Search Results (103)

Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, plays a central oncogenic role in the initiation and progression of diverse malignancies. Aberrant ALK activation generally results from structural alterations or dysregulated expression, leading to persistent activation of downstream signaling pathways that drive tumor cell proliferation, survival, and metastasis. ALK gene abnormalities predominantly encompass fusions, point mutations, and amplifications, with EML4-ALK-positive non–small cell lung cancer representing a canonical example. The advent of ALK-targeted inhibitors has constituted a major therapeutic milestone for ALK-positive tumors. From first-generation Crizotinib to third-generation Lorlatinib, successive agents have been refined for target selectivity, central nervous system penetration, and coverage of resistance-associated mutations, substantially improving patient survival and intracranial disease control. Nonetheless, the emergence of acquired resistance remains an overarching challenge, mediated by secondary kinase domain mutations, activation of bypass signaling pathways, and tumor phenotypic transformation. This review presents an integrative synthesis of ALK-targeted therapeutic developments, elucidates underlying resistance mechanisms, and surveys emerging strategies, providing a comprehensive perspective on current advances and future directions in precision management of ALK-driven malignancies. Full article

Objectives: The potential use of electron density (ED) and effective atomic number (Zeff) derived from dual-energy computed tomography (DECT) as novel quantitative imaging biomarkers for differentiating malignant brain tumors was investigated. Methods: Data pertaining to 136 patients with a pathological diagnosis of brain metastasis (BM), glioblastoma, and primary central nervous system lymphoma (PCNSL) were retrospectively reviewed. The 10th percentile, mean and 90th percentile values of conventional 120-kVp CT value (CTconv), ED, Zeff, and relative apparent diffusion coefficient derived from diffusion-weighted magnetic resonance imaging (rADC: ADC of lesion divided by ADC of normal-appearing white matter) within the contrast-enhanced tumor region were compared across the three groups. Furthermore, machine learning (ML)-based diagnostic models were developed to maximize diagnostic performance for each tumor classification using the indices of DECT parameters and rADC. Machine learning models were developed using the AutoGluon-Tabular framework with rigorous patient-level data splitting into training (60%), validation (20%), and independent test sets (20%). Results: The 10th percentile of Zeff was significantly higher in glioblastomas than in BMs (p = 0.02), and it was the only index with a significant difference between BMs and glioblastomas. In the comparisons including PCNSLs, all indices of CTconv, Zeff, and rADC exhibited significant differences (p < 0.001–0.02). DECT-based ML models exhibited high area under the receiver operating characteristic curves (AUC) for all pairwise differentiations (BMs vs. Glioblastomas: AUC = 0.83; BMs vs. PCNSLs: AUC = 0.91; Glioblastomas vs. PCNSLs: AUC = 0.82). Combined models of DECT and rADC demonstrated excellent diagnostic performance between BMs and PCNSLs (AUC = 1) and between Glioblastomas and PCNSLs (AUC = 0.93). Conclusion: This study suggested the potential of DECT-derived ED and Zeff as novel quantitative imaging biomarkers for differentiating malignant brain tumors. Full article

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. This review explains the connections between the genesis and progression of GBM and particular cellular tumorigenic mechanisms, such as angiogenesis, invasion, migration, growth factor overexpression, genetic instability, and apoptotic disorders, as well as possible therapeutic targets that help predict the course of the disease. Glioblastoma multiforme (GBM) diagnosis relies heavily on histopathological features, molecular markers, extracellular vesicles, neuroimaging, and biofluid-based glial tumor identification. In order to improve miRNA stability and stop the proliferation of cancer cells, nanoparticles, magnetic nanoparticles, contrast agents, gold nanoparticles, and nanoprobes are being created for use in cancer treatments, neuroimaging, and biopsy. Targeted nanoparticles can boost the strength of an MRI signal by about 28–50% when compared to healthy tissue or controls in a preclinical model like mouse lymph node metastasis. Combining the investigation of CNAs and noncoding RNAs with deep learning-driven global profiling of genes, proteins, RNAs, miRNAs, and metabolites presents exciting opportunities for creating new diagnostic markers for malignancies of the central nervous system. Artificial intelligence (AI) advances precision medicine and cancer treatment by enabling the real-time analysis of complex biological and clinical data through wearable sensors and nanosensors; optimizing drug dosages, nanomaterial design, and treatment plans; and accelerating the development of nanomedicine through high-throughput testing and predictive modeling. Full article

