Central Nervous System Disease Progression Research Articles

Abstract PO2-10-08: Contemporary HER2-Positive MBC Treatment Recommendations Among Community Healthcare Professionals: Analysis of an Online Interactive Decision Support Tool

Abstract Background: The management of HER2-positive (HER2+) metastatic breast cancer (MBC) has continued to evolve, with multiple FDA approvals of novel HER2-targeted agents since late 2019. Considering the growing HER2+ MBC treatment armamentarium, we sought to identify current practice patterns among community healthcare professionals (HCPs) for HER2+ MBC by comparing HCP and key opinion leader (KOL) treatment recommendations using an online decision support tool. Methods: An online decision support tool was developed with input from 5 KOLs to provide therapy recommendations for 630 HER2+ MBC patient case scenarios based on conventional considerations including distribution of metastatic disease, treatment history, duration of response, and specific comorbidities. HCP tool users entered specific patient criteria to define a case along with their intended management for each case. The tool then showed 5 KOL recommendations for the user-entered patient case, and the users were asked to indicate if the expert recommendations confirmed or changed their intended approach. An analysis of expert recommendations and user-selected therapy was performed. Results: Between November 2022 and July 2023, 313 patient cases were entered by 242 participating HCPs. HCP and KOL treatment recommendations were frequently discordant (Table). For patients with de novo HER2+ MBC (n = 55), there was strong concordance (63%; P = .0001) between HCP and KOL recommendations. However, weak treatment selection concordance (53%; P < .0001) was observed for patients with disease progression after standard neoadjuvant/adjuvant therapy with chemotherapy plus HER2-targeted agents (n = 57). In the second-line setting, 43% concordance was observed for patients with non‒central nervous system (CNS) disease progression without CNS progression after first-line therapy with THP (n = 67; P < .0001), whereas 61% concordance was observed for patients with non-CNS and CNS disease progression after first-line therapy with THP (n = 61; P < .0001). In the third-line setting, 31% concordance was observed for patients with non-CNS disease progression without CNS progression (n = 32; P < .0001), and 47% concordance was observed for patients with non-CNS and CNS disease progression (n = 19; P = .0009). For HCPs whose treatment plan did not match KOL recommendations in these scenarios, 62% indicated that KOL recommendations confirmed or changed their intended therapy, but 19% indicated that there were barriers to implementing those recommendations. Conclusions: These data suggest ongoing challenges to optimally incorporate novel HER2-targeted therapies in the care of patients with HER2+ MBC, particularly in the second line and beyond, but an online tool providing KOL advice on specific patient scenarios confirmed or changed the clinical approach for a majority of HCPs. Thus, continued development of resources for HCPs, including online decision support tools, may be increasingly important given the rapidly evolving treatment landscape. Table. Summary of Treatment Choices by KOLs or HCPs for Select Patient Scenarios Citation Format: Kristen Rosenthal, Sara Hurvitz, Komal Jhaveri, Heather McArthur, Sara Tolaney, Timothy Quill. Contemporary HER2-Positive MBC Treatment Recommendations Among Community Healthcare Professionals: Analysis of an Online Interactive Decision Support Tool [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-10-08.

A Highly Selective Implantable Electrochemical Fiber Sensor for Real-Time Monitoring of Blood Homovanillic Acid.

Homovanillic acid (HVA) is a major dopamine metabolite, and blood HVA is considered as central nervous system (CNS) dopamine biomarker, which reflects the progression of dopamine-associated CNS diseases and the behavioral response to therapeutic drugs. However, facing blood various active substances interference, particularly structurally similar catecholamines and their metabolites, real-time and accurate monitoring of blood HVA remains a challenge. Herein, a highly selective implantable electrochemical fiber sensor based on a molecularly imprinted polymer is reported to accurately monitor HVA in vivo. The sensor exhibits high selectivity, with a response intensity to HVA 12.6 times greater than that of catecholamines and their metabolites, achieving 97.8% accuracy in vivo. The sensor injected into the rat caudal vein tracked the real-time changes of blood HVA, which paralleled the brain dopamine fluctuations and indicated the behavioral response to dopamine increase. This study provides a universal design strategy for improving the selectivity of implantable electrochemical sensors.

