Purpose Stereotactic radiosurgery (SRS) yields excellent local control in patients with a limited number of brain metastases (BMs), but radiation-induced cerebral edema and radiation necrosis (RN) in particular pose as a dose-limiting late toxicity, with the same holding true after fractionated radiotherapy for glioma. In symptomatic patients, the first-line standard of care includes corticosteroids, which may, however, be counterproductive in the evolving era of immunotherapy. Boswellic acid (BA), available as an over-the-counter dietary supplement, has been suggested as a potential corticosteroid-sparing alternative due to its anti-inflammatory and anti-angiogenic effects. Methods We performed a comprehensive literature search of the MEDLINE, Embase, Scopus, and Cochrane databases, identifying publications reporting on the use of BA during or after brain irradiation in humans. Using the RAMESES framework, relevant data are summarized using a meta-narrative approach. Results Six records (three for edema reduction in large irradiated volumes and three for RN after SRS) were identified, encompassing 130 patients. Roughly half of patients benefited from BA (radiographically or clinically) and about one-third could successfully taper dexamethasone or prevent its long-term intake. Tolerability of BA was favorable, with mild gastrointestinal discomfort being reported most frequently. Current drawbacks include unknown optimal formulation as well as timing and dosing, a considerably large number of required daily capsules, and uncertain interactions with other drugs. Conclusion Overall, the clinical evidence on the use of BA for radiation-induced cerebral edema and RN is lacking and well-designed prospective trials are warranted to further investigate this potential low-cost corticosteroid-sparing option.

Abstract Background The discovery of cellular tumor networks in glioblastoma, with routes of malignant communication extending far beyond the detectable tumor margins, has highlighted the potential of supramarginal resection strategies. Retrospective data suggest that these approaches may improve long-term disease control. However, their application is limited by the proximity of critical brain regions and vasculature, posing challenges for validation in randomized trials. Anterior temporal lobectomy (ATL) is a standardized surgical procedure commonly performed in patients with pharmacoresistant temporal lobe epilepsy. Translating the ATL approach from epilepsy surgery to the neuro-oncological field may provide a model for investigating supramarginal resection in glioblastomas located in the anterior temporal lobe. Methods The ATLAS/NOA-29 trial is a prospective, multicenter, multinational, phase III randomized controlled trial designed to compare ATL with standard gross-total resection (GTR) in patients with newly-diagnosed anterior temporal lobe glioblastoma. The primary endpoint is overall survival (OS), with superiority defined by significant improvements in OS and non-inferiority in the co-primary endpoint, quality of life (QoL; “global health” domain of the European organization for research and treatment of cancer (EORTC) QLQ-C30 questionnaire). Secondary endpoints include progression-free survival (PFS), seizure outcomes, neurocognitive performance, and the longitudinal assessment of six selected domains from the EORTC QLQ-C30 and BN20 questionnaires. Randomization will be performed intraoperatively upon receipt of the fresh frozen section result. A total of 178 patients will be randomized in a 1:1 ratio over a 3-year recruitment period and followed-up for a minimum of 3 years. The trial will be supervised by a Data Safety Monitoring Board, with an interim safety analysis planned after the recruitment of the 57th patient to assess potential differences in modified Rankin Scale (mRS) scores between the treatment arms 6 months after resection. Assuming a median improvement in OS from 17 to 27.5 months, the trial is powered at > 80% to detect OS differences with a two-sided log-rank test at a 5% significance level. Discussion The ATLAS/NOA-29 trial aims to determine whether ATL provides superior outcomes at equal patients’ Qol compared to GTR in anterior temporal lobe glioblastoma, potentially establishing ATL as the surgical approach of choice for isolated temporal glioblastoma and redefining the standard of care for this patient population. Trial registration German Clinical Trials Register (DRKS00035314), registered on October 18, 2024.

