Extracranial Metastases Research Articles

10214-COT-24 A RARE CLINICAL CASE OF LUMBAR METASTASIS FROM GLIOSARCOMA

Abstract Gliosarcoma (GS) is a variant of glioblastoma (GBM) and has been shown to be prone to extracranial metastasis. We report a rare case of lumbar metastasis of Gliosarcoma (GS) based on histopathological findings.37-year-old male.He underwent emergency surgery for a left frontal subcortical hemorrhage. Pathological diagnosis confirmed GS. Postoperatively, the patient underwent conventional radiation chemotherapy. Later, in conjunction with cranioplasty, the remaining lesion was additionally excised and maintenance therapy was administered for 9 months. Subsequently, a follow-up MRI revealed an intracranial disseminated lesion, although the primary site was not affected. At the same time, he had difficulty moving due to back pain, and MRI revealed extracranial metastases in the second lumbar vertebra and retroperitoneum. Lumbar biopsy confirmed the diagnosis of metastasis. Pathological findings at the initial surgery showed that the tumor consisted of GS and gemistocyte-like components, and immunostaining and genetic findings showed IDH wild type GBM. Additional tissue samples showed predominantly gemistocyte-like components and no GS component, and the genetic profile was similar.Lumbar biopsies showed predominantly GS and no gemistocyte-like components. MGMT methylation changed from methylation-negative to positive and then negative by immunostaining and MS-PCR. In a previous report, Feldheim et al. performed a meta-analysis of MGMT methylation changes in relapsing GBM and reported increased methylation after relapse. In addition, Jimenez et al. quantitatively analyzed MGMT methylation in recurrent GBM by pyrosequencing and found an increased rate of methylation in about half of the cases. These reports indicate that MGMT methylation is altered following therapeutic intervention. In the present case, it was hypothesized that an intracranial lesion that was initially unmethylated was methylated by the intervention, but an unmethylated, treatment-resistant GS component metastasized to the extracranial space. The clinical course of this case was a rare example of evidence of a change in MGMT methylation due to therapeutic intervention.

Concomitant radiosurgical and targeted oncological treatment improves the outcome of patients with brain metastases from gastrointestinal cancer

BackgroundSo 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).MethodsSurvival 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.ResultsMultivariate 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.ConclusionGood 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.

A brief review of skull base chordomas

Skull base chrodomas are slow growing neoplasms usually located along the midline. They display a locally invasive nature with possibilities of extracranial metastasis. Presentation is usually late and depends upon the location and extent of the tumour. Management aims at gross total resection via open microsurgical or endoscopic approach followed by adjuvant radiotherapy. Prognosis may be good for the classical and chondroid subtypes but remains poor for de-differentiated type. Keywords: Chordoma, skull base, surgical management, radiotherapy.

Multi-omic profiling reveals discrepant immunogenic properties and a unique tumor microenvironment among melanoma brain metastases

Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.

NCMP-01. TREATMENT STRATEGIES IN PATIENTS WITH RENAL CELL CANCER AND BRAIN METASTASES

Abstract BACKGROUND Brain metastases (BM) significantly impact quality of life and survival in patients with metastatic renal cell cancer (mRCC). Based on the International Metastatic RCC Database Consortium (IMDC) risk classification, treatment strategies for patients with mRCC vary from systemic treatment with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) and/or immune checkpoint inhibitors (ICIs) to active surveillance (AS). Here, we describe the impact of treatment strategies on survival in patients with RCC and BM. METHODS We conducted a single-center, retrospective cohort study at Erasmus MC Cancer Institute (Rotterdam, Netherlands). All consecutive patients with RCC BM between 2011-2022 were included. Primary outcome was the BM-free survival, i.e. the time between diagnosis of extracranial metastases (ECM) and BM. Secondary outcome was overall survival (OS). RESULTS 46 patients with RCC BM were included: 25 (54.3%) had received prior systemic treatment for ECM, and 21 (45.7%) were treatment naive at diagnosis of BM. IMDC scores (favorable 12% resp. 0%, intermediate 48% resp. 64%, poor 24% resp. 0%, unknown 16% resp. 36%) were not significantly different (p=0.07) between these groups. In 39 (84.8%) of 46 patients, BM were metachronous ( >1 month) after ECM. In these patients (n=39), the median BM-free survival was 22.3 (IQR 5.7-46.7) months and was significantly longer (p=0.02) in previously treated patients (29.0 [IQR 12.6-57.0] months) as compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). However, median OS since ECM diagnosis (39.1 [IQR 16.5-111.5] months) was not significantly different (p=0.62) between previously treated and treatment naive patients. CONCLUSION Patients with RCC who received systemic treatment for ECM prior to BM diagnosis, had a longer BM-free survival as compared to patients without previous systemic treatment. These results emphasize the need for careful evaluation of AS in patients with mRCC, even in patients with a favorable prognostic profile.

