Dummy run for planning of isotoxic dose-escalated radiation therapy for glioblastoma used in the PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06).

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021.

Successful implementation of online educational lectures of the German Society for Radiation Oncology (DEGRO).

PURPOSE: Modern digital teaching formats have become increasingly important in recent years, in part due to the COVID-19 pandemic. In January 2021, an online-based webinar series was established by the German Society for Radiation Oncology (DEGRO) and the young DEGRO (yDEGRO) working group. In the monthly 120-minute courses, selected lecturers teach curricular content as preparation for the board certification exam for radiation oncology. METHODS: The evaluation of the 24 courses between 01.2021 and 12.2022 was performed using a standardized questionnaire with 21 items (recording epidemiological characteristics of the participants, didactic quality, content quality). A Likert scale (1-4) was used in combination with binary and open-ended questions. RESULTS: A combined total of 4200 individuals (1952 in 2021 and 2248 in 2022) registered for the courses, and out of those, 934 participants (455 in 2021 and 479 in 2022) later provided evaluations for the respective courses (36% residents, 35% specialists, 21% medical technicians for radiology [MTR], 8% medical physics experts [MPE]). After 2 years, 74% of the DEGRO Academy curriculum topics were covered by the monthly webinars. The overall rating by participants was positive (mean 2021: 1.33 and 2022: 1.25) and exceeded the curriculum offered at each site for 70% of participants. Case-based learning was identified as a particularly well-rated method. CONCLUSION: The DEGRO webinar expands the digital teaching opportunities in radiation oncology. The consistently high number of participants confirms the need for high-quality teaching and underlines the advantages of e­learning methods. Optimization opportunities were identified through reevaluation of feedback from course participants. In its design as a teaching format for a multiprofessional audience, the webinar series could be used as a practice model of online teaching for other disciplines.

Dosimetric feasibility analysis and presentation of an isotoxic dose-escalated radiation therapy concept for glioblastoma used in the PRIDE trial (NOA-28; ARO-2022-12).

Background and purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept. Materials and methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans. Results: Median NTCP of the reference plan (NTCPref) and of the experimental plan (NTCPex) were 0.24 (range 0.11-0.29) and 0.42 (range 0.18-0.54), respectively. NTCPex was a median of 1.77 (range 1.60-1.99) times as high as the NTXPref. In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66-2.35). The defined constraints for the organs at risk were feasible. Conclusion: When considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible.

Principles of oncology taught in a one-week course.

BACKGROUND: Growing challenges in oncology require evolving educational methods and content. International efforts to reform oncology education are underway. Hands-on, interdisciplinary, and compact course formats have shown great effectiveness in the education of medical students. Our aim was to establish a new interdisciplinary one-week course on the principles of oncology using state-of-the-art teaching methods. METHODS: In an initial survey, medical students of LMU Munich were questioned about their current level of knowledge on the principles of oncology. In a second two-stage survey, the increase in knowledge resulting from our recently established interdisciplinary one-week course was determined. RESULTS: The medical students' knowledge of clinically important oncological topics, such as the diagnostic workup and interdisciplinary treatment options, showed a need for improvement. Knowledge of the major oncological entities was also in an expandable state. By attending the one-week course on the principles of oncology, students improved their expertise in all areas of the clinical workup in oncology and had the opportunity to close previous knowledge gaps. In addition, students were able to gain more in-depth clinical knowledge on the most common oncological entities. CONCLUSION: The interdisciplinary one-week course on the principles of oncology proved to be an effective teaching method to expand the knowledge of the future physicians to an appropriate level. With its innovative and interdisciplinary approach, the one-week course could be used as a showcase project for the ongoing development of medical education in Germany.

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH-Wild-Type Glioblastoma.

