bluuebunny/crossref_metadata_2025 huggingface dataset:
P20.12.B INTEGRATED GENETIC ANALYSES OF IMMUNODEFICIENCY-ASSOCIATED EPSTEIN-BARR VIRUS- (EBV) POSITIVE PRIMARY CNS LYMPHOMAS
Authors: Kaulen L D , Denisova E , Hinz F , Hai L , Friedel D , Henegariu O , Hoffmann D , Ito J , Kourtesakis A , Lehnert P , Doubrovinskaia S , Karschnia P , von Baumgarten L , Kessler T , Baehring J , Brors B , Sahm F , Wick W
Published: October 2024

BACKGROUND

Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV+) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies.

MATERIAL AND METHODS

In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. Deconvolution of bulk RNA sequencing data was performed using CIBERSORTx to characterize the tumor microenvironment.

RESULTS

EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV- PCNSL. Instead, EBV+ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+ PCNSL.

CONCLUSION

In addition to novel insights into the pathobiology of EBV+PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.
P20.16.A PEDIATRIC CENTRAL NERVOUS SYSTEM TUMOR WITH CIC-LEUTX FUSION: A DIAGNOSTIC CHALLENGE
Authors: Hu W , Hou Y
Published: October 2024

BACKGROUND

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) recognized CIC-rearranged sarcoma as a distinct mesenchymal, non-meningothelial tumors, designated as CNS WHO grade 4. This entity is characterized by CIC fusion with various partners, notably NUMT1 or DUX4, serving as its key molecular feature and essential diagnostic criterion. However, due to their rarity, the genetic background, etiology and clinical implications of CIC-fused CNS tumors still remains elusive. In a recent study by Philipp Sievers et al., a set of CIC-fused pediatric high-grade neuroepithelial tumors exhibit a distinct DNA methylation profile (CIC-HGNET), differing from CIC-rearranged sarcomas and suggesting an intermediate malignancy grade.Does all the central nervous system CIC tumors are CIC sarcomas or CIC-HGNETs? In this multi-center study, we assembled a series of CIC-rearranged CNS tumors, specifically those with rare fusion partners. Our aim is to broaden the understanding and diversity of CIC-fused CNS tumors, and to discuss whether CNS tumors with CIC fusions merit classification as a unified entity.

MATERIAL AND METHODS

Using histological evaluation, immunohistochemistry, next generation sequencing and DNA methylation cluster analysis.

RESULTS

The final cohort included 13 CNS CIC-cases and 6 peripheral CIC sarcoma cases. We find that not all intracranial CIC tumors are CIC sarcomas. Unlike peripheral CIC sarcomas (common features are WT1 positive and GFAP/Olig2 negative with relatively abundant reticular fibers), pure intracranial CIC-LEUTX fusion tumors with some GFAP/Olig2/Syn expression, WT1 negative, and no reticular fibers are still neuroepithelial tumor, not sarcoma. CIC-HGNET does exist. However, CIC-HGNETs can’t include all the intracranial CIC tumors. There were still some cases that methylation failed to cluster, indicating new subtypes in CIC tumors (One case of PXA morphology clustered in GG and one case of embryonal tumor morphology clustered in independent group with near LGG-MYB and ependymoma-ZFTA). Although they are not CIC-HGNET, they also belong to CIC-NET, not sarcoma. This point requires special attention, because the two types of tumors have different treatments and different prognosis. The prognosis of neuroepithelial tumors with CIC-LEUTX fusion are much better than CIC sarcomas!

CONCLUSION

Pediatric central nervous system tumor with CIC fusion have heterogeneity. It manifests varied methylation signature and clinical characteristics. Whatever, there are two types in CNS tumor with CIC fusion. One is CIC sarcoma and the other is CIC-NET (including new type of CIC-HGNET).
P20.21.A SPINAL CORD ASTROBLASTOMA WITH EWSR1-BEND2 FUSION IN FEMALE PATIENTS: A REPORT OF FOUR CASES FROM CHINA AND A COMPREHENSIVE LITERATURE REVIEW
Authors: Fu L , Hu W , Xi S
Published: October 2024

BACKGROUND

Astroblastoma is an extremely rare central nervous system (CNS) tumor characterized by astroblastic pseudorosettes and vascular hyalinization. Despite these histologic hallmarks, its morphology can vary, occasionally resembling other CNS tumors like ependymoma. A novel tumor entity, astroblastoma, meningioma 1 (MN1)-altered, has been identified, featuring MN1 gene rearrangements typically involving BEN-domain containing 2 (BEND2) as a fusion partner. Most astroblastomas arise in the cerebral hemisphere.

MATERIAL AND METHODS

We present four cases of female patients with astroblastoma, focusing on their uncommon spinal cord location and the unique molecular feature of EWSR1-BEND2 fusion. All cases underwent next-generation sequencing (NGS), RNA sequencing (RNA-seq), and fluorescence in situ hybridization (FISH). Additionally, two cases underwent DNA methylation profiling.

RESULTS

These tumors displayed growth patterns akin to traditional intracranial astroblastomas, with three cases demonstrating high-grade histology, including elevated mitotic activity and necrosis. Interestingly, some cases exhibited positive staining for pan-cytokeratin (CK) and hormone receptors. Three out of the four patients experienced recurrence, underscoring the aggressive nature of this disease.

