Alveolar Rhabdomyosarcoma Research Articles

Combined low-pass whole genome and targeted sequencing in liquid biopsies for pediatric solid tumors

We designed a liquid biopsy (LB) platform employing low-pass whole genome sequencing (LP-WGS) and targeted sequencing of cell-free (cf) DNA from plasma to detect genome-wide copy number alterations (CNAs) and gene fusions in pediatric solid tumors. A total of 143 plasma samples were analyzed from 19 controls and 73 patients, including 44 bone or soft-tissue sarcomas and 12 renal, 10 germ cell, five hepatic, and two thyroid tumors. cfDNA was isolated from plasma collected at diagnosis, during and after therapy, and/or at relapse. Twenty-six of 37 (70%) patients enrolled at diagnosis without prior therapy (radiation, surgery, or chemotherapy) had circulating tumor DNA (ctDNA), based on the detection of CNAs from LP-WGS, including 18 of 27 (67%) patients with localized disease and eight of 10 (80%) patients with metastatic disease. None of the controls had detectable somatic CNAs. There was a high concordance of CNAs identified by LP-WGS to CNAs detected by chromosomal microarray analysis in the matching tumors. Mutations identified in tumor samples with our next-generation sequencing (NGS) panel, OncoKids®, were also detected by LP-WGS of ctDNA in 14 of 26 plasma samples. Finally, we developed a hybridization-based capture panel to target EWSR1 and FOXO1 fusions from patients with Ewing sarcoma or alveolar rhabdomyosarcoma (ARMS), respectively. Fusions were detected in the plasma from 10 of 12 patients with Ewing sarcoma and in two of two patients with ARMS. Combined, these data demonstrate the clinical applicability of our LB platform to evaluate pediatric patients with a variety of solid tumors.

Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance.

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.

11C-Methionine PET/CT and 18F-FDG PET/CT in the Evaluation of Adult Alveolar Rhabdomyosarcoma.

A 70-year-old man with a tumor in the nasal and paranasal space, was pathologically diagnosed with an alveolar rhabdomyosarcoma, with right cervical lymph node metastasis. Magnetic resonance imaging revealed a primary tumor in the nasal and paranasal sinuses, with associated intracranial infiltration. 11C-methionine positron emission tomography/computed tomography (PET/CT) revealed increased uptake in the primary tumor and right cervical lymph node metastasis. 18F-fluorodeoxyglucose PET/CT also revealed increased uptake in the primary tumor and right cervical lymph node. However, the physiological brain uptake overlapped with the primary tumor uptake. Our case suggests the usefulness of 11C-methionine PET/CT for accurately assessing the extent of alveolar rhabdomyosarcoma, especially in cases with intracranial infiltration or those approximating the brain.

PAX-FOXO1 fusion status in children and adolescents with alveolar rhabdomyosarcoma: Impact on clinical, pathological, and survival features.

Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer and cases with fusion PAX3-FOXO1 and PAX7-FOXO1 seem to have a poor prognosis. The aim is to evaluate whether PAX-FOXO1 alterations influence clinical outcome in childhood and adolescence population with ARMS. A population-based study was conducted between 2011 and 2016 in patients less than 17years with a diagnosis of ARMS. Overall survival (OS) depending on fusion status with clinical factors was analyzed. Out of 111 ARMS patients recorded in the French National Childhood Cancer Registry during the 2011-2016 period, 61% expressed PAX3-FOXO1, 15% expressed PAX7-FOXO1, 13% were FOXO1 fusion-positive without PAX specification, and 7% were PAX-FOXO1 negative (n=4 missing data). Compared to patients with PAX7-FOXO1 positive ARMS, those with PAX3-FOXO1 positive tumor were significantly older (10-17years: 57.4% vs. 29.4%), and had more often a metastatic disease (54.4% vs. 23.5%). Poorer 5-year OS for patients with PAX3-FOXO1 and PAX not specified FOXO1-positive tumor were observed (44.0% [32.0-55.4] and 35.7% [13.1-59.4], respectively). After adjustment for stage at diagnosis, patients with positive tumor for PAX3-FOXO1 were 3.6-fold more likely to die than those with positive tumor for PAX7-FOXO1. At the population level, PAX3-FOXO1 was associated with a significant higher risk of death compared to PAX7-FOXO1-positive and PAX-FOXO1-negative tumors, and could explain poorer 5-year OS observed in adolescence population diagnosed with ARMS. A continuous risk score derived from the combination of clinical parameters with PAX3-FOXO1 fusion status represents a robust approach to improving current risk-adapted therapy for ARMS.

