Pediatric Soft Tissue Sarcoma Research Articles

Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma by Molecular Detection of Disseminated Disease.

Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR. Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol. We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, and PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (CI), 17.5%-53.5%] for the 33/99 RNA-positive patients, versus 88.0% (95% CI, 78.9%-97.2%) for the 66/99 RNA-negative patients (P < 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%-73.4%) and 93.7% (95% CI, 86.6%-100.0%), respectively (P < 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23-28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model. This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.

Role of centers with different patient volumes in the management of rhabdomyosarcoma. An analysis by the Italian Pediatric Soft Tissue Sarcoma Committee.

The survival of children with rhabdomyosarcoma (RMS) has gradually improved as a result of the adoption of multidisciplinary treatments. Dedicated skills and facilities are indispensable and more readily available at reference centers. In this study, we examined the role of centers' experience (based on the number of patients treated) in their management of patients with RMS. We analyzed 342 patients with localized RMS enrolled in the European RMS 2005 protocol from October 2005 to December 2016 at 31 Italian centers that are part of the Soft Tissue Sarcoma Committee (STSC). We grouped the centers by the number of patients each one enrolled (Group 1: >40; Group 2: <40 and >10; and Group 3: <10), and compared a number of indicators to assess the appropriateness of patients' diagnostic workup and treatment and their survival. Overall, 74.6% of patients were treated at 10 centers, and only three of them classifiable as high-volume centers. Only minor differences emerged between the three patient groups in terms of diagnostic investigations and treatment modalities. Survival was similar in the three groups. Approximately, one in four children treated at the centers in Groups 2 and 3 traveled to another center for surgery or radiotherapy. Patients treated at STSC centers with different amounts of experience had similar results in terms of survival. This is attributable to all centers in the network adhering to protocol recommendations and receiving the STSC's support on diagnostics and multidisciplinary treatments for RMS.

Abstract 3022: Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma indentity

Abstract Rhabdomyosarcoma (RMS) is an embryonal tumor resembling developing skeletal muscle and the most common pediatric soft-tissue sarcoma. RMS is molecularly defined by the presence or absence of a fusion oncoprotein corresponding with the histological subtypes alveolar and embryonal RMS, respectively. Embryonal, or fusion-negative, RMS (FN-RMS) is heterogeneous in its molecular alteration profile; the major exception is the near universal PTEN promoter hypermethylation found in FN-RMS corresponding with decreased PTEN expression. PTEN's functional role in FN-RMS remains unclear as does PTEN's role in defining tumor fate decisions. Organismal cancer models can help elucidate these decisions by defining the potential tumor fate landscape that can occur in transformed multipotent progenitor cells. Our laboratory leverages a highly penetrant, early onset model of FN-RMS driven by the transdifferentiation of endothelial progenitors into skeletal muscle-like RMS cells by Hedgehog pathway activation. Therefore, our model is uniquely primed to empirically determine the core regulatory factors critical in FN-RMS initiation. Here, we conditionally deleted Pten in these cells (ASPcKO). ASPcKO tumors presented earlier than wild-type tumors and more closely resemble human FN-RMS with a less differentiated skeletal muscle state. These were unique characteristics of ASPcKO tumors as mice with homozygous loss of other tumor suppressors - Cdkn2a, Trp53, and Rb1 - did not recapitulate these phenotypes. We further probed the downstream transcriptional outputs of ASPcKO tumors revealing a profound increase in expression of the neural developmental transcription factors Dbx1 and Pax7. These outputs are functionally important as human FN-RMS patient-derived xenografts are dependent on both DBX1 and PAX7. Subsequently, we also show that DBX1 is a downstream transcriptional target of PAX7 highlighting how Pten loss engages a unique transcriptional program for tumor maintenance. PAX7 is also a core FN-RMS regulatory circuit component. To further interrogate the role of PAX7 on tumor initiation, we concomitantly deleted Pten and Pax7 in our FN-RMS model and found not only that Pax7 loss rescues the survival kinetics observed when Pten is lost, but also alters the developmental trajectory of the tumors that do develop. Instead of Smoothened trans-differentiating our aP2-Cre expressing primordial endothelial cell into a skeletal-muscle like FN-RMS, Pten and Pax7 loss dictates these endothelial cells to give rise to tumors with smooth muscle-like differentiation, including human-like leiomyosarcoma. Together, this synthetic essential interaction between Pten and Pax7 in FN-RMS stresses the importance of the bifunctional role of PAX7 in tumor initiation and maintenance and how specific tumor suppressor loss can engage developmental transcriptional programs to alter tumor fate. Citation Format: Casey G. Langdon, Katherine E. Gadek, Matthew R. Garcia, Kristin B. Reed, Madeline Bush, Jason A. Hanna, Catherine J. Drummond, Matthew C. Maguire, Patrick J. Leavey, David Finkelstein, Hongjian Jin, Jerold E. Rehg, Mark E. Hatley. Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma indentity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3022.