CONCLUSION

We suggest recognizing a new molecular subgroup of spinal astroblastoma and recommend testing newly diagnosed infratentorial astroblastomas for EWSR1-BEND2 fusion.
P22.01.A “IT FEELS LIKE I’M GRIEVING FOR SOMEONE THAT IS STILL ALIVE”: A QUALITATIVE STUDY OF THE EXPERIENCES OF NEURO-ONCOLOGY CAREGIVERS
Authors: Zanotto A , Goodall K , Ellison M , McVittie C
Published: October 2024

BACKGROUND

Informal caregiving of someone with a primary brain tumor is highly distressing and associated with an increased risk of depressive symptoms, anxiety, and caregiver burden. A brain tumor diagnosis poses unique symptoms and challenges, including an uncertain prognosis and related existential concerns, as well as neurological symptoms such as cognitive deficits or personality changes. Due to these characteristics and related care demands, family caregivers experience a different set of challenges compared to other types of cancer. The purpose of this qualitative study was to understand in-depth the experiences of informal caregivers’ coping, support needs, and changes in relationships while caring for a loved one with a brain tumor.

METHODS

In-depth interviews were conducted with 10 informal caregivers (3 spouses/partners, 4 parents, 2 children, and 1 sibling) of people with low- or high-grade tumor. The mean age of participants was 42 years (range 19-68 years), and 90% of participants were female (n = 9). Interviews were transcribed verbatim and analyzed using interpretative phenomenological analysis (IPA).

RESULTS

Participants experienced grief and feeling unappreciated, and were advocating for the person diagnosed. Caregivers described grieving for the loss of their loved one as they were before the diagnosis, but also for the loss of their previous lifestyle and the loss of a future together as they imagined it to be. There was a sense of uniqueness in caring for someone with a brain tumor. Participants felt unappreciated by society, particularly when comparing their current role to their professional identities. They were involved in the care decisions, researching treatment and support availability, and advocating for the needs of the person diagnosed.

CONCLUSION

The current findings highlight the importance of involving informal caregivers of persons with a brain tumor in the treatment process. It is crucial that their role is acknowledged and appreciated during interactions with healthcare professionals. Implications for communication with clinicians will be discussed.
P22.08.B INDICES OF SOCIOECONOMIC STATUS AND NEURO-ONCOLOGY CAREGIVERS’ RISK FOR IMMUNE DYFUNCTION
Authors: Sherwood P , Ho R , Ren D , Deng Z , Donovan H
Published: October 2024

BACKGROUND

In neuro-oncology, family income has been shown to impact both family caregiver and patient outcomes. In addition, subgroups of neuro-oncology caregivers have been shown to be at risk for immune dysfunction due to the stress of providing care. How socioeconomic status, particularly measures of socioeconomic status beyond simply income, plays a role in risk for altered cytokine levels is unexplored. The purpose of this analysis was to determine the effect of neighborhood level indices of socioeconomic status on Interleukin (IL)6, Il1ra, and C-reactive protein (CRP) levels in neuro-oncology family caregivers.

MATERIAL AND METHODS

Data were collected from 120 family caregivers of persons with a primary malignant brain tumor (NIH NR013170; only baseline data used for analysis). High sensitivity CRP, IL6, and IL1ra were assessed from five milliliters of blood obtained by standard venipuncture technique using sodium heparin tubes. Standardized neighborhood deprivation and social vulnerability levels were obtained using metrics from the United States Census Bureau which includes variables such as neighborhood unemployment, public transportation, education, health insurance coverage and family poverty levels. Final analyses were performed using multivariate linear regression adjusting for potential covariates.

RESULTS

Greater neighborhood deprivation was associated with higher CRP (p=0.05) and potentially (p=0.08) IL6 levels in family caregivers. Higher levels of social vulnerability (p=0.05) were also associated with higher CRP levels. All models adjusted for gender, age, race/ethnicity, any change in health over the two months prior to data collection, smoking, caffeine use, recent cold or fever, and number of comorbid conditions.

CONCLUSION

Recognizing the impact of characteristics placing neuro-oncology caregivers at risk for compromised immunity can inform health strategies and targeted interventions. Using indices of environmental vulnerability broader than simply income holds promise for targeting individuals for whom reduction of inflammation should be a primary target in order to improve quality of life and overall health outcomes.
P22.11.A POOR SELF-REPORTED PHYSICAL FUNCTIONING IN GLIOMA PATIENTS ACROSS THE DISEASE TRAJECTORY
Authors: Blom M E C , Gorter M , Belgers V , Röttgering J G , de Witt Hamer P C , van Lingen M R , Knoop H , Klein M , Douw L
Published: October 2024

BACKGROUND

Few studies have investigated physical functioning at multiple moments in the disease trajectory of glioma patients, nor have the correlates of physical functioning been determined. We therefore analyzed physical functioning in a large sample of glioma patients both at time of diagnosis and after primary treatment.

