Interpretation of intrafraction motion review data and method for verification.

The current clinical interface for Varian's intrafraction motion review (IMR) is limited, providing only qualitative data for review at the treatment console. This study provides a method of extracting and interpreting data from combined log files for quantitative evaluation. Combined log files acquired during patient treatment and a parsing code was developed to scan the combined log file looking for unique identifiers pertaining to the data of interest. We were able to extract clinically relevant parameters from the log files including date and time, gantry angle, expected marker position, found marker position, pixel size, and detection result. This study details how to compare IMR data to Calypso investigating dual-surrogates for intrafraction monitoring during treatment for other researchers to build on these methods. Understanding data recorded during treatment within the combined log files can be helpful in quality improvement of patient care by retrospectively reviewing intrafraction motion.

Plasma-based biomaterials for the treatment of cutaneous radiation injury.

Cutaneous wounds caused by an exposure to high doses of ionizing radiation remain a therapeutic challenge. While new experimental strategies for treatment are being developed, there are currently no off-the-shelf therapies for the treatment of cutaneous radiation injury that have been proven to promote repair of the damaged tissues. Plasma-based biomaterials are biologically active biomaterials made from platelet enriched plasma, which can be made into both solid and semi-solid forms, are inexpensive, and are available as off-the-shelf, nonrefrigerated products. In this study, the use of plasma-based biomaterials for the mitigation of acute and late toxicity for cutaneous radiation injury was investigated using a mouse model. A 2-cm diameter circle of the dorsal skin was irradiated with a single dose of 35 Gy followed by topical treatment with plasma-based biomaterial or vehicle once daily for 5 weeks postirradiation. Weekly imaging demonstrated more complete wound resolution in the plasma-based biomaterial vs. vehicle group which became statistically significant (p < 0.05) at weeks 12, 13, and 14 postmaximum wound area. Despite more complete wound healing, at 9 and 17 weeks postirradiation, there was no statistically significant difference in collagen deposition or skin thickness between the plasma-based biomaterial and vehicle groups based on Masson trichrome staining nor was there a statistically significant difference in inflammatory or fibrosis-related gene expression between the groups. Although significant improvement was not observed for late toxicity, plasma-based biomaterials were effective at promoting wound closure, thus helping to mitigate acute toxicity.

Commissioning and comprehensive evaluation of the ArcCHECK cylindrical diode array for VMAT pretreatment delivery QA.

We present commissioning and comprehensive evaluation for ArcCHECK as a QA equipment for volumetric-modulated arc therapy (VMAT), using the 6 MV photon beam with and without the flattening filter, and the SNC patient software (version 6.2). In addition to commissioning involving absolute dose calibration, array calibration, and PMMA density verification, ArcCHECK was evaluated for its response dependency on linac dose rate, instantaneous dose rate, radiation field size, beam angle, and couch insertion. Scatter dose characterization, consistency and symmetry of response, and dosimetry accuracy evaluation for fixed aperture arcs and clinical VMAT patient plans were also investigated. All the evaluation tests were performed with the central plug inserted and the homogeneous PMMA density value. Results of gamma analysis demonstrated an overall agreement between ArcCHECK-measured and TPS-calculated reference doses. The diode based field size dependency was found to be within 0.5% of the reference. The dose rate-based dependency was well within 1% of the TPS reference, and the angular dependency was found to be ± 3% of the reference, as tested for BEV angles, for both beams. Dosimetry of fixed arcs, using both narrow and wide field widths, resulted in clinically acceptable global gamma passing rates on the 3%/3mm level and 10% threshold. Dosimetry of narrow arcs showed an improvement over published literature. The clinical VMAT cases demonstrated high level of dosimetry accuracy in gamma passing rates.

Blinding of Residency Applications in Medical Physics: Promises and Pitfalls.

Purpose: The feasibility of blinding applications for a medical physics residency program has yet to be demonstrated in the literature. We explore the application of an automated approach with human review and intervention to blind applications during the annual medical physics residency review cycle. Methods and Materials: Applications were blinded using an automated process and used for the first phase of residency review in the program. We retrospectively compared self-reported demographic and gender data with blinded and nonblinded cohorts from 2 sequential years of review from a medical physics residency program. Demographic data were analyzed comparing applicants with candidates selected to move to the next phase of the review process. Interrater agreement was also evaluated from the applicant reviewers. Results: We show the feasibility of blinding applications for a medical physics residency program. We observed no more than a 3% difference between the gender selection within the first phase of application review but greater differences when examining race and ethnicity between the 2 methods. The greatest difference was shown to be between Asian and White candidates, where there are statistical differences in the scores in the rubric categories of essay and overall impression. Conclusions: We suggest that each training program critically evaluate its selection criteria for potential sources of bias within the review process. We recommend further critical investigation of processes to promote equity and inclusion to ensure the methods and outcomes are aligned with the mission of the program. Finally, we recommend that the common application provide an option for blinding applications at the source so this can be an option to facilitate efforts for evaluating unconscious bias in the review process.

