ObjectiveTo explore if there is an increased cancer risk associated with folic acid supplements given orally.DesignSystematic review and meta-analysis of controlled studies of folic acid supplementation in humans reporting cancer incidence and/or cancer mortality. Studies on folic acid fortification of foods were not included.Data sourcesCochrane Library, Medline, Embase and Centre of Reviews and Dissemination, clinical trial registries and hand-searching of key journals.ResultsFrom 4104 potential references, 19 studies contributed data to our meta-analyses, including 12 randomised controlled trials (RCTs). Meta-analysis of the 10 RCTs reporting overall cancer incidence (N=38 233) gave an RR of developing cancer in patients randomised to folic acid supplements of 1.07 (95% CI 1.00 to 1.14) compared to controls. Overall cancer incidence was not reported in the seven observational studies. Meta-analyses of six RCTs reporting prostate cancer incidence showed an RR of prostate cancer of 1.24 (95% CI 1.03 to 1.49) for the men receiving folic acid compared to controls. No significant difference in cancer incidence was shown between groups receiving folic acid and placebo/control group, for any other cancer type. Total cancer mortality was reported in six RCTs, and a meta-analysis of these did not show any significant difference in cancer mortality in folic acid supplemented groups compared to controls (RR 1.09, 95% CI 0.90 to 1.30). None of the observational studies addressed mortality.ConclusionsA meta-analysis of 10 RCTs showed a borderline significant increase in frequency of overall cancer in the folic acid group compared to controls. Overall cancer incidence was not reported in the seven observational studies. Prostate cancer was the only cancer type found to be increased after folic acid supplementation (meta-analyses of six RCTs). Prospective studies of cancer development in populations where food is fortified with folic acid could indicate whether fortification similar to supplementation moderately increases prostate cancer risk.

BackgroundPatients with end-stage renal disease (ESRD) are in need of renal replacement therapy as dialysis and/or transplantation. The prevalence of ESRD and, thus, the need for dialysis are constantly growing. The dialysis modalities are either peritoneal performed at home or hemodialysis (HD) performed in-center (hospital or satellite) or home. We examined effectiveness and cost-effectiveness of HD performed at different locations (hospital, satellite, and home) and peritoneal dialysis (PD) at home in the Norwegian setting.MethodsWe conducted a systematic review for patients above 18 years with end-stage renal failure requiring dialysis in several databases and performed several meta-analyses of existing literature. Mortality and major complications that required were our main clinical outcomes. The quality of the evidence for each outcome was evaluated using GRADE. Cost-effectiveness was assessed by developing a probabilistic Markov model. The analysis was carried out from a societal perspective, and effects were expressed in quality-adjusted life-years. Uncertainties in the base-case parameter values were explored with a probabilistic sensitivity analysis. Scenario analyses were conducted by increasing the proportion of patients receiving PD with a corresponding reduction in HD patients in-center both for Norway and Europian Union. We assumed an annual growth rate of 4% in the number of dialysis patients, and a relative distribution between PD and HD in-center of 30% and 70%, respectively.ResultsFrom a societal perspective and over a 5-year time horizon, PD was the most cost-effective dialysis alternative. We found no significant difference in mortality between peritoneal and HD modalities. Our scenario analyses showed that a shift toward more patients on PD (as a first choice) with a corresponding reduction in HD in-center gave a saving over a 5-year period of 32 and 10,623 million EURO, respectively, for Norway and the European Union.ConclusionsPD was the most cost-effective dialysis alternative and was comparable with HD regarding efficacy outcomes. There are significant saving potentials if more end-stage renal patients are started on PD instead of HD.

1 Measuring total plasma levels of disopyramide (DP) and the main metabolite mono‐N‐dealkyldisopyramide (MND) in patients on maintenance therapy with DP has shown concentrations of MND comparable with those of DP, with wide intersubject variations. 2 A method which permits simultaneous measurement of unbound fraction of DP and MND has been developed. 3 In healthy subjects the unbound fraction of both DP and MND was concentration dependent, i.e. increased with higher concentrations of DP or MND. 4 The plasma protein binding of DP is altered by varying concentrations of MND. Clinically relevant concentrations of MND may increase the unbound fraction of DP approximately twofold. 5 The plasma protein binding of MND is also altered by varying concentrations of DP. Variation in the concentration of DP from the lower to the upper part of the therapeutic range may cause a 1.5‐fold increase in the unbound fraction of MND. 6 In the assumed therapeutic range of 6‐15 mumol DP/L, the interpatient variance of unbound DP concentration might be ten‐fold or even higher. The present findings indicate the need for monitoring unbound drug concentrations in any attempt to establish plasma concentration/effect relationship.

ObjectiveTo assess the relative effectiveness and cost-effectiveness of seven new drugs (cobimetinib, dabrafenib, ipilimumab, nivolumab, pembrolizumab, trametinib and vemurafenib) used for treatment of patients with advanced malignant melanoma in the Norwegian setting.DesignA multiple technology assessment.PatientsPatients with advanced malignant melanoma aged 18 or older.Data sourcesA systematic search for randomised controlled trials in relevant bibliographic databases.MethodsWe performed network meta-analyses using both direct and indirect evidence with dacarbazine as a common comparator. We ranked the different treatments in terms of their likelihood of leading to the best results for each endpoint. The cost-utility analysis was based on a probabilistic discrete-time Markov cohort model. The model calculated the costs and quality-adjusted life years (QALYs) with different treatment strategies from a healthcare perspective. Sensitivity analysis was performed by means of Monte Carlo simulation.ResultsMonotherapies with a programmed cell death 1 (PD-1) immune-checkpoint-inhibitor had a higher probability of good performance for overall survival than monotherapies with ipilimumab or BRAF/MEK inhibitors. The combination treatments had all similar levels of effectiveness to the PD-1 immune-checkpoint-inhibitors.PD-1 immune-checkpoint-inhibitors are more effective and more costly compared with ipilimumab in monotherapy. Nivolumab in combination with ipilimumab had higher costs and the same level of effectiveness as the PD-1 immune-checkpoint-inhibitors in monotherapy.BRAF/MEK inhibitor combinations (dabrafenib and trametinib or vemurafenib and cobimetinib) had both similar effectiveness and cost-effectiveness; however, the combination therapies are more likely to give higher quality adjusted life year gains than BRAF or MEK inhibitor monotherapies, but to a higher cost.ConclusionsNone of the drugs investigated can be considered cost-effective at what has normally been considered a reasonable willingness-to-pay (WTP) in Norway. Price reductions (from the official list prices) in the region of 63%–84% would be necessary for these drugs to be cost-effective at a WTP of €55 850 per QALY.

Both users and health care personnel are highly satisfied with the Poison Center hotline. Even though the Norwegian health system does not necessarily save money by providing the service, the safety it provides cannot be measured in economic terms.