Radiation-related Side Effects Research Articles

Predicting radiotherapy response, Toxicities and quality-of-life related functional outcomes in soft tissue sarcoma of the extremities (PredicT) using dose–volume constraints development: a study protocol

IntroductionRadiotherapy improves local tumour control in patients with soft tissue sarcoma of the extremities (STSE) but it also increases the probability of long-term toxicities such as tissue fibrosis, joint stiffness...

Unbalanced core detector (UCD): a novel direct-reading dosimeter for FLASH radiotherapy

FLASH radiotherapy (FRT) is a novel radiotherapy technique based on dose rates that are several orders of magnitude greater than those used in conventional radiotherapy (40 Gy/s vs. 0.5–5 Gy/min). FRT is still in its preclinical and early clinical stage of development. However these studies indicate that FRT is more effective in sparing normal tissues from radiation-related side effects, as compared to conventional radiotherapy. This is the so-called "FLASH effect" and was observed with multi-MeV electron beams. Before FRT is made available to humans, more basic research is needed to fully understand its radiobiology fundamentals. Meanwhile, suitable radiation sources and dosimetric tools are gradually becoming available. Within this framework, INFN-LNF developed the Unbalanced Core Detector (UCD), a novel type of electron dosimeter designed to operate in the FRT domain. UCD main characteristics are the nearly isotropic response, the independence from the electron energy, the very high radiation resistance, the linearity up to dose rates of MGy/s and the possibility to record the time evolution of a single radiation pulse. UCD was tested using 7 and 9 MeV electron beams produced with the ElectronFlash accelerator from Sordina IORT Technologies (SIT S.p.A.) in Aprilia, Italy. UCD was used to measure dose distributions in a water phantom. The results well compare to those obtained with a flashDiamond detector from PTW.

Advancements in Adolescent Idiopathic Scoliosis Diagnosis: A Focus on Non-Invasive Techniques

Abstract: Adolescent idiopathic scoliosis (AIS) poses a significant health concern, affecting the spinal curvature of adolescents during their growth period. Early diagnosis of AIS is critical for effective intervention and management. However, conventional diagnostic methods often involve repetitive exposure to X-rays, which can lead to radiation-related side effects. This research paper explores the significance of early diagnosis in AIS and emphasizes the utilization of non-invasive techniques, particularly video raster stereography (VRS), combined with deep ensemble neural networks (DNNs) to enhance diagnostic accuracy while minimizing the risks associated with radiation exposure. We delve into the potential of DNNs in analyzing VRS data and compare its efficacy with other machine learning alternatives

Baseline total brain volume predicts changes in quality of life and overall survival after cranial radiotherapy in older patients with glioblastoma: Results from the prospective BRITER study.

Short-course partial brain radiotherapy ± chemotherapy for older patients with GBM extends survival but there is no validated evidence for prediction of individual risk of acute radiotherapy-related side effects. This prospective multicentre observational trial recruited patients with newly diagnosed GBM aged ≥65 planned for cranial radiotherapy. Baseline MRI scans were analyzed for markers of brain resilience including relative total brain volume (ratio of cerebrospinal fluid (CSF) volume to total intracranial volume (TIV)) and their relationship to change in quality of life (QoL). 126 patients enrolled: mean age 72 years (range 65-83). 77% had debulking surgery. 79% received radiotherapy with concurrent TMZ, and 21% received palliative radiotherapy alone. The median OS was 10.7 months. After accounting for age, sex, treatment, and baseline MoCA score, there was a relationship between baseline CSF:TIV and change in QoL score at 8 weeks post treatment. For each unit point of increase in CSF:TIV, there was a corresponding decrease in QoL score of 1.72 (95% CI -3.24 to -0.19 P = .027). 35 participants were too unwell to complete questionnaires or had died by the 8 week follow-up visit. In this subgroup, post hoc logistic regression showed baseline CSF:TIV was related to the risk of non-attendance (OR 1.35, 95% CI 1.01 to 1.80, P = .042). Cox regression models showed baseline CSF:TIV was associated with worsened OS (HR 1.41, 95% CI 1.19 to 1.66, P < .001). This study provides evidence to support the use of an imaging biomarker to help assess the risk:benefit ratio for radiotherapy.