Convection enhanced delivery of carboplatin in combination with radiotherapy for the treatment of brain tumors.

The purpose of this study was to further evaluate the therapeutic efficacy of convection enhanced delivery (CED) of carboplatin in combination with radiotherapy for treatment of the F98 rat glioma. Tumor cells were implanted stereotactically into the brains of syngeneic Fischer rats, and 13 or 17 d. later carboplatin (20 µg/10 µl) was administered by either CED over 30 min or by Alzet osmotic pumps (0.5 µg/µl/h for 168 h.) beginning at 7 d after tumor implantation. Rats were irradiated with a 15 Gy fractionated dose (5 Gy × 3) of 6 MV photons to the whole brain beginning on the day after drug administration. Other groups of rats received either carboplatin or X-irradiation alone. The tumor carboplatin concentration following CED of 20 µg in 10 µl was 10.4 µg/g, which was equal to that observed following i.v. administration of 100 mg/kg b.w. Rats bearing small tumors, treated with carboplatin and X-irradiation, had a mean survival time (MST) of 83.4 d following CED and 111.8 d following pump delivery with 40% of the latter surviving >180 d (i.e. cured) compared to 55.2 d for CED and 77.2 d. for pump delivery of carboplatin alone and 31.8 d and 24.2 d, respectively, for X-irradiated and untreated controls. There was no microscopic evidence of residual tumor in the brains of all long-term survivors. Not surprisingly, rats with large tumors had much shorter MSTs. Only modest increases in MSTs were observed in animals that received either oral administration or CED of temozolomide plus X-irradiation (23.2 d and 29.3 d) compared to X-irradiation alone. The present survival data, and those previously reported by us, are among the best ever obtained with the F98 glioma model. Initially, they could provide a platform for a Phase I clinical trial to evaluate the safety and potential therapeutic efficacy of CED of carboplatin in patients with recurrent glioblastomas, and ultimately a Phase II trial of carboplatin in combination with radiation therapy.

A novel percutaneous tracheostomy technique to reduce aerosolisation during the COVID-19 pandemic: A description and case series.

Background: COVID-19 is a global pandemic with many patients requiring prolonged mechanical ventilation. COVID-19 is associated with laryngeal oedema and a high rate of reintubation and difficult airway. Tracheostomy insertion is an aerosol generating procedure, so we strived to make our novel technique safe for operator and patient. Aim: To share our experience of a novel percutaneous tracheostomy technique, based on a case series of 18 patients with COVID-19 pneumonitis. Method: Our novel percutaneous tracheostomy technique is a landmark-based approach without bronchoscopic confirmation of the correct needle placement. Blunt dissection using tracheal dilators onto the tracheal rings facilitates first pass needle insertion into the trachea. The tracheal tube is retracted into the supraglottic airway, the cuff overinflated, and a wet throat pack inserted to reduce aerosolisation. Results: From March 2020 to May 2020, 38 patients with suspected or confirmed COVID-19 presented to Royal Bolton Hospital requiring invasive ventilation. 18 patients underwent percutaneous tracheostomy. 6 patients have been decannulated, 12 patients died. Mean time from intubation to tracheostomy was 6.1 days and from tracheostomy to decannulation 20.6 days. No operator developed COVID-19 symptoms. Conclusions: Despite the low numbers our novel technique appears to be safe, but confirmation requires a larger controlled trial. As an institution we have avoided difficulties with reintubation and reduced our drug usage.

Prospective dual-surrogate validation study of periodic imaging during treatment for accurately monitoring intrafraction motion of prostate cancer patients.

