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Background: Rhabdomyosarcoma survivors have an increased risk of developing second malignant neoplasms (SMN); this risk is traditionally attributed to the effects of multidisciplinary management required for cure. However, the impact of constitutional predisposition has not been properly analyzed., Methods: We analyzed the risk of SMN among 1,151 children diagnosed with rhabdomyosarcoma and reported to the Surveillance, Epidemiology, and End Results registries (SEER-9) from 1973 to 2010. Standardized incidence ratios (SIR) and corresponding 95% confidence intervals (CI) were calculated using SEERStat 8.1.2., Results: Children with pleomorphic and embryonal rhabdomyosarcoma had an increased risk of developing a SMN (SIR = 15.77, 95%CI 1.91-56.96 and SIR = 5.6, 95%CI 3.32-8.85, respectively). The risk was age-dependent; the highest was among children <2 years (SIR = 13.38, 95%CI 4.34-31.22) and the lowest was in children >10 years (SIR = 3.35, 95%CI 1.53-6.35). The risk for the youngest patients was higher for those with embryonal rhabdomyosarcoma (SIR = 14.72, 95%CI 4.01-37.70) compared to other histiotypes. Additionally, the risk of SMN was independent of the use of radiation to the primary (SIR = 6.50, 95%CI 3.97-10.03 and SIR = 4.57, 95%CI 2.09-8.68, for children receiving and not receiving radiation, respectively). The pattern of SMN observed was consistent with the Li-Fraumeni spectrum., Conclusions: Children with rhabdomyosarcoma are at high risk of developing SMN. This risk is higher for a subgroup of young children with pleomorphic and embryonal histologies, and is independent of the use of radiation. This suggests that a subgroup of children with pleomorphic and embryonal rhabdomyosarcoma may have a constitutional cancer predisposition., (© 2015 Wiley Periodicals, Inc.)

Hedgehog (Hh) pathway activation in R26-SmoM2;CAGGS-CreER mice, which carry a tamoxifen-inducible activated Smoothened allele (SmoM2), results in numerous microscopic tumor foci in mouse skeletal muscle. These tumors exhibit a highly differentiated myogenic phenotype and resemble human fetal rhabdomyomas. This study sought to apply previously established strategies to isolate lineally distinct populations of normal mouse myofiber-associated cells in order to examine cellular heterogeneity in SmoM2 tumors. We demonstrate that established SmoM2 tumors are composed of cells expressing myogenic, adipocytic and hematopoietic lineage markers and differentiation capacity. SmoM2 tumors thus recapitulate the phenotypic and functional hetereogeneity observed in normal mouse skeletal muscle. SmoM2 tumors also contain an expanded population of PAX7+ and MyoD+ satellite-like cells with extremely low clonogenic activity. Selective activation of Hh signaling in freshly isolated muscle satellite cells enhanced terminal myogenic differentiation without stimulating proliferation. Our findings support the conclusion that SmoM2 tumors represent an aberrant skeletal muscle state and demonstrate that, similar to normal muscle, myogenic tumors contain functionally distinct cell subsets, including cells lacking myogenic differentiation potential., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in <30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusion-positive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry., (Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.)

Soft-tissue sarcomas are heterogeneous cancers that can present with tissue-specific differentiation markers. To examine the cellular basis for this histopathological variation and to identify sarcoma-relevant molecular pathways, we generated a chimeric mouse model in which sarcoma-associated genetic lesions can be introduced into discrete, muscle-resident myogenic and mesenchymal cell lineages. Expression of Kirsten rat sarcoma viral oncogene [Kras(G12V)] and disruption of cyclin-dependent kinase inhibitor 2A (CDKN2A; p16p19) in prospectively isolated satellite cells gave rise to pleomorphic rhabdomyosarcomas (MyoD-, Myogenin- and Desmin-positive), whereas introduction of the same oncogenetic hits in nonmyogenic progenitors induced pleomorphic sarcomas lacking myogenic features. Transcriptional profiling demonstrated that myogenic and nonmyogenic Kras; p16p19(null) sarcomas recapitulate gene-expression signatures of human rhabdomyosarcomas and identified a cluster of genes that is concordantly up-regulated in both mouse and human sarcomas. This cluster includes genes associated with Ras and mechanistic target of rapamycin (mTOR) signaling, a finding consistent with activation of the Ras and mTOR pathways both in Kras; p16p19(null) sarcomas and in 26-50% of human rhabdomyosarcomas surveyed. Moreover, chemical inhibition of Ras or mTOR signaling arrested the growth of mouse Kras; p16p19(null) sarcomas and of human rhabdomyosarcoma cells in vitro and in vivo. Taken together, these data demonstrate the critical importance of lineage commitment within the tumor cell-of-origin in determining sarcoma histotype and introduce an experimental platform for rapid dissection of sarcoma-relevant cellular and molecular events.

