) from whom ≥1 kidney was transplanted. Observed rates of ACGF within 3 years were similar between recipient groups (15.5% in AKI vs 15.1% ideal comparator allografts, P = 0.2). After risk adjustment, ACGF was slightly higher among recipients of AKI kidneys (adjusted hazard ratio 1.05, 95% confidence interval: 1.01-1.09). The mean 12-month eGFR for AKI kidney recipients was lower, but differences were not clinically important (56.6 vs 57.5 mL/min/1.73m 2 for ideal comparator kidneys; P < 0.001). There were 2888 kidneys discarded from donors with AKI, age ≤65 years, without hypertension or diabetes, and terminal creatinine ≤4 mg/dL. CONCLUSION: Kidney allografts from donors with persistent AKI are often discarded, yet those that were transplanted did not have clinically meaningful differences in graft survival and function.

Incidence of acute rejection and patient survival in combined heart-liver transplantation.

Combined heart-liver transplantation (CHLT) is indicated for patients with concomitant end-stage heart and liver disease or patients with amyloid heart disease where liver transplantation mitigates progression. Limited data suggest that the liver allograft provides immunoprotection for heart and kidney allografts in combined transplantation from the same donor. We hypothesized that CHLT reduces the incidence of acute cellular rejection (ACR) and the development of de novo donor-specific antibodies (DSAs) compared with heart-alone transplantation (HA). We conducted a retrospective analysis of 32 CHLT and 280 HA recipients in a single-center experience. The primary outcome was incidence of ACR based on protocol and for-cause myocardial biopsy. Rejection was graded by the International Society of Heart and Lung Transplantation guidelines with Grade 2R and higher considered significant. Secondary outcomes included the development of new DSAs, cardiac function, and patient and cardiac graft survival rates. Of CHLT patients, 9.7% had ACR compared with 45.3% of HA patients (p < 0.01). Mean pretransplant calculated panel reactive antibody (cPRA) levels were similar between groups (CHLT 9.4% vs. HA 9.5%; p = 0.97). Among patients who underwent testing, 26.9% of the CHLT and 16.7% of HA developed DSA (p = 0.19). Despite the difference in ACR, patient and cardiac graft survival rates were similar at 5 years (CHLT 82.1% vs. HA 80.9% [p = 0.73]; CHLT 82.1% vs. HA 80.9% [p = 0.73]). CHLT reduced the incidence of ACR in the cardiac allograft, suggesting that the liver offers immunoprotection against cellular mechanisms of rejection without significant impacts on patient and cardiac graft survival rates. CHLT did not reduce the incidence of de novo DSA, possibly portending similar long-term survival among cardiac allografts in CHLT and HA.

Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury.

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

Liver Transplantation Outcomes in a U.S. Multicenter Cohort of 789 Patients With Hepatocellular Carcinoma Presenting Beyond Milan Criteria.

BACKGROUND AND AIMS: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). APPROACH AND RESULTS: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001). CONCLUSIONS: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Kidney transplantation and donation in the transgender population: A single-institution case series.

The medical needs of the transgender population are increasingly recognized within the US health care system. Hormone therapy and gender-affirming surgery present distinct anatomic, hormonal, infectious, and psychosocial issues among transgender kidney transplant donors and recipients. We present the first reported experience with kidney transplantation and donation in transgender patients. A single-center case series (January 2014-December 2018) comprising 4 transgender kidney transplant recipients and 2 transgender living donors was constructed and analyzed. Experts in transplant surgery, transplant psychiatry, transplant infectious disease, pharmacy, and endocrinology were consulted to discuss aspects of care for these patients. Four transgender patients identified as male-to-female and 2 as female-to-male. Three of 6 had gender-affirming surgeries prior to transplant surgery, 1 of whom had further procedures posttransplant. Additionally, 4 patients were on hormone therapy. All 6 had psychiatric comorbidities. The 4 grafts have done well, with an average serum creatinine of 1.45 mg/dL at 2 years (range 1.01-1.85 mg/dL). However, patients encountered various postoperative complications, 1 of which was attributable to modified anatomy. Thus, transgender kidney transplant patients can present novel challenges in regard to surgical considerations as well as pre- and posttransplant care. Dedicated expertise is needed to optimize outcomes for this population.

Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). BACKGROUND: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. METHODS: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. RESULTS: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil-lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). CONCLUSIONS: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection.

To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28 min warm-IRI, and collected the ACR and IRI kidneys as well as their respective native and collateral control kidneys. We extracted metabolites from the kidney tissues and found the lysine catabolite saccharopine 12.5-fold enriched in IRI kidneys, as well as the immunometabolites itaconate and kynurenine in ACR kidneys. Saccharopine accumulation is known to be toxic to mitochondria and may contribute to IRI pathophysiology, while itaconate and kynurenine may be reflective of counterregulatory responses to immune activation in ACR.

Application of Prescription Drug Monitoring Program to detect underreported controlled substance use in patients evaluated for liver transplant.

Presurgical controlled substance use predicts postoperative complications, increased readmissions, and mortality. We aimed to examine if a Prescription Drug Monitoring Program (PDMP) would detect underreported controlled substance use in patients undergoing liver transplant evaluation. We performed a retrospective cohort study at a tertiary referral center of patients undergoing liver transplant evaluation in 2017. PDMP reviews were performed on all 360 patients and urine drug screen (UDS) results were reviewed when available to evaluate dispensed controlled substances. These results were compared to the patient's self-reported medication list at evaluation to identify any underreporting. The primary outcome was the number of self-reported controlled substance discrepancies on the medication list identified by PDMP and UDS at the time of evaluation. Among the 360 patients, 87 (24%) had a discrepancy where PDMP revealed a controlled substance prescription that the patient did not report on their medication list. Seventy-seven (67/87) of these discrepancies involved opiates. Of the 360 patients, 219 (61%) had a negative UDS, but 70 (32%) of these patients had at least one controlled substance listed on PDMP. PDMP is a promising screening tool when used in conjunction with the UDS for detecting underreported controlled substance use in liver transplant candidates.

Transplanting hepatitis C virus-infected hearts into uninfected recipients: A single-arm trial.

The advent of direct-acting antiviral therapy for hepatitis C virus (HCV) has generated tremendous interest in transplanting organs from HCV-infected donors. We conducted a single-arm trial of orthotopic heart transplantation (OHT) from HCV-infected donors into uninfected recipients, followed by elbasvir/grazoprevir treatment after recipient HCV was first detected (NCT03146741; sponsor: Merck). We enrolled OHT candidates aged 40-65 years; left ventricular assist device (LVAD) support and liver disease were exclusions. We accepted hearts from HCV-genotype 1 donors. From May 16, 2017 to May 10, 2018, 20 patients consented for screening and enrolled, and 10 (median age 52.5 years; 80% male) underwent OHT. The median wait from UNOS opt-in for HCV nucleic-acid-test (NAT)+ donor offers to OHT was 39 days (interquartile range [IQR] 17-57). The median donor age was 34 years (IQR 31-37). Initial recipient HCV RNA levels ranged from 25 IU/mL to 40 million IU/mL, but all 10 patients had rapid decline in HCV NAT after elbasvir/grazoprevir treatment. Nine recipients achieved sustained virologic response at 12 weeks (SVR-12). The 10th recipient had a positive cross-match, experienced antibody-mediated rejection and multi-organ failure, and died on day 79. No serious adverse events occurred from HCV transmission or treatment. These short-term results suggest that HCV-negative candidates transplanted with HCV-infected hearts have acceptable outcomes.

An Advanced Practice Practitioner-Based Program to Reduce 30- and 90-Day Readmissions After Liver Transplantation.