BACKGROUND AND PURPOSE: The goal of this prospective study is to validate the use of periodic imaging during treatment with a fiducial marker detection algorithm using radiofrequency transponders for prostate cancer patients undergoing treatment for radiation therapy. MATERIALS AND METHODS: Ten male patients were enrolled in this study and treated for prostate cancer with implanted electromagnetic monitoring beacons. We evaluated the accuracy and limitations of Intrafraction Motion Review (IMR) by comparing the known locations of the beacons using the electromagnetic monitoring system to the position data reported from IMR images. RESULTS: A total of 4054 images were taken during treatment. The difference in vector magnitude of the two methods is centered around zero (mean: 0.03 cm, SD: 0.16 cm) and Lin's Concordance Correlation Coefficient (CCC) is 0.99 (95% CI: 0.98, 1) overall. The Euclidean distance between the two methods was close to zero (median: 0.09 cm, IQR: 0.06, 0.14 cm). The difference in distance between any two markers was centered around zero (mean: 0.01 cm, SD: 0.12 cm) and Lin's CCC is 0.97 (95% CI: 0.96, 0.98) overall. CONCLUSION: The accuracy of the algorithm for detected markers within the 2D images is comparable to electromagnetic monitoring for fiducial identification when detected. IMR could provide an alternate solution for patients with contraindications of use of an electromagnetic monitoring system and a cost effective alternative to the acquisition of an additional system for patient monitoring, but does not provide data for pre-treatment set-up verification and real-time 3D positioning during treatment.

Reverse mapping of normal tissue complication probabilities onto dose volume histogram space: the problem of randomness of the dose volume histogram sampling.

A very important issue in contemporary inverse treatment radiotherapy planning is the specification of proper dose-volume constraints limiting the treatment planning algorithm from delivering high doses to the normal tissue surrounding the tumor. Recently we have proposed a method called reverse mapping of normal tissue complication probabilities (NTCP) onto dose-volume histogram (DVH) space, which allows the calculation of appropriate biologically based dose-volume constraints to be used in the inverse treatment planning. The method of reverse mapping requires random sampling from the functional space of all monotonically decreasing functions in the unit square. We develop, in this paper, a random function generator for the purpose of the reverse mapping. Since the proposed generator is based on the theory of random walk, it is therefore designated in this work, as a random walk DVH generator. It is theoretically determined that the distribution of the number of monotonically decreasing functions passing through a point in the dose volume histogram space follows the hypergeometric distribution. The proposed random walk DVH generator thus simulates, in a random fashion, trajectories of monotonically decreasing functions (finite series) that are situated in the unit square [0, 1] X [1,0] using the hypergeometric distribution. The DVH generator is an important tool in the study of reverse NTCP mapping for the calculation of biologically based dose-volume constraints for inverse treatment planning.

Treating cutaneous T-cell lymphoma with highly irregular surfaces with photon irradiation using rice as tissue compensator.

PURPOSE: Cutaneous T-cell lymphoma (CTCL) is known to have an excellent response to radiotherapy, an important treatment modality for this disease. In patients with extremity and digit involvement, the irregular surface and depth variations create difficulty in delivering a homogenous dose using electrons. We sought to evaluate photon irradiation with rice packing as tissue equivalence and determine clinical tolerance and response. MATERIALS AND METHODS: Three consecutive CTCL patients with extensive lower extremity involvement including the digits were treated using external beam photon therapy with rice packing for tissue compensation. The entire foot was treated to 30-40 Gy in 2-3 Gy per fraction using 6 MV photons prescribed to the mid-plane of an indexed box filled with rice in which the foot was placed. Treatment tolerance and response were monitored with clinical evaluation. RESULTS: All patients tolerated the treatment without treatment breaks. Toxicities included grade 3 erythema and desquamation with resolution within 4 weeks. No late toxicities were observed. All patients had a partial response by 4 weeks after therapy with two patients achieving a complete response. Patients reported improved functionality after treatment. No local recurrence has been observed. CONCLUSION: Tissue compensation with rice packing offers a convenient, inexpensive, and reproducible method for the treatment of CTCL with highly irregular surfaces.

Tumoricidal activity of low-energy 160-KV versus 6-MV X-rays against platinum-sensitized F98 glioma cells.

