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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 -
Cancers May 2021Natural killer (NK) cells play a key role in the control of cancer development, progression and metastatic dissemination. However, tumor cells develop an array of... (Review)
Review
Natural killer (NK) cells play a key role in the control of cancer development, progression and metastatic dissemination. However, tumor cells develop an array of strategies capable of impairing the activation and function of the immune system, including NK cells. In this context, a major event is represented by the establishment of an immunosuppressive tumor microenvironment (TME) composed of stromal cells, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells and cancer cells themselves. The different immunoregulatory cells infiltrating the TME, through the release of several immunosuppressive molecules or by cell-to-cell interactions, cause an impairment of the recruitment of NK cells and other lymphocytes with effector functions. The different mechanisms by which stromal and tumor cells impair NK cell function have been particularly explored in adult solid tumors and, in less depth, investigated and discussed in a pediatric setting. In this review, we will compare pediatric and adult solid malignancies concerning the respective mechanisms of NK cell inhibition, highlighting novel key data in neuroblastoma and Wilms' tumor, two of the most frequent pediatric extracranial solid tumors. Indeed, both tumors are characterized by the presence of stromal cells acting through the release of immunosuppressive molecules. In addition, specific tumor cell subsets inhibit NK cell cytotoxic function by cell-to-cell contact mechanisms likely controlled by the transcriptional coactivator TAZ. These findings could lead to a more performant diagnostic approach and to the development of novel immunotherapeutic strategies targeting the identified cellular and molecular targets.
PubMed: 34069127
DOI: 10.3390/cancers13102374 -
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 -
Cell Reports Oct 2022Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant...
Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant cells in PNTs are theorized to interconvert between adrenergic/noradrenergic and mesenchymal/neural crest cell states. Here, single-cell RNA-sequencing analysis of 10 PNTs demonstrates extensive transcriptomic heterogeneity. Trajectory modeling suggests that malignant neuroblasts move between adrenergic and mesenchymal cell states via an intermediate state that we term "transitional." Transitional cells express programs linked to a sympathoadrenal development and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature is predictive of poor prognosis compared with adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identifies a similar transitional H3K27-acetylation super-enhancer landscape. Collectively, our study supports the concept that PNTs have phenotypic plasticity and uncovers potential biomarkers and therapeutic targets.
Topics: Adrenergic Agents; Ganglioneuroblastoma; Ganglioneuroma; Humans; Neuroblastoma; RNA
PubMed: 36198269
DOI: 10.1016/j.celrep.2022.111455 -
Translational Oncology Aug 2021Neuroblastoma (NB) is the most common extracranial solid tumor in children and originates from sympathoadrenal or Schwann cell precursors derived from neural crest....
Neuroblastoma (NB) is the most common extracranial solid tumor in children and originates from sympathoadrenal or Schwann cell precursors derived from neural crest. These neural crest derivatives also constitute the hematopoietic and mesenchymal stem cells in bone marrow (BM) that is the most frequent site of NB metastasis and relapse. In NB patients, NB cells have been pathologically detected in BM and peripheral blood (PB), and minimal residual disease (MRD) in BM and PB (BM-MRD and PB-MRD) can be monitored by quantitating several sets of NB-associated mRNAs (NB-mRNAs). Although previous studies have shown varying degrees of correlation between BM-MRD and PB-MRD, the underlying factors and/or mechanisms remains unknown. In the present study, we determined the levels of BM-MRD and PB-MRD by quantitating seven NB-mRNAs in 133 pairs of concurrently collected BM and PB samples from 19 high-risk NB patients with clinical disease evaluation, and examined their correlation in overall and subgroups of sample pairs. The levels of BM-MRD and PB-MRD were moderately (r = 0.418, p < 0.001) correlated with each other in overall sample pairs. The correlation became strong (r = 0.725, p < 0.001), weak (r = 0.284, p = 0.008), and insignificant (p = 0.194) in progression, stable, and remission subgroups of sample pairs, respectively. It also became stronger in subgroups of sample pairs with poor treatment responses and poor prognostic factors. Present study suggests that MRD in high-risk NB shows a dynamic and disease burden-dependent correlation between BM and PB.
