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Molecules (Basel, Switzerland) Jul 2023Rhabdomyosarcoma (RMS) is a malignant tumour of the soft tissues. There are two main histopathological types: alveolar and embryonal. RMS occurs mainly in childhood and...
Rhabdomyosarcoma (RMS) is a malignant tumour of the soft tissues. There are two main histopathological types: alveolar and embryonal. RMS occurs mainly in childhood and is a result of the deregulation of growth and differentiation of muscle cell precursors. There is an increasing amount of data indicating that numerous epigenetic alterations within chromatin and histone proteins are involved in the pathogenesis of this malignancy. Histone acetylation is one of the most important epigenetic modifications that is catalysed by enzymes from the group of histone acetyltransferases (HAT). In this study, the impact of the natural histone acetyltransferase inhibitors (HATi)-garcinol (GAR) and anacardic acid (AA)-on the biology of RMS cells was evaluated through a series of in vitro tests measuring proliferation, viability, clonogenicity, cell cycle and apoptosis. Moreover, using oligonucleotide microarrays and real-time PCR, we identified several genes whose expression changed after GAR and AA treatment. The examined HATi significantly reduce the invasive phenotype of RMS cells by inhibiting the growth rate, viability and clonogenic abilities. What is more, these substances cause cell cycle arrest in the G2/M phase, induce apoptosis and affect the genetic expression of the endoplasmic reticulum stress sensors. GAR and AA may serve as promising potential anti-cancer drugs since they sensitize the RMS cells to chemotherapeutic treatment.
Topics: Humans; Histone Acetyltransferases; Histones; Cell Proliferation; Rhabdomyosarcoma; Cell Line, Tumor
PubMed: 37513165
DOI: 10.3390/molecules28145292 -
BMC Cancer Oct 2023Rhabdomyosarcoma is the most common soft tissue sarcoma in children, but rare in adults. Para-meningeal rhabdomyosarcoma in head and neck (PM-HNRMS) is less applicable...
BACKGROUND
Rhabdomyosarcoma is the most common soft tissue sarcoma in children, but rare in adults. Para-meningeal rhabdomyosarcoma in head and neck (PM-HNRMS) is less applicable for surgery due to the anatomic reason. PM-HNRMS has a poor prognosis in children. However, its clinical outcomes remain unclear in adults due to the rarity. Further, there is almost no detailed data about salvage therapy.
METHODS
We retrospectively examined the adult patients with PM-HNRMS treated at institutions belonging to the Kyushu Medical Oncology Group from 2009 to 2022. We evaluated the overall survival (OS) and progression-free survival (PFS) of the patients who received a first-line therapy. We also reviewed the clinical outcomes of patients who progressed against a first-line therapy and received salvage therapy.
RESULTS
Total 11 patients of PM-HNRMS received a first-line therapy. The characteristics were as follows: median age: 38 years (range 25 - 63 years), histology (alveolar/spindle): 10/1, and risk group (intermediate/high): 7/4. As a first-line therapy, VAC and ARST0431-based regimen was performed in 10 and 1 patients, respectively. During a first-line therapy, definitive radiation for all lesions were performed in seven patients. The median PFS was 14.2 months (95%CI: 6.0 - 25.8 months): 17.1 months (95%CI: 6.0 - not reached (NR)) for patients with stage I-III and 8.5 months (95%CI: 5.2 - 25.8 months) for patients with stage IV. The 1-year and 3-year PFS rates were 54.5% and 11.3% for all patients. Median OS in all patients was 40.8 months (95%CI: 12.1 months-NR): 40.8 months (95%CI: 12.1 - NR) for patients with stage I-III and NR for patients with stage IV. The 5-year OS rate was 48.5% for all patients. Among seven patients who received salvage therapy, three are still alive, two of whom remain disease-free for over 4 years after completion of the last therapy. Those two patients received multi-modal therapy including local therapy for all detected lesions.
CONCLUSION
The cure rate of adult PM-HNRMS is low in spite of a first-line therapy in this study. Salvage therapy might prolong the survival in patients who received the multi-modal therapy including local therapy for all detected lesions.
Topics: Adult; Humans; Middle Aged; Head and Neck Neoplasms; Japan; Neoplasm Recurrence, Local; Retrospective Studies; Rhabdomyosarcoma; Salvage Therapy
PubMed: 37904096
DOI: 10.1186/s12885-023-11528-4 -
Nature Communications Feb 2024Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1...
Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.
Topics: Child; Humans; Paired Box Transcription Factors; Rhabdomyosarcoma, Alveolar; Cell Line, Tumor; Rhabdomyosarcoma; Forkhead Box Protein O1; Oncogene Proteins, Fusion; Gene Expression Regulation, Neoplastic; PAX3 Transcription Factor; Jumonji Domain-Containing Histone Demethylases; Histone Demethylases
PubMed: 38402212
DOI: 10.1038/s41467-024-45902-y -
Clinical Cancer Research : An Official... Sep 2023Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC...
PURPOSE
Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701).
PATIENTS AND METHODS
Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT).
RESULTS
Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response.
CONCLUSIONS
The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.
Topics: Humans; Animals; Mice; Child; Adolescent; Young Adult; Adult; Dasatinib; src-Family Kinases; Insulin-Like Growth Factor I; Receptor, IGF Type 1; Rhabdomyosarcoma; Antineoplastic Combined Chemotherapy Protocols; Maximum Tolerated Dose
PubMed: 37398992
DOI: 10.1158/1078-0432.CCR-23-0709 -
Cells Jul 2021Rhabdomyosarcoma (RMS), is the most frequent soft tissue tumor in children that originates from disturbances in differentiation process. Mechanisms leading to the...
Rhabdomyosarcoma (RMS), is the most frequent soft tissue tumor in children that originates from disturbances in differentiation process. Mechanisms leading to the development of RMS are still poorly understood. Therefore, by analysis of two RMS RH30 cell line subclones, one subclone PAX7 negative, while the second one PAX7 positive, and comparison with other RMS cell lines we aimed at identifying new mechanisms crucial for RMS progression. RH30 subclones were characterized by the same STR profile, but different morphology, rate of proliferation, migration activity and chemotactic abilities in vitro, as well as differences in tumor morphology and growth in vivo. Our analysis indicated a different level of expression of adhesion molecules (e.g., from VLA and ICAM families), myogenic microRNAs, such as miR-206 and transcription factors, such as MYOD, MYOG, SIX1, and ID. Silencing of PAX7 transcription factor with siRNA confirmed the crucial role of PAX7 transcription factor in proliferation, differentiation and migration of RMS cells. To conclude, our results suggest that tumor cell lines with the same STR profile can produce subclones that differ in many features and indicate crucial roles of PAX7 and ID proteins in the development of RMS.
Topics: Animals; Cell Adhesion Molecules; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Differentiation Proteins; Mice, Inbred NOD; Mice, SCID; MicroRNAs; Neoplasm Invasiveness; PAX7 Transcription Factor; Rhabdomyosarcoma, Alveolar; Signal Transduction; Tumor Burden; Mice
PubMed: 34440639
DOI: 10.3390/cells10081870 -
BMJ Case Reports Apr 2022Rhabdomyosarcoma is a rare mesenchymal malignancy with four different morphological subtypes: alveolar, embryonal, pleomorphic and spindle cell/sclerosing. It is the...
Rhabdomyosarcoma is a rare mesenchymal malignancy with four different morphological subtypes: alveolar, embryonal, pleomorphic and spindle cell/sclerosing. It is the most common soft tissue sarcoma of children and adolescents but occurs less commonly in adults. We describe a male patient in his 20s with sclerosing rhabdomyosarcoma of the left cheek who developed an isolated free flap donor site metastasis in the first instance but subsequently progressed with bilateral pulmonary metastases. Multidisciplinary team involvement in a sarcoma specialist centre is essential and collaboration between the pathologist, radiologist, head and neck surgeon, orthopaedic surgeon, radiation oncologist and medical oncologist were integral in providing optimal management in this patient. Furthermore, this case report highlights this phenomenon of implantation metastasis in a patient with rhabdomyosarcoma, and emphasises the importance of surgical barriers between the resection and reconstruction teams in an oncological case.
Topics: Adolescent; Adult; Cheek; Child; Free Tissue Flaps; Humans; Male; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Soft Tissue Neoplasms
PubMed: 35393277
DOI: 10.1136/bcr-2021-248390 -
Journal of Neurological Surgery. Part... Aug 2022The role of surgery in management of sinonasal rhabdomyosarcoma (SNRMS) has traditionally been limited, owing to anatomic and technological challenges and the...
