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Purpose: Randomized studies demonstrated the oncological equivalence of (ultra-)hypofractionation compared to a 5-week schedule in postoperative radiotherapy of breast cancer. Due to the low incidence and long latency of secondary malignancies, there are currently no reliable clinical data regarding the influence of fractionation regimens on the development of secondary malignancies., Material and Methods: For 20 patients with right or left-sided breast cancer, postoperative treatment plans were created using 3D-CRT (n = 10) or VMAT (n = 10) for three different fractionation schedules: 5-week schedule with 50.4Gy in 1.8Gy (28fx), hypofractionation with 40.05Gy in 2.67Gy (15fx) and ultra-hypofractionation with 26Gy in 5.2Gy (5fx). The EARs (absolute additional cases of disease per 10,000 patient-years) for secondary malignancies in the lung, contralateral breast, esophagus, liver, thyroid, spinal cord, bones and soft tissue were calculated using a fraction-dependent dose-response model., Results: Based on risk modulation, (ultra-)hypofractionation resulted in significantly lower EARs for lung cancer (LC), contralateral breast cancer (CBC) and soft tissue sarcoma (STS) (p < .001). For the ultra-hypofractionated dose concept the median EARs for LC, CBC and STS were 42.8 %, 39.4 % and 58.1 % lower compared to conventional fractionation and 31.2 %, 25.7 % and 20.3 % compared to hypofractionation. The influence of fractionation on the risk of secondary malignancies for LC and CBC was less pronounced with 3D-CRT than with VMAT. For STS, however, the influence of fractionation was greater with 3D-CRT than with VMAT., Conclusion: Based on this simulation study (ultra-)hypofractionated postoperative breast cancer irradiation may be associated with a lower risk of secondary malignancies compared to a 5-week schedule., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Salvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure., Objective: This study aims to evaluate prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model's performance, aiming to improve clinical management of recurrent prostate cancer., Methods: This multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET-based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions., Results: Baseline characteristics of 1029 patients undergoing sRT PSMA-PET-based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (<66 Gy in 57/979, 5.8% vs 46/50, 92% of patients; P<.001). The RSF model, validated internally and externally, demonstrated robust predictive performance (Harrell C-index range: 0.54-0.91) across training and validation datasets, outperforming a previously published nomogram., Conclusions: The developed RSF model demonstrates enhanced predictive accuracy, potentially improving patient outcomes and assisting clinicians in making treatment decisions., (©Ali Janbain, Andrea Farolfi, Armelle Guenegou-Arnoux, Louis Romengas, Sophia Scharl, Stefano Fanti, Francesca Serani, Jan C Peeken, Sandrine Katsahian, Iosif Strouthos, Konstantinos Ferentinos, Stefan A Koerber, Marco E Vogel, Stephanie E Combs, Alexis Vrachimis, Alessio Giuseppe Morganti, Simon KB Spohn, Anca-Ligia Grosu, Francesco Ceci, Christoph Henkenberens, Stephanie GC Kroeze, Matthias Guckenberger, Claus Belka, Peter Bartenstein, George Hruby, Louise Emmett, Ali Afshar Omerieh, Nina-Sophie Schmidt-Hegemann, Lucas Mose, Daniel M Aebersold, Constantinos Zamboglou, Thomas Wiegel, Mohamed Shelan. Originally published in JMIR Cancer (https://cancer.jmir.org), 20.09.2024.)

Percutaneous implants osseointegrated into the residuum of a person with limb amputation need to provide mechanical stability and protection against infections. Although significant progress has been made in the biointegration of percutaneous implants, the problem of forming a reliable natural barrier at the level of the surface of the implant and the skin and bone tissues remains unresolved. The use of a microporous implant structure incorporated into the Skin and Bone Integrated Pylon (SBIP) should address the issue by allowing soft and bone tissues to grow directly into the implant structure itself, which, in turn, should form a reliable barrier to infections and support strong osseointegration. To evaluate biological interactions between dermal fibroblasts and MC3T3-E1 osteoblasts in vitro, small titanium discs (with varying pore sizes and volume fractions to achieve deep porosity) were fabricated via 3D printing and sintering. The cell viability MTT assay demonstrated low cytotoxicity for cells co-cultured in the pores of the 3D-printed and sintered Ti samples during the 14-day follow-up period. A subsequent Quantitative Real-Time Polymerase Chain Reaction (RT-PCR) analysis of the relative gene expression of biomarkers that are associated with cell adhesion (α2, α5, αV, and β1 integrins) and extracellular matrix components (fibronectin, vitronectin, type I collagen) demonstrated that micropore sizes ranging from 200 to 500 µm of the 3D printed and sintered Ti discs were favorable for dermal fibroblast adhesion. For example, for representative 3D-printed Ti sample S6 at 72 h the values were 4.71 ± 0.08 (α2 integrin), 4.96 ± 0.08 (α5 integrin), 4.71 ± 0.08 (αV integrin), and 1.87 ± 0.12 (β1 integrin). In contrast, Ti discs with pore sizes ranging from 400 to 800 µm demonstrated the best results (in terms of marker expression related to osteogenic differentiation, including osteopontin, osteonectin, osteocalcin, TGF-β1, and SMAD4) for MC3T3-E1 cells. For example, for the representative 3D sample S4 on day 14, the marker levels were 11.19 ± 0.77 (osteopontin), 7.15 ± 0.29 (osteonectin), and 6.08 ± 0.12 (osteocalcin), while for sintered samples the levels of markers constituted 5.85 ± 0.4 (osteopontin), 4.45 ± 0.36 (osteonectin), and 4.46 ± 0.3 (osteocalcin). In conclusion, the data obtained show the high biointegrative properties of porous titanium structures, while the ability to implement several pore options in one structure using 3D printing makes it possible to create personalized implants for the best one-time integration with both skin and bone tissues.

Purpose: For women with locoregionally advanced cervical cancer, the standard of care treatment is the curatively intended chemoradiation therapy (CRT). A relationship between bone marrow (BM) dose-volume histograms (DVHs) and acute hematological toxicity (HT) has been debated recently. Aim of this study was the evaluation of BM dose constraints and HT in a contemporary patient cohort., Methods: Radiation treatment plans of 31 patients with cervical cancer (FIGO stage IIB-IVB) treated with intensity-modulated radiotherapy and simultaneous chemotherapy were explored retrospective. Pelvic bones (PB) and femoral heads (FH) were contoured and DVHs were correlated with white blood cells (WBC), hemoglobin levels and platelets., Results: Comparing the absolute blood levels with the dose volumes of both FH and PB the data showed a significant correlation between WBC and the median dose of the FH and the median dose, V 30Gy , V 40Gy and V 50Gy of the PB. A correlation between the toxicity grade of anemia and mean dose, maximum dose and V 5Gy of the PB was found. Counting the highest grade of HT of all three blood levels of each patient, significant correlations were found for the mean and median dose, V 30Gy , V 40Gy and V 50Gy of the PB., Conclusion: The results show that blood levels may correlate with distinct dosimetric subvolumes of critical bone marrow compartments with a potential impact on therapeutic outcome and treatment-related toxicity. The data presented are in line with the previous findings on the relevance of dosimetric exposure of pelvic bony subvolumes., (© 2024. The Author(s).)

