A multi-institutional series of a novel, recurrent TRIM24::MET fusion-driven infant-type hemispheric glioma reveals significant clinico-pathological heterogeneity.

Within the past decade, incremental integration of molecular characteristics into the classification of central nervous system neoplasms increasingly facilitated precise diagnosis and advanced stratification, beyond potentially providing the foundation for advanced targeted therapies. We report a series of three cases of infant-type hemispheric glioma (IHG) involving three infants diagnosed with neuroepithelial tumors of the cerebral hemispheres harboring a novel, recurrent TRIM24::MET fusion. Histopathology showed glial tumors with either low-grade or high-grade characteristics, while molecular characterization found an additional homozygous CDKN2A/B deletion in two cases. Two patients showed leptomeningeal dissemination, while multiple supra- and infratentorial tumor manifestations were found in one case. Following subtotal resection (two cases) and biopsy (one case), treatment intensity of adjuvant chemotherapy regimens did not reflect in the progression patterns within the reported cases. Two patients showed progression after first-line treatment, of which one patient died not responding to tyrosine kinase inhibitor cabozantinib. As the detection of a recurrent TRIM24::MET fusion expands the spectrum of renowned driving fusion genes in IHG, this comparative illustration may indicate a distinct clinico-pathological heterogeneity of tumors bearing this driver alteration. Upfront clinical trials of IHG promoting further characterization and the implementation of individualized therapies involving receptor tyrosine kinase inhibition are required.

Radiation-Induced DNA Damage in Uveal Melanoma Is Influenced by Dose Delivery and Chromosome 3 Status.

Purpose: The purpose of this study was to analyze the extent of DNA breaks in primary uveal melanoma (UM) with regard to radiotherapy dose delivery (single-dose versus fractionated) and monosomy 3 status. Methods: A total of 54 patients with UM were included. Stereotactic radiotherapy (SRT) was performed in 23 patients, with 8 undergoing single-dose SRT (sdSRT) treatment and 15 receiving fractionated SRT (fSRT). DNA breaks in the enucleated or endoresected tumors were visualized by a TUNEL assay and quantified by measuring the TUNEL-positive area. Protein expression was analyzed by immunohistochemistry. Co-detection of chromosome 3 with proteins was performed by immuno-fluorescent in situ hybridization. Results: The amount of DNA breaks in the total irradiated group was increased by 2.7-fold (P < 0.001) compared to non-irradiated tissue. Tumors treated with fSRT were affected more severely, showing 2.1-fold more DNA damage (P = 0.007) compared to the cases after single (high) dose irradiation (sdSRT). Monosomy 3 tumors showed less DNA breaks compared to disomy 3 samples (P = 0.004). The presence of metastases after radiotherapy correlated with monosomy 3 and less DNA breaks compared to patients with non-metastatic cancer in the combined group with fSRT and sdSRT (P < 0.05). Conclusions: Fractionated irradiation led to more DNA damage than single-dose treatment in primary UM. As tumors with monosomy 3 showed less DNA breaks than those with disomy 3, this may indicate that they are less radiosensitive, which may influence the efficacy of irradiation.

Online Adaptive MR-Guided Ultrahypofractionated Radiotherapy of Prostate Cancer on a 1.5 T MR-Linac: Clinical Experience and Prospective Evaluation.

