Pediatric Soft Tissue Sarcoma Research Articles

Radiotherapy for pediatric non-rhabdomyosarcoma soft tissue sarcomas: a comprehensive review.

For children with non-rhabdomyosarcoma soft tissue sarcomas, a risk-adapted treatment approach is generally used in order to minimize treatment-related morbidity and mortality in low-risk patients and maximize the benefit in high-risk patients. Our aim in this review is to discuss the prognostic factors, riskadapted treatment options and the details of radiotherapy. The publications reached by searching the keywords `pediatric soft tissue sarcoma`, `nonrhabdomyosarcoma soft tissue sarcoma (NRSTS)`, and `radiotherapy` in Pubmed database were evaluated in detail. Today, based on prospective COG-ARST0332 and EpSSG studies, a risk-adapted multimodal treatment approach has become the standard in pediatric NRSTS. According to them, adjuvant chemotherapy/ radiotherapy can be safely omitted in low-risk patients, while adjuvant chemotherapy/radiotherapy or both are recommended in intermediate and high-risk groups. Recent prospective studies for pediatric patients have reported excellent treatment outcomes with smaller radiotherapy fields and lower doses than adult series. The primary goal of surgery is maximal tumor resection with negative margins. In cases that are initially unresectable, neoadjuvant chemotherapy and radiotherapy should be considered. A risk-adapted multimodal treatment approach is the standard in pediatric NRSTS . Surgery alone is sufficient in low-risk patients, and adjuvant therapies may safely be omitted. On the contrary, in intermediateand high-risk patients, adjuvant treatments should be applied to reduce recurrence rates. In unresectable patients, the chance of surgery increases with the neoadjuvant treatment approach and thus treatment results may improve. In the future, outcome might be improved with further clarification of molecular features and targeted therapies in such patients.

Time to broaden the eligibility criteria in paediatric oncology trials? An analysis of patients with rhabdomyosarcoma non-eligible to the EpSSG RMS2005 trial

PurposeClinical trials include a series of eligibility and exclusion criteria that define the study population to reduce inter-patient heterogeneity and increase safety. Little is known about children with oncological diseases excluded from trials because they do not satisfy these criteria. We analysed the eligibility criteria adopted in the European paediatric Soft tissue sarcoma Study Group RMS2005 study and the survival of non-eligible patients.Patients and methodsRMS2005 run from 10/2005–12/2016. Eligibility criteria were age ≤ 25 years; pathologically proven diagnosis of rhabdomyosarcoma (RMS); no evidence of metastases; no pre-treatment; no pre-existing conditions preventing treatment; no previous malignant tumours and an interval between diagnostic surgery and the start of treatment ≤ 8 weeks. Clinical characteristics, 5-year progression-free survival (PFS), and overall survival (OS) were analysed for eligible and non-eligible patients.ResultsThe 79 non-eligible patients (4.3% of registered patients) were older than eligible patients (p<0.0001), with RMS arising in favourable sites (p = 0.004) and completely resected at diagnosis (p<0.0001). PFS for non-eligible vs. eligible patients was 67.1% (95%CI 55.3–76.5) vs. 71.5% (95%CI 69.3–73.6) (p = 0.23) and OS 77.1% (95%CI 65.7–85.1) vs. 80.4% (95%CI 78.4–82.3) (p = 0.12), respectively. Patients with a delayed start of treatment or pre-treated had significantly better PFS than those with a pre-existing condition (p = 0.0004).Conclusionnon-eligible patients data should be systematically collected. This will be important to confirm that trial eligibility criteria for patients with RMS could be modified without jeopardising results and increasing study enrolment and generalisability of results.

Using Evidence-Based Medicine to Support Clinical Decision-Making in RMS

The foundations of evidence-based practice are the triad of patient values and preferences, healthcare professional experience, and best available evidence, used together to inform clinical decision-making. Within the field of rhabdomyosarcoma, collaborative groups such as the European Paediatric Soft Tissue Sarcoma Group (EpSSG) have worked to develop evidence to support this process. We have explored many of the key research developments within this review, including patient and public involvement, decision-making research, research into areas other than drug development, core outcome sets, reporting and dissemination of research, evidence synthesis, guideline development and clinical decision rules, research of research methodologies, and supporting research in RMS.

