Metastatic Brain Tumors Research Articles

NCOG-04. MEMORY TRACT SPARING USING DIFFUSE TENSOR IMAGING IN RADIATION PLANNING OF PRIMARY BRAIN TUMORS

Abstract INTRODUCTION Radiation therapy (RT) is a critical treatment modality for both primary and metastatic brain tumors, yet approximately 30% of patients experience cognitive decline post-radiotherapy. This cognitive toxicity is linked to low radiation doses affecting neural stem cells in the hippocampal dentate gyrus. Hippocampal Avoidance (HA)-Whole Brain Radiotherapy (WBRT) combined with Memantine has shown promising outcomes in preserving cognitive function and quality of life (QOL) in patients with brain metastases, suggesting it should be the standard of care for those with good performance status and no hippocampal metastases. METHODS We conducted a prospective trial approved by the IRB (SMC0307-23), including patients aged 18 and above with primary brain tumors post-resection or biopsy. Exclusion criteria included multifocal glioma crossing to the other hemisphere. RT was delivered to a total dose of 60Gy in 30 fractions with concomitant TMZ. Diffusion tensor imaging (DTI) was performed to map hippocampal-associated white matter tracts. Memory fiber tracts and hippocampi were contoured and integrated into RT planning using Eclipse treatment planning software. Dosimetric analyses compared two plans: one with memory fiber constraints and one without. RESULTS Twelve patients with low-grade gliomas were included, with successful contouring of memory fibers and hippocampi. VMAT treatment plans met dose constraints for memory fibers, with an average mean dose of 10.1 Gy. The average MoCA score before RT was 27.1 and 26.4 at six months post-treatment, with a p-value of 0.07. Excluding one patient, the scores were 27.1 and 26.6, respectively (p=0.13). CONCLUSION MRI planning using DTI for memory fiber detection and incorporation into RT planning via VMAT techniques enables hippocampal and associated white fiber sparing, potentially preserving cognitive function. Preliminary cognitive data are promising, supporting the need for further validation in a larger cohort.

SURG-07. QUANTIFYING THE RISK OF SHORT TERM SEIZURES FOLLOWING LASER INTERSTITIAL THERMAL THERAPY

Abstract BACKGROUND Tumor-related epilepsy is a common sequela of both primary and metastatic brain tumors, as well as radiation necrosis (RN). Laser interstitial thermal therapy (LITT) is an effective option for lesional cytoreduction but induces transient peritumoral edema that typically resolves within 3 months of the procedure. Accordingly, we quantified the risk of seizure development early post-LITT in patients with tumors or RN of diverse histologies. METHODS Patients treated with LITT for brain tumors or radiation necrosis at a high-volume center from 2015 – 2021 with at least 3 months of clinical follow-up were evaluated for seizure risk and time to discontinuation of anti-epileptic drugs (AEDs) for at least 4 weeks, with censoring at death or last follow-up. RESULTS One-hundred and seventeen patients met inclusion criteria, and 22 (19%) experienced a post-LITT seizure within 3 months of surgery. Those with pre-LITT seizures (P = 0.03), prior whole-brain radiation (WBRT) (P = 0.0099), or lower pre-operative KPS (P = 0.04) were more likely to have a post-LITT seizure. Frontal lobe tumors appeared to be more frequently associated with seizures (68% vs 45%, P = 0.06). Prior WBRT, odds ratio (OR) 4.27 (95% CI 1.01 – 18.55), P = 0.047 and pre-LITT seizure, OR 5.39 (95% CI 1.87 – 16.31), P = 0.002 remained predictive on multivariate analyses. Successful AED weaning occurred at a median of 1.68 months (no seizure within 3-months group) versus undefined for patients experiencing seizures (P = 0.015). Post-LITT seizures within 3 months were associated with worsened post-LITT overall survival, 5.95 vs 17.2 months, P < 0.0001. DISCUSSION Prior seizure history or previous WBRT pose a risk of breakthrough seizures following laser ablation. Neurosurgeons should consider extended AED treatment or referral for management of tumor-related epilepsy in patients with these neurologic risk factors.

