Embryonal Rhabdomyosarcoma Research Articles

Non-Puerperal Uterine Inversion Caused by Embryonal Rhabdomyosarcoma in an Adolescent: A Case Report

Introduction: Non-puerperal uterine inversion is an uncommon gynecologic emergency that can be triggered by either malignant or, more commonly, benign tumors. Uterine sarcoma, including the rare subtype known as embryonal rhabdomyosarcoma, is among the malignant causes. The management of this condition poses a significant challenge for surgeons. Case Report: A 15-year-old nulliparous and virgin female arrived at the emergency department in hemorrhagic hypovolemic shock, experiencing pelvic discomfort and expelling endometrial tissue through the vagina. She underwent a total abdominal hysterectomy with bilateral oophorectomy, a pathological examination revealed that the uterine inversion was caused by embryonal rhabdomyosarcoma. Subsequently, the patient was referred to an oncologist for chemotherapy. Conclusion: Rapid perioperative diagnosis can be achieved through physical examination and magnetic resonance imaging (MRI), with histopathological examination serving as the definitive diagnostic confirmation tool.

Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo

Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7Cre-ER-T2/+; NrasLSL-G12D/+; p53fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS.

Imaging of Vaginal Yolk Sac Tumor: 2 Case Reports and Literature Review

Our article reports on two cases of pediatric vaginal yolk sac tumors (YSTs), underscoring the diagnostic challenges posed by their similarities to other vaginal tumors, particularly in differentiating from embryonal rhabdomyosarcoma based on clinical and radiological presentations. Emphasizing the critical role of MRI, histological examination, and alpha-fetoprotein levels in diagnosis, we highlight the complexities of treatment, which has evolved from radical surgeries to more conservative approaches with adjuvant chemotherapy, aiming to preserve future sexual and reproductive functions. Our findings advocate for individualized treatment plans and stress the importance of accurate diagnosis and the potential need for alternative therapeutic strategies in cases of atypical response to treatment.

The Effect of Socioeconomic Status and Race/Ethnicity on the Risk of Presenting With Advanced Stage at Diagnosis in Embryonal Tumors.

We evaluated whether socioeconomic status (SES), race/ethnicity, and their interaction were associated with the presentation of advanced stage at diagnosis in embryonal tumors. Children 0 to 19 years of age diagnosed with embryonal tumors between 2006 and 2018 were identified from the US Surveillance, Epidemiology, and End Results program database specialized with Census Tract SES/Rurality. SES quintile was derived from a composite index for census tracts. We performed logistic regression to estimate odds ratios (ORs) and 95% confidence intervals by SES and race/ethnicity, adjusting for sex, age, and diagnosis year. Overall, no significant associations were found between either SES or race/ethnicity and the risk of presenting with advanced stage at diagnosis, although patterns of risk reductions were observed in atypical teratoid/rhabdoid tumors and embryonal rhabdomyosarcoma with increasing SES. In the stratified analysis, decreased odds of presenting with advanced-stage embryonal rhabdomyosarcoma were observed for Hispanics with higher SES (OR: 0.24, 95% Confidence Interval: 0.08-0.75) compared with Hispanics with lower SES. Future studies incorporating individual-level SES, cancer-specific staging information, and potential demographic, clinical, epidemiological, and genetic risk factors are warranted to confirm our findings.

Genomic profiling of pleomorphic rhabdomyosarcoma reveals a genomic signature distinct from that of embryonal rhabdomyosarcoma.

Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle-aged adults and showing a variable degree of skeletal muscle differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well-characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA-targeted Next generation sequencing (NGS) panels (MSK-IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31-76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm-level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression-free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable.

Sarcoma Botryoides a Rare Pediatric Pelvic Tumor: A Case Report and Literature Revue

Sarcoma botryoides, a variant of embryonal rhabdomyosarcoma, represents the predominant malignant tumor affecting the genitourinary (GU) system in children under 15 years of age. Among GU tract malignancies in this age group, the embryonal subtype of habdomyosarcoma is the most prevalent. In young and adolescent individuals, the cervix and uterus are affected; whereas in infants, vaginal lesions are more common. Imaging plays a crucial role not only in the initial diagnosis but also in long‑term follow‑up of genital rhabdomyosarcoma. Although the magnetic resonance imaging features of GU tract rhabdomyosarcomas have been escribed, there have been relatively few radiological reports in the literature regarding the botryoid variant. This article aims to illustrate and describe the imaging appearance of this rare tumor. We present a case of a one-year-old male who presented with a rapidly growing pelvic mass, crying and straining on micturition and difficulty in passing stool and urine. An abdomino-pelvic CT scan and MRI were performed. He had been examinated under anesthesia and biopsy. Histology confirmed sarcoma botryoides.