Metastatic rhabdomyosarcoma with exclusive distant lymph node involvement: A European Pediatric Soft tissue sarcoma Study Group (EpSSG) report.

The prognosis of patients with metastatic rhabdomyosarcoma (RMS) is not uniformly poor. Tumors with nodal involvement beyond the first lymph node station are currently considered to have distant metastases. The aim of this study is to evaluate the characteristics and outcome of RMS patients with distal nodal involvement as the only site of metastasis. This study included all patients with a diagnosis of RMS and distant nodal involvement as the only metastatic site, enrolled in the European Pediatric Soft tissue sarcoma Study Group (EpSSG) protocols. Treatment comprised chemotherapy, surgery, and/or radiotherapy. The main outcome measures were event-free survival (EFS) and overall survival (OS). A total of 22 patients (median age 7.1years, range 1.4-16.7) fit the inclusion criteria. The extremities were the most common primary tumor site (59%). Twenty-one patients had regional and distant nodal involvement, 12 were PAX3/7-FOXO1 positive. Twenty patients had radiotherapy including 16 to the nodal metastatic area. After a median follow-up of 53.9months (range 22.8-110.5), 15 patients remain in complete remission, seven had progressive disease or relapse, and six of them died. The 3-year EFS and OS were 67.1% (95% confidence interval [CI]: 42.9-82.9) and 71.9% (95% CI: 47.7-86.3), respectively. Patients with fusion-negative tumors had better outcomes than those with fusion-positive tumors (3-year EFS 100% vs. 46.6%; p=.04). In our experience, patients with RMS and distant lymph node involvement as the only site of metastasis present an outcome superior than other metastatic patients and comparable to patients with locoregional nodal involvement. In particular, excellent outcomes were seen in the limited number of patients with fusion-negative tumors.

Malignant ectomesenchymoma in children: The European pediatric Soft tissue sarcoma Study Group experience.

Malignant ectomesenchymoma (MEM) is an extremely rare soft tissue tumor typical of young children, currently included in the category of skeletal muscle malignancies and characterized by a neuroblastic component. This study describes a series of 10 patients prospectively registered in the European paediatric Soft tissue sarcoma Study Group (EpSSG) database Of the 10 cases, seven had an initial local diagnosis of rhabdomyosarcoma. All patients received chemotherapy according to rhabdomyosarcoma strategy, four had radiotherapy. Overall, six patients were alive in first remission, two in second remission and one after second tumor. Only the patient with initially metastatic tumor died of disease.

Rhabdomyosarcoma xenotransplants in zebrafish embryos.

Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. High-risk and metastatic disease continues to be associated with very poor prognosis. RMS model systems that faithfully recapitulate the human disease and provide rapid, cost-efficient estimates of antitumor efficacy of candidate drugs are needed to facilitate drug development and personalized medicine approaches. Here, we present a new zebrafish-based xenotransplant model allowing for rapid and easily accessible drug screening using low numbers of viable tumor cells and relatively small amounts of water-soluble chemicals. Under optimized temperature conditions, embryonal RMS xenografts were established in zebrafish embryos at 3h postfertilization (hpf). In proof-of-principle experiments, chemotherapy drugs with established clinical anti-RMS efficacy (vincristine, dactinomycin) and the mitogen-activated protein kinase kinase inhibitor trametinib were shown to significantly reduce the cross-sectional area of the tumors by 120hpf. RMS xenograft models in zebrafish embryos henceforth could serve as a valuable addition to cell culture and mammalian models of RMS and represent a rapid and cost-effective solution for preclinical candidate drug testing.