Abstract A003: HPV infection causes dependence on alternative DNA damage response pathways providing cancer specific targets for radiosensitization

Abstract Targeted radiosensitization is an attractive approach to improving the efficacy of radiotherapy in cancer treatment. However, drugs targeting ubiquitous DNA damage response (DDR) pathways are not cancer specific and can increase radiation related side effects. Thus, there is an unmet clinical need for tumor specific molecular targets. To address this need we sought to identify DNA damage signaling pathways that are unique to cancer cells. We hypothesized that by expressing its genome in host cells high-risk Human Papilloma Virus (HPV) can rewire DNA damage signaling making HPV-positive tumor cells dependent on alternative pathways to survive radiation, which can be exploited for targeted radiosensitization of HPV-induced cancers. Using a CRISPR/Cas9 screen in cells that selectively express HPV16 proteins E6 or E7 we uncovered genes that cells rely on to survive radiation-induced DNA damage in the context of E6 or E7 expression. We demonstrate that targeting these newly identified genes sensitizes cancer cells to radiation specifically in the presence of E6 or E7. We provide mechanistic insights showing that E6 and E7 alter the cellular epigenome by inhibiting histone lysine acetylation and tri-methylation, respectively. In this setting, a member of a centromeric protein complex identified in the screen is critical for mitotic progression and survival in E6-expressing cells following radiation exposure. Deletion of this factor resulted in delayed mitotic progression, chromosomal missegregation and rapid post-mitotic death in irradiated HPV-positive cells, a phenotype that was mitigated by ablation of E6 expression. Furthermore, we identified an E3 ubiquitin ligase that promotes survival in E7-expressing cells following radiation exposure by alleviating perturbations during DNA replication. Together, we have uncovered DDR pathways that are critical for cell survival after radiation exposure specifically in HPV-positive cells. Our findings suggest that expression of viral proteins E6 and E7 rewires DNA damage signaling networks causing dependence on alternative response pathways. We propose that these pathways can be targeted for tumor-specific radiosensitization of HPV-induced cancers. Citation Format: Michael Goldstein, Akhil Kotwal, Nishanth Gabriel, William Buchser, Monica Sentmanat, Stephanie Markovina, Julie Schwarz, Xia Cui. HPV infection causes dependence on alternative DNA damage response pathways providing cancer specific targets for radiosensitization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A003.

Ruthenium‐ 106 brachytherapy in the treatment of central choroidal melanoma

Aims/Purpose: Choroidal melanoma is the most common ocular malignancy. Depending on the size of the tumour and its location in relation different treatment options are available. Brachytherapy with β‐emitting Ruthenium‐ 106 plaque is an effective and widely used treatment. The treatment of juxtapapillary and juxtafoveolar choroidal melanoma is challenging because it involves the macula and optic nerve. Studies have shown that central choroidal melanomas have a high recurrence rate.Methods: A total of 56 eyes of 56 patients with central choroidal melanoma were included in this retrospective study and treated with Ru‐106 brachytherapy between January 2011 and July 2020 in our institution. As central choroidal melanomas were defined all juxtafoveolar melanomas with a posterior edge touching an optic disc‐ fovea‐ radius around the fovea (about 5 mm). We measured visual acuity, recurrence, radiation related side effects and metastasis. The mean follow‐ up time was 66 (6–136) months.Results: Of the 56 eyes, 8 eyes (14%) showed a recurrence during the follow‐ up period. It was shown that the choroidal melanomas closer to the optic disc have a higher recurrence rate than the once close to the macula (69% vs. 95%). A radiation retinopathy was detected in 7 eyes (13%), a radiation opticopathy in 7 eyes (13%) and a radiation maculopathy in 10 eyes (17.9%). 6 eyes (11%) had to be enucleated because of recurrence or radiation complication.Conclusions: Ruthenium brachytherapy is an effective therapy for central choroidal melanoma with a rate of preserving the eye of 89%. The localization of the choroidal melanoma near the optic disc goes ahead with a higher rate of complications and recurrences.

