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Acta Neuropathologica Communications Mar 2024Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and...
Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4 years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33 months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.
Topics: Humans; Brain Neoplasms; Nuclear Proteins; Transcription Factors; Central Nervous System Neoplasms; Neoplasms, Germ Cell and Embryonal; Bromodomain Containing Proteins; Cell Cycle Proteins; Forkhead Transcription Factors; Homeodomain Proteins
PubMed: 38500181
DOI: 10.1186/s40478-024-01746-7 -
Journal of Ophthalmology 2024This study was designed to review the primary sites, clinical manifestations, imaging features, treatments, and outcomes of 36 patients with orbital metastasis in North...
PURPOSE
This study was designed to review the primary sites, clinical manifestations, imaging features, treatments, and outcomes of 36 patients with orbital metastasis in North China.
METHODS
This was a retrospective review of 36 patients with orbital metastasis at Tianjin Eye Hospital between January 2010 and December 2020 in North China as well as a review of the literature.
RESULTS
Thirty-six patients were included in the study; 17 were male, and 19 were female, with an age range of 1-82 years (average 54.9 ± 19.8 years). All the tumours were unilateral. The mean duration from the onset of orbital signs to presentation at the hospital was 2.4 months (range 1-10 months). Breast carcinoma, gastrointestinal tract carcinoma, and lung carcinoma were the most common histological types. Proptosis, ocular pain, and diplopia were the most common clinical manifestations. The superior orbit was the most common quadrant involved. All patients received comprehensive therapy, including surgery, radiotherapy, or chemotherapy. The average follow-up time was 2.45 years (range 7 months to 5.5 years). Ten patients in this study died as a result of disseminated metastasis from the primary tumour.
CONCLUSIONS
In North China, the most common primary cancer that metastasizes to the orbit is breast cancer, followed by gastrointestinal tract carcinoma and lung cancer. The increasing trend of orbital gastrointestinal tract metastases in North China in recent years is noteworthy. The survival rate of patients with orbital metastasis of neuroblastoma is low.
PubMed: 38370869
DOI: 10.1155/2024/3394425 -
Theranostics 2024The tumor-associated disialoganglioside GD2 is a immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma....
The tumor-associated disialoganglioside GD2 is a immunotherapy target in neuroblastoma and other childhood tumors, including Ewing sarcoma and osteosarcoma. GD2-targeting antibodies proved to be effective in neuroblastoma and GD2-targeting chimeric antigen receptors (CAR)- expressing T cells as well as natural killer T cells (NKTs) are emerging. However, assessment of intra- and intertumoral heterogeneity has been complicated by ineffective immunohistochemistry as well as sampling bias in disseminated disease. Therefore, a non-invasive approach for the assessment and visualization of GD2 expression is of upmost interest and might enable a more appropriate treatment stratification. Recently, [Cu]Cu-NOTA-ch14.18/CHO (Cu-GD2), a radiolabeled GD2-antibody for imaging with Positron-Emission-Tomography (PET) was developed. We here report our first clinical patients' series (n = 11) in different pediatric tumors assessed with Cu-GD2 PET/MRI. GD2-expression in tumors and tissue uptake in organs was evaluated by semiquantitative measurements of standardized uptake values (SUV) with PET/MRI on day 1 p.i. (n = 11) as well as on day 2 p.i. (n = 6). In 8 of 9 patients with suspicious tumor lesions on PET/MRI at least one metastasis showed an increased Cu-GD2 uptake and a high tracer uptake (SUV > 10) was measured in 4 of those 8 patients. Of note, sufficient image quality with high tumor to background contrast was readily achieved on day 1. In case of Cu-GD2-positive lesions, an excellent tumor to background ratio (at least 6:1) was observed in bones, muscles or lungs, while lower tumor to background contrast was seen in the spleen, liver and kidneys. Furthermore, we demonstrated extensive tumor heterogeneity between patients as well as among different metastatic sites in individual patients. Dosimetry assessment revealed a whole-body dose of only 0.03 mGy/MBq (range 0.02-0.04). Cu-GD2 PET/MRI enables the non-invasive assessment of individual heterogeneity of GD2 expression, which challenges our current clinical practice of patient selection, stratification and immunotherapy application scheme for treatment with anti-GD2 directed therapies.