Survival and Treatment Outcome of Pediatric Soft Tissue and Bone Sarcomas in Tanzania

<h3>Purpose/Objective(s)</h3> Pediatric sarcomas are aggressive solid childhood tumors which often present with distant metastatic disease. Muhimbili National Hospital (MNH) treats most of the childhood cancers diagnosed in Tanzania adapting management strategies from established treatment protocols conducted in the Europe. The objective of this study is to describe treatment and overall survival (OS) for pediatric sarcoma treated at MNH. <h3>Materials/Methods</h3> Eligible patients had confirmed histological diagnosis of bone or soft tissue sarcoma treated at MNH between 2011 and 2016. Treatment by stage was documented. Imaging response was assessed as: complete response (CR), partial response (PR), no response (NR); OS was assessed at 2-years. <h3>Results</h3> 135 cases were retrospectively analyzed; 89 (66%) were STS; 46 (34%) were bone sarcomas. 193 treatments were administered including surgery 82 (42.5%), chemotherapy 74 (38.3%), and radiation therapy 11 (8%). A subset of patients received multimodal therapy that included surgery, chemotherapy, and radiation therapy. 26 (13%) palliative care treatments were delivered to those with advanced stage disease. Response rates for STS: 37 (42%) CR, 12 (14%) PR, 38 (43%) NR and for bone sarcoma: 14 (30%) CR, 4 (9%) PR, 28 (61%) NR. 2-year OS for early-stage STS and bone sarcoma was significantly higher at 75% and 90% respectively compared to late-stage disease 21% and 25% (p<0.001). <h3>Conclusion</h3> This is the first report to document treatment and outcome for pediatric sarcomas in Tanzania. We show that early-stage disease is potentially curable while advanced stage disease has significantly worse outcomes. Patents with stage IV disease are likely to receive palliative care only. Future studies are needed to explore reasons for high rates of incomplete treatment with chemotherapy and no radiation therapy in Tanzania.

An Electrochemical Immunoassay System for Measuring Circulating Protein Biomarkers of Pediatric Soft Tissue Sarcoma

The combination of simple, inexpensive 3D-printed flow cells with electrochemical biosensors has recently emerged a promising strategy for detecting molecular biomarkers of disease. In this study, we report a multiplex electrochemical immunoassay based on pencil graphite electrode arrays, 3D-printed flow cells and magnetic bead bioconjugates for simultaneous detection of three biomarker proteins (cancer antigen 125 (CA-125), midkine (MK) and osteopontin (OPN)) linked to pediatric soft tissue sarcoma (PSTS). Magnetic bead bioconjugates are functionalized with large amounts of antibody and enzyme labels according to a previously reported strategy,1 pencil graphite electrodes are modified with gold nanoparticles and antibodies for specific capture of bioconjugate-labeled biomarkers, and 3D-printed flow cells to facilitate amperometric detection. Using this immunoassay platform, detection limits for CA-125, MK and OPN that are 100 times lower than those obtained using commercial enzyme-linked immunosorbent assay (ELISA) can be achieved. The combination of low-cost pencil graphite electrode arrays with the convenience of multi-labeled magnetic bead bioconjugates and simplicity of 3D-printed flow-cells results in a promising electrochemical biosensing strategy for biomarker proteins CA-125, MK, and OPN in human serum samples.Reference(1) Malhotra, R.; Patel, V.; Chikkaveeraiah, B. v.; Munge, B. S.; Cheong, S. C.; Zain, R. B.; Abraham, M. T.; Dey, D. K.; Gutkind, J. S.; Rusling, J. F. Ultrasensitive Detection of Cancer Biomarkers in the Clinic by Use of a Nanostructured Microfluidic Array. Analytical Chemistry 2012, 84 (14), 6249–6255. https://doi.org/10.1021/ac301392g.

141P Comprehensive genomic profiling-based precision oncology in the management of rare paediatric soft tissue sarcomas

Soft tissue sarcomas are a heterogeneous group of malignant tumours, accounting for the fifth most common paediatric cancer. Next-generation sequencing-based (NGS) comprehensive genomic profiling (CGP) of paediatric soft tissue sarcomas tumours associated with a poor prognosis can identify actionable biomarkers and determine prognostic and therapeutic stratification of patient management.