The use of hypofractionated radiotherapy in prostate cancer has been increasingly evaluated, whereas accumulated evidence demonstrates comparable oncologic outcomes and toxicity rates compared to normofractionated radiotherapy. In this prospective study, we evaluate all patients with intermediate-risk prostate cancer treated with ultrahypofractionated (UHF) MRI-guided radiotherapy on a 1.5 T MR-Linac within our department and report on workflow and feasibility, as well as physician-recorded and patient-reported longitudinal toxicity. A total of 23 patients with intermediate-risk prostate cancer treated on the 1.5 T MR-Linac with a dose of 42.7 Gy in seven fractions (seven MV step-and-shoot IMRT) were evaluated within the MRL-01 study (NCT04172753). The duration of each treatment step, choice of workflow (adapt to shape-ATS or adapt to position-ATP) and technical and/or patient-sided treatment failure were recorded for each fraction and patient. Acute and late toxicity were scored according to RTOG and CTC V4.0, as well as the use of patient-reported questionnaires. The median follow-up was 12.4 months. All patients completed the planned treatment. The mean duration of a treatment session was 38.2 min. In total, 165 radiotherapy fractions were delivered. ATS was performed in 150 fractions, 5 fractions were delivered using ATP, and 10 fractions were delivered using both ATS and ATP workflows. Severe acute bother (G3+) regarding IPS-score was reported in five patients (23%) at the end of radiotherapy. However, this tended to normalize and no G3+ IPS-score was observed later at any point during follow-up. Furthermore, no other severe genitourinary (GU) or gastrointestinal (GI) acute or late toxicity was observed. One-year biochemical-free recurrence survival was 100%. We report the excellent feasibility of UHF MR-guided radiotherapy for intermediate-risk prostate cancer patients and acceptable toxicity rates in our preliminary study. Randomized controlled studies with long-term follow-up are warranted to detect possible advantages over current state-of-the-art RT techniques.

App-based assessment of patient-reported outcomes in the Molecular Tumor Board in the Center for Personalized Medicine-(TRACE).

Background: Biomarker-based therapies are increasingly used in cancer patients outside clinical trials. Systematic assessment of patient-reported outcomes (PRO) is warranted to take patients' perspectives during biomarker-based therapies into consideration. We assessed the feasibility of an electronic PRO assessment via a smartphone application. Methods: An interdisciplinary expert panel developed a smartphone application based on symptom burden and health-related quality of life (HRQoL) metrics reported in a retrospective analysis of 292 neuro-oncological patients. The app included validated assessments of health-related quality of life (HRQoL), the burden of symptoms, and psychological stress. Feasibility and usability were tested in a pilot study. Semi-structured interviews with patients and health care professionals (HCP) were conducted, transcribed, and analyzed according to Mayring´s qualitative content analysis. Furthermore, we assessed compliance and descriptive data of ePROs. Results: A total of 14 patients have been enrolled, (9 female, 5 male). A total of 4 HCPs, 9 patients, and 1 caregiver were interviewed regarding usability/feasibility. The main advantages were the possibility to complete questionnaires at home and comfortable implementation in daily life. Compliance was high, for example, 82% of the weekly distributed NCCN distress thermometer questionnaires were answered on time, however, with interindividual variability. We observed a median distress score of 5 (range 0-10, 197 results, n = 12, weekly assessed) and a median Global health score of 58.3 according to the EORTC QLQ-C30 instrument (range 16.7-100, 77 results, n = 12, monthly assessed). Conclusions: This pilot study proved the feasibility and acceptance of the app. We will therefore expand its application during biomarker-guided therapies to enable systematic PRO assessments.

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.

Brachytherapy for rhabdomyosarcoma: Survey of international clinical practice and development of guidelines.

BACKGROUND AND PURPOSE: The purpose of this study was to address the lack of published data on the use of brachytherapy in pediatric rhabdomyosarcoma by describing current practice as starting point to develop consensus guidelines. MATERIALS AND METHODS: An international expert panel on the treatment of pediatric rhabdomyosarcoma comprising 24 (pediatric) radiation oncologists, brachytherapists and pediatric surgeons met for a Brachytherapy Workshop hosted by the European paediatric Soft tissue Sarcoma Study Group (EpSSG). The panel's clinical experience, the results of a previously distributed questionnaire, and a review of the literature were presented. RESULTS: The survey indicated the most common use of brachytherapy to be in combination with tumor resection, followed by brachytherapy as sole local therapy modality. HDR was increasingly deployed in pediatric practice, especially for genitourinary sites. Brachytherapy planning was mostly by 3D imaging based on CT. Recommendations for patient selection, treatment requirements, implant technique, delineation, dose prescription, dose reporting and clinical management were defined. CONCLUSIONS: Consensus guidelines for the use of brachytherapy in pediatric rhabdomyosarcoma have been developed through multicenter collaboration establishing the basis for future work. These have been adopted for the open EpSSG overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma (FaR-RMS).