A woman in her 40s with a history of ER/PR+, HER2-negative breast cancer presented with a seizure three years after mastectomy. Magnetic resonance imaging (MRI) revealed a right caudate head mass, which was concerning for either high-grade glioma or metastatic disease, but biopsy was deemed too high risk. Cerebrospinal fluid (CSF) tumor-derived DNA (tDNA) analysis by next-generation sequencing (NGS) was ordered, revealing a gain-of-function variant in PIK3CA, ERBB2 copy number gain, and high aneuploidy, findings consistent with breast cancer brain metastasis. Based on these results, the patient was treated with stereotactic radiosurgery (SRS) followed by trastuzumab deruxtecan, a HER2-targeted therapy. This case highlights the diagnostic and therapeutic value of CSF tDNA analysis in central nervous system (CNS) lesions when biopsy is not feasible. The report also illustrates how clonal evolution, such as acquired ERBB2 amplification, can occur in metastatic disease and influence treatment decisions. Full article

Breast cancer is a leading cause of central nervous system (CNS) metastases in women, often associated with poor prognosis and limited therapeutic options. However, molecular differences between primary tumors and CNS metastases remain underexplored. We aimed to characterize transcriptomic differences between primary breast tumors and matched CNS metastases and identify immune-related biomarkers associated with metastatic progression and patient outcomes. Transcriptomic profiling was based on 11 matched FFPE sample pairs (primary tumor and CNS metastasis). Paired formalin-fixed paraffin-embedded (FFPE) samples from primary tumors (T1) and CNS metastases (T2) were analyzed using the NanoString nCounter^® platform and the PanCancer IO 360™ Gene Expression Panel. Differential gene expression, Z-score transformation, and heatmap visualization were performed in R. In silico survival analyses for overall survival (OS) and recurrence-free survival (RFS) were conducted using publicly available TCGA and GEO datasets. Forty-five genes were significantly differentially expressed between the T1 and T2 samples. Immune-related genes such as CXCL9, IL7R, CD79A, and CTSW showed consistent downregulation in CNS metastases. High expression of CXCL9 and CD79A was associated with improved OS and RFS, whereas high IL7R and CTSW expression correlated with worse outcomes. These findings indicate immune suppression as a hallmark of CNS colonization. Comparative transcriptomic analysis further underscored the distinct molecular landscapes between primary and metastatic tumors. This study highlights transcriptional signatures associated with breast cancer CNS metastases, emphasizing the role of immune modulation in metastatic progression. The identified genes have potential as prognostic biomarkers and therapeutic targets, supporting the need for site-specific molecular profiling in metastatic breast cancer management. Full article

Background/Objectives: Radiotherapy for tumors of the central nervous system (CNS) could be improved by incorporating advanced imaging techniques into treatment planning and response assessment. The objective of this narrative review is to highlight the recent developments in magnetic resonance imaging (MRI) and positron emission tomography (PET) for applications in CNS radiotherapy. Methods: Recent articles were selected for discussion, covering the following topics: advanced imaging on MRI-linear accelerators for early response assessment in glioma; PET for guiding treatment planning and response assessment in glioma; and contrast-enhanced imaging and metabolic imaging for differentiating tumor progression and radiation necrosis for brain metastasis treatment. Where necessary, searches of scholarly databases (e.g., Google Scholar, PubMed) were used to find papers for each topic. The topics were chosen based on the perception of promise in advancing specific applications of CNS radiotherapy and not covered in detail elsewhere. This review is not intended to be comprehensive. Results: Advanced MRI sequences and PET could have a substantial impact on CNS radiotherapy. For gliomas, the tumor response to therapy could be assessed much earlier than using the conventional technique of measuring changes in tumor size. Using advanced imaging on combined imaging/therapy devices like MR-Linacs would enable response monitoring throughout radiotherapy. For brain metastases, radiation necrosis and tumor progression might be reliably differentiated with imaging techniques sensitive to perfusion or metabolism. However, the lack of level 1 evidence supporting specific uses for each imaging technique is an impediment to widespread use. Conclusions: Advanced MRI and PET have great promise to change the standard of care for CNS radiotherapy, but clinical trials validating specific applications are needed. Full article

