Search

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.

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.

There is increasing evidence that estrogen is responsible for improved outcomes in female kidney transplant recipients. Although the exact mechanism is not yet known, estrogen appears to exert its protective effects by ameliorating ischemia-reperfusion injury (IRI). In this study, we have examined whether the beneficial effects of exogenous estrogen in renal IRI are replicated by therapy with any one of several selective estrogen receptor modulators.C57BL/6 adult mice underwent standardized warm renal ischemia for 28 min after being injected with the selective estrogen receptor modulators, raloxifene, lasofoxifene, tamoxifen, bazedoxifene, or control vehicle (dimethyl sulfoxide), at 16 and 1 h before IRI. Plasma concentrations of blood urea nitrogen and creatinine were assessed 24, 48, 72, and 96 h post-IRI. Tissue was collected 30 d postischemia for fibrosis analysis using Sirius Red staining.Raloxifene treatment in female mice resulted in significantly lower blood urea nitrogen and creatinine after IRI and significantly lower fibrosis 30 d following IRI.Raloxifene is protective against both acute kidney injury and fibrosis resulting from renal IRI in a mouse model.

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.

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).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 time12 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).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.

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.Kidneys from donors with AKI are often discarded and may provide an opportunity to selectively expand the donor pool.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 creatinine1.5mg/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.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; P0.001). There were 2888 kidneys discarded from donors with AKI, age ≤65 years, without hypertension or diabetes, and terminal creatinine ≤4 mg/dL.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.

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.

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.

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.

Transplant eligibility for hepatocellular carcinoma (HCC) is determined by the imaging identification of tumor burden within the Milan criteria. Transjugular intrahepatic portosystemic shunt(s) (TIPS) reduce portal hypertension but may impact HCC visualization. It was hypothesized that the presence of pretransplant TIPS would correlate with occult HCC and reduced survival. A single-center, retrospective, case control study was performed among liver transplant recipients with HCC (2000-2017). The primary endpoint was occult disease on explant pathology. Backward stepwise logistic regression was performed. The secondary endpoints disease-free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and Cox regression analysis. Of 640 patients, 40 had TIPS and more frequently exhibited occult disease (80.0% versus 43.1%; P

International audience; Vascularized composite allografts may be more susceptible to rejection than other types of organ transplants, particularly in sensitized recipients. We describe a successful transatlantic bilateral hand transplant in a 40-year old woman who was highly sensitized to class II HLA antigens including HLA-DPB1 (UNet CPRA = 86%). Prior to transplantation, we selected an upper limb donor based on HLA class II matching and absence of donor specific antibodies, given evidence that class II mismatches are associated with acute cellular rejection in hand transplants. The patient was conditioned using five doses of thymoglobulin, and her immunosuppression included tacrolimus, rapamycin, mycophenolate, and prednisone. Post-transplant, the patient non-DSA anti-HLA antibody levels drastically increased, but only transiently and weak DSAs developed, which became undetectable by two months posttransplant. Following transplantation, periodic biopsies over 6 months indicated no evidence of rejection except for transient Banff grade 1 and one sample with grade 2 acute rejection. There was no evidence of rejection on her recent 1-year follow-up. The patient is currently healthy, has recovered protective sensibility, and is regaining excellent function. This case highlights the importance of pre-transplantation planning, donor selection/compatibility, and ethical considerations in the ultimate success of VCA.