Evolution of a Meningothelial Meningioma: From WHO Grade 1 to Anaplastic Grade 3 with Extracranial Metastasis Including Extensive Liver Metastasis.

A 61-year-old patient was diagnosed with a left-sided falx meningioma. Histopathological analysis following extirpation showed a meningothelial meningioma ZNS WHO grade 1 with sparse mitoses. Over the course of 12 years, the patient received irradiation (54.0 Gy), peptide radio-receptor therapy (177Lu-DOMITATE) and targeted therapy (mTOR inhibitor). Follow-up imaging revealed an increased size of the residual tumor. Due to increased liver function parameters, imaging of the liver was performed, showing widespread space-occupying lesions with atypical appearance. Biopsy revealed metastasis of the meningioma, now with 2.7 mitoses/mm2, necrosis and homozygous CDKN2A/B deletion, corresponding to an anaplastic CNS meningioma WHO grade 3. A second small meningioma on the left petroclival side has been consistent in size over 12 years. Metastatic meningiomas pose a pertinent clinical challenge due to poor prognosis. The lung, bone, liver and cervical lymph nodes are the most common sites of extracranial metastasis. According to the World Health Organization criteria, the most important predictive factor for recurrence and metastasis is the tumor grade.

Preoperative growth dynamics of untreated glioblastoma: Description of an exponential growth type, correlating factors, and association with postoperative survival.

Background: Little is known about the growth dynamics of untreated glioblastoma and its possible influence on postoperative survival. Our aim was to analyze a possible association of preoperative growth dynamics with postoperative survival. Methods: We performed a retrospective analysis of all adult patients surgically treated for newly diagnosed glioblastoma at our center between 2010 and 2020. By volumetric analysis of data of patients with availability of ≥3 preoperative sequential MRI, a growth pattern was aimed to be identified. Main inclusion criterion for further analysis was the availability of two preoperative MRI scans with a slice thickness of 1 mm, at least 7 days apart. Individual growth rates were calculated. Association with overall survival (OS) was examined by multivariable. Results: Out of 749 patients screened, 13 had ≥3 preoperative MRI, 70 had 2 MRI and met the inclusion criteria. A curve estimation regression model showed the best fit for exponential tumor growth. Median tumor volume doubling time (VDT) was 31 days, median specific growth rate (SGR) was 2.2% growth per day. SGR showed negative correlation with tumor size (rho = -0.59, P < .001). Growth rates were dichotomized according to the median SGR.OS was significantly longer in the group with slow growth (log-rank: P = .010). Slower preoperative growth was independently associated with longer overall survival in a multivariable Cox regression model for patients after tumor resection. Conclusions: Especially small lesions suggestive of glioblastoma showed exponential tumor growth with variable growth rates and a median VDT of 31 days. SGR was significantly associated with OS in patients with tumor resection in our sample.

Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3.

BACKGROUND: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. METHODS: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. RESULTS: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. CONCLUSION: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

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.

Multimodal Therapy with Consolidating Haploidentical Stem Cell Transplantation and Dinutuximab Beta for Patients with High-Risk Neuroblastoma and Central Nervous System Relapse.

Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains poor. We retrospectively reviewed data from 13 patients with HRNB and CNS relapse who received multimodal therapy with consolidating haploidentical stem cell transplantation (haplo-SCT) followed by dinutuximab beta ± subcutaneous interleukin-2 (scIL-2). Following individual relapse treatment, patients aged 1-21 years underwent haplo-SCT with T/B-cell-depleted grafts followed by dinutuximab beta 20 mg/m2/day × 5 days for 5-6 cycles. If a response was demonstrated after cycle 5 or 6, patients received up to nine treatment cycles. After haplo-SCT, eight patients had a complete response, four had a partial response, and one had a stable disease. All 13 patients received ≥3 cycles of immunotherapy. At the end of the follow-up, 9/13 patients (66.7%) demonstrated complete response. As of July 2023, all nine patients remain disease-free, with a median follow-up time of 5.1 years since relapse. Estimated 5-year event-free and overall survival rates were 55.5% and 65.27%, respectively. Dinutuximab beta ± scIL-2 following haplo-SCT is a promising treatment option with a generally well-tolerated safety profile for patients with HRNB and CNS relapse.