The 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients. Methods: Patients were included who had newly diagnosed, histologically confirmed isocitrate dehydrogenase (IDH)-wild-type glioblastoma with available TSPO PET before either normofractionated radiotherapy combined with temozolomide or hypofractionated radiotherapy. SUVmax on TSPO PET, TSPO binding affinity status, tumor volumes on MRI, and further clinical data, such as O 6-alkylguanine DNA methyltransferase (MGMT) and telomerase reverse transcriptase (TERT) gene promoter mutation status, were correlated with patient survival. Results: Forty-five patients (median age, 63.3 y) were included. Median SUVmax was 2.2 (range, 1.0-4.7). A TSPO PET signal was associated with survival: High uptake intensity (SUVmax > 2.2) was related to significantly shorter overall survival (OS; 8.3 vs. 17.8 mo, P = 0.037). Besides SUVmax, prognostic factors for OS were age (P = 0.046), MGMT promoter methylation status (P = 0.032), and T2-weighted MRI volume (P = 0.031). In the multivariate survival analysis, SUVmax in TSPO PET remained an independent prognostic factor for OS (P = 0.023), with a hazard ratio of 2.212 (95% CI, 1.115-4.386) for death in cases with a high TSPO PET signal (SUVmax > 2.2). Conclusion: A high TSPO PET signal before radiotherapy is associated with significantly shorter survival in patients with newly diagnosed IDH-wild-type glioblastoma. TSPO PET seems to add prognostic insights beyond established clinical parameters and might serve as an informative tool as clinicians make survival predictions for patients with glioblastoma.

Current situation in radiation oncology residency-Results of a national survey performed by the working group Young DEGRO of the German Society of Radiation Oncology.

BACKGROUND: The aim of this study was to assess the current status of the radiation oncology (RO) residency programs in Germany. For this, RO residents and RO specialists were surveyed regarding the current situation of the RO residency training and the working conditions in Germany. METHODS: The Continuing Education Section of the Young DEGRO (yDEGRO) Working Group of the German Society of Radiation Oncology (DEGRO) developed a survey to assess (1) the overall satisfaction, learning objectives, and teaching methods used during training; and (2) the perception of the importance of specific disease patterns in RO training. Open-ended questions were also asked to elicit opinions on areas for improvement. From 21 November to 27 December 2022, RO residents registered with DEGRO and/or in the working group yDEGRO were invited to participate anonymously in an online questionnaire. RESULTS: Overall, 97 participants completed the survey, including 65 RO residents (67%) and 32 RO specialists (33%); 66 (68%) of the respondents reported being employed in the university setting, 23 (23.7%) in the non-university setting, and 8 (8.3%) in private practice. Within the training, heterogeneity was found in the teaching methods used. In terms of knowledge transfer, the greatest importance was accorded to annual continuing education discussions with the head of the residency training (92.8%), participation in tumor boards (85.6%), written training concepts (81.4%), and evaluations at the beginning (76.3%) and end of a rotation (80.4%). The arithmetic mean of satisfaction with specialist training was 6/10 points (SD: 1.99); 88.7% of respondents would like to see a nationally uniform and mandatory curriculum in RO residency training. CONCLUSION: The study provides suggestions for improving RO medical training in Germany: further development of accompanying education and training programs in cooperation with professional associations, e.g., the DEGRO, structured feedback, and supervision.

Importance of interdisciplinarity in modern oncology: results of a national intergroup survey of the Young Oncologists United (YOU).

PURPOSE: Modern, personalized treatment concepts in oncology require an interdisciplinary and multiprofessional collaboration. In addition to its relevance in patient care, interdisciplinary collaboration is also becoming increasingly important in clinical research as well as medical education and resident training in oncology. METHODS: Between November 2021 and March 2022, an online survey was conducted among German early career research groups, represented by Young Oncologists United (YOU). The aim was to identify the status and need for interdisciplinarity at clinic, educational, and research levels. RESULTS: A total of 294 participants completed the questionnaire in full. 90.7% of the respondents fully or predominantly agreed with the statement that interdisciplinary work plays a major role in their daily clinical work. 78.9% wished for more interdisciplinary collaboration. Of the 49.7% of participants who have never participated in an interdisciplinary research project, 80.1% said they would like to participate in such a study project in the future. Lack of time resources, too much organizational effort, and possible political conflicts between institutions were identified as factors that make practical implementation difficult. 74.1% declared their willingness to become active in an oncology early career research group. CONCLUSION: Interdisciplinary collaboration has become increasingly important in oncology. Networks that span different disciplines could help to promote interdisciplinary research projects among young scientists and improve exchange in professional practice and education with the implication of improved patient care.

