Childhood Soft Tissue Sarcomas
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Childhood soft tissue sarcomas account for approximately 10% of all childhood cancers. About half of all childhood soft tissue sarcomas are rhabdomyosarcoma, which arises from skeletal muscle, these are most common between the ages of 2 and 6. The other soft tissue sarcomas of childhood include a wide range of different histologies including fibrosarcoma, leiomyosarcoma, liposarcoma, schwannoma, soft tissue Ewing's / peripheral neuroectodermal tumours, synovial sarcoma and many other types. These non-rhabdo sarcomas are more common in adults, but these tumours usually behave quite differently in children compared to the same tumours in adults

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Latest Research Publications

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Information for Health Professionals / Researchers (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Sole CV, Calvo FA, Polo A, et al.
Anticipated intraoperative electron beam boost, external beam radiation therapy, and limb-sparing surgical resection for patients with pediatric soft-tissue sarcomas of the extremity: a multicentric pooled analysis of long-term outcomes.
Int J Radiat Oncol Biol Phys. 2014; 90(1):172-80 [PubMed] Related Publications
PURPOSE: To perform a joint analysis of data from 3 contributing centers within the intraoperative electron-beam radiation therapy (IOERT)-Spanish program, to determine the potential of IOERT as an anticipated boost before external beam radiation therapy in the multidisciplinary treatment of pediatric extremity soft-tissue sarcomas.
METHODS AND MATERIALS: From June 1993 to May 2013, 62 patients (aged <21 years) with a histologic diagnosis of primary extremity soft-tissue sarcoma with absence of distant metastases, undergoing limb-sparing grossly resected surgery, external beam radiation therapy (median dose 40 Gy) and IOERT (median dose 10 Gy) were considered eligible for this analysis.
RESULTS: After a median follow-up of 66 months (range, 4-235 months), 10-year local control, disease-free survival, and overall survival was 85%, 76%, and 81%, respectively. In multivariate analysis after adjustment for other covariates, tumor size >5 cm (P=.04) and R1 margin status (P=.04) remained significantly associated with local relapse. In regard to overall survival only margin status (P=.04) retained association on multivariate analysis. Ten patients (16%) reported severe chronic toxicity events (all grade 3).
CONCLUSIONS: An anticipated IOERT boost allowed for external beam radiation therapy dose reduction, with high local control and acceptably low toxicity rates. The combined radiosurgical approach needs to be tested in a prospective trial to confirm these results.

Related: Synovial Sarcoma

Tremblay AM, Missiaglia E, Galli GG, et al.
The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation.
Cancer Cell. 2014; 26(2):273-87 [PubMed] Related Publications
The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.

Highfill SL, Cui Y, Giles AJ, et al.
Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy.
Sci Transl Med. 2014; 6(237):237ra67 [PubMed] Related Publications
Suppression of the host's immune system plays a major role in cancer progression. Tumor signaling of programmed death 1 (PD1) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of tumor immune escape. We sought to target these pathways in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood. Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit. RMS induced robust expansion of CXCR2(+)CD11b(+)Ly6G(hi) MDSCs, and CXCR2 deficiency prevented CD11b(+)Ly6G(hi) MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2(+)CD11b(+)Ly6G(hi) MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also produce CXCR2 ligands, including CXCL8. Patients with metastatic pediatric sarcomas display elevated serum CXCR2 ligands, and elevated CXCL8 is associated with diminished survival in this population. We conclude that accumulation of MDSCs in the tumor bed limits the efficacy of checkpoint blockade in cancer. We also identify CXCR2 as a novel target for modulating tumor immune escape and present evidence that CXCR2(+)CD11b(+)Ly6G(hi) MDSCs are an important suppressive myeloid subset in pediatric sarcomas. These findings present a translatable strategy to improve the efficacy of checkpoint blockade by preventing trafficking of MDSCs to the tumor site.

Related: Monoclonal Antibodies CXCL1 Cytokines Rhabdomyosarcoma

Grimsby GM, Harrison CB
Ewing sarcoma of the scrotum.
Urology. 2014; 83(6):1407-8 [PubMed] Related Publications
Nonosseous Ewing sarcoma commonly occurs in the extremities or deep soft tissues. However, cutaneous and subcutaneous locations have been reported. A 3-year-old boy presented with a 2-year history of a painless, slowly growing mid-scrotal mass. Pathology after surgical excision revealed the lesion to be Ewing sarcoma. The patient is free of metastatic disease and is currently undergoing chemotherapy. Soft-tissue malignancies must be kept in the differential diagnosis of any solid paratesticular mass in a child. Although rhabdomyosarcoma is the most common, as this case demonstrates, other rare sarcomas are also possible.

Related: Ewing's Sarcoma Testicular Cancer

Kerouanton A, Jimenez I, Cellier C, et al.
Synovial sarcoma in children and adolescents.
J Pediatr Hematol Oncol. 2014; 36(4):257-62 [PubMed] Related Publications
Synovial sarcoma (SS) is a high-grade soft tissue sarcoma characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma soft tissue sarcoma in childhood and adolescence. Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient's age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor according to the "rhabdomyosarcoma philosophy." In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control. The authors propose an update of SS in the pediatric population and analyze their results to those obtained in adults.

