Alveolar Rhabdomyosarcoma Research Articles

Unveiling the Unusual: Mediastinal Rhabdomyosarcoma in an Adult Patient

Abstract Introduction/Objective We present a case of a 55-year-old female with a history of hypertension, diabetes, hyperlipidemia, chronic kidney disease (CKD), and asthma, who presented with a mediastinal mass. Methods/Case Report A needle core biopsy of the mediastinal mass was performed. Microscopic examination showed a proliferation of primitive appearing, moderately pleomorphic cells with features suggestive of rare strap cells of rhabdomyosarcoma. Immunohistochemical staining was positive for desmin and myogenin, consistent with rhabdomyosarcoma. Further cytogenetic analysis for FOXO1 translocation, was performed. Results (if a Case Study enter NA) Cytogenetic analysis was negative for FOXO1 translocation by FISH, ruling out alveolar rhabdomyosarcoma. Despite negative cytogenetic findings, the morphology and immunoprofile were consistent with rhabdomyosarcoma. However, the possibility of rhabdomyosarcoma occurring within a mediastinal teratoma, germ cell tumor, or carcinosarcoma was noted. Conclusion This case highlights the challenge of diagnosing rhabdomyosarcoma in adults, especially when presenting as a mediastinal mass. The histologic and immunophenotype supported the diagnosis of rhabdomyosarcoma. However understanding the primary of the lesion in the hilum is more diffecult. physical examination releave no lesion on the extremities. CT scan of the abdomen and pelvis reveals no other lesion. making the metastasis unlikely.This case underscores the importance of thorough diagnostic evaluation, including histopathology and immunohistochemistry, in the assessment of unusual neoplasms, which can impact treatment decisions and prognosis. Further studies are warranted to elucidate the molecular mechanisms underlying rhabdomyosarcoma in adults and its association with other mediastinal tumors. This case report contributes to the evolving understanding of rare malignancies and their implications for pathology and laboratory medicine practice.

Nuclear DUX4 immunohistochemistry is a highly sensitive and specific marker for the presence of CIC::DUX4 fusion in CIC-rearranged sarcomas: a study of 48 molecularly confirmed cases.

CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms. Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic smallround cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion. DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

SPIN-03 PROFILE OF MALIGNANT SPINAL CORD COMPRESSION AMONG CHILDREN AT A SINGLE CENTRE IN JOHANNESBURG, SOUTH AFRICA

Abstract OBJECTIVE Malignant spinal cord compression (MSCC) in children can lead to permanent neurological deficits and therefore warrants urgent referral, prompt diagnosis and treatment. There is limited data on paediatric MSCC in Sub-Saharan Africa. The objective was to assess the characteristics, aetiology, clinical presentation, treatment and long-term outcomes of MSCC. METHODS Records of 23 patients with MSCC were retrospectively assessed over a 15-year period (2008-2023) at Charlotte Maxeke Johannesburg Academic Hospital in Johannesburg, South Africa. RESULTS The median age of MSCC diagnosis was four years (range: 5 months to 15 years). The median interval between symptom onset and confirmed diagnosis was three months (1 week to 20 months). MSCC’s leading causes were central nervous system tumours (30%), lymphomas (22%), sarcomas (17%), germ cell tumours (9%), teratoid tumours (9%), neuroblastomas (9%) and leukaemias (4%). Commonest presenting symptoms were motor deficits (96%), pain (35%) and sphincter dysfunction (22%). Magnetic resonance imaging (MRI) of the spine was diagnostic in all cases. The primary tumour was managed using a multimodality approach: 70% underwent neurosurgical intervention and 39% received radiotherapy. The median follow-up duration was two years (1 month to 15 years). There were six deaths (two cases of ependymoma and a case each of glioblastoma multiforme, alveolar rhabdomyosarcoma, acute lymphoblastic leukaemia and Burkitt lymphoma) at a median interval of 4.5 months from diagnosis (1 month to 2 years). The commonest long-term sequelae were motor deficits (52%) and sphincter dysfunction (26%) and 22% of patients were asymptomatic. CONCLUSION We documented longer diagnostic delays than published in the literature and recommend increased awareness and rapid referral to decrease permanent sequelae. Patients presenting with new-onset neurological deficits suggestive of MSCC should have urgent radiological imaging; preferably MRI, followed by prompt referral to a specialised centre with an experienced multidisciplinary team.

