Tumor Hypoxia Heterogeneity Affects Radiotherapy: Inverse-Percolation Shell-Model Monte Carlo Simulations

Tumor hypoxia was discovered a century ago, and the interference of hypoxia with all radiotherapies is well known. Here, we demonstrate the potentially extreme effects of hypoxia heterogeneity on radiotherapy and combination radiochemotherapy. We observe that there is a decrease in hypoxia from tumor periphery to tumor center, due to oxygen diffusion, resulting in a gradient of radiative cell-kill probability, mathematically expressed as a probability gradient of occupied space removal. The radiotherapy-induced break-up of the tumor/TME network is modeled by the physics model of inverse percolation in a shell-like medium, using Monte Carlo simulations. The different shells now have different probabilities of space removal, spanning from higher probability in the periphery to lower probability in the center of the tumor. Mathematical results regarding the variability of the critical percolation concentration show an increase in the critical threshold with the applied increase in the probability of space removal. Such an observation will have an important medical implication: a much larger than expected radiation dose is needed for a tumor breakup enabling successful follow-up chemotherapy. Information on the TME’s hypoxia heterogeneity, as shown here with the numerical percolation model, may enable personalized precision radiation oncology therapy.

Novel Criteria for Intratumoral Budding with Prognostic Relevance for Colon Cancer and Its Histological Subtypes

Peritumoral budding and intratumoral budding (ITB) are important prognostic factors for colorectal cancer patients. Scientists worldwide have investigated the role of budding in tumor progression and its prognosis, but guidelines for reliably identifying tumor buds based on morphology are lacking. In this study, next-generation tissue microarray (ngTMA®) construction was used for tumor bud evaluation, and highly detailed rule-out annotation was used for tumor definition in pancytokeratin-stained tissue sections. Initially, tissues of 245 colon cancer patients were evaluated with high interobserver reliability, and a concordance of 96% was achieved. It was shown that high ITB scores were associated with poor distant metastasis-free survival (p = 0.006 with a cut-off of ≥10 buds). This cut-off was defined as the best maximum value from one of two/three ngTMA® cores (0.6 mm diameter). ITB in 30 cases of mucinous, medullary, and signet ring cell carcinoma was analyzed for the subsequent determination of differences in tumor bud analyses between those subtypes. In conclusion, blinded randomized punched cores in the tumor center can be useful for ITB detection. It can be assumed that this method is suitable for its adoption in clinical routines.

Six-month follow-up of functional status in discharged patients with coronavirus disease 2019

Background The long-term functional outcome of discharged patients with coronavirus disease 2019 (COVID-19) remains unresolved. We aimed to describe a 6-month follow-up of functional status of COVID-19 survivors. Methods We reviewed the data of COVID-19 patients who had been consecutively admitted to the Tumor Center of Union Hospital (Wuhan, China) between 15 February and 14 March 2020. We quantified a 6-month functional outcome reflecting symptoms and disability in COVID-19 survivors using a post-COVID-19 functional status scale ranging from 0 to 4 (PCFS). We examined the risk factors for the incomplete functional status defined as a PCFS > 0 at a 6-month follow-up after discharge. Results We included a total of 95 COVID-19 survivors with a median age of 62 (IQR 53–69) who had a complete functional status (PCFS grade 0) at baseline in this retrospective observational study. At 6-month follow-up, 67 (70.5%) patients had a complete functional outcome (grade 0), 9 (9.5%) had a negligible limited function (grade 1), 12 (12.6%) had a mild limited function (grade 2), 7 (7.4%) had moderate limited function (grade 3). Univariable logistic regression analysis showed a significant association between the onset symptoms of muscle or joint pain and an increased risk of incomplete function (unadjusted OR 4.06, 95% CI 1.33–12.37). This association remained after adjustment for age and admission delay (adjusted OR 3.39, 95% CI 1.06–10.81, p = 0.039). Conclusions A small proportion of discharged COVID-19 patients may have an incomplete functional outcome at a 6-month follow-up; intervention strategies are required.

