Study protocol: PreOperative Brain Irradiation in Glioblastoma (POBIG) - A phase I trial.

Background: Glioblastoma is a high-grade aggressive neoplasm whose outcomes have not changed in decades. In the current treatment pathway, tumour growth continues and remains untreated for several weeks post-diagnosis. Intensified upfront therapy could target otherwise untreated tumour cells and improve the treatment outcome. POBIG will evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma, assessed by the maximum tolerated dose (MTD) and maximum tolerated irradiation volume (MTIV). Methods: POBIG is an open-label, dual-centre phase I dose and volume escalation trial that has received ethical approval. Patients with a new radiological diagnosis of glioblastoma will be screened for eligibility. This is deemed sufficient due to the high accuracy of imaging and to avoid treatment delay. Eligible patients will receive a single fraction of preoperative radiotherapy ranging from 6 to 14 Gy followed by their standard of care treatment comprising maximal safe resection and postoperative chemoradiotherapy (60 Gy/30 fr) with concurrent and adjuvant temozolomide). Preoperative radiotherapy will be directed to the part of the tumour that is highest risk for remaining as postoperative residual disease (hot spot). Part of the tumour will remain unirradiated (cold spot) and sampled separately for diagnostic purposes. Dose/volume escalation will be guided by a Continual Reassessment Method (CRM) model. Translational opportunities will be afforded through comparison of irradiated and unirradiated primary glioblastoma tissue. Discussion: POBIG will help establish the role of radiotherapy in preoperative modalities for glioblastoma. Trial registration: NCT03582514 (clinicaltrials.gov).

A Monte Carlo study of different LET definitions and calculation parameters for proton beam therapy.

The strongin vitroevidence that proton Relative Biological Effectiveness (RBE) varies with Linear Energy Transfer (LET) has led to an interest in applying LET within treatment planning. However, there is a lack of consensus on LET definition, Monte Carlo (MC) parameters or clinical methodology. This work aims to investigate how common variations of LET definition may affect potential clinical applications. MC simulations (GATE/GEANT4) were used to calculate absorbed dose and different types of LET for a simple Spread Out Bragg Peak (SOBP) and for four clinical PBT plans covering a range of tumour sites. Variations in the following LET calculation methods were considered: (i) averaging (dose-averaged LET (LETd) & track-averaged LET); (ii) scoring (LETdto water, to medium and to mass density); (iii) particle inclusion (LETdto all protons, to primary protons and to particles); (iv) MC settings (hit type and Maximum Step Size (MSS)). LET distributions were compared using: qualitative comparison, LET Volume Histograms (LVHs), single value criteria (maximum and mean values) and optimised LET-weighted dose models. Substantial differences were found between LET values in averaging, scoring and particle type. These differences depended on the methodology, but for one patient a difference of ∼100% was observed between the maximum LETdfor all particles and maximum LETdfor all protons within the brainstem in the high isodose region (4 keVµm-1and 8 keVµm-1respectively). An RBE model using LETdincluding heavier ions was found to predict substantially different LET-weighted dose compared to those using other LET definitions. In conclusion, the selection of LET definition may affect the results of clinical metrics considered in treatment planning and the results of an RBE model. The authors' advocate for the scoring of dose-averaged LET to water for primary and secondary protons using a random hit type and automated MSS.

Automated Monte-Carlo re-calculation of proton therapy plans using Geant4/Gate: implementation and comparison to plan-specific quality assurance measurements.