Potential of pre-operative MRI features in glioblastoma to predict for molecular stem cell subtype and patient overall survival.

AIM OF THE STUDY: A molecular signature based on 10 mRNA abundances that characterizes the mesenchymal-to-proneural phenotype of glioblastoma stem(like) cells (GSCs) enriched in primary culture has been previously established. As this phenotype has been proposed to be prognostic for disease outcome the present study aims to identify features of the preoperative MR imaging that may predict the GSC phenotype of individual tumors. MATERIAL/METHODS: Molecular mesenchymal-to-proneural mRNA signatures and intrinsic radioresistance (SF4, survival fraction at 4 Gy) of primary GSC-enriched cultures were associated with survival data and pre-operative MR imaging of the corresponding glioblastoma patients of a prospective cohort (n = 24). The analyzed imaging parameters comprised linear vectors derived from tumor volume, necrotic volume and edema as contoured manually. RESULTS: A necrosis/tumor vector ratio and to a weaker extent the product of this ratio and the edema vector were identified to correlate with the mesenchymal-to-proneural mRNA signature and the SF4 of the patient-derived GSC cultures. Importantly, both parameter combinations were predictive for overall survival of the whole patient cohort. Moreover, the combination of necrosis/tumor vector ratio and edema vector differed significantly between uni- and multifocally recurring tumors. CONCLUSION: Features of the preoperative MR images may reflect the molecular signature of the GSC population and might be used in the future as a prognostic factor and for treatment stratification especially in the MGMT promotor-unmethylated sub-cohort of glioblastoma patients.

Increasing Patient Safety and Treatment Quality by Using Intraoperative MRI for Organ-Preserving Tumor Resection and High-Dose Rate Brachytherapy in Children with Bladder/Prostate and Perianal Rhabdomyosarcoma.

In children with bladder/prostate (BP) and perianal rhabdomyosarcoma (RMS), we use a hybrid treatment concept for those suitable, combining organ-preserving tumor resection and high-dose rate brachytherapy (HDR-BT). This treatment concept has been shown to improve outcomes. However, it is associated with specific challenges for the clinicians. The exact position of the tubes for BT is a prerequisite for precise radiotherapy. It can finally be determined only with an MRI or CT scan. We evaluated the use of an intraoperative MRI (iMRI) to control the position of the BT tubes and for radiotherapy planning in all patients with BP and perianal RMS who received the above-mentioned combination therapy in our department since January 2021. iMRI was used in 12 children. All tubes were clearly localized. No adverse events occurred. In all 12 children, radiotherapy could be started on time. In a historical cohort without iMRI, this was not possible in 3 out of 20 children. The use of iMRI in children with BP and perianal RMS improved patient safety and treatment quality. This technology has proven to be successful for the patient population we have defined and has become a standard procedure in our institution.

Automatic AI-based contouring of prostate MRI for online adaptive radiotherapy.