Purpose:The role of radiotherapy in the context of limited liver metastases is emerging rapidly with a variety of available technical approaches. Here, we provide a dosimetric comparison of three different radiotherapy modalities for non-resected liver metastases. Methods:This multicentric study included 30 patients previously treated for solitary liver metastases. Interstitial high dose-rate brachytherapy (HDR), stereotactic body radiation therapy (SBRT), and kilovoltage electronic brachytherapy (eBT) with a single dwelling point, as an in this context novel modality, were planned with a 25-Gy single fraction and dosimetrically compared. The primary endpoint was difference in healthy liver tissue exposure. Secondary endpoints included target volume coverage, dose to the surrounding organs at risk (OARs), and radiation treatment time. Results:The median (range) lesion volume was 9.3 (2.5 - 29.7) cm3. Electronic BT yielded a significantly better OAR dose sparing compared to SBRT. Radiation exposure to the healthy liver was significantly lower with eBT (V9.1 Gy 13.8 [3.4-41.6] cm3) and HDR (49.2 [12.7-116.8] cm3) when compared with SBRT (98.8 [54.3-303.7] cm3; p < 0.001 for both). Mean treatment time was shortest for SBRT (6.1 min vs. 7.8 min for HDR [p = 0.003] vs. 16.1 min for eBT [p < 0.001]). Equally, CTV D90% and D95% were superior for SBRT (p < 0.001 vs. HDR and eBT). Conclusion:Minimally invasive single-catheter eBT provides a new potential approach in the context of unresectable liver metastases, with optimal OAR dose sparing, yet suboptimal target volume coverage. Combining the advantages of both modalities, a multi-dwelling eBT approach as in HDR might ease applicability in clinical routine with optimized target coverage while maintaining excellent OAR doses. Future prospective investigations are required to further define its role within well-established liver-directed therapies.

Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients' families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including MSH2 hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.

Abstract BACKGROUND Pediatric central nervous system (CNS) tumors can occur as first manifestations of cancer predisposition syndromes (CPS) resulting from pathogenic variants in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Early detection of MMR deficiencies (MMRD) may warrant the therapeutic use of checkpoint inhibitors and enable genetic consulting for the patient’s families. METHODS We prospectively screened 128 pediatric high-grade gliomas (pedHGG) for MMR protein expression by immunohistochemistry (IHC) as part of the HIT-HGG-2013 clinical trial. We compared IHC results to independently collected patient information on CPS including MMRD to test the method’s efficiency in screening for Lynch syndrome and Constitutional MMRD syndrome CMMRD. RESULTS From 128 successfully tested tumors, ten cases (10/128, 7.8%), showed loss of expression of at least one of the MMR proteins. In seven of the ten affected patients (7/128, 5.5%), genetic testing uncovered heterozygous (6/10) or homozygous (1/10) pathogenic germline variants in MMR genes (MLH1, MSH2 or MSH6) confirming the diagnosis of Lynch syndrome respectively CMMRD. In three cases (3/128 2.3%), MMR alterations were restricted to tumor tissue. The group of diffuse midline gliomas, H3 K27-altered, (67/128, 52.3%) did not show MMR alterations, while either somatic or germline MMR mutations were detected in two of eight patients with diffuse hemispheric glioma, H3 G34-mutant. In 88 patients (88/128, 68.8%) either clinical or molecular-genetic information on CPS could be provided. All ten patients with signs of MMRD were successfully detected by IHC from tumor tissue. CONCLUSIONS IHC for MMR proteins represents a highly sensitive screening method for MMRD in pedHGG. Considering the occurrence of at least 11.5% (7/61) of MMRD in pediatric patients with diffuse high-grade glioma excluding DMG, MMRD IHC should be part of routine diagnostics as cost-effective, broadly available and robust screening method.

PURPOSE:After surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy by enabling superior organ-at-risk preservation, reduction of in-hospital times, and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess the safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). METHODS AND MATERIALS:In a multicentric approach incorporating individual patient data from 6 international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis, leptomeningeal spread, local control, distant brain progression (DBP), and estimated overall survival. RESULTS:In total, 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow-up was 13.2 (range, 1.2-102.4) months, and the median IORT dose was 25 (range, 18-30) Gy prescribed to the applicator surface. There was 1 grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative radiation necrosis rate was observed. The 1-year local control rate was 98.0%, and the 1-year DBP-free survival rate was 60.0%. Median time to DBP was 5.5 (range, 1.0-18.5) months in the subgroup of patients experiencing DBP, and the cumulative leptomeningeal spread rate was 4.9%. The median estimated overall survival was 26 (range, 1.2 to not reached) months with a 1-year survival rate of 74.0%. Early initiation of immunotherapy/TTs was associated with a nonsignificant trend toward improved DBP rate and overall survival. CONCLUSIONS:The combination of ICIs/TTs with IORT for resected BMs does not seem to increase toxicity and yields encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial.

