Therapy and survival after recurrence of Ewing’s tumors: the Rizzoli experience in 195 patients treated with adjuvant and neoadjuvant chemotherapy from 1979 to 1997

Bacci, Gaetano; Ferrari, Stefano; Longhi, Alessandra; Donati, Davide María; Paolis, Massimiliano De; Forni, Cristiana; Versari, Michela; Setola, Elisabetta; Briccoli, A; Barbieri, Enza

doi:10.1093/annonc/mdg457

Cited by 113 publications

(131 citation statements)

References 13 publications

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“…Some tissues had excessive necrosis (Bologna system 2-3) 60 induced by neoadjuvant chemotherapy. 61,62 These same problems have been also described in previous studies. 21,45 Based on the present data, we recommend the use of both RT-PCR and FISH as complementary analyses; had we only used one or the other for each patient, the number of uninformative cases would have been higher.…”

Section: Discussionsupporting

confidence: 83%

Molecular Diagnosis in Ewing Family Tumors

Gamberi

Cocchi

Benini

et al. 2011

The Journal of Molecular Diagnostics

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The Ewing's family of tumors (EFTs) are characterized by chimeric transcripts generated by specific chromosomal rearrangements. The most common fusions are between the EWSR1 gene on chromosome 22 and the ETS family of transcription factors; rarely, FUS (on chromosome 16) substitutes for EWSR1. The detection of specific translocations using molecular analysis is now a routine part of the pathological examination of EFT. Here, we report our experience with molecular diagnosis of EFT during the 4 years (2006 -2009) at the Rizzoli Institute. We analyzed 222 consecutive tumors with a presumptive diagnosis of EFT using molecular techniques and IHC. We found five distinct types of EWSR1-FLI1 fusion transcripts resulting from translocation t(11;22), three types of EWSR1-ERG transcripts resulting from t(21;22), and one type of t(2;22) resulting in EWSR1-FEV fusion. Molecular investigation validated 92% of cases ultimately diagnosed as EFT; IHC validated 76% of the cases. Thus, despite the difficulties and limitations associated with both molecular and IHC analysis on fresh and formalin-fixed, paraffin-embedded tissue, a combination of these techniques is the best approach to enhancing the accuracy of EFT diagnosis. We also present our method for choosing which molecular techniques to apply. Finally, we collected the most prevalent breakpoints reported in the literature, indicating which exons are involved, the sequence breakpoints, and the NCBI reference sequences. Ewing's sarcoma (ES) is a highly malignant small round cell tumor (SRCT) that can arise in both bone and soft tissues of children and young adults. Rarely, it occurs also in adults.1,2 It is the second most common pediatric bone tumor after osteosarcoma, accounting for ϳ30% of all primary bone tumors in this age group. 1,3,4 Based on their shared immunophenotypes and molecular parameters, several diagnostic entities that were previously considered distinct are now assembled as a single entity, the Ewing's sarcoma family of tumors (EFTs). These include bone and extraskeletal Ewing's sarcoma, primitive neuroectodermal tumor (PNET), and Askin tumor of the thoracopulmonary region. 1,5-7The histological evaluation of EFT is based on morphological, immunophenotypic, and molecular features. The morphology of ES is variable. These tumors are frequently composed of uniform small round cells with round nuclei containing fine chromatin, scanty clear or eosinophilic cytoplasm, and indistinct cytoplasmic membranes. In less differentiated cases, tumor cells are larger, with prominent nucleoli and irregular contours. The cytoplasm frequently contains PAS-positive diastase-resistant glycogen. PNET is characterized by HomerWright rosettes, which are typical of neuroectodermic differentiation. 6,8,9 Immunohistochemical analysis (IHC), the first ancillary technique used in pathology to confirm the diagnosis of EFT, can distinguish among different variants. The immunohistochemical features of ES are positivity for CD99, FLI1, and caveolin 1 antigens, whereas PNET also shows immun...

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Section: Discussionsupporting

confidence: 83%

Molecular Diagnosis in Ewing Family Tumors

Gamberi

Cocchi

Benini

et al. 2011

The Journal of Molecular Diagnostics

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“…Late relapse (≥2 years from the time of original diagnosis), lung-only metastases, local recurrence that can be treated with radical surgery, and intensive chemotherapy are the most favorable prognostic factors, whereas early relapse (<2 years from the time of original diagnosis) with metastases in lungs and/or other sites, recurrence at local and distant sites, elevated LDH level at initial diagnosis, and initial recurrence are considered adverse prognostic factors. [53][54][55][56] In a recent retrospective analysis, site of first relapse and time to first relapse were significant prognostic factors for adult patients with localized Ewing sarcoma. 57 The probability of 5-year postrelapse survival was 50% and 13% for patients with local and distant relapse, respectively.…”