Propofol-induced transient arginine vasopressin deficiency.

We describe and characterise the case of a 26-year-old female undergoing surgery for a right-sided sinonasal alveolar rhabdomyosarcoma who developed profound, transient arginine vasopressin deficiency (AVP-D, formerly central diabetes insipidus (DI)) associated with anaesthesia. In this case report, we characterise the development of AVP-D with serial copeptin and paired urine and serum osmolality measurements. Based on the anaesthetic agent's profile and the literature, we attribute this presentation to propofol exposure. We present a description of the literature on anaesthesia-associated DI as well as poignant learning points. Exposure to anaesthetic agents is a rare cause of self-limited but sudden and profound arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R). Sevoflurane has been associated with AVP-R and propofol with AVP-D, although the responsible agent may be difficult to identify. Differentiation of AVP-R and AVP-D can be made based on copeptin concentration, where available, or clinical response to desmopressin. Whilst the patient is anaesthetised, intravenous fluid replacement should be targeted to match urine output until the patient is able to drink to thirst. This should be clearly communicated to staff and the patient. Rapid resolution of AVP-R/AVP-D when the causative agent is discontinued has been reported with both propofol and sevoflurane. As such, switching the agent used to maintain anaesthesia may terminate increased urine output in a clinically meaningful timeframe.

Caspase-Activated DNase localizes to cancer causing translocation breakpoints during cell differentiation.

Caspase activated DNase (CAD) induced DNA breaks promote cell differentiation and therapy-induced cancer cell resistance. CAD targeting activity is assumed to be unique to each condition, as differentiation and cancer genesis are divergent cell fates. Here, we made the surprising discovery that a subset of CAD-bound targets in differentiating muscle cells are the same genes involved in the genesis of cancer-causing translocations. In muscle cells, a prominent CAD-bound gene pair is Pax7 and Foxo1a, the mismatched reciprocal loci that give rise to alveolar rhabdomyosarcoma. We show that CAD-targeted breaks in the Pax7 gene are physiologic to reduce Pax7 expression, a prerequisite for muscle cell differentiation. A cohort of these CAD gene targets are also conserved in early differentiating T cells and include genes that spur leukemia/lymphoma translocations. Our results suggest the CAD targeting of translocation prone oncogenic genes is non-pathologic biology and aligns with initiation of cell fate transitions.

Head and neck sarcomas: Thirty years of experience in a tertiary referral center in Brazil.

This study analyzed the demographics, clinicopathological, treatment, and survival characteristics of head and neck sarcomas (HNS) diagnosed in a tertiary reference center in Brazil. HNS cases were retrospectively retrieved from the Department of Pathological Anatomy of the School of Medical Sciences of the State University of Campinas. The medical records were examined to extract demographic, clinicopathological, and follow-up information. The Pearson chi-square test, Kaplan-Meier curve, and Cox proportional hazards regression model were employed to identify survival and potential prognostic factors. A total of 47 patients were included in the study. The majority were men (61.7%) with a mean age of 38.9 years. The nasal cavity (34.0%) was the most common anatomical site. The lesions are usually presented as volume increases (78.7%). The most common histological subtypes were chondrosarcoma, osteosarcoma, and alveolar rhabdomyosarcoma. Surgical excision alone was the most common treatment modality. Local recurrence was observed in 10 cases, and metastases in 3 cases. During a mean follow-up period of 71.9 months, from diagnosis to the last follow-up, 31 patients (65.9%) were alive without the disease. A total of 10 patients (21.3%) died of the HNS for a mean follow-up period of 14.3 months. The time to presentation of more than 6 months (p = 0.0309) and the presence of metastases (p = 0.0315) were identified as prognostic factors for survival, while male sex was found to be an independent prognostic factor for recurrence. In conclusion, the results of this study indicate that the occurrence of a shorter lesion time to presentation and the presence of metastases were associated with a reduction in survival rates in patients with HNS.