Skin inflammation with the potential sequel of moist epitheliolysis and edema constitute the most frequent breast radiotherapy (RT) acute side effects. The aim of this study was to compare the predictive value of tissue-derived radiomics features to the total breast volume (TBV) for the moist cells epitheliolysis as a surrogate for skin inflammation, and edema. Radiomics features were extracted from computed tomography (CT) scans of 252 breast cancer patients from two volumes of interest: TBV and glandular tissue (GT). Machine learning classifiers were trained on radiomics and clinical features, which were evaluated for both side effects. The best radiomics model was a least absolute shrinkage and selection operator (LASSO) classifier, using TBV features, predicting moist cells epitheliolysis, achieving an area under the receiver operating characteristic (AUROC) of 0.74. This was comparable to TBV breast volume (AUROC of 0.75). Combined models of radiomics and clinical features did not improve performance. Exclusion of volume-correlated features slightly reduced the predictive performance (AUROC 0.71). We could demonstrate the general propensity of planning CT-based radiomics models to predict breast RT-dependent side effects. Mammary tissue was more predictive than glandular tissue. The radiomics features performance was influenced by their high correlation to TBV volume., (© 2024. The Author(s).)

Molecular chaperones, especially 70 kDa heat shock protein, in addition to their intracellular localization in cancer cells, can be exposed on the surface of the plasma membrane. We report that the membrane-associated chaperone mHsp70 of malignant brain tumors is required for high migratory and invasive activity of cancer cells. Live-cell inverted confocal microscopy of tumor samples from adult (n = 23) and pediatric (n = 9) neurooncologic patients showed pronounced protein expression on the membrane, especially in the perifocal zone. Mass spectrometry analysis of lipid rafts isolated from tumor cells confirmed the presence of the protein in the chaperone cluster (including representatives of other families, such as Hsp70, Hsc70, Hsp105, and Hsp90), which in turn, during interactome analysis, was associated with proteins involved in cell migration (e.g., Rac1, RhoC, and myosin-9). The use of small-molecule inhibitors of HSP70 (PES and JG98) led to a substantial decrease in the invasive potential of cells isolated from a tumor sample of patients, which indicates the role of the chaperone in invasion. Moreover, the use of HSP70 inhibitors in animal models of orthotopic brain tumors significantly delayed tumor progression, which was accompanied by an increase in overall survival. Data demonstrate that chaperone inhibitors, particularly JG98, disrupt the function of mHsp70, thereby providing an opportunity to better understand the diverse functions of this protein and offer aid in the development of novel cancer therapies., Significance: Membrane-bound mHsp70 is required for brain tumor cell migration and invasion and therefore could be employed as a target for anticancer therapies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background and Purpose: In a relevant number of primary breast cancer patients, lymphatic drainage to the contralateral internal mammary nodes (cIMN) is being observed. Nevertheless, so far lymphatic drainage pathway to the cIMN is largely neglected during adjuvant radiotherapy., Materials and Methods: This study evaluated the incidental dose to the cIMN for 120 volumetric modulated arc therapy (VMAT) treatment plans for node positive breast in dependence of internal mammary node irradiation (IMNI) and deep inspiration breath hold (DIBH). Additionally, incidental dose distribution to the cIMN based on the field design in the MA20, EORTC22922/10925 and AMAROS trials was assessed., Results: The incidental dose (Dmean ± SD) to the cIMN-CTV was 13.0 (±4.7) Gy with a maximum dose of < 30 Gy in 113/120 cases. If IMNI was included (n = 80), the Dmean to the cIMN-CTV was significantly higher compared to no IMNI, but still comparably low (n = 40; 14.3 Gy vs. 9.6 Gy; p = 0.0001). Furthermore, the dose in the cIMN during free breathing (n = 80) was higher compared to DIBH (n = 40; 13.9 Gy vs. 11.2 Gy; p = 0.002).Simulated treatment plans based on the randomized RNI trials revealed neglectable dose coverage of the cIMN (Dmean 1.0-1.8 Gy) for all protocols., Conclusion: Neither in the randomized RNI trials nor during contemporary treatment techniques clinically relevant dose distribution to the cIMN was observed. Further studies are warranted to assess the potential impact of intended irradiation of cIMN in high-risk patients., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.E.C. received third party funding from the German Research Foundation and the European Union as well as consulting fees from Icotec AG (Switzerland), HMG Systems Engineering GmbH (Germany), Bristol Myers Squibb BMS (Germany). Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (most speaking appointments include reimbursement of travel costs − does not apply for virtual appointments): Roche, BMS, Brainlab, AstraZeneca, Accuray, Dr. Sennewald, Daiichi Sankyo, Elekta, Medac, med update GmbH. All other authors declare that they have no conflicts of interests., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Molecular glioblastoma (molGB) does not exhibit the histologic hallmarks of a grade 4 glioma but is nevertheless diagnosed as glioblastoma when harboring specific molecular markers. MolGB can easily be mistaken for similar-appearing lower-grade astrocytomas. Here, we investigated how advanced imaging could reflect the underlying tumor biology., Methods: Clinical and imaging data were collected for 7 molGB grade 4, 9 astrocytomas grade 2, and 12 astrocytomas grade 3. Four neuroradiologists performed VASARI-scoring of conventional imaging, and their inter-reader agreement was assessed using Fleiss κ coefficient. To evaluate the potential of advanced imaging, 2-sample t test, 1-way ANOVA, Mann-Whitney U, and Kruskal-Wallis test were performed to test for significant differences between apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) that were extracted fully automatically from the whole tumor volume., Results: While conventional VASARI imaging features did not allow for reliable differentiation between glioma entities, rCBV was significantly higher in molGB compared to astrocytomas for the 5th and 95th percentile, mean, and median values ( P  < .05). ADC values were significantly lower in molGB than in astrocytomas for mean, median, and the 95th percentile ( P  < .05). Although no molGB showed contrast enhancement initially, we observed enhancement in the short-term follow-up of 1 patient., Discussion: Quantitative analysis of diffusion and perfusion parameters shows potential in reflecting the malignant tumor biology of molGB. It may increase awareness of molGB in a nonenhancing, "benign" appearing tumor. Our results support the emerging hypothesis that molGB might present glioblastoma captured at an early stage of gliomagenesis., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

GBM WHO CNS Grade 4 represents a major challenge for oncology due to its aggressive behavior. Conventional imaging has restrictions in detecting tumor recurrence. This prospective study aims to identify gene-based biomarkers in whole blood instead of isolating exosomes for the early detection of tumor recurrence. Blood samples (n = 33) were collected from seven GBM patients at time points before and after surgery as well as upon tumor recurrence. Four tumor tissue samples were assessed in parallel. Next-generation sequencing (NGS), including mRNA-seq and small RNA-seq, was used to analyze gene expression profiles in blood samples and tumor tissues. A novel filtering pipeline was invented to narrow down potential candidate genes. In total, between 6-93 mRNA and 1-19 small RNA candidates could be identified among the seven patients. The overlap of genes between the patients was minimal, indicating significant inter-individual variance among GBM patients. In summary, this prospective study supports the applicability of gene expression measurements in whole blood for the detection of tumor recurrence. It might provide an alternative to the challenging workflow of liquid biopsy after laborious exosome isolation from whole blood.