MATERIAL AND METHODS

In this retrospective study (patients were diagnosed between 2007-2023), the self-reported physical functioning subscale of the 36-Item Short Form Health Survey (SF-36) was used. Each patient was matched with two general population controls based on age, sex, and educational level. First, we compared physical functioning at time of diagnosis and after treatment with matched controls. Next, we determined correlates of patients’ physical functioning at both time points, namely age, sex, educational level, tumor histology, location, lateralization and grade, type of treatment, presence of epilepsy, usage of dexamethasone, Karnofsky Performance Status (KPS) and the National Institutes of Health Stroke Scale (NIHSS). Finally, in patients with assessments both at diagnosis and after treatment, we determined change in physical functioning over time.

RESULTS

We included 260 glioma patients at time of diagnosis and 109 glioma patients after treatment. Compared to controls, physical functioning of patients was significantly lower at the time of diagnosis (p = 0.022) and after treatment (p = 0.002). At both time points, poorer physical functioning was associated with having a tumor grade III, and KPS lower than 80. Moreover, at diagnosis only, poorer physical functioning correlated with lower educational level and right-sided tumor lateralization. Within the 77 glioma patients with data available at both time points, there was a large individual variability in change over time (28% increased; 40% decreased), but there was no significant change at the group level (p = 0.300).

CONCLUSION

Physical functioning is poor in glioma patients, regardless of phase of the disease. The main correlates of poor physical functioning are tumor and patient characteristics, such as KPS, tumor grade, educational level, tumor lateralization. Interestingly, neurological deficits were not related to physical functioning. Interventions aimed at improving physical functioning in glioma patients should be explored.
P23.05.B LOCKED-IN SYNDROME: A CHALLENGING COMPLICATION FOR SURGERY OF FORAMEN MAGNUM MENINGIOMAS: A SYSTEMATIC REVIEW AND ILLUSTRATIVE CASE
Authors: Torio J R , Meceda E , Concepcion C , Sylva J
Published: October 2024

BACKGROUND

Locked-in syndrome (LiS) as a complication from foramen magnum meningiomas (FMM) surgery is rare but impactful. Its exact occurrence rate isn’t well-documented due to its scarcity, often emerging from surgical maneuvers near the brainstem.

MATERIAL AND METHODS

We present a case of a 63-year-old female who was admitted for 5-month history of progressive bilateral lower extremity weakness who underwent a left suboccipital craniectomy, C1 laminectomy under neuronavigation and intra-operative neuromonitoring for MEP and SEP. We did a systematic search using MeSH keywords “Foramen Magnum Meningioma”, “Surgical Outcomes”, “Surgical Complications” and “Locked-In Syndrome” on November 26 2023, across multiple databases: PubMed, Google Scholar and Cochrane Library, wherein nine studies were included in the final qualitative analysis.

RESULTS

Majority of the surgically managed cases had FMM located anterolaterally with a median size of 2.06 -6.7cm. 32 cases had tumors encasing the vertebral artery. Morbidity rate was 38.6%, with most of the complications involved neurologic deficits secondary to the proximity of lesions to the brainstem and lower cranial nerves and hydrocephalus. No literature was able to report incidence of locked-in syndrome.

CONCLUSION

Incidence of LiS as a complication of FMM surgery is low but can have significant implications. Although vascular related etiology portends higher mortality as compared to non-vascular causes, role of prompt stroke treatments such as EVT can increase chance of better recovery. Outcomes tend to be challenging with limited prospects for complete recovery.
P25.04.B TEN YEARS EXPERIENCE OF THE “BRAIN TUMOR CENTER” OF ALMADA
Authors: Casimiro C D , Silva M , Monteiro J , Viegas C , Cunha e Sá M
Published: October 2024

BACKGROUND

The growing scientific knowledge on brain tumors and the progressive complexity of therapeutic options requires a multidisciplinary approach in a specialized environment. Brain tumor centers (BTC) are crucial in various aspects of assistance given to patients. Since 2013 our BTC assists in the diagnosis, treatment and monitoring of neuro-oncological patients in a multidisciplinary setting involving neurosurgery, neuro-oncology, medical oncology, radiotherapy, neuroradiology, pathology, rehabilitation, neuropsychology, palliative care, nursing and social care.

METHODS

Review of the data-set and activities of our BTC since its foundation.

RESULTS

Our BTC maintained an initial yearly growth and admitted 2055 patients during this period (~206 yearly). Patients were referred via primary care, regional hospitals or by admission for urgent care. The average time between proposal and surgery was ~16 days, with ~23 days until pathology results. Primary tumors of the central nervous system (CNS), namely glial tumors, were most frequent (54% of patients in 2023), followed by metastatic disease (36%, notably from lung origin). During this period, 17% of the diagnosis were made by biopsy and 6% of tumors were resected during awake surgery. Follow-up was carried out in accordance with evidence based international clinical guidelines, within the framework of a multidisciplinary neuro-oncology discussion where cases are presented, and exams and treatments are reviewed. Around ~11 patients were discussed per meeting, with ~24 meetings yearly. Overall, chemotherapy was proposed to 30% of patients, radiotherapy to 26% and radiosurgery to 8,5%.

DISCUSSION

Our BTC was founded to solve shortcomings identified in the treatment of patients and to create an organizational structure to optimizes their care. The multidisciplinary meetings have a distinct importance allowing the individual analysis of each case. Data recording contributes to epidemiological registries and must embrace the continuous neuro-oncology updates. Our data reinforces the need to guarantee fluid coordination and continuity of care, avoiding duplication of services, delays and waste of resources. The role of a nurse-coordinator is essential for the monitoring, coordination and follow-up of patients. The importance of efficient administrative work also cannot be understated. Besides wanting to receive the best treatment, patients wish to be cared for with dignity and respect and have their opinion taken into account. A guidance manual is being updated with the main aspects surrounding clinical care.

