Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Xenografting for disease modeling of intramedullary spinal cord tumors: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: The overall incidence of intramedullary spinal cord tumors (IMSCT) remains low and clinical trials or standardized treatment strategies are missing. Therefore, multiple animal-based xenograft models (AXM) have been developed to foster preclinical research efforts on IMSCT. We constructed a systematic literature review to summarize and compare all AXM for IMSCT, published until April 16, 2018. METHODS: The review was conducted using 4 independent research databases following the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included, if they reported on surgical transplantation of tumor cells or tumor tissue to the spinal cord. Methodological study quality was assessed according to the SYRCLE (systematic review center for laboratory animal experimentation) risk of Bias tool. RESULTS: Systematic search yielded 20 publications dealing with AXM for IMSCT. In summary, 4 tumor entities were analyzed in 23 experiments using ~337 animals, mainly investigating glioblastoma or gliosarcoma biology. Studies varied regarding the use of engrafted animals, surgical techniques and tumor burden. Most commonly authors used heterotopic, transdural injection of immortalized brain tumor cell lines (1 × 105 in 5 µl) into the thoracic spinal cord of immunocompromised rats. Quality assessment demonstrated an unclear risk of bias in most cases. CONCLUSION: Although different AXM for IMSCT have been described so far, one rat model is technically feasible, enables robust experiments and demonstrates reproducible results. However, there is a need for new AXM using orthotopic engraftment of patient-derived tumor cells and for genetically engineered animal models.

11C-MET PET/MRI for detection of recurrent glioma.

INTRODUCTION: Radiological assessment of brain tumors is widely based on the Radiology Assessment of Neuro-Oncology (RANO) criteria that consider non-specific T1 and T2 weighted images. Limitation of the RANO criteria is that they do not include metabolic imaging techniques that have been reported to be helpful to differentiate treatment related changes from true tumor progression. In the current study, we assessed if the combined use of MRI and PET with hybrid 11C-MET PET/MRI can improve diagnostic accuracy and diagnostic confidence of the readers to differentiate treatment related changes from true progression in recurrent glioma. METHODS: Fifty consecutive patients with histopathologically proven glioma were prospectively enrolled for a hybrid 11C-MET PET/MRI to differentiate recurrent glioma from treatment induced changes. Sole MRI data were analyzed based on RANO. Sole PET data and in a third evaluation hybrid 11C-MET-PET/MRI data were assessed for metabolic respectively metabolic and morphologic glioma recurrence. Diagnostic performance and diagnostic confidence of the reader were calculated for the different modalities, and the McNemar test and Mann-Whitney U Test were applied for statistical analysis. RESULTS: Hybrid 11C-MET PET/MRI was successfully performed in all 50 patients. Glioma recurrence was diagnosed in 35 of the 50 patients (70%). Sensitivity and specificity were calculated for MRI (86.11% and 71.43%), for 11C-MET PET (96.77% and 73.68%), and for hybrid 11C-MET-PET/MRI (97.14% and 93.33%). For diagnostic accuracy hybrid 11C-MET-PET/MRI (96%) showed significantly higher values than MRI alone (82%), whereas no significant difference was found for 11C-MET PET (88%). Furthermore, by rating on a five-point Likert scale significantly higher scores were found for diagnostic confidence when comparing 11C-MET PET/MRI (4.26 ± 0,777) to either PET alone (3.44 ± 0.705) or MRI alone (3.56 ± 0.733). CONCLUSION: This feasibility study showed that hybrid PET/MRI might strengthen RANO classification by adding metabolic information to conventional MRI information. Future studies should evaluate the clinical utility of the combined use of 11C-MET PET/MRI in larger patient cohorts.

In vivo differentiation of human periodontal ligament cells leads to formation of dental hard tissue.

OBJECTIVE: Following trauma, periodontal disease, or orthodontic tooth movement, residual periodontal ligament (PDL) cells at the defect site are considered mandatory for successful regeneration of the injured structures. Recent developments in tissue engineering focus, as one pillar, on the transplantation of PDL cells to support periodontal regeneration processes. Here, we examined the ability of osteogenically predifferentiated PDL cells to undergo further osteoblastic or cementoblastic differentiation and to mineralize their extracellular matrix when transplanted in an in vivo microenvironment. MATERIALS AND METHODS: Using collagen sponges as carriers, osteogenically predifferentiated human PDL cells were transplanted subcutaneously into six immunocompromised CD-1® nude mice. Following explantation after 28 days, osteogenic and cementogenic marker protein expression was visualized immunohistochemically. RESULTS: After 28 days, transplanted PDL cells revealed both cellular, cytoplasmatic and extracellular immunoreactivity for the chosen markers alkaline phosphatase, osteopontin, PTH-receptor 1, and osteocalcin. Specific osteogenic and cementoblastic differentiation was demonstrated by RUNX2 and CEMP1 immunoreactivity. Early stages of mineralization were demonstrated by calcium and phosphate staining. CONCLUSION: Our results reinforce the previously published reports of PDL cell mineralization in vivo and further demonstrate the successful induction of specific osteogenic and cementogenic differentiation of transplanted human PDL cells in vivo. These findings reveal promising possibilities for supporting periodontal remodeling and regeneration processes with PDL cells being potential target cells with which to influence the process of orthodontically induced root resorption.