Embryonal and alveolar rhabdomyosarcoma in adolescents/young adults, adults and older adults: a population-based cohort study.

The clinical characteristics, outcomes, and prognostic factors of adult embryonal rhabdomyosarcomas (ERMS) and alveolar rhabdomyosarcomas (ARMS), particularly the differences among adolescents/young adults (AYA), adults, and older adults, remain unclear. We assessed the clinicopathological features and survival outcomes of adult patients with ERMS and ARMS in Japan and to compare these features among AYA, adult, and older adult patients. We retrospectively analyzed data from the Bone and Soft Tissue Tumor Registry of Japan and enrolled patients aged ≥15years with ERMS and ARMS. Disease-specific overall survival (DOS) was estimated using the Kaplan-Meier method, and a Cox regression model was used to identify prognostic factors. Among 184 patients with ERMS and ARMS (median age, 27years; interquartile range, 18-49years), a high rate of distant and regional nodal metastases was initially observed in 65 (35%) and 66 (36%) cases, respectively. Older age and distant metastasis at first presentation were statistically poor prognostic factors, and histological subtype and site of tumor origin were not associated with DOS. In patients with localized ERMS and ARMS, older age and nodal metastasis were poor prognostic factors; the 5-year DOS rates of patients with and without nodal metastasis were 23% and 72%, respectively. Older patients with rhabdomyosarcoma had a dismal prognosis, and distant metastasis was a poor prognostic factor. The prognostic factors differed between adult and pediatric patients with rhabdomyosarcoma; biological analyses, such as genome analysis of adult rhabdomyosarcoma and clinical trials with pediatric oncologists, are needed to improve the prognosis of adult rhabdomyosarcoma.

Bone marrow disease in rhabdomyosarcoma visualized by 2-[18F]fluorodeoxyglucose positron emission tomography/computed tomography

Bone marrow metastases—noted in 6% of patients with rhabdomyosarcoma—have been linked to very poor outcomes. Bilateral bone marrow sampling from iliac crests has been the gold standard for bone marrow examination in rhabdomyosarcoma, but sampling errors due to patchy bone marrow involvement may limit its sensitivity. Here, we report the case of a 6-year-old boy with embryonal rhabdomyosarcoma of the skull base and multiple 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG)-avid bone marrow metastases visualized by positron emission tomography and computed tomography (2-[18F]FDG PET/CT). His bone marrow aspirates were tumor-free. This case illustrates the diagnostic value of 2-[18F]FDG PET/CT in the detection of bone marrow metastases in rhabdomyosarcoma patients, which may re-shape the definition of bone marrow disease and, ultimately, alter disease staging and risk stratification.

Embryonal rhabdomyosarcoma of hard palate: a case report and review of literature

Rhabdomyosarcomas are the most common malignant soft tissue tumors in children and adolescents. Around 40% of cases are diagnosed in head and neck region with orbit and face being the commonly involved areas. Oral lesions account for less than 10%. We report a case of embryonal RMS in a 4-year-old boy who presented with a polypoid mass in the hard palate. Though majority of the oral lesions encountered in children are benign, a small but significant percentage may be representative of an aggressive malignant tumor. Differentiating benign and malignant oral lesions is mandatory for optimal diagnostic strategies.

The "Other" Uterine Mesenchymal Neoplasms: Recent Developments and Emerging Entities.

Uterine mesenchymal neoplasms are a challenging group of tumors that often show overlapping morphologic features and immunohistochemical profiles. The increasing use of molecular testing in these tumors has enabled a better appreciation of their pathobiology, resulting in a wave of emerging neoplasms and improved characterization of ones previously considered exceptionally rare. Identification of specific molecular alterations has permitted targeted therapy options in tumors that were typically unresponsive to conventional therapies, as well as recognition that a subset can have a hereditary basis. This review will discuss the more "common" of the uncommon uterine mesenchymal neoplasms, including inflammatory myofibroblastic tumor, perivascular epithelioid cell tumor, uterine tumor resembling ovarian sex cord tumor, and embryonal rhabdomyosarcoma. This will be followed by an overview of emerging entities, including NTRK-rearranged uterine sarcoma, SMARCA4-deficient uterine sarcoma, KAT6B/A::KANSL1 fusion uterine sarcoma, and MEIS1::NCOA2/1 fusion sarcoma.