Adult intracranial ependymoma-relevance of DNA methylation profiling for diagnosis, prognosis, and treatment.

BACKGROUND: A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. METHODS: Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). RESULTS: The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes. CONCLUSIONS: DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

Dose-escalated re-irradiation improves outcome in locally recurrent head and neck cancer - Results of a large multicenter analysis.

To determine efficacy and prognostic parameters of definitive re-irradiation of locoregionally recurrent squamous cell carcinoma of the head and neck (HNSCC). MATERIALS AND METHODS: Patients with locoregionally recurrent or second primary HNSCC undergoing re-irradiation with modern radiotherapy technique were eligible for this multicentric retrospective analysis. Main endpoints were overall survival (OS), progression-free survival (PFS) and locoregional control (LC). Univariate analyses were performed using the Kaplan Meier Method (log-rank). For multivariable analysis, Cox regression was used. RESULTS: A total of 253 patients treated between 2009 and 2020 at 16 university hospitals in Germany were included. The median follow up was 27.4 months (range 0.5-130). The median OS and PFS were 13.2 (CI: 10.7 - 15.7) months and 7.9 (CI: 6.7 - 9.1) months, respectively, corresponding to two-year OS and PFS rates of 29 % and 19 %. Rates of locoregional progression and "in-field-failure" were 62 % and 51 % after two years. Multivariable Cox regression analysis identified good ECOG performance status and high radiation dose as independent prognostic parameters for OS. Doses above 50 Gy (EQD2) achieved longer median OS of 17.8 months (vs 11.7 months, p < 0.01) and longer PFS of 9.6 months (vs 6.8 months, p < 0.01). In addition, there was a trend for worse survival in patients with tracheostomy (multivariable, p = 0.061). Concomitant systemic therapy did not significantly impact PFS or OS. CONCLUSION: Re-irradiation of locally recurrent or second primary HNSCC is efficient, especially if doses above 50 Gy (EQD2) are delivered. ECOG performance score was the strongest prognostic parameter for OS and PFS.

18F-FET PET radiomics-based survival prediction in glioblastoma patients receiving radio(chemo)therapy.

BACKGROUND: Quantitative image analysis based on radiomic feature extraction is an emerging field for survival prediction in oncological patients. 18F-Fluorethyltyrosine positron emission tomography (18F-FET PET) provides important diagnostic and grading information for brain tumors, but data on its use in survival prediction is scarce. In this study, we aim at investigating survival prediction based on multiple radiomic features in glioblastoma patients undergoing radio(chemo)therapy. METHODS: A dataset of 37 patients with glioblastoma (WHO grade 4) receiving radio(chemo)therapy was analyzed. Radiomic features were extracted from pre-treatment 18F-FET PET images, following intensity rebinning with a fixed bin width. Principal component analysis (PCA) was applied for variable selection, aiming at the identification of the most relevant features in survival prediction. Random forest classification and prediction algorithms were optimized on an initial set of 25 patients. Testing of the implemented algorithms was carried out in different scenarios, which included additional 12 patients whose images were acquired with a different scanner to check the reproducibility in prediction results. RESULTS: First order intensity variations and shape features were predominant in the selection of most important radiomic signatures for survival prediction in the available dataset. The major axis length of the 18F-FET-PET volume at tumor to background ratio (TBR) 1.4 and 1.6 correlated significantly with reduced probability of survival. Additional radiomic features were identified as potential survival predictors in the PTV region, showing 76% accuracy in independent testing for both classification and regression. CONCLUSIONS: 18F-FET PET prior to radiation provides relevant information for survival prediction in glioblastoma patients. Based on our preliminary analysis, radiomic features in the PTV can be considered a robust dataset for survival prediction.