Vascularized composite allotransplantation (VCA) allows tissue replacement after devastating loss but is currently limited in application and may be more widely performed if maintenance immunosuppression was not essential for graft acceptance. We tested whether peri-transplant costimulation blockade could prolong VCA survival and required donor bone-marrow cells, given that bone-marrow might promote graft immunogenicity or graft-versus-host disease. Peritransplant CD154 mAb/rapamycin (RPM) induced long-term orthotopic hindlimb VCA survival (BALB/c->C57BL/6), as did CTLA4Ig/RPM. Surprisingly, success of either protocol required a bone-marrow-associated, radiation-sensitive cell population, since long-bone removal or pre-transplant donor irradiation prevented long-term engraftment. Rejection also occurred if Rag1−/− donors were used, or if donors were treated with a CXCR4 inhibitor to mobilize donor BM cells pre-transplant. Donor bone-marrow contained a large population of Foxp3+ T-regulatory (Treg) cells, and donor Foxp3+ Treg depletion, by diphtheria toxin administration to DEREG donor mice whose Foxp3+ Treg cells expressed diphtheria toxin receptor, restored rejection with either protocol. Rejection also occurred if CXCR4 was deleted from donor Tregs pre-transplant. Hence, long-term VCA survival is possible across a full MHC disparity using peritransplant costimulation blockade-based approaches, but unexpectedly, the efficacy of costimulation blockade requires the presence of a radiation-sensitive, CXCR4+ Foxp3+ Treg population resident within donor BM.

To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28 minutes 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.

Background Organs from hepatitis C virus (HCV)-infected deceased donors are often discarded. Preliminary data from 2 small trials, including THINKER-1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), suggested that HCV-infected kidneys could be safely transplanted into HCV-negative patients. However, intermediate-term data on quality of life and renal function are needed to counsel patients about risk. Objective To describe 12-month HCV treatment outcomes, estimated glomerular filtration rate (eGFR), and quality of life for the 10 kidney recipients in THINKER-1 and 6-month data on 10 additional recipients. Design Open-label, nonrandomized trial. (ClinicalTrials.gov: NCT02743897). Setting Single center. Participants 20 HCV-negative transplant candidates. Intervention Participants underwent transplant with kidneys infected with genotype 1 HCV and received elbasvir-grazoprevir on posttransplant day 3. Measurements The primary outcome was HCV cure. Exploratory outcomes included 1) RAND-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) quality-of-life scores at enrollment and after transplant, and 2) posttransplant renal function, which was compared in a 1:5 matched sample with recipients of HCV-negative kidneys. Results The mean age of THINKER participants was 56.3 years (SD, 6.7), 70% were male, and 40% were black. All 20 participants achieved HCV cure. Hepatic and renal complications were transient or were successfully managed. Mean PCS and MCS quality-of-life scores decreased at 4 weeks; PCS scores then increased above pretransplant values, whereas MCS scores returned to baseline values. Estimated GFRs were similar between THINKER participants and matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs. 66.2 mL/min/1.73 m2; 95% CI for between-group difference, -4.2 to 7.5 mL/min/1.73 m2) and 12 months (median, 72.8 vs. 67.2 mL/min/1.73 m2; CI for between-group difference, -7.2 to 9.8 mL/min/1.73 m2). Limitation Small trial. Conclusion Twenty HCV-negative recipients of HCV-infected kidneys experienced HCV cure, good quality of life, and excellent renal function. Kidneys from HCV-infected donors may be a valuable transplant resource. Primary funding source Merck.

T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in post-translational modifications (PTMs) of histones and many non-histone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg-dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.

Kidney Allocation System (KAS) was enacted in 2014 to improve graft utility, while facilitating transplantation of highly-sensitized patients and preserving pediatric access to high-quality kidneys. Central to this system is the Kidney Donor Profile Index (KDPI), a metric intended to predict transplant outcomes based on donor characteristics but derived using only adult donors. We posited that KAS had inadvertently altered the profile and quantity of kidneys made available to pediatric recipients. This question arose from our observation that most pediatric donors carry a KDPI over 35 and have therefore been rendered relatively inaccessible to pediatric recipients under KAS. Here we explore early trends in pediatric transplantation following KAS, including 1) use of pediatric donors, 2) use of Public Health System (PHS) high infectious risk donors, 3) wait time, and 4) living donor transplantation. We note some concerning preliminary changes following KAS implementation, including the allocation of fewer deceased donor pediatric kidneys to children and stagnation in pediatric wait times. Moreover, the poor predictive power of the KDPI for adult donors appears to be even worse when applied to pediatric donors. These early trends warrant further observation and consideration of changes in pediatric kidney allocation if they persist. This article is protected by copyright. All rights reserved.