EPID-01. ANTINEOPLASTIC, RADIATION, AND SYNCHRONICITY EFFECTS ON BRAIN METASTASIS SURVIVAL: A RETROSPECTIVE POPULATION-BASED STUDY

Abstract INTRODUCTION Brain metastases (BM) are the most common central nervous system tumors. The impact of oncological treatment on the prevention of BM is not well-defined. We report the effects of chemotherapy and radiotherapy directed at primary cancer on synchronous and metachronous BM survival. METHODS A large nationwide multi-institutional claims-based platform (TriNetX Diamond Network) was queried. Patients diagnosed during 2013-2023 with the 15 most common primary cancers that metastasize to the brain were included. Metachronous was defined as BM diagnosed > 2 months after primary cancer. Cohorts were propensity score matched for age, extracranial metastasis, and adjuvant therapy. Kaplan-Meier plots were used to compare survival. RESULTS 113,827 (38%) patients with synchronous and 187,036 (62%) with metachronous BM were identified. Patients with synchronous BM had 26 months shorter median survival compared to metachronous BM (11 vs. 37 months, HR 2.17, 95%CI 2.14-2.19, P< 0.0001). However, no survival advantage was observed from the time of BM diagnosis (11 vs. 12 months, HR 1.06, 95%CI 1.05-1.08, P=0.411). Antineoplastic treatment prior to BM improved median BM-free survival by 13 months (4 vs. 18 months, HR 1.66, 95%CI 1.77-1.82, P < 0.0001) and median OS by 17 months (25.15 vs. 42.26 months, HR 1.48, 95%CI 1.46-1.51, P< 0.0001). Radiation therapy prior to BM incurred a significant but smaller increase in median BM-free survival by 6 months (5 vs. 11 months, HR 1.27, 95%CI 1.26-1.29, P< 0.0001) and median OS by about 3 months (30.13 vs. 32.82 months, HR 1.06, 95%CI 1.04-1.08, P < 0.0001). CONCLUSION Once BM is diagnosed, the synchronicity of diagnosis does not predict survival. Antineoplastic and radiation treatment directed at primary cancer may improve BM-free survival and OS. Studies characterizing the BM-free effects of molecular markers, chemotherapy, and radiotherapy are necessary to improve screening, prevention, and treatment.

NCMP-16. A CASE OF WIDESPREAD EXTRACRANIAL METASTASES FROM A GLIOSARCOMA

Abstract BACKGROUND: Glioblastoma (GBM) with sarcomatous features (gliosarcoma) accounts for 2-8% of all glioblastomas1,2, characterized by a biphasic histopathology pattern consisting of glial and sarcomatous components. While GBMs generally do not metastasize outside the central nervous system (CNS), GS has been associated with extracranial metastases in up to 11% of cases3. Case presentation: A 58-year-old right-handed woman with a GBM presented to our institution for a second opinion. She was initially diagnosed 18 months prior and had received radiotherapy with concurrent temozolomide. Her adjuvant temozolomide was discontinued due to rash, and she started on bevacizumab. Her tumor progressed and she sought additional treatment options. On her initial presentation, she was tachycardic with leukocytosis, prompting admission. A chest CT showed thoracic adenopathy, multiple bilateral pulmonary nodules, and a large left malignant pleural effusion. Bronchoscopy revealed spindle cell sarcomatoid neoplasm raising the possibility of metastasis from a CNS primary tumor. Additionally, the patient endorsed development of subacute radicular pain in her bilateral lower extremities as well as weakness. MRI of total spine revealed multilevel osseous and epidural lesions, infiltrating the paraspinal muscles and thickening of cauda roots with concern for leptomeningeal disease. A subsequent PET-CT showed increased FDG avidity in these lesions. Reevaluation of the initial CNS pathology confirmed the presence of mesenchymal/sarcomatous differentiation, consistent with a diagnosis of GS. As confirmed by autopsy, the patient eventually passed away due to widespread and metastatic disease. Discussion: While GBM rarely metastasizes outside the CNS, GBM with sarcomatous features are more likely to exhibit extracranial metastasis. Our patient had widespread involvement, including the lungs, heart, liver, omentum, and bone. Metastasis was thought most likely once EBUS of the lung returned with sarcomatous features. Clinicians should therefore maintain a high suspicion for metastases when dealing with patients diagnosed with GS.

Extracranial metastasis of brain glioblastoma outside CNS: Pathogenesis revisited.

The most prevalent malignant tumor of the CNS in adults is glioblastoma. Despite undergoing surgery and chemoradiotherapy, the prognosis remains unfavorable, with a median survival period ranging between 15 and 20 months. The incidence of glioblastoma metastasis outside CNS is uncommon with only 0.4%-2% reported rate, compared to other tumors that exhibit a 10% incidence rate of metastasis to the brain. On average, it takes about 11 months from the time of initial diagnosis for the tumor to spread beyond CNS. Consequently, the prognosis for metastatic glioblastoma is grim, with a 6-month survival rate following diagnosis. The rarity of extracranial metastasis is attributed to the blood-brain barrier and lack of a lymphatic drainage system, although rare cases of hematogenous spread and direct implantation have been reported. The possible mechanisms remain unclear and require further investigation. Risk factors have been widely described, including previous craniotomy or biopsies, ventricular shunting, young age, radiation therapy, prolonged survival time, and tumor recurrence. Due to the lack of understanding about extracranial metastasis of glioblastoma pathogenesis, no effective treatment exists to date. Aggressive chemotherapies are not recommended for metastatic glioblastoma as their side effects may worsen the patient prognosis. The optimal treatment for extracranial metastasis of glioblastoma requires further investigation with a wide inclusion of patients. This review discusses the possible causes, factors, and underlying mechanisms of glioblastoma metastasis to different organs.