Screening Cerebrospinal Fluid for Aggressive B-Cell Lymphoma: Significance of Clonal Populations Found with 8-Color Flow Cytometry

Background: Secondary central nervous system (CNS) lymphoma confers a poor prognosis, and prompt identification is critical for guiding management. Over the last decade, we have employed cerebrospinal fluid (CSF) analysis with 8-color flow cytometry (FCM) in screening patients deemed at risk of CNS relapse. However, there is little data to guide interpretation and management of positive results, and concurrent clinical and radiographic features of FCM positive (FCM+) patients, remain areas of uncertainty. Methods: We analyzed newly diagnosed (ND) and relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) and high grade B cell lymphoma (HGBCL) patients who underwent a screening lumbar puncture (LP) from 2011-2020. Clinical, imaging, and CSF findings (differential, cytology, FCM) were collected. Patients with prior CNS involvement or FCM showing CLL/low-grade B-NHL were excluded. “FCM-only” patients were defined as FCM+ but without any other evidence of CNS spread (negative cell count/cytology, MRI, and no symptoms), whereas others were deemed to have overt CNS disease. Results: There were 415 LPs among 361 patients (243 ND, 172 R/R). 21 (5%) patients were FCM+, 10 ND and 11 R/R patients (Table 1). Four had FCM-only involvement (2 ND, 2 R/R). Among these, the clonal population was 1.63% of WBC (range, 0.3-2.7%), and 3 had concurrent bone marrow (BM) or peripheral blood (PB) involvement. All 4 received intrathecal (IT) therapy. At median follow up of 23 months, 3 (75%) have died (2 from CNS disease progression, 1 unknown due to loss in follow up), and 1 remains alive in remission 44 months later following IT methotrexate (MTX) and CAR T-cell therapy. 17 had overt CNS disease (8 ND, 9 R/R). The clonal population was 9% (range, 0.2-98%). Eight (47%) had concurrent BM or PB involvement. Twelve (70%) received IV high dose MTX, and the remainder received only IT therapy. At median follow up of 42 months, 9 (53%) have relapsed (2 CNS only, 1 systemic, 6 both), and 9 have died. Median time to CNS relapse was 5 months. Conclusions: CSF 8 color FCM screening of DLBCL/HGBCL patients yields a low proportion of positive results, mostly in the setting of overt CNS disease. However, even FCM-only patients had poor outcomes (2/4 with CNS progression), suggesting that blood contamination does not explain CSF findings, and that these patients should be approached as secondary CNS involvement. Better pt selection for CSF screening is needed to reduce unnecessary LPs. Intensified or novel approaches for all FCM+ patients are needed.

Pertuzumab plus high-dose trastuzumab for HER2-positive breast cancer with brain metastases: PATRICIA final efficacy data

The PATRICIA study (NCT02536339) examined the efficacy and safety of pertuzumab plus high-dose trastuzumab in patients with HER2-positive metastatic breast cancer (MBC) with progressive central nervous system (CNS) metastases following radiotherapy. Primary analysis confirmed CNS objective response rate (ORR) was 11% (95% confidence interval [CI]: 3–25); clinical benefit rate (CBR) was 68% (4 months) and 51% (6 months). We report final efficacy data after a further 21-months of follow-up, updated safety, survival, and patient-reported outcomes (PROs). Patients received standard-dose pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Primary endpoint: confirmed ORR (CNS) per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary endpoints were response duration, CBR, progression-free survival (PFS), overall survival (OS), safety, and PROs. By clinical cut-off, 39 patients had completed or discontinued treatment. Confirmed ORR (CNS) was 11% (95% CI: 3.0–25.4). Median CNS-PFS was 4.6 months (95% CI: 4.0–8.9), as was median CNS-PFS or systemic PFS (95% CI: 4.0–8.9); median OS was 27.2 months (95% CI: 16.1–not reached). CBR in the CNS was 51% (19 patients, 95% CI: 34.4–68.1) at 6 months. Two patients remained on treatment until study closure, achieving stable disease for 4.1 and 4.8 years. Treatment-related grade 3/4 adverse events occurred in 7.7% of patients. Patients with confirmed partial response or stable disease (≥4 months) in the CNS had stable PROs over time. Pertuzumab plus high-dose trastuzumab represents a reasonable non-chemotherapeutic treatment option for selected patients with HER2-positive MBC with CNS metastases.

The Interplay between Mitochondrial Dysfunction and Ferroptosis during Ischemia-Associated Central Nervous System Diseases.