OBJECTIVES: Software re-calculation of proton pencil beam scanning plans provides a method of verifying treatment planning system (TPS) dose calculations prior to patient treatment. This study describes the implementation of AutoMC, a Geant4 v10.3.3/Gate v8.1 (Gate-RTion v1.0)-based Monte-Carlo (MC) system for automated plan re-calculation, and presents verification results for 153 patients (730 fields) planned within year one of the proton service at The Christie NHS Foundation Trust. METHODS: A MC beam model for a Varian ProBeam delivery system with four range-shifter options (none, 2 cm, 3 cm, 5 cm) was derived from beam commissioning data and implemented in AutoMC. MC and TPS (Varian Eclipse v13.7) calculations of 730 fields in solid-water were compared to physical plan-specific quality assurance (PSQA) measurements acquired using a PTW Octavius 1500XDR array and PTW 31021 Semiflex 3D ion chamber. RESULTS: TPS and MC showed good agreement with array measurements, evaluated using γ analyses at 3%, 3 mm with a 10% lower dose threshold:>94% of fields calculated by the TPS and >99% of fields calculated by MC had γ ≤ 1 for>95% of measurement points within the plane. TPS and MC also showed good agreement with chamber measurements of absolute dose, with systematic differences of <1.5% for all range-shifter options. CONCLUSIONS: Reliable independent verification of the TPS dose calculation is a valuable complement to physical PSQA and may facilitate reduction of the physical PSQA workload alongside a thorough delivery system quality assurance programme. ADVANCES IN KNOWLEDGE: A Gate/Geant4-based MC system is thoroughly validated against an extensive physical PSQA dataset for 730 clinical fields, showing that clinical implementation of MC for PSQA is feasible.

Pitfalls in the beam modelling process of Monte Carlo calculations for proton pencil beam scanning.

OBJECTIVE: Monte Carlo (MC) simulations substantially improve the accuracy of predicted doses. This study aims to determine and quantify the uncertainties of setting up such a MC system. METHODS: Doses simulated with two Geant4-based MC calculation codes, but independently tuned to the same beam data, have been compared. Different methods of MC modelling of a pre-absorber have been employed, either modifying the beam source parameters (descriptive) or adding the pre-absorber as a physical component (physical). RESULTS: After the independent beam modelling of both systems in water (resulting in excellent range agreement) range differences of up to 3.6/4.8 mm (1.5% of total range) in bone/brain-like tissues were found, which resulted from the use of different mean water ionisation potentials during the energy tuning process. When repeating using a common definition of water, ranges in bone/brain agreed within 0.1 mm and gamma-analysis (global 1%,1mm) showed excellent agreement (>93%) for all patient fields. However, due to a lack of modelling of proton fluence loss in the descriptive pre-absorber, differences of 7% in absolute dose between the pre-absorber definitions were found. CONCLUSION: This study quantifies the influence of using different water ionisation potentials during the MC beam modelling process. Furthermore, when using a descriptive pre-absorber model, additional Faraday cup or ionisation chamber measurements with pre-absorber are necessary. ADVANCES IN KNOWLEDGE: This is the first study quantifying the uncertainties caused by the MC beam modelling process for proton pencil beam scanning, and a more detailed beam modelling process for MC simulations is proposed to minimise the influence of critical parameters.

Cognitive screening tools for identification of dementia in illiterate and low-educated older adults, a systematic review and meta-analysis.

BACKGROUND: The majority of older adults with dementia live in low- and middle-income countries (LMICs). Illiteracy and low educational background are common in older LMIC populations, particularly in rural areas, and cognitive screening tools developed for this setting must reflect this. This study aimed to review published validation studies of cognitive screening tools for dementia in low-literacy settings in order to determine the most appropriate tools for use. METHOD: A systematic search of major databases was conducted according to PRISMA guidelines. Validation studies of brief cognitive screening tests including illiterate participants or those with elementary education were eligible. Studies were quality assessed using the QUADAS-2 tool. Good or fair quality studies were included in a bivariate random-effects meta-analysis and a hierarchical summary receiver operating characteristic (HSROC) curve constructed. RESULTS: Forty-five eligible studies were quality assessed. A significant proportion utilized a case-control design, resulting in spectrum bias. The area under the ROC (AUROC) curve was 0.937 for community/low prevalence studies, 0.881 for clinic based/higher prevalence studies, and 0.869 for illiterate populations. For the Mini-Mental State Examination (MMSE) (and adaptations), the AUROC curve was 0.853. CONCLUSION: Numerous tools for assessment of cognitive impairment in low-literacy settings have been developed, and tools developed for use in high-income countries have also been validated in low-literacy settings. Most tools have been inadequately validated, with only MMSE, cognitive abilities screening instrument (CASI), Eurotest, and Fototest having more than one published good or fair quality study in an illiterate or low-literate setting. At present no screening test can be recommended.