Simplification and first validation of a short battery of patient questionnaires for clinical management of HIV-infected patients: The HIV-SQUAD (Symptom Quality of life Adherence) Questionnaire.

PURPOSE: Questionnaires assessing patient-reported outcomes in HIV are either too long or not HIV-specific. Our aim was to develop and validate a simplified HIV patient questionnaire. METHOD: 607 HIV patients treated with a combination of antiretroviral (ARV) drugs were enrolled in an observational, longitudinal study. Questionnaires covering health-related quality of life (HRQoL), satisfaction, tolerability, and adherence were administered at baseline (BL) and Month 3 (M3). The items were selected according to their content and discriminant properties. The simplified questionnaire was then administered at Month 12 (M12). Psychometric properties of physical wellbeing, psychological well-being, and global HRQoL scores were assessed. RESULTS: The simplified questionnaire included 12 HRQoL items, 13 side-effects items, and one visual analog scale (VAS) measuring adherence. The principal component analysis (PCA) confirmed the validity of the global HRQoL score. The multivariate analysis showed acceptable-to-good internal consistency of the three scores. Convergent and discriminant validity were excellent for the physical score. The global score showed significant differences according to time since diagnosis, hepatitis coinfection, CD4 count, and viral load. CONCLUSION: This questionnaire deals with the major aspects of HIV patient perceptions. The global HRQoL score is well correlated to the surrogate markers of HIV. Such a questionnaire may represent a new tool for the therapeutic management of HIV-infected patients. Further steps are required to complete these results.

Comparative bioavailability study of zidovudine administered as two different tablet formulations in healthy adult subjects.

AIM: Zidovudine is a synthetic nucleoside analogue of thymidine with activity against the human immunodeficiency virus type 1 (HIV-1). In patients with HIV infections or the acquired immunodeficiency syndrome (AIDS), zidovudine is a first-line therapy that was shown to reduce morbidity, mortality, and hospitalization. A generic formulation of zidovudine offers the possibility of considerable savings to HIV/AIDS patients in developed and Third World countries. The objective of the current study was to characterize the pharmacokinetic and safety profiles of zidovudine administered as a generic tablet formulation relative to the innovator product. VOLUNTEERS AND METHODS: A total of 68 healthy adult volunteers received a 300 mg oral dose of zidovudine as the generic formulation (AVIRO-Z 300 mg tablet, Ranbaxy Laboratories Limited) and as the innovator product (Retrovir tablet, GlaxoSmithKline) in a randomized, 2-way crossover study. Multiple blood samples were collected over 12 hours and plasma concentrations of zidovudine were assayed using an LC/MS/MS method with an analytical range of 5.00 to 2,000 ng/ml. Pharmacokinetic parameters were calculated using non-compartmental methods. RESULTS: Mean plasma concentrations of zidovudine declined in a mono-exponential manner, with mean concentration values falling below the limit of quantitation 12 hours after administration of both formulations. Mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), mean area under the curve from time 0 to infinity (AUC(0-infinity)) and peak plasma concentrations (C(max)) of zidovudine for the generic tablet formulation (2,220.6 ng x h/ml, 2,236.0 ng x h/ml and 1,087.9 ng/ml, respectively) were very similar to those observed for the innovator product (2,139.7 ng x h/ml, 2,158.6 ng x h/ml and 1,066.5 ng/ml, respectively). Ratios of least-squares means and 90% confidence intervals of AUC(0-t) AUC(0-infinity) and C(max) between the 2 formulations were within 80-125%, suggesting that the two tablet formulations displayed similar rate and extent of bioavailability. The oral clearance (CL/F) of zidovudine for the generic and innovator formulations were 2.11 1/h/kg and 2.16 1/h/kg, respectively. For the two formulations, adverse events were similar in nature and frequency. CONCLUSION: Since the two formulations displayed similar in vivo delivery rate of zidovudine in the bloodstream, the generic tablet formulation of zidovudine developed by Ranbaxy should be equally effective as the innovator product and is expected to produce considerable cost-savings in AIDS patients worldwide.

Rapid change of quantal size in PC-12 cells detected by neural networks.

The basic building block of synaptic transmission-the number of molecules released per vesicle (quantal size (QS)) often changes with stimulation, but there is no agreement about what factors regulate it. To throw more light on this problem spontaneous quantal release was recorded amperometrically in PC-12 cells. Amperometric current spikes, representing single vesicle release, were detected by thresholding and were separated from spurious events on the basis of their amplitude and time course using a pattern recognition system based on the principal component neural network methods. The frequency of current spikes, their amplitude, quantal size, rise time and decay time were typically non-stationary, even in the absence of stimulation. Their running values changed much more than those of memoryless stationary random data with the same probability density distribution. Irrespective of how much the quantal size, rise and decay times varied, their amplitude dependence remained constant, or changed with a very different time course. In conclusion, the quantal size is highly labile in PC-12 cells. The lability does not appear to result from the changes of fusion pore dynamics or the mechanism of release of vesicular content, but because of the preferential release of large vesicles.