Marwan Abouljoud

Use of Yttrium-90 Glass Microspheres (TheraSphere) for the Treatment of Unresectable Hepatocellular Carcinoma in Patients with Portal Vein Thrombosis

PURPOSE Intra-arterial injection of Yttrium-90 glass microspheres ((90)Y- microS; TheraSphere, MDS Nordion, Ottawa, Canada) is indicated for treatment of unresectable hepatocellular carcinoma (HCC) in the presence of acceptable liver function. This study presents hepatic toxicity results after unilobar and bilobar intra-arterial administration of (90)Y- microS in patients with unresectable HCC who had known portal vein thrombosis (PVT) without evidence of cavernous transformation. MATERIALS AND METHODS Fifteen patients with unresectable HCC and PVT of one or both first order and related segmental portal venous branches received a total of 29 infusions of (90)Y- microS for treatment of HCC. All patients had pretreatment evaluation including: computed tomography (CT) imaging, alpha-fetoprotein (AFP) levels, liver function tests, technetium-99m macroaggregated albumin ((99)Tc-MAA) scan for evaluation of lung and visceral shunting, and angiography with visualization into the portal venous phase. (90)Y- micro S dose was based on lobar hepatic volume with adjustment for lung shunt activity. Liver toxicity was assessed by serum total bilirubin graded for severity according to the NIH NCI Clinical Toxicity Criteria (CTC version 2.0). Other adverse events were reported according to the standards established by the Society of Interventional Radiology. RESULTS There were no procedural complications with delivery of (90)Y- microS, and treatment was well tolerated by all patients. Increased post-treatment bilirubin levels were observed across all treatments in five patients, four of whom had CT or AFP evidence of intrahepatic disease progression. After initial treatment, two patients developed bilirubin toxicity (grades 1 and 2); one patient demonstrated an increment in bilirubin toxicity grade (grade 1 to grade 3) and one patient had an improvement in grade after initial treatment. There were no new treatment-related toxicities in nine patients after a second treatment. CONCLUSIONS (90)Y- microS treatment was well tolerated and appears to be safe to use in patients with compromised portal venous flow in one or both first order and related segmental portal venous branches and no evidence of cavernous transformation. In patients who did not exhibit disease progression, there appeared to be no clinically significant change in bilirubin.

One‐Year Results with Extended‐Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients

Once‐daily tacrolimus extended‐release formulation (Prograf XL, formerly referred to as MR or MR4) was compared with the twice‐a‐day tacrolimus formulation (TAC) and cyclosporine microemulsion (CsA), all administered in combination with mycophenolate mofetil (MMF), corticosteroids and basiliximab induction, in a phase 3, randomized (1:1:1), open‐label trial in 638 de novo kidney transplant recipients. In combination with MMF and corticosteroids, XL had an efficacy profile comparable to TAC and CsA. XL/MMF and TAC/MMF were statistically noninferior at 1‐year posttransplantation to CsA/MMF for the primary efficacy endpoint, efficacy failure (death, graft loss, biopsy‐confirmed acute rejection (BCAR) or lost to follow‐up). One‐year patient and graft survival were 98.6% and 96.7% in the XL/MMF group, 95.7% and 92.9% in TAC/MMF group and 97.6% and 95.7% in CsA/MMF group. The safety profile of XL in comparison with CsA was similar to that observed with TAC in this study and consistent with previously published reports of TAC in comparison with CsA. The results support the safety and efficacy of tacrolimus in combination with MMF, corticosteroids and basiliximab induction, as well as XL as a safe and effective once‐daily dosing alternative.

Ischemia time impacts recurrence of hepatocellular carcinoma after liver transplantation

Although experimental evidence has indicated that ischemia‐reperfusion (I/R) injury of the liver stimulates growth of micrometastases and adhesion of tumor cells, the clinical impact of I/R injury on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has not been fully investigated. To study this issue, we conducted a retrospective review of the medical records of 391 patients from two transplant centers who underwent LT for HCC. Ischemia times along with other tumor/recipient variables were analyzed as risk factors for recurrence of HCC. Subgroup analysis focused on patients with HCC who had pathologically proven vascular invasion (VI) because of the associated increased risk of micrometastasis. Recurrence occurred in 60 patients (15.3%) with median time to recurrence of 0.9 years (range, 40 days‐4.6 years). Cumulative recurrence curves according to cold ischemia time (CIT) at 2‐hour intervals and warm ischemia time (WIT) at 10‐minute intervals showed that CIT >10 hours and WIT >50 minutes were associated with significantly increased recurrence (P = 0.015 and 0.036, respectively). Multivariate Coxs regression analysis identified prolonged cold (>10 hours; P = 0.03; hazard ratio [HR] = 1.9) and warm (>50 minutes; P = 0.003; HR = 2.84) ischemia times as independent risk factors for HCC recurrence, along with tumor factors, including poor differentiation, micro‐ and macrovacular invasion, exceeding Milan criteria, and alpha‐fetoprotein >200 ng/mL. Prolonged CIT (P = 0.04; HR = 2.24) and WIT (P = 0.001; HR = 5.1) were also significantly associated with early (within 1 year) recurrence. In the subgroup analysis, prolonged CIT (P = 0.01; HR = 2.6) and WIT (P = 0.01; HR = 3.23) were independent risk factors for recurrence in patients with VI, whereas there was no association between ischemia times and HCC recurrence in patients with no VI. Conclusion: Reducing ischemia time may be a useful strategy to decrease HCC recurrence after LT, especially in those with other risk factors. (Hepatology 2015;61:895–904)