Surfaceome Profiling of Cell Lines and Patient-Derived Xenografts Confirm FGFR4, NCAM1, CD276, and Highlight AGRL2, JAM3, and L1CAM as Surface Targets for Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis for patients with high-grade and metastatic disease is still very poor, and survivors are burdened with long-lasting side effects. Therefore, more effective and less toxic therapies are needed. Surface proteins are ideal targets for antibody-based therapies, like bispecific antibodies, antibody-drug conjugates, or chimeric antigen receptor (CAR) T-cells. Specific surface targets for RMS are scarce. Here, we performed a surfaceome profiling based on differential centrifugation enrichment of surface/membrane proteins and detection by LC-MS on six fusion-positive (FP) RMS cell lines, five fusion-negative (FN) RMS cell lines, and three RMS patient-derived xenografts (PDXs). A total of 699 proteins were detected in the three RMS groups. Ranking based on expression levels and comparison to expression in normal MRC-5 fibroblasts and myoblasts, followed by statistical analysis, highlighted known RMS targets such as FGFR4, NCAM1, and CD276/B7-H3, and revealed AGRL2, JAM3, MEGF10, GPC4, CADM2, as potential targets for immunotherapies of RMS. L1CAM expression was investigated in RMS tissues, and strong L1CAM expression was observed in more than 80% of alveolar RMS tumors, making it a practicable target for antibody-based therapies of alveolar RMS.

GLI1 Immunohistochemistry Distinguishes Mesenchymal Neoplasms With GLI1 Alterations From Morphologic Mimics.

Glioma-associated oncogene 1 ( GLI1 ) alterations have been described in pericytoma with t(7;12), gastroblastoma, plexiform fibromyxoma, and an emerging class of GLI1 -rearranged or amplified mesenchymal neoplasms including "nested glomoid neoplasm". The immunophenotype of these tumor types is nonspecific, making some cases difficult to diagnose without sequencing. The utility of GLI1 immunohistochemistry (IHC) in distinguishing nested glomoid neoplasms and pericytomas with t(7;12) from morphologic mimics is unknown. To investigate the diagnostic value of GLI1 IHC, we determined its sensitivity and specificity in a "test cohort" of 23 mesenchymal neoplasms characterized by GLI1 alterations, including 12 nested glomoid neoplasms (7 GLI1 -rearranged, 4 GLI1 amplified, and 1 unknown GLI1 status), 9 pericytomas with t(7;12), 1 gastroblastoma, and 1 malignant epithelioid neoplasm with PTCH1 :: GLI1 fusion. GLI1 IHC was 91.3% sensitive in this cohort; all tumors except 2 pericytomas with t(7;12) expressed GLI1. GLI1 was also expressed in 1 of 8 (12%) plexiform fibromyxomas. Nineteen of 22 GLI1-positive tumors showed nuclear and cytoplasmic staining, while 3 showed nuclear staining only. GLI1 IHC was 98.0% specific; among morphologic mimics [40 well-differentiated neuroendocrine tumors, 10 atypical lung carcinoids, 20 paragangliomas, 20 glomus tumors, 20 solitary fibrous tumors, 10 Ewing sarcomas, 10 alveolar rhabdomyosarcomas (ARMS), 10 BCOR -altered sarcomas, 10 myoepitheliomas, 9 myopericytomas, 9 epithelioid schwannomas, 9 ossifying fibromyxoid tumors, 10 biphasic synovial sarcomas, 10 PEComas, 31 gastrointestinal stromal tumors, 10 inflammatory fibroid polyps, 11 pseudoendocrine sarcomas], 5 of 249 tumors expressed GLI1 (2 well-differentiated neuroendocrine tumors, 1 ARMS, 1 Ewing sarcoma, 1 BCOR -altered sarcoma). GLI1 IHC was also performed on a separate cohort of 13 molecularly characterized mesenchymal neoplasms in which GLI1 copy number gain was identified as a putatively secondary event by DNA sequencing (5 dedifferentiated liposarcoma [DDLPS], 2 adenosarcomas, 2 unclassified uterine sarcomas, 1 leiomyosarcoma, 1 ARMS, 1 intimal sarcoma, 1 osteosarcoma); 2 DDLPS, 1 ARMS, and 1 unclassified uterine sarcoma expressed GLI1. Lastly, because pleomorphic sarcomas sometimes show GLI1 amplification or copy number gain, GLI1 IHC was performed on a separate "pleomorphic sarcoma" cohort: GLI1 was expressed in 1 of 27 DDLPS, 1 of 9 leiomyosarcomas, and 2 of 10 pleomorphic liposarcomas, and it was negative in 23 well-differentiated liposarcomas and 9 unclassified pleomorphic sarcomas. Overall, GLI1 IHC was 91.3% sensitive and 98.0% specific for mesenchymal tumor types with driver GLI1 alterations among morphologic mimics. GLI1 expression was less frequent in other tumor types with GLI1 copy number gain. Given its specificity, in the appropriate morphologic context, GLI1 IHC may be a useful diagnostic adjunct for mesenchymal neoplasms with GLI1 alterations.