The role of surgery in management of sinonasal rhabdomyosarcoma (SNRMS) has traditionally been limited, owing to anatomic and technological challenges and the established role of systemic therapy. Herein, we report our institutional experience with surgical management of SNRMS, with a particular focus on operative approaches, extent and outcomes. This study is a retrospective cohort study. This study was conducted at a single-institution, academic center. Patients of any age with histologically confirmed RMS of the nasal cavity, maxillary, ethmoid, frontal, or sphenoid sinus, nasolacrimal duct, or nasopharynx presenting between 1994 and 2020 were included in this study. Demographics, tumor characteristics, operative settings, complications and recurrence, and survival outcomes were the primary outcomes of this study. Our study cohort comprised of 29 patients (mean [range] age: 27.0 [3.1-65.7], = 12 [41%] female). Tumors of the nasal cavity ( = 10, 35%) and ethmoid sinuses ( = 10, 35%) and those with alveolar histology ( = 21, 72%) predominated. Patients who had surgery as part of their treatment ( = 13, 45%) had improved distant metastasis-free survival (DMFS) overall (hazard ratio [HR]: 0.32, 95% CI: 0.11, 0.98, = 0 ) as compared with those who did not have surgery. Surgical approaches included open ( = 7), endoscopic ( = 4), and combined ( = 2). Eight of these 13 patients (62%) had an R0 resection. Additionally, surgical salvage of recurrent disease was employed in five patients (17%). SNRMS is an aggressive malignancy with a high rate of recurrence and spread requiring a multidisciplinary approach for optimal outcomes. Our data supports an expanding role for surgery for SNRMS given its feasibility, tolerability, and potential to improve outcomes.
PubMed: 35903658
DOI: 10.1055/s-0041-1736590 -
Frontiers in Pediatrics 2021The head and neck (HN) are the most frequent sites of pediatric rhabdomyosarcoma (RMS). Alveolar RMS (ARMS) represents ~20% of all RMS cases and frequently spread to...
INTRODUCTION
The head and neck (HN) are the most frequent sites of pediatric rhabdomyosarcoma (RMS). Alveolar RMS (ARMS) represents ~20% of all RMS cases and frequently spread to lymph nodes (LNs). The aim was to report locoregional control, event-free survival (EFS), and overall survival (OS), according to clinical and pathological features, LN staging, and treatment modalities.
METHODS
The study included all patients prospectively enrolled in EpSSG RMS 2005 study under 21 years of age with localized HN ARMS and diagnosed between 2005 and 2016 in France. Medical data including imaging, surgical report, and radiation therapy planes were analyzed.
RESULTS
Forty-eight patients (median age 6 years; range 4 months-21 years), corresponding to 30 parameningeal and 18 non-parameningeal ARMS, were included. There were 33 boys (69%). Tumor locations included the following: orbit ( = 7) among which four cases had bone erosion, paranasal sinuses and nasal cavity ( = 16), deep facial spaces ( = 10), nasolabial fold ( = 8), and other non-parameningeal HN sites ( = 7). A fusion transcript of PAX3-FOXO1 or PAX7-FOXO1 was expressed in 33 of the 45 cases (73%) with molecular analysis. At diagnosis, 10 patients had primary resection of the primary tumor (PRPT) (none with microscopic complete resection) and 9 had LN staging. After induction chemotherapy, 26 patients (54%) had secondary resection of the primary tumor (SRPT) and 13 patients (27%) had cervical LN dissection. A total of 43 patients (90%) were treated with radiation therapy.With a median follow-up of 7 years (range 2-13 years), 5-year OS and EFS were 78% (95% CI, 63-88%) and 66% (95% CI, 51-78%), respectively. We observed 16 events (10 deaths): 4 local, 4 regional, 1 local and regional, and 7 metastatic. In univariate analysis, OS was only superior for patients under 10 years of age ( = 0.002), while -negative ARMS, SRPT for parameningeal ARMS, and LN surgery were associated with significantly better EFS.
CONCLUSION
Our study confirms a better outcome for fusion-negative ARMS and ARMS in children under 10 years. Moreover, LN surgery and SRPT of parameningeal tumor may improve EFS of ARMS. Larger studies are needed to confirm our findings.
