Giovanna Saracino

Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells

Cancer vaccines aim at inducing (a) tumor-specific effector T cells able to reduce/eliminate the tumor mass, and (b) long-lasting tumor-specific memory T cells able to control tumor relapse. We have shown earlier, in 18 human histocompatibility leukocyte antigen (HLA)-A*0201 patients with metastatic melanoma, that vaccination with peptide-loaded CD34–dendritic cells (DCs) leads to expansion of melanoma-specific interferon γ–producing CD8+ T cells in the blood. Here, we show in 9 out of 12 analyzed patients the expansion of cytolytic CD8+ T cell precursors specific for melanoma differentiation antigens. These precursors yield, upon single restimulation with melanoma peptide–pulsed DCs, cytotoxic T lymphocytes (CTLs) able to kill melanoma cells. Melanoma-specific CTLs can be grown in vitro and can be detected in three assays: (a) melanoma tetramer binding, (b) killing of melanoma peptide–pulsed T2 cells, and (c) killing of HLA-A*0201 melanoma cells. The cytolytic activity of expanded CTLs correlates with the frequency of melanoma tetramer binding CD8+ T cells. Thus, CD34-DC vaccines can expand melanoma-specific CTL precursors that can kill melanoma antigen–expressing targets. These results justify the design of larger follow-up studies to assess the immunological and clinical response to peptide-pulsed CD34-DC vaccines.

Preoperative and perioperative predictors of the need for renal replacement therapy after orthotopic liver transplantation

Background. Acute renal failure developing after orthotopic liver transplantation (OLTx) requiring renal replacement heralds a poor prognosis. Our center has previously reported a 1-year survival of only 41.8%. We undertook this study to determine whether we could identify preoperative and perioperative factors that would predict which patients are at risk. Methods. OLTxs performed between January 1, 1996, and December 31, 2001, were included in our retrospective database review. Combined kidney-liver transplants or patients with preoperative renal replacement therapy (RRT) were excluded. A total of 724 OLTxs were studied, which were divided into group I: no RRT, n=637; group II: hemodialysis only post-OLTx, n=17; and group III: continuous RRT post-OLTx, n=70. Univariate and stepwise logistic multivariate analyses were performed. Results. Preoperative serum creatinine greater than 1.9 mg/dL (odds ratio [OR] 3.57), preoperative blood urea nitrogen greater than 27 mg/dL (OR 2.68), intensive care unit stay more than 3 days (OR 10.23), and Model for End-Stage Liver Disease score greater than 21 (OR 2.5) were significant. A clinical prediction model was constructed: probability of requiring dialysis posttransplant=(−2.4586+1.2726 [creatinine >1.9] + 0.9858 [blood urea nitrogen >27] + 0.4574 [Model for End-Stage Liver Disease score >21] + 1.1625 [intensive care unit days >3]). A clinical prediction rule for patients with a score greater than 0.12 was applied to OLTx recipients who underwent transplantation in 2002. A total of 15 of 20 patients who received RRT and 111 of 121 who did not were correctly classified with the model. Conclusions. This model allowed us to identify patients at high risk for developing the need for RRT postoperatively. Strategies for these patients to prevent or ameliorate acute renal failure and reduce the need for RRT postoperatively are needed.

Role of magnetic resonance elastography in compensated and decompensated liver disease

