OBJECTIVE:Seizures are among the most common symptoms of cerebral arteriovenous malformations (AVMs). Although the main goal of AVM treatment remains complete obliteration, seizure control has become an important treatment aspect in recent years. Thus, we analyzed seizure control following Gamma Knife Radiosurgery (GKRS) treatment at our department in patients with AVMs. METHODS:We analyzed 130 patients with AVMs who had at least one seizure before treatment with GKRS at our tertiary referral center between 1992 and 2022. We analyzed predictors for treatment success, including AVM size, Virginia Radiosurgery AVM Scale, Radiosurgery-Based AVM Score, Spetzler-Ponce class, Spetzler-Martin grade, localization, and identified independent predictors of seizure persistence. RESULTS:Median follow-up was 9.7 years. Improved seizure control was documented for 89% of patients. Seizure-free status after radiosurgery was achieved for 78% of patients. Spetzler-Ponce class C (odds ratio [OR] = 4.6) and having multiple seizures before the first GKRS treatment (OR = 3.5) were independent predictors for seizure persistence. Still, 72% of patients with multiple seizures prior to AVM treatment were seizure-free at last follow-up. Among patients with multiple seizures, having a high-grade AVM was identified as an independent predictor of seizure persistence (OR = 12.1). SIGNIFICANCE:GKRS, as a stand-alone management option or in combination with endovascular therapy, is an effective treatment option in AVM management, not only to achieve AVM obliteration but also to control AVM-related seizures. The Spetzler-Ponce class is a powerful predictor of seizure persistence at last follow-up, especially in patients with multiple seizures prior to treatment.

PURPOSE:Given the early recurrence of brain metastasis (BM), identifying factors that drive BM progression is of clinical interest. This study investigates genetic, epigenetic, and inflammatory signatures in progressive BM following different therapeutic approaches. METHODS:A total of 153 patients who underwent surgical resection for progressive BM were grouped according to the therapeutic strategies prior to the first BM resection: prior radiation (n = 43), systemic therapy (n = 37), combined radiation and systemic treatment (n = 10), and treatment-naive patients (n = 63). Among the treatment-naive patients, 35/63 (55.5%) experienced another intracranial relapse and underwent a second resection (=relapse group), enabling paired analyses. Of these, 23/35 (65.7%) received no therapy between resections; 12/35 (34.3%) received CNS-directed radiotherapy. Tissue samples were analysed using whole-exome sequencing, DNA methylation profiling, and immunohistochemistry. RESULTS:BM resected after progression following prior cranial radiotherapy (43/153, 28.1%) showed significantly lower densities of CD3 + , CD8 + , and CD45RO + cells together with increased FOXP3 + cell density compared with treatment-naïve BM (63/153, 41.2%; median CD3 +: 71 vs. 494 cells/mm²; CD8 +: 44 vs. 187 cells/mm²; CD45RO+: 104 vs. 302 cells/mm²; FOXP3 +: 215 vs. 41 cells/mm²). In the paired analyses, progressive specimen after prior radiation were likewise associated with significantly reduced CD3 + , CD8 + , and CD45RO + and increased FOXP3 + cell densities compared with the matched baseline specimen. In contrast, no genetic alterations or differences in DNA methylation patterns between irradiated and non-irradiated matched samples were identified. CONCLUSION:Progressive BM following cranial radiotherapy demonstrated a distinct immune marker profile consistent with a more immunoregulatory, rather immunosuppressive tumour microenvironment. No therapy-associated genetic or epigenetic alterations were identified. Further prospective studies are warranted to determine whether these immune alterations reflect treatment-related effects or biological features associated with resistance following radiotherapy.