Histone variant H3.3 promotes metastasis in alveolar rhabdomyosarcoma.

The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto. In this study, we show that histone variant H3.3 is overexpressed in alveolar RMS (ARMS), an aggressive subtype of RMS. Functionally, knockdown of H3F3A, which encodes for H3.3, significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent in vivo. Using RNA-sequencing and ChIP-sequencing analyses, we identified melanoma cell adhesion molecule (MCAM/CD146) as a direct downstream target of H3.3. Loss of H3.3 resulted in a reduction in the presence of active marks and an increase in the occupancy of H1 at the MCAM promoter. Cell migration and invasion were rescued in H3F3A-depleted cells through MCAM overexpression. Moreover, we identified G9a, a lysine methyltransferase encoded by EHMT2, as an upstream regulator of H3F3A. Therefore, this study identifies a novel H3.3 dependent axis involved in ARMS metastasis. These findings establish the potential of MCAM as a therapeutic target for high-risk ARMS patients. © 2022 The Pathological Society of Great Britain and Ireland.

Alveolar rhabdomyosarcoma: novel surrogate markers associated with oncogenic translocation

Anomalies of the FOXO1 gene in alveolar rhabdomyosarcoma are associated with a worse clinical prognosis, which determines the high value of studying the status of this gene when choosing a therapy strategy. The «gold standard» for determining FOXO1 gene rearrangements is currently the fluorescent in situ hybridization (FISH) technique. Study of the relationship between canonical FOXO1 translocation and immunohistochemical expression of new surrogate markers in alveolar rhabdomyosarcoma to determine their predictive value. 139 cases of rhabdomyosarcoma were retrospectively studied. The study used tissue matrix technology (TMA). On sections obtained from TMA blocks, the FISH technique was implemented using the locus-specific probe MetaSystems XL FOXO1 Break Apart (Metasystems, Germany). Immunohistochemical studies were performed on similar sections from TMA blocks with OLIG2 (Cell Marque Antibodies, clone 211F1.1) and MUC4 (Cell Marque Antibodies, clone 8G7) antibodies. The final expression analysis and statistical processing using a 2x2 contingency table and Fisher's exact test passed 111 cases (76 without FOXO1 rearrangement and 35 with rearrangement). The specificity of OLIG2 and MUC4 expression for FOXO1-rearranged alveolar rhabdomyosarcoma was 85.53% and 80.26%, respectively (p<0.01). The present study confirms the high predictive value of the expression of surrogate markers OLIG2 and MUC4 in determining the genetic status of alveolar rhabdomyosarcoma, which makes it possible to predict with high specificity the detection of the FOXO1 gene rearrangement.