Abstract P61: Distinct Roles of BRD4 Isoforms in Tumor Progression and Metastasis in Embryonal Rhabdomyosarcoma

Abstract The deregulation of BRD4, a bromodomain and extraterminal (BET) protein, has been implicated in various cancers, positioning it as a promising target for drug development. Yet, the specific roles of the two primary BRD4 isoforms, BRD4-L and BRD4-S, remain poorly understood across most cancer types. This knowledge gap poses challenges in assessing the effectiveness of pan-BET inhibitors as potential therapies. This study seeks to address this gap by employing functional and transcriptomic analyses to elucidate the distinct contributions of BRD4 isoforms in embryonal rhabdomyosarcoma (ERMS). Through a comprehensive investigation, the research uncovers that BRD4-L and BRD4-S isoforms exert discrete functions in ERMS. Specifically, BRD4-L is found to exert an oncogenic role by inhibiting myogenic differentiation, partially through the activation of myostatin expression. Importantly, depletion of BRD4-L in vivo is shown to impede tumor progression without significantly affecting metastasis. In contrast, the absence of BRD4-S has an unexpected impact-while it has a minimal effect on tumor growth, it markedly enhances metastatic potential in vivo. Intriguingly, the depletion of BRD4-S leads to the heightened presence of BRD4-L and RNA Polymerase II at integrin gene promoters, consequently activating these genes. This novel insight underscores that BRD4-S acts as a gatekeeper, restraining the full scope of oncogenic activities driven by BRD4-L. Collectively, this study reveals distinctive roles for BRD4 isoforms and uncovers a delicate interplay in ERMS. Importantly, the findings indicate that pan-BRD4 inhibition might not be the optimal therapeutic strategy for ERMS due to the intricate interplay between isoforms. By illuminating the intricate functions of BRD4 isoforms, this research advances our understanding of the complex regulatory mechanisms underlying tumor progression and metastasis in ERMS. Citation Format: Dipanwita Das, Jia Yu Leung, Amos Hong Pheng Loh, Reshma Taneja. Distinct Roles of BRD4 Isoforms in Tumor Progression and Metastasis in Embryonal Rhabdomyosarcoma [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P61.

Abstract LB204: EHMT1 mediates cellular motility in embryonal rhabdomyosarcoma by activating SOX8 expression

Abstract Embryonal Rhabdomyosarcoma (ERMS) stands as the prevailing subtype of Rhabdomyosarcoma (RMS), the most prevalent pediatric soft tissue sarcoma. With a survival rate below 20% in the metastatic stage, RMS lacks targeted drug therapies, emphasizing the need for novel treatment avenues. Genomic analyses have unveiled a low incidence of somatic mutations in RMS, highlighting the substantial role of epigenetic modifiers in oncogenesis.This investigation focuses on EHMT1's involvement in ERMS oncogenesis. Our findings illuminate EHMT1 as a pivotal contributor to the migratory and invasive capabilities of ERMS cells, both in vitro and in vivo. Transcriptomic analysis following EHMT1 depletion unveils significant alterations in pathways crucial for cell migration and invasion. Specifically, the transcription factor SOX8, essential for cellular motility, experiences a substantial reduction upon EHMT1 loss. Notably, the phenotypic effects of EHMT1 loss are mirrored upon SOX8 depletion.Further RNA-Sequencing of SOX8-depleted cells exposes the downregulation of multiple integrin genes. Mechanistically, we delineate EHMT1's role in the upregulation of SOX8 through the regulation of BRD4 expression, influencing its occupancy at the promoter. This study unravels a novel EHMT1-SOX8 axis as a key driver of metastasis in ERMS, providing valuable insights for potential therapeutic interventions in this challenging clinical landscape. Citation Format: Dipanwita Das, Upasana Bajaj, Jia Yu Leung, Nurul Fateha Binti Abdul Rashi, Vinay Tergaonkar, Reshma Taneja. EHMT1 mediates cellular motility in embryonal rhabdomyosarcoma by activating SOX8 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB204.

NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis. We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing. Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations. Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma.

The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.