CONCLUSIONS

The last 10 years of an organized BTC made possible to gather relevant clinical information and to improve on the multidisciplinary care given to our neuro-oncological patients.
P26.04.A CASEIN KINASE 2 INHIBITOR, CX-4945, INDUCES APOPTOSIS AND RESTORES BLOOD BRAIN BARRIER HOMEOSTASIS IN A PRECLINICAL MODEL OF GLIOBLASTOMA
Authors: Caffo M , Casili G , Filippone A , Bova V , Mannino D , Salako A , Scuderi S , Bulzomì M , Campolo M , Esposito E
Published: October 2024

BACKGROUND

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the central nervous system (CNS). Casein kinase 2 (CK2), a serine/threonine kinase, has been reported to have a dual action, regulating cellular processes and acting as an oncogenic promoter of tumor development. Here, we aimed to study the effect of CK2 inhibition by CX-4945 in U87 and hCMEC/D3 cells.

MATERIAL AND METHODS

U87 cells were treated with CX-4945 (5, 10 and 15 μM) for 24 hrs, while the hCMEC/D3 cell line were first stimulated with lipopolysacharide (LPS) and then treated with CX-4945 (5, 10 and 15 μM). Cytotoxicity tests, Western blot analysis and Immunofluorescence were performed to study the involvement of the different pathways.

RESULTS

We found that CX-4945 suppressed proliferation, reduced the inflammatory pathway and angiogenesis, oxidative stress, attenuated the activation of neurotrophic factors (NFs), while enhancing the apoptosis pathway. Furthermore, it promoted the restoration tight junctions.

CONCLUSION

These new insights into CK2 molecular signaling in GBM and blood brain barrier (BBB) demonstrate that CX-4945 may represent a promising approach for future GBM therapy, not only in the tumor microenvironment but also at the BBB.
P26.05.B DOSE-DEPENDENT DISTRIBUTION OF METHOTREXATE IN THE JUVENILE PIG BRAIN FOLLOWING INTRAVENOUS HIGH-DOSE METHOTREXATE INFUSION
Authors: Rasmussen T , Guscott M , Bascal Z , Ward S , Howard S , Buddington R K , Palmfeldt J , Mikkelsen T S
Published: October 2024

BACKGROUND

High-dose methotrexate (HD-MTX) is an essential element in the treatment of numerous cancers, including pediatric acute lymphoblastic leukemia with central nervous system involvement, and malignant brain tumors. However, our understanding of MTX distribution and elimination within the brain is incomplete. This limits the development of optimal dosing strategies. Additionally, while HD-MTX is effective, it is also known to cause acute central nervous system (CNS) toxicity in some patients. The exact mechanisms behind this toxicity are still unknown but is assumed by many to be linked to MTX mediated changes in brain metabolism. This calls for further investigation into MTX distribution and elimination within the brain, alongside a deeper understanding of MTX-induced changes in brain metabolism.

MATERIAL AND METHODS

This study assessed MTX levels in the brain of healthy, anesthetized juvenile pigs following a four-hour intravenous infusion of either standard 5 g/m2 HD-MTX or an increased dose of 20 g/m2 very high-dose MTX (VHD-MTX). A microdialysis probe was inserted into the cerebral frontal lobe to assess extracellular fluid MTX concentration. Blood plasma and urine samples were also collected. MTX concentrations were measured across samples using a highly sensitive liquid chromatography-mass spectrometry (LC-MS).

RESULTS

Serial samples of microdialysate, plasma, and urine were successfully collected from sedated pigs and MTX was detectable across all samples. The median MTX exposure represented as area under the drug concentration curve (AUC) in plasma and microdialysate was increased 3.6-fold and 3.1-fold respectively at the end of the four-hour infusion of VHD-MTX compared to HD-MTX. This increase was 4.9-fold and 3.1-fold after an additional four hours of observation post MTX-infusion (p < 0.05, n=12).

CONCLUSION

This study is part of a larger investigation exploring the use of VHD-MTX in treating CNS cancers. The results demonstrate a dose dependent increase in MTX exposure in extracellular fluid of the cerebral frontal lobe as demonstrated by microdialysis. Further studies using this model will investigate the effects of combining VHD-MTX with strategies to manage systemic toxicity. Additionally, we will employ explorative LC-MS metabolomics to assess changes in the metabolomic profile in CNS samples to address possible changes that could explain the phenomenon of CNS toxicity.
P26.09.A METFORMIN REPURPOSING FOR GLIOBLASTOMA TREATMENT
Authors: Barciszewska A , Belter A , Barciszewski J F , Gawrońska I , Giel-Pietraszuk M , Naskręt-Barciszewska M Z
Published: October 2024