Metastatic appendicular soft tissue sarcoma: treatment and survival outcomes of 2,553 patients from the SEER database

Introduction: Patients with soft tissue sarcoma (STS) that present with metastasis at diagnosis have a dire prognosis. Within this patient population, we sought to assess: (1) demographic and clinical characteristics, (2) metastatic patterns, (3) treatment strategies, and (4) disease-specific survival (DSS). Materials and Methods: The SEER database was queried to identify patients with histologically confirmed STS of the pelvis or extremity. Univariate and multivariate analysis was performed using the Cox proportional hazards model. Disease-specific survival (DSS) was analyzed using the Kaplan-Meier method. Results: A total of 22,683 patients were retrieved, out of which 2,553 (11.3%) had metastasis at diagnosis. Leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), liposarcoma, synovial sarcoma, spindle cell sarcoma, and alveolar rhabdomyosarcoma (A-RMS) were the six most common STS presenting with metastasis. Among patients with metastasis, 53.7% and 33.2% of patients had primary tumors located in the lower limb and pelvis, respectively. Lung was the most common site of metastasis in all subtypes except A-RMS, in which bone metastases and lymph node (LN) predominated (85.2% and 62.1%, respectively). Chemotherapy and radiotherapy were associated with higher DSS (HR = 0.788 and HR = 0.755, respectively). Five-year DSS was below 20% in all tumor histologies. Two-year DSS for patients with synchronous lung and liver metastases was 28%. Conclusion: Although the lung was the most common site of metastasis, metastatic patterns are highly variable depending on tumor histology. Metastatic A-RMS is most commonly presented with regional LN and bone involvement. Disease-specific survival remained poor for patients with metastatic disease at presentation regardless of (neo)-adjuvant radiotherapy or chemotherapy.

National assessment of lymph node status indicators & predictors in pediatric head and neck rhabdomyosarcomas in the US.

Assessing the prognostic utility of lymph node status in pediatric rhabdomyosarcoma (RMS) patients and identifying demographic and clinical predictors of positive lymph node status among pediatric rhabdomyosarcoma patients. Retrospective cohort study of head and neck RMS in patients with and without positive lymph node metastasis. National Cancer Database (NCDB) was queried for patients of young (0-11 years) and adolescent (12-21 years) ages with head and neck RMS and confirmed positive or negative lymph node metastasis status. Descriptive analyses, Kaplan-Meier survival analyses, and multivariate logistic regressions were performed on extracted demographic and clinical characteristics. Among 272 head and neck RMS patients, 146 (54%) were found to have positive lymph node metastasis. Alveolar RMS (n=147, 54%) followed by embryonal RMS (n=74, 27%) were the most represented histology types. Positive lymph node metastasis conferred significantly decreased survivability (p<0.001) with a median survival period of 36.42 months compared to negative lymph node metastasis with a period of 53.47 months. Older age showed markedly increased odds (OR-2.02; 95%CI 1.22-3.38) of having lymph node metastasis when controlling for sex, race, insurance status, and Charlson-Comorbidity score. Alveolar histologies showed markedly increased odds of having lymph node metastasis (OR-3.21; 95%CI 1.96-5.31); embryonal histologies showed markedly decreased odds of having lymph node metastasis (OR-0.32; 95%CI 0.18-0.56) CONCLUSIONS: This study highlights the significant prognostic value of lymph node status among pediatric head and neck rhabdomyosarcoma patients while showcasing crucial demographic and pathological predictors of lymph node metastasis in said patients. Use of lymph node status in pediatric head and neck rhabdomyosarcoma will present future steps towards improving its clinical course.

Primary Cutaneous Diffuse Large B Cell Lymphoma, Leg Type: A Rare Neoplasm Masquerading as Squamous Cell Carcinoma

Primary Cutaneous Diffuse Large B Cell Lymphoma, Leg Type (PCDLBCL, LT) comprises 4% of all cutaneous lymphomas, and it presents as an aggressive form of lymphoma. Rarely do pathologist/cytologists find specimens of PCDLBCL, LT on Fine Needle Aspiration Cytology (FNAC). The mimickers on FNAC are metastatic small cell carcinoma, Merkel Cell Carcinoma (MCC), Malignant Melanoma (MM), Cutaneous Alveolar Rhabdomyosarcoma and Primary Cutaneous Ewing's Sarcoma (PCES). A 75-year-old female patient presented in the Department of Surgery with multiple nodules on the leg for three months. On cytology small round cell tumour with possibility of non hodgkin lymphoma was given and biopsy was advised. The confirmation of PCDLBCL, LT on cytology is not recommended however, it is emphasised that it can be picked up on FNAC and distinguished from its mimickers. Because of the aggressive nature and poor prognosis with the frequent relapses and tendency for extracutaneous spread, it is considered to be a distinct type of cutaneous lymphoma which needs to be diagnosed and treated as early as possible.