QOL-23. BASELINE TOTAL BRAIN VOLUME PREDICTS FOR POORER QOL AND REDUCED OVERALL SURVIVAL AFTER CRANIAL RADIOTHERAPY IN OLDER PATIENTS WITH GLIOBLASTOMA (GBM): RESULTS FROM THE PROSPECTIVE BRITER STUDY

Abstract GBM incidence peaks in the 7th and 8th decades of life with prognosis worsening with age. Short-course partial brain radiotherapy, +/- chemotherapy, extends survival but there is no validated evidence for prediction of individual risk of acute radiotherapy related side effects. BRITER, a prospective multicentre observational trial, recruited patients with newly diagnosed GBM aged ≥ 65 planned for cranial radiotherapy. Baseline MRI scans were analysed for 5 putative markers of brain resilience including relative total brain volume (ratio of cerebrospinal fluid (CSF) volume to total intracranial volume (TIV)) and their relationship to change in QoL. 126 patients were enrolled; mean age 72 years (range 65-83); 67% men, 33% women. 4% had a radiological diagnosis, 19% biopsy and 77% had debulking surgery. 21% received palliative radiotherapy alone (25% 30Gy/6#, 75% 40Gy/15#), 79% received radiotherapy with concurrent TMZ (47% 40Gy/15#, 53% 60Gy/30#). Median OS was 11.3 months. After accounting for age, sex, treatment and baseline MoCA score, there was a significant relationship between baseline CSF:TIV ratio and change in QoL score at 8 weeks post treatment. For each unit point of increase in CSF:TIV ratio, there was a corresponding decrease in EORTC QLC C30 QoL score by a factor of 1.27 (coefficient -1.27, 95% CI -3.24 to -0.19 p = 0.02). 35 participants were too unwell to complete questionnaires or had died by the 8 week follow up visit. In this subgroup, post hoc logistic regression showed baseline CSF:TIV ratio was related to risk of non-attendance (OR 1.35, 95% CI 1.01-1.80, p = 0.04). Cox regression models were fitted for time to death in 88 participants who had analysable baseline MRI sequences. Baseline CSF:TIV was associated with worsened OS (HR 1.41, 95% CI 1.19-1.66, p &amp;lt; 0.001). This unique prospective study indicates that baseline imaging parameters can predict the impact of cranial radiotherapy on QoL and OS.

Active Breathing Coordinator reduces radiation dose to the stomach in patients with left breast cancer

Background/Purpose Gastric dose parameters comparison for deep inspiration breath-hold (DIBH) or free breathing (FB) mode during radiotherapy (RT) for left-sided breast cancer patients (LSBCPs) has not been investigated before. This study aimed to analyze the impact of Active Breath Coordinator (ABC)-DIBH technique on the dose received by the stomach during RT for LSBCPs and to provide organ-specific dosimetric parameters. Materials and methods The study included 73 LSBCPs. The dosimetric parameters of the stomach were compared between FB and DIBH mode. The correlation between the stomach volume and dosimetric parameters was analyzed. Results Compared to FB mode, statistically significant reductions were observed in gastric dose parameters in ABC-DIBH mode, including Dmax (46.60 vs 17.25, p < 0.001), D1cc (38.42 vs 9.60, p < 0.001), Dmean (4.10 vs 0.80, p < 0.001), V40Gy (0.50 vs 0.00, p < 0.001), V30Gy (6.30 vs 0.00, p < 0.001), V20Gy (20.80 vs 0.00, p < 0.001), V10Gy (51.10 vs 0.77, p < 0.001), and V5Gy (93.20 vs 9.60, p < 0.001). ABC-DIBH increased the distance between the stomach and the breast PTV when compared to FB, from 1.3 cm to 2.8 cm (p < 0.001). Physiologic decrease in stomach volume was not found from FB to ABC-DIBH (415.54 cm3 vs 411.61 cm3, p = 0.260). The stomach volume showed a positive correlation with V40Gy (r2 = 0.289; p < 0.05), V30Gy (r2 = 0.287; p < 0.05), V20Gy (r2 = 0.343; p < 0.05), V10Gy (r2 = 0.039; p < 0.001), V5Gy (r2 = 0.439; p < 0.001), Dmax (r2 = 0.269; p < 0.05) and D1cc (r2 = 0.278; p < 0.05) in FB mode. While in ABC-DIBH mode, most stomach dosimetric parameters were not correlated with gastric volume. Conclusions The implementation of ABC-DIBH in LSBCPs radiotherapy resulted in lower irradiation of the stomach. Larger stomach volume was associated with statistically significantly higher dose irradiation in FB mode. To reduce radiotherapy related side effects in FB mode, patients should be fast for at least 2 hours before the CT simulation and treatment.

Use of botulinum toxin in the management of radiotherapy side effects.