An unusual distant metastases of epithelioid glioblastoma detected by 18-F FDG PET/CT

Epithelioid glioblastoma is a rare, aggressive subtype of glioblastoma, which was officially recognized by the World Health Organization classification of the central nervous system in 2016. Here, we represent the case of a 19-year-old female with epithelioid glioblastoma whose extracranial metastasis was detected on 18F 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18-F FDG PET/CT).

A Survival Score for Patients Treated with Whole-Brain Radiotherapy plus Simultaneous Integrated Boost for Brain Metastases

Different types of radiotherapy (RT) are used for brain metastases including whole-brain RT (WBRT) and local therapies (radiosurgery, fractionated stereotactic RT). WBRT plus simultaneous integrated boost (WBRT+SIB) is another treatment option that was reported to improve intracranial control and overall survival (OS) when compared to WBRT alone. This study aimed to create a score to identify patients who may not benefit from this approach due to poor OS. In 128 patients treated with WBRT+SIB for brain metastases (2014-2021), year of RT, interval from tumor diagnosis to RT, WBRT+SIB regimen [(14 x (2.5 + 0.5) Gy vs. 18 x (2.0 + 0.5) Gy], pre-RT systemic treatment, age, gender, performance score, primary tumor type, N lesions, and extracranial metastases were retrospectively evaluated for OS. Univariate analyses (UVA) were performed with Kaplan-Meier method and log-rank test. Factors that showed significant (p<0.05), a strong trend (p<0.07) or a trend (p<0.14) in UVA were included in a Cox proportional hazards model (MVA). To create the appropriate OS score, three models were created, one including factors significant on MVA, a second including factors with p<0.07 on UVA, and a third one including factors with p<0.14 on UVA. For each factor, 6-month OS rates (%) were divided by 10 and resulting points were added for each patient. Based on patient scores, three prognostic groups were designed for each model. Positive predictive values (PPV) of correct prediction of death ≤6 and OS ≥6 months were calculated. On UVA, KPS >80 (p<0.001) and ≤3 lesions (p = 0.006) were associated with OS, age ≤64 years (p = 0.061) showed a strong trend, and no extracranial metastases (p = 0.128) a trend. On MVA, KPS (HR: 0.40, 95% CI: 0.27-0.61, p<0.001) and N lesions (HR: 1.81, 95% CI: 1.23-2.65, p = 0.002) were significant; age (HR: 1.12, 05% CI: 0-76-1.66, p = 0.57) and extracranial metastases (HR: 1.19, 95% CI: 0.79-1.78, p = 0.40) were not significant. In Model 1 (including only KPS and N lesions), groups were 5, 6-8 and 9 points with 6-month OS rates of 15%, 38% and 57%, respectively. PPVs to predict death and OS were 85% and 57%, respectively. In Model 2 (KPS, N lesions, age), groups were 8, 9-12 and 13 points with 6-month OS rates of 17%, 33% and 75%, respectively. PPVs were 83% and 75%, respectively. In Model 3 (KPS, N lesions, age, extracranial metastases), groups were 11, 12-16 and 17 points with 6-month OS rates of 14%, 34% and 78%, respectively. PPVs were 86% and 78%, respectively. All three models achieved high accuracy regarding prediction of death ≤6 months and can help identify patients who may not be ideal candidates for WBRT+SIB. For prediction of OS ≥6 months, Models 2 and 3 were superior. Since differences between Models 2 and 3 were marginal and correct identification of extracranial metastases (Model 3) may require extensive staging, Model 2 appears preferable.

Stereotactic Radiosurgery (SRS) for Brain Metastasis in the Era of Evolving Systemic Treatment (Immunotherapy or Targeted Therapy) in Patients with Non-Small Cell Lung Cancer (NSCLC)