Hospital readmissions after liver transplantation (LT) are common and associated with increased morbidity and cost. High readmission rates at our center motivated a change in practice with adoption of a nurse practitioner (NP)-based posttransplant care program. We sought to determine if this program was effective in reducing 30- and 90-day readmissions after LT and to identify variables associated with readmission. We performed a retrospective cohort study of all patients undergoing LT from July 1, 2014, to June 30, 2017, at a tertiary LT referral center. A NP-based posttransplant care program with weekend in-house nurse coordination providers and increased outpatient NP clinic availability was instituted on January 1, 2016. Postdischarge readmission rates at 30 and 90 days were compared in the pre-exposure and postexposure groups, adjusting for associated risk factors. A total of 362 patients were included in the analytic cohort. There were no significant differences in demographics, comorbidities, or index hospitalization characteristics between groups. In the adjusted analyses, the risk of readmission in the postexposure group was significantly reduced relative to baseline at 30 days (hazard ratio [HR] 0.60, 95% confidence interval [CI], 0.39-0.90; P = 0.02) and 90 days (HR, 0.49; 95% CI, 0.34-0.71; P < 0.001). Risk factors positively associated with 30-day readmission included peritransplant dialysis (HR, 1.70; 95% CI, 1.13-2.58; P = 0.01) and retransplant on index hospitalization (HR, 10.21; 95% CI, 3.39-30.75; P < 0.001). Male sex was protective against readmission (HR, 0.66; 95% CI, 0.45-0.97; P = 0.03). In conclusion, implementation of expanded NP-based care after LT was associated with significantly reduced 30- and 90-day readmission rates. LT centers and other service lines using significant postsurgical resources may be able to reduce readmissions through similar programs.

Association of Kidney Transplant Center Volume With 3-Year Clinical Outcomes.

RATIONALE & OBJECTIVE: A robust relationship between procedure volume and clinical outcomes has been demonstrated across many surgical fields. This study assessed whether a center volume-outcome relationship exists for contemporary kidney transplantation, specifically for diabetic recipients, older recipients (aged ≥65 years), and recipients of high kidney donor profile index (KDPI ≥ 85) kidneys. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult kidney-only transplant recipients who underwent transplantation between 2009 and 2013 (N = 79,581). EXPOSURES: The primary exposure variable was center volume, categorized into quartiles based on the total kidney transplantation volume. Quartile 1 (Q1) centers performed a mean of fewer than 66 kidney transplantations per year, whereas Q4 centers performed a mean of more than 196 kidney transplantations per year. OUTCOMES: All-cause graft failure and mortality within 3 years of transplantation. ANALYTICAL APPROACH: Multivariable Cox frailty models were used to adjust for donor characteristics, recipient characteristics, and cold ischemia time. RESULTS: Minor differences in rates of 3-year deceased donor all-cause graft failure across quartiles of center volume were observed (14.9% for Q1 vs 16.7% for Q4), including in subgroups (diabetic recipients, 18.4% for Q1 vs 19.7% for Q4; older recipients, 19.4% for Q1 vs 22.5% for Q4; recipients of high KDPI kidneys, 26.5% for Q1 vs 26.5% for Q4). Results were similar for 3-year mortality. After adjustment for donor, recipient, and graft characteristics using Cox regression, center volume was not significantly associated with all-cause graft failure or mortality within 3 years, except that diabetic recipients at Q3 centers had slightly lower mortality (compared with Q1 centers, adjusted HR of 0.85 [95% CI, 0.73-0.99]). LIMITATIONS: Potential unmeasured confounding from patient comorbid conditions and organ selection. CONCLUSIONS: These findings provide little evidence that care in higher volume centers is associated with better adjusted outcomes for kidney transplant recipients, even in populations anticipated to be at increased risk for graft failure or death.

Incidence of Occult Intrahepatic Metastasis in Hepatocellular Carcinoma Treated With Transplantation Corresponds to Early Recurrence Rates After Partial Hepatectomy.

OBJECTIVE: This study aimed to compare the incidence of radiologically unrecognized (occult) hepatocellular carcinoma (HCC) lesions in explant hepatectomy specimens from orthotopic liver transplants (OLTs) performed for HCC with rates of HCC intrahepatic recurrence after resection. SUMMARY OF BACKGROUND DATA: Resection of HCC is associated with high rates of intrahepatic HCC recurrence. However, it is unclear whether these recurrences represent incomplete resection of unrecognized metastatic lesions from the primary tumor or subsequent de novo tumor formation due to inherent biological proclivity for HCC formation. METHODS: We collected patient, tumor, and pathology data on HCC patients treated surgically from 3696 OLTs in the Organ Procurement and Transplantation (OPTN) national database, 299 OLTs at a single transplant center, and 232 partial hepatectomies from a hepatobiliary cancer center. RESULTS: In the OPTN and high-volume transplant center cohorts, 37% and 42% of patients had occult HCC lesions on explant pathology, respectively. Among cancer center patients, the 2-year recurrence rate was 46%, and 74% of patients who recurred presented with liver only recurrence. CONCLUSION: Although the transplant and resection populations differ, occult multifocality is common in transplant explants and similar to the 46% early recurrence rate following partial hepatectomy. These data suggest that noncurative resection often results from occult intrahepatic multifocality present at the time of resection rather than a malignant predisposition of the remnant liver with de novo tumorigenesis.

