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A Randomized Trial of Magnesium Oxide and Oral Carbon Adsorbent for Coronary Artery Calcification in Predialysis CKD.
Sakaguchi, Y, Hamano, T, Obi, Y, Monden, C, Oka, T, Yamaguchi, S, Matsui, I, Hashimoto, N, Matsumoto, A, Shimada, K, et al
Journal of the American Society of Nephrology : JASN. 2019;(6):1073-1085
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BACKGROUND Developing strategies for managing coronary artery calcification (CAC) in patients with CKD is an important clinical challenge. Experimental studies have demonstrated that magnesium inhibits vascular calcification, whereas the uremic toxin indoxyl sulfate aggravates it. METHODS To assess the efficacy of magnesium oxide (MgO) and/or the oral carbon adsorbent AST-120 for slowing CAC progression in CKD, we conducted a 2-year, open-label, randomized, controlled trial, enrolling patients with stage 3-4 CKD with risk factors for CAC (diabetes mellitus, history of cardiovascular disease, high LDL cholesterol, or smoking). Using a two-by-two factorial design, we randomly assigned patients to an MgO group or a control group, and to an AST-120 group or a control group. The primary outcome was percentage change in CAC score. RESULTS We terminated the study prematurely after an interim analysis with the first 125 enrolled patients (of whom 96 completed the study) showed that the median change in CAC score was significantly smaller for MgO versus control (11.3% versus 39.5%). The proportion of patients with an annualized percentage change in CAC score of ≥15% was also significantly lower for MgO compared with control (23.9% versus 62.0%). However, MgO did not suppress the progression of thoracic aorta calcification. The MgO group's dropout rate was higher than that of the control group (27% versus 17%), primarily due to diarrhea. The percentage change in CAC score did not differ significantly between the AST-120 and control groups. CONCLUSIONS MgO, but not AST-120, appears to be effective in slowing CAC progression. Larger-scale trials are warranted to confirm these findings.
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Gastric and Postgastric Processing of 13C Markers Renders the 13C Breath Test an Inappropriate Measurement Method for the Gastric Emptying of Lipid Emulsions in Healthy Adults.
Parker, HL, Liu, D, Curcic, J, Ebert, MO, Schwizer, W, Fried, M, Steingoetter, A
The Journal of nutrition. 2017;(7):1258-1266
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Background: Breath tests (BTs) present an alternative gastric-emptying (GE) measure. However, their efficacy in the measurement of the GE rate of lipid emulsions (LEs) is unknown.Objective: The objective of this work was to investigate the validity of 13C BTs as a measure of fat GE rate in LEs.Methods: The lipophilic 13C octanoate (OCC) BT marker was investigated for fat GE with the hydrophilic 13C sodium acetate (ACC) and the triglyceride 13C trioctanoin (TCC) markers as comparators. Data from 2 randomized studies were combined [50 healthy participants; 25 men, mean ± SD age: 23 ± 2.8 y; mean ± SD body mass index (in kg/m2): 22.4 ± 1.7]. Each participant was given either an acid-stable LE (LE1) or an acid-unstable LE (LE4) at each visit. Twenty-three participants underwent simultaneous MRI. The effect of LEs on 13CO2 excretion profiles was determined. The BT half-emptying times (BT T50) were validated with the MRI half-emptying time of the ingested fat volume (MRI T50).Results: The effect of LEs on 13CO2 excretion depended on the properties of the 13C marker. T50 for OCC was shorter by 98 min for LE1 than for LE4 (P < 0.001). Other markers showed either no LE dependency or a longer T50 for LE1 than for LE4. No difference in T50 between OCC and ACC was detected in LE1. In LE4, the T50 was longer by 154 min (P < 0.0001). There was some concordance between MRI T50 and OCC BT T50 for LE1 (rc = 0.7). No other marker showed any concordance with fat GE. 13C-Nuclear magnetic resonance in vitro findings were compatible with changes in the kinetics of phase transfer of OCC dependent on its protonation state.Conclusions: The structure of fat present in the stomach affects 13CO2 excretion. The chemical properties of the 13C marker and their gastric and postgastric interaction with fat renders 13CO2 excretion an inappropriate measure of LE emptying in healthy adults. This trial was registered at clinicaltrials.gov as NCT02226029 and NCT02602158.
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Sex-Specific Associations between One-Carbon Metabolism Indices and Posttranslational Histone Modifications in Arsenic-Exposed Bangladeshi Adults.