Topics: Child; Humans; Antibodies, Monoclonal; Neuroblastoma; Positron-Emission Tomography
PubMed: 38323317
DOI: 10.7150/thno.92481 -
Translational Pediatrics Jan 2024Neuroblastoma (NB) is a common malignant tumor in children, and its treatment remains challenging. Precision medicine, as an individualized treatment strategy, aims to... (Review)
Review
BACKGROUND AND OBJECTIVE
Neuroblastoma (NB) is a common malignant tumor in children, and its treatment remains challenging. Precision medicine, as an individualized treatment strategy, aims to improve efficacy and reduce toxicity by combining unique patient- and tumor-related factors, bringing new hope for NB treatment. In this article, we review the evidence related to precision medicine in NB, with a focus on potential clinically actionable targets and a series of targeted drugs associated with NB.
METHODS
We conducted an extensive search in PubMed, EMBASE, and Web of Science using key terms and database-specific strategies, filtered for time and language, to ensure a comprehensive collection of literature related to precision medicine in NB. The main search terms consisted of "neuroblastoma", "precision medicine", "pediatrics", and "targeting". The articles included in this study encompass those published from 1985 to the present, without restrictions on the type of articles.
KEY CONTENT AND FINDINGS
ALK inhibitors and MYCN inhibitors have been developed to interfere with tumor cell growth and dissemination, thereby improving treatment outcomes. Additionally, systematic testing to identify relevant driver mutations is crucial and can be used for diagnosis and prognostic assessment through the detection of many associated molecular markers. Furthermore, liquid biopsy, a non-invasive tumor detection method, can complement tissue biopsy and play a role in NB by analyzing circulating tumor DNA and circulating tumor cells to provide genetic information and molecular characteristics of the tumor. Recently, trials conducted by many pediatric oncology groups have shown the urgent need for new approaches to cure relapsed and refractory patients.
CONCLUSIONS
The purpose of this review is to summarize the latest advances in clinical treatment of NB, to better understand and focus on the development of promising treatment approaches, and to expedite the transition to the precision medicine clinical relevance in NB patients.
PubMed: 38323175
DOI: 10.21037/tp-23-557 -
BioRxiv : the Preprint Server For... Jan 2024Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and...
Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and targeted treatments improving survival rates, nearly 50% of patients with high-risk neuroblastoma will ultimately succumb to their disease. Dysregulation of the epithelial-mesenchymal transition (EMT) is a key mechanism of tumor cell dissemination, resulting in metastasis and poor outcomes in many cancers. Our prior work identified PRMT5 as a key regulator of EMT via methylation of AKT at arginine 15, enhancing the expression of EMT-driving transcription factors and facilitating metastasis. Here, we identify that PRMT5 directly regulates the transcription of the epidermal growth factor receptor (EGFR). PRMT5, through independent modulation of the EGFR and AKT pathways, orchestrates the activation of NFκB, resulting in the upregulation of the pro-EMT transcription factors ZEB1, SNAIL, and TWIST1. Notably, EGFR and AKT form a compensatory feedback loop, reinforcing the expression of these EMT transcription factors. Small molecule inhibition of PRMT5 methyltransferase activity disrupts EGFR/AKT signaling, suppresses EMT transcription factor expression and ablates tumor growth . Our findings underscore the pivotal role of PRMT5 in the control of the EMT program in high-risk neuroblastoma.
PubMed: 38260418
DOI: 10.1101/2024.01.03.574104 -
International Journal of Molecular... Jul 2023High-risk neuroblastoma remains a profound clinical challenge that requires eradication of neuroblastoma cells from a variety of organ sites, including bone marrow,...