Section: Treating Relapsed/refractory Diseasementioning

confidence: 99%

NCCN Guidelines Insights: Bone Cancer, Version 2.2017

Biermann

Chow

Reed

et al. 2017

J Natl Compr Canc Netw

237

187

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“…The efflux pumps are identified as ATP-binding cassette (ABC) transporters characterized with their homologous ATPbinding domains, including P-glycoprotein (Pgp), an MDR1 gene product, and multidrug resistance-associated protein 1 (MRP1). 13,14 Because key drugs in chemotherapy for OS and EFTs, including adriamycin (Dox), [15][16][17] are the substrates of Pgp and MRP1, 18 drug resistance in OS and EFTs might be related to these efflux pumps.A recent study demonstrated that FK228 exhibited potent antitumor effects on OS. 19 We have also demonstrated that HDACIs induced p21 expression in EFT cells, which was inhibited by EWS-Fli1 fusion protein, and in addition we showed that the induced p21 led EFT cells to growth arrest at the G1 phase in the cell cycle.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Involvement of P‐glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug‐resistant osteosarcoma and Ewing's sarcoma cells

Okada

Tanaka

Nakatani

et al. 2005

Intl Journal of Cancer

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Despite recent improvements in multimodal therapies for osteosarcoma (OS) and Ewing's family of tumors (EFTs), the prognosis of relapsed cases remains very poor because of the resistance to chemotherapy. Histone deacetylase inhibitors (HDACIs), including members of the cyclic tetrapeptide family such as FK228 and apicidin, are novel antitumor agents that can induce cell cycle arrest and apoptosis in various cancer cells. HDACIs also exhibit potent antitumor effects on OS and EFTs. However, to date there have been no studies to our knowledge reporting the effects of HDACIs on drug-resistant OS and EFTs. Here, we demonstrated that FK228 and apicidin exhibited strong resistance in doxorubicin-resistant clones of OS and EFTs expressing P-glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1) and that P-gp and MRP1 might play a crucial role in the resistance mechanism to FK228 and apicidin. A P-gp inhibitor (verapamil) and an MRP1 inhibitor (MK571) could independently reverse the resistance to FK228 and apicidin in the drug-resistant clones. Moreover, the combination of verapamil and MK571 could enhance HDACI-induced cell number reduction in drug-resistant clones to a similar extent as that in their parental clones. Although these findings suggest the difficulty in treating drug-resistant tumors expressing P-gp and/or MRP1 with these HDACIs, the combination of P-gp and MRP1 inhibitors might reverse the resistance to the HDACIs in the treatment of those tumors. Because HDACIs are potent and promising antitumor drugs and seem to be close to clinical use, it is necessary to pay attention to the resistance mechanisms against HDACIs. ' 2005 Wiley-Liss, Inc.Key words: HDAC inhibitor; FK228 (Depsipeptide, FR901228); apicidin; P-gp; MRP1 Histone deacetylase inhibitors (HDACIs) are novel and promising antitumor agents. Previous studies demonstrated that HDACIs can activate transcription of specific genes via the accumulation of histone acetylation and subsequently cause a variety of phenotypic changes, including cell cycle arrest, morphologic reversion of transformed cells, differentiation and apoptosis. 1-3 A number of HDACIs exert antitumor effects on several cancers and are under clinical trials. Among them, FK228, a cyclic tetrapeptide acting as an HDACI, has been reported to show strong antitumor effects on various types of malignant tumors. 4 FK228 is under phase II clinical trials for relapsed or refractory cases of leukemia and advanced or metastatic colorectal cancer. Apicidin is a novel HDACI and another member of the cyclic tetrapeptide family with a potent broad spectrum of antiproliferative activity against various cancer cell lines, 5,6 and its structure is related to FK228.Osteosarcoma (OS) and Ewing's family of tumors (EFTs) are the two most frequent primary malignant bone tumors in childhood and adolescence. Despite marked improvements in the multimodal therapies and outcome, systemic relapses are observed in approximately 30-40% of cases and prognosis is very poor.7-10 It has been reported...

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Therapy and survival after recurrence of Ewing’s tumors: the Rizzoli experience in 195 patients treated with adjuvant and neoadjuvant chemotherapy from 1979 to 1997

Cited by 113 publications

References 13 publications

Molecular Diagnosis in Ewing Family Tumors

Molecular Diagnosis in Ewing Family Tumors

NCCN Guidelines Insights: Bone Cancer, Version 2.2017

Involvement of P‐glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug‐resistant osteosarcoma and Ewing's sarcoma cells

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