Liver paired exchange: Can the liver emulate the kidney?

Kidney paired exchange (KPE) constitutes 12% of all living donor kidney transplantations (LDKTs) in the United States. The success of KPE programs has prompted many in the liver transplant community to consider the possibility of liver paired exchange (LPE). Though the idea seems promising, the application has been limited to a handful of centers in Asia. In this article, we consider the indications, logistical issues, and ethics for establishing a LPE program in the United States with reference to the principles and advances developed from experience with KPE. Liver Transplantation 24 677-686 2018 AASLD.

Impact of prolonged dialysis prior to renal transplantation.

INTRODUCTION: The new kidney allocation system (KAS) prioritizes patients based on date of dialysis initiation or waitlisting, whichever is earlier. We hypothesized that this change would increase transplant rates for patients with prolonged pretransplant dialysis times (DT) and aimed to assess the impact of prolonged DT on post-transplant outcomes. METHODS: We used United Network for Organ Sharing registry data to assess outcomes for patients added to the renal transplant waitlist from January 1, 1998 to December 31, 2010 and patients transplanted from January 1, 1998 to December 3, 2012. RESULTS: Compared with patients transplanted pre-emptively, patients with <5 years, 5-9 years, and ≥10 years DT had progressively decreased graft and patient survival (P < .001). The rates of short-term complications including delayed graft function, graft loss within 30 days, and patient death within 30 days were significantly higher in cohorts with ≥10 years DT than in cohorts with less DT (P < .001). CONCLUSIONS: Patients with pretransplant DT of ≥10 years had worse outcomes than patients pre-emptively transplanted or transplanted with shorter DT. Durations of dialysis dependence beyond 10 years were associated with further deterioration in short-term but not long-term post-transplant outcomes.

Combination of Neoadjuvant Transcatheter Arterial Chemoembolization and Orthotopic Liver Transplantation for the Treatment of Cirrhotomimetic Hepatocellular Carcinoma.

PURPOSE: To examine differences in outcome and response of cirrhotomimetic (CMM) hepatocellular carcinoma (HCC) to a combination of bridging transcatheter arterial chemoembolization and orthotopic liver transplantation (OLT) compared with non-CMM HCC. MATERIALS AND METHODS: All patients with pathologically proven CMM HCC who underwent bridging transcatheter arterial chemoembolization before OLT between 2007 and 2013 (n = 23) were retrospectively compared with a control group of patients with pathologically proven non-CMM HCC (n = 46). RESULTS: There were 29 tumors in the CMM HCC group and 64 tumors in the non-CMM group identified and treated. Objective response rate on MR imaging at 1 and 3 months after transcatheter arterial chemoembolization for CMM HCC tumors (including patients with complete and partial response) was 93.1% and 86.4% compared with 85.2% and 93.2% for non-CMM tumors without statistically significant difference (P = .54 and P = .09, respectively). Pathologic study of liver explants showed complete tumor necrosis in 62.3% of non-CMM tumors (38/61) compared with 10.3% of CMM tumors (3/29) (P < .0001). Overall 2-year survival after transcatheter arterial chemoembolization and OLT was significantly lower for patients with CMM HCC compared with patients non-CMM HCC (65.2% vs 87%, P = .03). Patients with CMM HCC with extranodular tumor extension involving > 50% of liver parenchyma had worse survival with mean 2-year survival of 402 days ± 102 vs 656 days ± 39 for the remaining patients with CMM HCC (P = .02). CONCLUSIONS: Despite similar early imaging response rates, CMM HCC tumors had markedly lower rates of complete pathologic necrosis on liver explants and were associated with reduced survival after OLT compared with conventional HCCs.