High-risk neuroblastoma remains a profound clinical challenge that requires eradication of neuroblastoma cells from a variety of organ sites, including bone marrow, liver, and CNS, to achieve a cure. While preclinical modeling is a powerful tool for the development of novel cancer therapies, the lack of widely available models of metastatic neuroblastoma represents a significant barrier to the development of effective treatment strategies. To address this need, we report a novel luciferase-expressing derivative of the widely used Th-MYCN mouse. While our model recapitulates the non-metastatic neuroblastoma development seen in the parental transgenic strain, transplantation of primary tumor cells from disease-bearing mice enables longitudinal monitoring of neuroblastoma growth at distinct sites in immune-deficient or immune-competent recipients. The transplanted tumors retain GD2 expression through many rounds of serial transplantation and are sensitive to GD2-targeted immune therapy. With more diverse tissue localization than is seen with human cell line-derived xenografts, this novel model for high-risk neuroblastoma could contribute to the optimization of immune-based treatments for this deadly disease.
Topics: Mice; Humans; Animals; N-Myc Proto-Oncogene Protein; Mice, Transgenic; Neuroblastoma; Adaptation, Physiological; Acclimatization
PubMed: 37569447
DOI: 10.3390/ijms241512071 -
Oncology Letters Aug 2023Bone marrow metastasis (BMM) refers to the metastasis of malignant tumours originating from nonhematopoietic tissues to the bone marrow. The nonhematopoietic malignant...
Bone marrow metastasis (BMM) refers to the metastasis of malignant tumours originating from nonhematopoietic tissues to the bone marrow. The nonhematopoietic malignant tumour cells metastasize to the bone marrow via heterogeneous dissemination or direct invasion to form metastases and the bone marrow is infiltrated by tumour cells, resulting in the destruction of its structure and the development of haematopoietic disorders. In the present study, the clinical characteristics, prognosis and treatment of BMMs were investigated. The main clinical manifestations were moderate anaemia and thrombocytopenia. Out of 52 cases, a total of 18 patients were not treated and the remaining patients underwent chemotherapy, radiotherapy, surgery or autologous stem cell transplantation in the Affiliated Tumour Hospital of Tianjin Medical University from September 2010 to October 2021. The primary tumours of bone marrow metastatic cancer were usually neuroblastoma and tumours originating from the breast and stomach. When bone metastases occur, patients are not necessarily accompanied by BMMs. In the present study, bone metastases occurred mainly in patients with breast and prostate cancers. The median overall survival of patients treated with antitumor therapy was significantly higher than that of untreated patients (11.5 vs. 3.3 months P<0.01). For patients with BMM, it is of great importance to actively evaluate the patient's condition and select the appropriate treatment plan for improving their prognosis.
PubMed: 37415634
DOI: 10.3892/ol.2023.13918 -
Cureus May 2023Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant tumor of neuroectodermal origin that arises from the olfactory epithelium. We...
Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant tumor of neuroectodermal origin that arises from the olfactory epithelium. We present a case of ENB metastasizing through the leptomeningeal route to the spinal dura, which was treated with CyberKnife (CK) stereotactic radiosurgery (SRS), and aim to assess the safety and effectiveness of SRS in such cases. To the best of our knowledge, this is the first case report in the literature that discusses ENB spinal leptomeningeal metastases treated with CK radiosurgery. We retrospectively review the clinical and radiological outcomes in a 70-year-old female with ENB metastasis to the spine. Progression-free survival (PFS), overall survival (OS), and local tumor control (LTC) are investigated. In our patient, ENB had been diagnosed at the age of 58 years and spinal metastases had been first noted at the age of 65 years. A total of six spinal lesions received CK SRS. Lesions were present at the level of C1, C2, C3, C6-C7, T5, and T10-11. The median target volume was 0.72 cc (range: 0.32-2.54). A median marginal dose of 24 Gy was delivered to the tumors with a median of three fractions to a median isodose line of 80% (range: 78-81). LTC at the 24-month follow-up was 100%. PFS and OS were 27 months and 40 months, respectively. No adverse radiation effects were reported. Even though the treated spinal lesions remained stable, the number of new metastatic lesions had increased with progressive osseous and dural metastatic lesions within the cervical, thoracic, and lumbar spine at the last follow-up. SRS provides relatively good LTC for patients with ENB metastasizing to the spine, with no radiation-induced adverse events.
