bluuebunny/crossref_metadata_2025_split huggingface dataset:
P12.20.B [18F]FDG PET/CT BRAIN SCAN IN THE EVALUATION OF NEUROTOXICITY IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH CAR-T
Authors: Asadurova S , Lorenzo C , Simó M , Ariño H , Vilaseca A , Zabalza A , Iacoboni G , Carpio C , Barba P 
Published: October 2024

Abstract

BACKGROUND
Neurotoxicity is one of the serious and life-threatening complications of CAR-T treatment in patients with diffuse large B-cell lymphoma. Our objective is to identify the findings in brain PET/CT, their evolution over time, and their clinical correlation. We also aim to compare the sensitivity of PET/CT with magnetic resonance imaging (MRI).

MATERIAL AND METHODS
This prospective study includes 33 patients with diffuse large B-cell lymphoma treated with CAR-T therapy. Whole-body and brain [18F]FDG PET/CT scans were performed pre-treatment and 30 days post-therapy. In cases of suspected immune effector cell-associated neurotoxicity syndrome (ICANS), urgent structural imaging (CT or MRI) and [18F]FDG PET/CT brain scans were conducted, among other tests.

RESULTS
The mean age was 62±12 years, with a male-to-female ratio of 19:14. 70% of patients (23/33) developed grade 1, 2, or 3 cytokine release syndrome (CRS). 27% (9/33), all with prior CRS, showed symptoms of ICANS (3/9 G1, 3/9 G2 and 3/9 G3 ICANS). The most common symptoms were tremor, disorientation, and bradypsychia, starting on average on the 7th day post-infusion (range 1 to 10). Urgent [18F]FDG PET/CT brain scans were performed on 7 of the 9 ICANS patients, showing diffuse cortical hypometabolism compatible with encephalopathy in 5 (5/7) and no significant findings in 2/7. At the 30-day post-treatment evaluation, complete normalization was observed in 2/5 patients, improvement with persistent mild global cortical hypometabolism in 2/5, and one patient (1/5) died before the 30 days (with G3 ICANS and severe cortical and subcortical hypometabolism on PET imaging). Urgent brain MRI was performed on the 7 patients with ICANS and urgent [18F]FDG PET brain scans, and it was normal in 5/7 and pathological in 2/7 (both with grade 3 ICANS).

CONCLUSION
[18F]FDG PET/CT brain scan is useful for the diagnosis and follow-up of patients with CAR-T related neurotoxicity (ICANS) and shows greater sensitivity than MRI. Future studies should determine the relationship between acute phase PET findings and long-term prognosis.
P13.02.A A CLINICALLY RELEVANT IN VIVO MODEL RECAPITULATES THE LATE EFFECTS OF RADIOTHERAPY IN CHILDHOOD MEDULLOBLASTOMA SURVIVORS
Authors: Egnuni T , Castle J , Shaw G , Weller D , Fielder E , Singh M , Skinner R , von Zglinicki T , Clifford S , Miwa S , Hicks D , Short S C 
Published: October 2024

Abstract

BACKGROUND
Medulloblastoma (MB) is the most common malignant brain tumour in children, with a 5-year survival rate of up to 80%. However, survival is often accompanied by debilitating late-effects that occur as a result of the cranial-radiotherapy. Survivors typically experience increased frailty, reduced physical functioning and impaired neurocognitive functioning. Here, we describe a clinically relevant in vivo model that recapitulates age-equivalent MB radiotherapy dose, and the resulting late-effect profile with potential for future intervention studies.

MATERIAL AND METHODS
Thirty-six male C57BL/6J juvenile mice at 35 postnatal days (PND) were randomly allocated into 3 equal groups (G1-G3). G1 mice received sham treatment; G2 mice received 10 fractions of 3Gy whole brain cranial-radiotherapy (CRT; human-equivalent of 37.5Gy EQD2) and G3 mice received CRT with 3x 3Gy of posterior fossa boost (PFB) in addition (48.75Gy EQD2). The Small Animal Radiation Research Platform (SARRP) was used to deliver radiation using a 10mm x 10mm collimator with gantry running from - 60° to 60°. Frailty, physical functioning and neurocognitive impairment were longitudinally assessed using frailty index (FI), grip strength test, rotarod test, Y-maze and Barnes maze up to PND394.

