bluuebunny/crossref_metadata_2025_split huggingface dataset:
P11.34.A MULTIFACTORIAL ANALYSIS OF SURGICAL TREATMENT OF INTRACRANIAL METASTASES IN ELDERLY PATIENTS
Authors: Gubian A , Sulejmani A , Ruder A M , Giordano F , Rinkel G , Etminan N , Brehmer S 
Published: September 2023

Abstract

BACKGROUND
Due to increasing age of the population, the number of elderly patients with brain metastasis accessible for surgery is increasing. The higher risk of peri-procedural complications and a reduced ability to tolerate aggressive treatment are often thought to limit intracranial surgery in older patients. However, little data are available on results of surgical brain metastasis treatment in elderly. In a subset of older patients who underwent surgical removal of brain metastases, we assessed the influence of age on survival and postoperative dependency.

MATERIAL AND METHODS
This is a retrospective observational study of patients over 65 years of age who underwent surgery for intracranial metastases between 2015 and 2022 at the Department of Neurosurgery, University Hospital Mannheim (Germany). The population was divided into group A (65-74 years old) and group B (75 years or older). The Eastern Cooperative Oncology Group (ECOG) score was used to assess functional status and independence. The primary endpoints were overall survival and the likelihood of remaining independent (ECOG &lt;3) at 6 weeks. A wide range of clinical and radiological baseline factors were analysed.

RESULTS
80 patients were included in the analysis. The mean age in the overall cohort was 73.2 years, and 74% of patients had a preoperative ECOG score of 2 or less. 48 patients were included in group A and 32 in group B. The 1-, 2- and 3-year probabilities of overall survival were 31%, 23% and 16% in group A and 38%, 23% and 23% in group B (p-value=0.61). Functional status in the overall cohort remained stable after surgery for most patients (70%), while 17% experienced a decline and 13% an improvement. 42 (88%) and 43 (90%) patients in group A were independent before and after surgery, respectively. 27 (84%) and 26 (81%) patients in group B were independent before and after surgery, respectively. 33 (69%) patients in group A and 19 (59%) patients in group B were independent at follow-up (p=0.65). No significant difference was found between the two groups for independence status preoperatively, postoperatively as well as at follow-up (p-values 0.69, 0.29 and 0.32, respectively).

CONCLUSION
In our analysis, neither survival nor outcome after surgery for brain metastases showed a correlation with age. Age alone should not be a barrier to intracranial surgery in carefully selected elderly patients with intracranial metastases.
P11.37.B RADIOSURGERY-ASSOCIATED NEW-ONSET FACIAL SPASM AFTER THE TREATMENT OF VESTIBULAR SCHWANNOMA IS ASSOCIATED WITH INCIDENCE OF RECURRENCE
Authors: Wang S , Naros G , van Eck A , Horstmann G , Tatagiba M 
Published: September 2023

Abstract

BACKGROUND
Facial function preservation in the care of vestibular schwannoma (VS) is pre-dominantly measured in motoric function (e.g. House-Brackman (HB)). Facial spasm (FS) has been reported to be a possible side-effect in the radiosurgical treatment of VS. However, the exact incidence of FS is still unclear.

MATERIAL AND METHODS
This study aims to study the incidence of FS in the treatment of VS. Patient medical records of patients treated by treatment of VS between 2004 and 2020 ere analyzed retrospectively. Patient and tumor characteristics were analyzed (i.e., sex, age, tumor extension and size, intracanalicular extension).

RESULTS
N=104/1’998 (5%) of all patients treated by SRS presented with new-onset FS postinterventionally. FS was unrelated to tumor size. The incidence of new-onset FS was significantly higher in women (6%) compared to men (4%) (p=0.032). From all patients with FS, N=24/104 (23%) of new onset FS appeared after Re-SRS (second SRS treatment). In primary SRS therapy, facial spasm was associated with a higher recurrence rate of N=20/80 (25%) vs N=252/1"894 (13%) in nonFS patients (p=0.007). N=65/104 (62%) were permanent FS, whereas N=41/104 (39%) recovered spontaneously between 4 and 34 months, postinterventionally. The proportion (76%) of FS patients had tumors with extensive intra-canalicular extension (OHATA A-B) was higher in compared to a nonFS control group (64%) (p=0.015).

