John Ramage

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.

Intractable liver allograft rejection remains an important cause of graft loss. In this present study, we evaluated the role of oral FK 506 in 30 rejection episodes resistant to conventional cyclosporin-based triple immunosuppression in a series of 28 patients. Rejection was reversed in 11 (91.7%) of 12 patients for intractable acute rejection and in 10 (58.8%) of 17 patients for chronic rejection. A progressive decline in serum bilirubin was observed within 14 days in those successfully salvaged and a serum bilirubin of less than 200 micromol/l at the time of FK 506 conversion in the chronic rejection subgroup was found to be good predictor of response (specificity 100%, sensitivity 60%). New onset diabetes mellitus (29%) and reversible renal impairment (32%) were the commonest adverse events observed. Eleven (52%) of the responding patients successfully discontinued corticosteroid medication and are currently on FK 506 monotherapy. FK 506 therapy has a significant impact in the control of both intractable acute and chronic allograft rejection with an acceptable toxicity profile.

Results: There were six females and four males (age range 24–56) with onset of post-transplant lymphoproliferative disorder-symptoms ranging from 3 to 72 months post transplant. Sites of post-transplant lymphoproliferative disorder included liver (n=4), lymph nodes (n=5), ...

Clinicians use fibrosis in a liver biopsy to predict clinical outcomes of chronic liver disease. The performance of non-invasive tests has been evaluated against histological assessment of fibrosis but use of clinical outcomes as the reference standard would be ideal. The enhanced liver fibrosis (ELF) test was derived and validated in a large cohort of patients and shown to have high diagnostic accuracy (area under the curve (AUC)=0.80 95% CI 0.76 to 0.85) in identification of significant fibrosis on biopsy. To evaluate ELF performance in predicting clinical outcomes by following up the original ELF cohort. Patients recruited to the ELF study at seven English centres were followed up for liver morbidity and mortality by examination of clinical data. Defaulting/discharged patients were followed up by family practitioner questionnaires. Primary outcome measure was liver-related morbidity/liver-related death. 457 patients were followed up (median 7 years), with ascertainment of clinical status in 92%. There were 61 liver-related outcomes (39 deaths). Survival analysis showed that the ELF score predicts liver outcomes, with people having the highest ELF scores being significantly more likely to have clinical outcomes than those in lower-score groups. A Cox proportional hazards model showed fully adjusted HRs of 75 (ELF score 12.52-16.67), 20 (10.426-12.51) and 5 (8.34-10.425) compared with patients with ELF <8.34. A unit change in ELF is associated with a doubling of risk of liver-related outcome. An ELF test can predict clinical outcomes in patients with chronic liver disease and may be a useful prognostic tool in clinical practice.