The Future of Basic Science in Academic Surgery: Identifying Barriers to Success for Surgeon-scientists.

OBJECTIVE: The aim of this study was to examine the challenges confronting surgeons performing basic science research in today's academic surgery environment. SUMMARY OF BACKGROUND DATA: Multiple studies have identified challenges confronting surgeon-scientists and impacting their ability to be successful. Although these threats have been known for decades, the downward trend in the number of successful surgeon-scientists continues. Clinical demands, funding challenges, and other factors play important roles, but a rigorous analysis of academic surgeons and their experiences regarding these issues has not previously been performed. METHODS: An online survey was distributed to 2504 members of the Association for Academic Surgery and Society of University Surgeons to determine factors impacting success. Survey results were subjected to statistical analyses. We also reviewed publicly available data regarding funding from the National Institutes of Health (NIH). RESULTS: NIH data revealed a 27% decline in the proportion of NIH funding to surgical departments relative to total NIH funding from 2007 to 2014. A total of 1033 (41%) members responded to our survey, making this the largest survey of academic surgeons to date. Surgeons most often cited the following factors as major impediments to pursuing basic investigation: pressure to be clinically productive, excessive administrative responsibilities, difficulty obtaining extramural funding, and desire for work-life balance. Surprisingly, a majority (68%) did not believe surgeons can be successful basic scientists in today's environment, including departmental leadership. CONCLUSIONS: We have identified important barriers that confront academic surgeons pursuing basic research and a perception that success in basic science may no longer be achievable. These barriers need to be addressed to ensure the continued development of future surgeon-scientists.

Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). SUMMARY BACKGROUND DATA: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. METHODS: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). RESULTS: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). CONCLUSIONS: Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.

Same policy, different impact: Center-level effects of share 35 liver allocation.

Early studies of national data suggest that the Share 35 allocation policy increased liver transplants without compromising posttransplant outcomes. Changes in center-specific volumes and practice patterns in response to the national policy change are not well characterized. Understanding center-level responses to Share 35 is crucial for optimizing the policy and constructing effective future policy revisions. Data from the United Network for Organ Sharing were analyzed to compare center-level volumes of allocation-Model for End-Stage Liver Disease (aMELD) ≥ 35 transplants before and after policy implementation. There was significant center-level variation in the number and proportion of aMELD ≥ 35 transplants performed from the pre- to post-Share 35 period; 8 centers accounted for 33.7% of the total national increase in aMELD ≥ 35 transplants performed in the 2.5-year post-Share 35 period, whereas 25 centers accounted for 65.0% of the national increase. This trend correlated with increased listing at these centers of patients with Model for End-Stage Liver Disease (MELD) ≥ 35 at the time of initial listing. These centers did not overrepresent the total national volume of liver transplants. Comparison of post-Share 35 aMELD to calculated time-of-transplant (TOT) laboratory MELD scores showed that only 69.6% of patients transplanted with aMELD ≥ 35 maintained a calculated laboratory MELD ≥ 35 at the TOT. In conclusion, Share 35 increased transplantation of aMELD ≥ 35 recipients on a national level, but the policy asymmetrically impacted practice patterns and volumes of a subset of centers. Longer-term data are necessary to assess outcomes at centers with markedly increased volumes of high-MELD transplants after Share 35. Liver Transplantation 23 741-750 2017 AASLD.

New Solutions to Reduce Discard of Kidneys Donated for Transplantation.

Kidney transplantation is a cost-saving treatment that extends the lives of patients with ESRD. Unfortunately, the kidney transplant waiting list has ballooned to over 100,000 Americans. Across large areas of the United States, many kidney transplant candidates spend over 5 years waiting and often die before undergoing transplantation. However, more than 2500 kidneys (>17% of the total recovered from deceased donors) were discarded in 2013, despite evidence that many of these kidneys would provide a survival benefit to wait-listed patients. Transplant leaders have focused attention on transplant center report cards as a likely cause for this discard problem, although that focus is too narrow. In this review, we examine the risks associated with accepting various categories of donated kidneys, including discarded kidneys, compared with the risk of remaining on dialysis. With the goal of improving access to kidney transplant, we describe feasible proposals to increase acceptance of currently discarded organs.