CONCLUSION
FS is a SRS therapy-related side effect with an overall incidence of 5%. Women were more commonly affected by new-onset SRS. Second-line SRS has the highest risk for new-onset FS. FS was associated with a higher incidence of recurrence compared to non-FS VS patients. Patients" consultation should address the relevant side effect.
P11.46.A ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA
Authors: Arrillaga-Romany I , Lassman A , McGovern S L , Mueller S , Nabors L B , van den Bent M , Vogelbaum M , Allen J E , Melemed A S , Tarapore R , Wen P Y , Cloughsey T 
Published: September 2023

Abstract

BACKGROUND
H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease.

MATERIAL AND METHODS
ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023.
P11.49.B STEREOTACTIC RADIOSURGERY FOR CRANIAL AND SPINAL HEMANGIOBLASTOMAS: A SINGLE-INSTITUTION SERIES
Authors: Yoo K H , Park D J , Marianayagam N J , Gu X , Pollom E L , Soltys S G , Chang S D , Meola A 
Published: September 2023

Abstract

BACKGROUND
Stereotactic radiosurgery (SRS) has been an attractive treatment modality for both cranial and spinal hemangioblastomas, especially for multiple lesions commonly associated with von Hippel-Lindau (VHL) disease. This study aims to provide the largest long-term analysis of treatment efficacy and adverse effects of SRS for cranial and spinal hemangioblastomas at a single institution.

MATERIAL AND METHODS
We evaluated the clinical and radiological outcomes of patients with hemangioblastomas treated with CyberKnife SRS at our institute from 1998 to 2022. The follow-up data were available for 135 hemangioblastomas in 35 patients. Twenty-eight patients had 123 hemangioblastomas associated with VHL and 7 had 12 sporadic hemangioblastomas. The median age was 36 years and the median tumor volume accounted for 0.4 cc. The SRS was administered with the median single-fraction equivalent dose (SFED) of 18 Gy to the 77% median isodose line.

RESULTS
At a median follow-up of 57 months (range: 3-260), only 20 (16.2%) of the VHL-associated and 1 (8.3%) sporadic hemangioblastomas progressed. The 5-year local tumor control (LTC) rate was 91.3% for all hemangioblastomas, 91.7% among the sporadic lesions, and 92.9% in VHL patients. SRS improved tumor-associated symptoms of 98 (74.8%) of 131 symptomatic hemangioblastomas, including headache, neck pain, dizziness, visual disturbances, dysesthesia, ataxia, motor impairment, seizures, and dysphagia. Two patients developed radiation necrosis (5.7%) and 1 of them required surgical resection.

CONCLUSION
SRS is a safe and effective treatment option for patients with hemangioblastomas in critical locations such as the brainstem, cervicomedullary junction, and spinal cord, and in patients with multiple hemangioblastomas associated with VHL disease.
P11.64.A TREATMENT STRATEGIES BEFORE THE DIAGNOSIS OF BRAIN METASTASIS IN PATIENTS WITH RENAL CELL CANCER (RCC)
Authors: Derks S H A E , van der Meer E L , Joosse A , de Jonge M , Slagter C , Schouten J W , Oomen-de Hoop E , Smits M , van den Bent M J , Jongen J L M , van der Veldt A A M 
Published: September 2023

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 &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 (&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.
P11.82.A TARGETING THE GLIOBLASTOMA MASTER REGULATOR C/EBPß: A PHARMACOKINETIC AND PHARMACODYNAMIC NEOADJUVANT STUDY OF ST101
Authors: Iwamoto F , Al Dalahmah O , Manjrekar K , Levrero C , Michel R , Bargo A , Kaesshaefer S , Butowski N , Peters K , Buerki R , Bexon A , Vainstein-Haras A 
Published: September 2023

Abstract

BACKGROUND
The vast amounts of genomics, epigenomics and transcriptomics data in glioblastoma (GBM) have yet to translate into better outcomes to most patients. One of the main challenges is to how to best integrate these diverse layers of omics to personalize and improve the treatment of glioblastomas. Cancer master regulators are often transcription factors (TFs), which control the expression of many genes and considered promising antitumor targets. CCAAT/enhancer-binding protein β (C/EBPβ) is an abundantly-expressed transcription factor (Zahnow 2009). C/EBPβ was previously described as a master regulator in GBM (Carro 2010). ST101 is a first-in-class cell-penetrating peptide antagonist of C/EBPβ with known ability to cross the blood-brain barrier. We have demonstrated potent anti-tumor activity with ST101 in multiple in vivo models including glioblastoma. Based on early efficacy data on the initial clinical study including objective responses in GBM, we designed this surgical study to further understand the antitumor mechanisms of ST101.

