tbuckley/cabot-search huggingface dataset:
P12.15.B PROGNOSTIC VALUE OF CD8+ T-CELLS INFILTRATION IN GLIOMA PATIENTS TREATED WITH IMMUNOTHERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: X Cai, B Westerman, D Wang, J Garcia Vallejo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive subtype of glioma with a five-year survival of 7·2 %. Immunotherapy has become a promising approach in the treatment of it. However, no improved prognosis was reached yet in phase III immunotherapy trials of glioma. Highly intertumoral heterogeneity was one of the reasons for this outcome. Hence, identifying patients who will respond to immunotherapy has become a core task in the research of GBM. In non-CNS malignancy, CD8+ tumor infiltrating lymphocytes (TILs) within tumor has been associated with response to immunotherapy and prognosis. However, no consensus was reached regarding the value of CD8+ TILs in predicting glioma patients’ response to immunotherapy. In this meta-analysis, we investigated the prognostic predictive value of infiltrating CD8+ TIL in glioma patients treated with immunotherapy. MATERIAL AND METHODS PubMed and Web of Science were searched from 1st of January 2000 up to 15th of May 2023. Quality assessment was performed using ROBINS-I and JBI critical appraisal check list. Subgroup analyses were conducted according to clinical indicators. The protocol of the meta-analysis was registered on PROSPERO (CRD42023425790). RESULTS A total of 8550 records were identified after the duplicates were removed, with 272 records remained for full text screening. Nine records with 187 GBM participants were included in the meta-analysis. Most of them are from Phase I or Phase II clinical trials. The immunotherapies utilized in these studies included peptide vaccination, oncolytic viral vectors therapy, DC vaccination, immune checkpoint inhibitors, and CAR-NK. Overall, no statistically significant effect of CD8+TIL infiltration was observed on overall survival (OS), progress-free survival (PFS), and survival time after immunotherapy. The subgroup analysis on peptide vaccination showed that patients with high CD8+TIL infiltration tended to have a lower OS (HR = 6·57; 95% CI: 1·12, 38·58; P = 0·037). In the subgroup analyses on male (HR = 12·34; 95% CI: 1·09, 139·18; P = 0·042) and recurrence (HR = 0·08; 95% CI: 0·01, 0·79; P = 0·030), CD8+TIL infiltration showed important effect on PFS. CONCLUSION In general, CD8+ TIL infiltration has no prognostic predictive value in GBM patients treated with immunotherapy. However, there is predictive value for OS in the subpopulation of peptide vaccination treated GBM patients.
P12.16.A PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY IN A WOMEN TREATED BY DARATUMUMAB AND LENALIDOMIDE FOR A MULTIPLE MYELOMA: A CASE REPORT
Authors: A Silva Gomes, Q Perlot, C D’Aout
Journal: Neuro-Oncology (2024)

Abstract Progressive multifocal leukoencephalopathy (PML) is a potentially fatal demyelinating disease of the central nervous system caused by reactivation of the John Cunningham virus (JCV) and occurs mainly in immunocompromised patients with lymphoproliferative and myeloproliferative disorders, human immunodeficiency virus (HIV) infection or immunomodulatory therapy. The aim of this article is to present the atypical case of a 72-year-old woman with IgG-kappa multiple myeloma (MM) treated with DRD (D: daratumumab; R: lenalidomide; D: dexamethasone), who was admitted to our neurology department in August 2023 after developing left hemiparesis and gait disorder within a few weeks after 2 years of treatment. A preliminary brain magnetic resonance imaging (MRI) revealed the presence of multiple hyperintense white matter lesions on fluid attenuated inversion recovery (FLAIR), with a predilection for the cerebellum, brainstem bridge and right temporal lobe. Despite a comprehensive workup that included an initial lumbar puncture, the precise etiology of the lesions remained elusive. Clinical improvement enabled the patient to be discharged home, but she was subsequently readmitted to the hospital due to the onset of a major cerebellar syndrome. An increase in leukopathy was demonstrated on cerebral MRI, with a particular focus on the cerebellar region. Suspecting PML, a second lumbar puncture was performed and the polymerase chain reaction (PCR) was positive for JCV. Sadly, despite the administration of an experimental therapy, the patient died within weeks of diagnosis. The literature reports several cases of PML associated with therapies used in MM, including lenalidomide and daratumumab. However, to the best of our knowledge, only one case has been described under the DRD regimen by Seko et al. In conclusion, it is crucial to increase clinical surveillance in patients receiving DRD therapy in order to promptly identify any potential neurological deterioration. Furthermore, it is vital to screen for the possibility of PML, an extremely rare but serious complication of this treatment, and to promptly discontinue the therapy in the event of its occurrence.
