Evaluation of sodium borocaptate (BSH) and boronophenylalanine (BPA) as boron delivery agents for neutron capture therapy (NCT) of cancer: an update and a guide for the future clinical evaluation of new boron delivery agents for NCT.

Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10, a stable isotope, is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form, which undergoes instantaneous nuclear fission to produce high-energy, tumoricidal alpha particles. The primary purpose of this review is to provide an update on the first drug used clinically, sodium borocaptate (BSH), by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug, boronophenylalanine (BPA), which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas. Subsequently, BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers, specifically brain tumors and recurrent tumors of the head and neck region. The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with high-grade gliomas. First, we will summarize the studies that were carried out in Japan with BSH and subsequently at our own institution, The Ohio State University, and those of several other groups. Second, we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT. Third, although there have been intense efforts to develop new and better boron delivery agents for BNCT, none of these have yet been evaluated clinically. The present report will provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.

Multi-phase failure modes and effects analysis for low dose bilateral whole lung irradiation of COVID-19 positive patients requiring respiratory ventilation.

PURPOSE: To identify high-priority risks in a clinical trial investigating the use of radiation to alleviate COVID-19 pneumonia using a multi-phase failure modes and effects analysis (FMEA). METHODS: A comprehensive FMEA survey of 133 possible causes of failure was developed for the clinical trial workflow (Phase I). The occurrence, severity, and detection risk of each possible cause of failure was scored by three medical physicists. High-risk potential failure modes were identified using the risk priority number (RPN) and severity scores, which were re-scored by 13 participants in radiation oncology (Phase II). Phase II survey scores were evaluated to identify steps requiring possible intervention and examine risk perception patterns. The Phase II participants provided consensus scores as a group. RESULTS: Thirty high-priority failure modes were selected for the Phase II survey. Strong internal consistency was shown in both surveys using Cronbach's alpha (αc ≥ 0.85). The 10 failures with the largest median RPN values concerned SARS-CoV-2 transmission (N = 6), wrong treatment (N = 3), and patient injury (N = 1). The median RPN was larger for COVID-related failures than other failure types, primarily due to the perceived difficulty of failure detection. Group re-scoring retained 8/10 of the highest-priority risk steps that were identified in the Phase II process, and discussion revealed interpretation differences of process steps and risk evaluation. Participants who were directly involved with the trial working group had stronger agreement on severity scores than those who were not. CONCLUSIONS: The high ranking of failures concerning SARS-CoV-2 transmission suggest that these steps may require additional quality management intervention when treating critically ill COVID-19+ patients. The results also suggest that a multi-phase FMEA survey led by a facilitator may be a useful tool for assessing risks in radiation oncology procedures, supporting future efforts to adapt FMEA to clinical procedures.

Technical note: Commissioning of a linear accelerator producing ultra-high dose rate electrons.

BACKGROUND: Ultra-high dose rate radiation (UHDR) is being explored by researchers in promise of advancing radiation therapy treatments. PURPOSE: This work presents the commissioning of Varian's Flash Extension for research (FLEX) conversion of a Clinac to deliver UHDR electrons. METHODS: A Varian Clinac iX with the FLEX conversion was commissioned for non-clinical research use with 16 MeV UHDR (16H) energy. This involved addition of new hardware, optimizing the electron gun voltages, radiofrequency (RF) power, and steering coils in order to maximize the accelerated electron beam current, sending the beam through custom scattering foils to produce the UHDR with 16H beam. Profiles and percent depth dose (PDD) measurements for 16H were obtained using radiochromic film in a custom vertical film holder and were compared to 16 MeV conventional electrons (16C). Dose rate and dose per pulse (DPP) were calculated from measured dose in film. Linearity and stability were assessed using an Advanced Markus ionization chamber. RESULTS: Energies for 16H and 16C had similar beam quality based on PDD measurements. Measurements at the head of the machine (61.3 cm SSD) with jaws set to 10×10 cm2 showed the FWHM of the profile as 7.2 cm, with 3.4 Gy as the maximum DPP and instantaneous dose rate of 8.1E5 Gy/s. Measurements at 100 cm SSD with 10 cm standard cone showed the full width at half max (FWHM) of the profile as 10.5 cm, 1.08 Gy as the maximum DPP and instantaneous dose rate of 2.E5 Gy/s. Machine output with number of pulses was linear (R = 1) from 1 to 99 delivered pulses. Output stability was measured within ±1% within the same session and within ±2% for daily variations. CONCLUSIONS: The FLEX conversion of the Clinac is able to generate UHDR electron beams which are reproducible with beam properties similar to clinically used electrons at 16 MeV. Having a platform which can quickly transition between UHDR and conventional modes (<1 min) can be advantageous for future research applications.