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer treatment that uses near-infrared light to activate a conjugate of a monoclonal antibody (mAb) and a photoactivatable silica phthalocyanine dye (IRDye700DX: IR700). Unlike conventional photodynamic therapy (PDT), NIR-PIT selectively destroys targeted tumor cells while preserving the surrounding normal tissue and providing superior tissue penetration. Recently, NIR-PIT has been approved for the treatment of unresectable recurrent head and neck cancers in Japan. It induces highly selective cancer cell death; therefore, it is expected to be a new curative treatment option for various cancers, including brain tumors. In this review, we compare the principles of NIR-PIT and PDT and discuss the potential applications of NIR-PIT for brain tumors. We selected targetable proteins across various types of brain tumors and devised a strategy to effectively pass the mAb–IR700 conjugate through the blood–brain barrier (BBB), which is a significant challenge for NIR-PIT in treating brain tumors. Innovative approaches for delivering the mAb–IR700 conjugate across the BBB include exosomes, nanoparticle-based systems, and cell-penetrating peptides. Small-molecule compounds, such as affibodies, are anticipated to rapidly accumulate in tumors within intracranial models, and our preliminary experiments demonstrated rapid uptake. NIR-PIT also induces immunogenic cell death and activates the anti-tumor immune response. Overall, NIR-PIT is a promising approach for treating brain tumors. It has the potential to overcome the limitations of conventional therapies and offers new hope to patients with brain tumors. Full article

Primary and secondary brain tumors have always been a challenge due to their high morbidity and poor prognosis. The incidence of brain metastasis is also increasing with the advent of effective new treatments. Traditional systemic treatments have historically had limited success, partly due to poor central nervous system (CNS) penetration. However, the advent in recent decades of new therapies that have shown high encephalic response rates are challenging this paradigm. ADCs represent a new class of compounds revolutionizing cancer treatment with high systemic response rates and lower toxicities. The continuing evolution of ADCs has shown that certain structural features such as payload, linker, and drug-to-antibody ratio (DAR) are essential in determining their efficacy at the encephalic level, and some ADCs have started to exhibit promising efficacy in treating primary and secondary brain tumors. Unfortunately, most patients with untreated encephalic metastases are excluded from clinical trials, with data primarily from retrospective studies or post hoc analyses. This review describes the early signs of ADC efficacy in brain tumors, the role of complementary treatments like radiation therapy, and critical points to improve ADC efficacy in brain malignancies. Full article

Lung cancer brain metastasis (LCBM) is a major contributor to cancer-related mortality, with a median survival of 8–16 months following diagnosis, despite advances in therapeutic strategies. The development of clinically relevant animal models is crucial for understanding the metastatic cascade and assessing therapies that can penetrate the blood–brain barrier (BBB). This review critically evaluates five primary LCBM modeling approaches—orthotopic implantation, intracardiac injection, stereotactic intracranial injection, carotid artery injection, and tail vein injection—focusing on their clinical applicability. We systematically compare their ability to replicate human metastatic pathophysiology and highlight emerging technologies for personalized therapy screening. Additionally, we analyze breakthrough strategies in central nervous system (CNS)-targeted drug delivery, including microparticle targeted delivery systems designed to enhance brain accumulation. By incorporating advances in single-cell omics and AI-driven metastasis prediction, this work provides a roadmap for the next generation of LCBM models, aimed at bridging preclinical and clinical research. Full article

Current in vitro models fail to recapitulate specific physiological properties of the human blood–brain barrier (BBB); hence the need for a reliable platform to study central nervous system diseases and drug permeability. To mimic the normally tight blood–brain interface, primary human endothelial cells (HAECs) and primary human astrocytes (A) were grown in a confined space of the physical scaffold created by gelatin methacrylate (GelMA) hydrogel to allow optimal astrocyte–endothelial cell direct/indirect interaction. Evidence for a physiologically relevant BBB was established by assessing the expression of tight junction markers conferring the barrier function, and by measuring biophysical attributes using the trans-endothelial electrical resistance (TEER) and the Evans blue albumin (EBA) permeability assay. An HAEC+A three-dimensional (3D) co-culture was associated with 12-fold higher claudin-5 (CLDN5) and cadherin-1 (CDH1 or Epithelial [E]-cadherin) transcriptional levels than two-dimensional (2D) models. This model conferred the highest TEER (45 Ω·cm²) in 3D HAEC+A, which value was 30 Ω·cm² in 2D (p < 0.01) and 25 Ω·cm² in 3D HAEC cultures (p < 0.001). Functionally, in 3D HAEC+A co-cultures, higher TEER resulted in 10-fold and 7-fold lower EBA permeability at 120 min, in HAECs alone or in to 2D co-cultures (p < 0.01). The established human primary cell model has acquired features mimicking the human BBB in vitro, and is now poised to be tested for the permeability of the BBB to pharmacological agents, parasites, cells (such as brain-tropic cancer cell metastasis) and any mechanisms that might involve traversing the BBB. Full article