BACKGROUND & AIMS Non-invasive predictors identifying subjects with compensated liver disease at highest risk for transitioning to a decompensated state are lacking. We hypothesized that liver shear stiffness as measured by magnetic resonance elastography is an important non-invasive predictor of hepatic decompensation. METHODS Among patients with advanced fibrosis undergoing magnetic resonance elastography (2007-2011), a baseline cohort and follow up cohort (compensated liver disease) were established. Cause specific cox proportional hazards analysis adjusting for competing risks was utilized to determine the association between elevated liver shear stiffness and development of decompensation (hepatic encephalopathy, ascites, variceal bleeding). RESULTS In the baseline cohort (n=430), subjects with decompensated liver disease had a significantly higher mean liver shear stiffness (6.8kPa, IQR 4.9-8.5) as compared to subjects with compensated liver disease (5.2kPa, IQR 4.1-6.8). After adjustment for Model for End Stage Liver Disease score, hepatitis C, age, gender, albumin, and platelet count, the mean liver shear stiffness (OR=1.13, 95% CI 1.03-1.27) was independently associated with decompensated cirrhosis at baseline. Over a median follow up of 27months (n=167), 7.2% of subjects with compensated disease experienced hepatic decompensation. In the follow up cohort, the hazard of hepatic decompensation was 1.42 (95% CI 1.16-1.75) per unit increase in liver shear stiffness over time. The hazard of hepatic decompensation was 4.96 (95% CI 1.4-17.0, p=0.019) for a subject with compensated disease and mean LSS value ⩾5.8kPa as compared to an individual with compensated disease and lower mean LSS values. CONCLUSION Baseline liver shear stiffness assessed by magnetic resonance elastography is independently associated with decompensated liver disease.

Report of a Phase II Study of Clofarabine and Cytarabine in De Novo and Relapsed and Refractory AML Patients and in Selected Elderly Patients at High Risk for Anthracycline Toxicity

PURPOSE To determine the efficacy and safety of clofarabine and cytarabine (Ara-C) in adult patients with relapsed or refractory acute myeloid leukemia (AML) and in elderly patients with untreated AML and heart disease. PATIENTS AND METHODS Patients with relapsed/refractory AML and older patients for whom there was a concern over toxicity from additional anthracyclines received 5 days of clofarabine, 40 mg/m(2) per day i.v. over 1 hour, followed 4 hours later by Ara-C, 1,000 mg/m(2) per day i.v. over 2 hours. RESULTS Thirty patients were enrolled. The median age was 67 years (range, 38-82 years) and 18 (60%) had received at least one prior therapy. Eleven (37%) patients had a history of cardiovascular disease and were considered to be at high risk for anthracycline toxicity. High-risk cytogenetic abnormalities were present in 14 (47%) patients. The overall response rate (complete remission [CR] plus partial remission) was 53%, including a CR in 14 patients (47%). Responses were observed in all cytogenetic risk groups and in patients who had received up to five prior therapies. The median disease-free survival interval was 9.5 months. The 30-day mortality rate was 20% (de novo AML, 8%; relapsed/refractory AML, 28%). Of the 14 patients achieving a CR, half were able to proceed to curative hematopoietic stem cell transplantation. CONCLUSIONS Clofarabine in combination with Ara-C is effective in both untreated and previously treated patients with AML. In addition, it represents a useful remission induction strategy to serve as a bridge to transplantation in older patients with AML.

Sirolimus and cardiovascular disease risk in liver transplantation.

Background Two adverse effects of sirolimus are hypertriglyceridemia and hypercholesterolemia. These elevated levels often lead clinicians to discontinue the sirolimus from concerns of an increased cardiovascular disease (CVD) risk; however, evidence suggests that sirolimus might be cardioprotective. There are no published reports of sirolimus CVD in liver transplantation. Methods We reviewed all 1812 liver recipients who underwent transplantation from 1998 to 2010, identifying a cohort using sirolimus as part of the initial immunosuppression (SRL Cohort) and a control group of the remaining patients from this period where SRL was never given (Non-SRL Control). A prospectively maintained database identified all episodes of myocardial infarction (MI), congestive heart failure (CHF), abdominal aortic aneurysm (AAA), and cerebrovascular accident and tracked triglyceride, high-density and low-density lipoproteins, and total cholesterol levels. A Framingham Risk Model calculated the predicted 10-year risk of CVD for both groups. Results The SRL Cohort (n=406) is older, more predominantly male, with more pretransplantation hypertension and diabetes and posttransplantation hypertension compared to Non-SRL Controls (n=1005). The SRL Cohort has significantly higher triglyceride, low-density lipoprotein, and cholesterol levels at 6 months and 1 year. There is no difference in MI incidence in the SRL Cohort (1.0% vs. 1.2%) and no difference in AAA, cerebrovascular accident, and CHF. The Framingham Risk Model predicts that the SRL Cohort should have almost double the 10-year risk of CVD compared to the Non-SRL Control (11% vs. 6%). Conclusions Sirolimus causes hypertriglyceridemia and hypercholesterolemia, but it does not increase the incidence of MI or other CVDs. Considering the SRL Cohort has more cardiac risk factors and nearly double 10-year predicted CVD risk, the fact that the CVD incidence is similar suggests that sirolimus is in fact cardioprotective.