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.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).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 involving50% 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).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.

BACKGROUND Vascularized composite allografts (VCA) are novel, life-enhancing forms of transplantation (Tx). However, host immune responses to the various VCA components, especially those involving skin, are complex and make selection of appropriate therapy challenging. Although the interplay between Foxp3+ T regulatory (Treg) cells and CD4 and CD8 effector T cells is of central importance in determining the acceptance or rejection of solid organ allografts, there is little information available concerning the contribution of Treg cells to VCA survival. In addition, the effects of therapeutic expansion in vivo of host Treg cell populations on VCA survival are unknown. METHODS We established a fully major histocompatibility complex-disparate (BALB/c- > C57BL/6) murine orthotopic forelimb Tx model to explore the benefits of pre- and post-Tx IL-2/anti-IL-2 monoclonal antibody complex (IL-2C) administration to expand the host Treg cell population and thereby attempt to promote Treg cell-dependent VCA survival. RESULTS Both strategies expanded the Treg cell population in vivo and prolonged VCA survival (P < 0.001), but IL-2C administration pre-Tx led to significantly longer survival compared with IL-2C administration post-Tx (P < 0.01). In addition, compared with post-Tx therapy, pre-Tx therapy resulted in an increased ratio of Treg cells to CD8+ T cells (P < 0.001), reduced proliferation of CD4 and CD8 effector T cells, and reduced production of IFN-γ. Optimal effects were seen when combined with rapamycin therapy, whereas the combination of IL-2C therapy plus calcineurin inhibitor was counterproductive. CONCLUSIONS Our studies involving different IL-2C-mediated Treg cell expansion strategies demonstrate that pre-Tx IL-2C therapy may be a useful component for developing strategies to promote VCA survival.

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).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.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).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, P0.001; 4+ LRTs: HR 2.5, P0.001), 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, P0.001) 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).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.

Summary Background Although heterologous vascular composite allotransplantation has become a burgeoning treatment option for adult amputees, there have been no successful cases previously reported in children. Here, we describe the surgical, immunological, and neurorehabilitation details with functional outcomes 18 months after heterologous bilateral hand and forearm transplantation in an 8-year-old child with quadrimembral amputations and a previous kidney transplant. Methods 2 years of extensive preparation by medical and surgical teams preceded the hand–forearm transplantation of this child. The initial immunosuppressive protocol included thymoglobulin, tacrolimus, prednisone, and mycophenolate mofetil. In July, 2015, our vascularised composite allotransplantation team did the first bilateral hand and forearm transplantation in a child, an 8-year-old boy with previous living-related kidney transplantation. The surgery included four teams working simultaneously on the donor and recipient limbs, aided by customised cutting guides that aimed to reduce ischaemia time. Following an extended length of time in hospital, skin biopsies and close monitoring of renal function and drug concentrations occurred weekly for the first 3 months and were slowly tapered to monthly, and then quarterly. Skin biopsies were also done when tissue rejection was suspected. Paediatric-specific rehabilitation techniques were applied to promote patient engagement during rehabilitation. Progress was assessed by monthly sensory and motor function tests during routine clinic visits and with serial functional brain imaging studies, including structural brain MRI, magnetoencephalography and transcranial magnetic stimulation. Findings The surgery lasted 10 h and 40 min. Vascular revision of the ulnar artery was required a few hours postoperatively. There were no further immediate postsurgical complications. Rejection episodes occurred throughout the first year but were reversed. An increase in serum creatinine led to the addition of sirolimus at 3 months after transplantation with concomitant reduction in tacrolimus targets. Sensibility to light touch was present by 6 months after transplantation. Intrinsic hand muscle innervation was present by 7–10 months after transplantation. At 18 months, the child had exceeded his previous adapted abilities. As of 18 months after transplantation surgery he is able to write and feed, toilet, and dress himself more independently and efficiently than he could do before transplantation. He remains on four immunosuppressive medications and functional neuroimaging studies have shown motor and somatosensory cortical reorganisation. Interpretation Hand transplantation in a child can be surgically, medically, and functionally successful under carefully considered circumstances. Long-term data on the functional trajectory, neurological recovery, psychological sequelae, and the potential late effect of immunosuppression are still needed to support broader implementation of paediatric vascular composite allotransplantation. Funding The Children's Hospital of Philadelphia.