PubMed: 37398775
DOI: 10.7759/cureus.39791 -
Cell & Bioscience May 2023Tumor hypoxia stimulates release of extracellular vesicles (EVs) that facilitate short- and long-range intercellular communication and metastatization. Albeit hypoxia...
BACKGROUND
Tumor hypoxia stimulates release of extracellular vesicles (EVs) that facilitate short- and long-range intercellular communication and metastatization. Albeit hypoxia and EVs release are known features of Neuroblastoma (NB), a metastasis-prone childhood malignancy of the sympathetic nervous system, whether hypoxic EVs can facilitate NB dissemination is unclear.
METHODS
Here we isolated and characterized EVs from normoxic and hypoxic NB cell culture supernatants and performed microRNA (miRNA) cargo analysis to identify key mediators of EVs biological effects. We then validated if EVs promote pro-metastatic features both in vitro and in an in vivo zebrafish model.
RESULTS
EVs from NB cells cultured at different oxygen tensions did not differ for type and abundance of surface markers nor for biophysical properties. However, EVs derived from hypoxic NB cells (hEVs) were more potent than their normoxic counterpart in inducing NB cells migration and colony formation. miR-210-3p was the most abundant miRNA in the cargo of hEVs; mechanistically, overexpression of miR-210-3p in normoxic EVs conferred them pro-metastatic features, whereas miR-210-3p silencing suppressed the metastatic ability of hypoxic EVs both in vitro and in vivo.
CONCLUSION
Our data identify a role for hypoxic EVs and their miR-210-3p cargo enrichment in the cellular and microenvironmental changes favoring NB dissemination.
PubMed: 37202777
DOI: 10.1186/s13578-023-01045-z -
Research (Washington, D.C.) 2023The recurrence and metastasis of children with mediastinal neuroblastoma (NB) are also occurred after surgery, chemotherapy, or radiotherapy. Strategies targeting the...
The recurrence and metastasis of children with mediastinal neuroblastoma (NB) are also occurred after surgery, chemotherapy, or radiotherapy. Strategies targeting the tumor microenvironment have been reported to improve survival; however, thorough investigations of monocytes and tumor-associated macrophages (Mϕs) with specialized functions in NB are still lacking. Our data first demonstrated polypyrimidine tract binding protein 2 (PTBP2) as a possible identifier in patients with mediastinal NB screened by proteomic profiling and that PTBP2 predicted good outcomes. Functional studies revealed that PTBP2 in NB cells induced the chemotactic activity and repolarization of tumor-associated monocytes and Mϕs, which, in turn, inhibited NB growth and dissemination. Mechanistically, PTBP2 prevents interferon regulatory factor 9 alternative splicing and upregulates signal transducers and activators of transcription 1 to stimulate C-C motif chemokine ligand 5 (CCL5) and interferon-stimulated gene factor-dependent type I interferon secretion, to induce monocyte/Mϕs chemotaxis, and to sustain monocytes in a proinflammatory phenotype. Our study defined a critical event of PTBP2-induced monocytes/Mϕs in NB progression and revealed that RNA splicing occurred by PTBP2 benefits immune compartmentalization between NB cells and monocytes. This work revealed the pathological and biological role of PTBP2 in NB development and indicates that PTBP2-induced RNA splicing benefits immune compartmentalization and predicted a favorable prognosis in mediastinal NB.
PubMed: 37040518
DOI: 10.34133/research.0033