Proton Irradiation Research Articles

A spatially resolved analysis of dislocation loop and nanohardness evolution in proton irradiated Zircaloys

Proton irradiation is increasingly used as a surrogate for neutron irradiation, providing similar damage structures at significantly lower costs and less time compared to neutron irradiation. However, in contrast to neutrons, protons produce a depth dependent damage profile that incorporates a plateau region and a Bragg peak in the tens of microns region depending on the material and proton energy. Here we demonstrate that this depth dependent damage can be utilised to obtain new understanding about irradiation induced damage at different dose levels from a single sample by combining spatially resolved micro-beam synchrotron X-ray diffraction-based dislocation analysis and nanoindentation. For this purpose, and to study the damage evolution starting from very early stages, we have investigated microstructure evolution and hardening behaviour of Zircaloy-2 and Zircaloy-4 proton irradiated samples between 0.01 dpa and 17 dpa at 350 °C. The results highlight good agreements of SRIM-based damage depth predictions with irradiation-induced dislocation appearance and nanohardness. However, at even relatively low damage levels within the plateau region, dislocation line density and nanohardness profiles appear saturated across the entire irradiated region, even when the dpa levels differed significantly. When relating dislocation loop line densities to nanohardness, it was found that from a certain point hardness increased only very slightly with increasing line densities. This apparent discrepancy can be explained by a decreasing loop size for the highest line densities identified by from the diffraction line profile analysis and the application of a Dispersed Barrier Hardening model that relates obstacle strength to dislocation loop size.

MRI-based radiomic features for identifying recurrent prostate cancer after proton radiation therapy.

Magnetic Resonance Imaging (MRI) evaluation of recurrent prostate cancer (PCa) following proton beam therapy is challenging due to radiation-induced tissue changes. This study aimed to evaluate MRI-based radiomic features so as to identify the recurrent PCa after proton therapy. We retrospectively studied 12 patients with biochemical recurrence (BCR) following proton therapy. Two experienced radiologists identified prostate lesions from multi-parametric MRI (mpMRI) images post-proton therapy and marked control regions of interest (ROIs) on the contralateral side of the prostate gland. A total of 210 radiomic features were extracted from lesions and control regions on the T2-weighted (T2WI) and Apparent Diffusion Coefficient (ADC) image series. Recursive Feature Elimination with Cross-Validation method (RFE-CV) was used for feature selection. A Multilayer Perceptron (MLP) neural network was developed to classify three classes: cancerous, benign, and healthy tissue. The 12-core biopsy results were used as the gold standard for the segmentations. The classifier performance was measured using specificity, sensitivity, the area under receiver operating characteristic curve (AUC), and other statistical indicators. Based on biopsy results, 10 lesions were identified as PCa recurrence while eight lesions were confirmed to be benign. Ten radiomic features (10/210) were selected to build the multi-class classifier. The radiomics classifier gave an accuracy of 0.83 in identifying cancerous, benign, and healthy tissue with a sensitivity of 0.80 and specificity of 0.85. The model yielded an AUC of 0.87, 95% CI [0.72-1.00] in differentiating cancer from the benign and healthy tissues. Our proof-of-concept study demonstrates the potential of using radiomic features as part of the differential diagnosis of PCa on mpMRI following proton therapy. The results need to be validated in a larger cohort.

Creating uniform cluster dose spread-out Bragg peaks for proton and carbon beams.