Tumors are a heterogeneous group of cell masses originating in various organs or tissues. The cellular composition of the tumor cell mass interacts in an intricate manner, influenced by humoral, genetic, molecular, and tumor microenvironment cues that dictate tumor growth or suppression. As a result, tumors undergo a period of a dormant state before their clinically discernible stage, which surpasses the clinical dormancy threshold. Moreover, as a genetically imprinted strategy, early-seeder cells, a distinct population of tumor cells, break off to dock nearby or extravasate into blood vessels to secondary tissues, where they form disseminated solitary dormant tumor cells with reversible capacity. Among the various mechanisms underlying the dormant tumor mass and dormant tumor cell formation, heat shock proteins (HSPs) might play one of the most important roles in how the dormancy program plays out. It is known that numerous aberrant cellular processes, such as malignant transformation, cancer cell stemness, tumor invasion, metastasis, angiogenesis, and signaling pathway maintenance, are influenced by the HSPs. An accumulating body of knowledge suggests that HSPs may be involved in the angiogenic switch, immune editing, and extracellular matrix (ECM) remodeling cascades, crucial genetically imprinted strategies important to the tumor dormancy initiation and dormancy maintenance program. In this review, we highlight the biological events that orchestrate the dormancy state and the body of work that has been conducted on the dynamics of HSPs in a tumor mass, as well as tumor cell dormancy and reactivation. Additionally, we propose a conceptual framework that could possibly underlie dormant tumor reactivation in metastatic relapse.

Metastasis-directed therapy has the potential to improve progression-free and overall survival in oligometastatic disease (OMD). For breast cancer, however, randomized trials have failed so far to confirm this finding. Because the concept of metastasis-directed therapy in OMD is highly dependent on the accuracy of the imaging modality, we aimed to assess the impact of 18 F-FDG PET/CT on the definition of OMD in breast cancer patients. Methods: Eighty patients with a total of 150 18 F-FDG PET/CT images (between October 2006 and January 2022) were enrolled in this retrospective study at the Technical University of Munich. The inclusion criteria were OMD, defined as 1-5 distant metastases, at the time of 18 F-FDG PET/CT. For the current study, we systemically compared the metastatic pattern on 18 F-FDG PET/CT with conventional CT. Results: At the time of 18 F-FDG PET/CT, 21.3% of patients ( n = 32) had a first-time diagnosis of metastatic disease, 40.7% ( n = 61) had a previous history of OMD, and 38% ( n = 57) had a previous history of polymetastatic disease. In 45.3% of cases, the imaging modality ( 18 F-FDG PET/CT vs. conventional CT) had an impact on the assessment of whether OMD was present. An identical metastatic pattern was observed in only 32% of cases. 18 F-FDG PET/CT detected additional metastases in 33.3% of cases, mostly in the nonregional lymph node system. Conclusion: The use of 18 F-FDG PET/CT had a substantial impact on the definition of OMD and detection of metastatic pattern in breast cancer. Our results emphasize the importance of establishing a standardized definition for imaging modalities in future trials and clinical practices related to metastasis-directed therapy in breast cancer patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Approximately 25-50% of patients undergoing radiotherapy (RT) experience psychological distress and anxiety, which can detrimentally affect both their quality of life and treatment outcomes. While previous research has demonstrated that relaxation exercises can enhance the tolerability of RT and alleviate associated stress and anxiety, the specific needs for such therapies in radiation oncology remain under-explored. This study aims to investigate the demand for and preferences toward relaxation exercises among radiotherapy patients, addressing a critical gap in patient-centered care., Methods: A prospective pseudonymized survey study using a one-time paper-based questionnaire was conducted from 2022 to 2023 among patients undergoing curative-intent RT for breast cancer or patients undergoing palliative RT for bone metastases. Patients were asked in a 11-item questionnaire about their anxiety, pre-existing practice of relaxation exercises/interventions, their interest in relaxation exercises, and preferences on the type and format of instruction. Data were analyzed descriptively., Results: 100 patients (74 female and 26 male) responded, of whom 68 received curative-intent adjuvant RT and 32 palliative RT. Median age was 62 years. 78% of patients indicated a desire to be actively involved in their radiotherapy, but only 27% had used relaxation exercises prior to RT. 44.8% of both curatively and palliatively treated patients who wanted to be actively involved in their therapy desired to learn how to best relax. 56.4% of respondents were willing to spend extra time learning offered exercises., Conclusion: The survey indicates that patients undergoing RT, both for curative or palliative intent, desire relaxation exercises to relieve stress and anxiety from RT. It is therefore important to assess the need for relaxation interventions in individual patients and to develop suitable programs or collaborate with other healthcare professionals to meet these needs., (© 2024. The Author(s).)

Background: Meningiomas are the most common primary brain tumors. While most are benign (WHO grade 1) and have a favorable prognosis, up to one-fourth are classified as higher-grade, falling into WHO grade 2 or 3 categories. Recently, an integrated risk score (IRS) pertaining to tumor biology was developed and its prognostic relevance was validated in a large, multicenter study. We hypothesized imaging data to be reflective of the IRS. Thus, we assessed the potential of a machine learning classifier for its noninvasive prediction using preoperative magnetic resonance imaging (MRI)., Methods: In total, 160 WHO grade 2 and 3 meningioma patients from 2 university centers were included in this study. All patients underwent surgery with histopathological workup including methylation analysis. Preoperative MRI scans were automatically segmented, and radiomic parameters were extracted. Using a random forest classifier, 3 machine learning classifiers (1 multiclass classifier for IRS and 2 binary classifiers for low-risk and high-risk prediction, respectively) were developed in a training set (120 patients) and independently tested in a hold-out test set (40 patients)., Results: Multiclass IRS classification had a test set area under the curve (AUC) of 0.7, mostly driven by the difficulties in clearly separating medium-risk from high-risk patients. Consequently, a classifier predicting low-risk IRS versus medium-/high-risk showed a very high test accuracy of 90% (AUC 0.88). In particular, "sphericity" was associated with low-risk IRS classification., Conclusion: The IRS, in particular molecular low-risk, can be predicted from imaging data with high accuracy, making this important prognostic classification accessible by imaging., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

So far, the cellular origin of glioblastoma (GBM) needs to be determined, with prevalent theories suggesting emergence from transformed endogenous stem cells. Adult neurogenesis primarily occurs in two brain regions: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Whether the proximity of GBM to these neurogenic niches affects patient outcome remains uncertain. Previous studies often rely on subjective assessments, limiting the reliability of those results. In this study, we assessed the impact of GBM's relationship with the cortex, SVZ and SGZ on clinical variables using fully automated segmentation methods. In 177 glioblastoma patients, we calculated optimal cutpoints of minimal distances to the SVZ and SGZ to distinguish poor from favorable survival. The impact of tumor contact with neurogenic zones on clinical parameters, such as overall survival, multifocality, MGMT promotor methylation, Ki-67 and KPS score was also examined by multivariable regression analysis, chi-square test and Mann-Whitney-U. The analysis confirmed shorter survival in tumors contacting the SVZ with an optimal cutpoint of 14 mm distance to the SVZ, separating poor from more favorable survival. In contrast, tumor contact with the SGZ did not negatively affect survival. We did not find significant correlations with multifocality or MGMT promotor methylation in tumors contacting the SVZ, as previous studies discussed. These findings suggest that the spatial relationship between GBM and neurogenic niches needs to be assessed differently. Objective measurements disprove prior assumptions, warranting further research on this topic., Competing Interests: The authors declare no conflicts of interest.