BIOM-28. WHOLE EXOME TUMOR MOLECULAR PROFILING FROM CEREBROSPINAL FLUID (CSF): PRELIMINARY RESULTS OF A PILOT STUDY

Abstract BACKGROUND Tissue sampling for molecular profiling has become an integral part of the diagnosis, prognosis, and management of CNS malignancies. However, many tumors are surgically inaccessible, and even biopsy of accessible lesions conveys some risk, and the possibility of sampling error. We evaluated the accuracy and potential utility of CSF liquid biopsy for identifying mutations in patients with intracranial tumors. METHODS CSF samples were collected from ventricular reservoirs and stored at -80 degrees Celsius until analyzed. Cell-free nucleic acids were extracted, concentrated, and quantified. Samples over 110ng quantification were normalized to 110ng and input into library prep. Library prep was done using v3.5 of Caris Assure and whole exome sequencing in an S2 FC on a Novaseq 6000. Bioinformatic analysis was performed. RESULTS CSF samples were obtained from 20 patients (10 gliomas, 5 CNS lymphomas, 5 metastases), 19 of whom also had tumor specimens available. Two hundred eighty-one mutations were identified: 17 (6.6%) in tumor only, 184 (72.4%) in CSF only, and 80 (31.5%) in both. Key alterations found in CSF include: IDH, TERT, ATRX in gliomas, and MYD88, PIM1, BCL2, TERT in lymphomas. Glioma CSF with IDH1 mutations did not have PTEN mutations (with one exception, in which the CSF was collected 3 years after the tissue). Targetable mutations in metastases included PIK3CA, NF1, and BRCA. CONCLUSION These preliminary results suggest that CSF liquid biopsy may be useful for identifying mutations in primary and metastatic brain tumors. Serial sampling is feasible, and may disclose changes in diagnostic and/or driver mutations over time, with important therapeutic and diagnostic implications. Many mutations were found in CSF alone. CSF may capture the entire molecular landscape of the tumor, overcoming the sampling error inherent in tissue biopsies. Prospective studies are underway to further elucidate the clinical applications of this technique.

TMIC-10. GENETIC LANDSCAPE OF BRAIN METASTASIS IN TRIPLE-NEGATIVE-BREAST CANCER: COMPARISON OF PAIRED PRIMARY AND METASTATIC TUMOR USING SPATIAL TRANSCRIPTOMIC ANALYSIS

Abstract The survival rate of individuals diagnosed with breast cancer has shown improvement over time, primarily attributed to advancements in early detection methods and the implementation of proactive treatment strategies. However, it is concerning that the incidence of breast cancer continues to rise, thereby leading to a corresponding increase in mortality rates among female breast cancer patients. Among these, the presence of brain metastasis is associated with a worse prognosis in individuals with breast cancer. Notably, triple-negative breast cancer exhibits a heightened propensity for the development of brain metastasis. Furthermore, there has been a notable rise in the duration of breast cancer survival, leading to a concomitant increase in the occurrence of metastatic cancer throughout the course of the disease. Presently, a greater number of patients are experiencing brain metastases, surpassing the figures reported in current statistical data. In instances of metastatic cancer, a distinct microenvironment that is particular to the tumor is formed in a distant location. The comprehension of the molecular genetic and immunological mechanisms involved in the several phases of brain metastasis, including tumor cell invasion, engraftment, and proliferation, has significant importance in the context of patient treatment and prognosis prediction. However, it is worth noting that a well-defined scientific foundation in this area is currently absent. The objective of this study was to analyze the molecular genetic characteristics of triple-negative breast cancer primary tumors and brain metastasis tumors. This was achieved by utilizing spatial transcriptome analysis technology to compare the differences in genetic profiles between the tumor cells and the surrounding tumor microenvironment. The findings of this study allowed for a comprehensive comparison of the tumor microenvironment at each site. In order to validate alterations in gene expression of various constituents and elucidate the mechanisms behind metastasis, it is imperative to conduct spatial confirmation.

