bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereotactic Radiosurgery for WHO Grade 2 and 3 Oligodendroglioma: An International Multicenter Study
Authors: Langlois Anne-Marie , Iorio-Morin Christian , Kallos Justiss , Niranjan Ajay , Lunsford L. Dade , Peker Selcuk , Samanci Yavuz , Park David J. , Barnett Gene H. , Liscak Roman , Simonova Gabriela , Sheehan Jason P. , Pikis Stylianos , Mantziaris Georgios , Lee Cheng-Chia , Yang Huai-Che , Bowden Gregory N. , Mathieu David 
Published: March 2024

INTRODUCTION:
Oligodendrogliomas are primary brain tumors classified as IDH-mutant and 1p19q co-deleted in the 2021 WHO Classification. Surgery, fractionated radiotherapy and chemotherapy are well established treatments for these tumors, but there are few studies evaluating the efficacy of stereotactic radiosurgery (SRS). As these tumors are less infiltrative than astrocytomas and typically recur locally, they could be appropriate for local therapy such as SRS.

METHODS:
This was a retrospective multicenter study performed through the International Radiosurgery Research Foundation (IRRF). Adult patients were included if they underwent single-fraction SRS for a grade 2 or 3 oligodendroglioma. The primary endpoints were overall survival and progression-free survival. Secondary endpoints included clinical evolution and occurrence of adverse radiation events or other complications.

RESULTS:
Eight institutions submitted data for a total of 55 patients with a median clinical follow-up of 24 months. Median age at treatment was 46 years old and median pre-treatment KPS was 90. Median treatment volume was 4cc and median marginal dose delivered was 15Gy. The KPS remained stable post-SRS in 51% and worsened in 46.7% of patients, most often due to tumor progression (73.1%). Radiation-induced changes occurred in 29.6% of which 4 patients were symptomatic. Median progression-free survival was 17 months, with actuarial rates of 60.1% at 1 year, 31% at 2 years and 24.4% at 5 years after SRS. Median overall survival post-SRS was 58 months, with actuarial rates of 91.5% at 1 year, 83.4% at 2 years and 49.3% at 5 years post-SRS. Factors significantly associated with worsened survival were WHO grade 3 and prior radiotherapy and chemotherapy. Factors significantly associated with worsened PFS were WHO grade 3, prior radiotherapy and chemotherapy and higher treatment marginal dose.

CONCLUSIONS:
SRS appears to be a valuable management option for oligodendrogliomas.
Skull-Derived Myeloid Cells Augment T Cell Responses and Suppress Glioblastoma Growth
Authors: Lad Meeki , Young Jacob , Salha Diana , Lui Austin , Aghi Manish Kumar 
Published: March 2024

INTRODUCTION:
Recent studies have implicated skull marrow as a functional myeloid reservoir in CNS pathology. However, its contribution to malignancy remains unexplored.

METHODS:
Fluorescently labeled calvarial flaps were transplanted onto syngeneic glioblastoma-bearing mice, followed by flow cytometric profiling of tumor-infiltrative leukocytes. To assay the functional relevance of SDMCs, tumor-bearing C57BL/6 mice were treated with preemptive calvarial ablation (13 Gy irradiation), or conversely intracalvarial AMD3100 to augment myeloid egress from marrow niches. Tumor burden was monitored via survival and bioluminescent imaging.

RESULTS:
72 h following CMFDA-stained calvarial transplantation into tumor-bearing Balb/C mice, 40.3% of tumor-infiltrative myeloid cells were fluorescent and thus skull-derived; transplantation in an alternative longitudinal model (GFP+ flaps, C57BL/6) validated that SDMCs were robust and viable at 3 weeks post-operatively. As MHCII+ cells were disproportionately enriched among SDMCs (87.9% vs 67.3%, p = 0.012), we interrogated the immunogenicity of these cells through targeted ablation. Skull-ablated mice had reduced infiltration by antigen-presenting cells than controls (cDCs: 1.1% vs 4.5%, p = 0.002; macrophages: 14.4% vs 36.6%, p < 0.001) and 6-fold greater necrosis (67.7% vs 13.5% apoptotic, p < 0.001), suggesting an impaired ability to mount a controlled, adaptive immune response. The stimulatory role of SDMCs was further demonstrated via intracalvarial AMD3100 administration, which through its promotion of myeloid precursor egress (0.26% vs 0.02%, p < 0.001) and cDC2 infiltration (10.4% vs 3.0%, p = 0.003) yielded robust CD4+ T cell activation and effector memory differentiation. These differences were clinically meaningful, as skull irradiation accelerated tumor growth and attenuated survival compared to controls, while AMD3100 treatment accomplished the opposite (median OS: 17d vs 22d, p < 0.001; 26.5d vs 22d, p = 0.006).