Background and Purpose: Many patients with solid tumors develop brain metastases (BM). With more patients surviving long-term, preservation of neurocognitive function gains importance. In recent years, several methods to delay cognitive deterioration have been tested in clinical trials. However, knowledge on the extent to which these neuroprotective strategies have been implemented in clinical practice is missing., Materials and Methods: We performed an online survey regarding treatment patterns of BM in German-speaking countries, focused on the use of neuroprotective approaches. The survey was distributed among radiation oncologists (ROs) registered within the database of the German Society for Radiation Oncology (DEGRO)., Results: Physicians of 78 centers participated in the survey. Whole brain radiotherapy (WBRT) is still preferred by 70 % of ROs over stereotactic radiotherapy (SRT) in patients with 6-10 BM. For 4-5 BM WBRT is preferred by 23 % of ROs. The fraction of ROs using hippocampal sparing (HS) in WBRT has increased to 89 %, although the technique is used on a regular basis only by a minority (26 %). The drug memantine is not widely prescribed (14% of ROs). A trend was observed for university hospitals to implement neuroprotective approaches more frequently., Conclusion: There is considerable heterogeneity regarding the treatment of BM in German-speaking countries and a general standard of care is lacking. Neuroprotective strategies are not yet standard approaches in daily clinical routine, although usage is increasing. Further clinical trials, as well as improvement of technical opportunities and reimbursement, might further shift the treatment landscape towards neuroprotective radiation treatments in the future., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: Brain metastases (BM) are a common and challenging issue, with their incidence on the rise due to advancements in systemic therapies and increased patient survival. Most patients present with single BM, some of them without any further extracranial metastasis (i.e., solitary BM). The significance of postoperative intracranial tumor volume in the treatment of singular and solitary BM is still debated., Objective: This study aimed to determine the impact of resection and postoperative tumor burden on overall survival (OS) in patients with single BM., Methods: Patients with surgically treated single BM between 04/2007-01/2020 were retrospectively included. Residual tumor burden (RTB) was determined by manual segmentation of early postoperative brain MRI (72 h). Survival analyses were performed using Kaplan-Meier estimates for univariate analysis and Cox regression proportional hazards model for multivariate analysis, using preoperative Karnofsky performance status scale (KPSS), age, sex, RTB, incomplete resection and singular/solitary BM as covariates., Results: 340 patients were included, median age 64 years (54-71). 119 patients (35%) had solitary BM, 221 (65%) singular BM. Complete resection (RTB=0) was achieved in 73%, median preoperative tumor burden was 11.2 cm3 (5-25), and RTB 0 cm3 (0-0.2). Median OS of patients with singular BM was 13 months (4-33) vs 20 months (5-92) for solitary BM; p=0.062. Multivariate analysis revealed singular BM as independent risk factor for poorer OS: HR 1.840 (1.202-2.817), p=0.005. Complete vs. incomplete resection showed no significant OS difference (13 vs. 13 months, p=0.737). When focusing on solitary BM, complete resection led to a longer OS than incomplete resection (21 vs. 8 months), without statistical significance(p=0.250). Achieving RTB=0 resulted in higher OS for patients with solitary BM compared to singular BM (21 vs. 12 months, p=0.027). Patients who received postoperative radiotherapy (RT) had significantly longer OS compared to those without it (14 vs. 4 months, p<0.001), with favorable OS in those receiving stereotactic radiosurgery (SRS) (15 months (3-42), p<0.001) or hypofractionated stereotactic radiotherapy (HSRT)., Conclusion: When complete intracranial tumor resection RTB=0 is achieved, patients with solitary BM have a favorable outcome compared to singular BM. Singular BM was confirmed as independent risk factor. There is a strong presumption that complete resection leads to an improved oncological prognosis. Patients with solitary BM tend to benefit with a favorable outcome following complete resection. Hence, surgical resection should be considered as a treatment option for patients presenting with either no or minimal extracranial disease. Furthermore, the highly favorable impact of postoperative RT on OS was demonstrated and confirmed, especially with SRS or HSRT., Competing Interests: BM works as consultants for Brainlab Brainlab AG, Feldkirchen. In addition, BM works as a consultant for Medtronic, Spineart, Icotec, Relievant and Depuy/Synthes, as a member of their advisory boards. Furthermore, BM reports financial relationships with Medtronic, Ulrich Medical, Brainlab, Spineart, Icotec, Relievant and Depuy/Synthes. He received personal fees and research grants for clinical studies from Medtronic, Ulrich Medical, Brainlab, Icotec and Relievant. All of this happened independently of the submitted work. BM receives royalties from and holds a patent with Spineart. All of the named potential conflicts of interest are unrelated to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Baumgart, Anetsberger, Aftahy, Wiestler, Bernhardt, Combs, Meyer, Schneider, Meyer and Gempt.)

Background & Aims: Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I., Methods: CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1-10.5 Gy (total doses 32.4-42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks., Results: Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression., Conclusions: CIRT of HCC yields excellent local control without dose-limiting toxicity., Impact and Implications: To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials., Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT01167374)., Competing Interests: PH and JL are funded by the Physician-Scientist Program of Heidelberg University, Faculty of Medicine. PH received fees for an advisory board from NovoCure GmbH. FW received speaker fees from AstraZeneca and Merck Sharp & Dohme. JD received grants from Accuray International Sàrl, Merck Serono GmbH, CRI – The Clinical Research Institute GmbH, View Ray Inc., Accuray Incorporated, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Siemens Healthcare GmbH, Quintiles GmbH, NovoCure, Pharmaceutical Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr Pychlau GmbH, Nanobiotix A.A. and IntraOP Medical outside the submitted work. JHR received speaker fees and travel reimbursement from ViewRay Inc., travel reimbursement from IntraOP Medical and Elekta Instrument AB, and a grant from IntraOP Medical outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