STEM-09. A GROUP 3 MEDULLOBLASTOMA STEM CELL PROGRAM IS MAINTAINED BY OTX2-MEDIATED ALTERNATIVE SPLICING

Abstract Group 3 medulloblastomas (MBs) are highly metastatic pediatric brain tumors with limited therapeutic options. The transcription factor orthodenticle homeobox 2 (OTX2) is a known driver and molecular hallmark of Group 3 MB. We previously demonstrated that OTX2 regulates Group 3 MB cell fate decisions that favor self-renewal or stemness and the retention of a primitive cerebellar rhombic lip signature. Here, we show that OTX2-regulated alternative splicing (AS) is a major driver of Group 3 MB progression. Surprisingly, the functional role of post-transcriptional events, such as AS, in Group 3 MB development has never been explored. This gene regulatory layer represents an untapped source of therapeutic targets. Using a combination of TurboID, RNA-sequencing and single cell RNA-seq, we characterized the Group 3 primary MB AS landscape with a focus on genes that control MB stem cells. OTX2 associates with the multimeric Large Assembly of Splicing Regulators (LASR) complex through protein-protein interactions and can directly or indirectly bind RNA. Together, OTX2 and LASR complex proteins oversee a pro-tumorigenic splicing program that is mirrored in the human cerebellar rhombic lip origins and is associated with Group 3γ MBs that exhibit the worst prognosis. Among our core set of OTX2-regulated spliced genes, periphilin 1 (PPHLN1) is expressed in the most primitive cerebellar rhombic lip stem cells, and mimicking PPHLN1 AS by pre-treating cells with a splice blocking antisense morpholino reduces tumor growth while increasing survival in vivo. We propose that OTX2-mediated AS is a key determinant of cell fate decisions favoring the maintenance of the stem cell state. Targeting transcription factors like OTX2 is notoriously difficult; thus, our work offers fresh opportunities to exploit MB-specific AS events therapeutically to abrogate tumor progression.

NCMP-14. RADIOGRAPHIC RESPONSE TO BEVACIZUMAB IN TREATING RADIATION NECROSIS AND ASSOCIATED EDEMA IN BRAIN TUMORS

Abstract OBJECTIVE This study evaluates the efficacy of bevacizumab in treating radiation necrosis (RN) and associated perilesional edema in brain tumors. We aimed to measure changes in radiologic volumes and clinical performance following treatment. MATERIALS AND METHODS We retrospectively reviewed patients treated with radiation therapy and/or stereotactic radiosurgery between September 2017 and August 2023. We identified 10 metastatic brain tumors and one glioblastoma with symptomatic RN. Diagnosis was primarily through MRI, with one case confirmed pathologically. All patients received bevacizumab (7.5 mg/kg every 3 weeks). Volumes of RN and perilesional edema were measured using gadolinium-enhanced T1-weighted and T2-weighted/FLAIR MRI, respectively, analyzed with Brainlab software. Volume changes and clinical symptoms, graded by the ECOG Performance Status (PS) scale, were recorded. RESULTS The minimal follow-up was 4 months. The 11 patients received a median of 2 bevacizumab cycles (range, 2-3). Pre-treatment median volumes (ranges) were: tumor/RN 5.45 cc (2.66-13.56), perilesional edema (T2, FLAIR) 53.93 cc (7.46-115.32), 58.01 cc (15.18-131.2). Post-treatment median volumes (ranges) were: tumor/RN 2.5 cc (2.23-7.23), perilesional edema (T2, FLAIR) 4.05 cc (3.08-11.18), 7.38 cc (2.887-17.647). Median percentage volume reductions were: tumor 39%, RN 38%, perilesional edema (T2, FLAIR) 80%, 79%. Significant reductions in edematous volumes were observed. Pre-treatment ECOG PS median was 2 (range 2-3); post-treatment ECOG PS median remained 2 (range 2-3). Clinical performance improved in most patients, with two exception where deterioration occurred after the third cycle despite initial improvement. CONCLUSION Bevacizumab is effective in reducing RN and perilesional edema, particularly within the first two cycles of treatment. Most patients showed clinical improvement, though further research is needed to optimize treatment and understand long-term outcomes.