Cerebral ischemia, a leading cause of disability and mortality worldwide, triggers a cascade of molecular and cellular pathologies linked to several central nervous system (CNS) disorders. These disorders primarily encompass ischemic stroke, Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and other CNS conditions. Despite substantial progress in understanding and treating the underlying pathological processes in various neurological diseases, there is still a notable absence of effective therapeutic approaches aimed specifically at mitigating the damage caused by these illnesses. Remarkably, ischemia causes severe damage to cells in ischemia-associated CNS diseases. Cerebral ischemia initiates oxygen and glucose deprivation, which subsequently promotes mitochondrial dysfunction, including mitochondrial permeability transition pore (MPTP) opening, mitophagy dysfunction, and excessive mitochondrial fission, triggering various forms of cell death such as autophagy, apoptosis, as well as ferroptosis. Ferroptosis, a novel type of regulated cell death (RCD), is characterized by iron-dependent accumulation of lethal reactive oxygen species (ROS) and lipid peroxidation. Mitochondrial dysfunction and ferroptosis both play critical roles in the pathogenic progression of ischemia-associated CNS diseases. In recent years, growing evidence has indicated that mitochondrial dysfunction interplays with ferroptosis to aggravate cerebral ischemia injury. However, the potential connections between mitochondrial dysfunction and ferroptosis in cerebral ischemia have not yet been clarified. Thus, we analyzed the underlying mechanism between mitochondrial dysfunction and ferroptosis in ischemia-associated CNS diseases. We also discovered that GSH depletion and GPX4 inactivation cause lipoxygenase activation and calcium influx following cerebral ischemia injury, resulting in MPTP opening and mitochondrial dysfunction. Additionally, dysfunction in mitochondrial electron transport and an imbalanced fusion-to-fission ratio can lead to the accumulation of ROS and iron overload, which further contribute to the occurrence of ferroptosis. This creates a vicious cycle that continuously worsens cerebral ischemia injury. In this study, our focus is on exploring the interplay between mitochondrial dysfunction and ferroptosis, which may offer new insights into potential therapeutic approaches for the treatment of ischemia-associated CNS diseases.

Biogenesis, function, and landscape of tsRNAs in central nervous system diseases

AbstractTransfer RNA‐derived small RNAs (tsRNAs) are fragments that originate from mature or precursor tRNAs and are a subclass of sRNAs. With the development of high‐throughput sequencing techniques, the real feature of tsRNAs has gradually been revealed. tsRNAs are functional fragments of distinct lengths produced by the cleavage of mature or precursor tRNAs by different ribonuclease enzymes. tsRNAs exert extensive functions, including gene silencing, translational regulation, and reverse transcriptional regulation, affecting cell viability and differentiation and participating in pathological processes of various diseases, including central nervous system (CNS) diseases. Emerging sequencing evidence indicates that tsRNAs are expressed differently in various CNS diseases, preliminary suggesting that tsRNAs are involved in the occurrence and progression of neurodegenerative diseases, stroke, glioma, epilepsy, and other CNS diseases. In addition, significant differences expression of extracellular tsRNAs in circulating or cerebrospinal fluid between patients and normal individuals have demonstrated the diagnostic and prognostic value of tsRNAs as biomarkers for liquid biopsy. In this review, we provide a detailed summary of the biogenesis, function, and chemical modification of tsRNAs, focusing on the current status and prospects of research on tsRNAs in neurodegenerative diseases, stroke, glioma, epilepsy, and others.

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer.

Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+NSCLC patients. Patients who started treatment with osimertinib for EGFRm+NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p=0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p=0.010). ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. No funding was received for this trial.

Research progress on acupuncture treatment in central nervous system diseases based on NLRP3 inflammasome in animal models.

Central nervous system (CNS) disorders exhibit complex neurophysiological and pathological mechanisms, which seriously affect the quality of life in patients. Acupuncture, widely accepted as complementary and alternative medicine, has been proven to exert significant therapeutic effects on CNS diseases. As a part of the innate immune system, NLRP3 inflammasome contributes to the pathogenesis of CNS diseases via regulating neuroinflammation. To further explore the mechanisms of acupuncture regulating NLRP3 inflammasome in CNS diseases, our study focused on the effects of acupuncture on neuroinflammation and the NLRP3 inflammasome in vascular dementia, Alzheimer's disease, stroke, depression, and spinal cord injury. This study confirmed that the activation of NLRP3 inflammasome promotes the development of CNS diseases, and inhibiting the activation of NLRP3 inflammasome is a potential key target for the treatment of CNS diseases. In addition, it is concluded that acupuncture alleviates neuroinflammation by inhibiting the activation of the NLRP3 inflammasome pathway, thereby improving the progression of CNS diseases, which provides a theoretical basis for acupuncture to attenuate neuroinflammation and improve CNS diseases.