Sinonasal Rhabdomyosarcoma in a Child: Case Report and Review of the Literature

Rhabdomyosarcoma is a malignant soft-tissue neoplasm of skeletal muscle origin, which predominantly affects the young population. Embryonal and alveolar are the most common histological subtypes of rhabdomyosarcoma. We present a case of a 3-year-old child with alveolar rhabdomyosarcoma arising from the left nasal cavity.

&lt;i&gt;FOXO1&lt;/i&gt;-negative alveolar rhabdomyosarcoma: a case report of a rare tumor

The results of modern research confirm the importance of an accurate assessment of the molecular pathogenesis of soft tissue tumors. The use of next-generation sequencing can be effective both for finding targets for targeted therapy and predicting aggressive behavior of tumors, and for clarifying the diagnosis in non-standard cases. Here, we report a case of FOXO1-negative alveolar rhabdomyosarcoma in a 3-year-old child. To verify the diagnosis of this patient, we used high-throughput sequencing. Using the Trusight Tumor 170 gene panel (Illumina, USA), we carried out molecular genetic testing of the patient’s tumor sample and discovered a rare NZD1-FGFR4 translocation that had not been previously reported to occur in alveolar rhabdomyosarcoma. The patient’s parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Analysis of anaplastic lymphoma kinase status in rhabdomyosarcomas: correlation with clinicopathological findings

Introduction. Rhabdomyosarcoma (RMS) is a highly malignant tumor occurring mostly in children. Multimodal therapy is currently promising, however, in patients with high risk (per the stratification scale) low survival rates are observed. There remains a necessity for new possibilities in treatment of this category of patients. Currently, anaplastic lymphoma kinase (ALK) is of considerable interest.Aim. To study expression of ALK as a potential target marker in RMS tissues.Materials and methods. In total, 202 histological RMS blocks were studied. ALK expression was qualitatively measured using immunohistochemistry, and its correlation with histological tumors subtype and patient’s clinical data was evaluated.Results. ALK expression in samples of alveolar RMS was observed in 68 % (41/60) of cases, samples of embryonal RMS in 30 % (26/87) cases, samples of spindle cell/sclerosing RMS in 7 % (1/14) of cases, samples of epithelioid RMS (EpiRMS) in 100 % (2/2) of cases. The study showed correlation between ALK expression and alveolar RMS subtype (р &lt;0.05). In all cases of alveolar RMS with focal ALK D5F3 expression, primarily low or moderate activity levels against anti-myogenin and MyoD1 were observed. ALK-positive samples in the embryonal and spindle cell/sclerosing RMS samples were rarer.Conclusion. The results show that ALK is a promising target for treatment of patients with RMS. Further study of additional genetic aberrations of ALK is planned which could serve as a springboard for development of targeted therapy.

Transcription regulators and ultra-rare and other rare translocation-related sarcomas treated with trabectedin: A proof of principle from a post-hoc analysis.

Among sarcomas, which are rare cancers with an incidence of <6 per 100.000/year cases, ultra-rare sarcomas have an incidence of approximately ≤1/1,000,000/year cases and altogether account for ~20% of all soft tissue sarcomas (STS) and bone sarcomas. The Italian Sarcoma Group has recently performed a non-interventional, retrospective TrObs study with data from 512 anthracycline-pretreated patients with advanced multiple STS histologies and treated with trabectedin (Palmerini, Cancers 2021; ClinicalTrials.gov Identifier: NCT02793050). A post-hoc analysis of case series to evaluate the efficacy and safety of trabectedin on patients with ultra-rare and other rare translocation-related sarcomas included in TrObs study was performed. Main outcomes comprised investigator-assessed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Thirty-six patients (18 women) with ultra-rare and other rare sarcoma and a median age of 53.0 years (range: 22-81) were included. Most patients had solitary fibrous tumor (SFT; n=11) followed by epithelioid sarcoma (n=5), malignant peripheral nerve sheath tumor (MPNST; n=4), extraskeletal myxoid chondrosarcoma (EMC; n=3), desmoplastic small round cell tumor (DSRCT; n=3), and alveolar soft part sarcoma (ASPS), rhabdomyosarcoma and clear cell sarcoma (n=2 each). Thirty-five patients had metastatic disease and 23 patients received trabectedin as a second-line treatment. Among 35 patients evaluable for response, two patients with SFT and ASPS had a partial response and one patient with DSRCT obtained a complete response, reaching an ORR of 8.6% (95% CI: 2.8-23.4%). Among patients with an ORR, 6-months PFS was 100% in patients with ASPS, 45.7% in patients with SFT and 33.3% in those with DSRCT. Two patients with epithelioid sarcoma and myoepithelioma had disease stabilization lasting >24 months. Nine patients had at least one grade 3/4 adverse event, mostly being bone marrow toxicity (n=6). Trabectedin has some anti-tumor activity in some ultra-rare and other rare sarcomas, particularly translocation-related sarcomas, with the well-known manageable safety profile.