Neoadjuvant/Perioperative Treatment Affects Spatial Distribution and Densities of Tumor Associated Neutrophils and CD8+ Lymphocytes in Gastric Cancer

Tumor associated neutrophils (TANs) and cytotoxic T cells (CTLs) are part of the tumor microenvironment of gastric cancer (GC). We explored their tumor biological significance in neoadjuvantly/perioperatively treated GC. Immunostaining was performed on whole tissue sections of 173 GCs, using antibodies directed against myeloperoxidase (MPO) and CD8. Stained specimens were digitalized, and the densities of TANs and CTLs were assessed separately in the mucosa, tumor surface, tumor center, invasion front, and tumor scar. The densities were correlated with clinicopathological patient characteristics. Compared with a historical cohort of 449 treatment naive GCs, the TAN density in the invasion front was significantly lower in neoadjuvantly/perioperatively treated GCs. TAN density in the tumor center and invasion front correlated with tumor regression. TAN density also correlated with CTL density in the tumor center and invasion front. A high density of CTL in the tumor center correlated with an improved overall survival and tumor specific survival. We show that neoadjuvant/perioperative (radio-) chemotherapy impacts on the immune microenvironment of GC, while also depending on sex. The density of TANs in neoadjuvantly/perioperatively treated GCs differed from findings made in a treatment naive GC cohort.

EXTH-40. MULTIDIMENSIONAL INTERROGATION OF GLIOBLASTOMA MICROENVIRONMENT TREATMENT RESPONSE IN EXPLANT CULTURES

The immune tumor microenvironment (iTME) of glioblastoma (GBM) contains microglial, macrophage, other myeloid cell populations and as adaptive immune cells. Recent therapeutic strategies for GBM aim at targeting iTME components to induce antitumoral immunity. A patient-tailored, ex vivo drug testing and response analysis platform would facilitate personalized therapy planning, provide insights into treatment-induced immune mechanisms in the iTME, and enable the discovery of biomarkers of response and resistance. Here, we generated patient-derived, live 3D GBM bioreactors from different tumor regions to assess iTME treatment responses to microglia modulators and immune checkpoint inhibitors. Intact GBM tissue specimens from the tumor center and periphery were cultured for 7 days in the presence or absence of anti-PD1, anti-CD47 antibodies or their combination. Tissues were analyzed by CODEX highly multiplexed microscopy using an immune-centered 54-marker panel, and changes in cytokine and chemokine levels in culture supernatants were investigated. A computational pipeline for integrative therapy response assessment was implemented. Explant cultures from n=8 IDH wt GBM were subjected to this integrative personalized analysis. Tissue integrity after 3D bioreactor cultures was comparable to tissue taken directly after surgery. FFPE CODEX workflow was feasible with adequate staining quality in bioreactor cultures. 850'000 single cells were segmented and clustered. Cellular composition between tumor center and the peripheral invasion zone differed significantly in immune phenotypes, cytokine profile and response to innate, adaptive or combinatorial local immunotherapies. Multiplexed cytokine analysis revealed IFNγ response signatures in a subset of center samples, whereas the peripheral invasion zone displayed a blunted cytokine response. This cytokine signature corresponded to cellular composition shifts within specific cellular neighborhoods. CD4 and CD8 T cells were invigorated and left their vascular niche. Our study demonstrates that local immunotherapies enable an active antitumoral immune response within the tumor center, and provides a multidimensional personalized framework for immunotherapy response assessment.

INNV-31. NEURO-ONCOLOGY OUTPATIENT SATISFACTION IS MAINTAINED IN THE ERA OF COVID-19 TELEMEDICINE

INTRODUCTION The use of telemedicine increased during the COVID-19 pandemic. However, the impact on patient satisfaction in the Neuro-oncology population is unknown. This quality improvement project compares outpatient satisfaction before and during the COVID-19 pandemic as well as in-person versus telemedicine platforms during the pandemic. METHODS We performed an IRB-exempt retrospective analysis of aggregate de-identified outpatient satisfaction scores among Neuro-oncology patients seen at The Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke University. The Clinician & Group Consumer Assessment of Healthcare Providers and Systems (CG-CAHPS) is a survey developed and distributed by Press Ganey Associates, and is the most widely used outpatient satisfaction survey in the United States. We compared pre-COVID-19 CG-CAHPS scores from patients who received in-person care at the PRBTC between April 2019 and March 2020 to COVID-19 pandemic CG-CAHPS scores (i.e. those who received either telemedicine or in-person care at the PRTBTC) from April 2020 to March 2021. RESULTS Approximately 1448 surveys were completed for both in-person and telemedicine visits. During the pandemic, 48.6% of surveys represented telemedicine, with monthly variations from 84.6% (April 2020) to 21.4% (March 2021). Patient satisfaction scores pre-COVID-19 were similar to those during the pandemic: overall provider rating from 0-10 (9.28 v 9.36), knowledge of medical history (96.9% v 95.4%), listens carefully (96.6% v 96.9%), shows respect (97.2% v 98.1%), and time spent (93.2% v 95.5%). During the COVID-19 pandemic, in-person and telemedicine demonstrate similar levels of satisfaction: overall provider rating from 0-10 (9.29 v 9.48), knowledge of medical history (94.9% v 96.1%), listens carefully (95.4% v 99.0%), shows respect (97.5% v 99.0%), and time spent (94.7% v 96.7%). CONCLUSION Outpatient satisfaction prior to and during the COVID-19 pandemic was similar. Patients reported similar satisfaction between in-person and telemedicine platforms. We support the ongoing use of telemedicine for outpatient Neuro-oncology.

