Timucin Taner

Pharmacologic, biologic, and genetic engineering approaches to potentiation of donorderived dendritic cell tolerogenicity1

There are various approaches to the enhancement of dendritic cell (DC) tolerogenicity for the promotion of cell or organ allograft survival. Both pharmacologic and biologic agents, including several commonly used immunosuppressive drugs, and specific anti-inflammatory cytokines inhibit DC maturation, whereas co-stimulation–blocking agents can also promote the induction of antigen-specific T-cell unresponsiveness by DC. Delivery of genes encoding molecules that subvert T-cell responses by various mechanisms, and targeting of DC migration by selective manipulation of chemokine and chemokine receptor expression, represent additional promising strategies. In this short review, the authors consider those approaches that have been used to promote the tolerogenicity of donor-derived DC in experimental models. Whereas most work to date has focused on myeloid DC, manipulation of other DC subsets may also offer potential for improving the outcome of transplantation and enhancing tolerance induction.

Adjunctive radiofrequency ablation of metastatic neuroendocrine cancer to the liver complements surgical resection

BACKGROUND Resection of liver metastases from neuroendocrine cancer (NEC) prolongs survival and provides durable symptom relief. Not all hepatic lesions are amenable to resection, particularly when there is multifocal involvement. In this study, it was hypothesized that ablation of concomitant non-resectable NEC liver metastases is safe and salvages patients who would not have been selected for cytoreductive surgery. METHODS   Patients who underwent adjuvant ablation of NEC liver metastases between 1995 and 2008 were reviewed. NEC was classified by patient and tumour characteristics. Regression and Kaplan-Meier models were used to compare variables and generate survival curves. RESULTS   Ninety-four patients underwent hepatic resection and intra-operative ablation of metastatic NEC. The median number of lesions ablated was 3, and median size was 1.4 cm. One abscess occurred at an ablation site. Local recurrence was detected in four patients (3.8%). Overall survival was 80% and 59% at 5 and 10 years. Age, gender, tumour type, grade, primary site and need for repeat ablation had no significant association with survival. The Ki67 proliferative index was a significant predictor of decreased survival. Symptom-free survival was 34% at 3 years and 16% at 5 years, independent of the tumour grade. CONCLUSION Concurrent ablation of NEC metastases to the liver not amenable to resection is safe and increases the candidacy of patients for cytoreductive surgery. Ablation performed intra-operatively and repeated post-operatively as needed provides significant symptom control regardless of the tumour grade.

Antibody-mediated rejection in liver transplantation: Current controversies and future directions

Interest in the role of donor‐specific human leukocyte antibodies in liver transplantation has been rekindled recently. Emerging evidence suggests that these antibodies may cause injury to the liver allograft. Here we review the clinical literature, highlight controversial results, and propose a path forward for the definition and better understanding of antibody‐mediated injury to the liver. Liver Transpl 20:514–527, 2014.

The Use of Human Acellular Dermal Matrix for Parastomal Hernia Repair in Patients with Inflammatory Bowel Disease : A Novel Technique to Repair Fascial Defects

PURPOSE: Parastomal hernias occur frequently in patients with inflammatory bowel disease who require a stoma and are associated with high recurrence rates. The tissue weakness at the site of hernia can be overcome by creating neofascia using two separate layers of human acellular dermal matrix. METHODS: Thirteen consecutive patients with inflammatory bowel disease with symptomatic parastomal hernia underwent open parastomal hernia repair at an academic tertiary referral center whereby the posterior and anterior rectus fascia at the stoma site was reconstructed with human acellular dermal matrix. Patients were followed prospectively for 290 ± 119 days (mean ± standard deviation), and data were reviewed for rate of postoperative complications, hernia recurrence, and patient satisfaction. RESULTS: Mean operative time was 233 ± 80 (range, 129-355) minutes. No intraoperative complications occurred. Average hospital stay was 8.1 ± 2.4 (range, 6-14) days. Postoperative complications included seroma formation, incisional separation (2 patients each, 15.4 percent), and superficial wound infection (1 patient, 7.7 percent). There were two cases of asymptomatic hernia recurrence as determined by computerized tomography. These patients did not require any intervention. Overall patient satisfaction with the procedure was high. CONCLUSIONS: In patients with parastomal hernia, reconstruction of the stoma site and abdominal wall with human acellular dermal matrix seems to be safe and results in high patient satisfaction.

Splenectomy for massive splenomegaly: long-term results and risks for mortality.

Objective: To evaluate long-term outcomes after splenectomy for massive splenomegaly in a series of 222 consecutive patients. Background: Splenectomy for massive splenomegaly (>1500 g) provides palliation but is associated with a high rate of perioperative complications in a population of patients with advanced hematological malignancies. Predictive factors for survival and whether the palliative goals are achieved in the long-term are not well defined. Methods: Patients with various hematological disorders who underwent splenectomy between 1998 and 2009 were followed until death or for at least 2 years. Linear and logistic regression analyses were used to ascertain the impact of demographical factors, diagnoses, and preoperative transfusion parameters on the postoperative survival. Results: Splenectomy for massive splenomegaly was performed most commonly for non-Hodgkin lymphoma (48%) and myeloid metaplasia (31%). Mean ± standard deviation splenic weight was 2731 ± 1393 g (range, 1500–13,085 g). Average operating time was 115 minutes, with a range from 46 to 346 minutes. Thirty-day mortality was 1.8%, and the complication rate was 20%. The most common complications were hemorrhage (9%) and portal venous thrombosis (9.9%). Relief from pressure-related symptoms was achieved in 98.5%, and durable remission of anemia and thrombocytopenia persisted in half of the patients at 2 years. Sex, age, and intraoperative blood loss were not significantly associated with survival. Preoperative need for red blood cell and platelet transfusions were the most significant risk factors associated with decreased survival. Conclusions: Splenectomy for massive splenomegaly can be performed safely and offers durable palliation. Preoperative transfusion requirement is an indicator of hematological disease severity and predictor of decreased survival.