BACKGROUND AND PURPOSE: MR-guided radiotherapy (MRgRT) online plan adaptation accounts for tumor volume changes, interfraction motion and thus allows daily sparing of relevant organs at risk. Due to the high interfraction variability of bladder and rectum, patients with tumors in the pelvic region may strongly benefit from adaptive MRgRT. Currently, fast automatic annotation of anatomical structures is not available within the online MRgRT workflow. Therefore, the aim of this study was to train and validate a fast, accurate deep learning model for automatic MRI segmentation at the MR-Linac for future implementation in a clinical MRgRT workflow. MATERIALS AND METHODS: For a total of 47 patients, T2w MRI data were acquired on a 1.5 T MR-Linac (Unity, Elekta) on five different days. Prostate, seminal vesicles, rectum, anal canal, bladder, penile bulb, body and bony structures were manually annotated. These training data consisting of 232 data sets in total was used for the generation of a deep learning based autocontouring model and validated on 20 unseen T2w-MRIs. For quantitative evaluation the validation set was contoured by a radiation oncologist as gold standard contours (GSC) and compared in MATLAB to the automatic contours (AIC). For the evaluation, dice similarity coefficients (DSC), and 95% Hausdorff distances (95% HD), added path length (APL) and surface DSC (sDSC) were calculated in a caudal-cranial window of ± 4 cm with respect to the prostate ends. For qualitative evaluation, five radiation oncologists scored the AIC on the possible usage within an online adaptive workflow as follows: (1) no modifications needed, (2) minor adjustments needed, (3) major adjustments/ multiple minor adjustments needed, (4) not usable. RESULTS: The quantitative evaluation revealed a maximum median 95% HD of 6.9 mm for the rectum and minimum median 95% HD of 2.7 mm for the bladder. Maximal and minimal median DSC were detected for bladder with 0.97 and for penile bulb with 0.73, respectively. Using a tolerance level of 3 mm, the highest and lowest sDSC were determined for rectum (0.94) and anal canal (0.68), respectively. Qualitative evaluation resulted in a mean score of 1.2 for AICs over all organs and patients across all expert ratings. For the different autocontoured structures, the highest mean score of 1.0 was observed for anal canal, sacrum, femur left and right, and pelvis left, whereas for prostate the lowest mean score of 2.0 was detected. In total, 80% of the contours were rated be clinically acceptable, 16% to require minor and 4% major adjustments for online adaptive MRgRT. CONCLUSION: In this study, an AI-based autocontouring was successfully trained for online adaptive MR-guided radiotherapy on the 1.5 T MR-Linac system. The developed model can automatically generate contours accepted by physicians (80%) or only with the need of minor corrections (16%) for the irradiation of primary prostate on the clinically employed sequences.

Clinical outcome of biomarker-guided therapies in adult patients with tumors of the nervous system.

Background: The clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study. Methods: molecular tumor board (MTB)@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the MTB, and collected prospective clinical outcome data. Results: Here, we present initial data of 661 adult patients with tumors of the nervous system enrolled by December 31, 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival ratio >1.3 in 31.3% of patients. Conclusions: Our study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies, and even clinical care.

The prognostic role of the immunohistochemical expression of S100 in meningiomas.

BACKGROUND: Despite best clinical management, meningioma patients experience tumor recurrence. Efforts have been made to improve the prognostic stratification of meningiomas. Recently, a multi-faceted molecular classification suggested that the marker S100 is associated with a favorable outcome, making a further analysis in a larger cohort interesting. MATERIALS AND METHODS: The immunohistochemical staining for S100 was analyzed in 1669 paraffin-embedded meningioma samples. The distribution and association with clinical data and progression-free survival via radiographic tumor recurrence were assessed. RESULTS: Of 1669 cases, 218 tumors showed strong S100 expression (13.1%). A significantly higher frequency of S100 positive meningiomas was observed in meningiomas of female patients, tumors with spinal and convexity/falx location, primary tumor surgery, NF2, higher extent of resection, lower WHO CNS grade, adjuvant radiotherapy and recurrence-free tumors during follow-up. Univariate analysis revealed a favorable progression-free survival for meningiomas with S100 expression (p = 0.0059) but not in the multivariate analysis. Higher S100 frequency was independently associated with female gender (p = 0.0003), NF2 (p < 0.0001), tumor location (p < 0.0001) and lower WHO CNS grade (p = 0.0133). CONCLUSIONS: The positive prognostic impact of S100 is mostly attributed to the confounding clinical factors gender, tumor location, NF2 status and WHO CNS grade.

Detailed functional results after bladder-preserving surgery and high-dose-rate brachytherapy in pediatric bladder/prostate rhabdomyosarcoma.

