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Current Oncology (Toronto, Ont.) Jun 2023The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer... (Review)
Review
The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer types. For our purposes, the focused metastatic malignancies include breast cancer, lung cancer, melanoma, primary central nervous system tumors, and hematologic cancers (lymphoma, leukemia, and multiple myeloma). Of note, our discussion was limited to cancer-specific leptomeningeal metastases secondary to the aforementioned primary cancers. LMD mechanisms secondary to non-cancerous pathologies, such as infection or inflammation of the leptomeningeal layer, were excluded from our scope of review. Furthermore, we intended to characterize general leptomeningeal disease, including the specific anatomical infiltration process/area, CSF dissemination, manifesting clinical symptoms in patients afflicted with the disease, detection mechanisms, imaging modalities, and treatment therapies (both preclinical and clinical). Of these parameters, leptomeningeal disease across different primary cancers shares several features. Pathophysiology regarding the development of CNS involvement within the mentioned cancer subtypes is similar in nature and progression of disease. Consequently, detection of leptomeningeal disease, regardless of cancer type, employs several of the same techniques. Cerebrospinal fluid analysis in combination with varied imaging (CT, MRI, and PET-CT) has been noted in the current literature as the gold standard in the diagnosis of leptomeningeal metastasis. Treatment options for the disease are both varied and currently in development, given the rarity of these cases. Our review details the differences in leptomeningeal disease as they pertain through the lens of several different cancer subtypes in an effort to highlight the current state of targeted therapy, the potential shortcomings in treatment, and the direction of preclinical and clinical treatments in the future. As there is a lack of comprehensive reviews that seek to characterize leptomeningeal metastasis from various solid and hematologic cancers altogether, the authors intended to highlight not only the overlapping mechanisms but also the distinct patterning of disease detection and progression as a means to uniquely treat each metastasis type. The scarcity of LMD cases poses a barrier to more robust evaluations of this pathology. However, as treatments for primary cancers have improved over time, so has the incidence of LMD. The increase in diagnosed cases only represents a small fraction of LMD-afflicted patients. More often than not, LMD is determined upon autopsy. The motivation behind this review stems from the increased capacity to study LMD in spite of scarcity or poor patient prognosis. In vitro analysis of leptomeningeal cancer cells has allowed researchers to approach this disease at the level of cancer subtypes and markers. We ultimately hope to facilitate the clinical translation of LMD research through our discourse.
Topics: Humans; Female; Positron Emission Tomography Computed Tomography; Meningeal Carcinomatosis; Breast Neoplasms; Magnetic Resonance Imaging; Hematologic Neoplasms
PubMed: 37366925
DOI: 10.3390/curroncol30060442 -
Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas.Acta Neuropathologica Jul 2023Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in...
Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2A) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2A meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.
Topics: Humans; Genes, p16; Meningioma; Cyclin-Dependent Kinase Inhibitor p16; Transcriptome; DNA Copy Number Variations; Homozygote; Sequence Deletion; Meningeal Neoplasms
PubMed: 37093270
DOI: 10.1007/s00401-023-02571-3 -
Nature Medicine Dec 2023Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and...
Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.
Topics: Humans; Biomarkers; Gene Expression Profiling; Meningeal Neoplasms; Meningioma; Neoplasm Recurrence, Local; Prospective Studies
PubMed: 37944590
DOI: 10.1038/s41591-023-02586-z -
Ugeskrift For Laeger Oct 2023In this case report a 54-year-old woman had an anterior clinoid process meningioma. She was initially diagnosed as having a cerebrovascular disease, however, her...
In this case report a 54-year-old woman had an anterior clinoid process meningioma. She was initially diagnosed as having a cerebrovascular disease, however, her stroke-like symptoms were most likely caused by internal carotid artery compression or vasospasm due to meningiomal involvement, but initially overlooked. Meningiomas are rarely reported as a cause of a stroke. A detailed evaluation can provide a high degree of confidence in differentiating stroke and non-stroke medical conditions, known as stroke mimics or chameleons, to be considered when a diagnosis of stroke has not been confirmed.