BACKGROUND AND OBJECTIVES:The gold standard for the evaluation of brain arteriovenous malformation (AVM) nidus occlusion after stereotactic radiosurgery is digital subtraction angiography (DSA), which is an invasive technique. We evaluated the role of MRI, especially arterial spin labeling (ASL) in the assessment of nidus occlusion after radiosurgery. DSA was used as the gold standard for comparison. METHODS:Fifty radiosurgically treated brain AVMs were included in this prospective single-center study. All patients underwent a standardized MRI protocol including following sequences: 2-dimensional T2w (TSE) in 3 planes, T1-weighted Magnetization Prepared Rapid Gradient Echo (MPRAGE), axial resolve diffusion-weighted imaging, ASL, time of flight, and time-resolved angiography with interleaved stochastic trajectories. Nidus obliteration according to the standardized MRI protocol was evaluated by an experienced neuroradiologist within 3 days after image acquisition and before DSA was subsequently performed as the reference standard. A second observer retrospectively rated MRI images of all 50 cases blinded to clinical and DSA data after the prospective study was concluded. RESULTS:All cases rated as obliterated by the MRI protocol were confirmed by DSA. However, 26 and 28 AVMs were rated as patent by the observers, which was verified in 22 (85/79%) cases by DSA. ASL had the highest sensitivity among all MRI sequences. In 3 patients, ASL was the only sequence that correctly revealed a residual nidus according to 1 observer. Overall, the sensitivity and specificity of the standardized MRI protocol for detection of a residual nidus were 100/100% and 86/79%, respectively. The interobserver agreement was excellent (κ = 0.92, 0.81-1.00). At last follow-up of this prospective study, 70% of AVMs were completely obliterated. CONCLUSION:MRI evaluation of nidus occlusion including ASL is highly sensitive for residual nidus detection and has a high potential to replace invasive DSA examinations for patients who underwent radiosurgery of brain AVMs.

Existing prognostic models for breast cancer (BC) brain metastases (BM) overlook neurological symptoms. Thus, we explored the incidence and prognostic relevance of neurological symptoms in a real-world cohort of BC patients with BM. The Vienna Brain Metastasis Registry identified BC patients with BM between 1992 and 2020, categorised by subtype: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−), HER2 overexpressing (HER2+), and triple-negative (TN). A total of 716 patients with BM from BC were included. In total, 80% (573/716) of the patients presented with neurological symptoms at BM diagnosis. Across all BC subtypes, asymptomatic patients presented with a significantly longer median OS from diagnosis of BM compared to symptomatic patients (p < 0.05; log-rank test; HR+ BC 29 vs. 9 months; HER2+ BC 24 vs. 12 months; TN 12 vs. 6 months). In multivariate analysis with the BC-specific Graded Prognostic Assessment (Breast-GPA: HR:1.4; 95% CI:1.3–1.5; p < 0.001), the presence of neurological symptoms at diagnosis (HR:1.6; 95% CI: 1.4–1.9; p < 0.001) presented as independently associated with OS from time of BM diagnosis, respectively. Neurological burden at BM diagnosis independently predicts survival in BC patients. Our findings emphasise incorporating the symptom status in the prognostic evaluation and reassessing BM screening in high-risk patients during prospective clinical trials.

OBJECTIVE:Recent treatment guidelines state that in patients with asymptomatic brain metastases (BMs), local treatment can be delayed until there is evidence of intracranial progression. However, while patients with symptomatic BMs typically require dexamethasone treatment, recent data on the impact of this medication on the outcomes of patients with BMs are lacking. Therefore, the authors conducted a prospective study to evaluate concomitant dexamethasone treatment in a population of radiosurgically treated patients with BMs from non-small cell lung cancer (NSCLC). METHODS:This prospective observational study included 129 radiosurgically treated patients with NSCLC BMs, a Karnofsky Performance Status ≥ 70, and no previous radiosurgical treatment. Patients were enrolled in the study between December 2019 and May 2023. For patient allocation, data on concomitant immunotherapy (IT) or targeted therapy (TT) and dexamethasone treatment were analyzed 30 days before and after the first Gamma Knife radiosurgery treatment (GKRS1). A cumulative dose threshold of 100 mg of dexamethasone was evaluated. RESULTS:The estimated median survival time after GKRS1 was significantly longer in female patients than in male patients and in patients with concomitant IT or TT versus those without. Of note, patients with a cumulative concomitant dexamethasone dose ≥ 100 mg at GKRS1 had a significantly shorter median survival after GKRS1 than the patients with a dose < 100 mg. Moreover, a univariable followed by multivariable Cox regression model revealed that a cumulative dexamethasone dose ≥ 100 mg at GKRS1 and male sex were independent prognostic factors for an increased risk of death. CONCLUSIONS:A cumulative dexamethasone dose ≥ 100 mg within 30 days before and after radiosurgery was identified as an independent risk factor for death. Consequently, even in the modern oncological era, the recommendation to delay local BM treatment should be critically reviewed, as the main reason for dexamethasone treatment is the presence of neurological symptoms caused by larger BMs and perifocal edema. Thus, the study data support early local BM treatment to avoid dexamethasone treatment for neurological symptoms caused by progressive BMs.