A pilot study to evaluate the combination of surgery and brachytherapy for local tumor control in young children with perianal rhabdomyosarcoma

BackgroundPerianal rhabdomyosarcoma ((P)RMS) are rare and have a poor prognosis. Data in young children are limited and local therapy is not well defined. Combined brachytherapy and surgery is routinely being used for RMS at other sites in children as it provides good oncologic outcomes and allows for organ-sparing surgery. The objective of this study was to evaluate this combination treatment for local tumor control and organ-sparing surgery in young children with (P)RMS. MethodsA retrospective review of the medical records of all children who underwent surgery and brachytherapy for (P)RMS at our institution since 2009 was conducted. ResultsSurgery for (P)RMS was performed in 6 patients at a median age of 19 months (range 8–50). Embryonal RMS was diagnosed in 4 patients and alveolar RMS in 2 patients, of which 1 patient had FOXO1 fusion-positive RMS. All patients underwent postoperative high-dose rate (HDR) brachytherapy. Organ-preserving surgery was achieved in 5 of 6 patients (83 %). In 1 patient, the entire sphincter was infiltrated, making organ-preserving resection impossible. 5 of 6 patients (83 %) exhibited an event-free and overall survival at a median follow-up of 26 months (range 8–107). One patient died due to locoregional recurrence. Complications were urethral leakage in 1 patient followed by urethral stenosis and delayed wound healing and vaginal stenosis in another patient. No patient reported fecal incontinence. ConclusionsCombined treatment with surgery and HDR brachytherapy is feasible in very young children with (P)RMS and leads to a favorable oncologic outcome. Preliminary data show a good functional preservation.

A bright future for multidisciplinary approach to cancer care in the setting of limited resource

We report a case of alveolar rhabdomyosarcoma of the infratemporal region in a female child. An 8year old female was diagnosed with alveolar rhabdomyosarcoma 10 years ago. A computed tomography (CT) scan showed large mass in the right pterygopalatine fossa extending into the buccal, masticator and parapharyngeal spaces with involvement of the pterygoid and masseter muscles.Several multidisciplinary discussions were held concerning the case to determine the best treatment strategy. Child received neoadjuvant chemotherapy followed by radiotherapy. Six months post radiotherapy, CT scan reported a residual lesion for which multiple biopsies showed no residual tumor.Patient is doing well 10 years after treatment with no evidence of recurrence,Notably, this was the first case discussed at the inception of the pediatric multidisciplinary tumor board.

Rhabdomyosarcoma of the Biliary Tract in Children: Analysis of Single Center Experience.

Rhabdomyosarcoma (RMS) of the biliary tract is a rare tumor in children, constituting 0.5-0.8% of all pediatric RMS. Still, it is the most common malignancy in this location in children. Due to its rarity and location, it may cause diagnostic and treatment difficulties. Above all, there are no therapeutic guidelines specific for this tumor location. The aim of the study was to present an analysis of our experience with the treatment of children with biliary tract rhabdomyosarcoma (RMS) and discuss clinical recommendations for this specific location published in the literature. A retrospective analysis of medical records of eight children with biliary tree RMS treated in one center between 1996-2022 was performed. Records of eight children, five boys and three girls aged 2 yrs 6 mo to 16 yrs 9 mo (median-6 yrs) were analyzed. All patients presented with jaundice as the first symptom. In two patients, initial diagnosis of a tumor was established. For the remaining six, the primary diagnoses were as follows: choledochal cyst-one, malformation of the biliary ducts-one, choledocholithiasis-one, cholangitis-three. In four patients, the extrahepatic bile ducts were involved; in four patients, both the intrahepatic and extrahepatic bile ducts were involved. Embryonal RMS was diagnosed in seven patients (three botryoides type). Alveolar RMS was found in one patient. Biopsy (three surgical, four during endoscopic retrograde cholangiopancreatography (ERCP)) was performed in seven patients. One child underwent primary partial tumor resection (R2). Seven patients received neoadjuvant chemotherapy, followed by delayed resection in five, including liver transplantation in one (five were R0). Two patients did not undergo surgery. Radiotherapy was administered in four patients (two in first-line treatment, two at relapse/progression). Six patients (75%) are alive with no evidence of disease, with follow-up ranging from 1.2 yrs to 27 yrs (median 11 yrs. and 4 mo.). Two patients died from disease, 2 y 9 mo and 3 y 7 mo from diagnosis. Children presenting with obstructive jaundice should be evaluated for biliary tract RMS. The treatment strategy should include biopsy and preoperative chemotherapy, followed by tumor resection and radiotherapy for residual disease and in case of relapse.