With evolving role for targeted and immunomodulatory agents, the survival rate of NSCLC has been improved even with brain metastasis. This study analyzed the outcome of brain metastasis treated with SRS in conjunction with immunotherapy and target therapy as well as chemotherapy. After obtaining institutional review board (IRB) approval, 229 patients with NSCLC with brain metastasis treated with SRS at our institution were retrospectively reviewed from 2008-2021. Demographic information (e.g., age, sex, race), performance status (PS), extracranial metastasis (ECM), sequence of systemic therapy (SST) and surgery for BM (SBM) were reviewed and collected. Overall survival (OS) and intracranial recurrence free survival (ICRFS) were analyzed using the Kaplan-Meier method/Cox regression, and time to each event were measured from the date of the first SRS treatment. All statistical analyses were performed using SAS version 9.4 (Carey, NC). Of the 229 pts, the median age of pts at first SRS was 64.1 (range, 34.8- 83.0 years). 38.6% were biomarker (EGFR/ALK/ROS/PDL1) positive, and 30% were PDL1 positive. 28.8 % had surgery before SRS. The median number of SRS was 1 (range, 1 - 6), and 10 patients received salvage whole brain radiation therapy (WBRT) after SRS. With a median follow-up of 9.6 months (mo), median OS and ICRFS were 14.0 mo and 8.1 mo respectively. On univariate outcome analysis, PS, ECM, SBM and PDL1 were associated with OS while biomarker, SBM and SST were closely related to ICRFS. Pts with poor PS had worse median OS of 8.3 mo compared to 29.1 mo with good PS (p = 0.001). Median OS for no ECM vs. ECM were 20.7 mo vs. 9.6 mo respectively (p = 0.002). Patients who underwent SBM initially had better median OS of 28.7 mo compared to 9.9 mo without SBM (p<0.001). There was a trend of significant impact of positive PDL1 on median OS (21.1 mo vs. 11.7 mo, p = 0.06). Similarly, SBM was found closely related to ICRFS with median ICRFS of 8.1 mo vs. 4.9 mo for those with and without SBM respectively. Both positive biomarker (13.1 mo vs. 6.4 mo, P = 0.17) and SRS first SST (8.1 mo vs. 4.9 mo, p = 0.11) demonstrated a trend of increased median ICRFS. On multivariable analyses, no SBM was linked with worse OS (HR: 1.85; 95% CI:1.15 - 2.97; p = 0.01) and decreased ICRFS (HR: 1.65; 95% CI: 1.09 - 2.51; p = 0.02). Of 31 pts with information on cause of death, 3.2% died from brain metastasis related cause. This study demonstrated effective treatment of brain metastasis in NSCLC with multiple SRSs, especially for patients with favorable prognosis. Of noticed there was only a small number of patients received salvage WBRT and most patients didn't die from brain metastasis related progression.

Upfront Osimertinib Alone vs. Osimertinib and Radiotherapy for the Treatment of EGFR-Positive NSCLC Brain Metastases: A Multi-Institutional Series

Given the increased brain penetrance of osimertinib, the role of upfront radiotherapy (RT) has been questioned for the management of patients with EGFR+ NSCLC brain metastases (BM). We conducted a multi-institutional review of patients with EGFR+ NSCLC treated with upfront osimertinib or osimertinib in combination with RT for new or progressing BM. Our multi-institutional analysis included 128 patients with 714 BM treated between 2013 and 2022. Two BM treatment groups were evaluated: (1) upfront osimertinib alone (n = 66) and (2) osimertinib + RT [whole brain radiation therapy or stereotactic/fractionated radiosurgery (SRS/FSRT)] prior or concurrently with osimertinib (n = 62)]; both groups began treatment within 2 months of BM diagnosis. Time-to-event analysis was conducted with the Kaplan-Meier (KM) method, and outcomes included intracranial control (IC) [both local and distant], intracranial progression free survival (IPFS), and overall survival (OS). A Cox proportional hazards model was utilized for multivariate analysis (MVA). Median follow-up from BM diagnosis was 33.9 months (0.13-76.2 months). No differences in age (p = 0.46), sex (p = 0.72), DS-GPA (p = 0.08), KPS (p = 0.57), number of BM (p = 0.19) or volume of BM (p = 0.45), RT dose (p = 0.45), number of systemic metastases (p = 0.88), and patients symptomatic at presentation (p = 1.0) were noted. Prior treatment of BM was more common in the osimertinib + RT group (50% osimertinib + RT and 27% osimertinib; p = 0.01). The 12-month KM rates for osimertinib vs osimertinib + RT groups for IC were 72% vs 73% (p = 0.33); IPFS 53% vs 66% (p = 0.007); and OS 65% vs 80% (p = 0.025). On MVA, higher KPS (p = 0.002) was associated with increased OS and no extracranial metastasis with increased OS (p = 0.01) and IPFS (p = 0.001). MVA showed no association between osimertinib vs osimertinib + RT for IC, IPFS, or OS. Of the 66 patients treated with upfront osimertinib, 18 patients (27%) with 31 lesions eventually required RT for intracranial progression with the majority 72% being treated with SRS/FSRT at median of 13.5 months (1-22 months) following the start of osimertinib. This study suggests that upfront osimertinib alone may provide sufficient intracranial control to allow RT to be deferred until further intracranial progression in select patients. Prospective trials are warranted to further guide treatment.