Many experimental and clinical studies are conducted to investigate the effects of various applications of botulinum toxin (BTx) in the treatment of radiation related side effects. There are no studies that show clear results about the positive and negative effects of its active clinical use in the long run, and discussions are ongoing. In addition, there is a need for various researches about how BTx can be used and how long it can be used, and the side effects it may cause. BTx-A, which is one of the options in the treatment of side effects that will occur due to radiotherapy, is an effective and safe option. Applying BTx injection to the right place with specific injection methods increases the effectiveness and safety of the treatment. It has been investigated whether BTx will be a potential tool to perfect the esthetic and functional results in reducing the chronic side effects associated with radiotherapy.

HPV Infection Causes Dependence on Alternative DNA Damage Response Pathways Providing Cancer Specific Targets for Radiosensitization

Cancer-specific radiosensitization is an attractive approach to improving the efficacy of radiotherapy. However, drugs targeting ubiquitous DNA damage response pathways are not cancer specific and can increase radiation related side effects. Thus, there is an unmet need for tumor specific molecular targets. This approach requires an identification of DNA damage signaling pathways that are unique to cancer cells. We hypothesized that by expressing its genome in the host cells HPV infection can rewire DNA damage signaling making HPV-positive tumor cells dependent on alternative pathways to survive radiation, which can be exploited for radiosensitization of HPV-induced cancers. We have performed a CRISPR/Cas9 screen in HPV-positive SiHa cells that either express HPV16 proteins E6 and E7 or contain a selective knock-out of E6 or E7. We used next-generation sequencing to determine the abundance of gRNA in cells that were mock-treated or irradiated. We identified genes that were required for survival of radiation specifically in the context of E6 or E7 expression. Results of the screen were validated by generating knock-outs of the discovered genes using CRISPR/Cas9. By applying an array of molecular tools to analyze cell survival, cell cycle progression and mitotic progression we assessed the role of these genes in radiation response in HPV-positive cancer cells. We have identified genes that are required for survival of radiation-induced DNA damage in the context of either E6 or E7 expression. We demonstrate that targeting these genes results in hypersensitization of cervical cancer cells to radiation specifically in the presence of E6 or E7. We show that the gene product required for survival in E6-expressing cells is critical for mitotic progression after radiation exposure serving as a member of a protein complex stabilizing the attachment of mitotic spindle to centromeres. We have uncovered specific genes that are critical for DNA damage response and cell survival after radiation exposure in HPV-positive cells. Our findings suggest that expression of the HPV proteins E6 and E7 rewires DNA damage signaling causing dependence on alternative response pathways. We propose that these pathways can be targeted for a tumor-specific radiosensitization of HPV-induced cancers.

P11.01.A BASELINE TOTAL BRAIN VOLUME PREDICTS FOR POORER QUALITY OF LIFE AND REDUCED OVERALL SURVIVAL AFTER CRANIAL RADIOTHERAPY IN OLDER PATIENTS WITH GLIOBLASTOMA (GBM): RESULTS FROM THE PROSPECTIVE BRITER STUDY

Abstract BACKGROUND GBM incidence peaks in the 7th and 8th decades, with median life expectancy of 3-6 months. Treatment decisions finely balance benefit to side-effects and worsening quality of life (QoL). Short-course partial brain radiotherapy, +/- chemotherapy, extends survival compared to supportive care but there is no validated evidence for prediction of individual risk of acute radiotherapy related side effects. We aimed to consider putative MRI markers of brain resilience and their relationship to change in QoL amongst older patients being treated for GBM with cranial radiotherapy. MATERIAL AND METHODS BRITER, a prospective multicentre observational trial, recruited patients with newly diagnosed GBM aged ≥ 65 planned for cranial radiotherapy. Baseline MRI scans were analysed for: relative total brain volume (ratio of cerebrospinal fluid (CSF) volume to total intracranial volume (TIV)), contralateral medial temporal lobe volume, number and volume of T1 white matter hypointensities, and Fazekas' scale of white matter change. Radiotherapy treatment volumes were obtained from planning software. RESULTS 126 patients were enrolled from 12 UK centres; mean age 72 years (range 65-83); 67% men, 33% women. 4% had a radiological diagnosis, 19% biopsy and 77% had debulking surgery. 21% received palliative radiotherapy alone (25% 30Gy/6#, 75% 40Gy/15#), 79% received radiotherapy with concurrent TMZ (47% 40Gy/15#, 53% 60Gy/30#). Median OS was 11.3 months. 56 participants completed all MRI sequences and QoL data points. After accounting for age, sex, treatment and baseline MoCA score, there was a significant relationship between baseline CSF:TIV ratio and change in QoL score. For each unit point of increase in CSF:TIV ratio, there was a corresponding decrease in EORTC QLC C30 QoL score by a factor of 1.27 (coefficient -1.27, 95% CI -3.24 to -0.19 p=0.02). 35 participants were too unwell to complete questionnaires or had died by the 8 week follow up visit. In this subgroup, post hoc logistic regression showed baseline CSF:TIV ratio was related to risk of non-attendance (OR 1.35, 95% CI 1.01-1.80, p=0.04). Cox regression models were fitted for time to death in 88 participants who had analysable baseline MRI sequences. Baseline CSF:TIV was associated with worsened OS (HR 1.41, 95% CI 1.19-1.66, p&amp;lt;0.001). CONCLUSION This unique prospective study indicates that baseline imaging parameters can predict the impact of cranial radiotherapy on QoL and OS. Due to frailty, there was a significant attrition rate in data return. 29% of participants were too unwell by 8 weeks post treatment to attend hospital, also predicted by baseline imaging. These results promote and enable discussion of individualised treatment options with older patients with GBM, differentiating those who are likely to suffer reduced QoL and short survival rather than benefit from radiotherapy