Evaluation of Hi-C Sequencing for Detection of Gene Fusions in Hematologic and Solid Tumor Pediatric Cancer Samples.

Hi-C sequencing is a DNA-based next-generation sequencing method that preserves the 3D genome conformation and has shown promise in detecting genomic rearrangements in translational research studies. To evaluate Hi-C as a potential clinical diagnostic platform, analytical concordance with routine laboratory testing was assessed using primary pediatric leukemia and sarcoma specimens. Archived viable and non-viable frozen leukemic cells and formalin-fixed paraffin-embedded (FFPE) tumor specimens were analyzed. Pediatric acute myeloid leukemia (AML) and alveolar rhabdomyosarcoma (A-RMS) specimens with known genomic rearrangements were subjected to Hi-C to assess analytical concordance. Subsequently, a discovery cohort consisting of AML and acute lymphoblastic leukemia (ALL) cases without known genomic rearrangements based on prior clinical diagnostic testing was evaluated to determine whether Hi-C could detect rearrangements. Using a standard sequencing depth of 50 million raw read-pairs per sample, or approximately 5X raw genomic coverage, we observed 100% concordance between Hi-C and previous clinical cytogenetic and molecular testing. In the discovery cohort, a clinically relevant gene fusion was detected in 45% of leukemia cases (5/11). This study provides an institutional proof of principle evaluation of Hi-C sequencing to medical diagnostic testing as it identified several clinically relevant rearrangements, including those that were missed by current clinical testing workflows.

Massive Bone Marrow Infiltration by Disseminated Alveolar Rhabdomyosarcoma Mimicking Acute Leukemia.

RMS is a malignant tumor of soft tissues affecting primarily children and adolescents. Around 6% to 23% RMS patients present bone marrow infiltration but leukemia-like involvement is very rare; in these patients cytomorphology on bone marrow smears can lead to misdiagnosis. Differential diagnosis with alveolar RMS should be kept in mind in every pediatric patient presenting with a marked bone marrow involvement in the absence of typical lymphoproliferative findings.

PAX fusion proteins deregulate gene networks controlling mitochondrial translation in pediatric rhabdomyosarcoma.

Alveolar rhabdomyosarcoma (ARMS) patients harboring PAX3-FOXO1 and PAX7-FOXO1 fusion proteins exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we developed a novel muscle progenitor model and used epigenomic approaches to unravel genome re-wiring events mediated by PAX3/7 fusion proteins. Importantly, these regulatory mechanisms are conserved across established ARMS cell lines, primary tumors, and orthotopic-patient derived xenografts. Among the key targets of PAX3- and PAX7-fusion proteins, we identified a cohort of oncogenes, FGF receptors, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. Our data suggest an explanation for the relative paucity of recurring mutations in this tumor, provide a compelling list of actionable targets, and suggest promising new strategies to treat this tumor.