Howe, CG, Liu, X, Hall, MN, Ilievski, V, Caudill, MA, Malysheva, O, Lomax-Luu, AM, Parvez, F, Siddique, AB, Shahriar, H, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2017;(2):261-269
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BACKGROUND Posttranslational histone modifications (PTHMs) are altered by arsenic, an environmental carcinogen. PTHMs are also influenced by nutritional methyl donors involved in one-carbon metabolism (OCM), which may protect against epigenetic dysregulation. METHODS We measured global levels of three PTHMs, which are dysregulated in cancers (H3K36me2, H3K36me3, H3K79me2), in peripheral blood mononuclear cells (PBMC) from 324 participants enrolled in the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults. Sex-specific associations between several blood OCM indices (folate, vitamin B12, choline, betaine, homocysteine) and PTHMs were examined at baseline using regression models, adjusted for multiple tests by controlling for the false discovery rate (PFDR). We also evaluated the effects of folic acid supplementation (400 μg/d for 12 weeks), compared with placebo, on PTHMs. RESULTS Associations between choline and H3K36me2 and between vitamin B12 and H3K79me2 differed significantly by sex (Pdiff < 0.01 and <0.05, respectively). Among men, plasma choline was positively associated with H3K36me2 (PFDR < 0.05), and among women, plasma vitamin B12 was positively associated with H3K79me2 (PFDR < 0.01). Folic acid supplementation did not alter any of the PTHMs examined (PFDR = 0.80). CONCLUSIONS OCM indices may influence PTHMs in a sex-dependent manner, and folic acid supplementation, at this dose and duration, does not alter PTHMs in PBMCs. IMPACT This is the first study to examine the influences of OCM indices on PTHMs in a population that may have increased susceptibility to cancer development due to widespread exposure to arsenic-contaminated drinking water and a high prevalence of hyperhomocysteinemia. Cancer Epidemiol Biomarkers Prev; 26(2); 261-9. ©2016 AACR.
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The effects of AST-120 on chronic kidney disease progression in the United States of America: a post hoc subgroup analysis of randomized controlled trials.
Schulman, G, Berl, T, Beck, GJ, Remuzzi, G, Ritz, E, Shimizu, M, Shobu, Y, Kikuchi, M
BMC nephrology. 2016;(1):141
Abstract
BACKGROUND The orally administered spherical carbon adsorbent AST-120 is used on-label in Asian countries to slow renal disease progression in patients with progressive chronic kidney disease (CKD). Recently, two multinational, randomized, double-blind, placebo-controlled, phase 3 trials (Evaluating Prevention of Progression in Chronic Kidney Disease [EPPIC] trials) examined AST-120's efficacy in slowing CKD progression. This study assessed the efficacy of AST-120 in the subgroup of patients from the United States of America (USA) in the EPPIC trials. METHODS In the EPPIC trials, 2035 patients with moderate to severe CKD were studied, of which 583 were from the USA. The patients were randomly assigned to two groups of equal size that were treated with AST-120 or placebo (9 g/day). The primary end point was a composite of dialysis initiation, kidney transplantation, or serum creatinine doubling. RESULTS The Kaplan-Meier curve for the time to achieve the primary end point in the placebo-treated patients from the USA was similar to that projected before the study. The per protocol subgroup analysis of the population from the USA which included patients with compliance rates of ≥67 % revealed a significant difference between the treatment groups in the time to achieve the primary end point (Hazard Ratio, 0.74; 95 % Confidence Interval, 0.56-0.97). CONCLUSIONS This post hoc subgroup analysis of EPPIC study data suggests that treatment with AST-120 might delay the time to primary end point in CKD patients from the USA. A further randomized controlled trial in progressive CKD patients in the USA is necessary to confirm the beneficial effect of adding AST-120 to standard therapy regimens. TRIAL REGISTRATION ClinicalTrials.gov NCT00500682 ; NCT00501046 .
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Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD.
Schulman, G, Berl, T, Beck, GJ, Remuzzi, G, Ritz, E, Arita, K, Kato, A, Shimizu, M
Journal of the American Society of Nephrology : JASN. 2015;(7):1732-46
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Reduced GFR in patients with CKD causes systemic accumulation of uremic toxins, which has been correlated with disease progression and increased morbidity. The orally administered spherical carbon adsorbent AST-120 reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in these patients. The multinational, randomized, double-blind, placebo-controlled Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials evaluated the effects of AST-120 on the progression of CKD when added to standard therapy. We randomly assigned 2035 adults with moderate to severe disease (serum creatinine at screening, 2.0-5.0 mg/dl for men and 1.5-5.0 mg/dl for women) to receive either placebo or AST-120 (9 g/d). The primary end point was a composite of dialysis initiation, kidney transplantation, and serum creatinine doubling. Each trial continued until accrual of 291 primary end points. The time to primary end point was similar between the AST-120 and the placebo groups in both trials (EPPIC-1: hazard ratio, 1.03; 95% confidence interval, 0.84 to 1.27; P=0.78) (EPPIC-2: hazard ratio, 0.91; 95% confidence interval, 0.74 to 1.12; P=0.37); a pooled analysis of both trials showed similar results. The estimated median time to primary end points for the placebo groups was 124 weeks for power calculations, but actual times were 189.0 and 170.3 weeks for EPPIC-1 and EPPIC-2, respectively. Thus, disease progression was more gradual than expected in the trial populations. In conclusion, the benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD is not supported by these data.
