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Frontiers in Oncology 2024Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue malignancy, characterized by high clinicalopathological and molecular heterogeneity. Preclinical models...
BACKGROUND
Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue malignancy, characterized by high clinicalopathological and molecular heterogeneity. Preclinical models are essential for advancing our understanding of RMS oncobiology and developing novel treatment strategies. However, the diversity of scholarly data on preclinical RMS studies may challenge scientists and clinicians. Hence, we performed a systematic literature survey of contemporary RMS mouse models to characterize their phenotypes and assess their translational relevance.
METHODS
We identified papers published between 01/07/2018 and 01/07/2023 by searching PubMed and Web of Science databases.
RESULTS
Out of 713 records screened, 118 studies (26.9%) were included in the qualitative synthesis. Cell line-derived xenografts (CDX) were the most commonly utilized (n = 75, 63.6%), followed by patient-derived xenografts (PDX) and syngeneic models, each accounting for 11.9% (n = 14), and genetically engineered mouse models (GEMM) (n = 7, 5.9%). Combinations of different model categories were reported in 5.9% (n = 7) of studies. One study employed a virus-induced RMS model. Overall, 40.0% (n = 30) of the studies utilizing CDX models established alveolar RMS (aRMS), while 38.7% (n = 29) were embryonal phenotypes (eRMS). There were 20.0% (n = 15) of studies that involved a combination of both aRMS and eRMS subtypes. In one study (1.3%), the RMS phenotype was spindle cell/sclerosing. Subcutaneous xenografts (n = 66, 55.9%) were more frequently used compared to orthotopic models (n = 29, 24.6%). Notably, none of the employed cell lines were derived from primary untreated tumors. Only a minority of studies investigated disseminated RMS phenotypes (n = 16, 13.6%). The utilization areas of RMS models included testing drugs (n = 64, 54.2%), studying tumorigenesis (n = 56, 47.5%), tumor modeling (n = 19, 16.1%), imaging (n = 9, 7.6%), radiotherapy (n = 6, 5.1%), long-term effects related to radiotherapy (n = 3, 2.5%), and investigating biomarkers (n = 1, 0.8%). Notably, no preclinical studies focused on surgery.
CONCLUSIONS
This up-to-date review highlights the need for mouse models with dissemination phenotypes and cell lines from primary untreated tumors. Furthermore, efforts should be directed towards underexplored areas such as surgery, radiotherapy, and biomarkers.
PubMed: 38371622
DOI: 10.3389/fonc.2024.1333129 -
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke... Feb 2024To analyze the treatment outcomes and prognoses of children with head and neck non-parameningeal rhabdomyosarcoma (HNnPM RMS). A retrospective analysis was performed...
To analyze the treatment outcomes and prognoses of children with head and neck non-parameningeal rhabdomyosarcoma (HNnPM RMS). A retrospective analysis was performed on the clinical data of children with HNnPM RMS admitted to Beijing Children's Hospital from September 2012 to September 2022. The clinical features, comprehensive treatment modes and prognoses of the patients were analyzed. The overall survival rate (OS) and event free survival rate (EFS) were calculated using the Kaplan-Meier method, and univariate analysis was performed using the Log-rank test. A total of 70 children were included in this study, 38 males and 32 females, with a median age of 47 months (2-210 months). Pathological subtypes including the embryonal in 27 cases, the alveolar in 36 cases and the spindle cell and sclerosing in 7 cases. Thirty children (83.3%) with alveolar type were positive for gene fusion. All 70 children underwent chemotherapy, including 38 with neoadjuvant chemotherapy and 32 with adjuvant chemotherapy. Sixty of 70 children underwent surgery, of whom, 10 underwent two or more surgeries. There were 63 children underwent radiotherapy, including 54 with intensity-modulated radiation therapy, 4 with particle implantation and 5 with proton therapy. The median follow-up was 45 (5-113) months, the 5-year OS was 73.2%, and the 5-year EFS was 57.7%. Univariate analysis showed lymph node metastasis (=5.022, =0.025), distant metastasis (=8.258, =0.004), and high Intergroup Rhabdomyosarcoma Study (IRS) group (=9.859, =0.029) as risk factors for poor prognosis. Before June 2016, the 5-year OS based on BCH-RMS-2006 scheme was 63.6%, and after 2016, the 5-year OS based on CCCG-RMS-2016 scheme was 79.6%. Multidisciplinary combined standardized treatment can offer good treatment outcome and prognosis for children with HNnPM RMS. Local control is a key to the efficacy of comprehensive treatment.
Topics: Child; Male; Female; Humans; Child, Preschool; Retrospective Studies; Rhabdomyosarcoma; Treatment Outcome; Prognosis; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38369791
DOI: 10.3760/cma.j.cn115330-20230712-00002 -
Frontiers in Immunology 2023The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers...
Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common and transcriptional silencing across advanced pediatric solid cancers.
The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of and transporter associated with antigen processing () genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers.