Purpose Intraoperative radiotherapy (IORT) has become a viable treatment option for resectable brain metastases (BMs). As data on local control and radiation necrosis rates are maturing, we focus on meaningful secondary endpoints such as time to next treatment (TTNT), duration of postoperative corticosteroid treatment, and in-hospital time. Methods Patients prospectively recruited within an IORT study registry between November 2020 and June 2023 were compared with consecutive patients receiving adjuvant stereotactic radiotherapy (SRT) of the resection cavity within the same time frame. TTNT was defined as the number of days between BM resection and start of the next extracranial oncological therapy (systemic treatment, surgery, or radiotherapy) for each of the groups. Results Of 95 BM patients screened, IORT was feasible in 84 cases (88%) and ultimately performed in 64 (67%). The control collective consisted of 53 SRT patients. There were no relevant differences in clinical baseline features. Mean TTNT (range) was 36 (9 − 94) days for IORT patients versus 52 (11 − 126) days for SRT patients (p = 0.01). Mean duration of postoperative corticosteroid treatment was similar (8 days; p = 0.83), as was mean postoperative in-hospital time (11 versus 12 days; p = 0.97). Mean total in-hospital time for BM treatment (in- and out-patient days) was 11 days for IORT versus 19 days for SRT patients (p  0.001). Conclusion IORT for BMs results in faster completion of interdisciplinary treatment when compared to adjuvant SRT, without increasing corticosteroid intake or prolonging in-hospital times. A randomised phase III trial will determine the clinical effects of shorter TTNT.

PURPOSE:Little is known about the effect of SARS-CoV-2 infection on glioblastoma (GBM) growth, metabolism, and prognosis. Immunological changes within GBM tissue are potentially symptomatic, underlining the urgent need for a better understanding of this phenomenon. To date, the complex underlying biology has not been fully elucidated. A decisive role of the tumor microenvironment (TME) and the components of the immune system acting within it is assumed. METHODS:Immunohistochemical staining of SARS-CoV-2 spike protein and immune cell infiltration of TME was performed on the tumor tissue of one patient. This patient developed hemiparesis 14 days after symptomatic SARS-CoV-2 infection, leading to tumor diagnosis. Subsequently and after biopsy, there was an unexpectedly good response to chemotherapy only. In looking for further evidence of the potential of SARS-CoV-2 to influence the course of GBM, two additional adult patients that had transient MRI changes and neurological deterioration following SARS-CoV-2 infection were evaluated. RESULTS:In the patient for whom neurological deterioration in the course of SARS-CoV-2 led to GBM diagnosis, immunohistochemistry revealed virus-specific protein accumulation in the tumor cells, microglial activation, and the formation of T-cell nodules. In the other two patients, the findings were compatible with symptomatic pseudoprogression that occurred in a temporal relationship with SARS-CoV-2 infection. CONCLUSION:The results indicate a possible association between clinically relevant changes in GBM biology and SARS-CoV-2 infection, with histological confirmation of SARS-CoV-2-associated changes within the tumor tissue. The exact pathomechanism and underlying inflammatory pathways require further investigation.

Background and Purpose: To investigate the effect of topical non-invasive physical plasma (NIPP), a volatile mix generated out of ambient air, on prevention of acute radiation dermatitis (RD) during and after whole-breast irradiation (WBI).Materials and Methods: Lateral and medial breast halves were randomised within each patient to receive either 120 s of NIPP or sham treatment daily during WBI. Standard skin care with urea lotion was applied to the whole breast. Blinded acute skin toxicity was assessed weekly for each breast half separately and included clinician(CTCAE) and patient-reported (modified RISRAS), and objective (spectrophotometry) assessments. As an additional external control, a comparable standard of care (SoC) patient collective from a previous prospective trial was used.Results: Sixty-four patients were included. There were no significant differences between breast halves. Post-hoc comparison with a similar SoC control collective revealed OR = 0.28 (95% CI 0.11-0.76; p = 0.014) for grade >= 2 RD upon WBI completion, along with less hyperpigmentation (p < 0.001), oedema (p = 0.020), dry (p < 0.001) and moist desquamation (p = 0.017), pain, itching, and burning (p < 0.001 for each). Tolerability of NIPP was excellent and side effects were not observed.Conclusion: Even though there were no differences between intrapatient-randomised breast halves, the overall incidence and severity of acute radiation-induced skin toxicity were considerably lower when compared to a prospectively collected SoC cohort. Our data suggest the potential benefit of NIPP in RD prevention. A randomised trial with a physical control group is warranted to confirm these promising results (DRKS00026225).