Flash Radiotherapy: Innovative Cancer Treatment

Flash radiotherapy (Flash-RT) is an innovative technique used in radiotherapy for cancer treatment because it delivers an extremely high dose of radiation (&gt;40 Gy/s) to the tumour in a very short period of time, typically within a fraction of a second. This ultra-fast delivery of radiation distinguishes Flash-RT from conventional radiotherapy, which typically involves the delivery of radiation over a longer time period, often several minutes. Studies conducted in cell and preclinical models suggested that Flash-RT may spare normal tissues from radiation-related side effects, such as skin toxicity, gastrointestinal complications, and damage to organs-at-risk. This is believed to be due to the unique normal tissue response to the ultra-high dose rate. Nevertheless, while Flash-RT shows promising results in preclinical and early clinical studies, one should note that the technique is still in the early stages of development. This entry provides a comprehensive exploration of the immense potentials of Flash-RT, covering its background, mechanisms, radiation sources, recent experimental findings based on cell and preclinical models, and future prospects. It aims to provide valuable insights into this innovative radiotherapy technology for anyone interested in the subject.

Role of sarcopenia on survival and treatment-related toxicity in head and neck cancer: a narrative review of current evidence and future perspectives.

The purpose of this article is to provide an up-to-date summary of sarcopenia and its clinical implications for patients with head and neck cancer (HNC). We conducted a literature review of recent studies investigating the prevalence of sarcopenia in HNC patients, its detection using MRI or CT scans, and its association with clinical outcomes such as disease-free and overall survival time, radiotherapy-related side effects, cisplatin toxicity, and surgical complications. Sarcopenia, characterized by low skeletal muscle mass (SMM), is a prevalent condition in HNC patients and can be effectively detected using routine MRI or CT scans. Low SMM in HNC patients is associated with increased risks of shorter disease-free and overall survival times, as well as radiotherapy-related side effects such as mucositis, dysphagia, and xerostomia. In addition, cisplatin toxicity is more severe in HNC patients with low SMM, leading to higher dose-limiting toxicity and treatment interruptions. Low SMM may also predict higher risks of surgical complications in head and neck surgery. Identifying sarcopenic patients can aid physicians in better riskstratifying HNC patients for therapeutic or nutritional interventions to improve clinical outcomes. Sarcopenia is a significant concern for HNC patients and can impact their clinical outcomes. Routine MRI or CT scans can effectively detect low SMM in HNC patients. Identifying sarcopenic patients can aid physicians in better risk-stratifying HNC patients for therapeutic or nutritional interventions to improve clinical outcomes. Further research is needed to explore the potential of interventions to mitigate the negative effects of sarcopenia in HNC patients.

Achieving Exceptional Cochlea Delineation in Radiotherapy Scans: The Impact of Optimal Window Width and Level Settings.