PURPOSE: In pediatric bladder/prostate-rhabdomyosarcoma, the rate of bladder preservation after neoadjuvant chemotherapy is high, with an excellent oncological outcome. Information about functional urological long-term outcomes is rare. METHODS: Data of all patients who had undergone bladder-preserving surgery with or without brachytherapy at our institution between 2009 and 2020 were analyzed retrospectively. Detailed urological function was assessed focusing on age-related continence, bladder capacity and urodynamic findings. RESULTS: We identified 40 patients, median age at surgery of 27 months (range 9-191), and 32 patients additionally received postoperative high-dose-rate brachytherapy. The median follow-up was 32.5 months (range 6-125). The bladder capacity increased from median 66.7% (21.1-180) of expected bladder capacity related to age 3 months after surgery to 87.4% (58.1-181.8) 9 months after surgery. In the group of aged > 6-year-old, continence was 94% (83% with brachytherapy, 100% without brachytherapy). Erectile function was normal in 92% (90% with brachytherapy, 100% without brachytherapy). Bladder capacity was more than 65% expected bladder capacity related to age in 70% (60% with brachytherapy, 86% without brachytherapy). 65% of all patients need neither anticholinergic drugs nor low-dose antibiotics (63% with brachytherapy, 71% without brachytherapy). CONCLUSIONS: Bladder preservation with good functional outcome can be achieved in localized bladder/prostate-rhabdomyosarcoma. In selected cases, supportive brachytherapy additionally contributes to an improvement in the oncological outcome with calculable risks for bladder and erectile function. Careful urological aftercare should be a fixed priority after oncological follow-ups.

Dose-escalated radiotherapy with simultaneous integrated boost for bone metastases in selected patients with assumed favourable prognosis.

BACKGROUND: Stereotactic body radiotherapy (SBRT) concepts for dose escalation are increasingly used for bone metastases in patients with oligometastatic or oligoprogressive disease. For metastases that are not suitable for SBRT-regimens, a treatment with 30/40 Gy with simultaneous integrated boost (SIB) in 10 fractions represents a possible regimen. The aim of this study was to investigate the feasibility of this concept and the acute and subacute toxicities. PATIENTS AND METHODS: Clinical records for dose-escalated radiotherapy of all consecutive patients treated with this regimen were evaluated retrospectively (24 patients with 28 target volumes for oncologic outcomes and 25 patients with 29 target volumes for treatment feasibility and dose parameters analysis). Analysis of radiotherapy plans included size of target volumes and dosimetric parameter for target volumes and organs at risk (OAR). Acute and subacute toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) V4.0. RESULTS: The most common localization was the spine (71.4%). The most common histology was prostate cancer (45.8%). Oligometastatic or oligoprogressive disease was the indication for dose-escalated radiotherapy in 19/24 patients (79.2%). Treatment was feasible with all patients completing radiotherapy. Acute toxicity grade 1 was documented in 36.0% of the patients. During follow up, one patient underwent surgery due to bone instability. The 1-year local control and patient-related progression-free survival (PFS) were 90.0 ± 6.7% and 33.3 ± 11.6%, respectively. CONCLUSIONS: Dose-escalated hypofractionated radiotherapy with simultaneous integrated boost for bone metastases resulted in good local control with limited acute toxicities. Only one patient required surgical intervention. The regimen represents an alternative to SBRT in selected patients.

Postoperative complications and oncologic outcomes after multimodal therapy of localized high risk soft tissue sarcoma.