RESULTS
No mice died from acute radiation toxicity and there was no significant difference in either survival or body weight loss among all treatment groups. There was no significant difference between G2 and G3 mice in most of the assessments, suggesting receipt of PFB caused no additional deficits. Assessment of frailty showed significantly higher FI in mice that received CRT at PND97 (p=0.001), PND130 (p=0.0001), PND191 (p=0.007) and PND233 (p=0.002) compared to the sham group. CRT treated mice had significantly reduced grip strength at PND233 (p=0.006; grip strength test) and poor body balance and co-ordination at PND172 (p=0.003; rotarod). Assessment of working memory using the Y-maze showed a significant memory deficit in CRT group at PND266 compared to sham treated group (p=0.009). Barnes-maze short-term memory (STM) and long-term memory (LTM) assessment at 24 hours and 7 days after training, respectively, showed significantly decreased LTM (p=0.029) but not STM (p=0.392) in CRT treated group compared to sham treated mice.

CONCLUSION
Our in vivo model showed that juvenile mice tolerated high doses of CRT. We demonstrated increased frailty, physical and neurocognitive impairments that coincides with the late-effect profile observed in CRT treated childhood MB survivors. Importantly, this clinically relevant in vivo model provides a baseline model for the future appraisal of interventions to alleviate the late-effects experienced by childhood MB survivors.
P13.05.B DYNAMICS OF POST-RADIOTHERAPY MORPHOLOGICAL CHANGES IN THE BRAIN
Authors: Turcas A , Tipcu A , Homorozeanu B , Cernea D , Turcas A , Leucuta D , Achimas-Cadariu P 
Published: October 2024

Abstract

BACKGROUND
Radiotherapy is essential in achieving local control for many brain tumours. However, it carries the risks of toxicities, including neuro-cognitive decline, with potential impact on quality of life. Several brain areas and structures are involved in cognition, but their radiosensitivity and clinical response to radiotherapy is not yet fully understood, and no dose-thresholds are yet established. We studied the dynamics of morphological changes on MRI imaging of 18 brain structures following radiotherapy and investigated predictive factors of their occurrence. Identifying such imaging biomarkers could help develop sparing strategies and improve treatment planning.

MATERIAL AND METHODS
We included 40 patients treated for gliomas in a tertiary cancer center between 2018-2022 and contoured a set of 18 structures on T1-MRI sequences acquired at 3, 6, 9 months, 1 and 2 years after treatment. Dosimetric data were extracted from dose-volume histograms of the delivered plan, and for each structure the baseline volume and volumes in dynamics were noted. Correlations were tested by calculating the Spearman coefficient (rho) and comparisons between different groups were made using the paired Wilcoxon test, with statistical significance for p&lt;0.05

RESULTS
The mean age at diagnosis was 47 years. All patients underwent pre-radiotherapy surgical resection. Twenty tumors were left-sided, 18 on right-sided, 1 infratentorial and 1 on the midline. Radiotherapy regimens were normo-fractionated (1.8-2Gy/fr) in 67.5% of cases, and the rest were hypofractionated (&gt;2.67Gy/fr). Most structures registered a slight increase in volume at 3 months, followed by a gradual decrease over the two-year follow-up A correlation was observed between the dynamics of Hippocampal and Putamen volumes with Dmean, with loss of 0.55% of Hippocampal volume with each additional 1 Gy added to Dmean (rho = -0.293, p = 0.054) and 0.45% decrease in Putamen volume for every additional 1 Gy for Dmean (rho = -0.373, p = 0.018). The magnitude of volumetric changes was not significantly associated with dose per fraction, patient age, or overall treatment time.

CONCLUSION
In our cohort of patients, we identified a particular pattern of post-irradiation volume dynamics in selected structures, with a slight increase in volume as an acute effect, followed by progressive, dose-dependent, late atrophy. Our results pave the way for further exploration and validation in subsequent studies, including prospective neurocognitive testing and correlation of dosimetric, volumetric and clinical data.
P13.06.A EVALUATION OF BBB PERMEABLE WEE1 AND CHK1 INHIBITORS IN COMBINATION WITH STANDARD OF CARE FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Scholefield E L , Gomez-Roman N 
Published: October 2024

Abstract

BACKGROUND
Glioblastoma (GBM) is a highly aggressive intracranial malignancy of unmet clinical need. Current therapies such as temozolomide (TMZ) chemotherapy exert suboptimal efficacy, necessitating new therapies such as those targeting nuclear kinases, Wee1 and Chk1. Wee1 and Chk1 are master regulators of S phase and G2/M arrest ensuring DNA replication and genomic stability. Wee1 via inhibitory phosphorylation of CDK1 regulates the intra-S phase checkpoint and G2/M arrest, while Chk1 via Cdc25 inhibition controls mitotic entry and replication fork regulation in S phase. Previous studies combining commercially available Wee1 inhibitor AZD1775 and Chk1 inhibitor AZD7762 showed synergism in melanoma cells. However, a prerequisite of GBM therapies is blood-brain barrier (BBB) penetrance for drugs, thus we assessed synergism in combinations of TMZ with novel Wee1 and Chk1 inhibitors specifically developed for BBB penetrance to deduce their potential for use in GBM treatment.