P12.18.A UNRAVELLING THE ACUTE, CHRONIC AND STEROID-REFRACTORY MANAGEMENT OF HIGH GRADE NEUROLOGICAL IMMUNE RELATED ADVERSE EVENTS: OUR EXPERIENCE AND LITERATURE FINDINGS
Authors: A Malvaso, P Giglio, L Diamanti, M Gastaldi, P Bini, E Marchioni
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurological immune-related adverse events (n-irAEs) are rare side effects of immune-checkpoint inhibitors (ICI). Their incidence is rising in tandem with the expansion of ICI oncological indications. N-irAEs are often severe, carrying a considerable risk of mortality and long-term disability. To date, strong scientific data is lacking to support the management of high-grade n-irAEs. We aim to present an updated depiction of the most documented and well-characterized therapies of high-grade n-irAEs with a particular focus on steroid-resistant clinical forms. MATERIAL AND METHODS A systematic literature search in PubMed, Scopus, Embase, and Google Scholar until January 31 2024 was performed, according to PRISMA guidelines. A total of 81 studies were included at least reporting the following details: (I) type of tumor, (II) ICI type, (III) the course of treatment, and (IV) the outcome. High-grade n-irAEs recent management guidelines were compared to real-life clinical settings. The frequency, clinical course and outcome were summarized through qualitative and quantitative analysis using GraphPad Prism Software. RESULTS We found a few poorly characterized cases of steroid-resistant n-irAEs and only aggregated data were usually available. The median time to onset of high-grade n-irAEs was 4 weeks (range:1-64 weeks) for both general and steroid-resistant clinical forms. Significant correlations were found between the high-grade n-irAEs phenotype, type of cancer and ICIs administered. Transverse myelitis represents the principal clinical phenotype associated with a higher steroid resistance rate (14-40%), followed by cranial neuropathies (23%) and CNS demyelinating disorders (4-13%). Nivolumab and Pembrolizumab were the ICIs associated most frequently with steroid-resistant irAEs (80-90%, p&amp;lt;0.01). In case of unresponsiveness to glucocorticoids, intravenously immunoglobulins (IVIg) is the most effective treatment followed by plasma exchange (PLEX) (p&amp;lt;0.01), although a proportion of high-grade CNS/PNS n-irAEs require additional immunosuppressants, such as Mycophenolate and/or Rituximab. CONCLUSION High-grade n-irAEs generally show clinical improvement following steroids-only therapy and after association therapy. We suggest that the estimated frequency of high-grade steroid-resistant n-irAEs should not be underestimated. Steroid-resistant n-irAEs mostly demonstrate clinical improvement after IVIg or PLEX therapy. Decisions about treatment should be made by a multidisciplinary board that includes the neurologist and oncologist. However, more standardized studies are needed in order to early detect and promptly treat these life-threatening conditions.
P17.10.A GENOMIC PROFILING OF CEREBROSPINAL FLUID CTDNA TO CHARACTERIZE MOLECULAR FEATURES AND MONITOR INTRACRANIAL RESPONSES OF OSIMERTINIB-RESISTANT NON-SMALL CELL LUNG CANCER PATIENTS WITH LEPTOMENINGEAL METASTASES
Authors: X Li, Y Hua, Y Xin, J An, X Ding, F Wei
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Leptomeningeal metastasis (LM) indicates an unfavorable prognosis in non-small cell lung cancer (NSCLC). Due to the blood-brain barrier, plasma is not an ideal medium to evaluate osimertinib resistance mechanisms in patients with LM. This study aimed to use cerebrospinal fluid (CSF) as a source of ctDNA for characterizing molecular features and monitoring intracranial responses from patients with leptomeningeal metastases who progressed on osimertinib. MATERIAL AND METHODS From Jan 2020 to Nov 2022, 65 patients with advanced NSCLC, including 30 osimertinib-treated patients, 7other TKI-treated patients, and 28 treatment-naïve patients, in Beijing Tiantan Hospital were enrolled in this study. CSF obtained via lumbar puncture was used for targeted sequencing and cytologic analysis. In parallel, paired plasma from 37 patients was also subjected to targeted sequencing. RESULTS Among 65 patients, the overall positive rate of CSF ctDNA was 77% (50/65), 94% (32/34) in patients with LM, and 58% (18/31) in patients with brain parenchymal metastases (p=0.0008). EGFR alterations were present in the CSF of 96% of patients who progressed on