OBJECTIVE:Since the publication of A Randomized Trial of Unruptured Brain AVMs (ARUBA), the management of unruptured brain arteriovenous malformations (bAVMs) has been controversially discussed. Long-term follow-up data on the exclusively conservative management of unruptured bAVMs are scarce. The authors evaluated the long-term outcomes of patients with unruptured untreated bAVMs in a real-life cohort.METHODS:A retrospective observational cohort of 107 patients (of 897 bAVM patients referred to the authors' institution) with a diagnosis of unruptured and conservatively managed bAVMs is presented. AVMs of all Spetzler-Martin grades were observed. The mean follow-up period was 84 months. In 44% of patients, a follow-up period of 5 years or longer was observed. A national death register comparison completed the outcome analysis.RESULTS:The median age at diagnosis, sex distribution, neurological presentation, and modified Rankin Scale score were comparable to the patients in the medical management arm of the ARUBA study. Patients were mainly young, predominantly male, and in good clinical condition. Similar to the ARUBA cohort, 77% of this study's cohort presented in an excellent clinical status at the time of last follow-up. However, 17% of patients had at least one hemorrhage, resulting in an overall annual hemorrhage risk of 2.7% in the observation period. Moreover, the cumulative 1-, 5-, and 10-year overall hemorrhage rates were 3.0%, 11.3%, and 15.3%, respectively. Consequently, the long-term follow-up AVM-related mortality rate amounted to 8%. The estimated median overall survival after AVM diagnosis was 19.3 years (95% CI 14.0-24.6 years). A multivariate Cox regression model revealed temporal and deep-seated localization as an independent risk factor for AVM hemorrhage, while the presence of seizures reached borderline significance as a risk factor.CONCLUSIONS:The authors' results represent the long-term course of unruptured untreated bAVMs. Their data support the conclusion that even in the post-ARUBA era, tailored active treatment options may be offered to patients with unruptured bAVMs. For patient counseling, individual risk factors should be weighed against the center's treatment-specific risks.

Background So far, only limited studies exist that evaluate patients with brain metastases (BM) from GI cancer and associated primary cancers who were treated by Gamma Knife Radiosurgery (GKRS) and concomitant immunotherapy (IT) or targeted therapy (TT). Methods Survival after GKRS was compared to the general and specific Graded Prognostic Assessment (GPA) and Score Index for Radiosurgery (SIR). Further, the influence of age, sex, Karnofsky Performance Status Scale (KPS), extracranial metastases (ECM) status at BM diagnosis, number of BM, the Recursive Partitioning Analysis (RPA) classes, GKRS1 treatment mode and concomitant treatment with IT or TT on the survival after GKRS was analyzed. Moreover, complication rates after concomitant GKRS and mainly TT treatment are reported. Results Multivariate Cox regression analysis revealed IT or TT at or after the first Gamma Knife Radiosurgery (GKRS1) treatment as the only significant predictor for overall survival after GKRS1, even after adjusting for sex, KPS group, age group, number of BM at GKRS1, RPA class, ECM status at BM diagnosis and GKRS treatment mode. Concomitant treatment with IT or TT did not increase the rate of adverse radiation effects. There was no significant difference in local BM progression after GKRS between patients who received IT or TT and patients without IT or TT. Conclusion Good local tumor control rates and low rates of side effects demonstrate the safety and efficacy of GKRS in patients with BM from GI cancers. The concomitant radiosurgical and targeted oncological treatment significantly improves the survival after GKRS without increasing the rate of adverse radiation effects. To provide local tumor control, radiosurgery remains of utmost importance in modern GI BM management.