PET/CT-based adaptive radiotherapy of locally advanced non-small cell lung cancer in multicenter yDEGRO ARO 2017-01 cohort study.

BACKGROUND: Stage III non-small cell lung cancer (NSCLC) represents a highly heterogeneous disease and treatment burden. Advances in imaging modality show promising results for radiotherapy planning. In this multicentric study, we evaluated the impact of PET/CT-based radiotherapy planning on the prognosis of patients with stage III NSCLC. METHOD AND PATIENTS: A retrospective observational cohort study (ARO 2017-01/NCT03055715) was conducted by the young DEGRO trial group of the German Society for Radiation Oncology (DEGRO) with the primary objective to assess the effect of tumour volume change during chemoradiotherapy and the secondary objective to assess the effect of treatment planning on survival. Three hundred forty-seven patients with stage III NSCLC treated at 21 university centers between January 2010 and December 2013 were enrolled in this trial. Patients received primary curative chemoradiotherapy with an intended dose of 50 Gy (hypofractionated) or > 60 Gy (normofractionated). To assess the effect of radiotherapy planning modality on overall survival, we used multivariate frailty models. Models were adjusted for gross tumor volume at the initiation of therapy, age, sex, simultaneous chemotherapy, lung comorbidities, RT dose and tumor grade. By considering the random effect, we can account for heterogeneity in survival and considered covariates within the model in relation to the study side. RESULTS: Patients were predominantly male (n = 269, 78.4%) with mainly adenocarcinoma (56.4%) and an average of 67.2 years. Adaptation of radiotherapy with consecutive reduction of irradiation volume showed no significant disadvantage for patient survival (HR = 1.21, 95% CI 0.89-1.64). The use of PET/CT co-registration in radiation planning tended to result in better oncologic outcomes, although no significant association could be shown (HR = 0.8, 95% CI 0.56-1.16). Centers with a consistent planning strategy performed better than those without a preferred planning method (0.62, 95% CI 0.41-0.94). CONCLUSION: A consistent planning strategy has positive effects on overall survival. The use of PET/CT-based adaptive radiotherapy planning shows a similar survival prospect with the prospective of lower treatment volumes. In future research, toxicities need to be analysed in order to assess such reasoning.

Innovative radiation oncology Together - Precise, Personalized, Human : Vision 2030 for radiotherapy & radiation oncology in Germany.

PURPOSE: Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. METHODS: The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives' final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. RESULTS: The strategy retreat's development process resulted in conception of the final vision "Innovative radiation oncology Together - Precise, Personalized, Human." The first term "Innovative radiation oncology" comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term "together" underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. "Precise" mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. "Personalized" emphasizes biology-directed individualization of radiation treatment. Finally, "Human" underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. CONCLUSION: The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.

A Privacy-Preserving Log-Rank Test for the Kaplan-Meier Estimator With Secure Multiparty Computation: Algorithm Development and Validation.

BACKGROUND: Patient data is considered particularly sensitive personal data. Privacy regulations strictly govern the use of patient data and restrict their exchange. However, medical research can benefit from multicentric studies in which patient data from different institutions are pooled and evaluated together. Thus, the goals of data utilization and data protection are in conflict. Secure multiparty computation (SMPC) solves this conflict because it allows direct computation on distributed proprietary data-held by different data owners-in a secure way without exchanging private data. OBJECTIVE: The objective of this work was to provide a proof-of-principle of secure and privacy-preserving multicentric computation by SMPC with real-patient data over the free internet. A privacy-preserving log-rank test for the Kaplan-Meier estimator was implemented and tested in both an experimental setting and a real-world setting between two university hospitals. METHODS: The domain of survival analysis is particularly relevant in clinical research. For the Kaplan-Meier estimator, we provided a secure version of the log-rank test. It was based on the SMPC realization SPDZ and implemented via the FRESCO framework in Java. The complexity of the algorithm was explored both for synthetic data and for real-patient data in a proof-of-principle over the internet between two clinical institutions located in Munich and Berlin, Germany. RESULTS: We obtained a functional realization of an SMPC-based log-rank evaluation. This implementation was assessed with respect to performance and scaling behavior. We showed that network latency strongly influences execution time of our solution. Furthermore, we identified a lower bound of 2 Mbit/s for the transmission rate that has to be fulfilled for unimpeded communication. In contrast, performance of the participating parties have comparatively low influence on execution speed, since the peer-side processing is parallelized and the computational time only constitutes 30% to 50% even with optimal network settings. In the real-world setting, our computation between three parties over the internet, processing 100 items each, took approximately 20 minutes. CONCLUSIONS: We showed that SMPC is applicable in the medical domain. A secure version of commonly used evaluation methods for clinical studies is possible with current implementations of SMPC. Furthermore, we infer that its application is practically feasible in terms of execution time.