The Efficacy and Limitations of Sirolimus Conversion in Liver Transplant Patients Who Develop Renal Dysfunction on Calcineurin Inhibitors

This study evaluates sirolimus in preserving renal function in 28 patients who developed renal insufficiency after liver transplantation. Patients with a creatinine level higher than 1.8 mg/ml were eligible for conversion. Of the 28 patients, 7 (25%) did not tolerate sirolimus, 6 (21%) progressed to end-stage renal disease (ESRD), and 14 (50%) have been maintained on sirolimus with stable renal function. The 28 patients overall had a decline in creatinine of 0.38 mg/dl (P D 0:029) at week 4, with a small increase by week 24. However, the subset of 14 patients who did not develop ESRD had a decline in creatinine that persisted to week 48. While the differences between those who developed ESRD and those with stable renal function were not statistically significant, the patients who developed ESRD had a higher creatinine at conversion (2.8 vs 2.3) and a lower creatinine clearance (36 vs 53 ml/min). Patients receiving sirolimus had a persistent rise in cholesterol (P < 0:05). The use of sirolimus to preserve renal function was limited by patients unable to tolerate drug (25%) and patients who developed ESRD (21%). A subgroup of patients (50%) had an improvementin creatinine that persisted for 48 weeks.

Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors

Early renal dysfunction following liver transplantation is associated with increased morbidity and mortality. To evaluate the impact of delayed initiation of calcineurin inhibitor on renal function, we conducted a retrospective study comparing 118 liver transplant recipients who received rabbit anti‐thymocyte globulin and delayed initiation of calcineurin inhibitor with 80 liver transplant recipients who received no antibody and early initiation of calcineurin inhibitor (control group). All patients received mycophenolate mofetil and steroids. Delayed calcineurin inhibitor initiation with anti‐thymocyte globulin was associated with significant improvement in renal function throughout the first year post‐transplant. At 12 months post‐transplant, patients treated with this regimen experienced lower serum creatinine (1.4 ± 0.5 versus 1.7 ± 0.5 mg/dL, P < 0.001), a higher estimated glomerular filtration rate (57.4 ± 20.5 versus 43.7 ± 14.4 mL/min/1.73 m2, P < 0.001), and less dependence on dialysis (0.8% versus 13%, P < 0.001) in comparison with no antibody and early calcineurin inhibitor initiation. Patient survival and graft survival were similar between groups; however, there was a trend of a lower incidence of early biopsy‐proven acute rejection with anti‐thymocyte globulin. Overall infection and cytomegalovirus infection were significantly lower in anti‐thymocyte globulin–treated patients, and there was no increased incidence of hepatitis C recurrence in comparison with controls. In conclusion, delayed initiation of calcineurin inhibitor with anti‐thymocyte globulin in liver transplant recipients is safe and is associated with improvements in renal function and a lower incidence of early acute rejection in comparison with no antibody and early initiation of calcineurin inhibitor. Liver Transpl 14:66–72, 2008.

Recurrence of non-alcoholic steatohepatitis and cryptogenic cirrhosis following orthotopic liver transplantation in the context of the metabolic syndrome.

Non‐alcoholic steatohepatitis (NASH) and cryptogenic cirrhosis (CC) are increasing indications for orthotopic liver transplantation (OLT). The aim of this study is to describe our outcomes and delineate predictors of recurrence of NASH and CC after OLT.

Cost-utility analysis of living-donor kidney transplantation followed by pancreas transplantation versus simultaneous pancreas-kidney transplantation

For a type I diabetic with end‐stage renal disease, the choice between a kidney‐alone transplant from a living‐donor (KA–LD) and a simultaneous pancreas–kidney (SPK) transplant remains a difficult one. The prevailing practice seems to favor KA–LD over SPK, presumably due to the superior long‐term renal graft survival in KA–LD and the elimination of the lengthy waiting time on the cadaver transplant list. In this study, two treatment options, KA–LD followed by pancreas‐after‐kidney (PAK) and SPK transplant, are compared using a cost–utility decision analysis model. The decision tree consisted of a choice between KA–LD+PAK and SPK. The analysis was based on a 5‐yr model and the measures of outcome used in the model were cost, utility and cost–utility. The expected 5‐yr cost was

Successful embolization of hepatocelluar carcinoma with yttrium-90 glass microspheres prior to liver transplantation

277 638 for KA–LD+PAK and

Mini‐incision right hepatic lobectomy with or without laparoscopic assistance for living donor hepatectomy

288 466 for SPK. When adjusted for utilities, KA–LD+PAK at a cost of

Left renal vein ligation: A technique to mitigate low portal flow from splenic vein siphon during liver transplantation

153 911 was less cost‐effective than SPK at a cost of