Paediatric non-rhabdomyosarcoma soft tissue sarcomas: the prospective NRSTS 2005 study by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG)

A standardised approach to treatment of paediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), which account for about 4% of childhood cancers, is still lacking. We report the results of the NRSTS 2005 protocol developed specifically by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) to determine a risk-adapted multimodal standard of care for this group of tumours. The EpSSG NRSTS 2005 study included two prospective, non-randomised, historically controlled trials (one on localised adult-type NRSTS and the other on localised synovial sarcoma) done at 100 academic centres and hospitals in 14 countries. Patients younger than 21 years with a pathologically proven diagnosis of synovial sarcoma or an adult-type NRSTS, no evidence of metastatic disease, no previous treatment other than primary surgery, and diagnostic specimens available for pathological review were included. Patients were stratified by surgical stage, tumour size, nodal involvement, tumour grade (for adult-type NRSTS), and tumour site (for synovial sarcoma). Patients were then divided into four treatment groups: surgery alone, adjuvant radiotherapy, adjuvant chemotherapy (with or without radiotherapy), or neoadjuvant chemotherapy (with or without radiotherapy). The main chemotherapy regimen was ifosfamide (3·0 g/m2 intravenously per day for 3 days) plus doxorubicin (37·5 mg/m2 intravenously per day for 2 days); only ifosfamide (3·0 g/m2 intravenously per day for 2 days) was given concomitantly with radiotherapy (delivered with three-dimensional conformal external beam technique, using conventional fractionation [1·8 daily fractions, 5 days per week] at a dose of 50·4 Gy or 54·0 Gy, to a maximum of 59·4 Gy). The number of chemotherapy cycles ranged from three to seven depending on the stage of the disease. The primary outcomes were event-free survival and overall survival. This study has been completed, and is registered under EudraCT, 2005-001139-31. Between May 31, 2005, and Dec 31, 2016, 1321 patients were enrolled, of whom 569 (206 with synovial sarcoma and 363 with adult-type NRSTS), with a median age of 12·6 years (IQR 8·2-14·9), were included in this analysis. With a median follow-up of 80·0 months (IQR 54·3-111·3) for the 467 patients alive, 5-year event-free survival was 73·7% (95% CI 69·7-77·2) and 5-year overall survival was 83·8% (95% CI 80·3-86·7). 5-year event-free survival was 91·4% (95% CI 87·0-94·4) and 5-year overall survival was 98·1% (95% CI 95·0-99·3) in the surgery alone group (n=250); 75·5% (46·9-90·1) and 88·2% (60·6-96·9) in the adjuvant radiotherapy group (n=17); 65·6% (54·8-74·5) and 75·8% (65·3-83·5) in the adjuvant chemotherapy group (n=93); and 56·4% (49·3-63·0) and 70·4% (63·3-76·4) in the neoadjuvant chemotherapy group (n=209). Reported severe adverse events included one case of generalised seizures (probably related to ifosfamide) and six cases of secondary tumours. Findings from the EpSSG NRSTS 2005 study help to define the risk-adapted standard of care for this patient population. Adjuvant treatment can be safely omitted in the low-risk population (classified here as the surgery alone group). Improving the outcome for patients with high-risk, initially resected adult-type NRSTS and those with initially unresectable disease remains a major clinical challenge. Fondazione Città della Speranza.