osimertinib, including L858R (64%), copy number gain (29%), exon 19 deletion (18%), T790M (11%), L861Q (7%), G719X (7%) and L747X (7%). EGFR-independent intracranial resistance mechanisms identified in CSF included activation in phosphatidylinositol 3-kinase (PI3K) pathways, RAS-mitogen-activated protein kinase (MAPK), cell-cycle gene alterations, MET amplification, oncogenic fusions. The VAF identified by CSF ctDNA was also higher than that of plasma ctDNA (15.5% versus 4.6%, P&amp;lt;0.001). In patients with LM, 75% of alterations were detected exclusively in CSF ctDNA and 13% in plasma ctDNA. The higher proportion of CSF ctDNA private mutations observed in patients with LM compared to those with PM. Serial surveillance of CSF ctDNA in 6 cases of LM patients treated with osimertinib found that the VAF of CSF ctDNA showed a highly consistent trend with the tumor cell fraction of cytology. CONCLUSION For EGFR-mutated NSCLC patients with LM, liquid biopsy of CSF is more sensitive than plasma to characterize osimertinib-resistant mechanisms and guide follow-up treatment. Serial surveillance of CSF ctDNA dynamics may reflect the intracranial tumor responses, which still needs to be validated in a large sample size.This study was supported by Beijing Municipal Education Commission-Beijing Natural Science Foundation Union Program(KZ202010025046), Beijing Natural Science Foundation (NO. 7242007) and Beijing Xisike Clinical Oncology Research Foundation(Y-2021AST/zd-0127).
P19.05.B CHROMOSOME 1P DELETION IS A NEGATIVE, INDEPENDENT, PROGNOSTIC FACTOR IN ATYPICAL MENINGIOMAS
Authors: D Mulone, S Pedron, S Alberti, G Zanconato, M Caffo, V Barresi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The treatment of patients with meningiomas is based on the degree of surgical excision and the tumor histological grade, which is determined according to the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Meningiomas are classified into three grades of malignancy, based on the presence of histopathological and molecular features. Grade 1 meningiomas do not require adjuvant treatment, while grade 3 tumors are generally treated with radiotherapy. For grade 2 meningiomas, which have a 50% 5-year recurrence-free survival rate and an uncertain prognosis, both radiotherapy and observation have been proposed. Consequently, identifying molecular factors that can predict the recurrence risk of grade 2 meningiomas and detect cases requiring adjuvant treatment has been a significant research issue in recent years. Several studies have found that chromosomal copy number variations, particularly the deletion of chromosome 1p, may be prognostically relevant in meningiomas. In this study, we examined 1p deletion in 79 grade 2 meningiomas of the atypical subtype and its correlation with clinico-pathological features and molecular group. MATERIAL AND METHODS Using Fluorescent In Situ Hybridization (FISH) and 1p36/1q25 dual color FISH probes, we analyzed 1p chromosome deletion in 79 meningiomas, which were histologically classified as atypical subtype and treated with gross total resection. Cases were classified as “1p deleted” when at least 50% of the nuclei had one signal for 1p and 2 signals for 1q. Data on recurrence-free survival (RFS) were available in 70 meningiomas. Molecular groups (MGs) were established using immunohistochemistry for MCM2 and ACADL as surrogates for proliferative and hypermetabolic MGs. Kaplan-Meier curves and the Mantel-Cox log-rank test were used to evaluate the association between 1p deletion and other clinical-pathological or molecular parameters and RFS. A chi-squared test was utilized to investigate correlations between 1p deletion and clinical-pathological features. RESULTS Chi-squared test revealed that 1p deletion was significantly associated with proliferative and hypermetabolic MG (P= 0.0128), mitotic index ≥6/1.6 mm2 (P= 0.0101), presence of necrosis (P= 0.0076) and recurrence (P= 0.0072). In addition, chromosome 1p deletion was significantly associated with a shorter RFS (P= 0.0196), and was an independent negative prognostic variable (P= 0.0159), along with necrosis (P= 0.0006) in multivariate analysis. CONCLUSION Chromosome 1p deletion, detected using FISH, is a robust negative prognostic factor, associated with high proliferation, in atypical meningiomas. Therefore, it could be used to identify cases at a higher risk of recurrence and which could benefit of adjuvant treatments.
