EFOMP policy statement 18: Medical physics education for the non-physics healthcare professions.

Although Medical Physics educators have historically contributed to the education of the non-physics healthcare professions, their role was not studied in a systematic manner. In 2009, EFOMP set up a group to research the issue. In their first paper, the group carried out an extensive literature review regarding physics teaching for the non-physics healthcare professions. Their second paper reported the results of a pan-European survey of physics curricula delivered to the healthcare professions and a Strengths-Weaknesses-Opportunities-Threats (SWOT) audit of the role. The group's third paper presented a strategic development model for the role, based on the SWOT data. A comprehensive curriculum development model was subsequently published, whilst plans were laid to develop the present policy statement. This policy statement presents mission and vision statements for Medical Physicists teaching non-physics users of medical devices and physical agents, best practices for teaching non-physics healthcare professionals, a stepwise process for curriculum development (content, method of delivery and assessment), and summary recommendations based on the aforementioned research studies.

Inhalation anesthesia and shielding devices to allow accurate preclinical irradiation of mice with clinical linac-based systems: Design and dosimetric characteristics.

This technical note describes two devices to enable accurate irradiation of mice on clinical linac-based systems. To study the effects of radiation in murine, preclinical animal models, controlled and accurate dosing is important. This is not only important when specific volumes need to be irradiated, but also when the whole animal body is irradiated. To enable both purposes, we designed two devices. One device to administer Total Body Irradiation (TBI) simultaneously to six, free walking mice, and a second device, denoted as target box, in which we irradiate specific parts of the mice whilst organs-at-risk (OAR) are protected. In this latter device, we can position the mice in multiple ways. One configuration allows to sedate twelve mice simultaneously by isoflurane inhalation anesthesia and protect the body by lead shielding to allow radiation of the head only. Alternatively, the target box can be used to sedate maximal 4 mice simultaneously to irradiate the flank or paws only. All these setups allow high experimental throughput and thus a minimal occupation of the clinical equipment. As measured, the delivered radiation dosages in the regions of interest were accurate for both devices. In this technical note, we describe the design and build of these devices.

IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis.

Leukemic stem cells (LSCs) are thought to be the major cause of the recurrence of acute myeloid leukemia (AML) due to their potential for self-renewal. To identify therapeutic strategies targeting LSCs, while sparing healthy hematopoietic stem cells (HSCs), we performed gene expression profiling of LSCs, HSCs, and leukemic progenitors all residing within the same AML bone marrow and identified insulin-like growth factor-binding protein 7 (IGFBP7) as differentially expressed. Low IGFBP7 is a feature of LSCs and is associated with reduced chemotherapy sensitivity. Enhancing IGFBP7 by overexpression or addition of recombinant human IGFBP7 (rhIGFBP7) resulted in differentiation, inhibition of cell survival, and increased chemotherapy sensitivity of primary AML cells. Adding rhIGFBP7 reduced leukemic stem and/or progenitor survival and reversed a stem-like gene signature, but it had no influence on normal hematopoietic stem cell survival. Our data suggest a potential clinical utility of the addition of rhIGFBP7 to current chemotherapy regimens to decrease AML relapse rates.

The Influence of Radiotherapy on the Mechanical Properties of Silicone Breast Implants.

BACKGROUND: Silicone breast implants have been used for decades for cosmetic breast augmentation or reconstruction after mastectomy. In selected cases, postmastectomy adjuvant radiotherapy is given with the breast implants in situ. Previous clinical studies have shown that radiotherapy may lead to complications such as capsular contracture and infection and that removal of the implant may be required. Yet, the effect of radiotherapy on silicone breast implants themselves is unknown. The aim of this study was to investigate if irradiation of breast implants influences their mechanical properties. METHODS: This was an ex vivo study on 32 ready-to-use silicone breast implants (Mentor and Silimed). Half of the implants of each brand were irradiated with 1 × 60 Gy, the other half were not irradiated. Tensile, mechanical hysteresis, and rheology tests were performed. Differences in mechanical properties between the irradiated and nonirradiated implants were determined. RESULTS: No significant differences were found in tensile strength, mechanical hysteresis, and rheological properties between irradiated and nonirradiated implants. CONCLUSIONS: Breast implants' mechanical properties for these 2 brands were not significantly affected after single-dose irradiation in an ex vivo setting.

Suitability of EBT3 GafChromic film for quality assurance in MR-guided radiotherapy at 0.35 T with and without real-time MR imaging.