Prediction of Neoadjuvant Chemotherapy Response in Osteosarcoma Using Convolutional Neural Network of Tumor Center 18F-FDG PET Images

We compared the accuracy of prediction of the response to neoadjuvant chemotherapy (NAC) in osteosarcoma patients between machine learning approaches of whole tumor utilizing fluorine−18fluorodeoxyglucose (18F-FDG) uptake heterogeneity features and a convolutional neural network of the intratumor image region. In 105 patients with osteosarcoma, 18F-FDG positron emission tomography/computed tomography (PET/CT) images were acquired before (baseline PET0) and after NAC (PET1). Patients were divided into responders and non-responders about neoadjuvant chemotherapy. Quantitative 18F-FDG heterogeneity features were calculated using LIFEX version 4.0. Receiver operating characteristic (ROC) curve analysis of 18F-FDG uptake heterogeneity features was used to predict the response to NAC. Machine learning algorithms and 2-dimensional convolutional neural network (2D CNN) deep learning networks were estimated for predicting NAC response with the baseline PET0 images of the 105 patients. ML was performed using the entire tumor image. The accuracy of the 2D CNN prediction model was evaluated using total tumor slices, the center 20 slices, the center 10 slices, and center slice. A total number of 80 patients was used for k-fold validation by five groups with 16 patients. The CNN network test accuracy estimation was performed using 25 patients. The areas under the ROC curves (AUCs) for baseline PET maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and gray level size zone matrix (GLSZM) were 0.532, 0.507, 0.510, and 0.626, respectively. The texture features test accuracy of machine learning by random forest and support vector machine were 0.55 and 0. 54, respectively. The k-fold validation accuracy and validation accuracy were 0.968 ± 0.01 and 0.610 ± 0.04, respectively. The test accuracy of total tumor slices, the center 20 slices, center 10 slices, and center slices were 0.625, 0.616, 0.628, and 0.760, respectively. The prediction model for NAC response with baseline PET0 texture features machine learning estimated a poor outcome, but the 2D CNN network using 18F-FDG baseline PET0 images could predict the treatment response before prior chemotherapy in osteosarcoma. Additionally, using the 2D CNN prediction model using a tumor center slice of 18F-FDG PET images before NAC can help decide whether to perform NAC to treat osteosarcoma patients.

Study of Diffusion Weighted Imaging Derived Diffusion Parameters as Biomarkers for the Microenvironment in Gliomas

ObjectivesTo explore the efficacy of diffusion weighted imaging (DWI)-derived metrics under different models as surrogate indicators for molecular biomarkers and tumor microenvironment in gliomas.MethodsA retrospective study was performed for 41 patients with gliomas. The standard apparent diffusion coefficient (ADCst) and ADC under ultra-high b values (ADCuh) (b values: 2500 to 5000 s/mm2) were calculated based on monoexponential model. The fraction of fast diffusion (f), pseudo ADC (ADCfast) and true ADC (ADCslow) were calculated by bi-exponential model (b values: 0 to 2000 s/mm2). The apparent diffusional kurtosis (Kapp) was derived from the simplified diffusion kurtosis imaging (DKI) model (b values: 200 to 3000 s/mm2). Potential correlations between DWI parameters and immunohistological indices (i.e. Aquaporin (AQP)1, AQP4, AQP9 and Ki-67) were investigated and DWI parameters were compared between high- and low-grade gliomas, and between tumor center and peritumor. Receiver operator characteristic (ROC) curve and area under the curve (AUC) were calculated to determine the performance of independent or combined DWI parameters in grading gliomas.ResultsThe ADCslow and ADCuh at tumor center showed a stronger correlation with Ki-67 than other DWI metrics. The ADCst, ADCslow and ADCuh at tumor center presented correlations with AQP1 and AQP4 while AQP9 did not correlate with any DWI metric. Kapp showed a correlation with Ki-67 while no significant correlation with AQPs. ADCst (p < 0.001) and ADCslow (p = 0.001) were significantly lower while the ADCuh (p = 0.006) and Kapp (p = 0.005) were significantly higher in the high-grade than in the low-grade gliomas. ADCst, f, ADCfast, ADCslow, ADCuh, Kapp at the tumor center had significant differences with those in peritumor when the gliomas grade became high (p < 0.05). Involving ADCuh and Kapp simultaneously into an independent ADCst model (AUC = 0.833) could further improve the grading performance (ADCst+ADCuh+Kapp: AUC = 0.923).ConclusionDifferent DWI metrics fitted within different b-value ranges (low to ultra-high b values) have different efficacies as a surrogate indicator for molecular expression or microstructural complexity in gliomas. Further studies are needed to better explain the biological meanings of these DWI parameters in gliomas.

