S. Friman

DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novorenal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C2monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft–Gault) was 63.6 ± 20.7 mL/min/1.73 m2in the CsA-ME cohort and 65.9 ± 23.1 mL/min/1.73 m2with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome.In this 6-month, open-label, randomized, multicenter study in de novo renal transplant patients, the primary safety endpoint of new-onset diabetes after transplant or impaired fasting glucose was significantly less frequent with cyclosporine microemulsion than tacrolimus, with no significant differences in short-term outcome. See also editorial by Van Hooff in this issue on page 1435. DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novorenal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C2monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft–Gault) was 63.6 ± 20.7 mL/min/1.73 m2in the CsA-ME cohort and 65.9 ± 23.1 mL/min/1.73 m2with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome. In this 6-month, open-label, randomized, multicenter study in de novo renal transplant patients, the primary safety endpoint of new-onset diabetes after transplant or impaired fasting glucose was significantly less frequent with cyclosporine microemulsion than tacrolimus, with no significant differences in short-term outcome. See also editorial by Van Hooff in this issue on page 1435.

DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). Primary endpoint: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p=0.001, p=0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p=0.016, p=0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable. DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). Primary endpoint: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p=0.001, p=0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p=0.016, p=0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.

The treatment for cholangiocarcinoma (CCA) remains a challenge because of the aggressive nature of the disease and the absence of effective treatments besides surgical resection (HR) and liver transplantation (LT). In intrahepatic CCA, HR remains the treatment of choice whereas with concomitant liver disease such as cirrhosis or primary sclerosing cholangitis (PSC), LT is the only option. Hilar CCA or Klatskin tumours have in recent decades been managed with a more aggressive surgical approach to achieve R0 resection. This approach usually involves preoperative portal embolisation, followed by liver resection – sometimes extensive and even with portal vein resection. The recent protocols that combine preoperative neoadjuvant chemoirridation and LT show promising results that need to be confirmed. The development of diagnostic modalities (tumour markers, cytology and radiology) are of the utmost importance to identify these patients at an early stage to preserve radical surgery possible. Cholangiocarcinoma (CCA) is a malignant disease of the epithelial cells in the intra- and extrahepatic bile ducts. While still a rare malignant disease, CCA is the second most common primary malignancy of the liver. The incidence is increasing; especially the incidence of intrahepatic CCA (1). The treatment of CCA is challenging as it is usually difficult to diagnose when radical surgical treatment, resection (HR) or liver transplantation (LT) is possible. The lack of effective medical treatment makes a radical surgical resection or hepatectomy the only therapeutic option. Most of the CCAs are unresectable at presentation and the prognosis for these patients is dismal.