Radiation Necrosis following SRS or FSRT with Higher BED for Brain Metastases >20 mm

In the RTOG 90-05 study, the maximum tolerated dose of single-fraction radiosurgery (SRS) for lesions 21-30 mm was 18 Gy (BED 45 Gy12). However, patients of the RTOG study were previously irradiated with median 60 Gy (brain tumors) or 30 Gy (brain metastasis). Thus, the max. tolerated BED for lesions not irradiated before may be >45 Gy12. This study investigated safety and efficacy of SRS or fractionated stereotactic radiotherapy (FSRT) with BED >49 Gy12 for radiotherapy-naive brain metastases >20 mm. Data of 169 patients who received SRS or FSRT alone with BED >49 Gy12 for 1-4 brain metastases (2011-2022) were retrospectively analyzed. Thirty-two patients had lesions >20 mm (21-30 mm, n = 27; 21-40 mm, n = 4; >40 mm, n = 1). SRS was performed with 20 Gy (n = 9; 53.3 Gy12) or 19 Gy (n = 2; 49.1 Gy12), prescribed to the 60-80% isodose line (PTV = GTV). FSRT was Linac-based delivering 3 x 10 Gy (n = 3; 55 Gy12), 3 x 11 Gy (n = 4; 63.3 Gy12), 7 x 6 Gy (n = 1; 63 Gy12), 9 x 5 Gy (n = 1; 63.8 Gy12), 10 x 4 Gy (n = 11; 53.3 Gy12), or 12 x 4 Gy (n = 1; 64 Gy12), prescribed to the 80% isodose line (PTV = GTV+1-2 mm). SRS and FSRT were compared for grade ≥2 radiation necrosis (RN), local control (LC) and survival (OS). Fractionation [SRS (n = 89) vs FSRT (n = 48)] and lesion size (≤20 vs >20 mm) were studied in terms of RN rates. Kaplan-Meier method and log-rank test were used for univariate analyses and the Cox proportional hazards model for multivariate analyses. In patients with lesions >20 mm, SRS and FSRT were compared (Fisher's exact/Chi square test) for age, gender, KPS, year of SRS/FSRT, primary tumor, number/site of lesions, systemic treatment, and extracranial metastases. In patients with lesions >20 mm, significantly more patients receiving SRS had a KPS >80 than patients treated with FSRT (91% vs 29%, p = 0.002); otherwise, distributions of patient characteristics were balanced. In patients with lesions >20 mm, SRS was associated with significantly higher RN rates at 1 year (50% vs 9%) and 2 years (50% vs 9%) on univariate analysis (p = 0.012), which remained on multivariate analysis (HR: 0.10; 95% CI: 0.01-0.94, p = 0.044). No significant differences were found for LC (p = 0.21) at 1 year (75% vs 70%) and 2 years (75% vs 53%), and OS (p = 0.09) at 1 year (36% vs 59%) and 2 years (27% vs 46%). In patients with lesions ≤20 mm, 1- and 2-year RN rates following SRS were both 4%, compared to 0% and 15% respectively after FSRT (p = 0.60). In the SRS group, RN rates were significantly higher with lesions >20 mm (vs ≤20 mm) on univariate (p<0.001) and multivariate (HR: 3.82, 95% CI: 1.70-8.58, p = 0.001) analyses. In the FSRT group, max. diameter had no significant impact on RN rates (p = 0.93). Given the limitations of this study, FSRT with BED >49 Gy12 appears associated with a low risk of RN when used for brain metastases >20 mm. SRS with 1x19-20 Gy may not be optimal for metastases >20 mm but appears safe for lesions ≤20 mm. Prospective trials are warranted.

P11.33.B A PATIENT WITH GLIOBLASTOMA AND EXTENSIVE EXTRANEURAL METASTASES - DOES MOLECULAR BIOLOGY PLAY A CRUCIAL ROLE?

Abstract BACKGROUND Extraneural metastases of glioblastoma (GBM) are rare, reported incidence in literature is 0.4% to 2%. There is a lack in epidemiological data, and what little exists is outdated. The most commonly reported sites of metastases are bone, lymph node and lung. There is an insufficient understanding of the biological mechanism of metastasis, nevertheless, surgical intervention and peritoneal seeding through a ventriculoperitoneal shunt have been postulated as rational routes for the tumor cells. However, reports show metastasizing GBM in patients where neither of these procedures have been performed and therefore biological aspects should be elucidated. Previously, some few genomic studies have shown high mutational burden and that some mutations are only detected in the metastases, indicating clonal evolution. Commonly TP53, TERT, PTEN and CDKN2A/B have been revealed as shared mutations. MATERIAL AND METHODS A 55-year-old man presented with approximately 2 months of progressive headache and behavioral changes. Brain MRI revealed a left temporal lesion suspicious of GBM and no extracranial metastasis was detected. The patient underwent near total surgical resection and completed Stupp protocol. Nine months later, he was admitted to the local hospital with reduced general condition, tachypneic and lower back pain, but subsequent CT of thorax and abdomen revealed multiple pathological lesions in mediastinum, bones, lung, soft tissue, and mesentery. MRI confirmed the findings and a large soft tissue lesion at the level of the 6th thoracic vertebrae, was biopsied and showed metastasis from GBM. There was also local progression of the primary tumor in the brain. Treatment strategy was changed to a combination of lomustine, vincristine and bevacizumab. It was collected blood samples from the patient in respect of circulating tumor cells. A molecular characterization of the tumor samples was performed. RESULTS The primary tumor was MGMT promotor methylated, IDH-1/-2 wildtype, had no TERT promotor mutation, TP53 wildtype and ATRX was intact. The biopsy of the paravertebral lesion showed infiltration of a low differentiated, highly cellular tumor. Immunohistochemically the tumor cells were positive for GFAP, OLIG2 and S100. The molecular features revealed no mutation in BRAF or NTRK. Interestingly, PD-L1 was extremely upregulated, may indicating a potential benefit of immune-checkpoint inhibitors for extraneural metastases. A literature survey is done to find out any risk factors for metastasis. CONCLUSION We report a rare case of GBM with extensive extraneural metastases. This underlines the importance of comparing molecular biology, localization, and other patient and tumoral factors in order to identify any specific risk factor for metastasis. In turn, helping to stratify the follow up of this subgroup in the future.