ANGI-04. DISTINCT EXPRESSION OF TARGET MOLECULES BETWEEN TUMOR CELLS IN CEREBROSPINAL FLUID AND LEPTOMENINGES FOR LEPTOMENINGEAL METASTASIS

Abstract PURPOSE Metastatic brain tumor frequently present with leptomeningeal metastasis. The leptomeningeal metastasis is usually diagnosed by cerebrospinal fluid (CSF) cytology and/or contrast enhanced magnetic resonance imaging. However, it remains to be known whether tumor cells from CSF faithfully represent the tumor cells of leptomeniges. Therefore, this study aimed to clarify the transcriptome differences between tumor cells from cerebrospinal fluid, and spinal cords METHODS MDA-MB-231 cells labeled with GFP and luciferase were injected into the right ventricle of immunodeficient mice. Tumor cells from cerebrospinal fluid, and spinal cords were sorted and analyzed the transcriptome differences by RNA sequencing, RESULTS RNA sequencing analysis showed distinct transcriptome profiles between tumor cells from cerebrospinal fluid and spinal cord. Genes related to ECM receptor interaction and PI3K-Akt signaling pathway such as COL1A1, COL1A2, THBS1 were significantly highly upregulated in tumor cells from spinal cord compared to those from CSF CONCLUSIONS Tumor cells from spinal cord had different characteristics in transcriptome from those from CSF. Different therapeutic strategies might be needed to regulate tumor cells from spinal cord and those from CSF.

CNSC-06. NAVIGATING BRAIN CANCER: PATIENT STORIES AND MEDICAL BREAKTHROUGH

Abstract The complex interplay of genetic mutation, dys regulated signalling pathways, Epigenetic modifications and Interaction with tumor microenvironment are the major aggravating factors for Brain Tumors. Neurological complications involve Increased Intracranial pressure, Seizures, Motor and Sensory deficits, Aphasia, Hydrocephaly, Behavioral and personality changes, Cerebellar Symptoms. It is diagnosed in a sequential steps. Collecting good history from patient in primary then examining the patient all through and making some investigations to come to a final diagnosis. On asking history to a patient he complains of recurrent convulsions, Personality changes and some motor activity deficit and loss of few senses. On examination we can reveal defect in cranial nerve functions, Motor or sensory deficits, loss of reflexes and coordination. Then Investigations being the next step for diagnosis, We ask the patient to undergo for a test for Blood Biomarkers and CSF analysis in case of suspection of metastatic Brain tumors. Biopsy to obtain for Histopathological Examination. Histopathological examination is done for analysis of genetic mutations and molecular markers. The other imaging techniques like MRI, MRS, CT, PET, EEG are done. This gives a clear picture of what actually caused tumor and shows a way for treatment. Now the treatment involves both Medical and Surgical treatment. Medical treatment includes Chemotherapy along with radiation therapy where the drugs given are Temozolomide and targeted therapy included EGFR BRAF inhibitors for glioblastoma and low grade gliomas respectively. Tumor treating fields- Optune is given. Surgical treatment involves Craniotomy for removal of primary Brain tumors, Neuro Endoscopy if tumor is present in ventricles or base of Brain, Laser interstitial Thermal therapy for deap seated and recurrent brain tumors. This is all about the treatment and now the patient management is very important for further clinical help. Physical, occupational and speech therapy helps patients recover. Symptomatic approach for inoperable tumors Provide comprehensive support for patients nearing end of life, Emphasise confidence and Quality of life.