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Randomized phase II trial of hypofractionated proton versus carbon ion radiation therapy in patients with sacrococcygeal chordoma-the ISAC trial protocol.
Uhl, M, Edler, L, Jensen, AD, Habl, G, Oelmann, J, Röder, F, Jäckel, O, Debus, J, Herfarth, K
Radiation oncology (London, England). 2014;:100
Abstract
BACKGROUND Chordomas are relatively rare lesions of the bones. About 30% occur in the sacrococcygeal region. Surgical resection is still the standard treatment. Due to the size, proximity to neurovascular structures and the complex anatomy of the pelvis, a complete resection with adequate safety margin is difficult to perform. A radical resection with safety margins often leads to the loss of bladder and rectal function as well as motoric/sensoric dysfunction. The recurrence rate after surgery alone is comparatively high, such that adjuvant radiation therapy is very important for improving local control rates. Proton therapy is still the international standard in the treatment of chordomas. High-LET beams such as carbon ions theoretically offer biologic advantages in slow-growing tumors. Data of a Japanese study of patients with unresectable sacral chordoma showed comparable high control rates after hypofractionated carbon ion therapy only. METHODS AND DESIGN This clinical study is a prospective randomized, monocentric phase II trial. Patients with histologically confirmed sacrococcygeal chordoma will be randomized to either proton or carbon ion radiation therapy stratified regarding the clinical target volume. Target volume delineation will be carried out based on CT and MRI data. In each arm the PTV will receive 64 GyE in 16 fractions. The primary objective of this trial is safety and feasibility of hypofractionated irradiation in patients with sacrococygeal chordoma using protons or carbon ions in raster scan technique for primary or additive treatment after R2 resection. The evaluation is therefore based on the proportion of treatments without Grade 3-5 toxicity (CTCAE, version 4.0) up to 12 months after treatment and/or discontinuation of the treatment for any reason as primary endpoint. Local-progression free survival, overall survival and quality of life will be analyzed as secondary end points. DISCUSSION The aim of this study is to confirm the toxicity results of the Japanese data in raster scan technique and to compare it with the toxicity analysis of proton therapy given in the same fractionation. Using this data, a further randomized phase III trial is planned, comparing hypofractionated proton and carbon ion irradiation. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01811394.
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AST-120 (spherical carbon adsorbent) in the treatment of perianal fistulae in mild-to-moderate Crohn's disease: FHAST-1, a phase 3, multicenter, placebo-controlled study.
Reinisch, W, Travis, S, Hanauer, S, Wang, H, Shara, N, Harris, MS
Inflammatory bowel diseases. 2014;(5):872-81
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BACKGROUND AST-120 (spherical carbon adsorbent) was previously reported to be effective for perianal fistula healing in Japanese patients with mild-to-moderate Crohn's disease. METHODS To evaluate the efficacy and safety of AST-120 in a Western population, a phase 3, multicenter, randomized, double-blind, placebo-controlled, study (FHAST-1) was conducted in adult patients with at least 1 draining perianal fistula and a Crohn's disease activity index <400. Patients received either AST-120 or matching placebo at a dose of 2 g 3 times daily for 8 weeks. The primary endpoint was the proportion of patients with treatment success, defined as a 50% reduction in the number of draining fistulae, at both weeks 4 and 8. A multivariate model was generated to assess covariates for treatment success among baseline variables. RESULTS Two hundred forty-nine patients were randomized (AST-120; n = 122; placebo, n = 127). The proportions of patients achieving the primary endpoint were no different between treatment groups (13.9% versus 16.5%, P = 0.6). No differences in fistula response were noted at week 4 (23.0% versus 25.2%, P = 0.77) or week 8 (27.0 versus 34.6%, P = 0.22). Serum C-reactive protein concentrations >0.6 mg/dL and Crohn's disease activity index scores >151 at baseline were associated with a reduced likelihood of treatment success (odds ratio, 0.40; confidence interval, 0.19-0.87; P = 0.02; and odds ratio, 0.45; confidence interval, 0.21-0.97; P = 0.04, respectively). CONCLUSIONS In this largest placebo-controlled trial to date to evaluate the impact of a therapeutic agent on perianal fistulae in Crohn's disease, the efficacy of AST-120 could not be confirmed. An inverse relationship was observed between both inflammatory and clinical disease activity and fistula response.
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Most blood biomarkers related to vitamin status, one-carbon metabolism, and the kynurenine pathway show adequate preanalytical stability and within-person reproducibility to allow assessment of exposure or nutritional status in healthy women and cardiovascular patients.