Prophylactic insertion of an external ventricular drainage (EVD) prior to the resection of posterior fossa metastases (PFMs) is a common approach to address postoperative transient and permanent hydrocephalus. However, predicting surgery-related hydrocephalus in the preoperative phase continues to be a challenge. This study aims to analyze the incidence, preoperatively collectable risk factors and necessity of perioperative external ventricular drainage placement after posterior fossa metastasis surgery. All patients undergoing surgery for PFMs at the authors’ neuro-oncological center between 2015 and 2021 were identified and assessed for postoperative hydrocephalus occurrence. Tumour volume, edema volume, and 4th ventricle volume were assessed on preoperative magnetic resonance imaging scans using the IntelliSpace Portal 5.0. A multivariable logistic regression analysis was performed to identify possible predictors for postoperative hydrocephalus occurrence. Postoperative hydrocephalus occurred in 14 of the 130 identified PFM patients (11

ZusammenfassungHintergrundDie Radiodermatitis (RD) ist die häufigste Nebenwirkung der Strahlentherapie (RT), wobei verschiedene pharmazeutische Optionen zur Vorbeugung/Behandlung zur Verfügung stehen. Unser Ziel war, die pharmazeutischen Behandlungsmuster für die RD unter strahlentherapeutischen Fachleuten zu ermitteln.MethodikWir haben eine Umfrage zum Thema RD in der deutschsprachigen radioonkologischen Gemeinschaft durchgeführt und ihre Meinung zu präventiven und therapeutischen pharmazeutischen Therapieansätzen betreffend die akute RD erfragt.Ergebnisse244 Angehörige zugehöriger Gesundheitsberufe nahmen teil. Dexpanthenol‐Lotion ist das am häufigsten verwendete Mittel sowohl zur Vorbeugung (53%) als auch zur Behandlung (76,9%) der RD, gefolgt von Harnstoff (29,8%) zur Vorbeugung und Kortikosteroiden (46,9%) zur Behandlung. Die Teilnehmer verwenden eine breite Palette an Substanzen, haben aber insgesamt wenig Erfahrung mit diesen. 32,5% der Teilnehmer empfehlen generell keine präventive Behandlung. 53,4% der Teilnehmer empfehlen Alternativmedizin. Obwohl selten eingesetzt, wurden Kortikosteroide als wirksamstes Behandlungsmittel angesehen, gefolgt von Dexpanthenol und Low‐Level‐Lasertherapie. Die Mehrheit der Teilnehmer bevorzugt die feuchte gegenüber der trockenen Behandlung der feuchten Desquamation und 43,8% verschreiben Antiseptika.SchlussfolgerungenDie pharmazeutische Behandlung der RD in der deutschsprachigen strahlentherapeutischen Fachwelt ist nach wie vor umstritten, sowie mitunter inkonsistent und nicht durch evidenzbasierte Medizin gestützt. Ein interdisziplinärer Konsens ist erforderlich, um die bestehenden Behandlungskonzepte zu verbessern.

Abstract BACKGROUND Fractionated stereotactic radiotherapy to the resection cavity boosts local control of resected brain metastases significantly. However, start of systemic tumor-directed treatment may be protracted and in-hospital times prolonged. Lately, lex-ioRT of BM has been described as a safe and effective one stop-shop treatment modality with a 1-year local control rate of up to 98% while potentially improving patient convenience. Study Design: The LEXIMATE-trial is a multicenter, international, randomized open-label confirmatory trial comparing lex-IORT with FSRT of resected BM. In the experimental arm, INTRABEAM (Carl Zeiss Meditec AG) is used to deliver IORT by application of 50-kV photons at a standard dose of 30 Gy prescribed to the applicator surface. Standard linear accelerator or Gamma Knife based FSRT (3-7 fractions) to the surgical bed is used in the control arm. The primary endpoint is the cumulative incidence of local recurrences (as per RANO-BM) considering death without prior local recurrence as competing event. Inclusion criteria include histologically confirmed BM with indication for resection according to EANO-ESMO/ASCO-SNO-ASTRO guidelines, ≤5 other brain lesions compatible with BM and amenable to radiosurgery and history of solid cancer or CT scan suggestive for localized or metastasized solid cancer (except germ cell tumors, lymphoma, small-cell lung cancer). The resection cavity must be <5cm in size, IORT doses to brainstem or optical tract may not exceed 8 Gy. Study design: Randomized, open-label, non-inferiority. Sample size: 70 patients per group to show a non-inferiority of the experimental therapy compared to the control therapy with a power of approximately 80%. DISCUSSION The best radio-oncologic procedure for resected BM remains under debate. The LEXIMATE-trial offers an opportunity to provide more solid prospective data on effectiveness, safety and patient comfort both for established and new RT techniques.