ABSTRACT Introduction: Gamma Knife radiosurgery (GKRS) has been demonstrated to be an effective and safe treatment method for dural arteriovenous fistulas (DAVFs). However, only few studies, mostly with limited patient numbers, have evaluated radiosurgery as a sole and upfront treatment option for DAVFs. Methods: 33 DAVF patients treated with GKRS as a stand-alone management at our institution between January 1992 to January 2020 were included. Obliteration rates, time to obliteration, neurological outcome, and complications were evaluated retrospectively. Results: A complete overall obliteration rate of 20/28 (71%) was achieved. The post-radiosurgery actuarial rates of obliteration at 2, 5, and 10 years were 53%, 71%, and 85%, respectively. No difference in time to obliteration between CCFs (14/28, 50%, 17 months; 95% CI: 7.4 - 27.2) and NCCFs (14/28, 50%, 37 months; 95% CI: 34.7 - 38.5; p=0.111) were found. Overall, the neurological outcome in our series was highly favorable at the time of the last follow-up. A complete resolution of symptoms was seen in two-thirds (20/30, 67%) of patients. One patient with multiple DAVFs suffered from an intracranial hemorrhage of the untreated lesion and died during the follow-up period, resulting in a yearly bleeding risk of 0.5%. No complications after radiosurgery were observed in our series. Conclusion: Our results show that Gamma Knife radiosurgery is a safe and effective stand-alone management option for selected DAVF patients.

Brain metastases (BM) in patients with thyroid cancer (TC) are rare with an incidence of 1% for papillary and follicular, 3% for medullary and up to 10% for anaplastic TC (PTC, FTC, MTC and ATC). Little is known about the characteristics and management of BM from TC. Thus, we retrospectively analyzed patients with histologically verified TC and radiologically verified BM identified from the Vienna Brain Metastasis Registry. A total of 20/6074 patients included in the database since 1986 had BM from TC and 13/20 were female. Ten patients had FTC, 8 PTC, one MTC and one ATC. The median age at diagnosis of BM was 68 years. All but one had symptomatic BM and 13/20 patients had a singular BM. Synchronous BM at primary diagnosis were found in 6 patients, while the median time to BM diagnosis was 13 years for PTC (range 1.9-24), 4 years for FTC (range 2.1-41) and 22 years for the MTC patient. The overall survival from diagnosis of BM was 13 months for PTC (range 1.8-57), 26 months for FTC (range 3.9-188), 12 years for the MTC and 3 months for the ATC patient. In conclusion, development of BM from TC is exceedingly rare and the most common presentation is a symptomatic single lesion. While BM generally constitute a poor prognostic factor, individual patients experience long-term survival following local therapy.

Abstract Background Immunotherapy (IO) has changed the treatment landscape of metastatic cancer patients, however, treatment resistance is frequent. We aimed to characterize the inflammatory tumor microenvironment in brain metastases (BM) after IO to gain a deeper understanding of immunologic escape mechanisms. Material and Methods Solid cancer patients who had BM resection after IO progression (IO cohort) were retrospectively identified. We analyzed tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) by immunohistochemistry. A control cohort of BM tissue samples without prior IO served for comparison (no immunotherapy cohort, NIO). Results Twenty-eight IO patients (12/28, 42.9% females; 16/28, 57.1% males; median 61 years; 14/28, 50% lung cancer; 5/28, 17.9% melanoma; 4/28, 14.3% renal cell carcinoma; 1/28, 3.6% breast cancer; 4/28, 14.3% other cancer entities) and 57 NIO patients (28/57, 49.1% females; 29/57, 50.9% males; median 58 years; 35/57, 61.4% lung cancer; 9/57, 15.8% breast cancer; 4/57, 7.0% melanoma; 3/57, 5.3% renal cell carcinoma; 6/57, 10.5% other cancer entities) were included. IO patients had a median of one (range 0-4) systemic therapy line prior to IO. Median time from last IO application until BM resection was 5.6 months (range 0.2-49.8 months). Patients received a median number of 7 (range 1-56) IO applications (14/28, 50% PD-1-targeting IO; 8/28, 28.6% PD-L1; 2/28, 7.1% CTLA4; 4/28, 14.3% CTLA4+PD-1; 3/28, 10.7% IO+chemotherapy). No statistically significant differences in the densities of investigated TILs or PD-L1 expression between the IO and the NIO cohort were observed. Patients of the IO cohort showed higher PD-L1 expression compared to the NIO cohort (57.1 vs. 42.1%, Chi-square, p>0.05). Overall survival (OS) was similar in both cohorts, with a median OS of 11.0 months (range 5.0-17.0) in the IO cohort and 11.0 months (range 5.5-16.5) in the NIO cohort. Conclusion Our findings show an upregulation of PD-L1 in BM occurring after prior IO therapy in the absence of other overt changes in the inflammatory microenvironment. Ongoing analyses in this cohort are investigating possible molecular driver of resistance by analyzing DNA methylation profiles of pre-and post-IO tissue samples of the IO cohort to potentially gain insights on inflammatory IO resistance mechanisms in BM patients.