Peer review analysis in the field of radiation oncology: results from a web-based survey of the Young DEGRO working group.

PURPOSE: To evaluate the reviewing behaviour in the German-speaking countries in order to provide recommendations to increase the attractiveness of reviewing activity in the field of radiation oncology. METHODS: In November 2019, a survey was conducted by the Young DEGRO working group (jDEGRO) using the online platform "eSurveyCreator". The questionnaire consisted of 29 items examining a broad range of factors that influence reviewing motivation and performance. RESULTS: A total of 281 responses were received. Of these, 154 (55%) were completed and included in the evaluation. The most important factors for journal selection criteria and peer review performance in the field of radiation oncology are the scientific background of the manuscript (85%), reputation of the journal (59%) and a high impact factor (IF; 40%). Reasons for declining an invitation to review include the scientific background of the article (60%), assumed effort (55%) and a low IF (27%). A double-blind review process is preferred by 70% of respondents to a single-blind (16%) or an open review process (14%). If compensation was offered, 59% of participants would review articles more often. Only 12% of the participants have received compensation for their reviewing activities so far. As compensation for the effort of reviewing, 55% of the respondents would prefer free access to the journal's articles, 45% a discount for their own manuscripts, 40% reduced congress fees and 39% compensation for expenses. CONCLUSION: The scientific content of the manuscript, reputation of the journal and a high IF determine the attractiveness for peer reviewing in the field of radiation oncology. The majority of participants prefer a double-blind peer review process and would conduct more reviews if compensation was available. Free access to journal articles, discounts for publication costs or congress fees, or an expense allowance were identified to increase attractiveness of the review process.

Improved risk stratification in younger IDH wild-type glioblastoma patients by combining a 4-miRNA signature with MGMT promoter methylation status.

BACKGROUND: The potential benefit of risk stratification using a 4-miRNA signature in combination with MGMT promoter methylation in IDH1/2 wild-type glioblastoma patients was assessed. METHODS: Primary tumors from 102 patients with comparable treatment from the LMU Munich (n = 37), the University Hospital Düsseldorf (n = 33), and The Cancer Genome Atlas (n = 32) were included. Risk groups were built using expressions of hsa-let-7a-5p, hsa-let-7b-5p, hsa-miR-615-5p, and hsa-miR-125a-5p to assess prognostic performance in overall survival (OS). MGMT promoter methylation and age were considered as cofactors. Integrated miRNA, DNA methylome, and transcriptome analysis were used to explore the functional impact of signature miRNAs. RESULTS: The 4-miRNA signature defined high-risk (n = 46, median OS: 15.8 months) and low-risk patients (n = 56, median OS: 20.7 months; univariable Cox proportional hazard analysis: hazard ratio [HR]: 1.8, 95% confidence interval [CI]: 1.14-2.83, P = .01). The multivariable Cox proportional hazard model including the 4-miRNA signature (P = .161), MGMT promoter methylation (P < .001), and age (P = .034) significantly predicted OS (Log-rank P < .0001). Likewise to clinical routine, analysis was performed for younger (≤60 years, n = 50, median OS: 20.2 months) and older patients (>60 years, n = 52, median OS: 15.8) separately. In younger patients, the 4-miRNA signature had prognostic value (HR: 1.92, 95% CI: 0.93-3.93, P = .076). Particularly, younger, MGMT methylated, 4-miRNA signature low-risk patients (n = 18, median OS: 37.4 months) showed significantly improved survival, compared to other younger patients (n = 32, OS 18.5 months; HR: 0.33, 95% CI: 0.15-0.71, P = .003). Integrated data analysis revealed 4-miRNA signature-associated genes and pathways. CONCLUSION: The prognostic 4-miRNA signature in combination with MGMT promoter methylation improved risk stratification with the potential for therapeutic substratification, especially of younger patients.