Exogenous Players in Mitochondria-Related CNS Disorders: Viral Pathogens and Unbalanced Microbiota in the Gut-Brain Axis.

Billions of years of co-evolution has made mitochondria central to the eukaryotic cell and organism life playing the role of cellular power plants, as indeed they are involved in most, if not all, important regulatory pathways. Neurological disorders depending on impaired mitochondrial function or homeostasis can be caused by the misregulation of "endogenous players", such as nuclear or cytoplasmic regulators, which have been treated elsewhere. In this review, we focus on how exogenous agents, i.e., viral pathogens, or unbalanced microbiota in the gut-brain axis can also endanger mitochondrial dynamics in the central nervous system (CNS). Neurotropic viruses such as Herpes, Rabies, West-Nile, and Polioviruses seem to hijack neuronal transport networks, commandeering the proteins that mitochondria typically use to move along neurites. However, several neurological complications are also associated to infections by pandemic viruses, such as Influenza A virus and SARS-CoV-2 coronavirus, representing a relevant risk associated to seasonal flu, coronavirus disease-19 (COVID-19) and "Long-COVID". Emerging evidence is depicting the gut microbiota as a source of signals, transmitted via sensory neurons innervating the gut, able to influence brain structure and function, including cognitive functions. Therefore, the direct connection between intestinal microbiota and mitochondrial functions might concur with the onset, progression, and severity of CNS diseases.

Vesicular Glutamate Transporters in Astrocytes as Potential New Therapeutic Targets: Astrocyte-targeted Viral Vectors Expressing Inhibitory Nanobodies

Astrocytes, the main Central Nervous System (CNS) glial cell type, actively release transmitters, including glutamate, and thereby participate in physiological brain information processing. However, dysregulated transmitter release from astrocytes can contribute to CNS disease pathogenesis and progression. Therefore, targeting astrocyte glutamate release is a promising new therapeutic strategy in hyper-glutamatergic brain conditions, as it does not directly block glutamatergic neurotransmission. Basing on the evidence that astrocytes express Vesicular Glutamate Transporters (VGLUT), in collaboration with other NCCR TransCure partners, we developed an innovative approach for astrocyte-selective delivery of nanobodies inhibiting VGLUT. We inserted the anti-VGLUT nanobody constructs in astrocyte-directed viral vectors that were administered peripherally, crossed the blood-brain-barrier and led to successful cell-specific CNS-wide expression of the nanobodies.

Risk of Radiation Pneumonitis in Patients Receiving Osimertinib and Thoracic Radiotherapy

Risk of Radiation Pneumonitis in Patients Receiving Osimertinib and Thoracic Radiotherapy

Real-Time Dynamic Collection of Hippocampal Extracellular Fluid from Conscious Rats Using a Microdialysis System.

A variety of central nervous system (CNS) diseases are associated with changes in the composition of hippocampal extracellular fluid (HECF). However, difficulty in obtaining HECF in real time from conscious rats has long restricted the evaluation of CNS disease progression and the effectiveness of ethnomedicine therapy. Encouragingly, a brain microdialysis technique can be used for continuous sampling with the advantages of dynamic observation, quantitative analysis, and a small sampling size. This allows the monitoring of changes in the extracellular fluid content for compounds from traditional herbs and their metabolites in the brain of living animals. The aim of this study was thus to accurately implant a cerebrospinal fluid microdialysis probe into the hippocampal region of Sprague Dawley (SD) rats with a three-dimensional brain stereotaxic apparatus, cutting off molecular weights greater than 20 kDa. The high-quality HECF was then obtained from conscious rats using a microdialysis sampling control system with an adjustable sampling rate from 2.87 nL/min - 2.98 mL/min. In conclusion, our protocol provides an efficient, rapid, and dynamic method to obtain HECF in awake rats with the help of microdialysis technology, which provides us with unlimited possibilities to further explore the pathogenesis of CNS-related diseases and evaluate drug efficacy.

Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression.

Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the progression of multiple tumors and CNS diseases. However, the relationships between pyroptosis and clinical prognosis and immune cell infiltration are unclear in glioma. In this study, we conducted a comprehensive exploration of pyroptosis in glioma. First, prognosis-related genes were screened at each key regulatory locus in the pyroptosis pathway, and the prognostic ability and coexpression relationships of GSDMD and its upstream pathway genes NLRC4/CASP1/CASP4 were identified and well validated in multiple datasets. Tissue microarray-based immunohistochemistry results showed higher levels of NLRC4 and N-terminal GSDMD in high-grade gliomas, providing conclusive evidence of pyroptosis in gliomas. The robustness of the prognostic model based on these four genes was well validated in TCGA and CGGA cohorts. Bulk RNA-seq-based analysis showed that the group defined as the high-risk group according to the model showed activation of multiple inflammatory response pathways and impaired synaptic gene expression and had a higher infiltration of bone marrow-derived macrophages (BMDMs) and a hypersuppressed immune microenvironment. More importantly, three independent single-cell RNA-seq (scRNA-seq) datasets demonstrated that tumor-infiltrating macrophages, particularly BMDMs but not tissue-resident microglia, showed significant coexpression of the GSDMD and CASP genes, and BMDMs from high-grade gliomas accounted for a higher proportion of immune infiltrating cells and had higher expression of pyroptosis genes. Finally, we revealed the activation of pathways in response to LPS/bacteria and oxidative stress during BMDM development toward the pyroptosis cell fate by pseudotime trajectory analysis, suggesting potential BMDM pyroptosis initiators. The above results provide not only novel insights into the pathological mechanisms of glioma but also novel therapeutic targets for glioma, suggesting the potential application of pyroptosis inhibitors (e.g., disulfiram).

Toward the next generation of vascularized human neural organoids.

Thanks to progress in the development of three-dimensional (3D) culture technologies, human central nervous system (CNS) development and diseases have been gradually deciphered by using organoids derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs). Selforganized neural organoids (NOs) have been used to mimic morphogenesis and functions of specific organs in vitro. Many NOs have been reproduced in vitro, such as those mimicking the human brain, retina, and spinal cord. However, NOs fail to capitulate to the maturation and complexity of in vivo neural tissues. The persistent issues with current NO cultivation protocols are inadequate oxygen supply and nutrient diffusion due to the absence of vascular networks. In vivo, the developing CNS is interpenetrated by vasculature that not only supplies oxygen and nutrients but also provides a structural template for neuronal growth. To address these deficiencies, recent studies have begun to couple NO culture with bioengineering techniques and methodologies, including genetic engineering, coculture, multidifferentiation, microfluidics and 3D bioprinting, and transplantation, which might promote NO maturation and create more functional NOs. These cutting-edge methods could generate an ever more reliable NO model in vitro for deciphering the codes of human CNS development, disease progression, and translational application. In this review, we will summarize recent technological advances in culture strategies to generate vascularized NOs (vNOs), with a special focus on cerebral- and retinal-organoid models.

Comparative Efficacy of Tyrosine Kinase Inhibitors and Antibody-Drug Conjugates in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A Systematic Review and Network Meta-Analysis.

Simple SummaryComparisons between the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs) in treating HER2-positive breast cancer brain metastasis (BCBM) patients have not previously been conducted. We performed a systematic review and Bayesian-based network meta-analysis to pool the estimates of progression-free survival, overall survival, and incidence of central nervous system (CNS) disease progression. The current study indicated that both T-DXd and T-DM1 presented better efficacy than TKIs regarding survival outcomes. Treatments containing neratinib or T-DM1 tended to rank the best in reducing the recurrent rate of CNS. Our study provides more evidence for the clinical decision making for patients with HER2-positive BCBM. More high-quality studies with standardized entry criteria and comparable CNS-related endpoints are warranted in the future.HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs), two categories of emerging agents in this field. We implemented a comprehensive literature search of PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences. A network meta-analysis following Bayesian approaches was performed. Pooled hazard ratios (HRs) and odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate progression-free survival (PFS), overall survival (OS), and the incidence of central nervous system (CNS) disease progression. Sixteen studies were included. Pairwise comparisons of PFS showed salient divergency between T-DXd and the physician’s choice of treatment (HR 0.17; 95% CrI 0.03–0.82) or afatinib (HR 0.14; 95% CrI 0.02–1.00). T-DXd and T-DM1 ranked first regarding PFS and OS, respectively, followed by TKI-containing regimens. The incidence of CNS disease progression was analyzed separately according to baseline BCBM status, among which neratinib-containing regimens were most likely to rank the best. In conclusion, ADCs including T-DXd and T-DM1 showed better efficacy than TKIs in the survival outcomes for HER2-positive BCBM patients. Treatments based on neratinib or T-DM1 revealed favorable results in reducing the recurrent rate of CNS.