Relapsing pediatric non-rhabdomyosarcoma soft tissue sarcomas: The impact of routine imaging surveillance on early detection and post-relapse survival

PurposeThe chances of patients with relapsing pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) being cured are limited. This retrospective single-institutional study examines the potential role of routine surveillance imaging for detecting recurrent tumor, and its impact on post-relapse survival. MethodsThe analysis concerned 86 patients < 21 years old with relapsing NRSTS treated from 1985 to 2020. Clinical findings, treatment modalities and survival were analyzed, comparing patients whose relapse was first suspected from symptoms (symptomatic group) with those whose relapse was detected by radiological surveillance (imaging group). ResultsTumor relapses were identified from clinical symptoms in 49 cases and on routine imaging in 37. Time to relapse was similar in the two groups. Routine imaging detected 6/32 local relapses and 31/48 distant relapses (and 79% of the cases of lung metastases). Overall survival (OS) at 5 years was 34.3% for the symptomatic group, and 24.0% for the imaging group (p-value 0.270). In patients with lung metastases at relapse, the 5-year OS was statistically better for the imaging group, that is, 25.8% versus 0% for the symptomatic group (p-value 0.044). ConclusionThis is the first study to explore the role of surveillance imaging in pediatric NRSTS. Judging from our findings, the value of routine scanning of primary sites seems limited, while radiological surveillance may help to detect lung metastases, improving survival for this patient category. The potentially negative effects of periodic radiological exams should be considered in deciding the optimal follow-up for patients off therapy.

A Grasp-Like Vaginal Lesion in a 15-Months-Old Child: A Case Report

<strong>Introduction and importance:</strong> Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma. It constitutes 4 – 6% of all malignancies in childhood. The botryoid variant is a type of ERMS that is the most common malignancy in the pediatric female genitourinary tract. ERMS of the vagina usually occurs in early childhood, whereas ERMS of the uterus occurs later in age. Since 1959, only 7 cases of uterine botryoid ERMS during infancy have been reported. <strong>Case presentation:</strong> A 15-months-old girl was admitted to our ED for three reddish, smooth, glistening, polypoidal masses protruding from her vaginal introitus for 9 days. The lesions had a suspicious “grape-like” appearance and tended to come in and out through the vaginal ostium. A pelvic US examination on the patient showed an inhomogeneous aspect of the uterus, which appeared to be occupied and stretched out by an iso-hypoechogenic solid tissue. Additionally, there were some hyperechogenic spots inside as well as evidence of vascular signals on color doppler. A surgical biopsy revealed a malignant mesenchymal tumor consistent with the diagnosis of embryonal rhabdomyosarcoma (ERMS), botryoid variant. <strong>Clinical Discussion:</strong> The patient completed her first cycle of chemotherapy with ifosfamide, vincristine, and dactinomycin (IVA). When she was 18 months old, she underwent a hysterectomy, which removed the entire mass with a Pfannenstiel approach. The postoperative course presented with no complications. Follow-up visits were scheduled quarterly. <strong>Conclusion:</strong> Botryoid ERMS of the uterus is a diagnosis not to be missed in an infant. Since rapid diagnosis and treatment are necessary, clinicians should be aware of its presentation to assure optimal management. <strong>Highlights:</strong> <ul><li>Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and constitutes 4–6% of all malignancies in childhood, most of which occur in the head and neck.</li><li>RMS of the vagina usually occurs in early childhood, in contrast with the ERMS the uterus which occurs at later age.</li><li>In this case RMS of the uterus occurred at very young age; since 1959, only 7 cases of uterine botryoid RMS of in infant have been reported.</li><li>It is an aggressive form associated with poor prognosis and is a diagnosis not to be missed in an infant.</li></ul>

Abstract B029: Flip-flopping of fusion-positive rhabdomyosarcoma regulating intratumoral heterogeneity for metastasis