BACKGROUND: Standard therapy for localized high-risk soft tissue sarcoma includes surgical resection and neoadjuvant or adjuvant radiation therapy (± chemotherapy and locoregional hyperthermia). No difference in oncologic outcomes for patients treated with neoadjuvant and adjuvant radiation therapy was reported, whereas side effect profiles differ. The aim of this analysis was to analyse oncologic outcomes and postoperative complications in patients treated with multimodal treatment. METHODS: Oncologic outcomes and major wound complications (MWC, subclassified as wound healing disorder, infection, abscess, fistula, seroma and hematoma) were evaluated in 74 patients with localized high-risk soft tissue sarcoma of extremities and trunk undergoing multimodal treatment, and also separately for the subgroup of lower extremity tumors. Clinical factors and treatment modalities (especially neoadjuvant vs. adjuvant radiotherapy) were evaluated regarding their prognostic value and impact on postoperative wound complications. RESULTS: Oncologic outcomes were dependent on number of high risk features (tumor size, depth to superficial fascia and grading), but not on therapy sequencing (however with higher risk patients in the neoadjuvant group). Different risk factors influenced different subclasses of wound healing complications. Slightly higher MWC-rates were observed in patients treated with neoadjuvant therapy, compared to adjuvant radiotherapy, although only with a trend to statistical significance (31.8% vs. 13.3%, p = 0.059). However, except for wound infections, no significant difference for other subclasses of postoperative complications was observed between neoadjuvant and adjuvant therapy. Diabetes was confirmed as a major risk factor for immune-related wound complications. CONCLUSION: Rates of major wound complications in this cohort are comparable to published data, higher rates of wound infections were observed after neoadjuvant radiotherapy. Tumor localization, patient age and diabetes seem to be major risk factors. The number of risk factors for high risk soft tissue sarcoma seem to influence DMFS. Neoadjuvant treatment increases the risk only for wound infection treated with oral or intravenous antibiotic therapy and appears to be a safe option at an experienced tertiary center in absence of other risk factors.

First Experience and Prospective Evaluation on Feasibility and Acute Toxicity of Online Adaptive Radiotherapy of the Prostate Bed as Salvage Treatment in Patients with Biochemically Recurrent Prostate Cancer on a 1.5T MR-Linac.

INTRODUCTION: Novel MRI-linear accelerator hybrids (MR-Linacs, MRL) promise an optimization of radiotherapy (RT) through daily MRI imaging with enhanced soft tissue contrast and plan adaptation on the anatomy of the day. These features might potentially improve salvage RT of prostate cancer (SRT), where the clinical target volume is confined by the mobile organs at risk (OAR) rectum and bladder. So far, no data exist about the feasibility of the MRL technology for SRT. In this study, we prospectively examined patients treated with SRT on a 1.5 T MRL and report on workflow, feasibility and acute toxicity. PATIENTS AND METHODS: Sixteen patients were prospectively enrolled within the MRL-01 study (NCT: NCT04172753). All patients were staged and had an indication for SRT after radical prostatectomy according to national guidelines. RT consisted of 66 Gy in 33 fractions or 66.5/70 Gy in 35 fractions in case of a defined high-risk region. On the 1.5 T MRL, daily plan adaption was performed using one of two workflows: adapt to shape (ATS, using contour adaptation and replanning) or adapt to position (ATP, rigid replanning onto the online anatomy with virtual couch shift). Duration of treatment steps, choice of workflow and treatment failure were recorded for each fraction of each patient. Patient-reported questionnaires about patient comfort were evaluated as well as extensive reporting of acute toxicity (patient reported and clinician scored). RESULTS: A total of 524/554 (94.6%) of fractions were successfully treated on the MRL. No patient-sided treatment failures occurred. In total, ATP was chosen in 45.7% and ATS in 54.3% of fractions. In eight cases, ATP was performed on top of the initial ATS workflow. Mean (range) duration of all fractions (on-table time until end of treatment) was 25.1 (17.6-44.8) minutes. Mean duration of the ATP workflow was 20.60 (17.6-25.2) minutes and of the ATS workflow 31.3 (28.2-34.1) minutes. Patient-reported treatment experience questionnaires revealed high rates of tolerability of the treatment procedure. Acute toxicity (RTOG, CTC as well as patient-reported CTC, IPSS and ICIQ) during RT and 3 months after was mild to moderate with a tendency of recovery to baseline levels at 3 months post RT. No G3+ toxicity was scored for any item. CONCLUSIONS: In this first report on SRT of prostate cancer patients on a 1.5 T MRL, we could demonstrate the feasibility of both available workflows. Daily MR-guided adaptive SRT of mean 25.1 min per fraction was well tolerated in this pretreated collective, and we report low rates of acute toxicity for this treatment. This study suggests that SRT on a 1.5 T MRL can be performed in clinical routine and it serves as a benchmark for future analyses.