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 success

Share 35 was implemented to provide improved access to organs for patients with Model for End-Stage Liver Disease (MELD) scores ≥ 35. However, little is known about the impact of Share 35 on organ offer acceptance rates. We evaluated all liver offers to adult patients who were ultimately transplanted between January 1, 2011 and December 31, 2015. The analyses focused on patients ranked in the top 5 positions of a given match run and used multilevel mixed-effects models, clustering on individual wait-list candidate and transplant center. There was a significant interaction between Share 35 era and MELD category (P < 0.001). Comparing offers to MELD score ≥ 35 patients, offers after Share 35 were 36% less likely to be accepted compared with offers to MELD score ≥ 35 patients before Share 35 (adjusted odds ratio, 0.64). There was no clinically meaningful difference in the donor risk index of livers that were declined for patients with an allocation MELD score ≥35 in the pre- versus post-Share 35 era. Organ offer acceptance rates for patients with an allocation MELD ≥ 35 decreased in every region after Share 35; the magnitude of these changes was bigger in regions 2, 3, 4, 5, 6, 7, and 11, compared with regions 8 and 9 that had regional sharing in place before Share 35. There were significant changes in organ offer acceptance rates at the center level before versus after Share 35, and these changes varied across centers (P < 0.001). In conclusion, in liver transplantation candidates achieving a MELD score ≥ 35, liver acceptance of offers declined significantly after implementation of Share 35. The alterations in behavior at the center level suggest that practice patterns changed as a direct result of Share 35. Changes in organ acceptance under even broader organ sharing (redistricting) would likely be even greater, posing major logistical and operational challenges, while potentially increasing discard rates, thus decreasing the total number of transplants nationally. Liver Transplantation 23 604-613 2017 AASLD.

Background Survival after solid organ transplantation(SOT) and hematopoietic cell transplantation(HCT) has increased over time. Despite these improvements, recipients of SOT are at increased risk for conditions leading to bone marrow failure, necessitating HCT. Moreover, recipients of HCT are at increased risk of developing organ failure, necessitating SOT. Complications of SOT and HCT have led the SOT and HCT communities to consider so-called, “sequential transplantation”; however, little data exists to inform outcomes and guide management decisions. We utilized data from the Center for International Blood and Marrow Transplant Research(CIBMTR) and the United Network for Organ Sharing(UNOS) to describe the characteristics and outcomes of patients with sequential transplantation in the United States. Methods A descriptive analysis of patients with sequential transplantation(SOT followed by HCT, HCT followed by SOT, HCT followed by SOT waitlist[WL]) was conducted. Analyses focused on SOT and HCT characteristics, outcomes including overall survival(OS) from first transplant and complications(graft-versus-host disease[GVHD] and SOT failure). Results We identified 258 patients registered with the CIBMTR and UNOS that had undergone sequential transplantation or been placed on the WL. Among patients who received a SOT followed by HCT(n=84), 50% underwent allogeneic HCT. In this group, there were 15 thoracic, 43 kidney, and 26 liver transplants performed prior to HCT, with living donation accounting for 23(54%) kidney and 2(8%) liver transplants. Five-year OS among recipients of SOT followed by HCT was 34%. Among patients who received an HCT followed by SOT(n=87) or HCT followed by WL(n=73), 45% underwent allogeneic HCT. Plasma cell disorder or multiple myeloma was the most common indication for HCT(48%).(Figure 1) There were 26 thoracic, 49 kidney, and 5 liver SOT procedures performed after initial HCT. Living donation accounted for 27(55%) kidney and 2(40%) liver transplants in this group. Five-year OS among recipients of HCT followed by SOT was 82%. Among all patients who underwent HCT, acute GVHD occurred in 47% and chronic GVHD in 53%. SOT graft failure occurred in 81(44%): 26(30%) SOT failures among HCT followed by SOT and 55(56%) SOT failures among SOT followed by HCT. Conclusion Sequential transplantation poses an enormous clinical challenge for members of the transplant community. OS among recipients of SOT followed by HCT is considerably less than OS among recipients of HCT followed by SOT. Additional analyses further characterizing outcomes of sequential transplantation and investigating potential factors associated with these outcomes are planned to assist SOT and HCT care providers in the management of these challenging clinical scenarios.