Background: Most clinical studies failed to elicit a strong antitumor immune response and subsequent systemic tumor regression after radiation therapy (RT), even in combination with the immune checkpoint inhibitors (ICI) anti-CTLA4 or anti-PD1. Mechanistically, type I interferon (IFN-I) activation is essential for the development of such abscopal effects (AE); however, mechanisms driving or limiting IFN-I activation are ill defined. Groundbreaking discoveries have shown that antibiotics (ABx) can affect oncological outcomes and that microbiota-derived metabolites can modulate systemic antitumor immunity. Recent studies have demonstrated that the bacterial metabolites desaminotyrosine (DAT) and indole-3-carboxaldehyde (ICA) can enhance IFN-I activation in models of inflammatory diseases., Materials and Methods: The subcutaneous bilateral MC38 tumor model is a widely used experimental tool to study the AE in mice. We applied it to explore the influence of broad-spectrum ABx, DAT and ICA on the AE after radioimmunotherapy (RIT). We performed 1x8 Gy of the primary tumor ± anti-CTLA4 or anti-PD1, and ± daily oral application of ABx or metabolites., Result: Combinatory ABx had neither a significant effect on tumor growth of the irradiated tumor nor on tumor progression of the abscopal tumor after RIT with anti-CTLA4. Furthermore, DAT and ICA did not significantly impact on the AE after RIT with anti-CTLA4 or anti-PD1. Surprisingly, ICA even appears to reduce outcomes after RIT with anti-CTLA4., Conclusion: We did not find a significant impact of combinatory ABx on the AE. Experimental application of the IFN-I-inducing metabolites DAT or ICA did not boost the AE after combined RIT. Additional studies are important to further investigate whether the intestinal microbiota or specific microbiota-derived metabolites modulate the AE., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Microbeam radiation therapy (MRT) is a still pre-clinical form of spatially fractionated radiotherapy, which uses an array of micrometer-wide, planar beams of X-ray radiation. The dose modulation in MRT has proven effective in the treatment of tumors while being well tolerated by normal tissue. Research on understanding the underlying biological mechanisms mostly requires large third-generation synchrotrons. In this study, we aimed to develop a preclinical treatment environment that would allow MRT independent of synchrotrons. We built a compact microbeam setup for pre-clinical experiments within a small animal irradiator and present in vivo MRT application, including treatment planning, dosimetry, and animal positioning. The brain of an immobilized mouse was treated with MRT, excised, and immunohistochemically stained against γH2AX for DNA double-strand breaks. We developed a comprehensive treatment planning system by adjusting an existing dose calculation algorithm to our setup and attaching it to the open-source software 3D-Slicer. Predicted doses in treatment planning agreed within 10% with film dosimetry readings. We demonstrated the feasibility of MRT exposures in vivo at a compact source and showed that the microbeam pattern is observable in histological sections of a mouse brain. The platform developed in this study will be used for pre-clinical research of MRT.

Background: In neuro-oncology, the inclusion of tumor patients in the molecular tumor board has only become increasingly widespread in recent years, but so far there are no standards for indication, procedure, evaluation, therapy recommendations and therapy implementation of neuro-oncological patients. The present work examines the current handling of neuro-oncological patients included in molecular tumor boards in Germany., Methods: We created an online based survey with questions covering the handling of neuro-oncologic patient inclusion, annotation of genetic analyses, management of target therapies and the general role of molecular tumor boards in neuro-oncology in Germany. We contacted all members of the Neuro-Oncology working group (NOA) of the German Cancer Society (DKG) by e-mail., Results: 38 responses were collected. The majority of those who responded were specialists in neurosurgery or neurology with more than 10 years of professional experience working at a university hospital. Molecular tumor boards (MTB) regularly take place once a week and all treatment disciplines of neuro-oncology patients take part. The inclusions to the MTB are according to distinct tumors and predominantly in case of tumor recurrence. An independently MTB member mostly create the recommendations, which are regularly implemented in the tumor treatment. Recommendations are given for alteration classes 4 and 5. Problems exist mostly within the cost takeover of experimental therapies. The experimental therapies are mostly given in the department of medical oncology., Conclusions: Molecular tumor boards for neuro-oncological patients, by now, are not standardized in Germany. Similarities exists for patient inclusion and interpretation of molecular alterations; the time point of inclusion and implementation during the patient treatment differ between the various hospitals. Further studies for standardization and harmonisation are needed. In summary, most of the interviewees envision great opportunities and possibilities for molecular-based neuro-oncological therapy in the future., (© 2024. The Author(s).)

Background: A reduced Karnofsky performance score (KPS) often leads to the discontinuation of surgical and adjuvant therapy, owing to a lack of evidence of survival and quality of life benefits. This study aimed to examine the clinical and treatment outcomes of patients with KPS < 70 after neurosurgical resection and identify prognostic factors associated with better survival., Methods: Patients with a preoperative KPS < 70 who underwent surgical resection for newly diagnosed brain metastases (BM) between 2007 and 2020 were retrospectively analyzed. The KPS, age, sex, tumor localization, cumulative tumor volume, number of lesions, extent of resection, prognostic assessment scores, adjuvant radiotherapy and systemic therapy, and presence of disease progression were analyzed. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with better survival. Survival > 3 months was considered favorable and ≤ 3 months as poor., Results: A total of 140 patients were identified. Median overall survival was 5.6 months (range 0-58). There was no difference in the preoperative KPS between the groups of > 3 and ≤ 3 months (50; range, 20-60 vs. 50; range, 10-60, p = 0.077). There was a significant improvement in KPS after surgery in patients with a preoperative KPS of 20% (20 vs 40 ± 20, p = 0.048). In the other groups, no significant changes in KPS were observed. Adjuvant radiotherapy was associated with better survival (44 [84.6%] vs. 32 [36.4%]; hazard ratio [HR], 0.0363; confidence interval [CI], 0.197-0.670, p = 0.00199). Adjuvant chemotherapy and immunotherapy resulted in prolonged survival (24 [46.2%] vs. 12 [13.6%]; HR 0.474, CI 0.263-0.854, p = 0.013]. Systemic disease progression was associated with poor survival (36 [50%] vs. 71 [80.7%]; HR 5.975, CI 2.610-13.677, p < 0.001]., Conclusion: Neurosurgical resection is an appropriate treatment modality for patients with low KPS. Surgery may improve functional status and facilitate further tumor-specific treatment. Combined treatment with adjuvant radiotherapy and systemic therapy was associated with improved survival in this cohort of patients. Systemic tumor progression has been identified as an independent factor for a poor prognosis. There is almost no information regarding surgical and adjuvant treatment in patients with low KPS. Our paper provides novel data on clinical outcome and survival analysis of patients with BM who underwent surgical treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Goldberg, Mondragon-Soto, Altawalbeh, Baumgart, Gempt, Bernhardt, Combs, Meyer and Aftahy.)

Background: The diffuse growth pattern of glioblastoma is one of the main challenges for accurate treatment. Computational tumor growth modeling has emerged as a promising tool to guide personalized therapy. Here, we performed clinical and biological validation of a novel growth model, aiming to close the gap between the experimental state and clinical implementation., Methods: One hundred and twenty-four patients from The Cancer Genome Archive (TCGA) and 397 patients from the UCSF Glioma Dataset were assessed for significant correlations between clinical data, genetic pathway activation maps (generated with PARADIGM; TCGA only), and infiltration ( D w ) as well as proliferation (ρ) parameters stemming from a Fisher-Kolmogorov growth model. To further evaluate clinical potential, we performed the same growth modeling on preoperative magnetic resonance imaging data from 30 patients of our institution and compared model-derived tumor volume and recurrence coverage with standard radiotherapy plans., Results: The parameter ratio D w /ρ ( P  < .05 in TCGA) as well as the simulated tumor volume ( P  < .05 in TCGA/UCSF) were significantly inversely correlated with overall survival. Interestingly, we found a significant correlation between 11 proliferation pathways and the estimated proliferation parameter. Depending on the cutoff value for tumor cell density, we observed a significant improvement in recurrence coverage without significantly increased radiation volume utilizing model-derived target volumes instead of standard radiation plans., Conclusions: Identifying a significant correlation between computed growth parameters and clinical and biological data, we highlight the potential of tumor growth modeling for individualized therapy of glioblastoma. This might improve the accuracy of radiation planning in the near future., Competing Interests: M.M. and F.S. serve as part-time consultants for Novocure GmbH., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