PubMed: 33993097
DOI: 10.1016/j.tranon.2021.101019 -
Frontiers in Cell and Developmental... 2020Neuroblastoma (NB) is a neural crest-derived tumor, which develops before birth or in early childhood, with metastatic dissemination typically preceding diagnosis....
Neuroblastoma (NB) is a neural crest-derived tumor, which develops before birth or in early childhood, with metastatic dissemination typically preceding diagnosis. Tumors are characterized by a highly heterogeneous combination of cellular phenotypes demonstrating varying degrees of differentiation along different lineage pathways, and possessing distinct super-enhancers and core regulatory circuits, thereby leading to highly varied malignant potential and divergent clinical outcomes. Cytoskeletal reorganization is fundamental to cellular transformations, including the processes of cellular differentiation and epithelial to mesenchymal transition (EMT), previously reported by our lab and others to coincide with chemotherapy resistance and enhanced metastatic ability of tumor cells. This study set out to investigate the ability of the neuronal miR-124-3p to reverse the cellular transformation associated with drug resistance development and assess the anti-oncogenic role of this miRNA in models of drug-resistant adrenergic (ADRN) and mesenchymal (MES) neuroblastoma cell lines. Low expression of miR-124-3p in a cohort of neuroblastomas was significantly associated with poor overall and progression-free patient survival. Over-expression of miR-124-3p inhibited cell viability through the promotion of cell cycle arrest and induction of apoptosis in addition to sensitizing drug-resistant cells to chemotherapeutics in a panel of morphologically distinct neuroblastoma cell lines. Finally, we describe miR-124-3p direct targeting and repression of key up-regulated cytoskeletal genes including , and and the reversal of the resistance-associated EMT and enhanced invasive capacity previously reported in our model (SK-N-ASCis24).
PubMed: 33330445
DOI: 10.3389/fcell.2020.559553 -
Frontiers in Molecular Neuroscience 2019Long non-coding RNAs (lncRNAs) have emerged as an important regulatory control in biological systems. Though the field of lncRNA has been progressing rapidly, a complete...
Long non-coding RNAs (lncRNAs) have emerged as an important regulatory control in biological systems. Though the field of lncRNA has been progressing rapidly, a complete understanding of the role of lncRNAs in neuroblastoma pathogenesis is still lacking. To identify the abrogated lncRNAs in primary neuroblastoma and in the metastasized as well as the relapsed form of neuroblastoma, we analyzed an RNA-seq dataset on neuroblastoma that is available online to identify the lncRNAs that could potentially be contributing to the biology of neuroblastoma. The identified lncRNAs were further scrutinized using a publicly available epigenetic dataset of neuroblastoma and a cancer database. After this cross-sectional study, we were able to identify three significant lncRNAs, , , and , which could serve as potential biomarkers in clinical studies of neuroblastoma pathogenesis.
PubMed: 31920530
DOI: 10.3389/fnmol.2019.00293 -
Clinical Cancer Research : An Official... Sep 2022[131I]meta-iodobenzylguanidine ([131I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However,...
PURPOSE
[131I]meta-iodobenzylguanidine ([131I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [211At]meta-astatobenzylguanidine ([211At] MABG) is an alpha particle emitter with higher biological effectiveness and short path length which effectively sterilizes microscopic residual disease. Here we investigated the safety and antitumor activity [211At]MABG in preclinical models of neuroblastoma.
EXPERIMENTAL DESIGN
We defined the maximum tolerated dose (MTD), biodistribution, and toxicity of [211At]MABG in immunodeficient mice in comparison with [131I]MIBG. We compared the antitumor efficacy of [211At]MABG with [131I]MIBG in three murine xenograft models. Finally, we explored the efficacy of [211At]MABG after tail vein xenografting designed to model disseminated neuroblastoma.
RESULTS
The MTD of [211At]MABG was 66.7 MBq/kg (1.8 mCi/kg) in CB17SC scid-/- mice and 51.8 MBq/kg (1.4 mCi/kg) in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Biodistribution of [211At]MABG was similar to [131I]MIBG. Long-term toxicity studies on mice administered with doses up to 41.5 MBq/kg (1.12 mCi/kg) showed the radiotherapeutic to be well tolerated. Both 66.7 MBq/kg (1.8 mCi/kg) single dose and fractionated dosing 16.6 MBq/kg/fraction (0.45 mCi/kg) × 4 over 11 days induced marked tumor regression in two of the three models studied. Survival was significantly prolonged for mice treated with 12.9 MBq/kg/fraction (0.35 mCi/kg) × 4 doses over 11 days [211At]MABG in the disseminated disease (IMR-05NET/GFP/LUC) model (P = 0.003) suggesting eradication of microscopic disease.