Abstract Of rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, higher metastatic propensity of fusion-positive rhabdomyosarcoma (FPRMS), a subtype with PAX3-FOXO1 fusion gene, than fusion-negative subtype (FNRMS) suggest that the fusion gene may stimulate metastasis. Recent single-cell level research revealed that FPRMS has heterogeneity in the expression levels of the fusion gene, i.e., PAX3-FOXO1 fusion protein (P3F-FP) and corresponding phenotypes related to metastasis, e.g., higher cell motility of cells with low P3F-FP (FPLow). However, it remains unclear how the fusion gene and its heterogeneous expression regulate metastasis. Interestingly, FPRMS shows collective invasion, distinct from individual invasion of FNRMS. The collective invasion is prevalently observed in invasive tumors and has higher metastatic potentials than individual invasion. Despite its substantial commonality with well-characterized individual invasion, its features stemming from multi-cellular organization cause distinct features, potentially related to its higher metastatic potentials. Specifically, heterogeneity of a collective cell group, i.e., the leader/follower coordination, regulates collective invasion. The collective cell mass consists of “leaders,” trailblazing invasion paths, and “followers”, spreading through the paths despite their less invasiveness. At the initiation step of metastasis, the mass may enrich the subpopulation of leaders, driving collective invasion. However, it may revert the enrichment at the colonization step, suppressing migration and promoting colonization driven by followers at the secondary tumor site. This well-tuned process upon each metastasis step suggests the significance of dynamic switching between leaders/followers, regulating collective invasion and, in turn, metastasis. Here, we suggest bistability, a system with two stable states, represents the leader/follower coordination in FPRMS. The bistable system exhibits switch-like transitions between the states. i.e., “flip-flopping.” The flip-flopping enables even a small input to drive an “on/off” transition towards leaders or the other, implying the dynamic switching corresponding to each metastasis step. We discovered two distinct subpopulations with leader-like fast migrating FPLow/follower-like slow FPHigh cells, representing bistability in FPRMS. Specifically, the marginal region of FPRMS cell mass where leaders mainly reside showed higher subpopulation of fast FPLow cells. The bistability requires double-positive/negative feedback in the signaling, regulating flip-flopping. We found that YAP signaling may establish double-negative feedback with P3F-FP, modulating the flip-flopping. Thus, we suggest that the fusion gene functions as a toggle switch of bistability, and its "flip-flopping" modulation of expression by YAP signaling may designate cells as leaders or followers, regulating collective invasion and, thus, metastasis. This project will shed light on the metastasis of FPRMS, potentially leading us to suppress its metastasis. Citation Format: JinSeok Park, Anthonios Chronopolous. Flip-flopping of fusion-positive rhabdomyosarcoma regulating intratumoral heterogeneity for metastasis [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B029.

Rhabdomyosarcoma with unknown primary tumor site: A report from European pediatric Soft tissue sarcoma Study Group (EpSSG).

Rhabdomyosarcoma (RMS) is an aggressive malignancy, and 20% of children present with metastases at diagnosis. Patients presenting with disseminated disease very occasionally have no clear evidence of a primary tumor mass. As these patients have rarely been investigated, we report on a series of patients with RMS and unknown primary tumor site registered in the Metastatic (MTS) RMS 2008 protocol (October 2008 to December 2016) coordinated by the European pediatric Soft tissue sarcoma Study Group. Patients were administered nine cycles of induction chemotherapy, and 48weeks of maintenance chemotherapy. Surgery and/or radiotherapy were planned after the first assessment of tumor response, and implemented after six cycles of chemotherapy. If feasible, radiotherapy to all sites of metastasis was recommended. We identified 10 patients with RMS and unknown primary site, most of them adolescents (median age 15.8years, range: 4.6-20.4). Nine had fusion-positive alveolar RMS. Multiple organ involvement was identified in seven patients, two only had bone marrow disease, and one only had leptomeningeal dissemination. All patients were given chemotherapy, four were irradiated, and none had surgery. Three patients underwent allogeneic bone marrow transplantation. At the time of this analysis, only two patients are alive in complete remission: one had received radiotherapy; and one had a bone marrow transplant. RMS with unknown primary tumor occurs mainly in adolescents and is typically fusion-positive alveolar. Radiotherapy may be important, but survival is poor and patients should be offered enrollment in investigational trials.

Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Standard of Care and Treatment Recommendations from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make the management of children and adolescents with these tumors complex and challenging. The overall cure rate for patients with NRSTS is around 70%, but survival depends on several prognostic variables, such as histotype and tumor grade, extent of disease and stage, tumor size, and tumor site. While surgery remains the mainstay of treatment for most of these tumors, a multimodal therapeutic approach including radiotherapy and chemotherapy is required in many cases. The EpSSG NRSTS 2005 study was the first prospective protocol tailored specifically to NRSTS. Together with the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG), the EpSSG NRSTS 2005 study currently represents the benchmark for these tumors, establishing risk-adapted standards of care. The EpSSG has developed common treatment recommendations for the large group of adult-type NRSTS (including synovial sarcoma), and specific treatment recommendations for other particular adult-type histologies (ie, alveolar soft-part sarcoma, clear cell sarcoma and dermatofibrosarcoma protuberans); other highly malignant tumors with a biology and clinical behavior differing from those of adult-type NRSTS (ie, rhabdoid tumors and desmoplastic small round cell tumor); and soft tissue tumors of intermediate malignancy (ie desmoid-type fibromatosis, inflammatory myofibroblastic tumors, and infantile fibrosarcoma). New effective drugs are needed for patients whose NRSTS carries the worst prognosis, ie, those with unresectable tumors, metastases at diagnosis, or relapsing disease. Progress in this area relies on our ability to develop international integrated prospective collaborations, both within existing pediatric oncology networks and, importantly, between the communities of specialists treating pediatric and adult sarcoma.

18F FDG PET-CT Super scan: Paediatric Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, making 50% of all diagnosed cases. It is a complex disease that has the potential to arise from any tissue of the body except the bones. There are four types of rhabdomyosarcoma; embryonal, botryoidal, alveolar and pleomorphic. [18F]-FDG PET-CT plays a vital role in staging, response evaluation and follow-up of the disease. Due to significant morbidity and mortality with high-risk disease, proper staging is of paramount importance. Staging of rhabdomyosarcoma depends on tumour localization, infiltration of local structures by the primary tumour, nodal involvement, and presence of visceral metastases. Without timely intervention, rhabdomyosarcoma progresses at an exponential speed.

Long-term Follow-up of Detaenial Sigmoid Neobladder Reconstruction for Paediatric Patients with Bladder and Prostate Rhabdomyosarcoma: Technique and Results from a Single High-volume Centre

BackgroundRhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma. Approximately 15–20% of RMS cases arise from the bladder and prostate (B/P). The optimal treatment strategy for B/P RMS remains unclear. ObjectiveTo retrospectively evaluate the applicability of our procedure performed to treat paediatric patients with B/P RMS. Design, setting, and participantsThis is a retrospective analysis from a single tertiary referral hospital. From August 2003 to March 2021, 62 children pathologically diagnosed with B/P RMS underwent radical cystectomy and orthotopic detaenial sigmoid neobladder reconstruction in our centre. Surgical procedureSurgical procedures included laparoscopic radical cystectomy and detaenial sigmoid neobladder reconstruction, which is demonstrated in the accompanying video. MeasurementsDemographic, clinical, and follow-up data were collected. Perioperative and long-term oncological and functional outcomes were reported. A logistic regression analysis was also performed. Results and limitationsAll surgeries, including three intracorporeal laparoscopic surgeries, were completed successfully. Of the 62 patients, 54 were alive without evidence of disease recurrence or metastasis at the last follow-up. Five of the 14 >12-yr-old boys reported that they experienced erections. Two female patients >12 yr old reported that they menstruated. However, this was a retrospective study conducted at a single centre with limited surgeon experience. ConclusionsOur results confirmed the safety and feasibility of primary orthotopic sigmoid neobladder reconstruction after radical cystectomy for paediatric patients with B/P RMS. Good outcomes in terms of oncological control and functional recovery were achieved. The high histocompatibility and tissue adaptability of children are inspiring. Patient summaryWe describe our stepwise technique of radical cystectomy and detaenial sigmoid neobladder reconstruction for paediatric patients with bladder and prostate rhabdomyosarcoma. With this technique, we were able to achieve good functional recovery without compromising cancer control and significantly increasing complications.

Creating a data commons: The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT).