Topics: Adolescent; Child; Humans; Antigen Presentation; Glioma; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; HLA Antigens; HLA-B Antigens; Sarcoma, Ewing; Animals; Young Adult
PubMed: 38318504
DOI: 10.3389/fimmu.2023.1265469 -
Academic Radiology Jun 2024We evaluate the role of apparent diffusion coefficient (ADC) histogram metrics in stratifying pediatric and young adult rhabdomyosarcomas.
INTRODUCTION
We evaluate the role of apparent diffusion coefficient (ADC) histogram metrics in stratifying pediatric and young adult rhabdomyosarcomas.
METHODS
We retrospectively evaluated baseline diffusion-weighted imaging (DWI) from 38 patients with rhabdomyosarcomas (Not otherwise specified: 2; Embryonal: 21; Spindle Cell: 2; Alveolar: 13, mean ± std dev age: 8.1 ± 7.76 years). The diffusion images were obtained on a wide range of 1.5 T and 3 T scanners at multiple sites. FOXO1 fusion status was available for 35 patients, nine of whom harbored the fusion. 13 patients were TNM stage 1, eight had stage 2 disease, nine were stage 3, and eight had stage 4 disease. 23 patients belonged to Clinical Group III and seven to Group IV, while two and five were CG I and II, respectively. Nine patients were classified as low risk, while 21 and five were classified as intermediate and high risk respectively. Histogram parameters of the apparent diffusion coefficient (ADC) map from the entire tumor were obtained based on manual tumor contouring. A two-tailed Mann-Whitney U test was used for all two-group, and the Kruskal-Wallis's test was used for multiple-group comparisons. Bootstrapped receiver operating characteristic (ROC) curves and areas under the curve (AUC) were generated for the statistically significant histogram parameters to differentiate genotypic and phenotypic parameters.
RESULTS
Alveolar rhabdomyosarcomas had a statistically significant lower 10th Percentile (586.54 ± 164.52, mean ± std dev, values are in ×10-6mm/s) than embryonal rhabdomyosarcomas (966.51 ± 481.33) with an AUC of 0.85 (95%CI. 0.73-0.95) for differentiating the two. The 10th percentile was also significantly different between FOXO1 fusion-positive (553.87 ± 187.64) and negative (898.07 ± 449.38) rhabdomyosarcomas with an AUC of 0.83 (95% CI 0.71-0.94). Alveolar rhabdomyosarcomas also had statistically significant lower Mean, Median, and Root Mean Squared ADC histogram values than embryonal rhabdomyosarcomas. Four, five, and seven of the 18 histogram parameters evaluated demonstrated a statistically significant increase with higher TNM stage, clinical group, assignment, and pretreatment risk stratification, respectively. For example, Entropy had an AUC of 0.8 (95% CI. 0.67-0.92) for differentiating TNM stage 1 from ≥ stage 2 and 0.9 (95% CI. 0.8-0.98) for differentiating low from intermediate or high-risk stratification.
CONCLUSION
Our findings demonstrate the potential of ADC histogram metrics to predict clinically relevant variables for rhabdomyosarcoma, including FOXO1 fusion status, histopathology, Clinical Group, TNM staging, and risk stratification.
Topics: Humans; Child; Diffusion Magnetic Resonance Imaging; Male; Female; Adolescent; Retrospective Studies; Young Adult; Rhabdomyosarcoma; Child, Preschool; Phenotype; Adult; Genotype; Infant; Image Interpretation, Computer-Assisted; Forkhead Box Protein O1
PubMed: 38296742
DOI: 10.1016/j.acra.2024.01.011 -
Journal of Natural Products Feb 2024Neopetrotaurines A-C (-), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a sp. marine...
Neopetrotaurines A-C (-), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a sp. marine sponge. These new compounds have proton-deficient structural scaffolds that are difficult to unambiguously assign using only conventional 2- and 3-bond H-C and H-N heteronuclear correlation data. Thus, the application of LR-HSQMBC and HMBC NMR experiments optimized to detect 4- and 5-bond long-range H-C heteronuclear correlations facilitated the structure elucidation of these unusual taurine-bridged marine metabolites. Neopetrotaurines A-C (-) showed significant inhibition of transcription driven by the oncogenic fusion protein PAX3-FOXO1, which is associated with alveolar rhabdomyosarcoma, and cytotoxic activity against PAX3-FOXO1-positive cell lines.
Topics: Animals; Porifera; Rhabdomyosarcoma, Alveolar; Cell Line; Alkaloids; Isoquinolines
PubMed: 38294825
DOI: 10.1021/acs.jnatprod.3c01041 -
Pediatric Blood & Cancer Apr 2024The impact of established prognostic factors on survival outcomes for childhood rhabdomyosarcoma (RMS) have not been well described in the adolescent and young adult...
INTRODUCTION
The impact of established prognostic factors on survival outcomes for childhood rhabdomyosarcoma (RMS) have not been well described in the adolescent and young adult (AYA) RMS patient population.