Related: Synovial Sarcoma

Seitz G, Dantonello TM, Kosztyla D, et al.
Impact of hemiscrotectomy on outcome of patients with embryonal paratesticular rhabdomyosarcoma: results from the Cooperative Soft Tissue Sarcoma Group Studies CWS-86, 91, 96 and 2002P.
J Urol. 2014; 192(3):902-7 [PubMed] Related Publications
PURPOSE: Children with paratesticular rhabdomyosarcoma have a favorable prognosis. Surgical treatment problems include inadequate primary transscrotal approaches, incomplete tumor resections and the need for secondary hemiscrotectomy. We evaluated the need for hemiscrotectomy regarding local relapse and outcome.
MATERIALS AND METHODS: A total of 173 patients with a diagnosis of paratesticular rhabdomyosarcoma were enrolled in the Cooperative Soft Tissue Sarcoma Studies between 1986 and 2008. Of the patients 17 were excluded due to an incomplete data set and alveolar histology. Thus, a total of 156 patients with embryonal subtype were analyzed. All patients were treated according to study protocols, which included multiagent chemotherapy, tumor resection and/or radiotherapy.
RESULTS: Mean ± SD 5-year overall survival rate was 91.5% ± 2.4% for patients with embryonal rhabdomyosarcoma. A total of 28 patients underwent transscrotal approaches initially. Of these patients 12 were treated with hemiscrotectomy (mean ± SD 5-year event-free survival 91.7% ± 8%) and 16 without hemiscrotectomy (93.8% ± 6.1%). Additionally 13 of 156 patients underwent an inguinal approach with hemiscrotectomy due to suspicious tumor infiltration of the scrotal skin (mean ± SD 5-year event-free survival 84.6% ± 10%). Relapse was observed in 3 of 12 patients after transscrotal approach with hemiscrotectomy (locoregional lymph node in 1 and metastasis in 2). One metastatic relapse was observed in the group undergoing a transscrotal approach without hemiscrotectomy. One of 13 patients treated with an inguinal approach and hemiscrotectomy had locoregional relapse and died of disease.
CONCLUSIONS: Hemiscrotectomy seems not to be mandatory in patients after transscrotal approaches regarding outcome and local relapse. Nevertheless, hemiscrotectomy probably should be performed if the scrotal skin is infiltrated.

Related: Testicular Cancer

Rudzinski ER, Anderson JR, Lyden ER, et al.
Myogenin, AP2β, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children's oncology group.
Am J Surg Pathol. 2014; 38(5):654-9 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Pediatric rhabdomyosarcoma (RMS) is traditionally classified on the basis of the histologic appearance into alveolar (ARMS) and embryonal (ERMS) subtypes. The majority of ARMS contain a PAX3-FOXO1 or PAX7-FOXO1 gene fusion, but about 20% do not. Intergroup Rhabdomyosarcoma Study stage-matched and group-matched ARMS typically behaves more aggressively than ERMS, but recent studies have shown that it is, in fact, the fusion status that drives the outcome for RMS. Gene expression microarray data indicate that several genes discriminate between fusion-positive and fusion-negative RMS with high specificity. Using tissue microarrays containing a series of both ARMS and ERMS, we identified a panel of 4 immunohistochemical markers-myogenin, AP2β, NOS-1, and HMGA2-which can be used as surrogate markers of fusion status in RMS. These antibodies provide an alternative to molecular methods for identification of fusion-positive RMS, particularly in cases in which there is scant or poor-quality material. In addition, these antibodies may be useful in fusion-negative ARMS as an indicator that a variant gene fusion may be present.

Related: Monoclonal Antibodies HMGA2 gene PAX7 gene

Kikuchi K, Hettmer S, Aslam MI, et al.
Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma.
PLoS Genet. 2014; 10(1):e1004107 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.

Related: Rhabdomyosarcoma FOXO1A gene PAX3 gene

Zin A, Bertorelle R, Dall'Igna P, et al.
Epithelioid rhabdomyosarcoma: a clinicopathologic and molecular study.
Am J Surg Pathol. 2014; 38(2):273-8 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and is mostly represented by the embryonal (ERMS) and alveolar (ARMS) histotypes. Whereas ERMS shows variable genetic alterations including TP53, RB1, and RAS mutations, ARMS carries a gene fusion between PAX3 or PAX7 and FOXO1. Epithelioid RMS is a morphologic variant of RMS recently described in adults. Five cases of epithelioid RMS were identified after histologic review of 85 cases of ARMS enrolled in Italian therapeutic protocols. Immunostaining analyses (muscle-specific actin, desmin, myogenin, AP-2β, EMA, cytokeratins, INI-1) and reverse transcription polymerase chain reaction assays to detect MyoD1, myogenin, and PAX3/7-FOXO1 transcripts were performed. In 4 cases DNA sequencing of TP53 was performed; and RB1 allelic imbalance and homozygous deletion were analyzed by quantitative real-time polymerase chain reaction. Histologically, epithelioid RMS displayed sheets of large cells without rhabdomyoblastic differentiation or anaplasia in 3 and prominent rhabdoid cells in 2; necrosis was evident in 4, often with a geographic pattern. Immunostainings for INI, desmin, myogenin (scattered cells in 4, diffuse in 1) were positive in all; EMA and MNF116 were positive in 2; AP-2β was negative. PAX3/7-FOXO1 transcripts were absent. In all cases RB1 was wild type, and a TP53 mutation at R273H codon was found in 1. All patients are in complete remission, with a median follow-up of 6 years. Epithelioid RMS may occur in children and is probably related to ERMS, as suggested by lack of fusion transcripts, weak staining for myogenin, negative AP-2β, evidence of TP53 mutation (although only in 1 case), and a favorable clinical course.