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.

Comparison of Gonadal Toxicity of Single-Fraction Ultra-High Dose Rate and Conventional Radiation in Mice.

Purpose: Increasing evidence suggests that ultra-high-dose-rate (UHDR) radiation could result in similar tumor control as conventional (CONV) radiation therapy (RT) while reducing toxicity to surrounding healthy tissues. Considering that radiation toxicity to gonadal tissues can cause hormone disturbances and infertility in young patients with cancer, the purpose of this study was to assess the possible role of UHDR-RT in reducing toxicity to healthy gonads in mice compared with CONV-RT. Methods and Materials: Radiation was delivered to the abdomen or pelvis of female (8 or 16 Gy) and male (5 Gy) C57BL/6J mice, respectively, at conventional (∼0.4 Gy/s) or ultrahigh (>100 Gy/s) dose rates using an IntraOp Mobetron linear accelerator. Organ weights along with histopathology and immunostaining of irradiated gonads were used to compare toxicity between radiation modalities. Results: CONV-RT and UHDR-RT induced a similar decrease in uterine weights at both studied doses (∼50% of controls), which indicated similarly reduced ovarian follicular activity. Histologically, ovaries of CONV- and UHDR-irradiated mice exhibited a comparable lack of follicles. Weights of CONV- and UHDR-irradiated testes were reduced to ∼30% of controls, and the percentage of degenerate seminiferous tubules was also similar between radiation modalities (∼80% above controls). Pairwise comparisons of all quantitative data indicated statistical significance between irradiated (CONV or UHDR) and control groups (from P ≤ .01 to P ≤ .0001) but not between radiation modalities. Conclusions: The data presented here suggest that the short-term effects of UHDR-RT on the mouse gonads are comparable to those of CONV-RT.

Assessment of MRI image distortion based on 6 consecutive years of annual QAs and measurements on 14 MRI scanners used for radiation therapy.

PURPOSE: To determine the magnitude of MRI image distortion based on 6 consecutive years of annual quality assurances/measurements on 14 MRI scanners used for radiation therapy and to provide evidence for the inclusion of additional margin for treatment planning. METHODS AND MATERIALS: We used commercial MRI image phantoms to quantitatively study the MRI image distortion over period of 6 years for up to 14 1.5 and 3 T MRI scanners that could potentially be used to provide MRI images for treatment planning. With the phantom images collected from 2016 to 2022, we investigated the MRI image distortion, the dependence of distortion on the distance from the imaging isocenter, and the possible causes of large distortion discovered. RESULTS: MRI image distortion increases with the distance from the imaging isocenter. For a region of interest (ROI) with a radius of 100 mm centered at the isocenter, the mean magnitude of distortion for all MRI scanners is 0.44 ± 0.18 mm $0.44 \pm 0.18\;{\rm{mm}}$ , and the maximum distortion varies from 0.52 to 1.31 mm $0.52\;{\rm{to}}\;1.31\;{\rm{mm}}$ depending on MRI scanners. For an ROI with a radius of 200 mm centered at the isocenter, the mean magnitude of distortion increases to 0.84 ± 0.45 mm $0.84 \pm 0.45\;{\rm{mm}}$ , and the range of the maximum distortion increases to 1.92 - 5.03 mm $1.92 - 5.03\;{\rm{mm}}$ depending on MRI scanners. The distortion could reach 2 mm at 150 mm from the isocenter. CONCLUSION: An additional margin to accommodate image distortion should be considered for treatment planning. Imaging with proper patient alignment to the isocenter is vital to reducing image distortion. We recommend performing image distortion checks annually and after major upgrade on MRI scanners.