METHODS
This is a retrospective analysis of patients with newly diagnosed RMS enrolled between 1997 and 2016 on seven previously reported Children's Oncology Group (COG) clinical trials. Demographics, clinical features, treatment details, and outcome data were collected. Five-year event-free survival (EFS) and overall survival (OS) were estimated for patients diagnosed at age 15-39 years and those diagnosed under age 15 years using the Kaplan-Meier method. Log-rank test was used to compare prognostic factors for EFS and OS. Factors significant in the univariable analysis were included in a Cox proportional hazards regression model. Nonsignificant covariates were removed from the multiple regression model.
RESULTS
Total 2151 patients including 402 AYAs were analyzed. AYAs were more likely to present with primary tumors ≥5 cm in size, metastatic disease, alveolar histology, and have FOXO1 fusions compared to children. Five-year EFS for the AYA cohort was 44.2% versus 67% for children (p < .001), and 5-year OS was 52% for the AYA cohort versus 78% for children (p < .001). Multivariable analysis revealed tumor site, size and invasiveness, clinical group, and histology were prognostic in AYAs.
CONCLUSION
AYAs with RMS have a poorer prognosis compared to younger children due to multiple factors. Further research focused on AYAs to better understand RMS biology and improve treatments is critical to improve survival.
Topics: Child; Humans; Adolescent; Young Adult; Adult; Retrospective Studies; Rhabdomyosarcoma; Prognosis; Rhabdomyosarcoma, Embryonal; Proportional Hazards Models; Soft Tissue Neoplasms
PubMed: 38282125
DOI: 10.1002/pbc.30847 -
Zhonghua Bing Li Xue Za Zhi = Chinese... Feb 2024
Topics: Humans; Rhabdomyosarcoma, Alveolar; Ascitic Fluid; Pleural Effusion
PubMed: 38281792
DOI: 10.3760/cma.j.cn112151-20231014-00261 -
Pediatric Blood & Cancer Apr 2024An international expert panel recently recommended 15 'non-stage prognostic indicators' (NSPIs) across eight childhood cancers, classified as essential or additional,...
BACKGROUND
An international expert panel recently recommended 15 'non-stage prognostic indicators' (NSPIs) across eight childhood cancers, classified as essential or additional, for collection in population-based cancer registries. We aimed to describe the incidence distribution and survival of each of these NSPIs.
PROCEDURES
Cases were extracted from the Australian Childhood Cancer Registry. The study cohort (n = 4187) comprised all children aged under 15 years diagnosed with an eligible cancer between 2010 and 2018, with follow-up until 31 December 2020. NSPI data were collected directly from each patient's medical records. Differences in 5-year relative survival were assessed using multivariable flexible parametric models, adjusted for sex and age group at diagnosis.
RESULTS
The availability of data varied, exceeding 85% for all essential NSPIs apart from histologic subtype for Wilms tumours (69%) and lineage for acute lymphoblastic leukaemia (78%). Information on additional NSPIs tended to be recorded less often, particularly cytogenetic subtype for non-alveolar rhabdomyosarcoma (28%) and astrocytoma (4%). Eight NSPIs exhibited a significant difference in survival, with the largest disparity occurring among children with astrocytoma according to tumour grade (5-year relative survival of 18% for grade IV disease compared with 99% for grade I disease; p < .001).
CONCLUSIONS
Our findings demonstrate that most of the recommended NSPIs can be retrieved from medical records in Australia in recent years, allowing the capability of assessing survival within patient subgroups of clinical interest. Reporting of NSPI data has the capability to inform local and global understanding of population-level disparities in childhood cancer survival.
Topics: Child; Humans; Infant; Neoplasms; Incidence; Prognosis; Australia; Astrocytoma; Registries; Kidney Neoplasms
PubMed: 38265260
DOI: 10.1002/pbc.30889 -
Cureus Dec 2023We report two cases of nasal alveolar rhabdomyosarcoma (ARMS) in adult patients from our center who presented with local mass effect and systemic involvement. Our first...
We report two cases of nasal alveolar rhabdomyosarcoma (ARMS) in adult patients from our center who presented with local mass effect and systemic involvement. Our first patient had spontaneous unilateral epistaxis. Her blood investigation showed severe thrombocytopenia, and the bone marrow biopsy result showed bone marrow infiltration by non-hematopoietic malignant cells. Nasal endoscopy showed a mass arising medial to the left middle turbinate. Our second patient presented with right eye proptosis, associated with blurring of vision. Nasal endoscopy showed a right whitish nasal mass arising lateral to the middle turbinate. Both patients were diagnosed by immunohistochemical analysis showing ARMS, a soft tissue malignancy uncommon in adults. RMS in adults has a worse prognosis. Hence, the management is challenging. Early diagnostic workup is essential for the commencement of early treatment for better oncological outcomes.
PubMed: 38222161
DOI: 10.7759/cureus.50430