Compensatory hypertrophy of the remaining kidney in medically complex living kidney donors over the long term.

Background The criteria for living kidney donation are changing, resulting in increased numbers of individuals with risk factors being accepted as donors. The long-term function and volume changes in the remaining kidney of these medically complex donors remain largely unknown. Methods Living kidney donors with three separate risk factors (older age, obesity, or hypertension) were reevaluated 5 years after donation. The function and volume of the remaining kidney were assessed and compared to those of standard donors. Results The body size correlated significantly with the kidney size and glomerular filtration rate (GFR) at the time of donation. Five years after donation, the remaining kidney size increased by a mean of 29.3%, and the GFR by 35.6%. The increase in GFR was uniform. In univariate analysis, neither the changes in the size nor the changes in the 1GFR were found to be associated with the risk factors. Conclusion Medically complex living donors demonstrate similar compensatory increase in function and volume of the remaining kidney compared to standard donors, 5 years after donation.

Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart–Liver Transplantation

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart–liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune‐mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol‐ and indication‐specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell–mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor‐specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody‐mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0–0.02; p < 0.0001), antibody‐mediated rejection (OR 0.04, 95% CI 0–0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07–0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report

The presence of preexisting (memory) or de novo donor‐specific HLA antibodies (DSAs) is a known barrier to successful long‐term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state‐of‐the‐art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.

Unique molecular changes in kidney allografts after simultaneous liver-kidney compared with solitary kidney transplantation

Kidney allografts transplanted simultaneously with liver allografts from the same donor are known to be immunologically privileged. This is especially evident in recipients with high levels of donor-specific anti-HLA antibodies. Here we investigated the mechanisms of livers protective impact using gene expression in the kidney allograft. Select solitary kidney transplant or simultaneous liver-kidney transplant recipients were retrospectively reviewed and separated into four groups: 16 cross-match negative kidney transplants, 15 cross-match positive kidney transplants, 12 cross-match negative simultaneous liver-kidney transplants, and nine cross-match-positive simultaneous liver-kidney transplants. Surveillance biopsies of cross-match-positive kidney transplants had increased expression of genes associated with donor-specific antigens, inflammation, and endothelial cell activation compared to cross-match-negative kidney transplants. These changes were not found in cross-match-positive simultaneous liver-kidney transplant biopsies when compared to cross-match-negative simultaneous liver-kidney transplants. In addition, simultaneously transplanting a liver markedly increased renal expression of genes associated with tissue integrity/metabolism, regardless of the cross-match status. While the expression of inflammatory gene sets in cross-match-positive simultaneous liver-kidney transplants was not completely reduced to the level of cross-match-negative kidney transplants, the downstream effects of donor-specific anti-HLA antibodies were blocked. Thus, simultaneous liver-kidney transplants can have a profound impact on the kidney allograft, not only by decreasing inflammation and avoiding endothelial cell activation in cross-match-positive recipients, but also by increasing processes associated with tissue integrity/metabolism by unknown mechanisms.

Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. The aim of this study was to analyze the long‐term outcomes for obese patients undergoing LT, including a noninvasive weight loss program and combined LT and sleeve gastrectomy (SG). Since 2006, all patients referred for LT with a body mass index (BMI) ≥35 kg/m2 were enrolled. Patients who achieved weight loss (BMI <35) underwent LT alone, and those who did not underwent simultaneous LT + SG. Analysis of long‐term outcomes for patients ≥3 years posttransplant was performed. Since 2006, there were 36 in the weight loss intervention (LT cohort) and 13 in the LT + SG cohort with >3 years of follow‐up, whereas overall, a total of 29 patients underwent LT + SG. Patients in the LT cohort had less severe obesity at enrollment (40.0 ± 2.7 vs. LT + SG cohort 46.0 ± 4.5; P < 0.001). In the LT cohort, 83.3% (30 of 36) achieved >10% loss in total body weight (TBW) pre‐LT. Three years posttransplant, 29.4% of patients in the LT cohort maintained >10% loss in TBW, whereas 100% of the LT + SG patients did (P < 0.001). Patients who underwent LT + SG maintained a significantly higher percentage of total body weight loss after 3 years of follow‐up (LT cohort 3.9 ± 13.3% vs. LT + S G cohort 34.8 ± 17.3%; P < 0.001). Patients in the LT + SG also had a lower prevalence of hypertension, insulin resistance, and hepatic steatosis and required fewer antihypertensive medications and lipid agents at last follow‐up. Conclusion: Whereas weight loss before transplantation was achieved by obese patients, weight regain was common in the LT cohort. Combined LT + SG resulted in more effective and more durable weight loss, as well as fewer metabolic complications at last follow‐up. (Hepatology 2018).