EPID-11. RATES OF CRANIOTOMIES FOR BRAIN METASTASES AFTER INTRODUCTION OF IMMUNOTHERAPY

Abstract Immunotherapy has revolutionized the treatment paradigm for patients with brain metastases and has been found to prolong overall survival. We sought to determine whether rates of craniotomies for the treatment of brain metastases has decreased since the introduction of immunotherapy into routine treatment regimens. Pathology records were queried at our institution from 2011-2022 to include all patients surgically treated for brain metastases. A total of 885 samples from 789 unique patients were analyzed. National data was queried from the NSQIP database from 2011-2022 to include patients surgically treated for brain metastases with a total of 14,494 cases. A Craniotomy for Metastases Index (CMI) was generated to reflect the total number of craniotomies performed over time. The most common institutional primary cancers were lung (46.1%), breast (17.4%), and gastrointestinal (10.1%), with the most common lung cancers being adenocarcinoma (57.11%) and non-small cell carcinoma (11.52%). The institutional CMI demonstrated a non-significant decrease in the number of craniotomies (R2=0.0545, p=0.46) across all time ranges, as well as no significant change in CMI when comparing rates from 2011-2016 and 2017-2022 (p=0.37). The national CMI demonstrated a significantly positive slope of 0.03 (R2=0.544, p=0.006), as well as a significant increase (p=0.005) in craniotomies when comparing rates from 2011-2016 and 2017-2022. Despite the growing use and efficacy of immunotherapy in the treatment of brain metastases and increasing overall survival, the rates of craniotomies had no change institutionally and increased nationally. Several reasons for these findings may include: longer overall survival of patients with systemic cancer can lead to the development of metastatic brain tumors later in their disease course, improvement of surgical techniques making resection safer, and variable response of patients to stereotactic radiosurgery (SRS). Further studies should be conducted to determine the effect of SRS on these findings. Surgical resection remains the mainstay in the treatment of brain metastases.

Immunotherapeutic and Targeted Strategies for Managing Brain Metastases from Common Cancer Origins: A State-of-the-Art Review.

This review examines contemporary strategies for managing brain metastases (BM) from common cancers such as lung, breast, and melanoma. We evaluate the efficacy and applicability of targeted therapies and immunotherapies, exploring their potential to cross the blood-brain barrier and improve patient outcomes. Recent studies have shown that tyrosine kinase inhibitors, immune checkpoint inhibitors, and ADCs effectively treat BM. These treatments can overcome the challenges posed by the blood-brain barrier and improve therapeutic outcomes. ADCs are promising because they can deliver cytotoxic agents directly to tumor cells, which reduces systemic toxicity and increases drug delivery efficiency to the brain. Personalized medicine is becoming increasingly significant in treatment decisions, with biomarkers playing an essential role. Advances in molecular genetics and drug development have led to more refined treatments, emphasizing the precision medicine framework. The management of BM is evolving, driven by drug efficacy, resistance mechanisms, and the need for personalized medicine. Integrating ADCs into treatment regimens represents a significant advancement in targeting metastatic brain tumors. Despite these advances, BM management still presents considerable challenges, requiring ongoing research and multi-institutional trials to optimize therapeutic strategies. This review outlines the current state and future directions in treating BM, highlighting the critical need for continued innovation and comprehensive clinical evaluations to improve survival rates and quality of life for affected patients.

Distinguishing clinical and imaging characteristics of primary central nervous system lymphoma from high-grade glioma and metastatic brain tumors.

The purpose of this retrospective analysis was to evaluate the clinical presentations, radiological characteristics, patient outcomes, and therapeutic approaches among individuals diagnosed with primary central nervous system lymphoma (PCNSL), high-grade glioma (HGG), and metastatic brain tumors (METS). We assembled a cohort of brain tumor patients from two medical centers, with two oncologists independently reviewing their clinical profiles. A retrospective examination of 87 PCNSL, 87 HGG, and 71 METS cases was performed to assess the aforementioned parameters. Notable variations were identified in the incidence of epileptic seizures and cognitive impairments between PCNSL and METS patients. Cerebral hemisphere involvement was predominantly observed in HGG and METS cases. PCNSL cases exhibited a higher likelihood of multiple lesions, whereas HGG showed a greater tendency for recurrence. The median survival times were established at 24.3months for PCNSL, 44.5months for HGG, and 27.1months for METS patients. In PCNSL cases, the number of lesions was identified as a significant predictor of mortality (P = 0.008). Our findings highlight the importance of clinical and imaging features in diagnosing PCNSL, which may present distinct features compared to HGG and METS.

ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.

Brain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchyma in vivo. Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical for in vivo breast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growth ex vivo and in vivo . These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.

An intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in patients with metastatic or primary brain tumors.