Related: Rhabdomyosarcoma

Amirian ES, Goodman JC, New P, Scheurer ME
Pediatric and adult malignant peripheral nerve sheath tumors: an analysis of data from the surveillance, epidemiology, and end results program.
J Neurooncol. 2014; 116(3):609-16 [PubMed] Related Publications
Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue sarcomas that arise predominantly from Schwann cells. Despite the fact that MPNSTs have high local recurrence rates and are generally associated with poor prognosis, little is known about prognostic factors or effective clinical management for this tumor type. The purpose of this study was to describe the distributions of patient and tumor characteristics and to identify predictors of cause-specific survival among MPNST cases reported to SEER between 1973 and 2008. Patient and tumor characteristics were compared between pediatric and adult MPNST cases. Cox regression and tree-based survival analysis were used to examine factors associated with MPNST-related mortality separately among adults and children. A total of 1,315 MPNST cases were isolated from the 1973-2008 SEER dataset. Among pediatric cases, sex, race, and radiation therapy predicted MPNST survival, whereas among adults, tumor site, tumor grade, number of primary tumors, and tumor size were significant predictors. As tumor size at diagnosis/resection may be the only somewhat "modifiable" prognostic factor, future studies should aim to identify biological and social attributes associated with tumor size at diagnosis, separately among individuals with and without NF-1, in order to help identify earlier opportunities for clinical intervention.

Related: USA

Sangiolo D, Mesiano G, Gammaitoni L, et al.
Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.
Cancer Res. 2014; 74(1):119-29 [PubMed] Related Publications
Unresectable metastatic bone sarcoma and soft-tissue sarcomas (STS) are incurable due to the inability to eradicate chemoresistant cancer stem-like cells (sCSC) that are likely responsible for relapses and drug resistance. In this study, we investigated the preclinical activity of patient-derived cytokine-induced killer (CIK) cells against autologous bone sarcoma and STS, including against putative sCSCs. Tumor killing was evaluated both in vitro and within an immunodeficient mouse model of autologous sarcoma. To identify putative sCSCs, autologous bone sarcoma and STS cells were engineered with a CSC detector vector encoding eGFP under the control of the human promoter for OCT4, a stem cell gene activated in putative sCSCs. Using CIK cells expanded from 21 patients, we found that CIK cells efficiently killed allogeneic and autologous sarcoma cells in vitro. Intravenous infusion of CIK cells delayed autologous tumor growth in immunodeficient mice. Further in vivo analyses established that CIK cells could infiltrate tumors and that tumor growth inhibition occurred without an enrichment of sCSCs relative to control-treated animals. These results provide preclinical proof-of-concept for an effective strategy to attack autologous sarcomas, including putative sCSCs, supporting the clinical development of CIK cells as a novel class of immunotherapy for use in settings of untreatable metastatic disease.

Related: Cytokines

Chen X, Stewart E, Shelat AA, et al.
Targeting oxidative stress in embryonal rhabdomyosarcoma.
Cancer Cell. 2013; 24(6):710-24 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.

Zhang M, Truscott J, Davie J
Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells.
Mol Cancer. 2013; 12(1):150 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
BACKGROUND: Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer that is the most common form of soft tissue tumors in children. RMS cells have many features of skeletal muscle cells, yet do not differentiate. Thus, our studies have focused on the defects present in these cells that block myogenesis.
METHODS: Protein and RNA analysis identified the loss of MEF2D in RMS cells. MEF2D was expressed in RD and RH30 cells by transient transfection and selection of stable cell lines, respectively, to demonstrate the rescue of muscle differentiation observed. A combination of techniques such as proliferation assays, scratch assays and soft agar assays were used with RH30 cells expressing MEF2D to demonstrate the loss of oncogenic growth in vitro and xenograft assays were used to confirm the loss of tumor growth in vivo.
RESULTS: Here, we show that one member of the MEF2 family of proteins required for normal myogenesis, MEF2D, is largely absent in RMS cell lines representing both major subtypes of RMS as well as primary cells derived from an embryonal RMS model. We show that the down regulation of MEF2D is a major cause for the failure of RMS cells to differentiate. We find that MyoD and myogenin are bound with their dimerization partner, the E proteins, to the promoters of muscle specific genes in RMS cells. However, we cannot detect MEF2D binding at any promoter tested. We find that exogenous MEF2D expression can activate muscle specific luciferase constructs, up regulate p21 expression and increase muscle specific gene expression including the expression of myosin heavy chain, a marker for skeletal muscle differentiation. Restoring expression of MEF2D also inhibits proliferation, cell motility and anchorage independent growth in vitro. We have confirmed the inhibition of tumorigenicity by MEF2D in a tumor xenograft model, with a complete regression of tumor growth.
CONCLUSIONS: Our data indicate that the oncogenic properties of RMS cells can be partially attributed to the loss of MEF2D expression and that restoration of MEF2D may represent a useful therapeutic strategy to decrease tumorigenicity.