Preliminary data have shown a close association of the generalized ionization cluster size dose (in short, cluster dose) with cell survival, independent of particle type, and energy, when cluster dose is derived from an ionization detail parameter preferred for its association with cell survival. Such results suggest cluster dose has the potential to replace RBE-weighted dose in proton and ion beam radiotherapy treatment plan optimization, should a uniform cluster dose lead to comparable biological effects. However, further preclinical investigations are warranted to confirm this premise. To present an analytical approach to create uniform cluster dose spread-out Bragg peaks (SOBP) for evaluation of the potential of cluster dose to result in uniform biological effect. We modified the coefficients of the Bortfeld and Schlegel weight formula, an analytical method typically used for the creation of radiation dose SOBP in particle therapy, to produce uniform cluster dose SOBP of different widths (1-5cm) at relevant clinical proton and carbon beam energies. Optimum parameters were found by minimization of the ratio between the maximum and minimum cluster dose in the SOBP region using the Nelder-Mead method. The coefficients of the Bortfeld and Schlegel weight formula leading to uniform cluster dose SOBPs were determined for each combination of beam energy and SOBP width studied. The uniformity of the resulting cluster dose SOBPs, calculated as the relative difference between the maximum and minimum cluster dose within the SOBP, was within 0.3%-3.5% for the evaluated proton beams and 1.3%-3.4% for the evaluated carbon beams. The modifications to the analytical approach to create radiation dose SOBPs resulted in uniform cluster dose proton and carbon SOBPs over a wide range of beam energies and SOBP widths. Such SOBPs should prove valuable in preclinical investigations for the selection of nanodosimetric quantities to be used in proton and ion therapy treatment planning.

Evolving Role of Proton Radiation Therapy in Clinical Practice.

With the expansion of proton radiation therapy centers across the United States and a gradually expanding body of academic evidence supporting its use, more patients are receiving-and asking about-proton therapy than ever before. Here, we outline, for nonradiation oncologists, the theoretical benefits of proton therapy, the clinical evidence to date, the controversies affecting utilization, and the numerous randomized trials currently in progress. We also discuss the challenges of researching and delivering proton therapy, including the cost of constructing and maintaining centers, barriers with insurance approval, clinical situations in which proton therapy may be approached with caution, and the issue of equitable access for all patients. The purpose of this review is to assist practicing oncologists in understanding the evolving role of proton therapy and to help nonradiation oncologists guide patients regarding this technology.

Resection of a Recurrent Lumbar Chordoma With Intradural Extension and Complex Dural Repair: 2-Dimensional Operative Video.

Chordomas are derived from embryonic notochord remnants and comprise 1%-4% of all bone tumors.1 Nearly all chordomas arise in the axial skeleton, with 50% in the sacrococcygeal region, 35% in the skull base and 15% within mobile spine vertebrae.1,2 Regional recurrence after en bloc surgery is common and 30%-40% of patients develop metastatic disease.3-6 In this operative video, we present a 41-year old man who previously underwent en bloc lateral L1 corpectomy and received high-dose hybrid photon and proton radiation therapy for treatment of his L1 chordoma. On surveillance imaging, 2 years post op MRI revealed recurrence of the chordoma, now extending to the L2-3 epidural space. Further radiation alone was considered but was not performed due to lack of separation between the tumor and neural elements, thus increasing the risk of radiation-induced neurological injury. Combination revision surgical resection with subsequent boost radiation therapy was pursued instead. The technical nuances to achieve complex ventral and dorsal dural repair after removal of a transdural lumbar chordoma are shown in detail. Postoperatively, the patient had no new neurological deficits. At 13 months postoperatively, he reports no new pain, can ambulate without assistance, and completed 33 treatments of radiation therapy with proton beam. The patient consented to the procedure and to the publication of his image.

Innovative Approach to Producing Palladium-103 for Auger-Emitting Radionuclide Therapy: A Proof-of-Concept Study.

Auger-emitting radionuclides, exemplified by Pd-103, exhibit considerable therapeutic potential in cancer treatment due to their high cytotoxicity and localized biological impact. Despite these advantages, the separation of such radionuclides presents a complicated challenge, requiring intricate and time-intensive "wet chemistry" methods attributed to the exceptional chemical inertness of the associated metals. This study proposes an innovative solution to this separation challenge through the design and implementation of a piece of radionuclide separation equipment (RSE). The equipment employs a dry distillation approach, capitalizing on differences in partial vapor pressures between irradiated and resulting radioactive metals, with a diffusion-driven extraction method applied to separate Pd-103 radionuclides generated via the proton irradiation of Rh-103 at cyclotron. Our optimization endeavors focused on determining the optimal temperature for effective metal separation and adjusting the diffusion, evaporation, and deposition rates, as well as addressing chemical impurities. The calculations indicate 17% ± 2% separation efficiency with our RSE. Approximately 77 ± 2% and 49 ± 2% of the deposited Pd-103 were isolated on substrates of Nb foil and ZnO-covered W disc, respectively. The proposed innovative dry distillation method that has been experimentally tested offers a promising alternative to conventional separation techniques, enabling enhanced purity and cost-efficient cancer treatment strategies.