With the opioid epidemic and expansion of “increased risk” (IR) classification, 25% of deceased donors are categorized Public Health Service Increased Risk (PHS-IR). Studies have assessed utilization of PHS-IR organs among adults, but little is known about pediatric recipients. This retrospective cohort study from 2004–2016 (IR period) aimed to: 1) assess IR kidney utilization patterns between adults and children; 2) identify recipient factors associated with transplant from IR donors among pediatric kidney recipients; and 3) determine geography’s role in IR kidney utilization for children. The proportion of pediatric recipients receiving IR kidneys was significantly lower than adults (p

Supplemental Digital Content is available in the text., Background. The clinical impact of weakly reactive pretransplant donor-specific antibody (DSA) in kidney transplantation is controversial. While some evidence suggests that weakly reactive DSA can lead to rejection, it is unclear which patients are at risk for rejection and whether posttransplant changes in weakly reactive DSA are clinically meaningful. Methods. We retrospectively studied 80 kidney transplant recipients with weakly reactive pretransplant DSA between 2007 and 2014. We performed a multivariate Cox regression analysis to identify immunologic factors most associated with risk of biopsy-proven rejection. Results. Biopsy-proven rejection occurred in 13 of 80 (16%) patients. The presence of both class I and II DSA before transplant (hazards ratio 17.4, P < 0.01) and any posttransplant increase in DSA reactivity above a mean fluorescence intensity of 3000 (hazards ratio 7.8, P < 0.01) were each significantly associated with an increased risk of rejection, which primarily occurred within the first 18 months. Conclusions. Pretransplant DSA class and DSA kinetics after transplantation are useful prognostic indicators in patients with weak DSA reactivity. These results identify a small, high-risk patient group that warrants aggressive posttransplant DSA monitoring and may benefit from alternative donor selection.

Animal models and observational human data indicate that complement, including C5a, pathogenically participates in ischemia reperfusion (IR) injury that manifests as delayed graft function (DGF) following deceased donor kidney transplantation. We report on the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent DGF in recipients of deceased donor kidney transplants in two related, investigator-sponsored, randomized controlled trials. Eight recipients from a single center were enrolled in a pilot study that led to a 19-subject multicenter trial. Together, 27 deceased donor kidney transplant recipients, 16 Ecu-treated and 11 controls, were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil with or without glucocorticoids, and followed for 6 months. Data analysis showed no epidemiological or transplant-related differences between study arms. Ecu was well tolerated with a similar severe adverse event incidence between groups. The DGF rate did not differ between Ecu-treated (44%) and control (45%, P = 1.0) subjects. Serum creatinine reduction in the first week after transplantation, and graft function up to 180-days post-transplant, were also similar. Ecu administration was safe but did not reduce the rate of DGF in a high-risk population of deceased donor recipients.

Recent evidence suggests that belatacept reduces the durability of preexisting antibodies to class I and class II human leukocyte antigens (HLAs). In this case series of 163 highly sensitized kidney transplant candidates whose calculated panel-reactive antibody (cPRA) activity was ≥98% to 100%, the impact of belatacept on preexisting HLA antibodies was assessed. Of the 163 candidates, 72 underwent transplantation between December 4, 2014 and April 15, 2017; 60 of these transplanted patients remained on belatacept consecutively for at least 6 months. We observed a decrease in the breadth and/or strength of HLA class I antibodies as assessed by FlowPRA in belatacept-treated patients compared to controls who did not receive belatacept. Specifically, significant HLA antibody reduction was evident for class I (P < .0009). Posttransplant belatacept-treated patients also had a clinically significant reduction in their cPRA compared to controls (P < .01). Collectively, these findings suggest belatacept can reduce HLA class I antibodies in a significant proportion of highly sensitized recipients and could be an option to improve pretransplant compatibility with organ donors.