Introduction Radiation therapy (RT) aims to maximize the dose to the target volume while minimizing the dose to organs at risk (OAR), which is crucial for optimal treatment outcomes and minimal side effects. The complex anatomy of the head and neck regions, including the cochlea, presents challenges in radiotherapy. Accurate delineation of the cochlea is essential to prevent toxicities such as sensorineural hearing loss. Educational interventions, including seminars, atlases, and multidisciplinary discussions, can improve accuracy and interobserver agreement in contouring. This study seeks to provide radiation oncology practitioners with the necessary window width and window level settings in computed tomography (CT) scans to accurately and precisely delineate the cochlea, using a pre-and post-learning phase approach to assess the change in accuracy. Methods and materials The study used the ProKnow Contouring Accuracy Program (ProKnow, LLC,Florida, United States), which employs the StructSure method and the Dice coefficient to assess the precision of a user's contour compared to an expert contour. The StructSure method offers superior sensitivity and accuracy, while the Dice coefficient is a more rudimentary and less sensitive approach. Two datasets of CT scans, one for each left and right cochlea, were used. The author delineated the cochlea before and after applying the proposed technique for window width and window level, comparing the results with those of the expert and general population. The study included a step-by-step method for cochlea delineation using window width and window level settings. Data analysis was performed using IBMSPSSStatistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, United States). Results The implementation of the proposed step-by-step method for adjusting window width and window level led to significant improvements in contouring accuracy and delineation quality in radiation therapy planning. Comparing pre- and post-intervention scenarios, the author exhibited increased StructSure scores (right cochlea: 88.81 to 99.15; left cochlea: 88.45 to 99.85) and Dice coefficient scores (right cochlea: 0.62 to 0.80; left cochlea: 0.73 to 0.86). The author consistently demonstrated higher contouring accuracy and greater similarity to expert contours compared to the group's mean scores both before and after the intervention. These results suggest that the proposed method enhances the precision of cochlea delineation in radiotherapy planning. Conclusion In conclusion, this study demonstrated that a step-by-step instructional approach for adjusting window width and window level significantly improved cochlea delineation accuracy in radiotherapy contouring. The findings hold potential clinical implications for reducing radiation-related side effects and improving patient outcomes. This study supports the integration of the instructional technique into radiation oncology training and encourages further exploration of advanced imaging processing and artificial intelligence applications in radiotherapy contouring.

Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro.

Radiation resistance and radiation-related side effects warrant research into alternative strategies in the application of this modality to cancer treatment. Designed in silico to improve the pharmacokinetics and anti-cancer properties of 2-methoxyestradiol, 2-ethyl-3-O-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) disrupts microtubule dynamics and induces apoptosis. Here, we investigated whether pre-exposure of breast cancer cells to low-dose ESE-16 would affect radiation-induced deoxyribonucleic acid (DNA) damage and the consequent repair pathways. MCF-7, MDA-MB-231, and BT-20 cells were exposed to sub-lethal doses of ESE-16 for 24 h before 8 Gy radiation. Flow cytometric quantification of Annexin V, clonogenic studies, micronuclei quantification, assessment of histone H2AX phosphorylation and Ku70 expression were performed to assess cell viability, DNA damage, and repair pathways, in both directly irradiated cells and cells treated with conditioned medium. A small increase in apoptosis was observed as an early consequence, with significant repercussions on long-term cell survival. Overall, a greater degree of DNA damage was detected. Moreover, initiation of the DNA-damage repair response was delayed, with a subsequent sustained elevation. Radiation-induced bystander effects induced similar pathways and were initiated via intercellular signaling. These results justify further investigation of ESE-16 as a radiation-sensitizing agent since pre-exposure appears to augment the response of tumor cells to radiation.

Overview of radiotherapy-induced chronic pain in childhood cancer survivors: A narrative review.

Radiotherapy is an important aspect of oncological treatment in several childhood cancers. However, radiotherapy is known to have numerous side effects, including detrimental effects on growth, neurocognitive impairment, and the development of secondary malignancies. One less studied long-term side effect of pediatric radiotherapy treatment is chronic pain. While the short-term toxicities of radiotherapy resolve over a few weeks to months, the chronic pain caused by radiotherapy-induced tissue damage can significantly affect children's quality of life. As long-term childhood cancer survivors age into adulthood, they are typically followed up by a wide variety of doctors, not all of whom may be familiar with radiotherapy-induced chronic pain and its management. The aim of this review is to discuss the various common manifestations of radiotherapy-related pain in children, as well as ways to identify and manage these. Common radiotherapy-related side effects leading to chronic pain symptoms include radiation fibrosis, enteritis, dermatitis, lymphedema, neuropathic pain, and effects on bone development. The pathophysiology, evaluation and management of these are briefly summarized in this review. This is followed by an overview of radiotherapy techniques that allow greater sparing of normal tissue, minimizing future painful side effects. Finally, the assessment of pain in children is described, as well as strategies for management, and red flag symptoms that should prompt urgent specialist referral. In conclusion, a good understanding of the long-term side effects of radiotherapy treatment in children is essential for the various medical professionals that follow-up the child in the years after treatment. For young children, the evaluation of pain is in itself a challenge, and effects on growth, development, and learning are crucial. For older children, social and psychological factors become increasingly important. As radiation therapy techniques continue to advance, the spectrum and incidence of chronic pain syndromes may change over time.