A framework for automated and streamlined kV cone beam computed tomography image quality assurance: a multi-institutional study.

The purpose of this study was to develop and evaluate a framework to support automated standardized testing and analysis of Cone Beam Computed Tomography (CBCT) image quality QA across multiple institutions. A survey was conducted among the participating institutions to understand the variability of the CBCT QA practices. A commercial, automated software platform was validated by seven institutions participating in a consortium dedicated to automated quality assurance. The CBCT image analysis framework was used to compare periodic QA results among 23 linear accelerators (linacs) from seven institutions. The CBCT image quality metrics (geometric distortion, spatial resolution, contrast, HU constancy, uniformity and noise) data are plotted as a function of means with the upper and lower control limits compared to the linac acceptance criteria and AAPM recommendations. For example, mean geometric distortion and HU constancy metrics were found to be 0.13 mm (TG142 recommendation: ≤2 mm) and 13.4 respectively (manufacturer acceptance specification: ≤±50).Image upload and analysis process was fully automated using a MATLAB-based platform. This analysis enabled a quantitative, longitudinal assessment of the performance of quality metrics which were also compared across 23 linacs. For key CBCT parameters such as uniformity, contrast, and HU constancy, all seven institutions used stricter goals than what would be recommended based on the analysis of the upper and lower control limits. These institutional goals were also found to be stricter than that found in AAPM published guidance. This work provides a reference that could be used to machine-specific optimized tolerance of CBCT image maintenance via control charts to monitor performance we well as the sensitivity of different tests in support of a broader quality assurance program. To ensure the daily image quality needed for patient care, the optimized statistical QA metrics recommended to using along with risk-based QA.

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.

Accelerators, Gantries, Magnets and Imaging Systems for Particle Beam Therapy: Recent Status and Prospects for Improvement.

The paper begins by emphasizing the clinical and commercial importance of proton or other charged particle such as carbon ion therapy, refers to the manufacturers of such systems of which more than 120 are installed or under construction worldwide by April 2021. A general review of charged particle therapy systems refers to six manufacturers and provides in tabular form some details of systems installed in the US, Europe, Asia, and elsewhere. In a description of the principles of particle beam therapy a comparison is made of the properties of photons (x-rays) versus protons and protons versus carbon ions. A brief discussion of accelerators in general is followed by descriptions of cyclotrons (including the isosynchronous cyclotron and the synchrocyclotron) and synchrotrons. An interesting case study describes the evolution of a normal-conducting 220 ton cyclotron into an iron-free synchrocyclotron weighing only 5 tons. The general principles of beam handling and gantry design are described. Subsequent sections describe gantry magnets in detail - normal conducting gantry magnets, superconducting gantry magnets for proton- and carbon therapy. Mention is made of a novel CERN-designed superconducting toroidal gantry for hadron therapy, GaToroid. This device, operating under steady state current and magnetic field, is able to deliver a beam at discrete angles over a range of treatment energies. Also considered are low temperature superconducting (LTS) and high temperature superconducting (HTS) magnet windings, and the choice of REBCO conductors for cryogen-free carbon-ion gantries. Finally, the paper mentions an important "Prospect for Improvement", viz: the introduction of MRI image guidance. A well-known property of the particle beam as it passes through tissue is its energy dependent absorption that rises to a pronounced peak (the Bragg peak) at the end of its range. In order to take advantage of this effect the exact targeting of the tumor and positioning of the patient should be guided by imaging visualization using X-ray, CT, and hopefully advanced MRI. Unlike MRI-guided photon therapy the direct interaction of the magnetic field with the charged particle beam presents a huge challenge such that MRI image-guided proton/particle therapy has not yet been available in clinical practice. Modeling studies have been undertaken on the general topic of beam-line/magnetic field interaction using, for example, the software GEANT4 (GEometry And Tracking) a platform for simulating the passage of charged particles through matter using a Monte Carlo method.