Paediatric non-rhabdomyosarcoma soft tissue sarcomas: towards global collaboration

During the past 50 years, rigorous clinical trials in paediatric oncology have iteratively improved risk stratification and risk-adapted therapy, dramatically improving 5-year survival among patients with childhood cancer in most European and North American countries to more than 80%.1 Largely overlooked during the first few decades of this transformation in paediatric cancer care were the so-called non-rhabdomyosarcoma soft tissue sarcomas, a diverse array of more than 30 different histological subtypes2 that collectively account for 4% of paediatric cancers.

European guideline for imaging in paediatric and adolescent rhabdomyosarcoma \u2014 joint statement by the European Paediatric Soft Tissue Sarcoma Study Group, the Cooperative Weichteilsarkom Studiengruppe and the Oncology Task Force of the European Society of Paediatric Radiology

Appropriate imaging is essential in the treatment of children and adolescents with rhabdomyosarcoma. For adequate stratification and optimal individualised local treatment utilising surgery and radiotherapy, high-quality imaging is crucial. The paediatric radiologist, therefore, is an essential member of the multi-disciplinary team providing clinical care and research. This manuscript presents the European rhabdomyosarcoma imaging guideline, based on the recently developed guideline of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) Imaging Committee. This guideline was developed in collaboration between the EpSSG Imaging Committee, the Cooperative Weichteilsarkom Studiengruppe (CWS) Imaging Group, and the Oncology Task Force of the European Society of Paediatric Radiology (ESPR). MRI is recommended, at diagnosis and follow-up, for the evaluation of the primary tumour and its relationship to surrounding tissues, including assessment of neurovascular structures and loco-regional lymphadenopathy. Chest CT along with [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT or PET/MRI are recommended for the detection and evaluation of loco-regional and distant metastatic disease. Guidance on the estimation of treatment response, optimal long-term follow-up, technical imaging settings and standardised reporting are described. This European imaging guideline outlines the recommendations for imaging in children and adolescents with rhabdomyosarcoma, with the aim to harmonise imaging and to advance patient care.

Clinical value of Next Generation Sequencing in Chinese pediatric soft tissue sarcoma: A multicenter data.

e22005 Background: To uncover the genomic characteristics as well as to, within the scope of pediatric soft tissue sarcoma (psts), assess the clinical value of Next Generation Sequencing (NGS), we present the first report of genomic profiles in Chinese psts. Methods: Tumor tissue, as well as peripheral blood from 41 psts patients, were collected in Sun Yat-Sen University Cancer Center, Shenzhen Children's Hospital and Nanfang Hospital. Samples were sequenced in a CLIA/CAP-accredited laboratory with a targeted NGS panel (Onco PanScan plus; GenetronHealth.inc) consisted of all exons of 831 cancer-related genes and mRNA of 395 genes. Bioinformatics analysis was conducted using a build-in computational pipeline. Results: A total of 41 samples consisted of five major histology types including rhabdomyosarcoma (RMS) (n = 11), fibrosarcoma (n = 4), Ewing's sarcoma (n = 4), INI1-deficient mesenchymal tumor (n = 4), and other mesenchymal tumors (n = 18). All patients were with doubtful diagnosis,advanced, relapsed, or refractory sarcoma, of which 85% samples were from initial diagnoses. In totally, we identified 116 somatic aberrations and 4 pathogenic or likely pathogenic germline mutations, with a median tumor mutational burden of 0.47/Mb (0–6.57). Genomic analysis revealed frequent alterations in TP53 (10%), NTRK fusion (10%), PAX3/7 fusion (8%), and ARID1A (7%). ARID1A (18% vs. 0%) and TP53 (18% vs. 3%) mutations were found with higher frequency compared with pediatric RMS data in a previous study (Jack et al 2014). ARID1A mutation was only reported in a RMS case report (Cramer et al 2017). Furthermore, the mutation of ARID1A potentially match PARP inhibitors, which may provide more therapeutic options. In addition, NGS aided pathologic diagnosis in 63% (26/41) patients. The proportion of confirmed diagnosis, differential diagnosis, and the excluded diagnosis was 41.5%, 12.2%, and 9.7%, respectively. Druggable alterations were detected in 39% patients (Table). Four patients received the treatment recommended by genetic testing, three of them with NTRK fusion were recruited in a matched clinical trial could be evaluated and showed partial remission upon Larotrectinib. Conclusions: We discovered ARID1A mutations, which potentially sensitive to PARP-inhibition, were at a higher incidence in Chinese RMS. This study demonstrated the value of NGS test in guiding the clinical practice of psts in Chinese population. [Table: see text]