Evaluation of in vitro irradiation setup: Designed for the horizontal beamline at the Danish Centre for Particle Therapy.

Radiobiological experimental setups are challenged by precise sample positioning along depth dose profile, scattering conditions, and practical difficulties that must be addressed in individual designs. The aim of this study was to produce cell survival curves with several irradiation modalities, by using a setup designed at the Danish Centre for Particle Therapy (DCPT) for in vitro proton irradiations using a horizontal beam line and thereby evaluating the setups use for in vitro irradiations experiments. The setup is a water phantom suitable for in vitro research with multiple irradiation modalities, in particular the pencil scanning proton beam available from a horizontal experimental beamline. The phantom included a water tank of 39.0 × 17.0 × 20.5 cm. Cell survival-curves were produced using the cell line V79 Chinese hamster lung fibroblast cells (V79s) in biological triplicates of clonogenic assays. Cell survival curves were produced with both a 18 MeV electron beam, 6 MV photon beam, and a Spread-Out Bragg Peak (SOBP) proton beam formed by pristine energies of 85-111 MeV where three positions were examined. Survival curves with uncertainty areas were made for all modalities. Dosimetric uncertainty amounted to, respectively, 4%, 3% and 3% for proton, electron, and high energy photon irradiations. Cell survival fraction uncertainty was depicted as the standard deviation between replications of the experiment. Cell survival curves could be produced with acceptable uncertainties using this novel water phantom and cellular laboratory workflow. The setup is useful for future in vitro irradiation experiments.

High dose proton and photon-based radiation therapy for 213 liver lesions: a multi-institutional dosimetric comparison with a clinical perspective

BackgroundStereotactic radiotherapy (SRT) and Proton therapy (PT) are both options in the management of liver lesions. Limited clinical-dosimetric comparison are available. Moreover, dose-constraint routinely used in liver PT and SRT considers only the liver spared, while optimization strategies to limit the liver damaged are poorly reported.MethodsPrimary endpoint was to assess and compare liver sparing of four contemporary RT techniques. Secondary endpoints were freedom from local recurrence (FFLR), overall survival (OS), acute and late toxicity. We hypothesize that Focal Liver Reaction (FLR) is determined by a similar biologic dose. FLR was delineated on follow-up MRI. Mean C.I. was computed for all the schedules used. A so-called Fall-off Volume (FOV) was defined as the area of healthy liver (liver-PTV) receiving more than the isotoxic dose. Fall-off Volume Ratio (FOVR) was defined as ratio between FOV and PTV.Results213 lesions were identified. Mean best fitting isodose (isotoxic doses) for FLR were 18Gy, 21.5 Gy and 28.5 Gy for 3, 5 and 15 fractions. Among photons, an advantage in terms of healthy liver sparing was found for Vmat FFF with 5mm jaws (p = 0.013) and Cyberknife (p = 0.03). FOV and FOVR resulted lower for PT (p < 0.001). Three years FFLR resulted 83%. Classic Radiation induced liver disease (RILD, any grade) affected 2 patients.ConclusionsCyberknife and V-MAT FFF with 5mm jaws spare more liver than V-MAT FF with 10 mm jaws. PT spare more liver compared to photons. FOV and FOVR allows a quantitative analysis of healthy tissue sparing performance showing also the quality of plan in terms of dose fall-off.