Validating kQ =1.0 assumption in TG51 with PTW 30013 farmer chamber for Varian TrueBeam's 2.5 MV imaging beam.

AAPM Report 142 recommends and the State of Ohio requires that the imaging dose be quantified in radiotherapy applications. Using the TG51 dose calibration protocol for MV Imaging dose measurement requires knowledge of the kQ parameter for the beam quality and the ionization chamber type under investigation. The %dd(10)x of the Varian TrueBeam 2.5 MV imaging beam falls outside the range of the available data for the calculation of the kQ value. Due to the similarities of the 2.5 MV imaging beam and the 60 Co beam, we and others made the assumption that kQ = 1.0 in TG51 calculations. In this study, we used the TG21 and TG51 calibration protocols in conjunction to validate that kQ = 1.0 for the 2.5 MV imaging beam using a PTW 30013 farmer chamber. Standard measurements for TG51 absolute dosimetry QA were performed at 100 cm SSD, 10 cm depth, 10 × 10 field size, delivering 100 Monitor Units to a waterproof Farmer Chamber (PTW TN30013) for both 2.5 and 6 MV. Both the TG21 and TG51 formalisms were used to calculate the dose to water per MU at dmax (Dw /MU) for the 6 MV beam. The calculated outputs were 1.0005 and 1.0004 cGy/MU respectively. The TG21 formalism was then used to calculate (Dw /MU) for the 2.5 MV imaging beam. This value was then used in the TG51 formalism to find kQ for the 2.5 MV imaging beam. A kQ value of 1.00 ± 0.01 was calculated for 2.5 MV using this method.

Quality assurance for a six degrees-of-freedom table using a 3D printed phantom.

PURPOSE: To establish a streamlined end-to-end test of a 6 degrees-of-freedom (6DoF) robotic table using a 3D printed phantom for periodic quality assurance. METHODS: A 3D printed phantom was fabricated with translational and rotational offsets and an imbedded central ball-bearing (BB). The phantom underwent each step of the radiation therapy process: CT simulation in a straight orientation, plan generation using the treatment planning software, setup to offset marks at the linac, registration and corrected 6DoF table adjustments via hidden target test, delivery of a Winston-Lutz test to the BB, and verification of table positioning via field and laser lights. The registration values, maximum total displacement of the combined Winston-Lutz fields, and a pass or fail criterion of the laser and field lights were recorded. The quality assurance process for each of the three linacs were performed for the first 30 days. RESULTS: Within a 95% confidence interval, the overall uncertainty values for both translation and rotation were below 1.0 mm and 0.5° for each linac respectively. When combining the registration values and other uncertainties for all three linacs, the average deviations were within 2.0 mm and 1.0° of the designed translation and rotation offsets of the 3D print respectively. For all three linacs, the maximum total deviation for the Winston-Lutz test did not exceed 1.0 mm. Laser and light field verification was within tolerance every day for all three linacs given the latest guidance documentation for table repositioning. CONCLUSION: The 3D printer is capable of accurately fabricating a quality assurance phantom for 6DoF positioning verification. The end-to-end workflow allows for a more efficient test of the 6DoF mechanics while including other important tests needed for routine quality assurance.

Likelihood of unacceptable normal tissue doses in breast cancer patients undergoing regional nodal irradiation in routine clinical practice.