CONCLUSIONS:
The preferential polarization of SDMCs into immunostimulatory APCs warrants the continued exploration of local marrow-targeting agents (e.g., AMD3100) as therapeutic modalities.
Increased Survival and Symptom Relief Following Palliative Cerebrospinal Fluid Diversion for Neoplastic Leptomeningeal Disease: A Case Series and Systematic Review
Authors: Wu Adela , Zhou James , Skirboll Stephen 
Published: March 2024

INTRODUCTION:
Leptomeningeal disease (LMD) indicates widespread or advanced cancer and can lead to symptomatic hydrocephalus, for which palliative cerebrospinal fluid (CSF) diversion may be indicated.

METHODS:
We analyzed survival and symptom relief outcomes from a 10-year period at a single institution of patients with LMD secondary to cancer, symptoms of obstructive hydrocephalus, and documented date of death. We also searched PubMed, Embase, and Web of Science from database inception until 8/20/2022, using search terms including ‘cancer’, ‘hydrocephalus’, and ‘shunt’. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed.

RESULTS:
In our series of 50 patients, 30 (60%) underwent CSF diversion surgery after LMD diagnosis with comparable median age in both surgery (58.4 ± 14.4 years) and non-surgery (57.8 ± 14.5 years) groups. Twenty-three patients (76.7%) achieved symptom relief. The surgery group lived longer after LMD diagnosis than patients in the non-surgery group (6.6 ± 6.0 vs. 1.3 ± 4.3 months, p < 0.001) and had higher likelihood of survival (hazard ratio 2.49, 95% confidence interval 1.37-4.52, p = 0.002). Median survival after surgery was 2.8 ± 3.8 months. Out of 23 articles reporting outcomes for 2895 patients, 995 (34.3%) presented with LMD. Postoperative complication rates were 0-37.7% with no cases of extraneural metastases. Symptom relief rates were 50-100%. Three studies reported median survival after surgery for LMD (2-3.3 months).

CONCLUSIONS:
A rare entity with dismal prognosis, LMD can present as symptomatic hydrocephalus in patients with cancer. Symptom relief can be achieved with palliative surgery for permanent CSF diversion with relatively low complication rates. Prospective studies are needed to further assess outcomes and needs of this patient population.
Characterization of Immune Cell Heterogeneity, Key B Cell Subtypes, and Macrophages Functions Using Multiplex Immunofluorescence and Single-cell RNA Sequencing in Chordomas
Authors: Arrieta Victor Andrés , Benotmane Jasim K. , Zhao Junfei , Dhiantravan Silpol , Hou David , Katz Joshua L. , Pandey Surya , Cholak Meghan E. , Han Yu , Bettegowda Chetan , Horbinski Craig , Miska Jason , Stupp Roger , Lesniak Maciej S. , Sonabend Adam M. , Wolinsky Jean-Paul , Heiland Henrik , Chang Catalina Lee 
Published: March 2024

INTRODUCTION:
Chordomas are rare tumors that arise from remnants of the notochord. The standard of care for chordoma remains only surgery and radiotherapy. Though checkpoint inhibition therapy shows promise, recent immunotherapy trials failed to reach endpoints. This emphasizes the need to comprehensively understand the tumor and peripheral immune landscape of chordomas to establish a rationale for immunotherapeutic intervention.

METHODS:
We analyzed and quantified the immune cell composition (CD3+, CD4+, CD8+, CD20+, and CD163+ cells) of 33 chordomas (14 clival, 3 cervical, 2 lumbar, and 14 sacral tumors) through multiplex immunofluorescence. In addition, we investigated the phenotype of tumor-infiltrating and peripheral B cells and myeloid cells from five chordoma patients employing single-cell RNA sequencing.

RESULTS:
Hierarchical clustering analysis of 33 chordomas identified 3 distinct clusters based on the relative abundance of B cells, T cells, and macrophages. Cluster 1 was characterized by moderate immune cell infiltration, cluster 2 was immune-desertic, and cluster 3 was highly infiltrated by B and T cells. Findings from single-cell transcriptomics revealed that regulatory B cells and plasma cells were the most abundant B cell populations infiltrating tumors. In addition, we found the presence of tumor-infiltrating macrophages with angiogenic and complement-related functions.