Production of 45Ti radioisotope by proton irradiation of natural scandium

45Ti is a positron emitter radioisotope with weak gamma radiation. As its half-life (T1/2 = 3.08 h) is in the same range that of 18F and comparable with 43,44Sc, it is a good metallic alternative for radio-labelling of different proteins and other applications in nuclear medicine. The activation cross section and yield for possible production routes have been measured by several authors for decades, but probably because of its weak gamma-line and the different measurement techniques the results are very different and confusing. In the present work proton induced reactions are investigated to gain reliable activation cross section for the 45Ti production from naturally monoisotopic scandium. The study also resulted in production cross sections of 44g,44m,43Sc and 44Ti as side products. The results are compared with the previous literature data and with the results of the latest TENDL version.

Degradation of electrical performance and radiation damage mechanism of cascode GaN HEMT with 80 MeV proton

In this paper, proton irradiations on Cascode GaN HEMT power device with an energy of 80 MeV and fluences of 2 × 1011 p/cm2 and 6 × 1011 p/cm2 have been carried out, where the threshold voltages drifted negatively by 20.55% and 28.17%, respectively. After two months of room temperature annealing, the threshold voltages recovered 0.22 V and 0.27 V, respectively. The ionizing deposition energy (IEL) was simulated by using Monte Carlo software and TCAD, it the results showed that the value of IEL in Si MOSFET is 5 ∼ 6 orders higher than that in GaN HEMT, while the value of the non-ionizing energy loss (NIEL) is one order higher than that in GaN HEMT. It means that the proton irradiation on the Cascode depleted GaN HEMT is more prone to produce displacement damage. As a large number of electrons and holes pairs were existed on the incident path of Si MOSFET under the proton irradiation, the produced electron will be captured by the gate oxide traps at the SiO2/Si interface, and the holes be captured by the defects generated in displacement damage, resulting in the accumulation of oxide trapped charges. Then, the electrical performance of Si MOSFET degrades seriously, thereby affecting the performance of the entire device. The studies will be helpful for the radiation hardening of Cascode GaN HEMT.

Laser interstitial thermal therapy as a radiation-sparing approach for central nervous system tumors in children with cancer predisposition syndromes: report of a child with Li-Fraumeni syndrome. Illustrative case.

Ionizing radiation and alkylating chemotherapies increase secondary malignancy risk in patients with cancer predisposition syndromes (CPSs), such as Li-Fraumeni syndrome. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has not been associated with mutagenic risks. We describe the case of a child with LFS and a history of treated choroid plexus carcinoma (CPC) who developed a second primary glial tumor that was safely treated with magnetic resonance imaging (MRI)-guided LITT. A 4-year-old male with left parietal World Health Organization grade III CPC associated with a TP53 germline mutation was evaluated. The patient underwent neoadjuvant platinum-based chemotherapy before near-total resection, followed by 131I-8H9 immunotherapy and 30 fractions of 54-Gy proton radiotherapy. He remained without evidence of disease for 2 years before developing a slow-growing mass adjacent to the left frontal ventricular horn. Stereotactic biopsy revealed a glial neoplasm. Given the nonsuperficial location and focality of the lesion, MRI-guided LITT was performed for ablative therapy. There were no complications, and 2 years of surveillance revealed continued retraction of the ablated tumor focus and no subsequent disease. Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

Improving the Accessibility and Efficiency of Proton Irradiations for 4He/3He Thermochronology

AbstractSynthesizing uniform and high concentrations of 3He within minerals via high‐energy proton irradiation is paramount for 4He/3He thermochronology and helium diffusion kinetic studies. Proton irradiations of geological material have hitherto exclusively been routinely conducted at the Francis H. Burr Proton Therapy Center (FHB); we thus explored alternative irradiation protocols at two European‐based facilities with the intention to improve the accessibility and efficiency in obtaining 4He/3He data. We conducted a single irradiation at the Paul Scherrer Institute (PSI) using an approach most similar to that used at FHB (wide, high‐energy beam), and four irradiations at the Helmholtz Zentrum Berlin (HZB) using a newly developed in‐vacuum irradiation protocol in a narrow, lower‐energy but high‐intensity beam. Internal shards of Durango apatite were irradiated in all experiments; 4He/3He release spectra and bulk 3He concentrations of PSI and HZB‐irradiated Durango shards were compared to those from FHB to assess the quality of each experiment in terms of the quantity and uniformity of synthesized 3He. While 3He was uniformly synthesized in PSI‐irradiated Durango shards, the bulk 3He concentration was below the required threshold due to limitations on the maximum allotted proton flux. Over the course of four irradiation experiments at HZB, the protocol evolved to ensure that uniform and high concentrations of 3He can be consistently induced. Furthermore, we demonstrate how HZB irradiations can be replicated using computer simulations, permitting the use of simulations to inform future modifications of the irradiation protocol in order to optimize the uniformity of the 3He distribution across all irradiated samples.