METHODS
we will recruit total of 12 newly diagnosed GBM and 6 recurrent patients. Recurrent GBM patients who are deemed surgical candidates will be treated with ST101 at the RP2D of 500 mg IV weekly for 2 to 4 weeks and then undergo standard of care surgical resection. After recovery from surgery, patients will continue ST101 until there is significant toxicity or tumor progression. 12 patients with newly diagnosed GBM who had undergone a prior biopsy or partial resection, and that upon further neurosurgical evaluation have an indication for additional debulking surgery will be eligible for this study. Patients will be treated with ST101 at the recommended phase 2 dose for 2 weeks and then undergo standard of care surgical resection. Patients will undergo standard of care treatment with radiation and temozolomide and continue ST101 after recovery from surgery. ST101 plasma concentration will be correlated with ST101 drug levels in enhancing and non-enhancing tumor tissue of recurrent and newly diagnosed patients. We will compare the molecular abnormalities in the post-treatment tissue through deep bulk whole-exome sequencing and mRNAseq against the intra-patient baseline tissue. Pharmacodynamics evaluation will focus on the expression of genes regulated by the transcription factor CEBPβ, such as BCL2, cyclins and cyclin-dependent kinases and inhibition of differentiation genes. Due to the diversity of cell types in the tumor microenvironment and the early data that ST101 can also reprogram M2 macrophages to M1 in addition to its direct antitumor effects, we will perform single nucleus RNAseq on these surgical specimens. Enrollment has started in January 2023 and 6 recurrent and 2 newly diagnosed patients have been accrued.
P11.85.B LONG-TERM OUTCOME AFTER INCOMPLETE RESECTION OF INTRAMEDULLARY GRADE II EPENDYMOMAS WITHOUT ADJUVANT RADIOTHERAPY
Authors: Chaskis E 
Published: September 2023

Abstract

BACKGROUND
Ependymomas are the most frequent intramedullary tumors in adults. While gross total resection is the aim of surgery, tumor infiltration might limit resection. In case of subtotal removal, the adjuvant management remains unclear. The aim of our study was to assess the need for adjuvant radiotherapy after incomplete resection of grade II intramedullary ependymomas (IME-II).

MATERIAL AND METHODS
We retrospectively reviewed all cases of IME-II operated in a single tertiary neurosurgical center from 2009 to 2018. Patients with anaplastic or myxopapillary ependymomas, and patients with a follow-up of less than 3 years were excluded.

RESULTS
We included 46 patients: 19 (41.3%) had gross total resection, 21 (45.7%) had subtotal resection and 6 (13%) had partial resection. None of the patients underwent adjuvant radiotherapy. Over a median follow-up of 79 months (range = 36-186), 7 patients presented a radiological tumor progression with a mean delay of 50.9 months (range =18-85), of which 2 were symptomatic (4.3%). Progression-free survival (PFS) was 90.1% at 5 years and 76.8% at 10 years. Extent of resection was the only significant risk factor for secondary tumor progression (p=0.012). 4 of the 7 patients with recurring IME-II were treated: 3 patients had a second surgery, leading to 2 GTR and 1STR, followed by radiotherapy in one case, and 1 patient underwent radiotherapy alone.

CONCLUSION
In this study, the rate of symptomatic progression and retreatment after incomplete resection of IME-II without adjuvant radiotherapy was low, supporting a conservative approach in such cases.
P12.01.A TUMOR CELL SENESCENCE AND IMMUNE MICROENVIRONMENT IN GLIOBLASTOMAS
Authors: Kim S , Roh T , Park T , Kim J 
Published: September 2023

Abstract

BACKGROUND
Cellular senescence (CS) is a state of irreversible cell cycle arrest, and the expression of p16INK4a in cells is one of the reliable markers for CS. However, senescent cells are metabolically active with the senescence-associated secretory phenotype (SASP), which can influence the tissue microenvironment by paracrine signaling to the adjacent tumor, non-tumor, and immune cells.

