Clinical Benefit-Risk Profile of Lenalidomide in Patients With Lower-risk Myelodysplastic Syndromes Without del(5q): Results of a Phase III Trial

BackgroundIn the phase III MDS-005 study of patients with lower-risk, non-del(5q) myelodysplastic syndromes, lenalidomide was associated with a higher rate of ≥ 8 weeks red blood cell transfusion independence (RBC-TI) compared with placebo, but also with a higher risk of hematologic adverse events (AEs).Patients and MethodsThis analysis evaluated the ratio of clinical benefit-risk in patients treated with lenalidomide or placebo, and assessed the effect of lenalidomide dose reductions on response. Clinical benefit was a composite endpoint defined as RBC-TI, transfusion reduction ≥ 4 units packed red blood cells, hemoglobin increase ≥ 1.5 g/dL, or cytogenetic response.ResultsThe rate of clinical benefit was higher with lenalidomide than with placebo (31.9% vs. 3.8%). The ratio of response (RBC-TI and clinical benefit) to risk (hematologic AEs) favored lenalidomide over placebo. Patients who underwent ≥ 1 lenalidomide dose reduction had a longer duration of treatment, received a higher cumulative dose, and were more likely to experience clinical benefit versus patients without dose reductions.ConclusionDespite the occurrence of hematologic AEs, the overall benefit-risk profile supported lenalidomide treatment. Appropriate management of hematologic AEs by dose reductions may help patients with myelodysplastic syndromes to remain on treatment and achieve clinical benefit.     

局部晚期非小细胞肺癌放疗剂量提升研究进展

局部晚期非小细胞肺癌的RTOG0617研究显示进一步提高放疗剂量并没有带来生存获益,这促进了剂量提升策略的改变。目前多项研究通¹⁸FDG高摄取区域局部加量、同步加量调强放疗、改变剂量分割模式等探索更为有效的剂量提升手段,并取得一系列进展。PET-CT技术及调强放疗技术的广泛应用,为放疗剂量优化和提升提供了广阔空间。     

Gamma-glutamyl transferase and risk of type II diabetes: an updated systematic review and dose-response meta-analysis

PurposeWe assessed the nature of the dose-response relationship between gamma-glutamyl transferase (GGT) levels and risk of incident type II diabetes mellitus (T2DM) in the general population.MethodsSystematic review and dose-response meta-analysis of published prospective studies. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science databases up to June 2014. We examined a potential nonlinear relationship using restricted cubic splines.ResultsOf the 300 titles reviewed, we included 24 cohort studies with data on 177,307 participants and 11,155 T2DM cases. In pooled analysis of 16 studies with relevant data, there was evidence of a nonlinear association between GGT and T2DM risk in both males (P for nonlinearity = .02) and females (P for nonlinearity = .0005). In a comparison of extreme thirds of baseline levels of GGT, relative risk for T2DM in pooled analysis of all 24 studies was 1.34 (95% confidence interval, 1.27–1.42). There was heterogeneity among the studies (P < .001), which was to a large part explained by blood sample used, study size, degree of confounder adjustment, and quality of studies.ConclusionsCirculating level of GGT contributes to an increased risk of T2DM in the general population in a nonlinear dose-response pattern.     

Design and characterization of an intracavitary ultrasound hyperthermia applicator for recurrent or residual lesions in the vaginal cuff

For evaluating the feasibility of treating recurrent lesions in the vaginal cuff by hyperthermia, a 2-element ultrasound applicator was designed, constructed and characterized. A half-cylindrical transducer ( d = 1 cm, length = 1 cm) was used to construct the 2-element ultrasound applicator. Each element of this applicator was operated at 1.5 MHz and characterized by measuring transducer efficiency and acoustic power distribution. Thermocouple probes were used to measure the temperature rise in the phantom. The element sizes used in this study were selected to be comparable to a high dose rate brachytherapy colpostat applicator. Each element was powered separately to achieve a desired temperature pattern in a target. The acoustic output power as a function of applied electric power of elements 1 and 2 were linear over this 1-40 W range and efficiencies were 32.2 &#45 3.4% and 46.2 &#45 0.8%, respectively. The temperature measurements in the phantom showed that a 6°C temperature rise was achieved 2 cm from the applicator surface. As a conclusion, the ability of the ultrasound colpostat applicator to be used for hyperthermia was demonstrated by measuring acoustic output power, ultrasound field distribution and temperature rise in the phantom. Based on the characteristics of this applicator, it has the potential to be useful for inducing hyperthermia to the vaginal cuff in the clinic.     

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.     

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.     

Carbon dioxide photolysis from 150 to 210 nm: Singlet and triplet channel dynamics,UV-spectrum,and isotope effects

We present a first principles study of the carbon dioxide (CO₂) photodissociation process in the 150- to 210-nm wavelength range, with emphasis on photolysis below the carbon monoxide + singlet channel threshold at ∼167 nm. The calculations reproduce experimental absorption cross-sections at a resolution of ∼0.5 nm without scaling the intensity. The observed structure in the 150- to 210-nm range is caused by excitation of bending motion supported by the deep wells at bent geometries in the and potential energy surfaces. Predissociation below the singlet channel threshold occurs via spin-orbit coupling to nearby repulsive triplet states. Carbon monoxide vibrational and rotational state distributions in the singlet channel as well as the triplet channel for excitation at 157 nm satisfactorily reproduce experimental data. The cross-sections of individual CO₂ isotopologues (¹²C¹⁶O₂, ¹²C¹⁷O¹⁶O, ¹²C¹⁸O¹⁶O, ¹³C¹⁶O₂, and ¹³C¹⁸O¹⁶O) are calculated, demonstrating that strong isotopic fractionation will occur as a function of wavelength. The calculations provide accurate, detailed insight into CO₂ photoabsorption and dissociation dynamics, and greatly extend knowledge of the temperature dependence of the cross-section to cover the range from 0 to 400 K that is useful for calculations of propagation of stellar light in planetary atmospheres. The model is also relevant for the interpretation of laboratory experiments on mass-independent isotopic fractionation. Finally, the model shows that the mass-independent fractionation observed in a series of Hg lamp experiments is not a result of hyperfine interactions making predissociation of ¹⁷O containing CO₂ more efficient.     

Long‐term outcomes of late course accelerated hyper‐fractionated radiotherapy for localized esophageal carcinoma in Mainland China: a meta‐analysis

Published data on the long‐term survival results of patients with localized esophageal carcinoma receiving late course accelerated hyper‐fractionated radiotherapy (LCAF RT) versus conventional fractionated radiotherapy (CF RT) are inconclusive. In order to derive a more precise estimation of the both treatment‐regimes, a meta‐analysis based on systematic review of published articles was performed. A meta‐analysis was performed using trials identified through Pubmed and Chinese national knowledge infrastructure. Results in 5‐year survival and 5‐year local control were collected from randomized trials comparing LCAF RT with CF RT. Review Manager (The Cochrane Collaboration, Oxford, England) and Stata software (Stata Corporation, College Station, TX, USA) were used for data management. A total of 11 trials were involved in this analysis with 572 cases and 567 controls. Our results showed that LCAF RT, compared with CF RT, significantly improved the 5‐year survival (odds ratio [OR]= 2.93, 95% confidence interval [CI]: 2.15–4.00, P < 0.00001) and 5‐year local control (OR = 3.96, 95% CI: 2.91–5.38, P < 0.00001). LCAF RT was more therapeutically beneficial than CF RT in the localized esophageal carcinoma.