Frailty Screening in Low- and Middle-Income Countries: A Systematic Review.

OBJECTIVES: To conduct a systematic review of frailty screening tools used in low- and middle-income countries (LMICs). DESIGN: Systematic review. SETTING: LMICs, as defined by the World Bank on June 30, 2014. PARTICIPANTS: Elderly adults (as defined by the authors) living in LMICs. MEASUREMENTS: Studies were included if the population under consideration lived in a LMIC, the study involved an assessment of frailty, the study population was elderly adults, and the full text of the study was available in English. The Medline, Embase, CINAHL and PsychINFO databases were searched up to June 30, 2014. RESULTS: Seventy studies with data from 22 LMICs were included in the review. Brazil, Mexico, and China provided data for 60 of the 70 studies (85.7%), and 15 countries contributed data to only one study. Thirty-six studies used the Fried criteria to assess frailty, 20 used a Frailty Index, and eight used the Edmonton Frailty Scale; none of the assessment tools used had been fully validated for use in a LMIC. CONCLUSION: There has been a rapid increase in the number of published studies of frailty in LMICs over the last 5 years. Further validation of the assessment tools used to identify frail elderly people in LMICs is needed if they are to be efficient in identifying those most in need of health care in such settings.

Can home monitoring reduce mortality in infants at increased risk of sudden infant death syndrome? A systematic review.

AIM: To conduct a systematic review to evaluate the effectiveness of home monitoring devices in the prevention of sudden infant death syndrome (SIDS). METHODS: Systematic literature review to June 30, 2010. RESULTS: Eleven unique studies were identified. Only one of these studies involved a comparison of home monitoring with a control intervention and so could be deemed level I evidence. The remaining studies constituted level III evidence. CONCLUSIONS: There is no high-level evidence that home monitoring may be of use in preventing SIDS; further research is needed.

Visual assessment of the spine bruckel instrument, a novel status tool to reflect appearance of the spine in patients with ankylosing spondylitis.

OBJECTIVE: The Visual Assessment of the Spine Bruckel Instrument (VASBI) is a new status tool developed by the Spondylitis Association of America and the University of Toronto to reflect spinal appearance in patients with ankylosing spondylitis (AS). Our objective was to validate the VASBI according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials filter (truth, discrimination, and feasibility). METHODS: Three hundred patients with AS were asked to rate their degree of perceived spinal deformity using the VASBI. To evaluate construct validity, VASBI scores were compared with functional outcome, spinal mobility, and radiographic spinal damage. Test-retest reliability was evaluated using kappa statistic (kappa). RESULTS: Patient VASBI demonstrated strong correlation with spinal mobility (r = 0.543) and moderate correlation with functional impairment (r = 0.490) and structural damage (r = 0.309). Reliability for VASBI was very good (kappa = 0.973, p < 0.001). CONCLUSION: The VASBI is a novel tool with practical applications in a busy clinical setting as it simplifies assessment of AS spinal deformity. Our study demonstrates that the VASBI has good feasibility, construct validity, and reliability.

Intralaboratory validation of cell-free translation assay for detecting ricin toxin biological activity.

