Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. This Phase I trial studied the safety and tolerability of a 2-6-week course (10-22 ...doses) of MGd with radiotherapy for glioblastoma multiforme.
A total of 33 glioblastoma multiforme patients received one of seven MGd regimens starting at 10 doses of 4 mg/kg/d MGd and escalating to 22 doses of 5.3 mg/kg/d MGd (5 or 10 daily doses then three times per week). The National Cancer Institute Cancer Therapy Evaluation Program toxicity and stopping rules were applied.
The maximal tolerated dose was 5.0 mg/kg/d MGd (5 d/wk for 2 weeks, then three times per week) for 22 doses. The dose-limiting toxicity was reversible transaminase elevation. Adverse reactions included rash/pruritus (45%), chills/fever (30%), and self-limiting vesiculobullous rash of the thumb and fingers (42%). The median survival of 17.6 months prompted a case-matched analysis. In the case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31) compared with the matched Radiation Therapy Oncology Group database patients with a median survival of 11.8 months (hazard ratio, 0.43; 95% confidence interval, 0.20-0.94).
The maximal tolerated dose of MGd with radiotherapy for glioblastoma multiforme in this study was 5 mg/kg/d for 22 doses (daily for 2 weeks, then three times weekly). The baseline survival calculations suggest progression to Phase II trials is appropriate, with the addition of MGd to radiotherapy with concurrent and adjuvant temozolomide.
Purpose
To investigate the necessity of extending the output factor table (OF Table) of the Varian EclipseTM Treatment Planning System for small field stereotactic radiosurgery (SRS) and stereotactic ...body radiosurgery (SBRT) treatments.
Methods
A new AcurosXB 15.6 beam model was created in the Eclipse Beam Configuration, which is identical to the one that has been used in the clinic with a default 3 × 3 cm to 40 × 40 cm OF Table, except the OF Table in the new model was extended to cover the range from 1 × 1 cm to 40 × 40 cm. 80 small square and rectangular output factors were measured on a Varian TrueBeam utilizing a Standard Imaging Exradin W2‐1×1 scintillator detector, inside a PTW BeamScan water tank with 95 cm SSD at 5 cm depth. Cerenkov contamination was corrected using a rectangular field method (2 cm × 15 cm field). Nine Radiosurgery plans with primary jaw setting ranging from 0.7 cm to 2.0 cm were evaluated by both beam models. The monitor unit (MU) differences between the two beam models were calculated for identical 3‐dimensional (3D) absolute dose distributions. Output factors, measured versus Eclipse calculated, were compared down to 0.5 × 0.5 cm primary jaw setting.
Results
For the 6FFF beam, the difference between the two beam models was ∼ 6% for 1 × 1 cm jaw settings and 4% at 1.5 × 1.5 cm, with the extended OF Table requiring higher MUs for the same dose prescription and same 3‐dimensional isodose distribution. For the 6MV beam, the corresponding difference is ∼7.5% for 1 × 1 cm, 5% for 1.5 × 1.5 cm, and 3% for 2 × 2 cm jaw settings, with the extended OF Table requiring higher MUs. For jaw settings smaller than 1 × 1 cm, measured dose can be considerably smaller than Eclipse predicted dose, even with the OF Table extension. This is reflected by the fact that the output factor for 0.5 × 0.5 cm, calculated via Eclipse external beam, was more than 30% greater than that measured for both 6FFF and 6MV beams.
Conclusions
Eclipse does a satisfactory job for primary jaw sizes down to 2 cm. For jaw settings smaller than 1.5 cm, the OF Table in Eclipse should be extended to improve the dose calculation accuracy.
To investigate the necessity of extending the output factor table (OF Table) of the Varian Eclipse
Treatment Planning System for small field stereotactic radiosurgery (SRS) and stereotactic body ...radiosurgery (SBRT) treatments.