RATIONALE & OBJECTIVE: A robust relationship between procedure volume and outcomes has been demonstrated across many surgical fields. This study assessed if a center volume-outcome relationship exists for contemporary kidney transplantation, specifically in increased-risk scenarios including: diabetic recipients, older recipients (age ≥ 65) or recipients of high kidney donor profile index (KDPI) ≥85 kidneys. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult kidney-only transplant recipients, transplanted between 2009–2013 (n=79,581). EXPOSURES: The primary exposure variable was center volume, which was categorized into quartiles (low, medium, medium-high, high) based on the total kidney transplant volume. Low-quartile centers performed a mean of 196 kidney transplants/year. OUTCOMES: All-cause graft failure or mortality within 3-years of transplant. ANALYTIC APPROACH: Multivariable Cox frailty models were used to adjust for donor characteristics, recipient characteristic and cold ischemia time. RESULTS: Minor differences in the rates of 3-year deceased donor all-cause graft failure across quartiles were observed (low-quartile centers=14.9% vs. high-quartile centers=16.7%) (subgroups: diabetic recipients at low-quartile centers=18.4% vs. high-quartile centers=19.7%; older recipients at low-quartile-centers=19.4% vs. high-quartile centers=22.5%; high KDPI kidney recipients at low-quartile centers=26.5% vs. high-quartile centers=26.5%). Results were similar for 3-year mortality. Adjusting for donor, recipient and graft characteristics using Cox models, center volume was not significantly associated with all-cause graft failure or mortality within 3 years, except that diabetic recipients at medium-high centers had slightly lower mortality (aHR 0.85; 95%CI 0.73–0.99; reference group was low-quartile centers). LIMITATIONS: Potential unmeasured confounding from patient co-morbidities and organ selection. CONCLUSIONS: These results provide little evidence that higher volume centers provide better adjusted outcomes for kidney transplant patients, even in populations anticipated to be at increased risk of graft failure or death.

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.

Death rates from drug overdoses have nearly doubled since 2003, with over 47 000 deaths in 2014. This is largely attributable to the opioid epidemic. If the unfortunate deaths of otherwise healthy people have yielded an increase in organ donors, then this might serve as perhaps the only comforting factor among this tragic and unnecessary loss of life. In this viewpoint, we present data from the Organ Procurement and Transplantation Network (OPTN) that show how the greatest relative increases in the mechanism of death among deceased donors from 2003 to 2014 were drug overdoses. Unfortunately, despite the absolute increase in the number of donors who died from a drug overdose, the mean organ yield was significantly lower than in other categories, in part due to concerns about disease transmission. In this paper, we present data on the changes in donation from donors with a drug overdose as a result of the opioid epidemic and discuss the need to educate transplant candidates and their physicians about the low risk of disease transmission compared to the greater risk of dying on a transplant waitlist.

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.

Summary: Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this “balancing act” remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces the expression of the transcription factor Spic selectively in patrolling monocytes and tissue macrophages by a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, Spic downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression in activated macrophages. Notably, interferon-gamma blocks Spic expression in a STAT1-dependent manner. High levels of interferon-gamma are indicative of ongoing infection, and in its absence, activated macrophages appear to engage a “default” Spic-dependent anti-inflammatory pathway. We also provide evidence for the engagement of this pathway in sterile inflammation. Taken together, our findings uncover a pathway wherein counter-regulation of Spic by NF-κB and STATs attune inflammatory responses and iron metabolism in macrophages.