MATERIAL AND METHODS
Primary patient-derived G7 GBM cells grown in stem-enriched conditions were used in medium-throughput ClonoScreen3D assays. 180 cells per well were seeded into Matrigel-coated 3D-Alvetex 96-well plates and incubated for 20 hours prior to drug treatment. Cells were incubated for 13 days before incubation with MTT reagent for manual colony quantification. Drugs tested were TMZ (0-3 µM); Chk1i-a (0-0.31 µM); Chk1i-b (0-0.31 µM); and Wee1i-a (0-0.31 µM) in a half-log serial dilution.

RESULTS
Treatment of G7 cells with Chk1i-b showed the highest single-agent activity (EC50=73 nM, confidence interval (CI)=0.677-0.774), followed by Chk1i-a (EC50 = 125 nM, CI=0.393-0.805) and TMZ (EC50=849 nM, CI=0.042-0.826) as assessed by clonogenic survival assay (CSA). TMZ+Chk1i-a showed the strongest synergism in combination in G7 cells (mean combination index score (CIS)=0.49), followed by Chk1i-a+Wee1i-a (mean CIS=0.52), and Chk1i-b+Wee1i-a (mean CIS=0.74). Wee1i-a+Chk1i-a caused the highest reduction in clonogenicity measured via CSA, while TMZ+Chk1i-a showed the strongest synergism in combination.

CONCLUSION
Our novel BBB-permeable Wee1 and Chk1 inhibitors show synergism inducing higher cell kill in patient-derived G7 GBM stem-like cells. Combinations will next be tested with radiation to deduce radiosensitisation effects. With synergism observed between novel BBB-penetrant Wee1 and Chk1 inhibitors, these drugs show potential in becoming viable new therapies for GBM treatment.
P13.09.B INVESTIGATING THE EFFECTS OF RADIATION FRACTION DOSES ON THE MOLECULAR BARRIER PERMEABILITY OF AN IN VITRO BLOOD-BRAIN BARRIER MODEL
Authors: Ozturk M , Caglar F , KOYLU M , KAMER S 
Published: October 2024

Abstract

BACKGROUND
Brain tumors and metastases are major causes of death. The blood-brain barrier (BBB) makes it difficult to treat these conditions as it prevents drugs from reaching the tumor. We aim to evaluate the BBB’s permeability changes caused by varying radiotherapy doses. This will help develop treatment strategies that can benefit from this impaired function.

MATERIAL AND METHODS
We used an in vitro model of BBB by seeding cells in a 24-well plate with a porous membrane-separated insert. Human umbilical vein endothelial cells (HUVEC) and human astrocyte cells (NHA) were used for seeding. Transendothelial electrical resistance (TEER) measurements verified the accuracy of the model. A device developed by the Department of Physics was used for TEER measurement. Radiation was delivered in single fractions of 2, 4, 6, 8, 16, and 25 Gy. After ionizing radiation, the cells were incubated with the TEER device for 72 hours, with measurements taken every two hours. In addition, glioblastoma (GBM) cell lines were seeded at the bottom of the 24-well plate where the insert was placed to assess drug dose efficiency, which can vary according to membrane permeability. Two different drugs were applied to the irradiated BBB model. Membrane permeability was determined by ELISA, MTT proliferation assay, and cell wound healing assay.

RESULTS
There was a significant decrease in TEER values in all dose groups after irradiation compared to the control group (p&lt;0.001). No significant difference was found when fraction doses were evaluated (p=0.639). The most significant dose-independent decrease occurred between hours 2 and 6. It was noted that the change in the rate of resistance decline increased in direct proportion to the dose. Temozolomide (TMZ), used to evaluate the proliferation of GBM cell lines seeded on the bottom after irradiation, was effective on GBM cell proliferation, and the lowest dose for effective permeability was 4 Gy. In the cell wound healing experiment performed as an indicator of repopulation and repair capacity, it was observed that while bridging started in the early hours after irradiation in the TMZ-treated groups at low fraction doses, there was no wound closure at the end of 72 hours at high fraction doses. When the results of ELISA measurements made after the application of trastuzumab (TRAS), which is 750 times larger than TMZ, were evaluated, TRAS levels below 500 ng/ml were found at doses of 2, 4, and 6 Gy. TRAS levels of 1500 ng/ml were measured at doses of 8, 16, and 25 Gy.