(1) Purpose: To assess the safety and effectivity of stereotactic body radiotherapy (SBRT) on spinal metastases utilizing a simultaneous integrated boost (SIB) concept in oligometastatic cancer patients. (2) Methods: 62 consecutive patients with 71 spinal metastases received SIB-SBRT between 01/2013 and 09/2022 at our institution. We retrospectively analyzed toxicity, local tumor control (LC), and progression-free (PFS) and overall survival (OS) following SIB-SBRT and assessed possible influencing factors (Kaplan-Meier estimator, log-rank test and Cox proportional-hazards model). (3) Results: SIB-SBRT was delivered in five fractions, mostly with 25/40 Gy ( n = 43; 60.56%) and 25/35 Gy ( n = 19, 26.76%). Estimated rates of freedom from VCF were 96.1/90.4% at one/two years. VCF development was significantly associated with osteoporosis ( p < 0.001). No ≥ grade III acute and one grade III late toxicity (VCF) were observed. Estimated LC rates at one/two years were 98.6/96.4%, and histology was significantly associated with local treatment failure ( p = 0.039). Median PFS/OS was 10 months (95% CI 6.01-13.99)/not reached. Development of metastases ≥ one year after initial diagnosis and Karnofsky Performance Score ≥ 90% were predictors for superior PFS ( p = 0.038) and OS ( p = 0.012), respectively. (4) Conclusion: Spinal SIB-SBRT yields low toxicity and excellent LC. It may be utilized in selected oligometastatic patients to improve prognosis. To the best of our knowledge, we provide the first clinical data on the toxicity and effectivity of SIB-SBRT in spinal metastases in a larger patient cohort.

Background: Despite advances in treatment for brain metastases (BMs), the prognosis for recurrent BMs remains poor and requires further research to advance clinical management and improve patient outcomes. In particular, data addressing the impact of tumor volume and surgical resection with regard to survival remain scarce., Methods: Adult patients with recurrent BMs between December 2007 and December 2022 were analyzed. A distinction was made between operated and non-operated patients, and the residual tumor burden (RTB) was determined by using (postoperative) MRI. Survival analysis was performed and RTB cutoff values were calculated using maximally selected log-rank statistics. In addition, further analyses on systemic tumor progression and (postoperative) tumor therapy were conducted., Results: In total, 219 patients were included in the analysis. Median age was 60 years (IQR 52-69). Median preoperative tumor burden was 2.4 cm 3 (IQR 0.8-8.3), and postoperative tumor burden was 0.5 cm 3 (IQR 0.0-2.9). A total of 95 patients (43.4%) underwent surgery, and complete cytoreduction was achieved in 55 (25.1%) patients. Median overall survival was 6 months (IQR 2-10). Cutoff RTB in all patients was 0.12 cm 3 , showing a significant difference ( p = 0.00029) in overall survival (OS). Multivariate analysis showed preoperative KPSS (HR 0.983, 95% CI, 0.967-0.997, p = 0.015), postoperative tumor burden (HR 1.03, 95% CI 1.008-1.053, p = 0.007), and complete vs. incomplete resection (HR 0.629, 95% CI 0.420-0.941, p = 0.024) as significant. Longer survival was significantly associated with surgery for recurrent BMs ( p = 0.00097), and additional analysis demonstrated the significant effect of complete resection on survival ( p = 0.0027). In the subgroup of patients with systemic progression, a cutoff RTB of 0.97 cm 3 ( p = 0.00068) was found; patients who had received surgery also showed prolonged OS ( p = 0.036). Single systemic therapy ( p = 0.048) and the combination of radiotherapy and systemic therapy had a significant influence on survival ( p = 0.036)., Conclusions: RTB is a strong prognostic factor for survival in patients with recurrent BMs. Operated patients with recurrent BMs showed longer survival independent of systemic progression. Maximal cytoreduction should be targeted to achieve better long-term outcomes.

Patients suffering from painful spinal bone metastases (PSBMs) often undergo palliative radiation therapy (RT), with an efficacy of approximately two thirds of patients. In this exploratory investigation, we assessed the effectiveness of machine learning (ML) models trained on radiomics, semantic and clinical features to estimate complete pain response. Gross tumour volumes (GTV) and clinical target volumes (CTV) of 261 PSBMs were segmented on planning computed tomography (CT) scans. Radiomics, semantic and clinical features were collected for all patients. Random forest (RFC) and support vector machine (SVM) classifiers were compared using repeated nested cross-validation. The best radiomics classifier was trained on CTV with an area under the receiver-operator curve (AUROC) of 0.62 ± 0.01 (RFC; 95% confidence interval). The semantic model achieved a comparable AUROC of 0.63 ± 0.01 (RFC), significantly below the clinical model (SVM, AUROC: 0.80 ± 0.01); and slightly lower than the spinal instability neoplastic score (SINS; LR, AUROC: 0.65 ± 0.01). A combined model did not improve performance (AUROC: 0,74 ± 0,01). We could demonstrate that radiomics and semantic analyses of planning CTs allowed for limited prediction of therapy response to palliative RT. ML predictions based on established clinical parameters achieved the best results., (© 2023. Springer Nature Limited.)

Neural-network-based outcome predictions may enable further treatment personalization of patients with head and neck cancer. The development of neural networks can prove challenging when a limited number of cases is available. Therefore, we investigated whether multitask learning strategies, implemented through the simultaneous optimization of two distinct outcome objectives (multi-outcome) and combined with a tumor segmentation task, can lead to improved performance of convolutional neural networks (CNNs) and vision transformers (ViTs). Model training was conducted on two distinct multicenter datasets for the endpoints loco-regional control (LRC) and progression-free survival (PFS), respectively. The first dataset consisted of pre-treatment computed tomography (CT) imaging for 290 patients and the second dataset contained combined positron emission tomography (PET)/CT data of 224 patients. Discriminative performance was assessed by the concordance index (C-index). Risk stratification was evaluated using log-rank tests. Across both datasets, CNN and ViT model ensembles achieved similar results. Multitask approaches showed favorable performance in most investigations. Multi-outcome CNN models trained with segmentation loss were identified as the optimal strategy across cohorts. On the PET/CT dataset, an ensemble of multi-outcome CNNs trained with segmentation loss achieved the best discrimination (C-index: 0.29, 95% confidence interval (CI): 0.22-0.36) and successfully stratified patients into groups with low and high risk of disease progression (p=0.003). On the CT dataset, ensembles of multi-outcome CNNs and of single-outcome ViTs trained with segmentation loss performed best (C-index: 0.26 and 0.26, CI: 0.18-0.34 and 0.18-0.35, respectively), both with significant risk stratification for LRC in independent validation (p=0.002 and p=0.011). Further validation of the developed multitask-learning models is planned based on a prospective validation study, which has recently completed recruitment.

Purpose: Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia., Experimental Design: A DNA-methylome-based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression-based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)-negative patients with HNSCC treated with primary radiochemotherapy (RCHT)., Results: Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P = 0.001) and overall survival (HR, 2.34; P = 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P = 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status., Conclusions: Our findings highlight an unexplored avenue for DNA methylation-based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors. See related commentary by Heft Neal and Brenner, p. 2954., (©2023 The Authors; Published by the American Association for Cancer Research.)

