Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: The CINDERELLA trial

<p>Abstract</p> <p>Background</p> <p>Treatment of patients with recurrent glioma includes neurosurgical resection, chemotherapy, or radiation therapy. In most cases, a full course of radiotherapy has been applied after primary diagnosis, therefore application of re-irradiation has to be applied cauteously. With modern precision photon techniques such as fractionated stereotactic radiotherapy (FSRT), a second course of radiotherapy is safe and effective and leads to survival times of 22, 16 and 8 months for recurrent WHO grade II, III and IV gliomas.</p> <p>Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.</p> <p>First Japanese Data on the evaluation of carbon ion radiation therapy for the treatment of primary high-grade gliomas showed promising results in a small and heterogeneous patient collective.</p> <p>Methods Design</p> <p>In the current Phase I/II-CINDERELLA-trial re-irradiation using carbon ions will be compared to FSRT applied to the area of contrast enhancement representing high-grade tumor areas in patients with recurrent gliomas. Within the Phase I Part of the trial, the Recommended Dose (RD) of carbon ion radiotherapy will be determined in a dose escalation scheme. In the subsequent randomized Phase II part, the RD will be evaluated in the experimental arm, compared to the standard arm, FSRT with a total dose of 36 Gy in single doses of 2 Gy.</p> <p>Primary endpoint of the Phase I part is toxicity. Primary endpoint of the randomized part II is survival after re-irradiation at 12 months, secondary endpoint is progression-free survival.</p> <p>Discussion</p> <p>The Cinderella trial is the first study to evaluate carbon ion radiotherapy for recurrent gliomas, and to compare this treatment to photon FSRT in a randomized setting using an ion beam delivered by intensity modulated rasterscanning.</p> <p>Trial Registration</p> <p>NCT01166308</p

Proton and carbon ion radiotherapy for primary brain tumors delivered with active raster scanning at the Heidelberg Ion Therapy Center (HIT): early treatment results and study concepts

<p>Abstract</p> <p>Background</p> <p>Particle irradiation was established at the University of Heidelberg 2 years ago. To date, more than 400 patients have been treated including patients with primary brain tumors. In malignant glioma (WHO IV) patients, two clinical trials have been set up-one investigating the benefit of a carbon ion (18 GyE) vs. a proton boost (10 GyE) in addition to photon radiotherapy (50 Gy), the other one investigating reirradiation with escalating total dose schedules starting at 30 GyE. In atypical meningioma patients (WHO °II), a carbon ion boost of 18 GyE is applied to macroscopic tumor residues following previous photon irradiation with 50 Gy.</p> <p>This study was set up in order to investigate toxicity and response after proton and carbon ion therapy for gliomas and meningiomas.</p> <p>Methods</p> <p>33 patients with gliomas (n = 26) and meningiomas (n = 7) were treated with carbon ion (n = 26) and proton (n = 7) radiotherapy. In 22 patients, particle irradiation was combined with photon therapy. Temozolomide-based chemotherapy was combined with particle therapy in 17 patients with gliomas. Particle therapy as reirradiation was conducted in 7 patients. Target volume definition was based upon CT, MRI and PET imaging. Response was assessed by MRI examinations, and progression was diagnosed according to the Macdonald criteria. Toxicity was classified according to CTCAE v4.0.</p> <p>Results</p> <p>Treatment was completed and tolerated well in all patients. Toxicity was moderate and included fatigue (24.2%), intermittent cranial nerve symptoms (6%) and single episodes of seizures (6%). At first and second follow-up examinations, mean maximum tumor diameters had slightly decreased from 29.7 mm to 27.1 mm and 24.9 mm respectively. Nine glioma patients suffered from tumor relapse, among these 5 with infield relapses, causing death in 8 patients. There was no progression in any meningioma patient.</p> <p>Conclusions</p> <p>Particle radiotherapy is safe and feasible in patients with primary brain tumors. It is associated with little toxicity. A positive response of both gliomas and meningiomas, which is suggested in these preliminary data, must be evaluated in further clinical trials.</p

Selenium uptake, translocation and speciation in wheat supplied with selenate or selenite