FLASH Proton Radiation Therapy Mitigates Inflammatory and Fibrotic Pathways and Preserves Cardiac Function in a Preclinical Mouse Model of Radiation-Induced Heart Disease

PurposeStudies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as “FLASH” radiotherapy, enhances the therapeutic index of radiation therapy (RT) by decreasing normal tissue damage while maintaining tumor response compared to conventional (or standard) RT. This study demonstrates the cardioprotective benefits of FLASH proton RT (F-PRT) compared to standard (conventional) proton RT (S-PRT), as evidenced by reduced acute and chronic cardiac toxicities. Methods and MaterialsMice were imaged using cone beam computed tomography to precisely determine the heart's apex as the beam isocenter. Irradiation was conducted utilizing a shoot-through technique with a 5mm diameter circular collimator. Bulk RNA-sequencing was performed on non-irradiated (NR) samples, as well as apexes treated with F-PRT or S-PRT, at 2 weeks following a single 40 Gy dose. Inflammatory responses were assessed through multiplex cytokine/chemokine microbead assay and immunofluorescence analyses. Levels of perivascular fibrosis were quantified using Masson's Trichrome and Picrosirius red staining. Additionally, cardiac tissue functionality was evaluated by 2D echocardiograms at 8 and 30 weeks post-PRT. ResultsRadiation damage was specifically localized to the heart's apex. RNA profiling of cardiac tissues treated with PRT revealed that S-PRT uniquely upregulated pathways associated with DNA damage response, induction of tumor necrosis factor superfamily and inflammatory response, while F-PRT primarily affected cytoplasmic translation, mitochondrion organization and ATP synthesis. Notably, F-PRT led to a milder inflammatory response, accompanied by significantly attenuated changes in TGF-β1 and αSMA levels. Critically, F-PRT decreased collagen deposition, and better preserved cardiac functionality compared to S-PRT. ConclusionsThis study demonstrated that F-PRT reduces the induction of an inflammatory environment with lower expression of inflammatory cytokines and profibrotic factors. Importantly, the results indicate that F-PRT better preserves cardiac functionality, as confirmed by echocardiography analysis, while also mitigating the development of long-term fibrosis.