Midttun, O, Townsend, MK, Nygård, O, Tworoger, SS, Brennan, P, Johansson, M, Ueland, PM
The Journal of nutrition. 2014;(5):784-90
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Knowledge of stability during sample transportation and changes in biomarker concentrations within person over time are paramount for proper design and interpretation of epidemiologic studies based on a single measurement of biomarker status. Therefore, we investigated stability and intraindividual vs. interindividual variation in blood concentrations of biomarkers related to vitamin status, one-carbon metabolism, and the kynurenine pathway. Whole blood (EDTA and heparin, n = 12) was stored with an icepack for 24 or 48 h, and plasma concentrations of 38 biomarkers were determined. Stability was calculated as change per hour, intraclass correlation coefficient (ICC), and simple Spearman correlation. Within-person reproducibility of biomarkers was expressed as ICC in samples collected 1-2 y apart from 40 postmenopausal women and in samples collected up to 3 y apart from 551 patients with stable angina pectoris. Biomarker stability was similar in EDTA and heparin blood. Most biomarkers were essentially stable, except for choline and total homocysteine (tHcy), which increased markedly. Within-person reproducibility in postmenopausal women was excellent (ICC > 0.75) for cotinine, all-trans retinol, cobalamin, riboflavin, α-tocopherol, Gly, pyridoxal, methylmalonic acid, creatinine, pyridoxal 5'-phosphate, and Ser; was good to fair (ICC of 0.74-0.40) for pyridoxic acid, kynurenine, tHcy, cholecalciferol, flavin mononucleotide, kynurenic acid, xanthurenic acid, 3-hydroxykynurenine, sarcosine, anthranilic acid, cystathionine, homoarginine, 3-hydroxyanthranilic acid, betaine, Arg, folate, total cysteine, dimethylglycine, asymmetric dimethylarginine, neopterin, symmetric dimethylarginine, and Trp; and poor (ICC of 0.39-0.15) for methionine sulfoxide, Met, choline, and trimethyllysine. Similar reproducibilities were observed in patients with coronary heart disease. Thus, most biomarkers investigated were essentially stable in cooled whole blood for up to 48 h and had a sufficient within-person reproducibility to allow one-exposure assessment of biomarker status in epidemiologic studies. The Western Norway B Vitamin Intervention Trial was registered at clinicaltrials.gov as NTC00354081.
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Randomised trial of proton vs. carbon ion radiation therapy in patients with chordoma of the skull base, clinical phase III study HIT-1-Study.
Nikoghosyan, AV, Karapanagiotou-Schenkel, I, Münter, MW, Jensen, AD, Combs, SE, Debus, J
BMC cancer. 2010;:607
Abstract
BACKGROUND Chordomas of the skull base are relative rare lesions of the bones. Surgical resection is the primary treatment standard, though complete resection is nearly impossible due to close proximity to critical and hence also dose limiting organs for radiation therapy. Level of recurrence after surgery alone is comparatively high, so adjuvant radiation therapy is very important for the improvement of local control rates. Proton therapy is the gold standard in the treatment of skull base chordomas. However, high-LET beams such as carbon ions theoretically offer biologic advantages by enhanced biologic effectiveness in slow-growing tumors. METHODS/DESIGN This clinical study is a prospective randomised phase III trial. The trial will be carried out at Heidelberger Ionenstrahl-Therapie centre (HIT) and is a monocentric study.Patients with skull base chordoma will be randomised to either proton or carbon ion radiation therapy. As a standard, patients will undergo non-invasive, rigid immobilization and target volume delineation will be carried out based on CT and MRI data. The biologically isoeffective target dose to the PTV in carbon ion treatment (accelerated dose) will be 63 Gy E ± 5% and 72 Gy E ± 5% (standard dose) in proton therapy respectively. Local-progression free survival (LPFS) will be analysed as primary end point. Toxicity and overall survival are the secondary end points. Additional examined parameters are patterns of recurrence, prognostic factors and plan quality analysis. DISCUSSION Up until now it was impossible to compare two different particle therapies, i.e. protons and carbon ions directly at the same facility.The aim of this study is to find out, whether the biological advantages of carbon ion therapy can also be clinically confirmed and translated into the better local control rates in the treatment of skull base chordomas. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01182779.
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Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: the CINDERELLA trial.
Combs, SE, Burkholder, I, Edler, L, Rieken, S, Habermehl, D, Jäkel, O, Haberer, T, Haselmann, R, Unterberg, A, Wick, W, et al
BMC cancer. 2010;:533
Abstract
BACKGROUND 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.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.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. METHODS DESIGN 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.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. DISCUSSION 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. TRIAL REGISTRATION NCT01166308.