Application of the International Society for Heart and Lung Transplantation (ISHLT) criteria for primary graft dysfunction after cardiac transplantation: outcomes from a high-volume centre

OBJECTIVES A standardized definition for primary graft dysfunction (PGD) after cardiac transplantation was recently proposed by the International Society of Heart and Lung Transplantation (ISHLT). We sought to characterize the outcomes associated with and identify risk factors for PGD following cardiac transplantation using these criteria at a high volume centre. METHODS Donor and recipient medical records of 201 consecutive adult cardiac transplantations performed between November 2012 and March 2015 were retrospectively reviewed. Patients undergoing isolated heart transplantation were diagnosed with none, mild, moderate, or severe PGD using ISHLT criteria. Cumulative survival was calculated according to the Kaplan–Meier method. Associations of risk factors for combined moderate/severe PGD were assessed with univariate and multivariate analyses. RESULTS A total of 191 consecutive patients underwent isolated heart transplantation, and 59 (30%) met ISHLT criteria for PGD: 35 (18%) mild, 8 (4%) moderate and 16 (8%) severe. Thirty-day/in-hospital mortality occurred in six (3%) patients, all of whom were diagnosed with severe PGD. Patients with moderate/severe PGD also had significantly increased intensive care unit length of stay (LOS), total LOS, reoperations for bleeding and postoperative infections. Survival at 1-year was diminished with increasing severity of PGD (none 93%, mild 94%, moderate 75% and severe 44%; log-rank P < 0.001). Elevated preoperative creatinine, pretransplantation hospitalized recipient and undersized donor were independently predictive of moderate/severe PGD. CONCLUSIONS A diagnosis of PGD portends worse outcomes including increased 30-day and 1-year mortality. The ISHLT diagnostic criteria for moderate and severe PGD identify and discriminate patients with PGD in a clinically relevant manner.

Ratio of hepatic arterial flow to recipient body weight predicts biliary complications after deceased donor liver transplantation

OBJECTIVES Adequate hepatic arterial (HA) flow to the bile duct is essential in liver transplantation. This study was conducted to determine if the ratio of directly measured HA flow to weight is related to the occurrence of biliary complications after deceased donor liver transplantation. METHODS A retrospective review of 2684 liver transplants carried out over a 25-year period was performed using data sourced from a prospectively maintained database. Rates of biliary complications (biliary leaks, anastomotic and non-anastomotic strictures) were compared between two groups of patients with HA flow by body weight of, respectively, <5 ml/min/kg (n = 884) and ≥5 ml/min/kg (n = 1800). RESULTS Patients with a lower ratio of HA flow to weight had higher body weight (92 kg versus 76 kg; P < 0.001) and lower HA flow (350 ml/min versus 550 ml/min; P < 0.001). A lower ratio of HA flow to weight was associated with higher rates of biliary complications at 2 months, 6 months and 12 months (19.8%, 28.2% and 31.9% versus 14.8%, 22.4% and 25.8%, respectively; P < 0.001). CONCLUSIONS A ratio of HA flow to weight of < 5 ml/min/kg is associated with higher rates of biliary complications. This ratio may be a useful parameter for application in the prevention and early detection of biliary complications.