Considering the rising detection of asymptomatic brain metastases (BM) during screening and staging procedures over the last decades, we aimed to evaluate the incidence, clinical characteristics and the prognostic value of neurological symptoms in BM from breast cancer. Patients with newly diagnosed BM from breast cancer (BC) were identified from the Vienna Brain Metastasis Registry. Patients were grouped into the three main subtypes: hormone receptor-positive/HER2 (human epidermal growth factor receptor 2)-negative breast cancer (HR BC), HER2 overexpressing BC (HER2 BC) and triple-negative BC (TN BC). A retrospective chart review and statistical outcome analyses were performed. 968 patients with BM from breast cancer (34.4% HR BC; 28.9% HER2 BC; 21.8% TN BC; 14.9% unknown receptor status) were included in the analysis. 81.6% (790/968) of the patients presented with neurological symptoms at BM diagnosis including focal deficits (695/790;88.0%), signs of increased intracranial pressure (388/790;49.1%), epileptic seizures (126/790;15.9%) and neuropsychological symptoms (133/790;16.8%). Patients with HER2 BC (66/280;23.6%) were significantly more often diagnosed with BM in absence of neurological symptoms during screening procedures compared to HR BC (62/333;18.6%) and TN BC (31/211;14.7%; chi-square test; p=0.043). Among all BC subtypes, asymptomatic patients presented with a significant longer median overall survival (OS) from diagnosis of BM compared to symptomatic patients (p<0.05; log-rank test; HR BC 20 vs. 9 months; HER2 BC 20 vs. 11 months; TN 11 vs. 5 months). In multivariate analysis, the breast cancer-specific Graded Prognostic Assessment (Breast-GPA: HR:1.4; 95% CI, 1.27-1.49; p<0.001) and the presence of neurological symptoms (HR:1.6; 95% CI, 1.35-1.95; p<0.001) presented as independently associated with survival prognosis from time of BM diagnosis respectively. Neurological symptoms are independently associated with overall survival in patients with BM from breast cancer. Our results highlight the need to incorporate neurological symptoms into the prognostic assessment of patients with BM from breast cancer.

Background Systemic inflammation measured by the neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) was shown to impact the survival prognosis in patients with extracranial solid cancer. Methods One thousand two hundred and fifty patients with newly diagnosed brain metastases (BM) were identified from the Vienna Brain Metastasis Registry. Results PLR and CRP/Alb were higher in patients with progressive extracranial disease and lower in patients with no evidence of extracranial disease. Lower NLR (cut-off = 5.07; 9.3 vs. 5.0 months), LLR (cut-off = 5.76; 10.0 vs. 5.3 months), PLR (cut-off = 335; 8.0 vs. 3.8 months), MLR (cut-off = 0.53; 6.0 vs. 3.5 months) and CRP/Alb (cut-off = 2.93; 8.5 vs. 3.7 months; p adj < 0.05) were associated with longer overall survival (OS). In multivariate analysis with graded prognostic assessment (hazard ratio (HR) 1.45; 95% confidence interval (CI): 1.32–1.59; p adj = 1.62e − 13 ) , NLR (HR 1.55; 95% CI: 1.38–1.75; p adj = 1.92e − 11), LLR (HR 1.57; 95% CI: 1.39–1.77; p adj = 1.96e − 11 ) , PLR (HR 1.60; 95% CI: 1.39–1.85; p adj = 2.87955e − 9), MLR (HR 1.41; 95% CI: 1.14–1.75; p adj = 0.027) and CRP/Alb (HR 1.83; 95% CI: 1.54–2.18; p adj = 2.73e − 10) remained independent factors associated with OS at BM diagnosis. Conclusions Systemic inflammation, measured by NLR, LLR, PLR, MLR and CRP/Alb, was associated with OS in patients with BM. Further exploration of immune modulating therapies is warranted in the setting of BM.