P11.40.A GLIOBLASTOMA WITH OSSEOUS METASTASES: A SINGLE INSTITUTION CASE SERIES

Abstract BACKGROUND Although glioblastoma (GBM) is the most common malignant primary brain tumor in adults, extracranial metastasis is rare, occurring in &amp;lt;2% of cases. This rarity has been attributed to the blood brain barrier, immunologic factors, lack of traditional lymphatics in the brain, and the poor prognosis of GBM, limiting its opportunity to metastasize. When GBM does metastasize, bone is the most common destination. GBM may spread hematogenously to bone, especially to vertebral bodies via the surrounding venous plexus. In this single-institution study, we review the clinical characteristics of GBM patients with osseous metastases and evaluate potential risk factors and prognostic significance. MATERIAL AND METHODS Using an institutional database, we identified and retrospectively analyzed 6 GBM patients with osseous metastases and studied their demographics, tumor genetics, clinical courses, and outcomes. RESULTS Five of 6 (83%) GBM patients with osseous metastases were male, with a median age of 46 years at GBM diagnosis (range: 20-84). All patients had IDH wild type and MGMT unmethylated GBM with mutations in TP53. Two patients (33%) were initially diagnosed with gliosarcoma. All patients were treated with surgical resection followed by radiation with concurrent and adjuvant temozolomide. Five patients (83%) received bevacizumab for vasogenic edema (n=4) or intracranial tumor progression (n=1) prior to bone metastasis diagnosis. Bone metastases were diagnosed a median of 12.2 months (range: 5.3-35.2) after GBM diagnosis and 4.8 months after starting bevacizumab (range: 3.5-13.2). Two patients (33%) received immune checkpoint inhibitor therapy and two patients (33%) received tumor-treating fields prior to bone metastasis discovery. Bone metastases were symptomatic in 2 patients, presenting with back pain (n=1) and leg weakness and urinary incontinence (n=1). Three patients (50%) had concurrent metastases to other organs. Osseous metastases were biopsy-confirmed in 3 (50%) cases, while the other 3 patients had no known alternative malignancy to explain their bone metastases. After osseous metastasis discovery, the median survival was 27 days (range: 13-225). CONCLUSION Most of our GBM patients with osseous metastases were male and most, but not all, were young at GBM diagnosis. Tumor genetics common to all patients included IDH wild type, MGMT unmethylated status, and TP53 mutation, which may be important for osseous metastasis. Most patients received bevacizumab, which may be associated with earlier metastasis. While rare, metastatic GBM should be within the differential for GBM patients with bone pain or progressive neurologic symptoms, as osseous metastases portend a dismal prognosis in an already aggressive malignancy.

P11.64.A TREATMENT STRATEGIES BEFORE THE DIAGNOSIS OF BRAIN METASTASIS IN PATIENTS WITH RENAL CELL CANCER (RCC)