Non-parameningeal head and neck rhabdomyosarcoma in children, adolescents, and young adults: Experience of the European paediatric Soft tissue sarcoma Study Group (EpSSG) – RMS2005 study

Background/objectivesThe primary aim of this study was to analyse and evaluate the impact of different local treatments on the pattern of relapse in children with primary head and neck non-parameningeal (HNnPM) rhabdomyosarcoma (RMS), treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 study. The secondary aim was to assess whether current risk stratification is valid for this specific site. Design/methodsThis study includes all patients with localised HNnPM RMS enrolled in the RMS2005 study between 2005 and 2016. Treatment comprised chemotherapy adapted to risk group, with local surgery and/or radiation therapy. The main outcome measures were event-free survival (EFS) and overall survival (OS). ResultsA total of 165 patients were identified; the median age was 6.4 years (range, 0.1–25). The most common tumour sites were cheek/chin (22%) and nasal ala/nasolabial fold (20%). Histology was unfavourable for 40%, and regional nodal involvement present in 26%. Local therapy included surgery (58%) and/or radiotherapy (72%) to primary tumour and/or regional lymph nodes. After a median follow-up of 66 months (range, 6–158), 42 patients experienced an event, and 17 are still alive. Tumour events were frequent in oral primary (36%), parotid site (26%), cheek/chin (24%), and nasal ala/nasolabial fold (24%) and included locoregional failure in 84% of cases. The 5-year EFS and OS were 75% (95% confidence interval [CI]: 67.3–81.2) and 84.9% (95% CI: 77.5–89.7), respectively. Favourable histology was associated with a better EFS (82.3% versus 64.6%; p = 0.02) and nodal spread with a worse OS (88.6% versus 76.1%; p = 0.04). Different sublocations within the HNnPM primary did not have significant impact on outcome. ConclusionLocoregional relapse/progression is the main tumour failure event in this site. Despite frequent unfavourable risk factors, HNnPM RMS remains a favourable location in the context of a risk-adapted strategy.

Pattern of Pediatric Soft Tissue and Bone Sarcomas at South Egypt Cancer Institute, Retrospective Study

Pattern of Pediatric Soft Tissue and Bone Sarcomas at South Egypt Cancer Institute, Retrospective Study

Non-rhabdomyosarcoma soft-tissue sarcoma.

Non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) comprise 4% of childhood cancers and consist of numerous histologic subtypes. Prognostic factors associated with poor outcome include high histologic grade, large tumor size, presence of metastases, and unresectability. Complete surgical resection is critical for the best oncologic outcomes and is prioritized in treatment algorithms. The use of radiation therapy (RT) and chemotherapy is based upon factors such as resectability, histologic grade, tumor size, and stage. North American and European trials are defining a risk-based approach to NRSTS to limit treatment-related toxicity and to maximize therapeutic efficacy. In this paper, we summarize the current roles of surgery, RT, and chemotherapy in NRSTS and describe ongoing research that is advancing the care of NRSTS patients.

Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target.

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion‐positive rhabdomyosarcoma, which expresses either PAX3‐FOXO1 or PAX7‐FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3‐FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient‐derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC‐209 and PTC‐028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.

Integrating irinotecan in standard chemotherapy: A novel dose-density combination for high-risk pediatric sarcomas.

Irinotecan is a drug active against pediatric sarcomas with a toxicity profile that theoretically allows for its association with more myelotoxic drugs. We examined the feasibility of a dose-density strategy integrating irinotecan in standard chemotherapy regimens for patients with high-risk sarcomas. Between November 2013 and January 2020, 23 patients ≤25years old were included in the study. Eleven patients newly diagnosed with metastatic disease received nine cycles of IrIVA (irinotecan-ifosfamide-vincristine-actinomycin D; ifosfamide 3g/m2 on days 1 and 2, vincristine 1.5mg/m2 on day 1, actinomycin D 1.5mg/m2 on day 1, irinotecan 20mg/m2 for 5 consecutive days starting on day 8) as first-line therapy. Two relapsed patients received IrIVA and 10 IrVAC (irinotecan-vincristine-actinomycin D-cyclophosphamide; cyclophosphamide 1.5g/m2 on day 1 instead of ifosfamide). Feasibility was assessed in terms of toxicity and time to complete the treatment. Seventeen rhabdomyosarcomas, four Ewing sarcomas, two desmoplastic small round cell tumors received a total of 181 cycles (range 2-10). Grade 4 neutropenia occurred in 62.4% of the cycles. Thirteen patients had febrile neutropenia. Diarrhea occurred in 14 cycles. The median time to complete the treatment was 195days (range 170-231), 83.4% of cycles were administered on time or with a delay <1week. With a median follow-up of 2.6years (range 0.2-5.0), 12 patients are alive, nine complete remissions, three with the disease. A dose-density strategy combining irinotecan with standard chemotherapy is feasible. This approach will be investigated in the next trial coordinated by the European pediatric Soft tissue sarcoma Study Group.

Embryonal rhabdomyosarcoma completely resected at diagnosis: The European paediatric Soft tissue sarcoma Study Group RMS2005 experience

BackgroundRhabdomyosarcoma (RMS) is the most common form of soft tissue sarcoma in children. We report the results of the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 study, which prospectively evaluated the reduction of chemotherapy in patients with embryonal RMS (ERMS) after initial surgery. MethodsBetween October 2005 and December 2016, all patients with localised ERMS with an initial microscopically complete resection (IRS group I) with lymph node-negative (N0) were prospectively enrolled in the low-risk (n = 70, subgroup A; age < 10 years and tumour size ≤ 5 cm) or standard-risk group (n = 108, subgroup B; age ≥ 10 years or tumour size > 5 cm. Subgroup A received 8 courses of vincristine and dactinomycin (VA) for 22 weeks; subgroup B received 4 courses of VA with ifosfamide (IVA) and 5 courses of VA for 25 weeks. ResultsThe 5-year event-free survival (EFS) and overall survival (OS) were 90.8% (95% confidence interval [CI]: 85.0–94.4) and 95.7% (95% CI: 90.5–98.1), respectively (n = 178). The EFS and OS were 95.5% (95% CI: 86.8–98.5) and 100% (subgroupA), and 87.8% (95% CI: 79.3–93.0) and 93.0% (95% CI: 84.8–96.8)(subgroup B), respectively. Bearman stage 2 veno-occlusive disease (VOD) occurred in 4 very young patients. ConclusionVA treatment for 8 courses was effective and well tolerated by the subgroup of patients with low-risk ERMS (group A). Four courses of IVA and 5 courses of VA instead of 9 courses of IVA also has very good results. Careful monitoring for liver toxicity is important in very young patients.European union drug regulating authorities clinical trials EUDRACT No. 2005-000217-35.