CONCLUSION
Our study demonstrates that different doses of ionizing radiation combined with chemotherapy may increase tumor access to therapeutic agents and evaluates the time course of this relationship. We conclude that permeability through the BBB is related to molecular weight, which increases proportionally with increasing dose fraction.
P13.11.A OUTCOMES FOLLOWING CYBERKNIFE FOR VESTIBULAR SCHWANNOMA: THE ST. BARTHOLOMEW’S HOSPITAL EXPERIENCE
Authors: Christodoulou P , Hill T , de Luna P , Parasekevopoulos D , McFeely G , Dean C , Bowles S , Cook J , Rozati H , Plowman P N , Burton K , Rashed S , Pollock J , Shoakazemi A , Lewis R 
Published: October 2024

Abstract

BACKGROUND
Vestibular schwannomata (VS) represent &lt;10% of brain tumours. Treatment strategies are surveillance, surgical resection, stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT). Since 2019 SRS/SRT has been delivered with CyberKnife (CK) at Barts. After analysis of dosimetry and verification, the GTV to PTV margin was reduced from 1mm to 0mm, and dose prescribed to the 50% isodose for a single fraction, or 65% if fractionated, with the aim of maintaining tumour control rates whilst sparing additional toxicity. PRV to OARs remained 1mm in both groups.

MATERIAL AND METHODS
patients were treated with 1mm GTV to PTV expansion (Group 1) and the remaining 57 patients were treated without additional PTV margin (Group 2). Post-treatment imaging and clinic letters were reviewed to assess rates of tumour control and reported adverse events. Results of reducing the PTV margin were compared with previous practice and against the International Stereotactic Radiosurgery Society (ISRS) guidelines. Median follow-up was 32.5 months, range 9 - 56 months.

RESULTS
All patients in group 1 were treated with 21Gy in 3 fractions. 16 patients in Group 2 (24%) were treated with a single 12Gy fraction. The median dose was 21Gy in 3 fractions, with no patients treated over more than 5 fractions. Change in PTV prescription did not affect tumour control rate. At the point of reporting, tumour control was achieved in 64/66 patients. 1 patient from group 1 proceeded to microsurgical resection at 3 months. The second patient, from group 2, declined surgery and continues with close surveillance. The majority of patients experienced no side effects (38 patients). The most common acute toxicity was headache (33% in group 1 vs 26% group 2), reduced hearing (33% vs 16%) and facial/trigeminal nerve deficit (11% vs 9%). Of those who experienced acute toxicity, for 17 patients (45%) it persisted for greater than 12 weeks, equally distributed between facial/trigeminal nerve deficits, reduced hearing or dizziness. Persistent toxicity was more common in Group 1 (55% vs 21%). 2 patients required V-P shunt insertion after treatment (one from group 1 and one from group 2).

CONCLUSION
Given the limitations of our small retrospective analysis it appears that CK is an effective and safe treatment for VS. Our rate of tumour control is comparable to international standards with improved rates of hearing preservation (79% vs 67%). Our data suggest reduced treatment margin does not have an impact on tumour control but is associated with reduced toxicity. The toxicity rates in group 2 are consistent with expected toxicity from published data. Long-term follow-up is required to further evaluate tumour control and late effects.
P13.17.A THE EFFECTS OF RADIOTHERAPY ON GREY AND WHITE MATTER VOLUME IN THE BRAINS OF PATIENTS WITH HEAD AND NECK CANCER
Authors: van der Weijden C W J , Wickborn K , Kramer M C A , Buunk A M , Spikman J M , Langendijk J A , van Zon-Meijer T W H , de Vries E F J , van der Hoorn A 
Published: October 2024

Abstract

BACKGROUND
Patients with head-and neck-cancer (HNC) often receive radiotherapy as part of their treatment. Due to the tumour location, exposure of the brain to irradiation is inevitable, but the brain is not confounded by effects of having an intracranial brain tumour. Detailed knowledge of radiotherapy-induced effects on the brain can help to improve treatment planning by optimizing radiation doses and avoiding critical brain structures, thereby reducing the risk of neurotoxicity while effectively treating the tumour and thus improving quality of life. As T1w MRI allows the quantification of grey matter and white matter volumes, it can be used as proxies to assess tissue alterations. Therefore, this study aims to evaluate whether changes in grey and/or white matter volume could be detected in patients with HNC treated with radiotherapy.

