Achieving therapeutic targets in renal anaemia: considering cost-efficacy

SUMMARY

Erythropoietin treatment for anaemia in chronic kidney disease (CKD) brings important clinical benefits, but restricted healthcare budgets necessitate value-for-money therapies, requiring economic considerations also to be taken into account when selecting a treatment regimen. Subcutaneous (SC) administration of epoetin is effective at a lower dose than intravenous (IV) administration, offering the potential for substantial reductions in costs of treatment. Unlike epoetin alfa, which is contra-indicated by the SC route in Europe in patients with CKD, epoetin beta (NeoRecormon*) can be safely and effectively given by either route. The multidose presentations of epoetin beta (Reco-Pen?, multidose vials) may provide further opportunity for dose reduction. The tolerability of SC epoetin beta is excellent and superior compared with epoetin alfa or darbepoetin alfa. Epoetin beta given once weekly is as effective as two- or three-times weekly, and the dosing frequency can be further reduced to once every 2^?weeks in patients who are stable on once-weekly dosing. Reduced dosing frequency is more convenient for the patient and may save nursing time in dialysis units. Overall, SC epoetin beta, compared with alternative treatments, may represent a cost-effective treatment option for anaemia management as it combines a well-established safety and efficacy record, favourable local tolerability, and the convenience of once-weekly dosing with the potential to reduce treatment costs by up to 30%.     

Towards offline PET monitoring of proton therapy at MedAustron

The characteristic depth-dose profile of protons traveling through material is the main advantage of proton therapy over conventional radiotherapy with photons or electrons. However, uncertainties regarding the range of the protons in human tissue prevent to exploit the full potential of proton therapy. Therefore, a non-invasive in-vivo dose monitoring is desired. At the ion beam center MedAustron in Wiener Neustadt/Austria, patient treatment with proton beams started in December 2016. A PET/CT is available in close vicinity of the treatment rooms, exclusively dedicated to offline PET monitoring directly after the therapeutic irradiation. Preparations for a patient study include workflow tests under realistic clinical conditions using two different phantoms, irradiated with protons prior to the scan in the PET/CT. GATE simulations of the C-11 production are used as basis for the prediction of the PET measurement. We present results from the workflow tests in comparison with simulation results, and by this, we demonstrate the applicability of the PET monitoring at the MedAustron facility.     

Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

精原干细胞体外转化和转分化的研究进展

精原干细胞(SSC)在睾丸曲细精管内微环境的精确调控下,只能单向分化为精子。然而,SSC可在特定条件下转化为多能干细胞,甚至直接重编程转分化为功能性终末分化细胞。该特殊潜能使其在再生和精准医学领域具有很好的运用前景。     

An Interactive RADIANCE Toolkit for Customizable CT Dose Monitoring and Reporting

The need for tools to monitor imaging-related radiation has grown dramatically in recent years. RADIANCE, a freely available open-source dose-monitoring tool, was developed in response to the need for an informatics solution in this realm. A number of open-source as well as commercial solutions have since been developed to enable radiology practices to monitor radiation dose parameters for modalities ranging from computed tomography to radiography to fluoroscopy. However, it is not sufficient to simply collect this data; it is equally important to be able to review it in the appropriate context. Most of the currently available dose-monitoring solutions have some type of reporting capability, such as a real-time dashboard or a static report. Previous versions of RADIANCE have included a real-time dashboard with pre-set screens that plot effective dose estimates according to different criteria, as well as monthly scorecards to summarize dose estimates for individuals within a radiology practice. In this work, we present the RADIANCE toolkit, a customizable reporting solution that allows users to generate reports of interest to them, summarizing a variety of metrics that can be grouped according to useful parameters. The output of the toolkit can be used for real-time dose monitoring or scheduled reporting, such as to a quality assurance committee. Making dose parameter data more accessible and more meaningful to the user promotes dose reduction efforts such as regular protocol review and optimization, and ultimately improves patient care by decreasing unnecessary radiation exposure.     

Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment

1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05 mg/kg day is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350 μg/L is proposed using a default relative source contribution for water of 20%.     

Salvage therapy for multidrug-resistant tuberculosis

Treatment of multidrug-resistant tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis resistant to both isoniazid and rifampicin, is challenging under the best of circumstances, and particularly in resource-limited settings. For patients who remain persistently sputum-culture-positive despite therapy with second-line TB drugs, treatment options are limited, especially if disease is too advanced for resective surgery. Salvage therapy refers to the design of a regimen combining new and previously used drugs in a final effort to attain sputum conversion before declaring treatment to have failed. We retrospectively evaluated the outcomes of salvage therapy in 213 Peruvian patients. Salvage regimens included a median of two new drugs (range 1–6) and nine (range 5–13) total (new plus previously used) drugs. The most frequently used new drug was moxifloxacin, followed by capreomycin, amoxicillin-clavulanate, kanamycin and clarithromycin. Culture conversion occurred in 65 (30.5%) patients. Salvage regimens that included moxifloxacin were significantly more likely to be followed by culture conversion (OR 2.2; p 0.02). Later-generation fluoroquinolones such as moxifloxacin should be used in salvage therapy but also in the initial treatment of MDR-TB, if the best clinical strategy is to use the most effective drugs when the patient has the best chance for cure. New TB drugs are most likely to be initially used in salvage patients, in conditions similar to those described here. Close bacteriological monitoring of these patients will be essential, as useful information about the best way to use these new drugs can be gained from analysis of salvage therapy cohorts.     

Glutathione S-transferase A1 (GSTA1) release,an early indicator of acute hepatic injury in mice

Three acute hepatic injury models (a CCl₄-induced model, APAP-induced model and ethanol-induced model) in mice were used to study the importance of GSTA1 in acute hepatic injury by comparison with a standard enzyme marker, alanine aminotransferase (ALT). GSTA1 release was demonstrated to be an earlier and more sensitive indicator of hepatotoxicity than was ALT. Significant increases in GSTA1 were detected at 2 h after CCl₄ exposure, while ALT was undetected at this time. GSTA1 was also a more sensitive indicator of hepatotoxicity than ALT after 6 h. In the APAP and ethanol models, GSTA1 was markedly increased earlier than ALT, at 2 h post exposure. The release of GSTA1 was significantly increased at a dose of 12.5 mg/kg (CCl₄ model), 100 mg/kg (APAP model) and 10 ml/kg (ethanol model), the lowest exposure concentration for each model. In contrast, AST release was not statistically significant. These results suggest that GSTA1 can be detected at low concentrations during the early stages of acute hepatic injury and that GSTA1 is a more sensitive and more accurate indicator than ALT.