BACKGROUND

Being the most common and aggressive malignant primary brain tumor in adults, glioblastoma (GBM) is, simultaneously, the best-studied central nervous system neoplasm with the continuous development of new treatments, including targeted therapies and immunotherapy, to improve outcomes for GBM patients. However, even with such a big effort, GBMs are still challenging to manage, with poor prognosis. Recurrence is certain, and the average survival time is relatively short. In the search for effective therapies, the focus switches now to existing drugs with the aim of repurposing. One of the possible candidates is the first-line drug for type 2 diabetes - metformin (MTF). It acts mainly through decreasing liver glucose production and improving insulin sensitivity. However, the exact mechanism of MTF’s action is not fully understood. Its positive influence is observed in many aspects of cardiovascular disease, gut microbiota modulation, hormonal balance, cancer prevention and treatment, as well as longevity and aging. These multiple effects highlight the potential of MTF as a versatile medication beyond its traditional use in diabetes. They also drive attention to possible underlying molecular processes responsible for such a broad action. The only phenomenon that can explain such a complex influence on diverse biological processes is epigenetics. One of the main epigenetic processes is DNA methylation, which directly influences gene expression. 5-methylcytosine (m5C) in DNA is the best-characterized epigenetic mark. Our project aimed to evaluate the total DNA methylation level after MTF administration on the GBM cell lines.

MATERIAL AND METHODS

Using the nucleotide post-labeling method, we analyzed the total amount of m5C in DNA of GBM (T98G, U138), and normal (HaCaT) cell lines treated with MTF.

RESULTS

No significant changes in total DNA methylation were observed in non-cancer cell lines (HaCaT) treated with MTF, due to small toxicity confirmed also with global DNA guanosine oxidation (8-oxo-dG). On the opposite, DNA hypomethylation was observed for GBM cell lines (T98G and U138) with increasing MTF concentration and incubation time. We also analyzed the combined effects of MTF with temozolomide (TMZ), the first-line chemotherapeutic for GBM. MTF potentiated the demethylating effect of TMZ. The concomitant application of both drugs induced DNA oxidation.

CONCLUSION

Total DNA methylation changes in GBM cell lines under MTF treatment suggest the new mechanism of that drug action and promote clinical implications for adjusting MTF and TMZ therapy in GBM patients. Our results show the potential and possible obstacles of the combined therapy of TMZ with MTF. Combined therapy with both drugs leads to total DNA hypomethylation. Therefore it is necessary to adjust MTF administration during TMZ therapy.

FUNDING

M.Z.N.-B. is supported by the OPUS 19 (2020/37/B/NZ5/03249)
P26.10.B OPTIMIZING DELIVERY OF CHEMOTHERAPEUTIC AGENTS BY INTRA-ARTERIAL INFUSION IN GLIOBLASTOMA
Authors: Latulippe J , Roy L , Gobeil F J , Fortin D
Published: October 2024

BACKGROUND

Being the most aggressive malignant primary brain tumor, glioblastoma (GBM) is a difficult disease to treat. The first line treatment consists in maximal resection followed by concomitant radiotherapy and temozolomide. However, most patients will relapse during the after treatment. The overall survival is only 14,6 months while the progression-free survival is 6,9 months. Even if the first-line treatment is well established, there is no consensus for the second line. At our institution, Dr. Fortin prioritize the intra-arterial (IA) administration of chemotherapeutic agents (CTA), which conveys a higher drug concentration to the tumor site. Carboplatin is the most used chemotherapeutic, but certain patients will not respond or will even develop chemoresistance to this treatment. Therefore, there is a strong need for bringing different CTAs into clinical care to offer more options. Topotecan, cytarabine and paclitaxel are molecules evaluated in this study since they are all already used intravenously (IV) in the treatment of GBMs.

MATERIAL AND METHODS

Since these agents have never been used for IA, we need to determine their maximal tolerable dose (MTD) to avoid any adverse effects. As such, healthy rats were given the CTA by retrograde infusion in the external carotid. They were euthanized five days following that surgery. After determining the right dosages, the survival study was initiated. Indeed, every CTAs were administered IA but also IV to compare both administrations. We used the Fischer-F98 glioma rat model. For the efficacy study, we implanted 10 000 F98 cells into the brain of the Fischer rats. At day 10, they received the treatment associated to their group. The animals were followed every day following the surgeries and were euthanized when their condition was too deteriorated. The IV doses used (found in the literature) were topotecan: 4 mg/kg, cytarabine: 40 mg/kg and paclitaxel: 10 mg/kg.

RESULTS

The doses found in the MTD study for topotecan and cytarabine were 4 mg/kg and 8,75 mg/kg respectively. However, paclitaxel was toxic when administered via IA, probably because of its lipidic vehicle. As for the efficacy study, the IA group of topotecan showed a promising outcome with a higher survival rate (29 days) compared to IV (23,5 days). As for cytarabine groups, IA was detrimental, with a 22 days median survival, compared to 26,5 days for the IV group.