Surgical management of paratesticular rhabdomyosarcoma: A consensus opinion from the Children's Oncology Group, European paediatric Soft tissue sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

The treatment of paratesticular rhabdomyosarcoma (PT-RMS) has varied over time and by cooperative group. The International Soft Tissue Sarcoma Database Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft tissue sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). The INSTRuCT surgical committee has been given charge of the development of internationally applicable consensus guidelines for the surgical treatment of rhabdomyosarcoma. This clinical consensus opinion document addresses accepted principles and areas of controversy, such as scrotal violation and retroperitoneal nodal evaluation, providing an evidence-based guideline for the surgical treatment for PT-RMS.

Paediatric soft tissue sarcomas in a resource constraint setting: Grade and stage at presentation and at oncologic intervention are usually of poor prognostic characteristics.

To describe the pattern of paediatric Rhabdomyosarcomas (RMS) and Non-Rhabdomyosarcomas (NRMS) with emphasis on the indices that affect survival outcomes. We reviewed all patients with histologically confirmed RMS and NRMS in the Departments of Pathology and Paediatrics, University College Hospital (UCH), Ibadan, Nigeria; in children aged 0-14years. The study period was January 1991 to December 2016. Information obtained included age, gender, morphology and site of the tumours. The tumour grade and pathologic/clinical staging of all patients were also obtained and verified by the clinical records. Tumour grading was carried out using the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) Sarcoma group grading system and staging was done using TNM. Follow up, survival information and final outcome were retrieved. The 104 patients included in the study had almost equal male-to-female ratio, age ranged between 5months and 14years (median 8.2years). Rhabdomyosarcoma had mean age of 5.6 (±3.8) years while that of NRMS was 9.2(±4.1) years. Overall, the modal age group was 5-9years. Rhabdomyosarcoma was the commonest histological type (76%), undifferentiated sarcomas (6.7%), fibrosarcoma (3.8%) and 2.9% each for synovial sarcoma and dermatofibrosarcoma protuberans. The common primary sites were the head and neck (including the orbit) 49 (47.1%), and the abdominopelvic 26 (25%) regions. Majority (89%) had histologic grade 3 at presentation. Seventy per cent and 64% of patients with RMS and NRMS, respectively, had high stage tumour at presentation. Median survival for all patients with Rhabdomyosarcoma was 45weeks with a 1-year survival of 43% and 2-year survival of 25%. Non-RMS (Dermatofibrosarcoma protuberans and Solitary fibrous tumours) had survival of over 4year's duration. Majority of our patients presented at a late stage with histologic high grade which confers poor prognosis and reduced chances for good overall survival outcome.

An aggressive locoregional orbital rhabdomyosarcoma and Li Fraumeni syndrome

Introduction. Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with 10 % of the cases occuring in the orbit. Patients often present with a rapidly developing proptosis and globe displacement. Aim. We aimed to present a very rare presentation of orbital RMS, with a giant exophytic orbital mass, a very rare presentation occuring in more advanced cases. Description of the case. A 3-year old girl presented to our hospital with a rapidly enlarging tissue like ulcerative mass. Her past medical history was remarkable with the diagnosis of embryonal rhabdomyosarcoma (RMS) and treatment with chemoradiotherapy at the age of 15 months. On magnetic resonance imaging (MRI), there was a giant heterogenously enhancing mass filling the right orbit and extending to the intracranial region. Li Fraumeni syndrome (LFS) was considered due to her sister death from neuroblastoma at an early age. Cytogenetic analysis revealed mutations of p53 gene, which supported our consideration. Conclusion. RMS is a highly malignant tumor which usually occurs sporadiacally. However, some rare syndromes are associated with increased incidence of RMS, such as LFS.