Novel PAX3::MAML3 Fusion Identified in Alveolar Rhabdomyosarcoma, Using DNA Methylation Profiling to Expand the Genetic Spectrum of “Fusion-Positive” Cases

Alveolar rhabdomyosarcoma (ARMS) with FOXO1 gene rearrangements is an aggressive pediatric rhabdomyosarcoma subtype that is prognostically distinct from embryonal rhabdomyosarcoma and fusion-negative ARMS. Here, we report 2 cases of ARMS with PAX3::MAML3 fusions. The tumors arose in an infant and an adolescent as stage IV metastatic disease (by Children’s Oncology Group staging system). Histologically, both cases were small round blue cell tumors arranged in vague nests and solid sheets that were diffusely positive for desmin and myogenin. By methylation profiling and unsupervised clustering analysis, the tumors clustered with ARMS with classic FOXO1 rearrangements and ARMS with variant PAX3::NCOA1/INO80D fusions, but not with biphenotypic sinonasal sarcoma (BSNS) with PAX3::MAML3/NCOA2/FOXO1/YAP1 fusions nor with other small round blue cell tumors, including embryonal rhabdomyosarcoma. The differentially methylated genes between ARMS and BSNS were highly enriched in genes involved in myogenesis, and 21% of these genes overlap with target genes of the PAX3::FOXO1 fusion transcription factor. On follow-up after initiation of vincristine/actinomycin/cyclophosphamide chemotherapy, the tumors showed partial and complete clinical responses, consistent with typical upfront chemotherapy responsiveness of ARMS with the classic FOXO1 rearrangement. We conclude that PAX3::MAML3 is a novel variant fusion of ARMS, which displays a methylation signature distinct from BSNS despite sharing similar PAX3 fusions. These findings highlight the utility of methylation profiling in classifying ARMS with noncanonical fusions.

ISLET-1 expression in soft tissue neoplasms reveals high sensitivity but moderate specificity for desmoplastic small round cell tumors and potential utility as a diagnostic biomarker

ISLET-1 (ISL1) is a LIM-homeodomain transcription factor. Selective ISL1 expression is shown in neuroendocrine, non-neuroendocrine, and some soft tissue tumors including desmoplastic small round cell tumor (DSRCT). We assessed the specificity of ISL1 (clone EP283, 1:500, Cell Marque) in 288 soft tissue tumors, which included 17 DSRCTs and other histologic mimics. Positive staining threshold for ISL1 was set to >10 % of neoplastic cell nuclei at moderate intensity. ISL1 IHC was positive in 15/16 (94 %) DSRCTs with 75 % showing diffuse (>50 %) expression. ISL1 was positive in 1/10 (10 %) Ewing sarcomas (EWS), 7/13 (54 %) alveolar rhabdomyosarcoma (RMS), 14/22 (63 %) embryonal RMS, 7/14 (50 %) synovial sarcomas, 15/16 (93 %) neuroblastoma, 1/5 (20 %) Wilms tumor, 2/4 (50 %) olfactory neuroblastoma, and all 9 Merkel cell carcinomas. Other tumors, including all CIC::DUX4 sarcomas, were negative except 3/27 leiomyosarcomas, and 1 each of angiosarcoma, myxoid liposarcomas, inflammatory myofibroblastic tumor, malignant peripheral nerve sheath tumor, tenosynovial giant cell tumor, dedifferentiated LPS, and 1 ectomesenchymoma. In summary, among the soft tissue tumors tested, ISL1 is a highly sensitive but moderately specific marker for DSRCT and may be useful to distinguish from round cell mimics including EWS and CIC::DUX4 sarcomas. The oncogenic role of ISL1 in these tumors warrants further investigation.

Antitumour effects of SFX-01 molecule in combination with ionizing radiation in preclinical and in vivo models of rhabdomyosarcoma