Dual PET Imaging of an H3K27M-Mutant Glioma With 18F-GE-180 and 18F-FET PET.

A 25-year-old man presented with headache and intracranial pressure symptoms. On MRI, an intracranial lesion was detected in the right thalamus with exophytic growth into the third ventricle and inhomogeneous contrast enhancement without necrosis. Dual amino acid (F-FET) and TSPO (F-GE-180) PET imaging showed high tumor-to-background ratios in both scans and a short time-to-peak in F-FET uptake dynamics. Biopsy revealed a diffuse midline glioma, H3K27M-mutant (WHO grade IV), a novel entity in the 2016 WHO classification with poor clinical outcome. Our case shows that the highly aggressive features of this tumor entity can be visualized in vivo by both PET modalities.

Margin reduction in radiotherapy for glioblastoma through 18F-fluoroethyltyrosine PET? - A recurrence pattern analysis.

BACKGROUND AND PURPOSE: 18F-fluoroethyltyrosine (18F-FET) PET is increasingly used in radiation treatment planning for the primary treatment of glioblastoma (GBM) patients additionally to contrast-enhanced MRI. To answer the question, whether a margin reduction in the primary treatment setting could be achieved through 18F-FET PET imaging, a recurrence pattern analysis was performed. PATIENTS AND METHODS: GBM patients undergoing 18F-FET PET examination before primary radiochemotherapy from 05/2009 to 11/2014 were included into the recurrence pattern analysis. Biological tumour volumes were semi-automatically created and fused with MR-based gross tumour volumes (MRGTVs). The pattern of recurrence was examined for MRGTVs and for PET-MRGTVs. The minimal margin including all recurrent tumour sites was assessed by gradual expansion of the PET-MRGTVs and MRGTVs until inclusion of all contrast-enhancing areas at recurrence. RESULTS: 36 GBM patients were included to the analysis. The minimal margin including all contrast enhancing tumour at recurrence was significantly smaller for the PET-MRGTVs compared to the MRGTVs (median 12.5 mm vs. 16.5 mm; p < 0.001, Wilcoxon-Test). PET-MRGTVs with 15 mm CTV margins were significantly smaller than MRGTVs with 20 mm CTV margins (median volume 255.92 vs. 258.35 cm3; p = 0.020, Wilcoxon-Test; excluding 3 cases with large non-contrast enhancing tumours). The pattern of recurrence of PET-MRGTVs with 15 mm CTV margins was comparable to MRGTVs with 20 mm CTV margins (32 vs. 30 central, 2 vs. 4 in-field, 2 vs. 2 ex-field and no marginal recurrences). CONCLUSION: Target volume delineation of GBM patients can be improved through 18F-FET PET imaging prior to primary radiation treatment, since vital tumour can be detected more accurately. Furthermore, the results suggest that CTV margins could be reduced through 18F-FET PET imaging prior to primary RT of GBM.

Report of first recurrent glioma patients examined with PET-MRI prior to re-irradiation.