P19.06.B EXPLORING FIBROBLAST ACTIVATING PROTEIN (FAP) EXPRESSION AS THERANOSTIC TARGET IN HIGH-GRADE MENINGIOMA
Authors: M J Mair, S Hartenbach, E Tomasich, S L N Maas, S A Bosch, G Widhalm, F Eckert, F Sahm, J A Hainfellner, M Hartenbach, A S Berghoff, M Preusser, N L Albert
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The therapeutic management of higher-grade meningiomas is challenging given their high recurrence rates and limited treatment options after exhaustion of local modalities. Radioligand therapies such as [177Lu]Lu-DOTATATE targeting somatostatin receptors (SSTR) have shown promising results in small clinical trials and retrospective case series. Further studies on theranostic approaches targeting fibroblast activating protein (FAP) are ongoing in a variety of extracranial solid tumors. MATERIAL AND METHODS Formalin-fixed, paraffin-embedded tumor samples of atypical (WHO grade 2) and anaplastic (WHO grade 3) meningioma were immunohistochemically stained for FAP and SSTR2a. Antibodies used were monoclonal rabbit anti-FAP (clone JA56-11, Thermo Fisher Scientific) and monoclonal rabbit anti-SSTR2a (clone EP149, Cell Marque). Panel sequencing for frequently altered genes in meningioma (NF2, TRAF7, KLF4, SMO, AKT1, TERT-promotor, ARID, SUFU, PIK3CA) was performed using Illumina NextSeq, and DNA methylation analysis was done using Illumina 850k chips. RESULTS In total, samples of 58 patients were used for analysis, of whom 35/58 (60.3%) were female and median age was 60 years (range: 19-83). Included specimen were from first resection in 39 cases (67.2%). Original histological diagnoses were atypical meningioma in 30/58 (51.7%), chordoid meningioma in 9/58 (15.5%), anaplastic meningioma in 18/58 (31.0%) and rhabdoid meningioma in 1/58 (1.7%). Reclassification according to WHO 2021 identified CNS WHO grade 2 in 39/58 (67.2%), CNS WHO grade 3 in 18/58 (31.0%) and CNS WHO grade 1 in 1/58 (1.7%) patients. FAP expression was observed in 15/58 (25.9%) included samples, most markedly at tumor borders and in stroma-rich areas. Of these, 12 (80.0%) also showed membranous staining for SSTR2a, of whom 6 showed strong, 3 medium and 3 weak positivity. FAP expression was associated with malignant biological behavior, as 12/18 (66.7%) of CNS WHO grade 3 tumors (compared to 3/39, 7.7% of CNS WHO 2, p &amp;lt; 0.001) and 4/5 (80.0%) samples with homozygous deletion in CDKN2A/B were FAP-positive (p = 0.013). In addition, FAP expression was more frequently observed in patients with NF2 mutations (10/25, 40.0%) than in those with wild-type NF2 (5/33, 15.2%, p = 0.032). FAP-positive samples were numerically more common among tumors of malignant (4/8, 50.0%) than intermediate (int-A/int-B: 7/27, 25.9%) or benign (ben-1/2/3: 4/23, 17.4%, p = 0.069) methylation classes. CONCLUSION FAP is expressed in a subset of higher-grade meningioma samples, and further investigation of FAP-targeted radioligands is warranted. Given that SSTR2a and FAP are frequently co-expressed, potential synergistic effects of combination treatments can be investigated.