MATERIAL AND METHODS
Patients with HNC that received radiotherapy (&gt;50 Gy) as part of their regular treatment were subjected to T1w (MP2RAGE) MRI at the start of radiotherapy and at the end of radiotherapy (0-14 days). Differences in grey and white matter volume of various brain regions in the posterior fossa, inferior temporal lobe, and medial temporal lobe (total 24 ROIs) between start and end of radiotherapy was determined. These brain regions were chosen, as they are closest to the tumour location. Differences in brain volumes were correlated to the radiation dose using Spearman correlations.

RESULTS
So far, 9 of 40 patients have been enrolled. They had a mean age of 50±15 years. Two were female and 7 male and 2 received photon radiotherapy and 7 proton radiotherapy. From evaluated brain regions, grey matter volume of the right middle and inferior temporal gyrus was significantly lower (p=0.043) after radiotherapy (8.39±0.87 mL) than before radiotherapy (8.87±1.01 mL). For other regions, no significant differences were observed. Only non-significant increases in white matter ROI volumes between start and end of radiotherapy were observed. Differences in brain region volumes between start and end of radiotherapy were not significantly correlated with the radiation dose, neither for grey matter (-0.30±0.30 ρ) for white matter (0.19±0.30 ρ).

CONCLUSION
With an inclusion of 9 out of 40 subjects, we mainly found non-significant changes in grey and white matter volumes after radiotherapy in HNC patients, although reductions in temporal grey matter reached significance. More inclusions are necessary to reach proper power and to determine whether changes in brain volumes can be used for early detection radiotherapy induced brain alterations and if they correlate with radiotherapy dose.

FUNDING
This study is supported by a VENI grant to Anouk van der Hoorn (no: 09150161910041).
P14.11.B DISTINGUISHING RESPONDERS FROM NON-RESPONDERS IN PATIENTS WITH GLIOBLASTOMA AFTER FIRST LINE THERAPY USING GRASP DCE-MRI
Authors: Vankan B , Rommers N , Psychogios M N , Todea R A 
Published: October 2024

Abstract

BACKGROUND
After completion of radiochemotherapy distinguishing responders from non-responders in glioblastoma patients with conventional sequences is still challenging. The purpose of this study is to investigate whether Golden Angle Radial Sparse Parallel Dynamic Contrast-Enhanced (GRASP DCE) MRI can aid in making this differentiation.

METHODS
In total, 66 patients with glioblastoma, diagnosed between 01/2017-12/2021 who had undergone first line therapy and developed new or enlarging contrast-enhancing lesions suspicious of tumor progression and had GRASP DCE-MRI, were analyzed. Using MRI follow-up, PET CT, histology as gold standard the scans were classified into two groups: responders and non-responders to first line therapy. The scans were then analyzed based on the time window after the completion of radiochemotherapy during which they had been completed (1-2, 3-4, 5-6, &gt;6 months) and then all together independent of the time window. To evaluate the accuracy of the DCE-MRI kinetics parameters in differentiating responders from non-responders, a descriptive analysis and a diagnostic accuracy analysis were performed using the area under the receiver operating characteristic curve.

RESULTS
In total, 138 GRASP DCE-MRI scans were analyzed. The peak enhancement (PE%) and the initial area under the curve for 30 seconds (IAUC 30) 60 seconds (IAUC 60), were consistently lower in the responders (n=63) than in the non-responders (n=75). Considering the scans independent of their time window, the PE% for responders vs non-responders was 29% IQR [26, 35] vs. 53% IQR [45, 69] respectively. The best threshold to differentiate the responders from non-responders was 41% (Sensitivity 89% (95% CI [83, 96]), Specificity 87% (95% CI [78, 95]), AUC 0.94 (95% CI [0.89, 0.98])). The IAUC 30 for responders vs. non-responders was 949 IQR [756, 1196] vs. 1627 IQR [1358, 2058] respectively. The best threshold to differentiate the responders from non-responders was 1079 (Sensitivity 93% (95% CI [87, 99]), Specificity 68% (95% CI [57, 79]), AUC 0.90 (95% CI [0.85, 0.94])). The IAUC 60 for responders vs. non-responders was 1847 IQR [1439, 2386] vs. 3337 IQR [2670, 3965] respectively. The best threshold to differentiate the responders from non-responders was 2614 (Sensitivity 79% (95% CI [69, 88]), Specificity 83% (95% CI [75, 92]), AUC 0.89 (95% CI [0.84, 0.94])).

CONCLUSION
The peak enhancement and the initial area under the curve (30 seconds), extracted from GRASP DCE MRI, considering all scans independent of their time window, had the best diagnostic accuracy to differentiate responders from non-responders in glioblastoma patients with a threshold of 41% vs 1079 respectively.