BACKGROUND AND PURPOSE: The advantage of combined PET-MRI over sequential PET and MRI is the high spatial conformity and the absence of time delay between the examinations. The benefit of this technique for planning of re-irradiation (re-RT) treatment is unkown yet. Imaging data from a phase 1 trial of re-RT for recurrent glioma was analysed to assess whether planning target volumes and treatment margins in glioma re-RT can be adjusted by PET-MRI with rater independent PET based biological tumour volumes (BTVs). PATIENTS AND METHODS: Combined PET-MRI with the tracer O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) prior to re-RT was performed in recurrent glioma patients in a phase I trial. GTVs including all regions suspicious of tumour on contrast enhanced MRI were delineated by three experienced radiation oncologists and included into MRI based consensus GTVs (MRGTVs). BTVs were semi-automatically delineated with a fixed threshold of 1.6 x background activity. Corresponding BTVs and MRGTVs were fused into union volume PET-MRGTVs. The Sørensen-Dice coefficient and the conformity index were used to assess the geometric overlap of the BTVs with the MRGTVs. A recurrence pattern analysis was performed based on the original planning target volumes (PTVs = GTV + 10 mm margin or 5 mm in one case) and the PET-MRGTVs with margins of 10, 8, 5 and 3 mm. RESULTS: Seven recurrent glioma patients, who received PET-MRI prior to re-RT, were included into the present planning study. At the time of re-RT, patients were in median 54 years old and had a median Karnofsky Performance Status (KPS) score of 80. Median post-recurrence survival after the beginning of re-RT was 13 months. Concomitant bevacizumab therapy was applied in six patients and one patient received chemoradiation with temozolomide. Median GTV volumes of the three radiation oncologists were 35.0, 37.5 and 40.5 cubic centimeters (cc) and median MRGTV volume 41.8 cc. Median BTV volume was 36.6 cc and median PET-MRGTV volume 59.3 cc. The median Sørensen-Dice coefficient for the comparison between MRGTV and BTV was 0.61 and the median conformity index 0.44. Recurrence pattern analysis revealed two central, two in-field and one distant recurrence within both, the original PTV, as well as the PET-MRGTV with a reduced margin of 3 mm. CONCLUSION: PET-MRI provides radiation treatment planning imaging with high spatial and timely conformity for high-grade glioma patients treated with re-RT with potential advancements for target volume delineation. Prospective randomised trials are warranted to further investigate the treatment benefits of PET-MRI based re-RT planning.

Single isocenter stereotactic radiosurgery for patients with multiple brain metastases: dosimetric comparison of VMAT and a dedicated DCAT planning tool.

BACKGROUND: In this dosimetric study, a dedicated planning tool for single isocenter stereotactic radiosurgery for multiple brain metastases using dynamic conformal arc therapy (DCAT) was compared to standard volumetric modulated arc therapy (VMAT). METHODS: Twenty patients with a total of 66 lesions who were treated with the DCAT tool were included in this study. Single fraction doses of 15-20 Gy were prescribed to each lesion. Patients were re-planned using non-coplanar VMAT. Number of monitor units as well as V4Gy, V5Gy and V8Gy were extracted for every plan. Using a density-based clustering algorithm, V10Gy and V12Gy and the volume receiving half of the prescribed dose were extracted for every lesion. Gradient indices and conformity indices were calculated. The correlation of the target sphericity, a measure of how closely the shape of the target PTV resembles a sphere, to the difference in V10Gy and V12Gy between the two techniques was assessed using Spearman's correlation coefficient. RESULTS: The automated DCAT planning tool performed significantly better in terms of all investigated metrics (p < 0.05), in particular healthy brain sparing (V10Gy: median 3.2 cm3 vs. 4.9 cm3), gradient indices (median 5.99 vs. 7.17) and number of monitor units (median 4569 vs. 5840 MU). Differences in conformity indices were minimal (median 0.75 vs. 0.73) but still significant (p < 0.05). A moderate correlation between PTV sphericity and the difference of V10Gy and V12Gy between the two techniques was found (Spearman's rho = 0.27 and 0.30 for V10Gy and V12Gy, respectively, p < 0.05). CONCLUSIONS: The dedicated DCAT planning tool performed better than VMAT in terms of healthy brain sparing and treatment efficiency, in particular for nearly spherical lesions. In contrast, VMAT can be superior in cases with irregularly shaped lesions.