CONCLUSIONS:
Our study provides crucial insights into the immune landscape of chordomas. The identification of distinct clusters based on immune cell infiltration emphasized the heterogeneity of chordomas. The findings from this study may serve as a foundation for future research and the development of targeted immunotherapies for chordomas.
Molecular Mechanism of Targeting Epithelial Membrane Protein-2 in Malignant Meningiomas
Authors: Yang Isaac , Mekonnen Mahlet , Chandla Anubhav , Aguirre Brian , Wadehra Madhuri 
Published: March 2024

INTRODUCTION:
Meningiomas compose approximately one third of all primary central nervous system neoplasms. While many meningiomas remain benign, as many as 35% of meningiomas are graded as atypical or anaplastic/malignant with a 5-y survival rate as low as 35%.

METHODS:
In collaboration with the UCLA Brain Tumor SPORE, we gathered a panel of malignant meningiomas (IOMM-LEE, CH157). To determine the function of EMP2, we created EMP2 vector control and knockdown models in both cell lines and have analyzed the cells by RNA sequencing, transcriptomic functional analysis, and migration assay.

RESULTS:
Gene functional analysis enriched for biological processes showed that knockdown of EMP2 inhibited multiple malignant pathways in these meningioma cells including the response to hypoxia, cell proliferation, invasion, and stem cell maintenance. Further analyses of EMP2 expression with other differentially expressed genes of interest revealed that VEGFA expression significantly decreased when EMP2 is knocked down (p < 0.001). Moreover, cellular migration and invasion regulated by EMP2 was tested in control and EMP2 knockdown malignant cells using a scratch assay, where knockdown of EMP2 reduced the rate of cell invasion by 50% (p = 0.0003). Additionally, anti- EMP2 mAb treatment in the control malignant cell line significantly reduced EMP2 mediated signal transduction (p = 0.0031).

CONCLUSIONS:
Our study is the first to demonstrate the modulation of EMP2 and its implications in malignant meningioma pathogenesis, VEGFA-HIF1α pathway, and stem cell regulation. Targeting EMP2 may result in therapeutic benefit in malignant meningiomas.
A Population-Based Analysis of Brain Metastasis Burden and Management in 8705 Small Cell Lung Cancer Patients
Authors: Gaebe Karolina , Erickson Anders , Leighl Natasha , Chan Kelvin , Lok Benjamin , Das Sunit 
Published: March 2024

INTRODUCTION:
Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for intracranial metastatic disease (IMD), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. These patients traditionally receive whole brain radiation therapy (WBRT) for IMD, however, a recent systematic review has indicated that OS following stereotactic radiosurgery (SRS) may be non-inferior compared with WBRT.

METHODS:
We included all patients diagnosed with SCLC between April 2007 and March 2018 identified through a provincial health administrative database. Information on patient and treatment characteristics, incidence and time to IMD, and OS from time of SCLC diagnosis were collected and analyzed using R.

RESULTS:
A total of 8705 patients were included. Median age was 68 years (range 18-103). Most patients presented with extensive disease (n = 5625) and were diagnosed after 2011 (n = 5768). Patients who received chemotherapy (n = 5563) had significantly longer OS than those who did not (median 10.64 vs 1.58 mo, HR 0.36, 95% CI 0.34-0.37). 6662 patients received brain imaging at the time of primary diagnosis (CT: 5126, MRI: 1536), and 88% of patients surviving longer than 6 mo received more than one follow-up brain scan. 31% developed IMD (synchronous: 1175, asynchronous: 1511) with median intracranial progression-free survival of 5.65 mo. Median OS of patients with IMD was 9.76 mo, 29 and 1300 received SRS and WBRT as first treatment for their IMD, respectively. OS was in favour of SRS over WBRT (median 20.47 vs 8.74 mo, HR 0.57, 95% CI 0.39-0.84), which remained significant in multivariate analysis (p < 0.001).