The 0.35 T 60Co MRIdian system (ViewRay Inc., Mountain View) has been in clinical use in our institution since May 2016. For quality assurance (QA) of dose delivery and end-to-end testing for this machine, a reliable dosimeter is required. However, it is possible that a magnetic field may cause perturbations to dosimetry measurements. For static magnetic fields, there is conflicting information in the literature concerning EBT film behaviour, while for real-time MR imaging such information is not available at all. The purpose of this study was to investigate the suitability of EBT3 GafChromic film for MRIdian QA, both with and without real-time MR imaging. EBT3 film sheets were irradiated in water using the MRIdian and a conventional linear accelerator (Linac) for reference. Dose calibration measurements were first performed up to 8 Gy for both machines. The MRIdian measurements were performed with and without real-time MR imaging. Second, film sheets were irradiated at seven different angles with respect to the B0-field. Optical density and dose values were analysed for the three colour channels. In both the film dose-response and B0-field orientation measurements, the mean dose values were within the 1% uncertainty range of prescribed dose values for the red and green channels, for both machines. There were no dose deviations detected between the MRIdian and Linac film measurements, nor for different B0-field orientations. In addition, the film dose-response measurements during real-time imaging were within 1.5% of the reference Linac measurements. EBT3 GafChromic film can be used for absolute dosimetry during real-time MR imaging independent of its orientation in the B0-field. This makes it a suitable dosimeter for patient-specific QA measurements and end-to-end testing of 0.35 T MRI-radiotherapy devices.

An on-site dosimetry audit for high-energy electron beams.

BACKGROUND AND PURPOSE: External dosimetry audits are powerful quality assurance instruments for radiotherapy. The aim of this study was to implement an electron dosimetry audit based on a contemporary code of practice within the requirements for calibration laboratories performing proficiency tests. This involved the determination of suitable acceptance criteria based on thorough uncertainty analyses. MATERIALS AND METHODS: Subject of the audit was the determination of absorbed dose to water, D w, and the beam quality specifier, R 50,dos. Fifteen electron beams were measured in four institutes according to the Belgian-Dutch code of practice for high-energy electron beams. The expanded uncertainty (k = 2) for the D w values was 3.6% for a Roos chamber calibrated in 60Co and 3.2% for a Roos chamber cross-calibrated against a Farmer chamber. The expanded uncertainty for the beam quality specifier, R 50,dos, was 0.14 cm. The audit acceptance levels were based on the expanded uncertainties for the comparison results and estimated to be 2.4%. RESULTS: The audit was implemented and validated successfully. All D w audit results were satisfactory with differences in D w values mostly smaller than 0.5% and always smaller than 1%. Except for one, differences in R 50,dos were smaller than 0.2 cm and always smaller than 0.3 cm. CONCLUSIONS: An electron dosimetry audit based on absorbed dose to water and present-day requirements for calibration laboratories performing proficiency tests was successfully implemented. It proved international traceability of the participants value with an uncertainty better than 3.6% (k = 2).

A cell-based high-throughput screening assay for radiation susceptibility using automated cell counting.

BACKGROUND: Radiotherapy is one of the mainstays in the treatment for cancer, but its success can be limited due to inherent or acquired resistance. Mechanisms underlying radioresistance in various cancers are poorly understood and available radiosensitizers have shown only modest clinical benefit. There is thus a need to identify new targets and drugs for more effective sensitization of cancer cells to irradiation. Compound and RNA interference high-throughput screening technologies allow comprehensive enterprises to identify new agents and targets for radiosensitization. However, the gold standard assay to investigate radiosensitivity of cancer cells in vitro, the colony formation assay (CFA), is unsuitable for high-throughput screening. METHODS: We developed a new high-throughput screening method for determining radiation susceptibility. Fast and uniform irradiation of batches up to 30 microplates was achieved using a Perspex container and a clinically employed linear accelerator. The readout was done by automated counting of fluorescently stained nuclei using the Acumen eX3 laser scanning cytometer. Assay performance was compared to that of the CFA and the CellTiter-Blue homogeneous uniform-well cell viability assay. The assay was validated in a whole-genome siRNA library screening setting using PC-3 prostate cancer cells. RESULTS: On 4 different cancer cell lines, the automated cell counting assay produced radiation dose response curves that followed a linear-quadratic equation and that exhibited a better correlation to the results of the CFA than did the cell viability assay. Moreover, the cell counting assay could be used to detect radiosensitization by silencing DNA-PKcs or by adding caffeine. In a high-throughput screening setting, using 4 Gy irradiated and control PC-3 cells, the effects of DNA-PKcs siRNA and non-targeting control siRNA could be clearly discriminated. CONCLUSIONS: We developed a simple assay for radiation susceptibility that can be used for high-throughput screening. This will aid the identification of molecular targets for radiosensitization, thereby contributing to improving the efficacy of radiotherapy.