Targeting PAK4 Inhibits Ras-Mediated Signaling and Multiple Oncogenic Pathways in High-Risk Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most prevalent pediatric soft-tissue sarcoma. Multimodal treatment, including surgery and traditional chemotherapy with radiotherapy, has contributed to improvements in overall survival rates. However, patients with recurrent or metastatic disease have 5-year survival rates of less than 30%. One reason for the lack of therapeutic advancement is identification and targeting of critical signaling nodes. p21-activated kinases (PAK) are a family of serine/threonine kinases downstream of multiple critical tumorigenic receptor tyrosine kinase receptors and oncogenic regulators, including IGFR and RAS signaling, that significantly contribute to aggressive malignant phenotypes. Here, we report that RMS cell lines and tumors exhibit enhanced PAK4 expression levels and activity, which are further activated by growth factors involved in RMS development. Molecular perturbation of PAK4 in multiple RMS models in vitro and in vivo resulted in inhibition of RMS development and progression. Fusion-positive and -negative RMS models were sensitive to two PAK4 small-molecule inhibitors, PF-3758309 and KPT-9274, which elicited significant antitumor and antimetastatic potential in several primary and metastatic in vivo models, including a relapsed RMS patient-derived xenograft model. Transcriptomic analysis of PAK4-targeted tumors revealed inhibition of the RAS-GTPase, Hedgehog, and Notch pathways, along with evidence of activation of antitumor immune response signatures. This PAK4-targeting gene signature showed prognostic significance for patients with sarcoma. Overall, our results show for the first time that PAK4 is a novel and viable therapeutic target for the treatment of high-risk RMS. SIGNIFICANCE: These data demonstrate a novel oncogenic role for PAK4 in rhabdomyosarcoma and show that targeting PAK4 activity is a promising viable therapeutic option for advanced rhabdomyosarcoma.

Pediatric Rhabdomyosarcomas: Three-Dimensional Radiological Assessments after Induction Chemotherapy Predict Survival Better than One-Dimensional and Two-Dimensional Measurements.

Simple SummaryThe prognostic significance of assessing radiological response after induction therapy for pediatric rhabdomyosarcoma (RMS) is still a matter of debate. In this retrospective study conducted at two centers on 66 non-metastatic RMS patients, we investigated the prognostic value of four radiological methods for measuring tumor response: 1D-RECIST (Response Evaluation Criteria in Solid Tumors), 2D-WHO (World Health Organization), 3D-EpSSG (European pediatric Soft tissue sarcoma Study Group) and 3D-Osirix. Patients were classified with each method as responders or non-responders based on the corresponding therapeutic cutoffs. Five-year event-free survival (5yr-EFS) was significantly longer for responders than for non-responders with all four methods, but the 3D assessments discriminated between the two groups better than 1D-RECIST or 2D-WHO. Inter-method agreement was excellent for 3D-EpSSG and 3D-Osirix, and moderate for the other comparisons. Inter-observer agreement was excellent with all methods except the 2D-WHO. Early tumor response was a significant prognostic factor in RMS, and the 3D-EpSSG and 3D-Osirix methods were better predictors of therapeutic response than the 1D-RECIST or 2D-WHO measurements. Radiological response to neoadjuvant chemotherapy is currently used to assess the efficacy of treatment in pediatric patients with rhabdomyosarcoma (RMS), but the association between early tumor response on imaging and survival is still controversial. The aim of this study was to investigate the prognostic value of assessing radiological response after induction therapy in pediatric RMS, comparing four different methods. This retrospective, two-center study was conducted on 66 non-metastatic RMS patients. Two radiologists measured tumor size on pre- and post-treatment magnetic resonance (MR) or computed tomography (CT) images using four methods: considering maximal diameter with the 1D-RECIST (Response Evaluation Criteria in Solid Tumors); multiplying the two maximal diameters with the 2D-WHO (World Health Organization); multiplying the three maximal diameters with the 3D-EpSSG (European pediatric Soft tissue sarcoma Study Group); obtaining a software-assisted volume assessment with the 3D-Osirix. Each patient was classified as a responder or non-responder based on the proposed thresholds for each method. Tumor response was compared with survival using Kaplan–Meier plots, the log-rank test, and Cox’s regression. Agreement between methods and observers (weighted-κ) was also calculated. The 5-year event-free survival (5yr-EFS) calculated with the Kaplan–Meier plots was significantly longer for responders than for non-responders with all the methods, but the 3D assessments differentiated between the two groups better than the 1D-RECIST or 2D-WHO (p1D-RECIST = 0.018, p2D-WHO = 0.007, p3D-EpSSG and p3D-Osirix < 0.0001). Comparing the 5yr-EFS of responders and non-responders also produced adjusted hazard ratios of 3.57 (p = 0.0158) for the 1D-RECIST, 5.05 for the 2D-WHO (p = 0.0042), 14.40 for the 3D-EpSSG (p < 0.0001) and 11.60 for the 3D-Osirix (p < 0.0001), indicating that the volumetric measurements were significantly more strongly associated with EFS. Inter-method agreement was excellent between the 3D-EpSSG and the 3D-Osirix (κ = 0.98), and moderate for the other comparisons (0.5 < κ < 0.8). The 1D-RECIST and the 2D-WHO tended to underestimate response to treatment. Inter-observer agreement was excellent with all methods (κ > 0.8) except for the 2D-WHO (κ = 0.7). In conclusion, early tumor response was confirmed as a significant prognostic factor in RMS, and the 3D-EpSSG and 3D-Osirix methods predicted response to treatment better than the 1D-RECIST or 2D-WHO measurements.