Eribulin is an inhibitor of microtubule dynamics. It is not as highly protein bound as the taxanes and is less vulnerable to extrusion by P-glycoprotein in the blood-brain barrier (BBB). These features predict that eribulin could play an active role in managing brain tumors. Indeed, the small amount of published clinical data indicates eribulin may have some efficacy against breast cancer brain metastases. To better understand the potential of eribulin for treating brain tumors, we performed an intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in cancer patients undergoing tumor resection. After tumor removal, two microdialysis catheters were inserted into peritumoral brain tissue. Approximately 24h after surgery, a single dose of eribulin 1.4mg/m2 was administered intravenously. Dialysate samples were collected continuously for 72h, with plasma samples collected in parallel. Eribulin concentrations were analyzed by tandem mass spectrometry. Dialysate samples from 12 intracerebral microdialysis catheters placed in 7 study participants were included in the analysis. A statistically significant difference was observed between eribulin concentrations in brain tissue where BBB was disrupted versus intact, with a difference in mean maximum concentrations on log2 scale of 3.37 (std err = 0.59, p-value = 0.005). Nonetheless, overall brain to plasma ratios of eribulin only ranged from 0.13 to 1.99%. Although we could detect higher concentrations of eribulin in brain tissue where BBB was disrupted, intracerebral eribulin levels were not sufficient to predict eribulin would have consistent clinically meaningful activity against tumors in the brain. NCT02338037 (January 9, 2015).

Endoscope-assisted treatment for delayed cystic radiation necrosis after stereotactic radiosurgery for metastatic brain tumors: illustrative cases.

Cystic formation due to radiation necrosis in metastatic brain tumors is a rare condition. Surgical intervention is necessary if symptoms develop. Additionally, excising radiation necrosis lesions within the cyst is essential to prevent recurrence. Neuroendoscopic surgery is a minimally invasive method suitable for treating cystic diseases and accessing deep lesions in the brain. The authors herein present a method for removing radiation necrotic tissue from deep lesions of cystic radiation necrosis using neuroendoscopy. Endoscopic surgery was performed in two patients with symptomatic cystic radiation necrosis. Both cases involved multilocular cysts, with radiation necrosis located deep within the cyst. The authors performed a small craniotomy of approximately 3 cm and opened the cyst. After removing its contents, an endoscope was used to closely observe the interior of the cyst. Removal of the septum within the cyst allowed the endoscope to be inserted deeply. The authors identified and excised the nodular lesion diagnosed as radiation necrosis in the deep tissue. Following the surgery, the cyst shrank rapidly, and symptoms disappeared. Both patients showed no recurrence of the lesions. The authors performed minimally invasive surgery and achieved good outcomes. Endoscopic surgery was considered beneficial for treating cystic radiation necrosis. https://thejns.org/doi/10.3171/CASE24250.

Multi-Site Benchmark Study for Standardized Relative Cerebral Blood Volume in Untreated Brain Metastases Using the DSC-MRI Consensus Acquisition Protocol.

A national consensus recommendation for the collection of DSC (dynamic susceptibility contrast) MRI perfusion data, used to create maps of relative cerebral blood volume (rCBV), has been recently established for primary and metastatic brain tumors. The goal was to reduce inter-site variability and improve ease of comparison across time and sites, fostering widespread use of this informative measure. To translate this goal into practice the prospective collection of consensus DSC-MRI data and characterization of derived rCBV maps in brain metastases is needed. The purpose of this multi-site study was to determine rCBV in untreated brain metastases in comparison to glioblastoma and normal appearing brain using the national consensus protocol. Subjects from three sites with untreated enhancing brain metastases underwent DSC-MRI according to a recommended option that uses a mid-range flip angle, GRE-EPI acquisition and the administration of both a pre-load and 2nd DSC-MRI dose of 0.1 mmol/kg GBCA. Quantitative maps of standardized rCBV (sRCBV) were generated and enhancing lesion ROIs determined from post-contrast T1-weighted images alone or calibrated difference maps, termed delta T1 (dT1) maps. Mean sRCBV for metastases were compared to normal appearing white matter (NAWM) and glioblastoma (GBM) from a previous study. Comparisons were performed using either the Wilcoxon signed-rank test for paired comparisons or the Mann-Whitney nonparametric test for unpaired comparisons. 49 patients with a primary histology of lung (n=25), breast (n=6), squamous cell carcinoma (SCC) (n=1), melanoma (n=5), gastrointestinal (GI) (n=3) and genitourinary (GU) (n=9) were included in comparison to GBM (n=31). The mean sRCBV of all metastases (1.83+/-1.05) were significantly lower (p=0.0009) than mean sRCBV for GBM (2.67±1.34) with both statistically greater (p<0.0001) than NAWM (0.68 +/- 0.18). Histologically distinct metastases are each statistically greater than NAWM (p<0.0001) with lung (p=0.0002) and GU (p=.02) sRCBV being significantly different than GBM sRCBV. 49 patients with a primary histology of lung (n=25), breast (n=6), squamous cell carcinoma (SCC) (n=1), melanoma (n=5), gastrointestinal (GI) (n=3) and genitourinary (GU) (n=9) were included in comparison to GBM (n=31). The mean sRCBV of all metastases (1.83+/-1.05) were significantly lower (p=0.0009) than mean sRCBV for GBM (2.67+1.34) with both statistically greater (p<0.0001) than NAWM (0.68 +/- 0.18). Histologically distinct metastases are each statistically greater than NAWM (p<0.0001) with lung (p=0.0002) and GU (p=.02) sRCBV being significantly different than GBM sRCBV. dT1=delta T1; GBCA=gadolinium-based contrast agent; NAWM=normal appearing white matter; normalized relative cerebral blood volume=nRCBV; relative cerebral blood volume=rCBV; standardized relative cerebral blood volume=sRCBV.