In this article, we will discuss the genesis, evolution, and progress of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT), which aims to foster international research and collaboration focused on pediatric soft tissue sarcoma. We will begin by highlighting the current state of clinical research for pediatric soft tissue sarcomas, including rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. We will then explore challenges and research priorities, describe the development of INSTRuCT, and discuss how the consortium aims to address key research priorities.

Strongylopus grayii tadpole blastema extract exerts cytotoxic effects on embryonal rhabdomyosarcoma cells

Amphibians have regenerative capacity and are resistant to developing cancer. This suggests that the developing blastema, located at the tissue regeneration site, may secrete anti-cancer factors. Here, we investigate the anti-cancer potential of tadpole tail blastema extracts (TAD) from the stream frog, Strongylopus grayii, in embryonal rhabdomyosarcoma (ERMS) cells. ERMS originates in skeletal muscle tissue and is a common pediatric soft tissue sarcoma. We show using MTT assays that TAD inhibited ERMS cell viability in a concentration-dependent manner, and phase contrast/fluorescent microscopy revealed that it induced morphological markers of senescence and apoptosis. Western blotting showed that this was associated with DNA damage (γH2AX) and activation of the p38/MAPK stress signaling pathway as well as molecular markers of senescence (p16INK4a), apoptosis (cleaved PARP), and inhibition of cell cycle promoters (cyclin A, CDK2, and cyclin B1). Furthermore, proteomics followed by gene ontology analyses showed that TAD treatment inhibited known tumor promoters and proteins required for cancer cell survival. Lastly, using the LINCS drug perturbation library, we show that there is an overlap between the proteomics signature induced by TAD and common anti-cancer drugs. Taken together, this study provides novel evidence that TAD exhibits cytotoxicity in ERMS cells.

Epithelioid hemangioendothelioma in children: The European Pediatric Soft Tissue Sarcoma Study Group experience.

The European pediatric Soft tissue sarcoma Study Group analyzed all children with epithelioid hemangioendothelioma prospectively registered in the NRSTS-05 (EUDRACT 2005-001139-31) and in MTS-2008 (NCT00379457) studies: 10 patients with localized and one with metastatic disease. Median age was 14.3 years (range, 9.0-18.8). Local therapy was initial primary surgery in seven cases, and five patients received systemic therapy. No patients received radiotherapy. After a median follow-up of 50 months (range, 6-176) for living patients, nine patients remain alive off therapy and two died. Five-year progression free and overall survivals are, respectively, 77.1% (95% confidence interval [CI]: 34.5-93.9) and 74.1% (95% CI: 28.1-93.0).

Immunoreactivity against fibroblast growth factor 8 in alveolar rhabdomyosarcoma patients and its involvement in tumor aggressiveness

ABSTRACT Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma characterized by a very poor prognosis when relapses occur after front-line therapy. Therefore, a major challenge for patients’ management remains the identification of markers associated with refractory and progressive disease. In this context, cancer autoantibodies are natural markers of disease onset and progression, useful to unveil novel therapeutic targets. Herein, we matched autoantibody profiling of alveolar RMS (ARMS) patients with genes under regulatory control of PAX3-FOXO1 transcription factor and revealed fibroblast growth factor 8 (FGF8) as a novel ARMS tumor antigen of diagnostic, prognostic, and therapeutic potential. We demonstrated that high levels of FGF8 autoantibodies distinguished ARMS patients from healthy subjects and represented an independent prognostic factor of better event-free survival. FGF8 was overexpressed in ARMS tumors compared to other types of pediatric soft tissue sarcomas, acting as a positive regulator of cell signaling. Indeed, FGF8 was capable of stimulating ARMS cells migration and expression of pro-angiogenic and metastasis-related factors, throughout MAPK signaling activation. Of note, FGF8 was found to increase in recurrent tumors, independently of PAX3-FOXO1 expression dynamics. Risk of recurrence correlated positively with FGF8 expression levels at diagnosis and reduced FGF8 autoantibodies titer, almost as if to suggest a failure of the immune response to control tumor growth in recurring patients. This study provides evidence about the crucial role of FGF8 in ARMS and the protective function of natural autoantibodies, giving new insights into ARMS biology and laying the foundations for the development of new therapeutic strategies.