BackgroundDespite a multimodal approach including surgery, chemo- and radiotherapy, the 5-year event-free survival rate for rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in childhood, remains very poor for metastatic patients, mainly due to the selection and proliferation of tumour cells driving resistance mechanisms. Personalised medicine-based protocols using new drugs or targeted therapies in combination with conventional treatments have the potential to enhance the therapeutic effects, while minimizing damage to healthy tissues in a wide range of human malignancies, with several clinical trials being started. In this study, we analysed, for the first time, the antitumour activity of SFX-01, a complex of synthetic d, l-sulforaphane stabilised in alpha-cyclodextrin (Evgen Pharma plc, UK), used as single agent and in combination with irradiation, in four preclinical models of alveolar and embryonal RMS. Indeed, SFX-01 has shown promise in preclinical studies for its ability to modulate cellular pathways involved in inflammation and oxidative stress that are essential to be controlled in cancer treatment.MethodsRH30, RH4 (alveolar RMS), RD and JR1 (embryonal RMS) cell lines as well as mouse xenograft models of RMS were used to evaluate the biological and molecular effects induced by SFX-01 treatment. Flow cytometry and the modulation of key markers analysed by q-PCR and Western blot were used to assess cell proliferation, apoptosis, autophagy and production of intracellular reactive oxygen species (ROS) in RMS cells exposed to SFX-01. The ability to migrate and invade was also investigated with specific assays. The possible synergistic effects between SFX-01 and ionising radiation (IR) was studied in both the in vitro and in vivo studies. Student’s t-test or two-way ANOVA were used to test the statistical significance of two or more comparisons, respectively.ResultsSFX-01 treatment exhibited cytostatic and cytotoxic effects, mediated by G2 cell cycle arrest, apoptosis induction and suppression of autophagy. Moreover, SFX-01 was able to inhibit the formation and the proliferation of 3D tumorspheres as monotherapy and in combination with IR. Finally, SFX-01, when orally administered as single agent, displayed a pattern of efficacy at reducing the growth of tumour masses in RMS xenograft mouse models; when combined with a radiotherapy regime, it was observed to act synergistically, resulting in a more positive outcome than would be expected by adding each exposure alone.ConclusionsIn summary, our results provide evidence for the antitumour properties of SFX-01 in preclinical models of RMS tumours, both as a standalone treatment and in combination with irradiation. These forthcoming findings are crucial for deeper investigations of SFX-01 molecular mechanisms against RMS and for setting up clinical trials in RMS patients in order to use the SFX-01/IR co-treatment as a promising therapeutic approach, particularly in the clinical management of aggressive RMS disease.

Pathologic features of head and neck adult rhabdomyosarcoma: Case series

IntroductionAdult Head and neck Rhabdomyosarcomas (HNRMS) are exceedingly rare and remain challenging for pathologists. Cases presentationFive cases of adult HNRMS (≥19 years) were retrieved from the archives of the Department of Pathology of Hospital of Specialities in Rabat (HSR) in Morocco, over 5 years. Clinical and pathologic findings from hematoxylin and eosin slides and immunohistochemistry for Desmin and Myogenin were reviewed. Clinical discussionThe median age was 33, with a men's predominance (3 M/2F). Histological analysis revealed three cases of Alveolar Rhabdomyosarcoma (RMS), one Pleomorphic RMS, and one spindle cell/sclerosing RMS. In addition to the typical histology observed in each RMS, we found tricky growth patterns that could be a source of misdiagnosis. All five cases demonstrated variable positivity for Desmin and Myogenin. ConclusionHNRMS cases have different pathological features than pediatric RMS cases. We identified rare subtypes such as pleomorphic and spindle cell/sclerotic RMS, which exhibit unusual morphological patterns.

The Prognostic Significance of Early Tumor Volume Change in Rhabdomyosarcoma

Purpose: To describe early tumor volume change in patients with rhabdomyosarcoma (RMS) and investigate its association with overall survival (OS) and local failure. Methods: This retrospective study included patients diagnosed with Group III/IV RMS with available CT and/or MRI scans at two-time points: 1) pre-therapy and 2) early therapy (acquired during weeks 8 – 12 of chemotherapy). Relative volumetric change (RVC) was calculated as the percentage of: (early therapy – pre-therapy volume)/ (pre-therapy volume). Cox regression was used to identify variables associated with overall survival (OS). The Fine-Gray model was used to estimate local failure. Results: Eligible patients (n=55) had the following characteristics: median age at diagnosis: 9.6 years and median follow-up: 30.4 months. Most tumors were alveolar (61.8%) followed by embryonal (34.6%) and spindle cell/sclerosing (4%). The median RVC was -86.4% with larger decreases observed in alveolar vs. non-alveolar RMS (-89.4 vs. -69.8%, p=0.043). For embryonal and spindle cell/sclerosing RMS, all of which were FOXO1 fusion negative, RVC was independently associated with OS (Hazard Ratio for every 50% reduction in RVC [HRRVC]: 0.5, 95% Confidence Interval [CI]: 0.26 – 0.96, p=0.037) and local failure (HRRVC: 0.57, 95% CI: 0.33 – 0.99, p=0.049). The predominant pattern of failure in embryonal and spindle cell/sclerosing RMS was local and most were Group III. Conclusion: There was a greater reduction in tumor volume in alveolar vs. non-alveolar RMS. Early tumor volume reduction was associated with OS and local failure in embryonal or spindle cell/sclerosing RMS, all of which were confirmed FOXO1 fusion negative and had higher incidence of local compared to distant failures.