Background: An accurate classification of patients with brain metastases (BMs) is an important foundation to guide individualised treatment decisions and to formulate BM cohorts for modern clinical trials. Methods: Six thousand and thirty-one patients with newly diagnosed BM from different solid tumours treated between 1986 and 2020 were identified from the Vienna Brain Metastasis Registry. Results: A rising fraction of patients presented with asymptomatic BM during the observation period (1986-1999: 20.2% vs 2010-2020: 30.6%; p < 0.001). Especially, oncogene-addicted non-small-cell lung cancer (NSCLC) and BRAF (v-Raf murine sarcoma viral oncogene homolog)-positive melanoma had a higher rate of asymptomatic BM presentation compared with wild-type tumours (p < 0.05). Significant changes of initial BM treatment approaches were observed with a decrease of neurosurgical procedures (1986-1999: 30.8% vs 2010-2020: 19.5%) and an increase of radiation treatments (1986-1999: 65.0% vs 2010-2020: 73.3%) and systemic therapies (1986-1999: 1.0% vs 2010-2020: 2.0%; p < 0.001). Median overall survival (OS) was heterogeneous between primary tumour entities but with an overall increase over the decades (median OS 1986-1999: 5 months vs 2010-2020: 7 months; p Z 0.001). Sur-vival times were longer in patients with oncogene-addicted NSCLC, BRAF-positive mela-noma and hormone receptor-positive breast cancer compared with the other cancer subtypes (p > 0.05). Conclusion: Our data highlight shifting trends in the symptomatic presentation and in treat-ment strategies of patients with BM over the last decades. Entity specific aspects and, in partic-ular, the presence of targetable driver mutation impact the clinical presentation and prognosis. Future BM specific trials need to address the modern composition of BM cohorts and the distinct clinical course of patients with targetable driver mutations. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

OBJECTIVE:The purpose of this study was to assess the impact of temporal muscle thickness (TMT), a surrogate marker for sarcopenia, in radiosurgically treated patients with brain metastases (BMs) from non-small cell lung cancer (NSCLC).METHODS:For 566 patients with BMs from NSCLC in the period between June 2012 and December 2019, TMT values were retrospectively measured on the planning brain magnetic resonance imaging (MRI) studies that had been obtained before their first Gamma Knife radiosurgery treatment (GKRS1). Predefined sex-specific TMT cutoff values were used to stratify the study cohort into patients at risk for sarcopenia and patients with normal muscle status. Cox regression models adjusted for other prognostic parameters were used to evaluate sarcopenia as an independent prognostic factor.RESULTS:In sarcopenia patients with a TMT below the sex-specific cutoff values, the risk of death was significantly increased (HR 1.908, 95% CI 1.550-2.349, p < 0.001). In addition, sarcopenia was revealed as an independent prognostic factor even after adjusting for age groups, sex, number of BMs, presence of extracranial metastases, NSCLC subtypes, Karnofsky Performance Status groups, recursive partitioning analysis classes, and concomitant immunotherapy or targeted therapy (HR 1.680, 95% CI 1.347-2.095, p < 0.001). However, patients at risk for sarcopenia showed no significant differences in the estimated mean time until local BM progression after GKRS1, compared to patients with normal muscle status (p = 0.639).CONCLUSIONS:TMT obtained from planning MRI studies is an independent prognostic marker in radiosurgically treated patients with BMs from NSCLC and may aid patient stratification in future clinical trials.