Economic evaluation of adverse events of dabrafenib plus trametinib versus nivolumab in patients with advanced BRAF-mutant cutaneous melanoma for adjuvant therapy in Germany.

Background: Adjuvant treatment options have become the standard therapy for stage III and IV resectable cutaneous melanoma. Two recent studies led to the registration of dabrafenib and trametinib as targeted therapies for BRAF-mutated melanoma, and of immunotherapy with nivolumab irrespective of BRAF-mutation status. Both therapies have different spectrums of adverse events. Objective: To estimate the financial impact of side effects from the perspective of the German statutory sick funds to compare both therapeutic options and to relate the burden to the overall costs of the treatment. STUDY DESIGN AND SETTING: Thirty-six adverse event categories for the combination of dabrafenib and trametinib ('combi treatment') and for nivolumab were extracted from the original publications of the studies named COMBI-AD and CheckMate 238. PATIENTS AND INTERVENTION: For all event categories a diagnosis and therapy recommendation were determined according to current national or international guidelines or from leading German textbooks. MAIN OUTCOME MEASURE: The resulting diagnostic steps, treatments, and therapies were evaluated with unit costs based on the German fee schedule for ambulatory physicians, the German G-DRG scheme, and the German drug price list. RESULTS: The number of events with nivolumab per one hundred treatments amounted to 3.8 mandatory hospitalizations, 3.5 emergency care events and 0.8 life-threatening events. For the combi treatment, the respective number of events per one hundred treatments was 2.7, 1.8, and 0.5. The overall cost burden was calculated as €899 for nivolumab and €861 for combi-treatment. CONCLUSION: The treatment of adverse events resulting from adjuvant melanoma therapy showed comparable costs for both therapies.

Interplay of the PtsN (EIIA(Ntr)) protein of Pseudomonas putida with its target sensor kinase KdpD.

The nitrogen phosphotransferase system (PTS(Ntr) ) of Pseudomonas putida is a multi-component regulatory device that participates in controlling a variety of physiological processes in a post-translational fashion. A general survey of genes regulated by PtsN exposed transcription of the kdpFABC operon is most conspicuously affected. Measurements of kdpFp promoter activity in different pts mutants showed that PtsN is responsible for repression of kdpFABC transcription. This effect could be assigned mainly to PtsN∼P, depending on the external K(+) concentration. Bacterial two-hybrid assays demonstrated that kdpFp regulation is implemented through direct interaction of the PtsN protein with the sensor kinase KdpD of the KdpD/KdpE two-component system. Interaction between KdpD and PtsN was detectable with a PtsN variant that imitates the non-phosphorylated form as well as with a PtsN type mimicking the phosphorylated form of PtsN. These results raise a regulatory scenario in which the Kdp system is regulated by the action of PtsN through direct interaction with the sensor kinase KdpD, and the outcome of such an interaction depends on the phosphorylation state of PtsN as well as on the external K(+) concentration.

Multi-objective optimization for the economic production of d-psicose using simulated moving bed chromatography.

The biocatalytic production of rare carbohydrates from available sugar sources rapidly gains interest as a route to acquire industrial amounts of rare sugars for food and fine chemical applications. Here we present a multi-objective optimization procedure for a simulated moving bed (SMB) process for the production of the rare sugar d-psicose from enzymatically produced mixtures with its epimer d-fructose. First, model parameters were determined using the inverse method and experimentally validated on a 2-2-2-2 lab-scale SMB plant. The obtained experimental purities (PUs) were in excellent agreement with the simulated data derived from a transport-dispersive true-moving bed model demonstrating the feasibility of the proposed design. In the second part the performance of the separation was investigated in a multi-objective optimization study addressing the cost-contributing performance parameters productivity (PR) and desorbent requirement (DR) as a function of temperature. While rare sugar SMB operation under conditions of low desorbent consumption was found to be widely unaffected by temperature, SMB operation focusing on increased PR significantly benefited from high temperatures, with possible productivities increasing from 3.4kg(Lday)(-1) at 20°C to 5kg(Lday)(-1) at 70°C, indicating that decreased selectivity at higher temperatures could be fully compensated for by the higher mass transfer rates, as they translate into reduced switch times and hence higher PR. A DR/PR Pareto optimization suggested a similar but even more pronounced trend also under relaxed PU requirements, with the PR increasing from 4.3kg(Lday)(-1) to a maximum of 7.8kg(Lday)(-1) for SMB operation at 50°C when the PU of the non-product stream was reduced from 99.5% to 90%. Based on the in silico optimization results experimental SMB runs were performed yielding considerable PRs of 1.9 (30°C), 2.4 (50°C) and 2.6kg(Lday)(-1) (70°C) with rather low DR (27L per kg of rare sugar produced) on a lab-scale SMB installation.