PubMed: 35186818
DOI: 10.3389/fped.2021.783754 -
Pakistan Journal of Medical Sciences 2020To investigate the clinical characteristics and treatment methods of rhabdomyosarcoma in children and the efficacy of the methods.
OBJECTIVE
To investigate the clinical characteristics and treatment methods of rhabdomyosarcoma in children and the efficacy of the methods.
METHODS
The clinical data of 30 children with rhabdomyosarcoma who were admitted to our hospital from August 2013 to August 2017 were retrospectively analyzed. The clinical characteristics were summarized, and the curative effect and prognosis were evaluated.
RESULTS
Among all the children (N=30), there were 20 males and 10 females, with a median age of 3.5 years. As to the primary site, there were 13 cases of head and neck, 11 cases of trunk, three cases of urogenital system and three cases of limbs. There were 25 cases of embryonic type, 4 cases of alveolar type and one case of polymorphic type. As regards clinical stage, there were one case of stage I, 9 cases of stage II, 13 cases of stage III and 7 cases of stage IV. There were one case of low risk, 19 cases of medium risk and 10 cases of high risk. Eight cases received surgery alone, 22 cases received combined treatment of surgery and chemotherapy (the chemotherapeutics followed three schemes, low-risk group (VAC+VA), moderate risk group (VAC) and high risk group (alternating use of VDC and IE). Among all the cases (N=30), there were 14 cases of complete remission (CR), five cases of partial remission (PR), four cases of stable disease (SD), and 7 cases of progressive disease (PD). The CR rate was (N=14, 46.7%). The three-year overall survival (OS) rate was (N=19, 63.3%). The clinical efficacy and prognosis of children receiving surgery and chemotherapy were better than those of children receiving surgery alone, and the difference was statistically significant (P<0.05).
CONCLUSION
Rhabdomyosarcoma in children frequently happens in the head, neck and trunk. Embryonic type is the main pathological type of rhabdomyosarcoma. Comprehensive and standardized treatment based on surgery and chemotherapy is an important way to improve the curative effect in the treatment of rhabdomyosarcoma in children.
PubMed: 32704291
DOI: 10.12669/pjms.36.5.1829 -
Journal of Clinical Oncology : Official... May 2023Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought to evaluate strategies for identifying circulating tumor...
PURPOSE
Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought to evaluate strategies for identifying circulating tumor DNA (ctDNA) in IR RMS and to determine whether ctDNA detection before therapy is associated with outcome.
PATIENTS AND METHODS
Pretreatment serum and tumor samples were available from 124 patients with newly diagnosed IR RMS from the Children's Oncology Group biorepository, including 75 patients with fusion-negative rhabdomyosarcoma (FN-RMS) and 49 with fusion-positive rhabdomyosarcoma (FP-RMS) disease. We used ultralow passage whole-genome sequencing to detect copy number alterations and a new custom sequencing assay, Rhabdo-Seq, to detect rearrangements and single-nucleotide variants.
RESULTS
We found that ultralow passage whole-genome sequencing was a method applicable to ctDNA detection in all patients with FN-RMS and that ctDNA was detectable in 13 of 75 serum samples (17%). However, the use of Rhabdo-Seq in FN-RMS samples also identified single-nucleotide variants, such as , previously associated with prognosis. Identification of pathognomonic translocations between or and by Rhabdo-Seq was the best method for measuring ctDNA in FP-RMS and detected ctDNA in 27 of 49 cases (55%). Patients with FN-RMS with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (event-free survival, 33.3% 68.9%; = .0028; overall survival, 33.3% 83.2%; < .0001) as did patients with FP-RMS (event-free survival, 37% 70%; = .045; overall survival, 39.2% 75%; = .023). In multivariable analysis, ctDNA was independently associated with worse prognosis in FN-RMS but not in the smaller FP-RMS cohort.
CONCLUSION
Our study demonstrates that baseline ctDNA detection is feasible and is prognostic in IR RMS.
Topics: Humans; Child; Prognosis; Circulating Tumor DNA; Rhabdomyosarcoma; Nucleotides; Rhabdomyosarcoma, Alveolar; Biomarkers, Tumor
PubMed: 36724417
DOI: 10.1200/JCO.22.00409