CONCLUSION

While topotecan and cytarabine could be given intra-arterially, only topotecan showed conclusive results with a higher survival rate. More animals will be added to this group to validate this outcome. Cytarabine does not appear to be a good option since the MTD IA dose yielded a worse survival rate than the dose administered via IV. As for paclitaxel, considering it cannot be used intra-arterially, intra-tumoral infusion will be tested to see if we can get positive results.
P27.04.A CLINICAL EXPERIENCES AND LEARNING CURVES FROM ROBOT-ASSISTED NEUROSURGICAL BIOPSIES WITH STEALTH AUTOGUIDEΤΜ
Authors: Ljungqvist J , Barchéus H , Abbas F , Ozanne A , Nilsson D , Corell A
Published: October 2024

BACKGROUND

Biopsies of intracranial lesions is a cornerstone in the diagnosis of unresectable tumors to guide neurooncological treatment; however, the procedure is also associated with risks. The results from the cranial robot guidance system Stealth AutoguideΤΜ were studied after introduction at a neurosurgical department. Primary aims include the presentation of clinical and radiological data, accuracy of radiological diagnosis, learning curves of the new technology, diagnostic yield, and precision. The secondary aim was to study complications.

METHODS

Retrospective data inclusion was performed on patients ≥18 years undergoing biopsy with Stealth AutoguideΤΜ due to suspected brain tumor in the first three years after introduction of the technique. Data regarding clinical characteristics, intraoperative variables, pathological diagnosis, and complications were recorded. Analyses of learning curves were performed.

RESULTS

A total of 79 procedures were performed on 78 patients with a mean age of 62 years (SD 12.7, range 23-82), 30.8% were female. Tumors were often multifocal (63.3%) and supratentorial (89.9%). The diagnostic yield was 87.3%. The first-hand radiological diagnosis was correct in 62.0%. A slight decrease in operation time was observed, although not significant. The surgeon contributed to 12% of the variability.

CONCLUSION

Robot-assisted biopsies with Stealth AutoguideΤΜ seem to be comparable, with regards to complications, to frame-based and other frame-less neurosurgical biopsies. Learning curves demonstrated no statistical differences in time of surgery and only 12% surgeon related variation (i.e. variation caused by change of performing surgeon), suggesting a successful implementation of this technical adjunct.
P27.10.B FACTORS INFLUENCING TIMELY DIAGNOSIS IN NEUROLYMPHOMATOSIS
Authors: Doubrovinskaia S , Egert A , Karschnia P , Scheffler G , Huttner A , Fulbright R , Baehring J M , Kaulen L D
Published: October 2024

BACKGROUND

Neurolymphomatosis refers to infiltration of the peripheral nervous system (PNS) by non-Hodgkin lymphoma (NHL). Diagnostic intervals in NL and factors facilitating or delaying diagnosis have not been thoroughly evaluated. We therefore aimed to analyze diagnostic intervals in a large cohort from a tertiary referral center.

MATERIAL AND METHODS

The quality control database at Yale Cancer Center, Section of Neuro-Oncology, was searched for neurolymphomatosis cases diagnosed between 2001-2021. Univariate analyses were performed to identify parameters influencing diagnostic intervals.

RESULTS

We identified 22 neurolymphomatosis cases including 7 without previous NHL (primary NL) and 15 with PNS relapse of NHL (secondary NL), which occurred after a median of 16 months (range: 4-144). Patients typically presented with painful polyneuropathy (73%), that was asymmetrical and rapidly progressive. Diagnosis was based on PNS biopsy (50%) or integration of neuroimaging findings (50%) with NHL history and diagnostic cerebrospinal fluid examinations. NL was diagnosed a median of 3 months (range: 1-12) after symptom onset. Secondary NL (median 2 vs 6 months; p =0.02), presentation with rapidly-progressive asymmetrical neuropathy (median 2 vs 6 months; p < 0.001), upfront evaluation with either MRI or FDG-PET (median 2 vs 5 months; p = 0.04), and absence of nerve root lesions (median 1.5 vs 4 months; p = 0.04) were associated with earlier diagnosis after symptom onset.

CONCLUSION

Diagnostic delays in NL are common, particularly in patients with primary disease, atypical clinical presentation, upfront assessment with conventional CT, and nerve root lesions. Findings may guide prompt initiation of appropriate diagnostic work-up in NL.
P27.16.A PREDICTIVE ROLE OF INTRACRANIAL PD-L1 EXPRESSION IN A REAL-WORLD COHORT OF NSCLC PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITION FOLLOWING BRAIN METASTASIS RESECTION
Authors: Murad S , Wasilewski D , Onken J , Höricke P , Bukatz J , Früh A , Shaked Z , Misch M , Kühl A , Klein O , Ehret F , Kaul D , Radbruch H , Capper D , Vajkoczy P , Horst D , Frost N , Bischoff P
Published: October 2024

BACKGROUND

Emerging evidence suggests that treatment of NSCLC brain metastases with immune checkpoint inhibitors (ICIs) is associated with response rates similar to those of extracranial disease. Programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) serves as a predictive biomarker for ICI response. However, the predictive value of brain metastasis specific (intracranial) PD-L1 TPS is not established. We investigated the role of intra- and extracranial PD-L1 TPS in NSCLC patients treated with ICI following brain metastasis resection.

MATERIAL AND METHODS

Clinical data from NSCLC patients treated with ICI following brain metastasis resection (n = 64) were analyzed. PD-L1 TPS of brain metastases (n = 64) and available matched extracranial tumor tissue (n = 44) were assessed via immunohistochemistry. Statistical analyses included cut point estimation via maximally selected rank statistics, Kaplan-Meier estimates, and multivariable Cox regression analysis for intracranial progression-free survival (icPFS), extracranial progression-free survival (ecPFS), and overall survival (OS).