SUMMARY Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD+-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression., Graphical Abstract, In Brief Quinn et al. report that lactate has an acidity-independent suppressive effect on effector T cell proliferation mediated through a shift from NAD+ to NADH (lactate-induced reductive stress). This impairs glycolysis and glucose-derived serine production, which is required for effector T cell proliferation.

BACKGROUND: 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 post-transplant 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. METHODS: We performed a retrospective cohort study of all patients undergoing LT from 7/½014 to 6/30/2017 at a tertiary LT referral center. A nurse practitioner (NP)-based post-transplant care program with weekend in-house nurse coordination providers and increased outpatient NP clinic availability was instituted on 1/½016. Post-discharge readmission rates at 30 and 90 days were compared in the pre- and post-exposure groups, adjusting for associated risk factors. RESULTS: A total 362 patients were included in the analytic cohort. There were no significant differences in demographics, comorbidities, or index hospitalization characteristics between groups. In adjusted analyses, the risk of readmission in the post-exposure 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

Objective Surgeon-scientists are an essential component of the field of academic surgery, contributing to the fundamental understanding of disease and the discovery of innovative therapies. Despite this recognized value, the current landscape of academic medicine presents significant barriers to establishing and maintaining a successful career as a surgeon performing basic/translational research. Our objective is to define these barriers to academic success for surgeons, and to provide a consensus strategy for optimizing the chances of success. Summary background data There is a significant decline in the proportion of academic surgeons who are pursuing basic science/translational research, which represents a potential threat to the very identify of the translational surgeon-scientist. Methods Based on published literature and expert opinion, the Basic Science Committee of the Society of University of Surgeons prepared this roadmap to encourage and guide the next generation of surgeon-scientists as they embark on their academic careers. Results This roadmap highlights key elements to consider in choosing an initial job and the importance of identifying a team of committed mentors. Expectations and guidelines for the first several years in practice are offered. Conclusions With guidance and mentorship, aspiring surgeonscientists can overcome the challenges inherent in choosing this career path and sustain the important legacy of those before them.

Background Kidney transplant induction therapy often includes inpatient administration of rabbit antithymocyte globulin (rATG) over multiple days. To reduce hospital length of stay (LOS) and drug expenditures, the rATG induction course was completed in the outpatient setting via peripheral intravenous administration. The present study assesses early readmission trends ascribable to an outpatient rATG administration protocol to ensure initial reduction in hospital LOS is sustained early after discharge. Methods This was a retrospective study of kidney recipient outcomes for patients transplanted between January 1, 2008, and February 29, 2016, immediately following implementation of an outpatient rATG protocol. Readmission data within 7 days of outpatient rATG administration were collected. The relatedness of rATG administration to an adverse drug reaction resulting in readmission was determined by the World Health Organization-Uppsala Monitoring Centre Causality Assessment Scale and the Naranjo Adverse Drug Reaction Probability Scale. Results A total of 1104 patients received outpatient doses of rATG and were included. An upward trend in kidney transplant volume and outpatient rATG administrations per year was found from 2008-2015. Following protocol implementation, the percentage of overall readmissions ranged from 9% to just over 12% from 2008-2014 and remained less than 10% for 2014 through 2016. The percentage of outpatient rATG infusions that potentially led to rATG-related readmissions was less than 4% per year over the study period. A total of 1124 hospital days were saved, 125 days per year on average. Conclusions Outpatient administration of rATG is feasible, safe, and did not increase readmissions in the period directly following administration. The findings of this analysis support our continued use of the outpatient rATG protocol at our institution.