Disease Control after Radiotherapy for Adult Craniopharyngioma: Clinical Outcomes from a Large Single-Institution Series

<h3>Purpose/Objective(s)</h3> To report disease control and treatment-related side effects among adult patients with craniopharyngioma treated with radiotherapy. <h3>Materials/Methods</h3> We performed a single-institution review of adult patients (>21 years old) with craniopharyngioma treated with radiotherapy either definitively or postoperatively for gross residual disease. We report disease control, survival, and radiotherapy-related side effects. <h3>Results</h3> A total of 49 adult patients with craniopharyngioma were included, 27 of whom were treated at initial presentation and 22 for recurrent disease following initial surgery and observation. Overall, 77% received radiotherapy post-operatively (either after primary surgery or surgery for recurrence). With a median clinical and radiographic follow-up of 4.2 (range, 0.4 to 21.6) years and 3.0 (range, 0 to 21.5) years, the 5- and 10-year local control rates were 100% and 94%, respectively. The 5- and 10-year overall survival rates were 80% and 66%, respectively. Eleven percent of patients experienced grade 2 vision deterioration and 18% suffered grade 2 endocrinopathies following radiotherapy. Six patients (12%) developed transient post-radiotherapy cyst enlargement. <h3>Conclusion</h3> Radiotherapy provides excellent disease control with acceptable toxicity among adult patients with craniopharyngioma. These data support the use of fractionated radiotherapy in adult patients with recurrent or gross residual disease after surgery. For inoperable patients or those with moderate or high surgical risk to neurologic and/or vascular structures, we advocate for limited surgical resection and postoperative radiotherapy to balance optimal tumor control with tumor- and treatment-related morbidity.

Enhanced Radiation-Sparing Effects of Ultra-High Dose Rate Proton Radiation (FLASH-RT) in a Human Induced Pluripotent Stem Cell-Derived Cerebral Organoid Model

<h3>Purpose/Objective(s)</h3> Superior normal tissue sparing with similar antitumoral effectiveness has been observed in preclinical animal models following delivery of radiation at ultra-high dose rates (FLASH-RT), relative to conventional dose rates (CONV-RT). Clinical application of FLASH-RT could reduce devastating radiation-related side effects for patients with aggressive brain tumors such as glioblastoma; however, the FLASH effect must be established in representative models of human systems before its implementation in the clinic. Our objective is to measure relevant response outcomes to proton FLASH-RT using advanced cerebral organoid (CO) models of normal and diseased human brain tissue, correspondingly generated with human induced pluripotent stem cells and patient-derived glioma stem-like cells (GSCs). <h3>Materials/Methods</h3> Mature COs were irradiated to 9 Gy using conventional (CONV, 0.2 Gy/s) and FLASH (100 Gy/s) dose rates using a proton beam and prepared for histological analysis at 30 days post-irradiation. Spatial distribution of hypoxia was visualized in COs by incubating for 2 hours with pimonidazole prior to preparation for histologic analysis. Image analysis was performed with QuPath. Lactate dehydrogenase (LDH) release, a marker of cell death, was sequentially quantified. COs implanted with GSCs expressing a luciferase reporter were co-cultured for 14 days and irradiated as above. Tumor cell proliferation was tracked via luciferase expression. <h3>Results</h3> At 2- and 4-days post-irradiation, there was an increase in LDH release for CONV versus FLASH-radiated COs (p<0.01, p<0.01 respectively) which normalized after 9 days. At 30 days, when specific cell populations in FLASH-radiated COs were histologically compared to CONV-radiated COs, there were higher numbers of proliferating neural progenitor cells (SOX2+/Ki67+, p<0.01), mature neurons (NeuN+, p=0.03), and deep cortical surface layer neurons (SATB2+, p=0.01). The spatial distribution of neural progenitor cells and mature neurons overlapped with hypoxic regions of the CO (pimonidazole+). A trend towards lower expression of activated microglia (IBA1+/CD68+) in FLASH-irradiated COs compared to CONV-radiated COs was noted (p=0.12). A 48.6% versus 51.2% reduction in tumor proliferation in FLASH versus CONV-irradiated GSC-laden-COs was observed at 4d post-irradiation (p=0.98). <h3>Conclusion</h3> We report preliminary findings of normal tissue toxicity reduction and iso-effective tumor response in a human-derived brain model following proton FLASH-RT. Potential protective effects following FLASH-RT to be further validated include preservation of specific cell populations within hypoxic niches including progenitor and differentiated neurons with a corresponding reduction in chronic neuroinflammation.