CONCLUSIONS:
OS for patients with SCLC remains poor and many patients present with IMD. Some patients with SCLC may benefit from SRS treatment.
Treatment Plan Optimization Following Laser Interstitial Thermal Therapy (LITT) for Recurrent Metastasis Using Cleveland Clinic Scaling System (CCSS)
Authors: Sabahi Mohammadmahdi , Santiago Raphael Bastianon , Naik Mihir , Adada Badih , Ranjan Surabhi , Borghei-Razavi Hamid 
Published: March 2024

INTRODUCTION:
Laser interstitial thermal therapy (LITT) is an effective treatment option for recurrent metastasis (RM). However, determining the best treatment approach for each patient following LITT remains challenging due to mixed pathology and lack of consensus. The Cleveland Clinic Scaling System (CCSS) has been proposed to facilitate decision-making in patients with radiation necrosis (RN) and/or RM following LITT.

METHODS:
We conducted a retrospective analysis of data from 20 patients who underwent LITT for RN and/or RM between 2019 and 2022 at Cleveland Clinic. Based on the symptomatic RN and/or RM which was confirmed by MRI, LITT, and biopsy were carried out. Three samples were acquired from the superficial, middle, and deep parts of each patient’s lesion. The samples were then classified into three main categories: RN, RM, or a mixture of the two, based on pathological results. Patient management was guided by our novel CCSS. According to CCSS, patients with 100% RN underwent continued observation with a 3-month MRI, individuals with >20% tumor component received a low-dose or standard-dose radiation therapy ± CNS-penetrating targeted therapy, while those with <20% tumor underwent short-term observation with 6-week MRIs ± CNS-penetrating targeted therapy.

RESULTS:
Among the patients, 57% were females, lung cancer was the most prevalent malignancy (61.4%), and the median age was 52 years (ranging from 25 to 83 years). Our analysis demonstrated that the application of the CCSS protocol significantly improved treatment outcomes after LITT, resulting in 93% lesion control at the 10-month follow-up.

CONCLUSIONS:
The use of the CCSS protocol can refine the treatment plan for patients with RN and/or RM following LITT. This approach has the potential to enhance patient safety by improving tumor control and minimizing unnecessary radiation.
Combinatorial Checkpoint Blockade and Laser Interstitial Thermal Therapy: A Single Center Study
Authors: Haskell-Mendoza Aden Pepe , Wachsmuth Lucas , Srinivasan Ethan , Jackson Joshua , Zaidi Saif , Reason Elle , Gonzalez Ariel Tomas , Schwalb Allison , Lerner Emily , Fecci Peter Edward 
Published: March 2024

INTRODUCTION:
Immune checkpoint blockade (ICB) has gained acceptance as a life-extending therapy in a variety of solid tumor types. For patients with brain metastases, combination stereotactic radiosurgery (SRS) and ICB remains an area of clinical equipoise. Similarly, for recurrent or difficult-to-access intracranial lesions, safety and synergy of laser interstitial thermal therapy (LITT) and ICB has yet to be explored.

METHODS:
In accordance with an IRB-approved protocol, all patients undergoing LITT at a tertiary center from 2015-2022 were retrospectively reviewed. Patients who received ICB within 6 weeks of LITT were included in the LITT + ICB cohort. Demographic, clinical, and survival data were collected.

RESULTS:
Combination LITT and ICB occurred in 25 patients with clinically recurrent tumors. The median cohort age was 62 (40-78) and 12 (48%) were female. The median KPS was 80 (50-100). The most common primary pathology was non-small cell lung cancer (NSCLC) in 15 patients (60%), followed by melanoma in 3 (12%); two high-grade gliomas were additionally treated. The majority of the cohort (24 patients, 96%) recieved single agent ICB in combination with LITT, with pembrolizumab (12, 48%) and nivolumab (6, 24%) most common. Median duration between ICB dosing and LITT was 2.85 (0.85-5.84) weeks. Ten patients (40%) had evidence of immune-related adverse events attributable to ICB, with only 1 event > grade 3 according to Common Terminology Criteria; 17 (68%) had a pre-LITT steroid requirement. Intracranial adverse events related to LITT were rare, with median overall survival for the cohort of 8.6 months (1.4-26.4 months).

CONCLUSIONS:
Combination LITT and ICB appears safe and feasible. No prospective studies have compared cytoreduction with LITT to LITT + ICB; construction of a matched NSCLC cohort is ongoing. Exploration of the immune consequences of LITT + ICB is needed.
PCV Adjuvant Therapy as a Preferred Treatment Option for Oligodendroglioma Patients: A Comparative Study With Temozolomide and Concurrent Radiotherapy
Authors: Chen Adrian , Begley Sabrina , Schulder Michael , Goenka Anuj 
Published: March 2024

INTRODUCTION:
When treating oligodendroglioma patients, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life.

