Rhabdomyosarcoma: New Windows of Opportunity

Breitfeld, Philip P.; Meyer, William H.

doi:10.1634/theoncologist.10-7-518

Cited by 106 publications

(87 citation statements)

References 94 publications

(98 reference statements)

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“…Clinical presentation is also less favorable. All retrospective studies note more aggressive disease with more unfavorable sites 1, 36, 37, 38, 39, more LN, more metastasis 9, 36, 40, 41, and more A‐RMS. Nevertheless, all parameters being equal, the outcome of adult patients with RMS is less favorable.…”

Section: Discussionmentioning

confidence: 99%

“…Rhabdomyosarcoma (RMS) accounts for <3% of adult soft tissue sarcoma but is the most frequent soft tissue sarcoma histological subtype before age 10 and the 4th most prevalent cancer during childhood 1, 2, 3, 4. Five‐year overall survival (OS) of children has dramatically improved in the last 30 years based on the results of successive studies of large multinational collaborative trials dedicated to children.…”

Section: Introductionmentioning

confidence: 99%

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Outcome of 449 adult patients with rhabdomyosarcoma: an observational ambispective nationwide study

et al. 2018

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Five‐year overall survival (OS) of localized RMS exceeds 70% in children (<18) but is very poor in adult patients. We analyzed the outcome and prognostic factors (PF) of a national series of adult patients with RMS in a large study. The study population consisted of two different cohorts: a retrospective cohort (157 adult patients treated in 13 reference centers between 05/1981 and 02/2010) and the prospective cohort (292 patients with RMS diagnosed and treated between 01/2010 and 12/2014 in France) included in the NetSarc database. A descriptive analysis of patients’ characteristics and prognostic factors was conducted on both series which were compared. In the retrospective series, histological subtypes were embryonal (E‐RMS) for 21% of patients, alveolar (A‐RMS) for 35% of patients, and “adult‐type” P‐RMS (pleomorphic, spindle cell RMS, not otherwise specified) (P) for 44% patients. This distribution significantly differed in the prospective cohort: A‐RMS: 18%; E‐RMS: 17%; and P‐RMS 65%. With a median follow‐up of 8.5 years, 5‐year OS for localized RMS and advanced RMS (with nodes and/or metastases) was 43% and 5%, respectively, (P < 0.0001), and median OS was 51, 33, and 16 months for E‐RMS, A‐RMS, and P‐RMS, respectively, in the retrospective cohort. The median OS was less than 40 months for the prospective nationwide cohort for the entire population. In a multivariate analysis of the retrospective study, independent prognostic factors for OS were A‐RMS, R0 resection, and adjuvant radiotherapy (RT). For localized RMS, age and use of pediatric chemotherapy (CT) regimen are independent prognostic factors. Adult patients with RMS have a poorer overall survival than pediatric patients, and survival varies considerably across histological subtypes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Outcome of 449 adult patients with rhabdomyosarcoma: an observational ambispective nationwide study

et al. 2018

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“…The outcome of patients with rhabdomyosarcoma (RMS) has greatly improved in the last few decades [1], thanks especially to the use of multidisciplinary treatments involving large numbers of patients. Such trials were initially conducted in the USA, by the Intergroup Rhabdomyosarcoma Study Group (IRSG) [2], and in Europe [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…The treatment plan was based on a risk-related approach, depending on the tumor's characteristics at diagnosis and the results of initial surgery. The primary aims of the RMS 79 protocol were: (1) to treat children with RMS and other sarcomas on a national basis; (2) to improve the survival rates (and patients' quality of life, trying to preserve organ function) in the frame of a multimodality treatment.…”

Section: Introductionmentioning

confidence: 99%

Long‐term results in childhood rhabdomyosarcoma: A report from the Italian cooperative study RMS 79

Bisogno

Pastore

Perilongo

et al. 2011

Pediatric Blood & Cancer

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BackgroundThe results obtained by protocols for children with rhabdomyosarcoma (RMS) have improved in recent decades. Survival curves usually reach a plateau 3 years after the diagnosis, suggesting that long‐term survival can be expected, but late events are known to occur. We analyzed the long‐term results of the RMS 79 protocol to investigate the type and impact of such events.ProcedureFrom 1979 to 1987, 163 children with RMS diagnosed at 21 Italian institutions were registered. Each institution was contacted every year to record patients' status after the end of treatment. When patients were lost to follow‐up, their status was checked by inquiring at the Registry Offices of the towns of residence and the cause of death or occurrence of second cancers was investigated by contacting the patients or their family by phone.ResultsOverall, 16 patients had late events, that is, 7 tumor recurrences, 6 second tumors, and 3 deaths due to treatment‐related complications. The overall survival rates dropped from 62.6 at 3 years to 52.8 at 20 years. By multivariate analysis, the characteristics influencing long‐term survival were histology, tumor site and size, and IRS group. Factors predictive of any kind of late event were tumor site and IRS group.ConclusionsMajor late events can significantly affect the long‐term survival of children with RMS. Modern protocols should provide for a much longer follow‐up than is usually considered to confirm the results achieved and enable possible correlations between primary treatment and late events to be investigated. Pediatr Blood Cancer 2012; 58: 872–876. © 2011 Wiley Periodicals, Inc.

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“…Current treatment strategies encompass a multimodal approach incorporating surgery, ionizing radiation (IR) and chemotherapy. 27 Evidence suggests that ceramide generation in response to IR and chemotherapeutics 1 is at least partly required for the efficient induction of apoptosis to achieve anti-tumorigenic efficacy. However, the effect of ceramide accumulation in RMS is currently unknown.…”

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confidence: 99%

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

et al. 2007

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The sphingoplipid ceramide is responsible for a diverse range of biochemical and cellular responses including a putative role in modulating cell cycle progression. Herein, we describe that an accumulation of ceramide, achieved through the exogenous application of C 6 -ceramide or exposure to sphingomyelinase, induces a G 2 arrest in Rhabdomyosarcoma (RMS) cell lines. Utilizing the RMS cell line RD, we show that this G 2 arrest required the rapid induction of p21 Cip1/Waf1 independent of DNA damage. This was followed at later time points (48 h) by the commitment to apoptosis. Apoptosis was prevented by Bcl-2 overexpression, but permitted the maintenance of elevated p21 Cip1/Waf1 protein expression and the stabilization of the G 2 arrest response. Inhibition of p21 Cip1/Waf1 protein synthesis with cyclohexamide (CHX) or silencing of p21 Cip1/Waf1 with siRNA, prevented ceramide-mediated G 2 arrest and the late induction of apoptosis. Further, adopting the recent discovery that murine double minute 2 (MDM2) controls p21 Cip1/Waf1 expression by presenting this CDK inhibitor to the proteasome for degradation, RD cells overexpressing MDM2 abrogated ceramide-mediated p21 Cip1/Waf1 induction, G 2 arrest and the late ensuing apoptosis. Collectively, these data further support the notion that ceramide accumulation can modulate cell cycle progression. Additionally, these observations highlight MDM2 expression and proteasomal activity as key determinants of the cellular response to ceramide accumulation.

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Rhabdomyosarcoma: New Windows of Opportunity

Cited by 106 publications

References 94 publications

Outcome of 449 adult patients with rhabdomyosarcoma: an observational ambispective nationwide study

Outcome of 449 adult patients with rhabdomyosarcoma: an observational ambispective nationwide study

Long‐term results in childhood rhabdomyosarcoma: A report from the Italian cooperative study RMS 79

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

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