Background/Objectives: Breast cancer is the most common malignancy in women and the second leading cause of cancer-related deaths globally. It is also the second most frequent source of brain metastases (BMs), contributing to 5–20% of cases. Despite this, routine brain imaging for screening is not recommended and is only conducted when clinical symptoms or physical findings suggest metastasis. This study aims to identify clinical predictors associated with overall survival (OS) and the timing of BM development in breast cancer patients. Methods: We performed a retrospective review of medical records for 113 patients diagnosed with BMs secondary to breast cancer at our institution between 2000 and 2020. Baseline demographic data and clinical characteristics related to BMs were collected. To identify factors associated with OS and time to BM development after breast cancer diagnosis, we conducted univariate analysis using Kaplan–Meier curves, bivariate analysis with the log-rank test, and multivariate analysis via the Cox Proportional Hazard model. Results: An early diagnosis of BMs was identified as a significant predictor of prolonged OS (aHR = 0.22; 95% CI: 0.049–0.98, p = 0.05). Post-menopausal status at breast cancer diagnosis (aHR = 1.69; 95% CI: 1.13–2.53, p = 0.01), Asian ethnicity (aHR = 2.30; 95% CI: 1.03–5.16, p = 0.04), and the ER+/HER2+ subtype (aHR = 2.06; 95% CI: 1.14–3.71, p = 0.02) were significantly associated with a shorter time to BM diagnosis. A subgroup analysis of patients with ER+ breast tumors revealed that Hispanic or Arabic ethnicity (aHR = 3.63; 95% CI: 1.34–9.81, p = 0.01) and stage IV diagnosis (aHR = 2.09; 95% CI: 1.16–3.76, p = 0.01) were significantly associated with shorter intervals to BM diagnosis. Conclusions: Breast cancer remains a significant global health burden for women, yet clear guidelines for routine BMs screening are still lacking. Early detection of BMs has been shown to notably improve long-term survival outcomes. Additionally, post-menopausal status, Hispanic or Arabic ethnicity, and the HER2+ tumor subtype are associated with shorter time to BM development, highlighting these factors as potential indicators for central nervous system screening. Full article

Background: The majority of gliomas are astrocytic in nature. Gliomas have the lowest survival rate among all tumors of the central nervous system (CNS), characterized by high aggressiveness and poor response to treatment. The tumor microenvironment is a source of cytokines such as IL-6, IFN-γ, VEGF, and PDGF-BB, secreted mainly by tumor and immune cells. These cytokines play a significant role in angiogenesis, invasion, and metastasis formation. In vitro and in vivo studies have shown that Brazilian green propolis, derived from Baccharis dracunculifolia DC and rich in artepillin C, exhibits anti-inflammatory, antimicrobial, chemopreventive, and anticancer activities. Additionally, it can penetrate the blood–brain barrier, demonstrating neuroprotective effects. The aim of the present study was to determine the concentration of selected cytokines produced by astrocytes of the CCF-STTG1 cell line, isolated from the brain of a patient with stage IV glioma (astrocytoma). Methods: The cytotoxicity of the EEP-B was evaluated using the MTT assay. Astrocytes were stimulated with LPS at a final concentration of 200 ng/mL and/or IFN-α at 100 U/mL, followed by incubation with EEP-B (25–50 µg/mL) and artepillin C (25–50 µg/mL) under 2-h hypoxia and normoxia conditions. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine kit. Results: The absence of cytotoxic effects of EEP-B and artepillin C on human astrocytes of the CCF-STTG1 lineage was demonstrated. Stimulation with LPS, IFN-α, and their combination (LPS + IFN-α) significantly increased the secretion of the tested cytokines compared to the control cell line. The most pronounced and statistically significant reduction in cytokine levels, particularly IL-6 and VEGF, was observed following EEP-B treatment at both tested concentrations under both hypoxic and normoxic conditions. Conclusions: Brazilian green propolis may serve as a potential immunomodulator in combination therapies for gliomas of varying malignancy grades. Full article