СРАВНИТЕЛЬНАЯ ОЦЕНКА ВЛИЯНИЯ ЛОКАЛЬНОГО ПРОТОННОГО ИЗЛУЧЕНИЯ В ДОЗЕ 30 ГР НА МЫШЕЙ ЛИНИЙ BALB/с И С57BL/6

Purpose: To evaluate the effect of local proton irradiation at a dose of 30 Gy on Balb/c and C57BL/6 mice in terms of the degree and dynamics of radiation-induced skin damage formation, changes in body weight and peripheral blood elements count. Material and methods: Experiments were performed on non-depilated male mice aged 7‒8 weeks from two strains: Balb/c and C57BL/6 (n=15). Local irradiation of the skin was carried out on the dorsal side of the animals using a scanning proton beam at an extended Bragg peak in the proton therapy complex «Prometheus» of the LPI Physico-technical Centre (Protvino) at a dose of 30 Gy with a proton energy of 87.8 MeV. During the irradiation session, animals were subjected to intraperitoneal anesthesia using a combination of Zoletil 100 (Virbac, France) and Xyla (Interchemie, Netherlands) in a previously determined ratio 1:3 (20‒40 mg/kg). Photographic documentation of radiation-induced skin damage was performed weekly for 70 days. Animals were examined daily for clinical manifestations of radiation-induced skin damage formation according to the RTOG international scale for 21 days following irradiation. The body weight dynamics of mice were evaluated one day before irradiation and then weekly for 70 days. Blood samples were collected from the tail vein by cutting the tip of the tail and analyzed using a DH36 Vet hematology analyzer (Dymind, China) one day before irradiation, one day and three days after irradiation, and weekly thereafter for 70 days. Experimental data were presented as mean ± standard deviation (M ± SD). Results: In this study, the impact of a single local exposure to proton radiation at a dose of 30 Gy on the degree and dynamics of radiation-induced skin damage formation was evaluated. It was demonstrated that Balb/c mice exhibited a higher frequency and degree of radiation-induced skin damage formation compared to the C57BL/6 mice. Analysis of body weight in mice after radiation exposure revealed no significant decrease in either mouse strain. A comparative analysis of the number of platelets, erythrocytes and hemoglobin concentration in both mouse strains did not reveal any changes, while a tendency towards a decrease in the number of leukocytes, lymphocytes, and granulocytes was observed in the irradiated Balb/c mice group compared to the control group. Conversely, in irradiated C57BL/6 mice, the number of lymphocytes was higher compared to control animals. Conclusion: In this study, Balb/c mice exhibited higher radiosensitivity compared to C57BL mice in response to a single local proton irradiation at a dose of 30 Gy.

Effect of Proton Irradiation on the Optical Properties and Defect Formation in Gd3AlxGa5 – xO12 (x = 2, 3) Crystals

Effect of Proton Irradiation on the Optical Properties and Defect Formation in Gd3AlxGa5 – xO12 (x = 2, 3) Crystals

Characterizing Proton-Induced Biological Effects in a Mouse Spinal Cord Model: A Comparison of Bragg Peak and Entrance Beam Response in Single and Fractionated Exposures

Proton relative biological effectiveness (RBE) is a dynamic variable influenced by factors like linear energy transfer (LET), dose, tissue type, and biological endpoint. The standard fixed proton RBE of 1.1, currently used in clinical planning, may not accurately represent the true biological effects of proton therapy (PT) in all cases. This uncertainty can contribute to radiation-induced normal tissue toxicity in patients. In late-responding tissues such as the spinal cord, toxicity can cause devastating complications. This study investigated spinal cord tolerance in mice subjected to proton irradiation and characterized the influence of fractionation on proton- induced myelopathy at entrance (ENT) and Bragg peak (BP) positions. Cervical spinal cords of 8-week-old C57BL/6J female mice were irradiated with single- or multi-fractions (18x) using lateral opposed radiation fields at 1 of 2 positions along the Bragg curve: ENT (dose-mean LET = 1.2 keV/μm) and BP (LET = 6.9 keV/μm). Mice were monitored over 1 year for changes in weight, mobility, and general health, with radiation-induced myelopathy as the primary biological endpoint. Calculations of the RBE of the ENT and BP curve (RBEENT/BP) were performed. Single-fraction RBEENT/BP for 50% effect probability (tolerance dose (TD50), grade II paresis, determined using log-logistic model fitting) was 1.10 ± 0.06 (95% CI) and for multifraction treatments it was 1.19 ± 0.05 (95% CI). Higher incidence and faster onset of paralysis were seen in mice treated at the BP compared with ENT. The findings challenge the universally fixed RBE value in PT, indicating up to a 25% mouse spinal cord RBEENT/BP variation for multifraction treatments. These results highlight the importance of considering fractionation in determining RBE for PT. Robust characterization of proton-induced toxicity, aided by in vivo models, is paramount for refining clinical decision-making and mitigating potential patient side effects.

Effect of proton radiation on gallium nitride light emitting diodes

The compound semiconductor gallium nitride offers enormous potential for facilitating economic expansion in the silicon-based semiconductor industry, which is currently seeing decreasing performance returns compared to investment costs. Its high electron mobility and electric field strength at the material level have already demonstrated enormous potential for photonics and high-frequency communications applications. However, its application in devices used in the radiation-prone environment is hindered by degradation and failure caused by the radiation. In this paper, the effect of proton radiation on the electrical properties of InGaN light emitting diodes (LEDs) for the fluence range of 1×1014 cm-2 to 3×1014 cm-2 is performed. On comparing the results before and after radiation, it is found that radiation mainly affected the reverse IV characteristics of the device with little or no effect on forward IV or CV characteristics. Apart from the electric properties, the optical properties of the LEDs show improvement after radiation as the light intensity increases post-irradiation.