P17.08.B EFFICACY AND SAFETY OF POSTOPERATIVE HYPOFRACTIONATED RADIOTHERAPY FOR RESECTED BRAIN METASTASES: INSIGHTS FROM A SINGLE-CENTRE EXPERIENCE
Authors: A Lucas Calduch, M Macià Garau, N García Expósito, G Plans Ahicart, A Rosselló Gómez, A Fernández Coello, N Vidal Sarro, I Modolell Farré, I Sancho Kolster, C Majós Torró, A Pons Escoda, M Simó Parra, R Velasco Fargas, M Ruíz Domínguez, M Alonso Becerra, P Cifre Serra, J Bruna Escuer
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The addition of radiotherapy (RT) improves local control after surgical resection of brain metastases (BM). The classical whole brain RT has been replaced by different types of focal irradiation. Hypofractionated stereotactic radiotherapy (HFSRT) is an effective option, but the procedure implies several uncertainties related to the volumes contouring, that may generate the risk of local control fail and/or the development of radionecrosis (RN) of the cavity wall. MATERIAL AND METHODS We have retrospectively reviewed the outcome of patients with surgically resected BM that have been adjuvantly treated with HSRT in our centre, during the period from 2015 to August 2023. RESULTS 83 patients have been identified. Median age was 58 (34-79). Males comprised 54% and 46% were females. Lung cancer was the most frequent primary tumour (51%), followed by breast (17%) and melanoma (15%). BM diagnose was synchronous to the primary in 36% of patients. The targeted BM was single in 87% of cases, and its median maximum diameter was 36 mm (13-75). Surgery was complete in 82% of cases. Clinical conditions before RT were favourable in 87% of patients (Karnofsky index ≥70) and DS-GPA (diagnosis-specific graded prognostic assessment) was ≥3 in 47%. Different ways of contouring the planning target volume (PTV) were identified, being the addition of 2 mm to the cavity the most frequent (44%). The median PTV was 29,9 cm3 (1,17-138,8). Regarding radiotherapy scheme, 27 Gy in 3 fractions were prescribed in 36% of patients; however, 30 Gy in 5 or 6 fractions were also frequently used (32%). Tolerance was excellent, except for one patient with Grade 3 seizures. The median interval between surgery and HFSRT was 56 days (r 45-69). After a median follow-up of 19 months, local control in surgical bed was obtained in 92,7% and 89,2% of cases at 1 and 2 years respectively. RN was observed in 15,6% of cases, with only 2,4% of grade 3. Cranial and extracranial progressions were seen in roughly half of patients (53% and 53,7% respectively). Specifically, leptomeningeal spread was seen in 26,5% of patients. Overall survival was 54% at 2 years. CONCLUSION HFSRT appears as a highly effective option to ensure local control after surgery in BM. Despite the uncertainties related to contouring and the high number of large cavities, the use of fractionated schemes allows a low incidence of serious RN.
P17.09.A EVALUATION OF SARCOPENIA AS A PROGNOSTIC FACTOR FOR SURVIVAL AFTER STEREOTACTIC RADIOTHERAPY AND RADIOSURGERY
Authors: J Cvek, M Palička, Š Reguli, L Knybel, R Lipina
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BM) occur in 20-40% of patients with primary extracerebral malignancies. Even with the development of increasingly effective systemic anticancer treatments, they represent a frequent challenge in oncology, and radiosurgery is becoming an increasingly preferred option for patients with this diagnosis. Sarcopenia is a condition in which there is a progressive loss of muscle mass, and one possible way of measuring this may be to evaluate the muscles in the skull region, specifically the musculus temporalis. The aim of this study is to analyze the clinical results and prognostic factors. MATERIAL AND METHODS In the period from August 2010 to 2020, 376 patients (200 men, 176 women) with brain metastases from solid tumors were treated with the CyberKnife device at the associated neuro-oncology center of the Ostrava University Hospital. Precise registration of á 1 mm CT and MR images (T1 with i.v. contrast agent) was used to define the target volume. A 0.2-1 mm margin was used to define the PTV. Dose calculation was performed using sequential optimization, and online image management was based on repeated planar imaging of the skull base along with comparison of reconstructed navigational CT projections. In addition to clinical data, musculus temporalis thickness measurements were retrospectively performed with bilateral averaging. RESULTS On the basis of the retrospective evaluation, 207 patients (55%) had solitary lesions and 169 (45%) had multiple lesions. The median age was 64 years (range 57-71).The prescribed total dose was 1x20-22 Gy per 50-70% isodose for solitary lesions up to 2 cm, and 3x9 Gy per 55%-65% isodose for larger lesions or multiple lesions. Generalization of non-small cell lung cancer was in 114 patients (30%), melanoma in 49 patients (13%), colorectal cancer and conventional renal cell carcinoma in 46 patients (12%), breast cancer in 43 patients (11%) and other solid tumors in 78 patients (21%). The median thickness of the musculus temporalis was 8.4 mm (7.2-9.8); when compared with the median thickness of the muscle of the general population adjusted for age, 53% of patients in our cohort showed evidence of sarcopenia. The median overall survival was 6 months and 5-year survival were 9%. In unifactorial analysis, renal cell carcinoma metastases showed the best prognosis, but in multifactorial analysis the difference was not statistically significant. Sarcopenia was a statistically significant factor for mortality at 6 months for the male subpopulation only, 69% vs. 48% (p=.005), the difference at 12 months was no longer significant, 84% vs. 74% (p=.083), and at 24 months the mortality was similar, 91% vs. 87% (p=.323). CONCLUSION Measurement of sarcopenia by musculus temporalis thickness appears to be a rapid and promising parameter that can be used to prognosticate patients.