Long-term toxicity of radiosurgery for ablation of ventricular tachycardia

Abstract Introduction There is a rising interest in using radiosurgery to modify arrhythmogenic substrate in patients with recurrent VT. However, data on the safety are still inadequate. Purpose This is update of toxicity evaluation based on the compilation from our case series, NIRA-VT and STAR-VT. Methods Between 2014 and March 2021, 36 patients (33 male, 3 females; mean age 66±10 years) with structural heart disease (ischemic cardiopathy, dilated cardiopathy or fibroma associated scar) from two electrophysiology centers in the Czech Republic (Trinec, Prague) underwent radiosurgery for recurrent VT. Radiosurgery was performed after at least one failed catheter ablation for VT. The critical part of the VT substrate was identified by electroanatomic mapping using a combination of voltage mapping, pace mapping, and activation mapping; and it was marked on a contrast-enhanced computer tomography study as a CTV. In NIRA-VT trial, CTV included scar based on PET/CT evaluation. Radiosurgery system with real-time motion tracking using the tip of the electrode of an indwelling defibrillator as a fiducial marker was used. A total radiation dose of 25 Gy was delivered to the ablation target in a single session during free breathing. Radiation-induced toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Only patients with follow up longer than 6 months were included in long term radiation related side effects evaluation. Results The mean CTV and PTV were 26±11 ml and 41±22 ml respectively. No patient exhibited acute (up to 3 months) elevation of troponin, pericardial effusion, or a decrease in left ventricular ejection fraction from baseline. Four patients developed acute mild nausea, which waned after antiemetic drugs. Long-term radiation related side effects were evaluated in 19 patients. Two patients (11%) presented radiological signs of lung fibrosis in small area in close distance from PTV. There was no significant decrease in left ventricular ejection fraction during follow up. Six patients (33%) gradually developed significant progression of known mitral regurgitation after SBRT, two (11%) of them had to undergo mitral valve replacement (grade 4 toxicity). Two cases of esophagitis (12%) were seen with one radiation toxicity related death (grade 5 toxicity) due to the unresectable esophagi-pericardial fistula (6%). Conclusions Our data indicate the feasibility of radiosurgery, majority of patients presented no/mild radiation related toxicity and decrease of VT burden. However, we have seen three cases of grade 4,5 toxicity. To further investigate long-term safety and efficacy of radiosuergery for VT, enrolling into a randomized prospective study is in progress. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020

Effectiveness of Standard Margin Stereotactic Radiosurgery Dose to Brain Metastases

This study aims to assess efficacy of a 15-Gy margin dose in terms with the hypothesis that efficacy will be comparable with historical controls with fewer radiation-related side effects. Patients who received single-fraction stereotactic radiosurgery (SRS) for metastatic brain tumors (prescribed 1500 cGy with 2-mm planning tumor volume) at the University of Missouri Hospital between 2004 and 2018 with at least 3 months of follow-up were retrospectively reviewed. Demographics, lesion dimensions, concurrent therapy, and treatment history before SRS were assessed. Outcomes included local control, distant control, radiation-related changes, survival, repeat SRS or whole-brain radiation therapy, and side effects. Data from the literature were pooled for a meta-analysis. A total of 142 patients had at least 3 months of follow-up data available. The 12-month actual local control rate among these patients was 92% per tumor. The overall intracranial control rate was 66.9% per patient. Radiation-related side effects occurred in 32.4% of patients (n= 46), with some patients having more than 1 side effect. Radiation-related radiographic changes occurred in 48 lesions (10.6%) in 37 patients (26%). Pathologically confirmed radiation necrosis occurred in 19 lesions (4%) and in 18 patients (12.6%). Local and distant control rates for this population was comparable with historical controls. Side effects in the literature are inconsistently reported, so rigorous comparative analysis is not possible. A single-fraction radiosurgery margin dose of 15 Gy to the planning tumor volume can effectively provide local control and distant control and is comparable with historical controls, which use 18-25 Gy, with a good toxicity profile.