METHODS:
87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis.

RESULTS:
The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in terms of age, tumor genetic profiling, extent of resection, or KPS score, however, the TMZ-based group had more patients receiving concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS [HR = 0.46, p = 0.04] and OS [HR = 0.26, p = 0.04] were significantly longer for those receiving PCV-based treatment compared to TMZ-based treatment. After adjusting for factors mentioned above, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p > 0.99).

CONCLUSIONS:
PCV confers improved progression-free survival than TMZ-based treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. As we anticipate the results of the CODEL trial, our findings suggest PCV-based therapy warrants consideration as a preferred therapeutic option for oligodendroglioma patients.
Next Generation Sequencing Mutational Profiles of Gliomas Reveal Clinical and Genetic Factors Predicting Refractory Postoperative Seizures
Authors: Shukla Poojan , Nguyen Minh P. , Young Jacob , Lee Anthony T. , Chang Edward 
Published: March 2024

INTRODUCTION:
Postoperative seizures are a common complication of gliomas following resection, but little is known about their course and the role of tumor biology in their development.

METHODS:
Single-center retrospective review of adults who underwent surgical management of glioma with targeted next generation sequencing of tumor samples obtained 2017-2020. Univariate analysis for relevant cohort characteristics and adjustment with multivariate regression was performed.

RESULTS:
Among 341 patients with at least 3 months of follow-up, 174 (51.0%) experienced postoperative seizures and 89 (26.1%) had refractory seizures, defined as seizures occurring monthly or more frequently. Patients with refractory seizures were younger, presented with seizure, had IDH-mutated tumors, and had recurrent tumors. Postoperative refractory seizures had a median length of 9.4 months. In a multivariate analysis adjusting for age, seizures at presentation, newly diagnosed or recurrent status, WHO grade, and IDH status, PIK3R1 mutation emerged as an independent predictor of increased odds of developing refractory seizures (log(OR) 0.89 [0, 1.8], p = 0.044) with PIK3CA mutations trending towards significance (log(OR) 0.66 [-0.12, 1.4], p = 0.09). In another stratified multivariate analysis, CKD4 (log(OR) 1.9 [0.42, 3.4], p = 0.014), PIK3CA (log(OR) 1.3 [0.15, 2.4], p = 0.026) emerged as predictors of refractory seizure among recurrent tumors while presenting with seizure (log(OR) 0.81, [0.08, 1.5], p = 0.03) was the only significant predictor among newly diagnosed tumors.

CONCLUSIONS:
PIK3R1 and PIK3CA mutations were independent predictors of increased odds of postoperative refractory seizures, with CDK4 mutations as an additional predictor among recurrent tumors. Seizures at presentation predicted refractory postoperative seizures in newly diagnosed tumors, suggesting the need for close clinical follow-up in these patients. Future analysis of this cohort will enable better characterization of the influence of tumor mutational profile on postoperative seizure activity.
Metabolomic Differentiation of Tumor Core vs. Edge in Glioma Via Machine Learning
Authors: Williams Brian Jeremy , Frieboes Hermann , Baxter Mary , Miller Hunter , Chen Joseph 
Published: March 2024

INTRODUCTION:
Gliomas exhibit high intra-tumor and inter-patient heterogeneity. Recently, it has been shown that the microenvironment and phenotype differ significantly between glioma core (inner) and edge (invasive) regions.

METHODS:
Paired glioma core and infiltrating edge samples were obtained from 27 human patients after craniotomy. Liquid-liquid metabolite extraction was performed on the samples, and metabolomic data was obtained via 2DLC-MS/MS. A boosted generalized linear model was employed to predict metabolomic profiles associated with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation.

RESULTS:
A panel of 52 of 160 metabolites were found to significantly differ between the glioma core and edge regions (p = 0.05). Top metabolites with significantly different relative abundances included nicotinamide, creatine, cystathione, D-pantothenic acid, and maleic acid. The machine learning model predicted MGMT promotor methylation status using 5 key metabolic features within the core and edge tissue specimens with AUROCEdge = 0.935 and AUROCCore = 0.959. Top metabolites associated with MGMT status in core included Y-L-glutamyl-L-glutamic acid, D-pantothenic acid, uric acid, and in edge included itaconic acid, N,N-dimethylarginine, cytosine.

CONCLUSIONS:
Key metabolic differences are identified between core and edge tissue in glioma and can predict MGMT status.