Precision radiotherapy for nasopharyngeal carcinoma

AbstractNasopharyngeal carcinoma(NPC) occurs frequently in Southern China, and radiotherapy is the main treatment method. At present, intensity‐modulated radiotherapy is widely used, which has improved efficacy in patients with NPC and reduced toxicity and side effects. Recently, helical tomography radiotherapy, proton radiotherapy, carbon particle radiotherapy, and other radiotherapy techniques have been used for the clinical treatment of NPC. Individualized nasopharyngeal cancer targets have also been explored. This paper reviews the research progress in radiotherapy techniques and target volume for NPC

Radiation-induced Bystander Effects on Glioblastoma Tumor Cells via NMDA Receptor Signaling.

Proton therapy has been widely applied on treating inaccessible and inoperable tumors, such as tumors deep within the brain or close to the critical brain stem. Nevertheless, the damaging effect of radiation for central nervous system (CNS) tumors is difficult to be confined within the irradiated region and has led to decline of neurological function in especially children with congenital CNS tumors. Currently, the involvement of n-methyl-d-aspartate (NMDA) receptors or secretary cytokines and chemokines in proton-induced bystander effects remains unclear. To understand the modulatory effects of NMDA receptor inhibition on the survival and proliferation of glioblastoma-derived cells, mesenchymal-like U373 cells were applied along with U87 neural glioblastoma cells for single doses of proton radiation at different LET in the presence or absence of pretreatment with memantine and/or collimation. Under collimation, neuronal tumor cells that are not directly irradiated (i.e., bystander cells) encounter similar biological effects potentially through cell coupling and synaptic transmission. Furthermore, whether proton LET plays a role in the mediation of bystander effect awaits to be elucidated. From this study, synaptic transmission was found to play differential roles in the proliferation of U373 and U87 cells after exposure to collimated radiation. Also, radiation-induced cell proliferation at the late stage was more correlated with bystander cell survival than early manifested γH2AX foci, suggesting that proton-induced glutamatergic synapse may act as a more important contributor than proton-induced direct effect on DNA double-stranded breaks to the late-stage responses of glioblastoma cells.

Performance and symptom validity indicators among children undergoing cognitive surveillance following treatment for craniopharyngioma.

Performance validity tests (PVTs) and symptom validity tests (SVTs) are essential to neuropsychological evaluations, helping ensure findings reflect true abilities or concerns. It is unclear how PVTs and SVTs perform in children who received radiotherapy for brain tumors. Accordingly, we investigated the rate of noncredible performance on validity indicators as well as associations with fatigue and lower intellectual functioning. Embedded PVTs and SVTs were investigated in 98 patients with pediatric craniopharyngioma undergoing proton radiotherapy (PRT). The contribution of fatigue, sleepiness, and lower intellectual functioning to embedded PVT performance was examined. Further, we investigated PVTs and SVTs in relation to cognitive performance at pre-PRT baseline and change over time. SVTs on parent measures were not an area of concern. PVTs identified 0-31% of the cohort as demonstrating possible noncredible performance at baseline, with stable findings 1 year following PRT. Reliable digit span (RDS) noted the highest PVT failure rate; RDS has been criticized for false positives in pediatric populations, especially children with neurological impairment. Objective sleepiness was strongly associated with PVT failure, stressing need to consider arousal level when interpreting cognitive performance in children with craniopharyngioma. Lower intellectual functioning also needs to be considered when interpreting task engagement indices as it was strongly associated with PVT failure. Embedded PVTs should be used with caution in pediatric craniopharyngioma patients who have received PRT. Future research should investigate different cut-off scores and validity indicator combinations to best differentiate noncredible performance due to task engagement versus variable arousal and/or lower intellectual functioning.