Related: Rhabdomyosarcoma

Hentz C, Barrett W
Efficacy and morbidity of temporary (125)I brachytherapy in pediatric rhabdomyosarcomas.
Brachytherapy. 2014 Mar-Apr; 13(2):196-202 [PubMed] Related Publications
PURPOSE: Rhabdomyosarcomas (RMSs) are the most common soft tissue tumors in the pediatric population. The American Brachytherapy Society provides recommendations for the use of brachytherapy (BRT) in the treatment of soft tissue sarcomas; yet, there are no clearly defined recommendations for the use of adjuvant BRT in treating RMSs in particular. Radiation therapy has an important role in maximizing local control, and BRT has the advantage over external beam radiation therapy of providing a high dose of radiation to the most susceptible area of recurrence, while delivering a lower dose to the surrounding normal tissue.
METHODS AND MATERIALS: This study examines a group of 8 pediatric patients with RMSs who were treated with temporary low-dose-rate (125)I BRT and investigates the efficacy and side effects of such treatment.
RESULTS: The results demonstrate a local recurrence rate of 12.5%, with minimal side effects occurring in the patients who had no prior radiation history. Each patient's side effects are discussed.
CONCLUSIONS: The high efficacy and ease of radiation protection for visitors establishes this as an effective treatment that is logistically convenient for patients and families. This is the first report of patients exclusively with RMSs being treated exclusively with (125)I BRT and demonstrates promising results.

Related: Brachytherapy Rhabdomyosarcoma

O'Neill AF, Dearling JL, Wang Y, et al.
Targeted imaging of Ewing sarcoma in preclinical models using a 64Cu-labeled anti-CD99 antibody.
Clin Cancer Res. 2014; 20(3):678-87 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
PURPOSE: Ewing sarcoma is a tumor of the bone and soft tissue characterized by diffuse cell membrane expression of CD99 (MIC2). Single-site, surgically resectable disease is associated with an excellent 5-year event-free survival; conversely, patients with distant metastases have a poor prognosis. Noninvasive imaging is the standard approach to identifying sites of metastatic disease. We sought to develop a CD99-targeted imaging agent for staging Ewing sarcoma and other CD99-expressing tumors.
EXPERIMENTAL DESIGN: We identified a CD99 antibody with highly specific binding in vitro and labeled this antibody with (64)Cu. Mice with either subcutaneous Ewing sarcoma xenograft tumors or micrometastases were imaged with the (64)Cu-labeled anti-CD99 antibody and these results were compared with conventional MRI and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) imaging.
RESULTS: (64)Cu-labeled anti-CD99 antibody demonstrated high avidity for the CD99-positive subcutaneous tumors, with a high tumor-to-background ratio, greater than that demonstrated with FDG-PET. Micrometastases, measuring 1 to 2 mm on MRI, were not detected with FDG-PET but were readily visualized with the (64)Cu-labeled anti-CD99 antibody. Probe biodistribution studies demonstrated high specificity of the probe for CD99-positive tumors.
CONCLUSIONS: (64)Cu-labeled anti-CD99 antibody can detect subcutaneous Ewing sarcoma tumors and metastatic sites with high sensitivity, outperforming FDG-PET in preclinical studies. This targeted radiotracer may have important implications for the diagnosis, surveillance, and treatment of Ewing sarcoma. Similarly, it may impact the management of other CD99 positive tumors.

Related: Bone Cancers Ewing's Sarcoma MIC2 Expression in Cancer

Ciarapica R, De Salvo M, Carcarino E, et al.
The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx).
Oncogene. 2014; 33(32):4173-84 [PubMed] Related Publications
The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.

Related: Apoptosis FOXO1A gene PAX3 gene

Sedrak MP, Parker DC, Gardner JM
Low-grade fibromyxoid sarcoma with nuclear pleomorphism arising in the subcutis of a child.
J Cutan Pathol. 2014; 41(2):134-8 [PubMed] Related Publications
Low-grade fibromyxoid sarcoma (LGFMS) represents a rare soft tissue tumor that was first characterized in 1987. LGFMS usually presents as a large, deeply situated mass in adults and is characterized by deceptively bland histopathologic features. LFGMS is less common in superficial soft tissue and in children. It is distinctly uncommon for LGFMS to exhibit nuclear pleomorphism. Herein, we present a case of a 10-year-old male who presented with a subcutaneous back mass that displayed features typical for LGFMS as well as scattered large, hyperchromatic and pleomorphic nuclei. The constellation of clinicopathologic features, including the young age of the patient, the small size and superficial location of the tumor and the presence of scattered nuclear pleomorphism are all unusual features for LGFMS. Fluorescent in situ hybridization (FISH) with a break-apart probe for FUS revealed the presence of a FUS gene rearrangement confirming the diagnosis of LGFMS. This case highlights the importance of maintaining a high index of suspicion for LGFMS even in the context of small, superficially-located tumors, pediatric patients or tumors with scattered nuclear pleomorphism.