Topics: Humans; Female; Middle Aged; Meningioma; Stroke; Sphenoid Bone; Carotid Artery, Internal; Meningeal Neoplasms
PubMed: 37873985
DOI: No ID Found -
The Kaohsiung Journal of Medical... Nov 2023
Topics: Humans; Meningioma; Lung Neoplasms; Tomography, X-Ray Computed; Meningeal Neoplasms
PubMed: 37698283
DOI: 10.1002/kjm2.12754 -
Current Oncology Reports Aug 2023Leptomeningeal disease (LMD) is a devastating complication of advanced metastatic cancer associated with a poor prognosis and limited treatment options. This study... (Review)
Review
PURPOSE OF REVIEW
Leptomeningeal disease (LMD) is a devastating complication of advanced metastatic cancer associated with a poor prognosis and limited treatment options. This study reviews the current understanding of the clinical presentation, pathogenesis, diagnosis, and treatment of LMD. We highlight opportunities for advances in this disease.
RECENT FINDINGS
In recent years, the use of soluble CSF biomarkers has expanded, suggesting improved sensitivity over traditional cytology, identification of targetable mutations, and potential utility for monitoring disease burden. Recent studies of targeted small molecules and intrathecal based therapies have demonstrated an increase in overall and progression-free survival. In addition, there are several ongoing trials evaluating immunotherapy in LMD. Though overall prognosis of LMD remains poor, studies suggest a potential role for soluble CSF biomarkers in diagnosis and management and demonstrate promising findings in patient outcomes with targeted therapies for specific solid tumors. Despite these advances, there continues to be a gap of knowledge in this disease, emphasizing the importance of inclusion of LMD patients in clinical trials.
Topics: Humans; Meningeal Neoplasms; Prognosis; Mutation
PubMed: 37256537
DOI: 10.1007/s11912-023-01432-2 -
Journal of Nanobiotechnology Aug 2023Lymph nodes targeted drug delivery is an attractive approach to improve cancer immunotherapy outcomes. Currently, the depth of understanding of afferent and efferent... (Review)
Review
Lymph nodes targeted drug delivery is an attractive approach to improve cancer immunotherapy outcomes. Currently, the depth of understanding of afferent and efferent arms in brain immunity reveals the potential clinical applications of lymph node targeted drug delivery in brain tumors, e.g., glioblastoma. In this work, we systematically reviewed the microenvironment of glioblastoma and its structure as a basis for potential immunotherapy, including the glial-lymphatic pathway for substance exchange, the lymphatic drainage pathway from meningeal lymphatic vessels to deep cervical lymph nodes that communicate intra- and extracranial immunity, and the interaction between the blood-brain barrier and effector T cells. Furthermore, the carriers designed for lymph nodes targeted drug delivery were comprehensively summarized. The challenges and opportunities in developing a lymph nodes targeted delivery strategy for glioblastoma using nanotechnology are included at the end.
Topics: Humans; Glioblastoma; Lymph Nodes; Brain Neoplasms; Brain; Drug Delivery Systems; Tumor Microenvironment
PubMed: 37542241
DOI: 10.1186/s12951-023-02011-0 -
Environment International May 2024Some have looked forward to the publication of the results of the COSMOS study on brain tumors, because the potential biases from retrospective investigations...
Some have looked forward to the publication of the results of the COSMOS study on brain tumors, because the potential biases from retrospective investigations predominating the search for brain tumor risks of mobile phone use since the late 1990 s were deemed unresolvable by further investigations of that type. Indeed, prospective cohort studies typically have the advantage of being not or less affected by differential exposure misclassification, recall and selection bias, and, as they proceed in the direction of the time arrow, results are more easily interpreted in terms of causation. However, results of the COSMOS study published now in this journal are not of help for the risk assessment of mobile phone use and do not support the conclusions of the authors that their findings "suggest that the cumulative amount of mobile phone use is not associated with the risk of developing glioma, meningioma, or acoustic neuroma".
Topics: Brain Neoplasms; Humans; Cell Phone; Prospective Studies; Cohort Studies; Bias; Risk Assessment; Glioma; Meningioma; Neuroma, Acoustic; Radiation Exposure; Young Adult; Adult; Middle Aged; Aged
PubMed: 38677087
DOI: 10.1016/j.envint.2024.108665