Background: The natural history of pediatric patients with metastasis of primary brain tumors within and outside the central nervous system is poorly understood, as too are possible clinical correlates with outcome. Correspondingly, the aim of this study was to interrogate a national database to characterize this diagnosis and its clinical course in pediatric patients. Methods: The U.S. National Cancer Database (NCDB) was interrogated between the years 2005–2016 for all patients aged 18 years and younger with a primary brain tumor diagnosis, as well as evidence of disease metastasis at initial diagnosis. Data were summarized and overall survival (OS) was modeled using Kaplan–Meier and Cox regression analyses. Results: Out of a total of 8615 pediatric brain tumor patients, 356 (4%) had evidence of metastasis at initial diagnosis. Compared to patients without metastasis, patients with metastasis were statistically younger, more often male, and less likely to have private health insurance (all p < 0.050). With respect to clinical characteristics, the primary tumors of patients with metastasis were statistically more likely to be located in the cerebellum; be of higher histologic grading, with a higher proportion of medulloblastoma diagnoses and lower proportion of malignant glioma and pilocytic astrocytoma diagnoses; and were more likely to be treated by subtotal surgical resection, chemotherapy and radiation therapy (all p < 0.050) when compared to patients without metastasis. Five-year OS for those with metastasis was significantly lower than those without (48% vs. 75%, p < 0.001), with the median overall survival for patients with metastasis being 53 months (95% CI 29–86). Multivariate analysis indicated that a shorter OS was independently associated with the primary diagnoses of malignant glioma (HR 27.7, p = 0.020) and Atypical Teratoid/Rhabdoid Tumor (ATRT, HR 41.1, p = 0.041) and with WHO grades 3 (HR 20.1, p = 0.012) and 4 (HR 11.5, p < 0.001). Longer OS was significantly and independently associated with surgery (HR 0.49, p < 0.001), chemotherapy (HR 0.53, p = 0.041), and radiation therapy (HR 0.57, p = 0.026). Conclusions: Although uncommon, pediatric brain tumors with evidence of metastasis at initial diagnosis will present with a distinct socioeconomic and clinical profile compared to patients without metastasis. Multiple predictors are independently associated with overall prognosis, and understanding these features should be validated in prospective efforts to identify vulnerable patients earlier in order to maximize the impact of treatment. Full article

The treatment of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients was dramatically revolutionized by the introduction of EGFR tyrosine kinase inhibitors in clinical practice, both in advanced and locally advanced/early stages. The present work focuses on osimertinib use in locally advanced and early NSCLC stages. Phase 3 clinical trials have supported the use of osimertinib as the new standard of care, both in the adjuvant setting and in locally advanced disease. The ADAURA study reported an overall survival (OS) advantage for adjuvant osimertinib in completely resected stage II-IIIA EGFR-mutant tumors, while the LAURA study proved a statistically significant benefit in progression-free survival (PFS) and a delay of central nervous system metastasis development in EGFR-mutant patients treated with osimertinib maintenance after concurrent chemoradiotherapy for locally advanced disease. In the neoadjuvant setting, data on osimertinib’s efficacy are conflicting; therefore, the Neo-ADAURA study is evaluating the efficacy and safety of neoadjuvant osimertinib alone or in combination with chemotherapy in patients with stage II-IIIB NSCLC and common EGFR mutations. We discuss several issues that need to be clarified, such as the efficacy of the drug on uncommon mutations, the long-term impact on survival, and the management of resistance mechanisms. Moreover, we report the studies that are trying to identify potential biomarkers of response, such as the circulating tumor DNA (ctDNA), with the aim of selecting patients who will benefit most from osimertinib. Full article

Leptomeningeal metastasis (LM) is a rare and challenging manifestation of advanced breast cancer (ABC) with severe morbidity and mortality. Patients with LM may be asymptomatic, or present with non-specific neurologic deficits, thereby possibly delaying diagnosis. Treatment typically requires a multimodal approach for effective management, symptom relief, and quality-of-life improvement. Trastuzumab-deruxtecan (T-DXd), a humanized monoclonal antibody drug conjugate, demonstrated efficacy across diverse breast cancer subtypes expressing variable levels of HER2 proteins. Currently, T-DXd is the standard of care for patients with advanced, pretreated, HER2 low breast cancer. There is limited evidence of the response of brain metastases (BM) and leptomeningeal metastases (LM) to T-DXd in HER2-low patients, with most data extrapolated from HER2-positive breast cancer studies. This case report presents the first documented instance of a patient with debilitating, symptomatic, untreated LM and hydrocephalus demonstrating a rapid and dramatic clinical response to T-DXd. This finding holds crucial clinical relevance, highlighting the potential benefit of initiating effective systemic therapy for LM early in treatment to address both central nervous system (CNS) and non-CNS disease burden, rather than delaying systemic therapy until after radiation therapy. Full article