Related: FISH Skin Cancer

Senerchia AA, Ribeiro KB, Rodriguez-Galindo C
Trends in incidence of primary cutaneous malignancies in children, adolescents, and young adults: a population-based study.
Pediatr Blood Cancer. 2014; 61(2):211-6 [PubMed] Related Publications
BACKGROUND: Skin cancer incidence among young adults is rising; however, the epidemiological characteristics of primary cutaneous lymphomas and cutaneous soft tissue sarcomas (CSTS) in individuals <30 years old has not been investigated. We analyzed the incidence and time-trends of primary cutaneous malignancies in children and adolescents/young adults (AYA).
PROCEDURE: SEER-17 and -13 data were used to assess the descriptive epidemiology and time-trends in incidence of primary cutaneous malignancies in children and AYA. SEERStat and Joinpoint softwares were utilized to estimate annual percent changes (APC) in incidence.
RESULTS: In total, 7,814 cases (ASR = 25.66/1,000,000 habitants) of primary skin cancers in <30 years old were diagnosed in 2000-2008. Females had a higher incidence of melanoma (risk ratio (RR) = 1.95; P < 0.001) and a lower risk of developing CSTS (RR = 0.64, P < 0.001). Compared to whites, blacks have a lower incidence of melanoma (RR = 0.03, P < 0.001), and higher risk of CSTS (RR = 2.28, P < 0.001). Melanoma increased in females over a 15-year period (1992-2006) (APC = 2.5, 95%CI = 1.8; 3.2), and the incidence of cutaneous T-cell lymphomas increased over the period 1992-2008 (APC = 9.5, 95% CI = 6.7; 12.4). CSTS incidence decreased among males over the period 1992-1999 (APC = -21.4, 95% CI -27.2; -15.1), particularly due to a decrease in Kaposi sarcoma incidence (AAPC 1992-2008 = -13.6, 95% CI = -22.4;-3.8), although with a notable racial disparity (whites, AAPC = -15.2, 95% CI = -23.2;-6.4; blacks, AAPC = -10.6, 95% CI = -13.2;-7.9).
CONCLUSIONS: Non-melanoma skin cancer is very rare in children and AYA. We have shown variation in time-trends in incidence as well as in incidence patterns by race, sex, age, and histologic type, highlighting the importance of descriptive epidemiology to better understand the characteristics of these malignancies.

Related: Haematological Malignancies & Realted Disorders Cutaneous T-cell lymphoma Melanoma Skin Cancer USA

Friedrich P, Ortiz R, Fuentes S, et al.
Barriers to effective treatment of pediatric solid tumors in middle-income countries: can we make sense of the spectrum of nonbiologic factors that influence outcomes?
Cancer. 2014; 120(1):112-25 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
BACKGROUND: The delivery of effective treatment for pediatric solid tumors poses a particular challenge to centers in middle-income countries (MICs) that already are vigorously addressing pediatric cancer. The objective of this study was to improve the current understanding of barriers to effective treatment of pediatric solid tumors in MICs.
METHODS: An ecologic model centered on pediatric sarcoma and expanded to country as the environment was used as a benchmark for studying the delivery of solid tumor care in MICs. Data on resources were gathered from 7 centers that were members of the Central American Association of Pediatric Hematologists and Oncologists (AHOPCA) using an infrastructure assessment tool. Pediatric sarcoma outcomes data were available, were retrieved from hospital-based cancer registries for 6 of the 7 centers, and were analyzed by country. Patients who were diagnosed from January 1, 2000 to December 31, 2009 with osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and other soft tissue sarcomas were included in the analysis. To explore correlations between resources and outcomes, a pilot performance index was created.
RESULTS: The analyses identified specific deficits in human resources, communication, quality, and infrastructure. The treatment abandonment rate, the proportion of metastatic disease at diagnosis, the relapse rate, and the 4-year abandonment-sensitive overall survival (AOS) rate varied considerably by country, ranging from 1% to 38%, from 15% to 54%, from 24% to 52%, and from 21% to 51%, respectively. The treatment abandonment rate correlated inversely with health economic expenditure per capita (r = -0.86; P = .03) and life expectancy at birth (r = -0.93; P = .007). The 4-year AOS rate correlated inversely with the mortality rate among children aged <5 years (r = -0.80; P = 0.05) and correlated directly with the pilot performance index (r = 0.98; P = 0.005).
CONCLUSIONS: Initiatives to improve the effectiveness of treatment for pediatric solid tumors in MICs are warranted, particularly for pediatric sarcomas. Building capacity and infrastructure, improving supportive care and communication, and fostering comprehensive, multidisciplinary teams are identified as keystones in Central America. A measure that meaningfully describes performance in delivering pediatric cancer care is feasible and needed to advance comparative, prospective analysis of pediatric cancer care and to define resource clusters internationally.