A new AcurosXB 15.6 beam model was created in the Eclipse Beam Configuration, which is identical to the one that has been used in the clinic with a default 3 × 3 cm to 40 × 40 cm OF Table, except the OF Table in the new model was extended to cover the range from 1 × 1 cm to 40 × 40 cm. 80 small square and rectangular output factors were measured on a Varian TrueBeam utilizing a Standard Imaging Exradin W2-1×1 scintillator detector, inside a PTW BeamScan water tank with 95 cm SSD at 5 cm depth. Cerenkov contamination was corrected using a rectangular field method (2 cm × 15 cm field). Nine Radiosurgery plans with primary jaw setting ranging from 0.7 cm to 2.0 cm were evaluated by both beam models. The monitor unit (MU) differences between the two beam models were calculated for identical 3-dimensional (3D) absolute dose distributions. Output factors, measured versus Eclipse calculated, were compared down to 0.5 × 0.5 cm primary jaw setting.
For the 6FFF beam, the difference between the two beam models was ∼ 6% for 1 × 1 cm jaw settings and 4% at 1.5 × 1.5 cm, with the extended OF Table requiring higher MUs for the same dose prescription and same 3-dimensional isodose distribution. For the 6MV beam, the corresponding difference is ∼7.5% for 1 × 1 cm, 5% for 1.5 × 1.5 cm, and 3% for 2 × 2 cm jaw settings, with the extended OF Table requiring higher MUs. For jaw settings smaller than 1 × 1 cm, measured dose can be considerably smaller than Eclipse predicted dose, even with the OF Table extension. This is reflected by the fact that the output factor for 0.5 × 0.5 cm, calculated via Eclipse external beam, was more than 30% greater than that measured for both 6FFF and 6MV beams.
Eclipse does a satisfactory job for primary jaw sizes down to 2 cm. For jaw settings smaller than 1.5 cm, the OF Table in Eclipse should be extended to improve the dose calculation accuracy.
Motexafin gadolinium (MGd) is an investigational pharmaceutical with radiation enhancing properties. Magnetic Resonance Imaging (MRI) was used to measure brain and tumor MGd levels to evaluate (1) ...the degree to which MGd passes through the intact blood brain barrier, and (2) the retention of MGd in tumor in patients with glioblastoma multiforme (GBM).
MRI studies were performed on GBM patients who participated in a phase I clinical trial in which MGd was given during standard fractionated radiation therapy. MGd was administered daily (Monday to Friday) for five or 10 doses as a loading regimen, followed by three times per week dosing as a maintenance schedule. T1-weighted MRI was performed at intervals throughout the course of the MGd administration and radiation therapy in the 33 participating patients. Eleven patients had pre- and post-MGd scans, allowing for study of MGd's normal blood brain barrier penetration. Twenty-two patients had adequate residual tumor for measurements to evaluate MGd retention in tumor during the course of MGd and radiation administration.
The studies of uninvolved brain tissue support the conclusion that MGd does not cross the intact blood brain barrier in detectable quantities. The tumor study showed MGd uptake during loading and maintenance without measurably significant fall off on non-dosage days during the maintenance dosing. Although the number of cases is small, the 10-day loading regimen showed greater drug loading and retention compared with the 5 days loading regimen.
The TG21 protocol introduced the Ngas calibration method for parallel plate chambers in high-energy electron beams. This calibration method was performed for a Markus parallel plate chamber in proton ...and electron beams of various energies as well as a 60Co beam. For an individual chamber, the Ngas value in proton beams differs from the Ngas value in cobalt and electron beams by the ratio of (W/e) for proton beams to that of a 60Co beam. While the replacement correction factor is essential for Markus chambers in low-energy electron beams, the results of our Nppgas measurements in proton beams showed that the Markus chamber does not need a replacement correction factor for therapeutic proton beams of energy 20-170 MeV. These results indicate that the 0.7-mm guard ring of the Markus chamber is adequate to prevent the in-scattering of secondary electrons produced by proton irradiation of the chamber wall or medium.