Neural Influences on Tumor Progression Within the Central Nervous System.

For decades, researchers have studied how brain tumors, the immune system, and drugs interact. With the advances in cancer neuroscience, which centers on defining and therapeutically targeting nervous system-cancer interactions, both within the local tumor microenvironment (TME) and on a systemic level, the subtle relationship between neurons and tumors in the central nervous system (CNS) has been deeply studied. Neurons, as the executors of brain functional activities, have been shown to significantly influence the emergence and development of brain tumors, including both primary and metastatic tumors. They engage with tumor cells via chemical or electrical synapses, directly regulating tumors or via intricate coupling networks, and also contribute to the TME through paracrine signaling, secreting proteins that exert regulatory effects. For instance, in a study involving a mouse model of glioblastoma, the authors observed a 42% increase in tumor volume when neuronal activity was stimulated, compared to controls (p < 0.01), indicating a direct correlation between neural activity and tumor growth. These thought-provoking results offer promising new strategies for brain tumor therapies, highlighting the potential of neuronal modulation to curb tumor progression. Future strategies may focus on developing drugs to inhibit or neutralize proteins and other bioactive substances secreted by neurons, break synaptic connections and interactions between infiltrating cells and tumor cells, as well as disrupt electrical coupling within glioma cell networks. By harnessing the insights gained from this research, we aspire to usher in a new era of brain tumor therapies that are both more potent and precise.

Metastatic prostate adenocarcinoma to the brain – a clinicopathologic analysis of 21 cases

BackgroundBrain metastasis from prostate adenocarcinoma (PCa) is rare, often leading to death within a year. Its infrequent occurrence and atypical histopathologic features contribute to lower consideration in the differential diagnosis of tumor brain metastasis. This study aims to assess the clinical characteristics and distinctive histopathologic features of metastatic PCa in the brain for timely and enhanced diagnostic accuracy.DesignA retrospective search spanning 20 years (2003–2022) was conducted on our archives and identified 21 cases diagnosed as “metastatic prostate adenocarcinoma (mPCa)” in brain biopsies and resections. All existing slides were thoroughly reviewed to evaluate the histopathology of the mPCa.ResultThe mean age at presentation for brain metastasis was 70 years. Of 21 cases, 5 were dural-based lesions, 16 were true intraparenchymal metastases, including 2 sellar/suprasellar masses, 3 frontal, 3 temporal, 3 occipital, 1 cerebellum, and 4 involving multiple brain lobes. The average interval between initial diagnosis and brain metastasis was 90.75 months. Notably, brain metastasis was the initial presentation for one patient, while another patient, initially diagnosed with prognostic grade group (GG) 2 PCa in 1/12 cores, presented with isolated brain metastasis two years later. Architecturally, tumor cells were arranged in sheets or nests in most cases; however, four cases showed histologic cribriform patterns, and five displayed papillary architecture. Cytohistology varied from uniform monomorphic to highly pleomorphic cells with prominent nucleoli (8/19) and high mitotic activity. Interestingly, 1 case showed small round blue cell morphology, another had focal areas of rhabdoid and spindle cell differentiation, and 6 had cytoplasmic clearing. Almost half of the cases (47%) showed necrosis.ConclusionmPCa to the brain can present with variable histomorphology. Therefore, consideration of mPCa in the differential diagnosis of metastatic brain lesions, even with non-suggestive imaging, is imperative in male patients with or without a history of primary disease. Accurate and prompt diagnosis is crucial, given the recent advancements in treatment that have improved survival rates.