Li SQ, Cheuk AT, Shern JF, et al.
Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534).
PLoS One. 2013; 8(10):e76551 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.

Related: Apoptosis Rhabdomyosarcoma

Parham DM, Barr FG
Classification of rhabdomyosarcoma and its molecular basis.
Adv Anat Pathol. 2013; 20(6):387-97 [PubMed] Related Publications
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, has traditionally been classified into embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS) for pediatric oncology practice. This review outlines the historical development of classification of childhood RMS and the challenges that have been associated with it, particularly problems with the diagnosis of "solid variant" ARMS and its distinction from ERMS. In addition to differences in clinical presentation and outcome, a number of genetic features underpin separation of ERMS from ARMS. Genetic differences associated with RMS subclassification include the presence of reciprocal translocations and their associated fusions in ARMS, amplification of genes in ARMS and its fusion subsets, chromosomal losses and gains that mostly occur in ERMS, and allelic losses and mutations usually associated with ERMS. Chimeric proteins encoded in most ARMS from the fusion of PAX3 or PAX7 with FOXO1 are expressed, result in a distinct pattern of downstream protein expression, and appear to be the proximate cause of the bad outcome associated with this subtype. A sizeable minority of ARMS lacks these fusions and shares the clinical and biological features of ERMS. A battery of immunohistochemical tests may prove useful in separating ERMS from ARMS and fusion-positive ARMS from fusion-negative ARMS. Because of limitation of predicting outcome solely based on histologic classification, treatment protocols will begin to utilize fusion testing for stratification of affected patients into low-risk, intermediate-risk, and high-risk groups.

Related: PAX7 gene FOXO1A gene PAX3 gene

Thacker MM
Malignant soft tissue tumors in children.
Orthop Clin North Am. 2013; 44(4):657-67 [PubMed] Related Publications
Soft tissue masses are frequently seen in children. Although most are benign or reactive, soft tissue sarcomas (STS)-both rhabdomyosarcoma (most common) and non-rhabdo STS, do occur in the extremities. Appropriate evaluation of extremity soft tissue tumors often includes a biopsy as the clinical and imaging features may not be enough to establish a definitive diagnosis. Much needs to be done for improving the treatment of these rare but often devastating sarcomas. Given the small numbers of these cases seen at various centers, collaborative efforts should be made to further our understanding and improve the management of these challenging cases.

Related: Cancer Cytogenetics

Chu WP
Anterior mediastinal alveolar rhabdomyosarcoma in an infant: rare site for a common paediatric tumour.
Hong Kong Med J. 2013; 19(5):458-9 [PubMed] Related Publications
Rhabdomyosarcoma is a common paediatric soft tissue tumour. However, the anterior mediastinum is an extremely rare site for its occurrence. This report describes the imaging and histological findings of such a tumour in a 4-month-old boy.

Alcorn KM, Deans KJ, Congeni A, et al.
Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging.
J Pediatr Surg. 2013; 48(9):1903-6 [PubMed] Related Publications
BACKGROUND: The purpose of this study was to report our experience with sentinel lymph node biopsy (SLNB) for pediatric soft tissue sarcomas to add to the limited literature about its feasibility, utility, and concordance with pre-operative imaging, including CT and (18)F-FDG PET (PET) scanning.
METHODS: Medical records of patients with a sarcoma who underwent SLNB as part of their treatment for a soft tissue sarcoma at our institution from 2000 to 2011 were identified and reviewed.
RESULTS: Eight patients underwent SLNB for soft tissue sarcoma during the study period. Two patients had positive SLNBs; both of these patients had rhabdomyosarcoma. Three patients with pathologically enlarged lymph nodes on CT scan underwent PET functional imaging prior to SLNB. The PET suggested the presence of nodal disease in all three patients; however, only one of these patients had a positive SLNB.
CONCLUSIONS: Our series confirms that SLNB is feasible in pediatric sarcoma patients. Small numbers preclude definitive conclusions regarding the utility of SLNB compared with PET, however our data suggest functional imaging alone may not be sufficient to definitively determine lymph node status in these patients. Surgical lymph node sampling may still need to be performed to accurately identify nodal status in pediatric patients with soft tissue sarcoma.