Targeted immunotherapy and nanomedicine for rhabdomyosarcoma: The way of the future.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%-70%) and alveolar RMS (aRMS; 20%-30%). The aggressive aRMS carry one of two characteristic chromosomal translocations that result in the expression of a PAX3::FOXO1 or PAX7::FOXO1 fusion transcription factor; therefore, aRMS are now classified as fusion-positive (FP) RMS. Embryonal RMS have a better prognosis and are clinically indistinguishable from fusion-negative (FN) RMS. Next to histology and molecular characteristics, RMS risk groupings are now available defining low risk tumors with excellent outcomes and advanced stage disease with poor prognosis, with an overall survival of about only 20% despite intensified multimodal treatment. Therefore, development of novel effective targeted strategies to increase survival and to decrease long-term side effects is urgently needed. Recently, immunotherapies and nanomedicine have been emerging for potent and effective tumor treatments with minimal side effects, raising hopes for effective and safe cures for RMS patients. This review aims to describe the most relevant preclinical and clinical studies in immunotherapy and targeted nanomedicine performed so far in RMS and to provide an insight in future developments.

Developmental and therapeutic implications of IL4ra expression for rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal muscle stem cells (satellite cells). To understand the function of Il4ra in this tumor initiation phase of RMS, we conditionally deleted Il4ra in genetically-engineered RMS mouse models. Nullizygosity of Il4ra altered the latency, site and/or stage distribution of RMS tumors compared to IL4RA intact models. Primary tumor cell cultures taken from the genetically-engineered models then used in orthotopic allografts further defined the interaction of satellite cells and RMS tumor cells in the context of tumor initiation: in alveolar rhabdomyosarcoma (ARMS), satellite cell co-injection was necessary for Il4ra null tumor cells engraftment, whereas in embryonal rhabdomyosarcoma (ERMS), satellite cell co-injection decreased latency of engraftment of Il4ra wildtype tumor cells but not Il4ra null tumor cells. When refocusing on Il4ra wildtype tumors by single cell sequencing and cytokine studies, we have uncovered a putative signaling interplay of Il4 from T-lymphocytes being received by Il4ra + rhabdomyosarcoma tumor cells, which in turn express Ccl2, the ligand for Ccr2 and Ccr5. Taken together, these results suggest that mutations imposed during tumor initiation have different effects than genetic or therapeutic intervention imposed once tumors are already formed. We also propose that CCL2 and its cognate receptors CCR2 and/or CCR5 are potential therapeutic targets in Il4ra mediated RMS progression.

An unusual presentation of orbital rhabdomyosarcoma: A case report

Orbital rhabdomyosarcoma (RMS) is the commonest orbital cancer in children. Capillary hemangioma (CH) is the commonest benign periorbital tumor in childhood. We present an unusual case of orbital RMS, which was initially diagnosed as an orbital CH. An 8-year-old girl presented with a right eye protrusion of 3 years’ duration. The protrusion increased with the Valsalva maneuver. There was no history of headache, remarkable weight loss, or swelling of any other parts of the body. A diagnosis of orbital hemangioma was made, and she was commenced on propranolol with some improvement, but she defaulted. When she was represented 4 years later, there was a huge mass surrounding the right eye, with blindness and intermittent bleeding. Orbital computed tomographic angiography revealed features of a very vascular mass with bony expansion of all the orbital walls. She underwent modified exenteration, and her histology revealed Alveolar RMS. These reports highlight an unusual presentation of orbital RMS.