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite modern, multimodal therapeutic options of surgery, chemotherapy, tumor-treating fields (TTF), and radiotherapy, the 5-year survival is below 10%. In order to develop new therapies, better preclinical models are needed that mimic the complexity of a tumor. In this work, we established a novel three-dimensional (3D) model for patient-derived GBM cell lines. To analyze the volume and growth pattern of primary GBM cells in 3D culture, a CoSeedis TM culture system was used, and radiation sensitivity in comparison to conventional 2D colony formation assay (CFA) was analyzed. Both culture systems revealed a dose-dependent reduction in survival, but the high variance in colony size and shape prevented reliable evaluation of the 2D cultures. In contrast, the size of 3D spheroids could be measured accurately. Immunostaining of spheroids grown in the 3D culture system showed an increase in the DNA double-strand-break marker γH2AX one hour after irradiation. After 24 h, a decrease in DNA damage was observed, indicating active repair mechanisms. In summary, this new translational 3D model may better reflect the tumor complexity and be useful for analyzing the growth, radiosensitivity, and DNA repair of patient-derived GBM cells.

Introduction: Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established., Methods: Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC., Results: OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007)., Conclusions: After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The brain is a common site for cancer metastases. In case of large and/or symptomatic brain metastases, neurosurgical resection is performed. Adjuvant radiotherapy is a standard procedure to minimize the risk of local recurrence and is increasingly performed as local stereotactic radiotherapy to the resection cavity. Both hypofractionated stereotactic radiotherapy (HFSRT) and single fraction stereotactic radiosurgery (SRS) can be applied in this case. Although adjuvant stereotactic radiotherapy to the resection cavity is widely used in clinical routine and recommended in international guidelines, the optimal fractionation scheme still remains unclear. The SATURNUS trial prospectively compares adjuvant HFSRT with SRS and seeks to detect the superiority of HFSRT over SRS in terms of local tumor control., Methods: In this single center two-armed randomized phase III trial, adjuvant radiotherapy to the resection cavity of brain metastases with HFSRT (6 - 7 × 5 Gy prescribed to the surrounding isodose) is compared to SRS (1 × 12-20 Gy prescribed to the surrounding isodose). Patients are randomized 1:1 into the two different treatment arms. The primary endpoint of the trial is local control at the resected site at 12 months. The trial is based on the hypothesis that HFSRT is superior to SRS in terms of local tumor control., Discussion: Although adjuvant stereotactic radiotherapy after resection of brain metastases is considered standard of care treatment, there is a need for further prospective research to determine the optimal fractionation scheme. To the best of our knowledge, the SATURNUS study is the only randomized phase III study comparing different regimes of postoperative stereotactic radiotherapy to the resection cavity adequately powered to detect the superiority of HFSRT regarding local control., Trial Registration: The study was retrospectively registered with ClinicalTrials.gov, number NCT05160818, on December 16, 2021. The trial registry record is available on  https://clinicaltrials.gov/study/NCT05160818 . The presented protocol refers to version V1.3 from March 21, 2021., (© 2023. The Author(s).)

Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making.

Type I interferons, particularly IFNα-2b, play essential roles in eliciting adaptive and innate immune responses, being implicated in the pathogenesis of various diseases, including cancer, and autoimmune and infectious diseases. Therefore, the development of a highly sensitive platform for analysis of either IFNα-2b or anti-IFNα-2b antibodies is of high importance to improve the diagnosis of various pathologies associated with the IFNα-2b disbalance. For evaluation of the anti-IFNα-2b antibody level, we have synthesized superparamagnetic iron oxide nanoparticles (SPIONs) coupled with the recombinant human IFNα-2b protein (SPIONs@IFNα-2b). Employing a magnetic relaxation switching assay (MRSw)-based nanosensor, we detected picomolar concentrations (0.36 pg/mL) of anti-INFα-2b antibodies. The high sensitivity of the real-time antibodies' detection was ensured by the specificity of immune responses and the maintenance of resonance conditions for water spins by choosing a high-frequency filling of short radio-frequency pulses of the generator. The formation of a complex of the SPIONs@IFNα-2b nanoparticles with the anti-INFα-2b antibodies led to a cascade process of the formation of nanoparticle clusters, which was further enhanced by exposure to a strong (7.1 T) homogenous magnetic field. Obtained magnetic conjugates exhibited high negative MR contrast-enhancing properties (as shown by NMR studies) that were also preserved when particles were administered in vivo. Thus, we observed a 1.2-fold decrease of the T2 relaxation time in the liver following administration of magnetic conjugates as compared to the control. In conclusion, the developed MRSw assay based on SPIONs@IFNα-2b nanoparticles represents an alternative immunological probe for the estimation of anti-IFNα-2b antibodies that could be further employed in clinical studies.

In human radiotherapy a safety margin (PTV margin) is essential for successful irradiation and is usually part of clinical treatment planning. In preclinical radiotherapy research with small animals, most uncertainties and inaccuracies are present as well, but according to the literature a margin is used only scarcely. In addition, there is only little experience about the appropriate size of the margin, which should carefully be investigated and considered, since sparing of organs at risk or normal tissue is affected. Here we estimate the needed margin for preclinical irradiation by adapting a well-known human margin recipe from van Herck et al. to the dimensions and requirements of the specimen on a small animal radiation research platform (SARRP). We adjusted the factors of the described formula to the specific challenges in an orthotopic pancreatic tumor mouse model to establish an appropriate margin concept. The SARRP was used with its image-guidance irradiation possibility for arc irradiation with a field size of 10 × 10 mm 2 for 5 fractions. Our goal was to irradiate the clinical target volume (CTV) of at least 90% of our mice with at least 95% of the prescribed dose. By carefully analyzing all relevant factors we gain a CTV to planning target volume (PTV) margin of 1.5 mm for our preclinical setup. The stated safety margin is strongly dependent on the exact setting of the experiment and has to be adjusted for other experimental settings. The few stated values in literature correspond well to our result. Even if using margins in the preclinical setting might be an additional challenge, we think it is crucial to use them to produce reliable results and improve the efficacy of radiotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Importance: Prostate-specific antigen membrane positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) after radical prostatectomy for patients with recurrent or persistent prostate cancer., Objective: To develop and validate a nomogram for prediction of freedom from biochemical failure (FFBF) after PSMA-PET-based sRT., Design, Setting, and Participants: This retrospective cohort study included 1029 patients with prostate cancer treated between July 1, 2013, and June 30, 2020, at 11 centers from 5 countries. The initial database consisted of 1221 patients. All patients had a PSMA-PET scan prior to sRT. Data were analyzed in November 2022., Exposures: Patients with a detectable post-radical prostatectomy prostate-specific antigen (PSA) level treated with sRT to the prostatic fossa with or without additional sRT to pelvic lymphatics or concurrent androgen deprivation therapy (ADT) were eligible., Main Outcomes and Measures: The FFBF rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse was defined as a PSA nadir of 0.2 ng/mL after sRT., Results: In the nomogram creation and validation process, 1029 patients (median age at sRT, 70 years [IQR, 64-74 years]) were included and further divided into a training set (n = 708), internal validation set (n = 271), and external outlier validation set (n = 50). The median follow-up was 32 months (IQR, 21-45 months). Based on the PSMA-PET scan prior to sRT, 437 patients (42.5%) had local recurrences and 313 patients (30.4%) had nodal recurrences. Pelvic lymphatics were electively irradiated for 395 patients (38.4%). All patients received sRT to the prostatic fossa: 103 (10.0%) received a dose of less than 66 Gy, 551 (53.5%) received a dose of 66 to 70 Gy, and 375 (36.5%) received a dose of more than 70 Gy. Androgen deprivation therapy was given to 325 (31.6%) patients. On multivariable Cox proportional hazards regression analysis, pre-sRT PSA level (hazard ratio [HR], 1.80 [95% CI, 1.41-2.31]), International Society of Urological Pathology grade in surgery specimen (grade 5 vs 1+2: HR, 2.39 [95% CI, 1.63-3.50], pT stage (pT3b+pT4 vs pT2: HR, 1.91 [95% CI, 1.39-2.67]), surgical margins (R0 vs R1+R2+Rx: HR, 0.60 [95% CI, 0.48-0.78]), ADT use (HR, 0.49 [95% CI, 0.37-0.65]), sRT dose (>70 vs ≤66 Gy: HR, 0.44 [95% CI, 0.29-0.67]), and nodal recurrence detected on PSMA-PET scans (HR, 1.42 [95% CI, 1.09-1.85]) were associated with FFBF. The mean (SD) nomogram concordance index for FFBF was 0.72 (0.06) for the internal validation cohort and 0.67 (0.11) in the external outlier validation cohort., Conclusions and Relevance: This cohort study of patients with prostate cancer presents an internally and externally validated nomogram that estimated individual patient outcomes after PSMA-PET-guided sRT.