Pathology of childhood rhabdomyosarcoma: A consensus opinion document from the Children's Oncology Group, European Paediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

The diagnosis and classification of rhabdomyosarcoma (RMS) has undergone several shifts over the last 30years. While the main diagnostic categories remained the same, changes in the histologic criteria necessary for diagnosis, as well as varied reliance on immunohistochemical and molecular data over time, have created confusion, particularly regarding how these shifts impacted risk stratification and enrollment onto clinical trials. The goal of this report is to review the evolution and current status of RMS diagnosis, focusing on diagnostic criteria in the Children's Oncology Group (COG), the European Paediatric Soft Tissue Sarcoma Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). In addition, we emphasize research tools used to classify RMS and address biological questions within current clinical trials run by each group. The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) initiative will maximize potential to optimize risk stratification by recognizing and accounting for differences in historical data and current practices.

Antitumor effects of curcumin in pediatric rhabdomyosarcoma in combination with chemotherapy and phototherapy invitro.

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, has an unfavorable outcome in advanced tumor stages with less than 30%failure‑free survival. Curcumin (CUR) is a promising drug in complementary oncology with few side effects but proven efficacy in various adult oncological entities. The present study analyzed the effects of CUR on pediatric (RMS) cell lines invitro. RMS cell lines (RD and RH30), and skeletal muscle cells (SKMC) were treated with different doses of CUR (1.5‑30µM) alone, with phototherapy (PDT, 488nm) or in combination with vincristine (VCR) or dactinomycin (DAC). MTT assays were used for analysis of RMS tumor cell viability. Clonal cell growth was assessed via colony forming assays and migration of the cells was analyzed with scratch tests. Annexin V staining was used to determine apoptosis in flow cytometry. Possible RMS resistance towards CUR after long‑term treatment was analyzed with MTT assays. CUR decreased cell viability in all assessed RMS cell lines in a concentration‑dependent manner with IC50=14‑20µM. CUR enhanced the effects of the cytotoxic drugs VCR or DAC, and led to reduced migration and increased cell apoptosis. In combination with PDT, CUR decreased the cell viability in minute quantities with up to a 10‑fold lower IC50 than without PDT. CUR effectively inhibited the malignant properties of pediatric RMS cells and should be focused on as a useful additional agent in standard chemotherapy of RMS in children.