Abstract BACKGROUND Metastatic renal cell cancer (mRCC) is known for its variable disease course and can be categorized according to the International Metastatic RCC Database Consortium (IMDC) criteria. As patients with mRCC who have a favorable IMDC score and/or a low tumor burden usually have an indolent disease course, watchful waiting is often considered in daily clinical practice. However, it is unknown whether watchful waiting impacts the development of brain metastasis (BM). Therefore, we investigated variables that may affect the interval between first diagnosis of mRCC and BM (BM-free interval) in patients with RCC and BM. MATERIAL AND METHODS A single-center, retrospective cohort study was performed at the Erasmus MC Cancer Institute (Rotterdam, the Netherlands). All consecutive patients with a diagnosis of RCC and BM between 01-01-2011 and 31-07-2022 were included. The primary outcome was the BM-free interval. Secondary outcomes were intracranial progression-free survival (iPFS), progression-free survival (PFS) and overall survival (OS), since diagnosis of BM. Subgroups included patients with and without systemic treatment prior to the diagnosis of BM. Kaplan-Meier (Logrank test) and Cox Proportional Hazards Model (Likelihood ratio test) analyses were performed with significance considered at p-values &amp;lt;0.05. RESULTS A total of 46 patients with RCC and BM were included; 80% was male and 89.1% had a clear cell RCC subtype. In 84.8% of patients, BMs were diagnosed metachronous (&amp;gt;1 month) after the diagnosis of extracranial metastasis (ECM) and 80.4% of patients had symptomatic BM at BM diagnosis. After the diagnosis of BM, the median iPFS was 7.6 (IQR 3.5-12.2) months, the median PFS was 3.7 (IQR 2.3-8.7) months and the median OS was 10.1 (IQR 5.1-22.8) months. Prior to the diagnosis of BM, 25 (54.3%) patients had received systemic therapy, whereas 21 (45.7%) patients were treatment naïve. The median BM-free interval was 22.3 (IQR 5.7-46.7) months. The median BM-free interval was significantly shorter for treatment naïve patients (6.8 [IQR 1.0-7.0] months) as compared to patients who received previous systemic therapy (29.0 [IQR 12.6-57.0]; p=0.02). In multivariate analysis, a longer BM-free interval was significantly associated with nephrectomy (HR 0.10 [95%CI 0.03-0.31]) and systemic treatment prior to BM diagnosis (HR 0.10 [95%CI 0.03-0.30]). CONCLUSION In this cohort of patients with RCC BM, patients who had not received systemic treatment for ECM were earlier diagnosed with BM than patients who had received prior systemic treatment. Although the retrospective nature of this small selective cohort is a limitation, these results indicate that watchful waiting should be carefully considered for patients with mRCC.

P17.08.A CLINICAL AND MOLECULAR CHARACTERIZATION OF EXTRACRANIAL METASTASES IN GLIOBLASTOMAS

Abstract BACKGROUND Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults, but in contrast to many other malignancies they rarely metastasize. Metastasizing GBMs cause both diagnostic and therapeutic challenges and are generally poorly investigated. Therefore, our aim was to characterize these tumors clinically and molecularly. MATERIAL AND METHODS We collected and examined the largest cohort to date of tissue from 16 glioma patients (14 GBMs and 2 lower-grade gliomas) with extracranial metastases, including metastases to scalp (7) lymph nodes (5), bone (2), liver (1), and upper neck (1). After histopathological re-evaluation of the tumors, we assessed the associated magnetic resonance imaging (MRI) scans. Paired samples from the primary tumors, recurrences and metastases were investigated by next-generation sequencing (NGS) analysis with the TSO500 panel, genome-wide 850 K methylation profiling and immunohistochemistry followed by artificial intelligence-based quantification of markers of stemness and immune cells in the tumor microenvironment (TME). RESULTS Clinically, the patients were comparable to other GBM patients (gender, age, treatment, and survival). 12/16 patients developed one or more intracranial recurrence(s). MRI scans revealed proximity of the brain tumors to dura, large vessels, and ventricles in a high proportion of the patients. Moreover, we found that (6/7) scalp lesions were in fact extracranial extensions of the brain tumors. NGS data showed that the metastases were clonally derived from the primary tumors and not from the brain recurrences. Methylation- and copy number analysis overall confirmed the initial diagnoses and revealed a patient-specific signature across paired samples in a majority of the patients. Additionally, we observed methylation subclass switch during tumor progression and identified differentially methylated regions enriched in the olfactory transduction pathway when comparing metastases to primary tumors. Levels of tumor stemness were generally preserved according to methylation-based stemness index and OLIG2 and SOX2 protein expression. Similarly, the composition of immune cells in the TME did not change significantly, as shown by cell-type deconvolution and immune cell quantification. CONCLUSION Extracranial metastases occurred as early events and overall preserved the tumor- and TME characteristics of the primary brain tumors. Factor such as brain tumor location, neurosurgery and epigenetic regulation of genes associated with olfactory transduction could be involved in glioblastoma metastasis.