Significance of measured intraoperative portal vein flows after thrombendvenectomy in deceased donor liver transplantations with portal vein thrombosis

Adequate portal vein (PV) flow in liver transplantation is essential for a good outcome, and it may be compromised in patients with portal vein thrombosis (PVT). This study evaluated the impact of intraoperatively measured PV flow after PV thrombendvenectomy on outcomes after deceased donor liver transplantation (DDLT). The study included 77 patients over a 16‐year period who underwent PV thrombendvenectomy with complete flow data. Patients were classified into 2 groups: high PV flow (>1300 mL/minute; n = 55) and low PV flow (≤1300 mL/minute; n = 22). Postoperative complications and graft survival were analyzed according to the PV flow. The 2 groups were similar in demographic characteristics. Low PV flow was associated with higher cumulative rates of biliary strictures (P = 0.02) and lower 1‐, 2‐, and 5‐year graft survival (89%, 85%, and 68% versus 64%, 55%, and 38%, respectively; P = 0.002). There was no difference in the incidence of postoperative PVT between the groups (1.8% versus 9.1%; P = 0.19). No biliary leaks or hepatic artery thromboses were reported in either group. By multivariate analyses, age >60 years (hazard ratio [HR], 3.04, 95% confidence interval [CI], 1.36‐6.82; P = 0.007) and low portal flow (HR, 2.31; 95% CI, 1.15‐4.65; P = 0.02) were associated with worse survival. In conclusion, PV flow <1300 mL/minute after PV thrombendvenectomy for PVT during DDLT was associated with higher rates of biliary strictures and worse graft survival. Consideration should be given to identifying reasons for low flow and performing maneuvers to increase PV flow when intraoperative PV flows are <1300 mL/minute. Liver Transplantation 23 1032–1039 2017 AASLD.

Clinical effectiveness of a pylorus-preserving procedure on total pancreatectomy with islet autotransplantation.

BACKGROUND The impact of pylorus preserving procedures (PP) on total pancreatectomy with islet autotransplantation (TPIAT) has not been examined. This study aimed to investigate the clinical impact of the PP on TPIAT. METHODS The Baylor Simmons Transplant Institute database was queried to identify seventy-three patients who underwent TPIAT from 2006 to 2014. All patients were investigated in postoperative complications, long-term nutritional status, and graft function. RESULTS Patients with PP did not face worse outcomes in terms of delayed gastric emptying and length of hospital stay. Also, nutritional status and metabolic outcome, such as body weight, serum albumin level, serum vitamin level, HbA1c level, graft survival rate and insulin independent rate, were similar between both groups. CONCLUSIONS Clinical results including the graft function indicated that patients undergoing TPIAT with PP did not amplify surgical complications such as delayed gastric emptying and showed no significant advantage of nutrition and metabolic outcome.

Low measured hepatic artery flow increases rate of biliary strictures in deceased donor liver transplantation: An age dependent phenomenon.

BackgroundThis study was conducted to determine effect of lower measured hepatic arterial (HA) flow (<400 mL/min) on biliary complications and graft survival after deceased donor liver transplantation. Hepatic artery is the main blood supply to bile duct and lack of adequate HA flow is thought to be a risk factor for biliary complications. MethodsA retrospective review of 1300 patients who underwent deceased donor liver transplantation was performed. Patients with arterial complications were excluded to eliminate potential contribution to biliary complications from HA thrombosis. Patients were divided into low (<400 mL/min; N = 201) and high (≥400 mL/min; N = 1099) HA flow groups. Incidence of biliary complications and graft survival were analyzed. ResultsHA flows less than 400 mL/min were associated with increased rate of biliary strictures in younger donors (<50 years old), and in patients with duct-to-duct anastomoses (P = 0.028). Lower HA flows were associated with decreased graft survival (P = 0.013). Donor older than 50 years was associated with increased rate of biliary strictures (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.14-2.45; P = 0.0085) and graft failure (HR, 1.68; 95% CI, 1.35-2.1; P <0.0001) on multivariate analyses. HA flow less than 400 mL/min was associated with biliary strictures (HR, 1.53; 95% CI, 1.04-2.24; P = 0.0297) on univariate analysis only. ConclusionsHA flow less than 400 mL/min was associated with higher rate of biliary strictures in younger donors with duct-to-duct reconstruction and lower graft survival. A consideration should be given to increase the intraoperative HA flow to prevent biliary strictures in such patients.