Germline Genetic Testing and Survival Outcomes Among Children With Rhabdomyosarcoma

Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma. To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma. In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023. The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set of 63 autosomal-dominant CPGs. Overall survival (OS) and event-free survival (EFS) were the main outcomes, using the Kaplan-Meier estimator to assess survival probabilities and the Cox proportional hazards regression model to adjust for clinical covariates. Analyses were stratified by tumor histology and the fusion status of PAX3 or PAX7 to the FOXO1 gene. In this study of 580 individuals with rhabdomyosarcoma, the median patient age was 5.9 years (range, 0.01-23.23 years), and the male-to-female ratio was 1.5 to 1 (351 [60.5%] male). For patients with CPVs in rhabdomyosarcoma-associated CPGs, EFS was 48.4% compared with 57.8% for patients without a CPV (P = .10), and OS was 53.7% compared with 65.3% for patients without a CPV (P = .06). After adjustment, patients with CPVs had significantly worse OS (adjusted hazard ratio [AHR], 2.49 [95% CI, 1.39-4.45]; P = .002), and the outcomes were not better among patients with embryonal histology (EFS: AHR, 2.25 [95% CI, 1.25-4.06]; P = .007]; OS: AHR, 2.83 [95% CI, 1.47-5.43]; P = .002]). These associations were not due to the development of a second malignant neoplasm, and importantly, patients with fusion-negative rhabdomyosarcoma who harbored a CPV had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma without CPVs (EFS: AHR, 1.35 [95% CI, 0.71-2.59]; P = .37; OS: AHR, 1.71 [95% CI, 0.84-3.47]; P = .14). There were no significant differences in outcome by CPV status of the 63 CPG set. This cohort study identified a group of patients with embryonal rhabdomyosarcoma who had a particularly poor outcome. Other important clinical findings included that individuals with TP53 had poor outcomes independent of second malignant neoplasms and that patients with fusion-negative rhabdomyosarcoma who harbored a CPV had outcomes comparable to patients with fusion-positive rhabdomyosarcoma. These findings suggest that germline CPV testing may aid in clinical prognosis and should be considered in prospective risk-based clinical trials.

Abstract 1972: Preclinical activity of the type II RAF inhibitor tovorafenib in tumor models harboring either a BRAF fusion or a NF1-LOF mutation

Abstract Genomic alterations and dysregulation of the MAPK pathway have been described in many different types of cancers. BRAF V600 point mutations and BRAF fusions, which are found in both pediatric and adult cancers, are oncogenic drivers that drive constitutive activation of the RAF pathway (Jones 2009, Yaeger 2019). Neurofibromatosis 1 (NF1) loss-of-function (LOF) mutations, which occur in many cancer types, result in decreased neurofibromin GAP function, thus activating RAS (Basu 1992). Tovorafenib is an investigational, selective, CNS-penetrant, small molecule type II RAF inhibitor which inhibits both RAF monomers and dimers and has been shown preclinically to impact the KIAA1549::BRAF fusion (Sun 2017). In this study, the impact of tovorafenib alone or in combination with MEK inhibitor, pimasertib, was explored in adult or pediatric tumor models harboring BRAF fusions or NF1-LOF mutations. At clinically relevant doses, tovorafenib treatment resulted in tumor regression in an AGK::BRAF fusion melanoma patient-derived xenograft (PDX) model in vivo. In contrast, little anti-tumor activity was observed in response to tovorafenib in vivo in two tumor models harboring NF1-LOF mutations. Ongoing PK-PD studies in both the AGK::BRAF fusion model and the NF1-LOF models will assess the extent and duration of target inhibition. In vitro, anti-proliferative activity of tovorafenib was also evaluated in NF1-LOF mutant tumor cell lines or PDX models of different tumor types, including melanoma, lung and malignant peripheral nerve sheath tumor (MPNST). While tovorafenib was potent in the BRAF V600E tumor cell line, little activity was observed in the NF1-LOF tumor cell lines. Modulation of phosphorylated-ERK (pERK) was also assessed. At very low concentrations, modest induction of pERK was observed in the NF1-LOF tumor cell lines, with inhibition at higher concentrations. In vitro combination studies were conducted using pimasertib and tovorafenib, or a tool compound. Synergy was observed in a NF1-LOF embryonal rhabdomyosarcoma PDX model ex vivo and a NF1-LOF MPNST cell line in vitro, suggesting that vertical pathway inhibition is impactful in the NF1-LOF mutant setting. Tovorafenib is currently being evaluated as a monotherapy in relapsed or progressive pediatric low-grade glioma (pLGG) harboring RAF alterations (NCT04775485) and in combination with pimasertib in patients ≥12 years of age with recurrent, progressive, or refractory solid tumors harboring MAPK pathway alterations (NCT04985604). Ongoing preclinical translational work will continue to explore potential biomarker-defined tumor indications for these agents. Citation Format: Shubhra Rastogi, Sam Perino, Madhu Lal-Nag, Yujin Wang, Samuel C. Blackman, Eleni Venetsanakos. Preclinical activity of the type II RAF inhibitor tovorafenib in tumor models harboring either a BRAF fusion or a NF1-LOF mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1972.