Single-cell map of diverse immune phenotypes in the metastatic brain tumor microenvironment of non-small-cell lung cancer

Single-cell map of diverse immune phenotypes in the metastatic brain tumor microenvironment of non-small-cell lung cancer

Instrumental activities of daily living in neuro-oncology: International validation of the EORTC IADL-BN32 questionnaire

BackgroundNeurocognitive impairments are common in patients with a brain tumour, and may negatively impact on functioning in daily life, particularly on instrumental activities of daily living (IADL). The EORTC IADL-BN32 questionnaire was developed to measure IADL in this patient population. MethodsIn this international validation study, we evaluated the EORTC IADL-BN32 questionnaire on several psychometric properties in a large sample of patients with a primary or metastatic brain tumour. We administered the 32-item questionnaire three times: at ‘baseline’, after 2 weeks and after 3 months. Procedures were in accordance with EORTC Quality of Life Group module development guidelines. ResultsIn total, 326 patients participated in the study. A bifactor scale structure showed satisfactory model fit measures, with five multi-item scales and two single items, and an IADL sum score. The internal consistency of the multi-item scales ranged from good to excellent (range Cronbach’s α: 0.86–0.97). We found significant differences in scale scores between patients with and without neurocognitive impairments or complaints, supporting the construct validity. Initial cross-cultural validity analyses showed indications of item response biases for certain items. Analyses indicated moderate to good test-retest agreement (intraclass correlation coefficient > 0.70) between baseline and the 2-week follow-up assessment for all but one scale. Deterioration of EORTC IADL-BN32 scale scores were consistent with clinically relevant deterioration on other functional measures with small to large effect sizes, however, subgroup sample sizes were small. ConclusionOverall, the EORTC IADL-BN32 questionnaire exhibited adequate to excellent psychometric properties. Cross-cultural validity and responsiveness should be further explored.

Brain tumoroids: treatment prediction and drug development for brain tumors with fast, reproducible and easy-to-use personalized models.

generation of patient avatar is critically needed in neuro-oncology for treatment prediction and preclinical therapeutic development. Our objective was to develop a fast, reproducible, low-cost and easy-to-use method of tumoroids generation and analysis, efficient for all types of brain tumors, primary and metastatic. tumoroids were generated from 89 patients: 81 primary tumors including 77 gliomas, and 8 brain metastases. Tumoroids morphology, cellular and molecular characteristics were compared with the ones of the parental tumor by using histology, methylome profiling, pTERT mutations and multiplexed spatial immunofluorescences. Their cellular stability overtime was validated by flow cytometry. Therapeutic sensitivity was evaluated and predictive factors of tumoroid generation were analyzed. All the tumoroids analyzed had similar histological (N=21) and molecular features (N=7) than the parental tumor. Median generation time was 5 days. Success rate was 65 %: it was higher for high grade gliomas and brain metastases versus IDH mutated low grade gliomas. For high-grade gliomas, neither other clinical, neuro-imaging, histological nor molecular factors were predictive of tumoroid generation success. The cellular organization inside tumoroids analyzed by MACSima revealed territories dedicated to specific cell subtypes. Finally, we showed the correlation between tumoroid and patient treatment responses to radio-chemotherapy and their ability to respond to immunotherapy thanks to a dedicated and reproducible 3D analysis workflow. patient-derived tumoroid model that we developed offers a robust, user-friendly, low-cost and reproducible preclinical model valuable for therapeutic development of all type of primary or metastatic brain tumors, allowing their integration into forthcoming early-phase clinical trials.