Challenges in central nervous system drug development：What pharmaceutical corporations are seeking

The science and technology infrastructure in drug discovery for central nervous system (CNS) diseases and disorders has been greatly developed over the past decade. Various hypotheses have been proposed about the pathogenesis and progression of CNS diseases and disorders, and efforts to develop new drugs for rare diseases are also becoming active. The drug modalities have expanded from small molecules to medium molecules, antibodies, proteins, nucleic acids, cells, and even digital, and the drug discovery process is changing dramatically. Drug discovery researchers require a wide variety of specialized knowledge and techniques. As research tools such as human induced pluripotent stem cells and genetically modified animals become increasingly complex, it is often difficult to prepare and procure them within a pharmaceutical corporation. Furthermore, patient stratification in clinical studies and translational research to predict the efficacy of drug candidates have become important pillars in drug discovery research. Under such circumstances, it is becoming difficult for pharmaceutical corporations to complete all elements necessary for drug discovery research on their own, and collaboration with partners with expertise is becoming essential to improve the quality and speed of research. In this presentation, I would like to introduce what corporations are seeking, hoping that this symposium will generate some ideas for new approaches and collaborations.

Roles of Ependymal Cells in the Physiology and Pathology of the Central Nervous System.

Ependymal cells are indispensable components of the central nervous system (CNS). They originate from neuroepithelial cells of the neural plate and show heterogeneity, with at least three types that are localized in different locations of the CNS. As glial cells in the CNS, accumulating evidence demonstrates that ependymal cells play key roles in mammalian CNS development and normal physiological processes by controlling the production and flow of cerebrospinal fluid (CSF), brain metabolism, and waste clearance. Ependymal cells have been attached to great importance by neuroscientists because of their potential to participate in CNS disease progression. Recent studies have demonstrated that ependymal cells participate in the development and progression of various neurological diseases, such as spinal cord injury and hydrocephalus, raising the possibility that they may serve as a potential therapeutic target for the disease. This review focuses on the function of ependymal cells in the developmental CNS as well as in the CNS after injury and discusses the underlying mechanisms of controlling the functions of ependymal cells.

POSB151 Brigatinib As a Leading Option to Manage Previously Not Treated Patients with Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer (ALK+ NSCLC) in Portugal

ALK+ NSCLC is an aggressive subtype of lung cancer with high rates of Central Nervous System (CNS) metastasis, with 15-35% of patients presenting brain metastases at diagnosis, leading to a major clinical burden and a high economic impact on national healthcare systems (NHS). Crizotinib, a first-generation tyrosine kinase inhibitor (TKI), currently used in the Portuguese setting as first-line (1L) treatment, has shown limited CNS efficacy – 70% of patients experience CNS disease progression during treatment with crizotinib.

PPARα Modulation-Based Therapy in Central Nervous System Diseases

The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.

Gliotoxicity and Glioprotection: the Dual Role of Glial Cells.

Glial cells (astrocytes, oligodendrocytes and microglia) are critical for the central nervous system (CNS) in both physiological and pathological conditions. With this in mind, several studies have indicated that glial cells play key roles in the development and progression of CNS diseases. In this sense, gliotoxicity can be referred as the cellular, molecular, and neurochemical changes that can mediate toxic effects or ultimately lead to impairment of the ability of glial cells to protect neurons and/or other glial cells. On the other hand, glioprotection is associated with specific responses of glial cells, by which they can protect themselves as well as neurons, resulting in an overall improvement of the CNS functioning. In addition, gliotoxic events, including metabolic stresses, inflammation, excitotoxicity, and oxidative stress, as well as their related mechanisms, are strongly associated with the pathogenesis of neurological, psychiatric and infectious diseases. However, glioprotective molecules can prevent or improve these glial dysfunctions, representing glial cells-targeting therapies. Therefore, this review will provide a brief summary of types and functions of glial cells and point out cellular and molecular mechanisms associated with gliotoxicity and glioprotection, potential glioprotective molecules and their mechanisms, as well as gliotherapy. In summary, we expect to address the relevance of gliotoxicity and glioprotection in the CNS homeostasis and diseases.