유잉 종양, Ewing sarcoma

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유잉 종양, Ewing sarcoma

[Please visit www.drleepediatrics.com-제 1권 솨청소년 응급의료- 제 2부  소아청소년 응급의료 -제12장: 소아청소년 혈액 림프 종양 질환 응급의료 (한글로 쓴) and www.drleepediatrics.com-Volum  1 Emergency Medical Care for Children and Adolescents – Part 2 Emergency Medical Care for Children and Adolescents – Chapter 12: Emergency Medical Care for Pediatric and Hematological Lymph Tumor Diseases (Written in English).]

  • 골격 악성종양의 일종이다. 
  • 사춘기 이전에도 생길 수 있지만 10~20세 사춘 아이들에게 더 잘 생긴다. 
  • 소아 골격 악성종양 중 두 번째로 흔한 골격 악성종양이다. 
  • 팔다리뼈, 장골, 등뼈, 흉골 등 장골의 골간이나 납작한 뼈에 더 잘 난다. 
  • 10세 이전 아이들에게는 골육종보다 유잉 종양이 더 난다.

유잉 종양의 증상 징후

  • 유잉종양의 19%에서 야간에 뼈 통증이 간헐적으로 오고 과도로 운동하면 통증이 더 한 것이 보통이다. 
  • 그 부위 외상을 입었을 때 외상의 정도에 비해 통증의 정도가 훨씬 더 심하게 나타난다. 
  • 20%에서 경미한 외상으로 통증이 있어 이 병을 처음 진단하기도 한다. 
  • 이 병을 처음 진단할 때 34%에서 뼈에 응어리가 만져진다. 
  • 이 병으로 생긴 통증은 몇 주 내지 몇 달간 자연히 없어졌다가 다시 재발될 수 있다. 
  • 통증, 부종, 운동 제한이 종양이 난 국소에 생기고 96%에서 통증, 16%에서 병리적 골절이 생길 수 있다. 
  • 열, 체중 감소, 종양이 난 국소에서 열이 나고 전염성 골수염과 관절염, 건염, 골격 양성종양, 골격 낭종, 전이 악성종양 등과 감별 진단해야 한다. 

유잉 종양의 진단

  • 골격 통증, 근육통, 관절통이 지속적으로 또는 간헐적으로 있고. 국소적으로 붓고 응어리가 만져지고 운동에 제한받으면 이 종양을 의심하고 그 부위 골격 X-선 사진검사, 골격 CT 스캔 검사, MRI 검사로 진단한다. 
  • CBC 피 검사, 소변검사, 적혈구 침강속도(ESR), 알칼린인산효소(알카린포스파타제)나 유산 탈수소효소 등 검사로 진단한다. 

유잉 종양의 치료

  • 조기에 전형외과 전문의, 종양전문의의 치료를 받아야 한다. 
  • 전신의 뼈들과 폐 등에 전이가 되어 있나 악성 종양 전이 전신 검사를 한다. 
  • 골수에 전이되어 있나 알아보기 위해 골수검사를 한다. 
  • 전이가 되지 않은 유잉 종양의 60~70%는 완치된다. 
  •  적극적 화학 요법 치료를 하고 관내 인공삽입물치료(endoprosthesis)도 할 수 있다.( 소스:  Children’s Hospital  at Montefiore)


Conventional and Experimental Therapeutic Approaches

Current management of primary Ewing’s sarcoma, which relies on a combination of cytotoxic drugs and local reduction through surgery, radiotherapy, or both, according to feasibility, has improved the 5-year survival rate among patients with localized disease from 10% in the era before chemotherapy to about 70% currently. Current regimens include intensive induction chemotherapy, comprising doxorubicin, etoposide, cyclophosphamide, vincristine, and ifosfamide, to reduce the size of the primary tumor and target micrometastatic disease, followed by consolidation chemotherapy to eliminate residual cells.69-71 European centers have designed trials of dose intensification through high-dose therapy, with autologous stem-cell rescue,69,71 whereas the Children’s Oncology Group has tested dose intensification through shortened intervals between doses (interval compression).70 Comparison of the two strategies suggests that the approach based on interval compression may be more effective and associated with fewer toxic effects.72 However, successfully treated patients are at risk for the development of long-term disabilities73 and other cancers, particularly chemotherapy-associated myeloid dysplastic syndrome or leukemia74 and radiation-associated sarcoma.75 Moreover, recurrent disease is currently incurable.

Although the obvious treatment strategy for Ewing’s sarcoma would be direct inhibition of the FET-ETS fusion protein, its lack of enzymatic activity and disordered structure make it difficult to target with currently available technology. Effective therapy will therefore have to rely on alternative mechanism-based approaches such as inhibition of effector molecules of the FET-ETS fusion protein, reversion of the FET-ETS–induced epigenetic modifications, targeting of molecules and signaling pathways that support and cooperate with fusion protein function, or a combination of these approaches. Several candidate effector molecules have been targeted, including the receptor tyrosine kinase insulin-like growth factor I receptor (IGF-IR), which is induced by EWS-FLI176 and is required for the transformation of fibroblasts.77 Despite the sensitivity of Ewing’s sarcoma cells to IGF-IR inhibition,78,79 in vivo studies using anti–IGF-IR antibodies have shown limited effectiveness.80,81 Poly(adenosine diphosphate–ribose) polymerase (PARP), which is implicated in DNA single-strand break base excision repair, is highly expressed in Ewing’s sarcoma, and in preclinical models, the response to PARP inhibitors was promising.82,83 However, the results of a clinical trial were disappointing.84

The small molecule YK-4-279 has shown promising results in Ewing’s sarcoma cell lines in vitro, as well as in xenografts.85 YK-4-279 inhibits the direct interaction between RNA helicase A and EWS-FLI1, disrupting EWS-FLI1 interactions within the spliceosomes and leading to an alternative splicing pattern that mimics EWS-FLI1 reduction.86 However, limited bioavailability and acquired resistance to the drug hampered its usefulness.87,88 The antibiotic enoxacin, which enhances TARBP2 activity and restores miRNA maturation, leads to the elimination of Ewing’s sarcoma–initiating cells in preclinical models, with a preeminent synergistic activity in combination with chemotherapy.89 Finally, inhibitors of the histone demethylase LSD1, implicated in transcriptional repression by EWS-FLI-1, induce apoptosis selectively in Ewing’s sarcoma cell lines and are currently being tested in a clinical study.90


A century after the seminal discovery of Ewing’s sarcoma, the prognosis for patients with localized forms of the tumor has improved dramatically, thanks to aggressive multimodal therapy. However, recurrent and metastatic disease remains a major challenge, and the inability to effectively target the fusion protein that drives the malignant process has led to continued exploration of alternative mechanism-based approaches. Although success has been limited thus far, investigation at the single-cell level is holding promise for the definition of subpopulations of cells that are responsible for driving the tumor and identification of their potential vulnerabilities. The lessons learned from Ewing’s sarcoma are not only forging new lines of thought in terms of therapeutic approaches but also providing a road map for addressing the pathogenesis of additional solid cancers in children driven by unique chromosomal translocations and aberrant fusion proteins.

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