PURPOSE: As indications for regional nodal irradiation (RNI) for breast cancer have expanded, so too has scrutiny over potential late toxicity from radiotherapy. This emphasizes the need for careful radiation treatment planning to maximize the therapeutic ratio. We sought to evaluate how often unacceptable doses (UDs) to organs at risk (OARs) occur and the associated factors for patients receiving RNI in daily practice. METHODS AND MATERIALS: Treatment records of patients who received RNI from February 2012 to May 2015 were studied. The NSABP B51/RTOG 1304 clinical dose-volume constraints for targets/OARs receiving RNI were used as the benchmark. Dose-volume histograms were analyzed for the rate of ≥1 UD delivered to the following organs: heart, mean >5 Gy; ipsilateral lung, V20 >35%, V10 >60%, V5 >70%; contralateral lung (CL), V5 >15%; and contralateral breast, V4.1 >5%. Logistic regression was used to test the association between UDs to OAR and key variables. RESULTS: Two hundred three consecutive cases received RNI (105 left, 98 right), to the chest wall in 171 (84%) and to the internal mammary nodes in 170 (84%); 77.4% of cases met all OAR constraints. The most common OAR UDs were delivered to the contralateral breast (n = 32, 15.7%) and ipsilateral lung V5 (n = 22, 10.8%). On multivariate analysis, use of intensity modulated radiation therapy (odds ratio [OR], 64.7; 95% confidence interval, 20.8-201.5; P < .001) and use of nodal boost (OR, 5.5; 95% confidence interval, 1.1-27.1; P = .04), but not internal mammary node irradiation (OR, 2.7; P = .35) or reconstruction (OR, 0.62; P = .33), were independently associated with higher OAR UD rate. For 3-dimensional conformal radiation therapy plans, 7.9% had OAR UDs. CONCLUSION: The OAR UD rate with 3-dimensional conformal radiation therapy ± deep inspiration breath-hold in routine clinical practice is low and not independently associated with internal mammary node irradiation or reconstruction presence. Women treated with intensity modulated radiation therapy had a significantly higher overall OAR UD rate, and clinicians should be aware of this as they initiate RNI 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.

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.

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.

Using NanoDot dosimetry to study the RS 2000 X-ray biological irradiator.

PURPOSE: To use NanoDot dosimeters to study the RS 2000 X-ray Biological Irradiator dosimetry characteristics and perform in vivo dosimetry for cell or small animal experiments. METHODS AND MATERIALS: We first calibrated the Landauer NanoDot(™) Reader by irradiating some NanoDot dosimeters with a set of known doses at specific positions defined by the irradiator. A group of five NanoDot dosimeters were placed at five specific positions where the dose rates were known and provided by the irradiator. Each group was irradiated for a set of times respectively. By correlating the readings of dosimeters with the given irradiated doses, we established the dose-reading relationship for the irradiator under the specific running condition. The established calibration curve was validated by exposing arbitrary known doses to a set of dosimeters, using the Landauer NanoDot(™) Reader to measure the doses, and then making the comparison between the two doses. To study the dose gradient of the X-ray inside the irradiated target (dose variation/cm), we placed dosimeters under different thicknesses of water-equivalent bolus and irradiated them, then measured the doses to determine the dose gradient. RESULTS: Using the method described above, we were able to calibrate the Landauer InLight NanoDot(™) Reader and use NanoDot dosimeters to measure the actual doses delivered to the targets for the cell/small animal experiments that use the RS 2000 X-ray Biological Irradiator. CONCLUSIONS: NanoDots are ideal dosimeters to use for in vivo dosimetry for cell/small animal irradiation experiments. The dose decrease inside the animal tissue is about 20% per cm.

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.

Comparison of intracerebral delivery of carboplatin and photon irradiation with an optimized regimen for boron neutron capture therapy of the F98 rat glioma.

In this report we have summarized our studies to optimize the delivery of boronophenylalanine (BPA) and sodium borocaptate (BSH) for boron neutron capture therapy (BNCT) of F98 glioma bearing rats. These results have been compared to a chemoradiotherapeutic approach using the same tumor model. The best survival data from our BNCT studies were obtained using a combination of BPA and sodium borocaptate BSH administered via the internal carotid artery, in combination with blood-brain barrier disruption (BBB-D). This treatment resulted in a mean survival time (MST) of 140 d with a 25% cure rate. The other approach combined intracerebral administration of carboplatin by either convection enhanced delivery (CED) or Alzet pump infusion, followed by external beam photon irradiation. This resulted in MSTs of 83 d and 112 d, respectively, with a cure rate of 40% for the latter. However, a significant problem that must be solved for both BNCT and this new chemoradiotherapeutic approach is how to improve drug uptake and microdistribution within the tumor.