Diaconescu S, Burlea M, Miron I, et al.
Childhood rhabdomyosarcoma. Anatomo-clinical and therapeutic study on 25 cases. Surgical implications.
Rom J Morphol Embryol. 2013; 54(3):531-7 [PubMed] Related Publications
UNLABELLED: Rhabdomyosarcomas (RMS) are the most frequent soft tissue sarcomas of childhood. Despite advances in knowledge about biological pathways of tumorigenesis, risk stratification and multimodal treatment, the immediate and long-term prognosis of these lesions in many countries with limited resources is still poor.
PATIENTS AND METHODS: Twenty-five histologically confirmed pediatric RMS were recorded during the period of study. Demography, clinical presentation, diagnostic means, pretreatment staging and post-surgical grouping, histological type, therapy and outcome were evaluated.
RESULTS: The mean age was 6.7 years; the group included 12 boys and 13 girls. Twelve lesions were localized in the genitourinary tract, eight in the trunk and extremities, two cases each in head and neck and retroperitoneum and one case in biliary tract. Primary surgical attempt was performed in 15 patients but only in nine of them underwent complete resection (three with free margins) other six cases achieving removal with residual disease. In 10 cases, solely biopsy was possible. Twenty-four patients received chemotherapy but only four cases performed radiation therapy. Overall survival rate was only 36% (nine cases).
CONCLUSIONS: As mean feature children from our series had late presentation with locally extended (bulky and node positive) lesions and unfavorable sites. Improved multimodal management of RMS in recent years will probably lead to better survival curves in an increasing number of cases and an outstanding outcome in children with locally advanced disease.

Related: Rhabdomyosarcoma

Zhang WL, Zhang Y, Huang DS, et al.
Clinical character of pediatric head and neck rhabdomysarcomas: a 7-year retrospective study.
Asian Pac J Cancer Prev. 2013; 14(7):4089-93 [PubMed] Related Publications
OBJECTIVE: The rhabdomysarcoma (RMS) is most common soft tissue carcinoma in children, mostly found in the head and neck with high degree of malignancy. The current study aimed to summarize clinical data and evaluate treatment outcome of cases in a single hospital.
METHODS: Forty-one (24 male, 17 female) children with newly diagnosed RMS in Beijing Tong Ren Hospital were enrolled between November, 2004 and May, 2011. The. Students' t and Chi tests were then performed on retrospectively reviewed clinical data, followed by survival analysis based on the Kaplan Meier method using SPSS 17.0 software.
RESULTS: Of all cases, 32 were treated by common chemotherapy, and 3 cases with stage III RMS received high-dose chemotherapy and auto-peripheral blood stem cell transplantation (APBSCT). Side-effects in the former were: I grade for 62.5% (20/32), II grade for 28.1% (9/32), III grade account for 9.275% (3/32). Side-effects of 3 cases with APBSCT: 2 were I grade, 1 was III grade. The median follow-up time of 41 RMS cases was 41 months. Four cases were lost to follow-up, 7 cases recurred, and 5 cases died of cerebral metastasis, witha total survival rate was 86.5% (32/37). CR rate was 67.6% (25/37), PR was 18.9% (7/37).
CONCLUSION: Multidiscipline treatment including chemotherapy, radiotherapy, surgery and auto-PBSCT is highly recommended for pediatric patients with head and neck RMS.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Rhabdomyosarcoma

Hishiki T, Saito T, Mitsunaga T, et al.
Optimal surgical treatment and urological outcomes in boys with pelvic and urogenital rhabdomyosarcomas and soft tissue sarcomas.
Pediatr Surg Int. 2013; 29(10):1077-82 [PubMed] Related Publications
BACKGROUND: Soft tissue sarcomas (STS) of pelvic origin in boys often involve the urogenital organs. The optimal extensiveness of radical surgery has long been an issue of discussion, since exenterative surgeries result in severe urogenital adverse effects. We conducted a retrospective review of patients with pelvic STS treated in two regional center hospitals and assessed the radicality of surgery and the functional outcome of the bladder.
PATIENTS: Medical records and surgical reports of nine cases (embryonal rhabdomyosarcoma 6, malignant triton tumor 2, suspected rhabdomyosarcoma 1) treated within 1997-2012 were reviewed. Site of origin was prostate in seven, retroperitoneal in two. Average follow-up period was 96 months.
TREATMENT AND OUTCOME: All cases were subjected to neoadjuvant chemotherapy. Response was PR in four, SD in two, and PD in two. Radical surgery resulted in gross total resection in eight, and partial resection in one. Three underwent cystoprostatectomy, two cases underwent prostatectomy, and bladder-preserving tumor resection was carried out in four cases. At the last follow-up, three retained a functional bladder. Two required augmentation cystoplasty with intestinal conduits.
CONCLUSIONS: The majority of the on-going clinical trials recommend conservative surgery for bladder/prostate rhabdomyosarcoma, and to preserve the bladder function particularly in chemosensitive tumors. Some other groups, however, advocate the importance of radical surgery to prevent local relapse. These reports include heterogenous group of patients in the cohort, and therefore it is difficult to draw a conclusion of which approach truly contributes to the survival of the patients better. Future studies should evaluate bladder and sexual function objectively to establish reliable evidence regarding the benefit and adverse effects of different surgical approaches. These data would be informative to optimize the treatment balance for children with pelvic rhabdomyosarcomas.