CONCLUSIONS
[211At]MABG has significant survival advantage in disseminated models of neuroblastoma. An alpha particle emitting radiopharmaceutical may be effective against microscopic disseminated disease, warranting clinical development.
Topics: 3-Iodobenzylguanidine; Alpha Particles; Animals; Astatine; Guanidines; Humans; Iodine Radioisotopes; Mice; Mice, Inbred NOD; Neoplasm Recurrence, Local; Neuroblastoma; Radiopharmaceuticals; Tissue Distribution; Tumor Cells, Cultured
PubMed: 35861867
DOI: 10.1158/1078-0432.CCR-22-0400 -
Head and Neck Pathology Sep 2021Neuroblastoma is the most common extracranial solid cancer of infancy, occurring mainly in the adrenal gland, with high metastatic potential. However, involvement of the... (Review)
Review
Neuroblastoma is the most common extracranial solid cancer of infancy, occurring mainly in the adrenal gland, with high metastatic potential. However, involvement of the head and neck region is rare. Here, we present two cases of metastatic neuroblastoma of childhood, in which a mandibular swelling was the first sign of disseminated disease. Case 1 describes a 4-year-old boy with a 2-week history of painful swelling in the left mandibular region, body soreness and weakness. Panoramic radiography and computed tomography showed a destructive lesion in the left mandibular ramus. Case 2 describes a 3-year-old boy with a 1-month history of swelling in the right mandibular area. Panoramic radiograph and cone-beam computed tomography showed a destructive lesion in the right body and ramus of the mandible, displacing tooth germs, with the destruction of vestibular and lingual bone cortices. In both cases, microscopic analyses revealed a diffuse proliferation of small, round, and blue cells with hyperchromatic nuclei and scant cytoplasm. While Case 1 was more undifferentiated, Case 2 presented eosinophilic areas suggestive of neuropil. A large immunohistochemical panel was performed, showing expression of neural markers such as CD56, neuron-specific enolase (in Case 2), chromogranin, and synaptophysin. Both lesions presented a high proliferation index (Ki67 > 70% and 80%, respectively). Positron emission tomography-computed tomography revealed ipsilateral adrenal primary lesions in both cases, with multiple bone metastatic lesions. Besides the mandible, multiple sites of the axial and appendicular skeleton were affected. Treatment consisted of induction chemotherapy, adrenalectomy, consolidation chemoradiotherapy, and post-consolidation therapy.
Topics: Adrenal Gland Neoplasms; Child, Preschool; Humans; Male; Mandibular Neoplasms; Neuroblastoma
PubMed: 33394374
DOI: 10.1007/s12105-020-01277-2 -
Cirugia Pediatrica : Organo Oficial de... Jan 2023Disseminated intravascular coagulation (DIC) is a rare oncological emergency. We report a pediatric neuroblastoma complicated with DIC which required...
BACKGROUND
Disseminated intravascular coagulation (DIC) is a rare oncological emergency. We report a pediatric neuroblastoma complicated with DIC which required thromboelastometry-guided surgery.
OBSERVATION
A 6-year-old female diagnosed with intermediate risk adrenal neuroblastoma developed tumor-related DIC after chemotherapy first cycle. She remained stable without clinical bleeding and emergent tumor resection guided by intraoperative-thromboelastometry was decided. DIC resolved early after surgery and complete remission was achieved.
CONCLUSION
Treatment of the underlying condition is critical to manage DIC. Thromboelastometry can guide goal-directed therapy, including surgery in pediatric patients. However, larger studies are needed to examine its applicability in different clinical settings, such as cancer related DIC.
Topics: Female; Humans; Child; Thrombelastography; Disseminated Intravascular Coagulation; Neuroblastoma
PubMed: 36629349
DOI: 10.54847/cp.2023.01.20