Isolated embryonal rhabdomyosarcoma of the anterior petrous bone in a young child: Focusing on the intra-operative diagnosis and differentials.

Rhabdomyosarcoma is a common soft tissue tumor, but isolated involvement of anterior portion of petrous bone is exceedingly rare. Here, we present a case of embryonal rhabdomyosarcoma involving the anterior petrous without involvement of the mastoid and middle ear. A 6-year-old boy presented with a progressive right side lower motor neuron facial paresis for 1-month duration along with headache and recurrent vomiting episodes. Radiology showed a contrast-enhancing lesion involving the right petrous apex. He underwent craniotomy and excision of the lesion. Based on the frozen section, a diagnosis of rhabdomyosarcoma was rendered, and gross total resection could be achieved. Postoperative course was uneventful. Isolated petrous bone involvement of embryonal rhabdomyosarcoma is a rare presentation. Intra-operative frozen section plays a key role in decision making regarding the extent of excision. Hence, a prompt and accurate diagnosis is essential in managing these cases.

In silico identification of chikungunya virus replication inhibitor validated using biochemical and cell-based approaches.

Discovering an alternative therapy with a long-lasting effect on symptoms caused by chikungunya virus (CHIKV) infection is prompted by the lack of a vaccine and the absence of safe, effective and non-toxic medications. One potential strategy is synthesizing or identifying small compounds that can specifically target the active site of an essential enzyme and prevent virus replication. Previous site-directed mutagenesis studies have demonstrated the crucial role of the macrodomain, which is a part of non-structural protein 3 (nsP3), in virus replication. Exploiting this fact, the macrodomain can be targeted to discover a natural substance that can inhibit its function and thereby impede virus replication. With this aim, the present study focused on potential CHIKV nsP3 macrodomain (nsP3MD) inhibitors through in silico, in vitro and cell-based methods. Through virtual screening of the natural compound library, nine nsP3MD inhibitors were initially identified. Molecular dynamics (MD) simulations were employed to evaluate these nine compounds based on the stability of their ligand-receptor complexes and energy parameters. Target analysis and ADMET (i.e. absorption, distribution, metabolism, excretion and toxicity) prediction of the selected compounds revealed their drug-like characteristics. Subsequent in vitro investigation allowed us to narrow the selection down to one compound, N-[2-(5-methoxy-1H-indol-3-yl) ethyl]-2-oxo-1,2-dihydroquinoline-4-carboxamide, which exhibited potent inhibition of CHIKV growth. This molecule effectively inhibited CHIKV replication in the stable embryonal rhabdomyosarcoma cell line capable of producing CHIKV. Our findings demonstrate that the selected compound possesses substantial anti-CHIKV nsP3MD activity both in vitro and in vivo. This work provides a promising molecule for further preclinical studies to develop a potential drug against the CHIKV.

Paratesticular Rhabdomyosarcoma: About 3 Cases and Literature Review

Paratesticular rhabdomyosarcoma is a rare and highly aggressive embryonal tumor in infancy and childhood. The tumor is intrascrotal, localized in the spermatic cord, the epididymis, or in the tunica vaginalis. Multimodality treatment should involve surgery, radiotherapy and chemotherapy, which are indicated according to risk groups. Prognosis is excellent for localized tumors, survival rates exceed 90%. We report three cases of embryonal paratesticular rhabdomyosarcoma treated in our institution.

Non-Puerperal Uterine Inversion Associated with Embryonal Rhabdomyosarcoma: A Case Report.

Non-Puerperal Uterine Inversion Associated with Embryonal Rhabdomyosarcoma: A Case Report.