Objectives Stereotactic body radiotherapy (SBRT) is potentially curative treatment for small hepatocellular carcinomas (HCC), but data are limited on its efficacy and toxicity. We hypothesized that SBRT can achieve excellent local control (LC) with acceptable toxicity treating HCC lesions, even in advanced cirrhosis. Materials and methods Thirty-seven nonmetastatic HCC patients received SBRT to 43 lesions between October 2012 and April 2016. Median dose was 50 Gy/5 fractions. All Child-Pugh (CP) ≥B patients underwent a planned 1-month break after the first 3 fractions to assess hepatic toxicity. Patients were treated without separately placed fiducial markers using Linac-based SBRT with breath-hold (67%) or 4D-computed tomography with compression belt (33%) to reduce motion. Patients underwent magnetic resonance imaging q3 months post-SBRT. Results Median age was 65 (range, 44 to 88). Pre-SBRT mean CP was 6.4 (range, A5 to C11). Nine (24%) had CP≥B8. Thirty-one of 33 patients (93%) had prior liver-directed therapy (median 2). Seventeen (40%) had solitary lesions. Median lesion diameter was 2.7 cm (range, 1.1 to 5.6). Median follow-up was 14 months (range, 2 to 45). There was 1 local failure (multifocal HCC with 3 prior transarterial chemoembolization). LC, freedom from liver progression, and overall survival at 12 months was 95%, 66%, 87% in the full cohort, and 100%, 76%, 93% for patients with solitary lesions. Four had grade 3 toxicity (ascites [n=2]/gastrointestinal bleed [n=1]/capsular pain [n=1]). Eight of 9 CP≥B8 patients had no grade ≥3 hepatic toxicity. Conclusions SBRT for HCC is well-tolerated even in patients with advanced cirrhosis and prior liver-directed treatment and provides excellent LC even for larger lesions that cannot be controlled with radiofrequency ablation. LC with SBRT compares favorably to other liver-directed therapies. Prospective studies comparing SBRT with other liver-directed therapies are warranted.

We report that human conventional CD15+ neutrophils can be isolated in the peripheral blood mononuclear cell (PBMC) layer during Ficoll gradient separation, and that they can impair T cell proliferation in vitro without concomitant neutrophil activation and killing. This effect was observed in a total of 92 patients with organ transplants, lung cancer or anxiety/depression, and in 18 healthy donors. Although such features are typically associated in the literature with the presence of certain myeloid-derived suppressor cell (PMN-MDSC) populations, we found that commercial centrifuge tubes that contained membranes or gels for PBMC isolation led to up to 70% PBMC contamination by CD15+ neutrophils, with subsequent suppressive effects in certain cellular assays. In particular, the suppressive activity of human MDSC should not be evaluated using lectin or microbead stimulation, whereas assays involving soluble or plate-bound antibodies or MLR are unaffected. We conclude that CD15+ neutrophil contamination, and associated effects on suppressor assays, can lead to significant artefacts in studies of human PMN-MDSC.

Patients with hepatocellular carcinoma (HCC) exceeding Milan criteria on explant pathology are at increased risk of recurrence and death. Discordance between contemporary magnetic resonance imaging (MRI) and explant pathology, and preoperative characteristics predictive of discordance are not well understood.Patients who underwent orthotopic liver transplantation for HCC after preoperative MRI were identified in a prospectively collected institutional database (January 2003 to December 2013). Patients were dichotomized to "within" or "outside" Milan criteria by both imaging and explant pathologic evaluation. Binary logistic regression and Kaplan-Meier methodology were used to identify independent predictors of imaging/pathologic discordance and its impact on posttransplant survival.Of 318 patients with HCC meeting Milan criteria by MRI at the time of orthotopic liver transplantation, 248 (78.0%) remained within a pathological correlate of Milan criteria on explant examination. Understaging was associated with worse median recurrence-free survival (64.0 months vs 140.0 months, P = 0.002) and overall survival (96.0 months vs 143.0 months, P = 0.005), and did not vary between patients exceeding criteria due to tumor explant greater than 5 cm, more than 3 tumor foci, or a tumor greater than 3 cm in the setting of multifocality. Discordance was independently associated with an increasing serum alpha fetal protein level (odds ratio, 2.82; 95% confidence interval, 1.37-5.79; P = 0.005).Underestimating HCC burden before liver transplant remains frequent despite contemporary imaging technologies. Patients with an increasing alpha fetal protein before transplantation may benefit from more frequent testing or novel neoadjuvant therapies.