RESULTS

PD-L1 expression was found in 54.7% of brain metastases and 68.2% of extracranial tumor tissues, with a median intra- and extracranial PD-L1 TPS of 7.5% (0 - 50%, IQR) and 15.0% (0 - 80%, IQR), respectively. In matched tissue samples, extracranial PD-L1 TPS was significantly higher than intracranial PD-L1 TPS (p = 0.013). Optimal cut points for intracranial and extracranial PD-L1 TPS varied according to outcome parameter assessed. Notably, patients with a high intracranial PD-L1 TPS (> 40%) exhibited significantly longer icPFS as compared to patients with a low intracranial PD-L1 TPS (≤ 40%). The cut point of 40% for intracranial PD-L1 TPS was independently associated with OS, icPFS and ecPFS in multivariable analyses.

CONCLUSION

Our study highlights the potential role of intracranial PD-L1 TPS in NSCLC, which could be used to predict ICI response in cases where extracranial tissue is not available for PD-L1 assessment as well as to specifically predict intracranial response.
P27.31.B VENOUS THROMBOEMBOLISM IN GLIOBLASTOMA POPULATION. INCIDENCE, RISK FACTORS AND SURVIVAL ANALYSIS
Authors: Meca Santamaria G , Comas Antón S , Hernandez Gonzalez A , Domenech Viñolas M , Izquierdo Gracia C , Muriel Sanchez R , Hostalot Panisello C , Teixidor Rodriguez P , Gutierrez Garcia B , Molero Savall J , Villà Freixa S
Published: October 2024

BACKGROUND

Patients diagnosed with Glioblastoma (GB) are at an increased risk of developing venous thromboembolism (VTE) compared to other cancers. This is a relevant clinical concern due to its associated comorbidity and risk of mortality. We analyzed the incidence and characteristics of symptomatic VTE in a cohort patient diagnosed with GB.

MATERIAL AND METHODS

A cohort of patients diagnosed and treated for GB between 2009 and 2023 were retrospectively analyzed. Patient-, tumor- and treatment-related variables were evaluated in order to determine risk factors for VTE development as well as the impact on survival.

RESULTS

Forty-seven (16.84 %) out of 279 patients developed symptomatic VTE. In 38.3% of patients, it was presented as deep vein thrombosis (DVT), in 14.9% as pulmonary thromboembolism, and 46.8% presented both events synchronously. DVT were located in the lower extremity in 94.8% of cases. The periods at greatest risk of VTE were the course of adjuvant Temozolomide (29.8% of events) during rescue treatment after relapse (25.5%) and the 4-week window between the end of radiotherapy and the start of adjuvant temozolomide (19,2%). No statistical impact on VTE development was found according to sex, age, pMGMT methylation status; Karnofsky performance status (≤70% versus >70%), presence of paresis and type of surgery. Neither the presence of one, two or more than three cardiovascular risk factors (hypertension, diabetes, dyslipidemia, obesity, heart disease, tobacco) were related to a higher risk of VTE. Median overall survival (OS) and relapse free survival (RFS) were 13,8 (95% CI 12,5-16,4) and 7,3 (95% CI 6,6-8,2) months respectively for all patients. The development of VTE did not show an impact in OS nor RFS. Among patients who developed EVT, the need for dexamethasone coverage at the time of the event resulted in a decreased median OS (21,8 vs 12,9 months; p<00.5) and RFS (15,7 vs 7,2 months; p<00.5).

CONCLUSION

In our sample, clinical features related to the patient, treatment or tumor were not associated to an increased risk of VTE and the occurrence of VTE did not impact survival. Despite these results, the development of VTE is associated with potential increased comorbidity and mortality, so it must be considered as relevant from the clinical and health management point of view. The increased risk of thromboembolic events in patients with GB compared to other neoplasms requires further study of biomarkers to identify those patients at higher risk in order to consider the need of VTE prophylaxis.
Low magnesium levels and prognosis in newly diagnosed diffuse large B-cell lymphoma
Authors: Gile Jennifer J , Maurer Matthew , Ruan Gordon J , Abeykoon Jithma P , Heimgartner Joy R , Baumann Nikola A , McMahon Molly , Lin Yi , Witzig Thomas E
Published: October 2024

Magnesium (Mg) is an essential element involved in cellular metabolism. We demonstrated that in patients with diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (SCT), those with a serum Mg < 2.0 mg/dL at the time of transplant had worse outcomes. In this study, we aimed to learn the prognostic value of low serum Mg in patients with untreated DLBCL. We analyzed serum from 408 patients and tested 2 Mg cutpoints—low (<1.7 mg/dL) and low normal (<2.0 mg/dL), a range we found associated with lower survival in the SCT group. We found 3% of patients with low levels and 23% with low normal levels. Low normal serum Mg levels were associated with a higher stage at diagnosis, more extranodal involvement, higher international prognostic index score, lower overall survival (OS), and event-free survival. These data warrant testing Mg replacement to a target of >2.0 mg/dL to learn if survival can be improved.
Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma
Authors: Tang Bixia , Xiao Jun , Chi Zhihong , Duan Rong , Cui Chuanliang , Si Lu , Liu Yixun , Hu Xuechun , Liu Zhi , Xiang Ping , Li Siming , Yan Xieqiao , Zhou Li , Li Juan , Li Yujie , Yu Xiaohui , Dai Xiangrong , Li Xiaoyi , Guo Jun , Sheng Xinan
Published: October 2024

Background

PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846).