Objective: Synovial sarcoma is the most common malignant nonrhabdomyosarcoma soft-tissue sarcoma in children. This article shows examples of synovial sarcoma in children and corresponding examples of benign mimics., Conclusion: It is important for radiologists to recognize the often nonaggressive appearance of synovial sarcoma in the pediatric population to guide surgical resection and expedite diagnosis before the development of locoregional spread or metastatic disease.

Ganglioside metabolism has been linked to the clinical and biological behavior of human neuroblastoma. This study investigated the importance of differences in complex "b" ganglioside (GD1b, GT1b, and GQ1b; designated CbG) expression in this tumor. Gangliosides of 74 neuroblastomas were analyzed by high-performance TLC. Associations of CbG expression with known prognostic markers and with event-free survival (EFS) were evaluated. Higher CbG expression characterized nonprogressive versus progressive tumors (median 41% versus 18% of total gangliosides; P = 0.001) and completely accounted for the observed higher overall "b" pathway ganglioside expression (median 81% versus 68%; P = 0.003). In contrast, expression of the structurally simpler "b" pathway gangliosides (GD2 and GD3) did not differ (median 31% versus 35%; P = 0.4). Absolute CbG content differed even more (median 93 versus 29 nmol/g among nonprogressive versus progressive tumors; P = 0.02) and was most striking in the case of GQ1b content (8-fold higher in nonprogressive tumors). High CbG (> or =35% of total gangliosides) expression was strongly predictive of a favorable outcome in: (a) the entire study population (90% versus 60% EFS at 25 months; P = 0.001); and (b) among patients assigned a low-risk status by a either single genetic or biochemical tumor marker (MYCN, DNA, NSE, or ferritin), or by both unamplified MYCN and aneuploid DNA (22-28% difference in EFS at 25 months). These data suggest that high tumor CbG content may substratify "good prognosis" neuroblastoma patients, identifying patients at very low risk of relapse or death, and that the biological roles of CbG in neuroblastoma will be of importance to define.

Tumor ganglioside metabolism has been implicated in modulating tumor formation and progression. We found previously that transient ganglioside depletion by inhibition of glucosylceramide synthesis of MEB4 melanoma cells in vitro reduced their tumorigenic capability. Here, we have established that treatment of the host with a novel p.o. inhibitor of glucosylceramide synthesis, the imino sugar OGT2378, inhibits MEB4 melanoma tumor growth in a syngeneic, orthotopic murine model. The glucosylceramide and ganglioside content of MEB4 cells exposed to 20 micro M OGT2378 in culture were reduced by 93 and >95%, respectively, without either cytotoxic or antiproliferative effects. Administered in the diet to C57BL/6 mice, 2500 mg/kg/day OGT2378 was well tolerated in vivo and biologically active, depleting host tissue (hepatic) gangliosides by 82% and tumor gangliosides by >98%. p.o. treatment with OGT2378 starting 3 days before intradermal tumor inoculation of 4 x 10(4) MEB4 cells, and continuing for 4 weeks, resulted in a 10-fold lower mean tumor volume at the end of treatment (60 versus 538 mm(3), P < 0.0001). Even when OGT2378 treatment was initiated 7 days after tumor inoculation, tumor growth was similarly impeded (61 versus 620 mm(3), P < 0.0001), demonstrating an effect on an established tumor. The effectiveness of p.o. OGT2378 in this murine model suggests that inhibition of glycosphingolipid synthesis is a promising and now feasible novel therapeutic approach to inhibit tumor progression.