The purposes of this study were (i) to investigate the differences in effects between 160-kV low-energy and 6-MV high-energy X-rays, both by computational analysis and in vitro studies; (ii) to determine the effects of each on platinum-sensitized F98 rat glioma and murine B16 melanoma cells; and (iii) to describe the in vitro cytotoxicity and in vivo toxicity of a Pt(II) terpyridine platinum (Typ-Pt) complex. Simulations were performed using the Monte Carlo code Geant4 to determine enhancement in absorption of low- versus high-energy X-rays by Pt and to determine dose enhancement factors (DEFs) for a Pt-sensitized tumor phantom. In vitro studies were carried out using Typ-Pt and again with carboplatin due to the unexpected in vivo toxicity of Typ-Pt. Cell survival was determined using clonogenic assays. In agreement with computations and simulations, in vitro data showed up to one log unit reduction in surviving fractions (SFs) of cells treated with 1-4 µg/ml of Typ-Pt and irradiated with 160-kV versus 6-MV X-rays. DEFs showed radiosensitization in the 50-200 keV range, which fell to approximate unity at higher energies, suggesting marginal interactions at MeV energies. Cells sensitized with 1-5 or 7 µg/ml of carboplatin and then irradiated also showed a significant decrease (P < 0.05) in SFs. However, it was unlikely this was due to increased interactions. Theoretical and in vitro studies presented here demonstrated that the tumoricidal activity of low-energy X-rays was greater than that of high-energy X-rays against Pt-sensitized tumor cells. Determining whether radiosensitization is a function of increased interactions will require additional studies.

Radiation therapy combined with intracerebral administration of carboplatin for the treatment of brain tumors.

BACKGROUND: In this study we determined if treatment combining radiation therapy (RT) with intracerebral (i.c.) administration of carboplatin to F98 glioma bearing rats could improve survival over that previously reported by us with a 15 Gy dose (5 Gy × 3) of 6 MV photons. METHODS: First, in order to reduce tumor interstitial pressure, a biodistribution study was carried out to determine if pretreatment with dexamethasone alone or in combination with mannitol and furosemide (DMF) would increase carboplatin uptake following convection enhanced delivery (CED). Next, therapy studies were carried out in rats that had received carboplatin either by CED over 30 min (20 µg) or by Alzet pumps over 7 d (84 µg), followed by RT using a LINAC to deliver either 20 Gy (5 Gy × 4) or 15 Gy (7.5 Gy × 2) dose at 6 or 24 hrs after drug administration. Finally, a study was carried out to determine if efficacy could be improved by decreasing the time interval between drug administration and RT. RESULTS: Tumor carboplatin values for D and DMF-treated rats were 9.4 ± 4.4 and 12.4 ± 3.2 µg/g, respectively, which were not significantly different (P = 0.14). The best survival data were obtained by combining pump delivery with 5 Gy × 4 of X-irradiation with a mean survival time (MST) of 107.7 d and a 43% cure rate vs. 83.6 d with CED vs. 30-35 d for RT alone and 24.6 d for untreated controls. Treatment-related mortality was observed when RT was initiated 6 h after CED of carboplatin and RT was started 7 d after tumor implantation. Dividing carboplatin into two 10 µg doses and RT into two 7.5 Gy fractions, administered 24 hrs later, yielded survival data (MST 82.1 d with a 25% cure rate) equivalent to that previously reported with 5 Gy × 3 and 20 µg of carboplatin. CONCLUSIONS: Although the best survival data were obtained by pump delivery, CED was highly effective in combination with 20 Gy, or as previously reported, 15 Gy, and the latter would be preferable since it would produce less late tissue effects.

Unique in vitro and in vivo thrombopoietic activities of ingenol 3,20 dibenzoate, a Ca(++)-independent protein kinase C isoform agonist.

Thrombopoiesis following severe bone marrow injury frequently is delayed, thereby resulting in life-threatening thrombocytopenia for which there are limited treatment options. The reasons for these delays in recovery are not well understood. Protein kinase C (PKC) agonists promote megakaryocyte differentiation in leukemia cell lines and primary cells. However, little is known about the megakaryopoietic effects of PKC agonists on primary CD34+ cells grown in culture or in vivo. Here we present evidence that the novel PKC isoform-selective agonist 3,20 ingenol dibenzoate (IDB) potently stimulates early megakaryopoiesis of human CD34+ cells. In contrast, broad spectrum PKC agonists failed to do so. In vivo, a single intraperitoneal injection of IDB selectively increased platelets in mice without affecting hemoglobin or white counts. Finally, IDB strongly mitigated radiation-induced thrombocytopenia, even when administered 24 hours after irradiation. Our data demonstrate that novel PKC isoform agonists such as IDB may represent a unique therapeutic strategy for accelerating the recovery of platelet counts following severe marrow injury.