The accuracy of frameless stereotactic intracranial radiosurgery.

PURPOSE: To determine the accuracy of frameless stereotactic radiosurgery using the BrainLAB ExacTrac system and robotic couch by measuring the individual contributions such as the accuracy of the imaging and couch correction system, the linkage between this system and the linac isocenter and the possible intrafraction motion of the patient in the frameless mask. MATERIALS AND METHODS: An Alderson head phantom with hidden marker was randomly positioned 31 times. Automated 6D couch shifts were performed according to ExacTrac and the deviation with respect to the linac isocenter was measured using the hidden marker. ExacTrac-based set-up was performed for 46 patients undergoing hypofractionated stereotactic radiotherapy for 135 fractions, followed by verification X-rays. Forty-three of these patients received post-treatment X-ray verification for 79 fractions to determine the intrafraction motion. RESULTS: The hidden target test revealed a systematic error of 1.5 mm in one direction, which was corrected after replacement of the system calibration phantom. The accuracy of the ExacTrac positioning is approximately 0.3 mm in each direction, 1 standard deviation. The intrafraction motion was 0.35±0.21 mm, maximum 1.15 mm. CONCLUSION: Intrafraction motion in the BrainLAB frameless mask is very small. Users are strongly advised to perform an independent verification of the ExacTrac isocenter in order to avoid systematic deviations.

Differential effects of combined Ad5- delta 24RGD and radiation therapy in in vitro versus in vivo models of malignant glioma.

PURPOSE: The integrin-targeted conditionally replicating adenovirus Ad5-delta 24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-delta 24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model. EXPERIMENTAL DESIGN AND RESULTS: Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-delta 24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-delta 24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-delta 24RGD with 1 x 5 Gy total body irradiation or with 2 x 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-delta 24RGD. CONCLUSIONS: Combined treatment with Ad5-delta 24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.

AdDelta24 and the p53-expressing variant AdDelta24-p53 achieve potent anti-tumor activity in glioma when combined with radiotherapy.

BACKGROUND: The conditionally replicating adenovirus (CRAd) AdDelta24-p53 replicates selectively in Rb mutant cells, and encodes the p53 suppressor protein. It has shown improved oncolytic potency compared to the parental control AdDelta24. As exogenous p53 has been shown to enhance radiosensitivity, the combination of AdDelta24-p53 and AdDelta24 with radiotherapy was assessed in vitro and in vivo against the therapy resistant gliomas. METHODS: In glioma cells, multicellular spheroids and animal xenografts the efficacy of combination therapy was assessed. P53 phosphorylation, induction of apoptosis and viral replication were determined following single or combination therapies. RESULTS: In vitro, AdDelta24-p53 was more effective against glioma cells than the control AdDelta24. Addition of irradiation equally increased the efficacy of both AdDelta24-p53 and AdDelta24 resulting in improved oncolysis compared to single agent treatment. Radiotherapy did not significantly change the replication kinetics of AdDelta24-p53 or AdDelta24. No detectable increase in p53 phosphorylation was observed but combination of radiotherapy and AdDelta24-p53 caused an increase in the percentage of apoptotic cells. In vivo, combination therapy with either AdDelta24 or AdDelta24-p53 significantly increased the number of mice demonstrating tumor regression (100%) as well as long-term survival (50%). No differences between viruses were noted. CONCLUSIONS: Exogenous p53 expression does not appear to increase the synergistic interaction of CRAds combined with radiotherapy. These results however do indicate that radiotherapy provides the time frame in which AdDelta24 and AdDelta24-p53 can eradicate established tumors that would otherwise escape treatment, and establishes the need to combine these modalities to form an effective anti-cancer treatment.

On the practice of the clinical implementation of enhanced dynamic wedges.

Practical aspects of the clinical implementation of enhanced dynamic wedges (EDW) replacing manual wedges are presented and discussed extensively. A comparison between measured and calculated data is also presented. Relative dose distributions and wedge factors were calculated with a commercially available treatment planning system and measured in a water-phantom and with an ionization chamber. Wedge factor calculations and measurements were also compared with an independent method of wedge factor calculations available from the literature. Aspects of the clinical implementation, such as safety and quality assurance, were evaluated. Measurements and calculations agreed very well and were slightly better than results of previous studies. Profiles and percentage depth doses (PDDs) agreed within 1% to 1.5% and within 0.5%, respectively. Measured and calculated wedge factors ratios agreed within 0.5% to 1%. Calculated and measured EDW dose distributions showed excellent agreement, both relative and absolute. However, for safe and practical use, specific aspects need to be taken into consideration. Once the treatment planning system is commissioned properly, the clinical implementation of EDW is rather straightforward.