P11.15.A IMPACT OF PERIOPERATIVE DEXAMETHASONE IN THE CONTEXT OF NEUROSURGICAL BRAIN METASTASIS RESECTION

Abstract BACKGROUND Patients with brain metastases that undergo brain metastasis resection regularly receive perioperative dexamethasone. We sought to evaluate whether perioperative dexamethasone in brain metastases is linked to survival. MATERIAL AND METHODS Retrospective data on perioperative dexamethasone dosage in resected brain metastasis patients at three hospital sites of the Charité from 2010-2022 were collected. Cut-off values for cumulative perioperative dexamethasone dose as a continuous predictor variable for survival were determined using maximally selected rank statistics. Patients were dichotomized based on determined cut-offs of cumulative dexamethasone (pre-operative: &amp;lt; 40 mg vs ≥ 40 mg; post-operative: &amp;lt; 180 mg vs ≥ 180 mg) and pre- and postoperative: &amp;lt; 281 mg vs ≥ 281 mg). Medical records included baseline demographic, radiological, histopathological and treatment-related characteristics. Based on cut-off values for dexamethasone downstream statistical analyses included Kaplan-Meier, Cox proportional hazards regression for overall survival with adjustment for potential confounders including age, gender, Karnofsky performance index and presence of extracranial metastasis via propensity score matching. RESULTS 539 patients were included. Median follow-up time was 58,97 months. After adjusting for age, gender, Karnofsky performance index and presence of extracranial metastasis patients with higher cumulative perioperative dexamethasone (≥281 mg) showed shorter survival (HR: 1.47 (1.20-1.80, p&amp;lt;0.001) as compared to patients with lower cumulative doses (&amp;lt;281 mg). This effect remained significant after correction for patients that died within 3 months after resection and for patients with KPS below 50% and, independently from this approach performing propensity score matched-based analysis of the total cohort of patients, respectively. CONCLUSION Cumulative perioperative dexamethasone is associated with decreased survival in the context of brain metastasis resection. Strict dosage, down taper or methods reducing corticosteroid dependency should be regularly evaluated in clinical practice in patients with brain metastases

​Occult extracranial malignancy after complete remission of pineal mixed germ cell tumors: a rare case report and literature review

Background​Extracranial metastasis can occur in intracranial germ cell tumors (GCTs), but it is very rare. Recurrence or metastasis of non-germinomatous germ cell tumors (NGGCTs) is often accompanied by elevated tumor markers. ​Occult extracranial metastases or recurrences with negative markers are often difficult to detect in time, resulting in a very poor prognosis.Case presentationA 12-year-old boy was admitted to our institution with dizziness, headache, vomiting, and sleepiness. Magnetic resonance imaging (MRI) showed a pineal mass, accompanied by a significant increase in serum alpha-fetoprotein (AFP). The patient subsequently underwent total removal of the tumor. Pathology revealed that the tumor was a mixed GCT, consisting of mature teratoma, germinoma, and yolk sac tumor. Intracranial GCT achieved complete remission after intensive adjuvant chemotherapy and radiotherapy. Regular follow-up MRI revealed no recurrence of the intracranial tumor and continued monitoring of tumor markers revealed no abnormalities. ​Eight months later, the patient was readmitted due to progressive abdominal pain. Imaging and physical examination revealed abdominal occupation and lymphatic mass in the neck. He received salvage chemotherapy, anti-PD-1 immunotherapy, and palliative chemotherapy, but still developed multiple organ dysfunction syndromes (MODS) due to tumor progression and eventually died after one month.Conclusions​This profound case suggests that intracranial NGGCTs may develop occult extracranial malignancy, which can be very severe at the time of clinical symptoms and has an extremely poor prognosis. Therefore, in addition to tumor marker monitoring, regular follow-up with extracranial imaging may be warranted to detect extracranial tumors as early as possible, although perhaps not as frequently as with neuroimaging.

Deep learning based automated epidermal growth factor receptor and anaplastic lymphoma kinase status prediction of brain metastasis in non-small cell lung cancer.

The aim of this study was to investigate the feasibility of developing a deep learning (DL) algorithm for classifying brain metastases from non-small cell lung cancer (NSCLC) into epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement groups and to compare the accuracy with classification based on semantic features on imaging. Data set of 117 patients was analysed from 2014 to 2018 out of which 33 patients were EGFR positive, 43 patients were ALK positive and 41 patients were negative for either mutation. Convolutional neural network (CNN) architecture efficient net was used to study the accuracy of classification using T1 weighted (T1W) magnetic resonance imaging (MRI) sequence, T2 weighted (T2W) MRI sequence, T1W post contrast (T1post) MRI sequence, fluid attenuated inversion recovery (FLAIR) MRI sequences. The dataset was divided into 80% training and 20% testing. The associations between mutation status and semantic features, specifically sex, smoking history, EGFR mutation and ALK rearrangement status, extracranial metastasis, performance status and imaging variables of brain metastasis were analysed using descriptive analysis [chi-square test (χ2)], univariate and multivariate logistic regression analysis assuming 95% confidence interval (CI). In this study of 117 patients, the analysis by semantic method showed 79.2% of the patients belonged to ALK positive were non-smokers as compared to double negative groups (P = 0.03). There was a 10-fold increase in ALK positivity as compared to EGFR positivity in ring enhancing lesions patients (P = 0.015) and there was also a 6.4-fold increase in ALK positivity as compared to double negative groups in meningeal involvement patients (P = 0.004). Using CNN Efficient Net DL model, the study achieved 76% accuracy in classifying ALK rearrangement and EGFR mutations without manual segmentation of metastatic lesions. Analysis of the manually segmented dataset resulted in improved accuracy of 89% through this model. Both semantic features and DL model showed comparable accuracy in classifying EGFR mutation and ALK rearrangement. Both methods can be clinically used to predict mutation status while biopsy or genetic testing is undertaken.