FOXO1 and PAX5 Rearrangement in Alveolar Rhabdomyosarcoma in Saudi Pediatric Patients

Objective: In this study, we investigate the molecular rearrangement of FOXO1 in alveolar rhabdomyosarcoma (ARHS) in Saudi pediatric patients. Method: We performed a molecular detection of molecular translocation in 30 pediatric cases of ARHS using FOXO1 dual color break-apart FISH probe (ZytoLight®, 13q14.11) and PAX5 dual color break-apart FISH probe (ZytoLight®, 9p13.2). Results: All analyzable cases of ARHS demonstrated FOXO1 translocation whereas PAX5 translocation was not detected in any case. Conclusion: Although the testing for PAX5 rearrangement was based on protein–protein network analysis, our study showed that PAX5 translocation is not conspicuous in ARHS. PAX7/3::FOXO1 fusion genes feature ARMS, rendering crossreactivity between PAX7 and PAX3 a possible explanation. Nevertheless, PAX5 immunoreactivity and molecular translocation could be an adjunctive pathway that is confined to aggressive ARMS.

Primary alveolar rhabdomyosarcoma of the breast skin: a case report and literature review

Alveolar rhabdomyosarcoma is one of the four subtypes of rhabdomyosarcoma identified by the World Health Organization. This type of malignant neoplasms more often affects deep soft tissues of extremities and occurs in young ages, regardless of gender. According to the medical literature, no more than 45 cases of the development of primary cutaneous rhabdomyosarcoma have been reported in the world. In this report, we describe a clinical case of a 40-year-old woman with primary localization of alveolar radbomyosarcoma in the skin of the mammary gland.

The botanical drug PBI-05204, a supercritical CO2 extract of Nerium oleander, sensitizes alveolar and embryonal rhabdomyosarcoma to radiotherapy in vitro and in vivo.

Treatment of rhabdomyosarcoma (RMS), the most common a soft tissue sarcoma in childhood, provides intensive multimodal therapy, with radiotherapy (RT) playing a critical role for local tumor control. However, since RMS efficiently activates mechanisms of resistance to therapies, despite improvements, the prognosis remains still largely unsatisfactory, mainly in RMS expressing chimeric oncoproteins PAX3/PAX7-FOXO1, and fusion-positive (FP)-RMS. Cardiac glycosides (CGs), plant-derived steroid-like compounds with a selective inhibitory activity of the Na+/K+-ATPase pump (NKA), have shown antitumor and radio-sensitizing properties. Herein, the therapeutic properties of PBI-05204, an extract from Nerium oleander containing the CG oleandrin already studied in phase I and II clinical trials for cancer patients, were investigated, in vitro and in vivo, against FN- and FP-RMS cancer models. PBI-05204 induced growth arrest in a concentration dependent manner, with FP-RMS being more sensitive than FN-RMS, by differently regulating cell cycle regulators and commonly upregulating cell cycle inhibitors p21Waf1/Cip1 and p27Cip1/Kip1. Furthermore, PBI-05204 concomitantly induced cell death on both RMS types and senescence in FN-RMS. Notably, PBI-05204 counteracted in vitro migration and invasion abilities and suppressed the formation of spheroids enriched in CD133+ cancer stem cells (CSCs). PBI-05204 sensitized both cell types to RT by improving the ability of RT to induce G2 growth arrest and counteracting the RT-induced activation of both Non-Homologous End-Joining and homologous recombination DSBs repair pathways. Finally, the antitumor and radio-sensitizing proprieties of PBI-05204 were confirmed in vivo. Notably, both in vitro and in vivo evidence confirmed the higher sensitivity to PBI-05204 of FP-RMS. Thus, PBI-05204 represents a valid radio-sensitizing agent for the treatment of RMS, including the intrinsically radio-resistant FP-RMS.