Related: Rhabdomyosarcoma

Schoot RA, McHugh K, van Rijn RR, et al.
Response assessment in pediatric rhabdomyosarcoma: can response evaluation criteria in solid tumors replace three-dimensional volume assessments?
Radiology. 2013; 269(3):870-8 [PubMed] Related Publications
PURPOSE: To investigate (a) interobserver variability for three-dimensional (3D) (based on European Pediatric Soft-Tissue Sarcoma Study Group [EpSSG] guidelines) and one-dimensional (1D) (based on Response Evaluation Criteria in Solid Tumors [RECIST]) response assessments, (b) intermethod variability between EpSSG guidelines and RECIST, and (c) clinically relevant consequences of interobserver and intermethod variability in pediatric patients with rhabdomyosarcoma.
MATERIALS AND METHODS: The study was approved by the Academic Medical Center Ethics Committee and the Great Ormond Street Hospital Ethics Committee; both committees waived the requirement for informed consent because of the retrospective nature of the study. Data were analyzed from 124 consecutive male and female children and young adults (age range, 1-18 years) with rhabdomyosarcoma at two institutions (1999-2009) with relevant imaging studies. Tumors were measured by two radiologists (1D and 3D measurements) at diagnosis and after induction chemotherapy. Interobserver variability was analyzed by using three different tests, and the intermethod variation was calculated.
RESULTS: Sixty-four eligible patients were included (median age, 4.6 years). Agreement between observers for EpSSG guidelines and RECIST was moderate (κ = 0.565 and 0.592, respectively); interobserver variation led to different potential treatment decisions in nine (14%) and 11 (17%) of the 64 patients, respectively. Comparison of EpSSG guidelines and RECIST resulted in 13 discrepant response classifications (20%), which were equally distributed (under- and overestimation of response) and led to consequences for treatment choice in five patients (8%).
CONCLUSION: EpSSG guidelines and RECIST are not interchangeable; neither technique demonstrated superiority in this study. These findings should be taken into account in future study protocol design. Online supplemental material is available for this article.

Related: Rhabdomyosarcoma

Miller SF
Imaging features of juxtacortical chondroma in children.
Pediatr Radiol. 2014; 44(1):56-63 [PubMed] Related Publications
BACKGROUND: Juxtacortical chondroma is a rare benign bone lesion in children. Children usually present with a mildly painful mass, which prompts diagnostic imaging studies. The rarity of this condition often presents a diagnostic challenge. Correct diagnosis is crucial in guiding surgical management.
OBJECTIVE: To describe the characteristic imaging findings of juxtacortical chondroma in children.
MATERIALS AND METHODS: We identified all children who were diagnosed with juxtacortical chondroma between 1998 and 2012. A single experienced pediatric radiologist reviewed all diagnostic imaging studies, including plain radiographs, CT, MR and bone scans.
RESULTS: Seven children (5 boys and 2 girls) with juxtacortical chondroma were identified, ranging in age from 6 years to 16 years (mean 12.3 years). Mild pain and a palpable mass were present in all seven children. Plain radiographs were available in 6/7, MR in 7/7, CT in 4/7 and skeletal scintigraphy in 5/7 children. Three lesions were located in the proximal humerus, with one each in the distal radius, distal femur, proximal tibia and scapula. Radiographic and CT features deemed highly suggestive of juxtacortical chondroma included cortical scalloping, underlying cortical sclerosis and overhanging margins. MRI features consistent with juxtacortical chondroma included isointensity to skeletal muscle on T1, marked hyperintensity on T2 and peripheral rim enhancement after contrast agent administration. One of seven lesions demonstrated intramedullary extension, and 2/7 showed adjacent soft-tissue edema.
CONCLUSION: Juxtacortical chondroma is an uncommon benign lesion in children with characteristic features on plain radiographs, CT and MR. Recognition of these features is invaluable in guiding appropriate surgical management.

Related: Bone Cancers

Bochennek K, Dantonello T, Koscielniak E, et al.
Response of children with stage IV soft tissue sarcoma to topotecan and carboplatin: a phase II window trial of the cooperative soft tissue sarcoma group.
Klin Padiatr. 2013; 225(6):309-14 [PubMed] Related Publications
To investigate antitumor activity and toxicity associated with combined topotecan and carboplatin treatment in children and adolescents with metastasized, untreated soft tissue sarcoma (STS).Patients (n=34) less than 21 years old and untreated, stage IV STS. Patients were treated with topotecan (1 mg/m²/d for 4 days) and carboplatin (150 mg/m²/d for 4 days) (TC course) during week 1 and 4 of a chemotherapy window trial, which was followed by chemotherapy and local therapy from week 6 on. We evaluated the side effects, toxicity and tumor response (using RECIST criteria) 6 weeks after starting the 2 TC chemotherapy courses.The objective response rate (ORR) was 38% (n=13 patients with a partial response (PR)), and a stable disease (SD) was reached in 11 cases. No patient showed a complete response (CR) of all metastatic lesions, although 1 patient showed a CR of the target lesion. 2 patients died of progress of disease (PD). Toxicity was mainly hematological (grade III/IV toxicity 79%), and nonhematological toxicities mainly included infection, fever, nausea,and vomiting. Regarding adverse events, 4 probable and 8 possible events related to study medication occurred among the 66 courses of TC.In conclusion, TC was potent against high-risk STS, but results and toxicity data were not superior to former published monotherapeutic topotecan therapies.

Related: Carboplatin Rhabdomyosarcoma Ewing's Sarcoma Synovial Sarcoma Topotecan

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