Selenite can be a dominant form of selenium (Se) in aerobic soils; however, unlike selenate, the mechanism of selenite uptake by plants remains unclear. Uptake, translocation and Se speciation in wheat (Triticum aestivum) supplied with selenate or selenite, or both, were investigated in hydroponic experiments. The kinetics of selenite influx was determined in short-term (30 min) experiments. Selenium speciation in the water-extractable fraction of roots and shoots was determined by HPLC-ICPMS. Plants absorbed similar amounts of Se within 1 d when supplied with selenite or selenate. Selenate and selenite uptake were enhanced in sulphur-starved and phosphorus-starved plants, respectively. Phosphate markedly increased K-m of the selenite influx. Selenate and selenite uptake were both metabolically dependent. Selenite was rapidly converted to organic forms in roots, with limited translocation to shoots. Selenomethionine, selenomethionine Se-oxide, Se-methyl-selenocysteine and several other unidentified Se species were detected in the root extracts and xylem sap from selenite-treated plants. Selenate was highly mobile in xylem transport, but little was assimilated to organic forms in 1 d. The presence of selenite decreased selenate uptake and xylem transport. Selenite uptake is an active process likely mediated, at least partly, by phosphate transporters. Selenite and selenate differ greatly in the ease of assimilation and xylem transport

Creative reminiscence as an early intervention for depression: results of a pilot project.

Reminiscence may help in resolving conflicts from the past and making up the balance of one’s life. Life-review may be further enhanced by the creative expression of memories in stories, poems or drawings. In this way people are encouraged to create and discover metaphors, images and stories that symbolically represent the subjective and inner meaning of their lives. In this article, a new intervention, which combines reminiscence and creative expression aimed at early treatment of depression, is described. A pilot project showed that the intervention Searching for the meaning in life may generate small-sized effects in reducing depression. Additionally, it appears to generate effects of medium size in enhancing mastery. Several possible ways to improve the effectiveness of the intervention are described

Determinants of selenium status in healthy adults

<p>Abstract</p> <p>Background</p> <p>Selenium (Se) status in non-deficient subjects is typically assessed by the Se contents of plasma/serum. That pool comprises two functional, specific selenoprotein components and at least one non-functional, non-specific components which respond differently to changes in Se intake. A more informative means of characterizing Se status in non-deficient individuals is needed.</p> <p>Methods</p> <p>Multiple biomarkers of Se status (plasma Se, serum selenoprotein P [SEPP1], plasma glutathione peroxidase activity [GPX3], buccal cell Se, urinary Se) were evaluated in relation to selenoprotein genotypes (GPX1, GPX3, SEPP1, SEP15), dietary Se intake, and parameters of single-carbon metabolism in a cohort of healthy, non-Se-deficient men (n = 106) and women (n = 155).</p> <p>Conclusions</p> <p>Plasma Se concentration was 142.0 ± 23.5 ng/ml, with GPX3 and serum-derived SEPP1 calculated to comprise 20% and 34%, respectively, of that total. The balance, comprised of non-specific components, accounted for virtually all of the interindividual variation in total plasma Se. Buccal cell Se was associated with age and plasma homocysteine (hCys), but not plasma Se. SEPP1 showed a quadratic relationship with body mass index, peaking at BMI 25-30. Urinary Se was greater in women than men, and was associated with metabolic body weight (kg^0.75), plasma folate, vitamin B₁₂and hCys (negatively). One <it>GPX1 </it>genotype (679T/T) was associated with significantly lower plasma Se levels than other allelic variants. Selenium intake, estimated from food frequency questionnaires, did not predict Se status as indicated by any biomarker. These results show that genotype, methyl-group status and BMI contribute to variation in Se biomarkers in Se-adequate individuals.</p

Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials

<p>Abstract</p> <p>Background</p> <p>Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.</p> <p>Methods/design</p> <p>We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.</p> <p>Discussion</p> <p>Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.</p

Prospective risk of stillbirth and neonatal complications in twin pregnancies: systematic review and meta-analysis.

OBJECTIVE: To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane databases (until December 2015). REVIEW METHODS: Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks' gestation. RESULTS: 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies) were included. In dichorionic twin pregnancies beyond 34 weeks (15 studies, 17 830 pregnancies), the prospective weekly risk of stillbirths from expectant management and the risk of neonatal death from delivery were balanced at 37 weeks' gestation (risk difference 1.2/1000, 95% confidence interval -1.3 to 3.6; I(2)=0%). Delay in delivery by a week (to 38 weeks) led to an additional 8.8 perinatal deaths per 1000 pregnancies (95% confidence interval 3.6 to 14.0/1000; I(2)=0%) compared with the previous week. In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2.5 per 1000 perinatal deaths, which was not significant (-12.4 to 17.4/1000; I(2)=0%). The rates of neonatal morbidity showed a consistent reduction with increasing gestational age in monochorionic and dichorionic pregnancies, and admission to the neonatal intensive care unit was the commonest neonatal complication. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies. CONCLUSIONS: To minimise perinatal deaths, in uncomplicated dichorionic twin pregnancies delivery should be considered at 37 weeks' gestation; in monochorionic pregnancies delivery should be considered at 36 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014007538