Motexafin Gadolinium (MGd) is an investigational radiation enhancer that has tumor-specific uptake. Furthermore, it is detectable by Magnetic Resonance Imaging (MRI) because the gadolinium within its ...molecular framework enhances the proton spin longitudinal relaxation of water molecules that can bind to it. In this dissertation research, MRI data that were collected in a Phase I clinical trial in which MGd was administered to glioblastoma multiforme (GBM) patients during standard radiation therapy (RT) were evaluated to answer the following five questions: (1) Does MGd cross the intact blood brain barrier? (2) Is MGd retained in tumor when the trial's dosing regimen was used? (3) How does MGd-induced enhancement of tumor MRI signal compare with that produced by a conventional MRI contrast agent? (4) Did MGd treatment during RT improve survival in GBM patients? (5) Can MRI relaxometry be used to obtain intratumoral MGd concentration? MGd-induced signal enhancement in T1-weighted magnetic resonance (MR) images was used to address questions 1 and 2. T1-weighted MR images obtained after administration of MGd were quantitatively compared to similar images obtained after administration of a conventional MRI contrast agent, gadodiamide (Omniscan®), in the same patients to address question 3. Kaplan-Meier survival analysis was used to answer question 4 with an UCLA clinical glioma database as case-matched controls. Question 5 was addressed by generating quantitative multi-parametric MR images from the raw images obtained during the trial. The findings are as follows: (1) MGd does not cross the intact blood brain barrier. (2) The dosing and maintenance regimen used in the trial were appropriate to maintain stable tumor MGd levels during RT. (3) MGd is less efficient than gadodiamide as an MRI contrast agent for GBM. (4) MGd administration in combination with RT failed to show survival benefit compared with RT alone. (5) Relaxometry maps were successfully generated and provided an estimate of tumor MGd concentrations.
Layered antiferromagnetism is the spatial arrangement of ferromagnetic layers with antiferromagnetic interlayer coupling. The van der Waals magnet chromium triiodide (CrI3) has been shown to be a ...layered antiferromagnetic insulator in its few-layer form, opening up opportunities for various functionalities in electronic and optical devices. Here we report an emergent nonreciprocal second-order nonlinear optical effect in bilayer CrI3. The observed second-harmonic generation (SHG; a nonlinear optical process that converts two photons of the same frequency into one photon of twice the fundamental frequency) is several orders of magnitude larger than known magnetization-induced SHG and comparable to the SHG of the best (in terms of nonlinear susceptibility) two-dimensional nonlinear optical materials studied so far (for example, molybdenum disulfide). We show that although the parent lattice of bilayer CrI3 is centrosymmetric, and thus does not contribute to the SHG signal, the observed giant nonreciprocal SHG originates only from the layered antiferromagnetic order, which breaks both the spatial-inversion symmetry and the time-reversal symmetry. Furthermore, polarization-resolved measurements reveal underlying C2h crystallographic symmetry-and thus monoclinic stacking order-in bilayer CrI3, providing key structural information for the microscopic origin of layered antiferromagnetism. Our results indicate that SHG is a highly sensitive probe of subtle magnetic orders and open up possibilities for the use of two-dimensional magnets in nonlinear and nonreciprocal optical devices.
Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers ...are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.
Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses
; however, the relationship between phenotypic characteristics and TCR ...properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8
T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide-human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire.
Developing a nanoscale, integrable, and electrically pumped single mode light source is an essential step toward on-chip optical information technologies and sensors. Here, we demonstrate nanocavity ...enhanced electroluminescence in van der Waals heterostructures (vdWhs) at room temperature. The vertically assembled light-emitting device uses graphene/boron nitride as top and bottom tunneling contacts and monolayer WSe2 as an active light emitter. By integrating a photonic crystal cavity on top of the vdWh, we observe the electroluminescence is locally enhanced (>4 times) by the nanocavity. The emission at the cavity resonance is single mode and highly linearly polarized (84%) along the cavity mode. By applying voltage pulses, we demonstrate direct modulation of this single mode electroluminescence at a speed of ∼1 MHz, which is faster than most of the planar optoelectronics based on transition metal chalcogenides (TMDCs). Our work shows that cavity integrated vdWhs present a promising nanoscale optoelectronic platform.
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