A cell-free translation (CFT) assay for determining ricin biological activity was validated. The statistical data from the validation study showed a high level of precision within and between runs of the assay. The assay was specific for determining ricin biological activity in food-based matrixes and discriminated ricin from other ribosome-inactivating proteins. The mean bias (relative error) between measured ricin concentrations of 3 validation samples and their nominal concentrations was 1.1, 6.6, and 20.3%, while the coefficient of variation (CV) was 14.1, 7.7, and 13.5%, respectively, demonstrating good precision, accuracy, and linearity. The CVs of ricin concentrations in 2 ricin-containing samples calculated from a dilution series were <5 and <12%, respectively, demonstrating very good parallelism. The analyte stability of ricin-containing samples stored for 1 month either at 4 or -20 degrees C, the stability of ricin stock solutions, and the results of assays executed by different analysts and using different luminometers were evaluated. The statistical validation data confirmed that the 4-parameter logistic equation, y = (a - d)/[1 + (x/c)b] + d, provided an accurate representation of a sigmoidal relationship between the measured response and the observed ricin concentration for the CFT assay.

Successful implementation of the National Institutes of Health Stroke Scale on a stroke/neurovascular unit.

The National Institutes of Health Stroke Scale (NIHSS) is accepted as the definitive clinical examination to assess stroke severity. This project examined barriers to implementation and NIHSS use by registered nurses on a stroke/neurovascular Unit. Staff members were surveyed to determine nurse-perceived barriers to the routine use of the NIHSS. Survey results were used to create interventions including staff education, emphasis on NIHSS assessment during interdisciplinary rounds, and use of pocket cards. When the survey was redistributed 9 months later to verify results of the quality improvement initiative and guide further interventions, NIHSS assessment had increased from 12% to 69%. NIHSS scores have been linked to an existing outcomes database to monitor acute stroke treatment and inpatient management outcomes.

Quantitative pupillometry, a new technology: normative data and preliminary observations in patients with acute head injury. Technical note.

The authors prospectively used a new hand-held point-and-shoot pupillometer to assess pupillary function quantitatively. Repetitive measurements were initially made in more than 300 healthy volunteers ranging in age from 1 to 87 years, providing a total of 2,432 paired (alternative right eye, left eye) measurements under varying light conditions. The authors studied 17 patients undergoing a variety of nonintracranial, nonophthalmological, endoscopic, or surgical procedures and 20 seniors in a cardiology clinic to learn more about the effects of a variety of drugs. Additionally, the authors carried out detailed studies in 26 adults with acute severe head injury in whom intracranial pressure (ICP) was continuously monitored. Finally, five patients suffering from subarachnoid hemorrhage were also studied. Quantitative pupillary measurements could be reliably replicated in the study participants. In healthy volunteers the resting pupillary aperture averaged 4.1 mm and the minimal aperture after stimulation was 2.7 mm, resulting in a 34% change in pupil size. Constriction velocity averaged 1.48 +/- 0.33 mm/second. Pupillary symmetry was striking in both healthy volunteers and patients without intracranial or uncorrected visual acuity disorders. In the 2,432 paired measurements in healthy volunteers, constriction velocity was noted to fall below 0.85 mm/second on only 33 occasions and below 0.6 mm/second on eight occasions (< one in 310 observations). In outpatients, the reduction in constriction velocity was observed when either oral or intravenous narcotic agents and diazepam analogs were administered. These effects were transient and always symmetrical. Among the 26 patients with head injuries, eight were found to have elevations of ICP above 20 mm Hg and pupillary dynamics in each of these patients remained normal. In 13 patients with a midline shift greater than 3 mm, elevations of ICP above 20 mm Hg, when present for 15 minutes, were frequently associated with a reduction in constriction velocity on the side of the mass effect to below 0.6 mm/second (51% of 156 paired observations). In five patients with diffuse brain swelling but no midline shift, a reduction in constriction velocities did not generally occur until the ICP exceeded 30 mm Hg. Changes in the percentage of reduction from the resting state following stimulation were always greater than 10%, even in patients receiving large doses of morphine and propofol in whom the ICP was lower than 20 mm Hg. Asymmetry of pupillary size greater than 0.5 mm was observed infrequently (< 1%) in healthy volunteers and was rarely seen in head-injured patients unless the ICP exceeded 20 mm Hg. Pupillometry is a reliable technology capable of providing repetitive data on quantitative pupillary function in states of health and disease.