Management challenges of sinonasal alveolar rhabdomyosarcoma in infanthood: case report and literature review

&lt;p class="abstract"&gt;Alveolar rhabdomyosarcoma (aRMS) is an aggressive soft tissue malignant neoplasm. It’s not known to occur often in the sinonasal region of an infant when compared with other histological types. And due to its aggressive nature in deep-seated locations, it’s often difficult to manage efficiently, thus associated with worse prognosis. In this article, a rare case of an infant with right sided sinonasal aRMS was reported. Eight month old child with two month history of right sided nasal blockage, watery discharge and a growth in the right nose. There was no epistaxis, palatal or neck swelling. On examination, a polypoid mass was completely occupying the right nasal cavity. There were no palpable cervical lymph nodes. Diagnosis of allergic rhinosinusitis with nasal polyposis was made. The mass progressed with associated ipsilateral cheek swelling extending to the nasal bridge. A greyish white, friable mass was biopsied and was diagnosed histologically as aRMS. The child had a debulking surgery and adjuvant chemotherapy. She later developed tumour lysis syndrome and died. Management of infanthood sinonasal aRMS is challenging especially in low socioeconomic region like ours. A multi-disciplinary approach with intensified multimodality therapy is crucial to improving the management outcomes and quality of life. In all, it is advisable to take closer look at any swelling in the paediatric age group by carefully evaluating it with high degree of suspicion, early diagnosis and individualized treatment.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;

Multimodality imaging evaluation of nasal sinus alveolar rhabdomyosarcoma: Two case reports

Rhabdomyosarcoma (RMS) is a common pleomorphic malignant soft tissue sarcoma in children and adolescents that originates from rhabdomyoblasts or mesenchymal precursor cells. Alveolar rhabdomyosarcoma (ARMS) mostly occurs in adolescents aged 10-15 years and is characterized by more aggressive behaviors and worse prognosis than other sarcomas, prone to lymphatic and hematogenous metastasis in the early stage as well as metastasizing to breast, testis, pancreas, and other parts. ARMS often occurs in the limbs and genitourinary system, however, head and neck ARMS are relatively rare when involving the nasal cavity or sinuses. The role of MRI and 18F-FDG positron emission tomography combined with computed tomography (PET/CT) remains to be established in ARMS. Case 1: An 18-year-old male was found with a left submandibular mass of approximately 1 cm in diameter 2 months ago, which gradually increased in size. CT showed multiple soft tissue masses in maxillofacial and neck regions and the lesions invaded the frontal lobe and the inner wall of the left orbital lobe. MRI showed the masses with hypointensity on T1WI, hyperintensity on T2WI, and diffusion-weighted imaging (DWI) with significant enhancement. 18F-FDG PET/CT showed multiple hypermetabolic lesions located in the maxillofacial, neck region, 3rd lumbar vertebra, and the right sacrum. A nasal endoscopic tumor biopsy and molecular testing finally helped to diagnose the ARMS. Case 2: A 14-year-old male presented with left maxillary pain with nasal congestion and left ocular swelling 15 days ago. CT demonstrated a soft tissue mass in the nasal cavity and sinuses with local protrusion into the left orbit. MRI showed the masses with a slightly low signal on T1WI, a high signal on T2WI, and DWI with significant heterogenous enhancement. 18F-FDG PET/CT showed hypermetabolic lesions in the left maxillofacial and neck regions. ARMS was finally diagnosed by a nasal endoscopic tumor biopsy and molecular testing. The patient had a recurrence of the lesion after chemotherapy and surgical resection and is currently undergoing radiation therapy. Nasal sinus ARMS is highly malignant with a poor prognosis. Accurate diagnosis relies not only on histopathology and immunohistochemistry examination but also on genetic detection of characteristic chromosomal translocations and fusion genes. Imaging methods, such as MRI and PET/CT can accurately assess the extent of the lesions and metastases, assist in the diagnosis of the disease and the selection of treatment regimens, provide precise localization for surgery, and help with treatment monitoring and follow-up.