MATERIAL AND METHODS
In the present study, we evaluated p16INK4a expression in glioblastoma and investigated its association with CS and SASPs. We analyzed the expression of p16INK4a in 73 glioblastomas by immunostaining. To examine the association of p16INK4a expression and CS, we performed senescence-associated β-galactosidase (SA-β-Gal) staining, a standard marker of CS, using glioblastoma cell lines and fresh frozen tumor tissues. For SASPs analysis, RNA sequencing with Gene Set Enrichment Analysis (GSEA) was performed.

RESULTS
Among 73 glioblastomas, twenty-eight cases (38.4%) revealed diffuse strong p16INK4a expression in tumor cells. The glioblastoma with diffuse p16INK4a expression (GMDP) patients were younger (52.4 vs. 59.2 years) and showed prolonged overall survival (median: 25.5 vs. 12.3 months) compared to those harboring negative expression. In vitro analysis, p16INK4a over-expressed glioblastoma cell line showed increased expression of SA-β-Gal which indicates CS. In addition, fresh frozen tissues from GMDP also revealed SA-β-Gal positivity. RNA sequencing analysis revealed that splicing or protein biosynthetic genes were enriched in GMDP, and GSEA showed significant enrichment of SASP genes (false discovery rate &lt;0.05), especially chemokines associated with monocytes and macrophages.

CONCLUSION
Our data suggest that increased expression of p16INK4a in glioblastoma is associated with tumor cell senescence, and SASPs from senescent tumor cells could be one of the crucial modulators in the tumor immune microenvironment.
P12.09.B SMAC MIMETICS REPROGRAMS GLIOBLASTOMA IMMUNE LANDSCAPE AND POLARIZES MICROGLIA TOWARD A PRO-INFLAMMATORY ANTI-TUMORAL PHENOTYPE
Authors: Snacel-Fazy E , Soubéran A , Colin C , Pagano A , Brustlein S , Grange M , Luche H , Siret C , Van De Pavert S , Debarbieux F , Rougon G , Figarella-Branger D , Tabouret E , Tchoghandjian A 
Published: September 2023

Abstract

BACKGROUND
Glioblastomas are the most aggressive brain tumors in adult characterized by an immunosuppressive microenvironment. They are invaded by tumor-associated macrophages (TAMs) supporting tumor growth and treatment escape. One current therapeutic challenge is to restore an immunocompetent environment to improve treatment efficiency. A better knowledge of spatial distribution and function of TAMs is needed to design new promising therapeutic strategies.

MATERIAL AND METHODS
We used small molecules SMAC mimetics (SM) which are inhibitor of apoptosis (IAP) antagonists to decipher spatial distribution and function of TAMs. By using a syngeneic glioblastoma mouse model, we performed whole mount stainings and brain clearing to investigate immune cells quantity, and spatial organization within tumors and related to tumor vessels. We then performed molecular mass cytometry (CYTOF) to accurately phenotype the immune cells involved in SM response and gain functional data. We finally used human derived glioblastoma models (explants, immune cells sorting and tumoroids) to investigate the clinical relevance of our results.

RESULTS
Results showed that SM promoted immune cells CD45+ quantity and penetration within tumors including microglia. The treatment increased monocyte-derived dendritic cells, CD8EM T cells, reactive microglia while decreasing anti-inflammatory macrophages and basal microglia. Furthermore, SM treatment decreased contacts between microglia and CD8 T cells, and microglia PDL1+. Thanks to the use of human derived model, we found that CD14 is decreased upon SM treatment. By using TCGA databases, we found that low level of CD14 expression was correlated with a better prognosis.

CONCLUSION
SM reprogram glioblastoma immune landscape and modulate immune cell infiltration and organization within tumors. Furthermore, microglia is a key mediator in SM response. The targeting of CD14, IAP and microglia would be a promising therapeutic strategy.