Background: The fifth version of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) in 2021 brought substantial changes. Driven by the enhanced implementation of molecular characterization, some diagnoses were adapted while others were newly introduced. How these changes are reflected in imaging features remains scarcely investigated., Materials and Methods: We retrospectively analyzed 226 treatment-naive primary brain tumor patients from our institution who received extensive molecular characterization by epigenome-wide methylation microarray and were diagnosed according to the 2021 WHO brain tumor classification. From multimodal preoperative 3T MRI scans, we extracted imaging metrics via a fully automated, AI-based image segmentation and processing pipeline. Subsequently, we examined differences in imaging features between the three main glioma entities (glioblastoma, astrocytoma, and oligodendroglioma) and particularly investigated new entities such as astrocytoma, WHO grade 4., Results: Our results confirm prior studies that found significantly higher median CBV ( p = 0.00003, ANOVA) and lower median ADC in contrast-enhancing areas of glioblastomas, compared to astrocytomas and oligodendrogliomas ( p = 0.41333, ANOVA). Interestingly, molecularly defined glioblastoma, which usually does not contain contrast-enhancing areas, also shows significantly higher CBV values in the non-enhancing tumor than common glioblastoma and astrocytoma grade 4 ( p = 0.01309, ANOVA)., Conclusions: This work provides extensive insights into the imaging features of gliomas in light of the new 2021 WHO CNS tumor classification. Advanced imaging shows promise in visualizing tumor biology and improving the diagnosis of brain tumor patients.

Chordomas are rare tumors of the embryologic spinal cord remnant. They are locally aggressive and typically managed with surgery and either adjuvant or neoadjuvant radiation therapy. However, there is great variability in practice patterns including radiation type and fractionation regimen, and limited high-level data to drive decision making. The purpose of this manuscript was to summarize the current literature specific to radiotherapy in the management of spine and sacral chordoma and to provide practice recommendations on behalf of the Spine Tumor Academy. A systematic review of the literature was performed using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) approach. Medline and Embase databases were utilized. The primary outcome measure was the rate of local control. A detailed review and interpretation of eligible studies is provided in the manuscript tables and text. Recommendations were defined as follows: (1) consensus: approved by >75% of experts; (2) predominant: approved by >50% of experts; (3) controversial: not approved by a majority of experts. Expert consensus supports dose escalation as critical in optimizing local control following radiation therapy for chordoma. In addition, comprehensive target volumes including sites of potential microscopic involvement improve local control compared with focal targets. Level I and high-quality multi-institutional data comparing treatment modalities, sequencing of radiation and surgery, and dose/fractionation schedules are needed to optimize patient outcomes in this locally aggressive malignancy.

Background and Purpose: In breast cancer patients, the increasing de-escalation of axillary surgery and the improving resolution of diagnostic imaging results in a more frequent detection of residual, radiographically suspect lymph nodes (sLN) after surgery. If resection of the remaining suspect lymph nodes is not feasible, a simultaneous boost to the lymph node metastases (LN-SIB) can be applied. However, literature lacks data regarding the outcome and safety of this technique., Materials and Methods: We included 48 patients with breast cancer and sLN in this retrospective study. All patients received a LN-SIB. The median dose to the breast or chest wall and the lymph node system was 50.4 Gy in 28 fractions. The median dose of the LN-SIB was 58.8 Gy / 2.1 Gy (56-63 Gy / 2-2.25 Gy). The brachial plexus was contoured in every case and the dose within the plexus PRV (+0.3-0.5mm) was limited to an EQD2 of 59 Gy. All patients received structured radiooncological and gynecological follow-up by clinically experienced physicians. Radiooncological follow-ups were at baseline, 6 weeks, 3 months, 6 months and subsequent annually after irradiation., Results: The median follow-up time was 557 days and ranged from 41 to 3373 days. Overall, 28 patients developed I°, 18 patients II° and 2 patients III° acute toxicity. There were no severe late side effects (≥ III°) observed during the follow-up period. The most frequent chronic side effect was fatigue. One patient (2.1 %) developed pain and mild paresthesia in the ipsilateral arm after radiotherapy. After a follow-up of 557 days (41 to 3373 days), in 8 patients a recurrence was observed (16.7%). In 4 patients the recurrence involved the regional lymph node system. Hence, local control in the lymph node drainage system after a median follow-up of 557 days was 91.6 %., Conclusion: If surgical re-dissection of residual lymph nodes is not feasible or refused by the patient, LN-SIB-irradiation can be considered as a potential treatment option. However, patients need to be informed about a higher risk of regional recurrence compared to surgery and an additional risk of acute and late toxicity compared to adjuvant radiotherapy without regional dose escalation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Klusen, Peiler, Schmidt, Kiechle, Muench, Asadpour, Combs and Borm.)

Background: The aim of this study was to develop and validate radiogenomic models to predict the MDM2 gene amplification status and differentiate between ALTs and lipomas on preoperative MR images., Methods: MR images were obtained in 257 patients diagnosed with ALTs ( n = 65) or lipomas ( n = 192) using histology and the MDM2 gene analysis as a reference standard. The protocols included T2-, T1-, and fat-suppressed contrast-enhanced T1-weighted sequences. Additionally, 50 patients were obtained from a different hospital for external testing. Radiomic features were selected using mRMR. Using repeated nested cross-validation, the machine-learning models were trained on radiomic features and demographic information. For comparison, the external test set was evaluated by three radiology residents and one attending radiologist., Results: A LASSO classifier trained on radiomic features from all sequences performed best, with an AUC of 0.88, 70% sensitivity, 81% specificity, and 76% accuracy. In comparison, the radiology residents achieved 60-70% accuracy, 55-80% sensitivity, and 63-77% specificity, while the attending radiologist achieved 90% accuracy, 96% sensitivity, and 87% specificity., Conclusion: A radiogenomic model combining features from multiple MR sequences showed the best performance in predicting the MDM2 gene amplification status. The model showed a higher accuracy compared to the radiology residents, though lower compared to the attending radiologist.