Computational modeling of thermal combination therapies by magneto-ultrasonic heating to enhance drug delivery to solid tumors

For the first time, inspired by magnetic resonance imaging-guidance high intensity focused ultrasound (MR-HIFU) technology, i.e., medication therapy and thermal ablation in one session, in a preclinical setting based on a developed mathematical model, the performance of doxorubicin (Dox) and its encapsulation have been investigated in this study. Five different treatment methods, that combine medication therapy with mild hyperthermia by MRI contrast ($$\gamma -{Fe}_{2}{O}_{3}$$ γ - Fe 2 O 3 ) and thermal ablation via HIFU, are investigated in detail. A comparison between classical chemotherapy and thermochemistry shows that temperature can improve the therapeutic outcome by stimulating biological properties. On the other hand, the intravascular release of ThermoDox increases the concentration of free drug by 2.6 times compared to classical chemotherapy. The transport of drug in interstitium relies mainly on the diffusion mechanism to be able to penetrate deeper and reach the cancer cells in the inner regions of the tumor. Due to the low drug penetration into the tumor center, thermal ablation has been used for necrosis of the central areas before thermochemotherapy and ThermoDox therapy. Perfusion of the region around the necrotic zone is found to be damaged, while cells in the region are alive and not affected by medication therapy; so, there is a risk of tumor recurrence. Therefore, it is recommended that ablation be performed after the medication therapy. Our model describes a comprehensive assessment of MR-HIFU technology, taking into account many effective details, which can be a reliable guide towards the optimal use of drug delivery systems.

OS09.3.A Caregiver burden of glioma patients: the impact of informal care

BACKGROUND Each year 1.300 new patients are diagnosed with a glioma in the Netherlands. Patients experience a substantial physical and cognitive decline during the course of the disease. The impact of neurological deterioration on social and family life is substantial. Caregivers give high demanding care to their partners for long periods of time, while they combine this care with many other tasks, as: care for children, administrative household tasks and securing the families financial situation through work. As a consequence caregivers experience a high burden.In this study, we evaluated the degree of caregiver burden, its impact on daily life and the preferred support needed. With better insight in caregivers needs, support for the caregivers can be optimized. MATERIAL AND METHODS The study was conducted at the Brain Tumor Center Amsterdam, the Netherlands, between March and June 2019. We prospectively collected information using two Dutch questionnaires: the “Experienced Burden of Care” (EDIZ) and the “Features of Caregiver Care” questionnaire. The questionnaires were handed out to 93 caregivers of glioma patients at the outpatient clinic. The data were analysed using descriptive statistics. RESULTS In the studied population, 36,6% of caregivers experienced a high burden (score 7–9 on EDIZ questionnaire). The features of caregiver care questionnaire showed that 11,2% was overloaded (score >31), and 57,3% nearly overloaded (score 22–30). Caregivers indicated that the continuous care for the patient and lack of time for their own needs were a major cause for the high burden they experienced. One third of the caregivers reported a substantial change in physical, mental and behavioural functioning of the patient during the study. Caregivers experienced a lack of support and information; they felt a need for more psychological support (34,9%) and advice how to deal with the cognitive and behavioural decline of the patient (33,3%). The need for information of caregivers varied, ranging from information on the course of the disease (28,6%) to information on the social support act (23,8%). The question when to receive additional information was answered by most caregivers to a ‘self-chosen point in time’ instead of set time points by the medical team. CONCLUSION The burden of caregivers of glioma patients is high; nearly 70% of caregivers are even (nearly) overloaded. Caregivers need information and support on different aspects of the disease. As these aspects vary between different caregivers and possibly during the disease course, support to caregivers should be structurally assessed. A better understanding of the caregivers needs in combination with active support could prevent dropout of caregivers and improve the quality of life of both caregivers and patients.