Methods

This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5 mg/kg) and nab-paclitaxel (260 mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival.

Results

Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached).

Conclusion

Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.
ASYMMETRIC LEAVES1 promotes leaf hyponasty in Arabidopsis by light-mediated auxin signaling
Authors: Lee Nayoung , Hwang Dae Yeon , Lee Hong Gil , Hwang Hyeona , Kang Hye Won , Lee Wonbok , Choi Min Gi , Ahn Ye Jin , Lim Chaemyeong , Kim Jeong-Il , Kwon Moonhyuk , Kim Sun Tae , Paek Nam-Chon , Cho Hyunwoo , Sohn Kee Hoon , Seo Pil Joon , Song Young Hun
Published: October 2024

In plants, balancing growth and environmental responses is crucial for maximizing fitness. Close proximity among plants and canopy shade, which negatively impacts reproduction, elicits morphological adjustments such as hypocotyl growth and leaf hyponasty, mainly through changes in light quality and auxin levels. However, how auxin, synthesized from a shaded leaf blade, distally induces elongation of hypocotyl and petiole cells remains to be elucidated. We demonstrated that ASYMMETRIC LEAVES1 (AS1) promotes leaf hyponasty through the regulation of auxin biosynthesis, polar auxin transport, and auxin signaling genes in Arabidopsis (Arabidopsis thaliana). AS1 overexpression leads to elongation of the abaxial petiole cells with auxin accumulation in the petiole, resulting in hyponastic growth, which is abolished by the application of an auxin transport inhibitor to the leaf blade. In addition, the as1 mutant exhibits reduced hypocotyl growth under shade conditions. We observed that AS1 protein accumulates in the nucleus in response to shade or far-red light. Chromatin immunoprecipitation analysis identified the association of AS1 with the promoters of YUCCA8 (YUC8) and INDOLE-3-ACETIC ACID INDUCIBLE 19 (IAA19). In addition, AS1 forms complexes with PHYTOCHROME-INTERACTING FACTORs in the nucleus and synergistically induces YUC8 and IAA19 expression. Our findings suggest that AS1 plays a crucial role in facilitating phenotypic plasticity to the surroundings by connecting light and phytohormone action.
Recipient selection for lung transplantation: perspective in decision-making
Authors: Saribas Ertan , Citak Sevinc
Published: October 2024

Background

To determine the conditions that prevented transplant in patients referred to our center due to end-stage lung disease.

Study design

Descriptive study.

Place and duration of the study

Department of lung transplant clinic, Koşuyolu High Specialization Education and Research Hospital, Istanbul, Turkey, from December 2017 to January 2022.

Methods

Patients with end-stage lung disease referred to our clinic were retrospectively evaluated with regard to reasons for exclusion, diagnosis, and demographic data. The Karnofsky Performance Status scoring scale was used to measure the functional status of the patients.

Results

A total of 311 patients were evaluated during the study period. The mean age was 44.2 (range 4–73) years. There were 207 (66.6%) male patients. The most common indications were idiopathic interstitial pneumonia in 104 (33.4%) patients, chronic obstructive pulmonary disease in 53 (17%) patients, bronchiectasis in 49 (15.7%) patients, and cystic fibrosis in 28 (9%) patients. Of the patients, 106 (34%) were not appropriate candidates for a lung transplant. The most common reasons for refusal were preventable situations such as activity limitation and poor performance in 53 (50%) patients, weight in 49 (46.2%) patients, and smoking in 10 (9.4%) patients.

Conclusion

Impaired performance status was the most common cause of lung transplant exclusion. Weight and smoking were preventable causes of exclusion. Implementing pulmonary rehabilitation in very few patients was the most important handicap. It is believed that providing optimal treatment with a multidisciplinary approach and timely referral to transplant centers will significantly reduce the reasons for exclusion.

Key message What is already known on this topic?  Referring lung transplant candidates to clinics at the earliest stage is essential for assessing their condition and exploring treatment options. What this study adds?  Factors like smoking, obesity, and muscle loss can hinder the transplantation process; thus, timely interventions are crucial. The primary reason for excluding candidates from lung transplantation is the decline in performance status. How this study might affect research, practice or policy?  Programs focused on smoking cessation, weight management, and muscle strengthening can play a vital role in enhancing patients’ health before transplantation. It is imperative to expand and enhance the accessibility of pulmonary rehabilitation programs.
Democracy, Liberal Zionism, and Civil-Military Relations in Israel: A Review Article
Authors: Lustick Ian S
Published: October 2024

Two books on civil-military relations in Israel, published eighteen years apart, focus on Israel's future as a Jewish democracy. Peri's 2006 volume depicts the security establishment as a threat to civilian rule, whereas Ziv, in his 2024 book, portrays waning political influence of the Israeli military and security services as associated with democratic backsliding. The authors each favor the two-state solution to the Israeli-Palestinian conflict but differ on whether opportunities for it have been missed because the military and security establishment has had too much or too little influence over government policy. Consideration of the one-state reality suggests the extent to which both arguments have been overtaken by events.