Recently, immunotherapeutic approaches have become a feasible option for a subset of pediatric cancer patients. Low MHC class I expression hampers the use of immunotherapies relying on antigen ...presentation. A well-established stemness score (mRNAsi) was determined using the bulk transcriptomes of 1134 pediatric small round blue cell tumors. Interestingly, MHC class I gene expression (HLA-A/-B/-C) was correlated negatively with mRNAsi throughout all diagnostic entities: neuroblastomas (NB) (n = 88, r = −0.41, p < 0.001), the Ewing’s sarcoma family of tumors (ESFT) (n = 117, r = −0.46, p < 0.001), rhabdomyosarcomas (RMS) (n = 158, r = −0.5, p < 0.001), Wilms tumors (WT) (n = 224, r = −0.39, p < 0.001), and central nervous system-primitive neuroectodermal tumors CNS-PNET (r = −0.49, p < 0.001), with the exception of medulloblastoma (MB) (n = 76, r = −0.24, p = 0.06). The negative correlation of MHC class I and mRNAsi was independent of clinical features in NB, RMS, and WT. In NB and WT, increased MHC class I was correlated negatively with tumor stage. RMS patients with a high expression of MHC class I and abundant CD8 T cells showed a prolonged overall survival (n = 148, p = 0.004). Possibly, low MHC class I expression and stemness in pediatric tumors are remnants of prenatal tumorigenesis from multipotent precursor cells. Further studies are needed to assess the usefulness of stemness and MHC class I as predictive markers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the ...Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance.
Methods
Second‐line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low‐ (LR), standard‐ (SR), and high‐risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline‐based regimen in the very high‐risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009–2018) were retrospectively analyzed.
Results
Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5‐year event‐free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5‐year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively.
Conclusion
Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma ...(STS) studies: CWS‐91, CWS‐96, and CWS‐2002P.
Methods
Patients were treated in CWS‐91 with four‐ (vincristine, dactinomycin, doxorubicin, and ifosfamide VAIA or cyclophosphamide VACA II) or five‐drug (+etoposide EVAIA) cycles, in CWS‐96 they were randomly assigned to receive VAIA or CEVAIE (+carboplatin and etoposide), and in CWS‐2002P with VAIA III plus optional maintenance therapy (MT) with cyclophosphamide and vinblastine. Local therapy consisted of resection and/or radiotherapy (RT).
Results
Two hundred forty‐three patients fulfilled the eligibility criteria. The 5‐year event‐free survival (EFS) and overall survival (OS) were 63% (95% confidence interval CI 57–69) and 73% (95% CI 67–79), respectively. The 5‐year EFS by study was 64% (95% CI 54–74) in CWS‐91, 57% (95% CI 48–66) in CWS‐96, and 79% (95% CI 67–91) in CWS‐2002P (n.s.). The 5‐year OS was 72% (95% CI 62–82) in CWS‐91, 70% (95% CI 61–79) in CWS‐96, and 86% (95% CI 76–96) in CWS‐2002P (n.s.). In CWS‐96, 5‐year EFS and OS in the VAIA arm versus the CEVAIE were 65% (95% CI 52–81) versus 55% (95% CI 39–76) log‐rank p = .13, and 85% (95% CI 75–96) versus 61% (95% CI 45–82), log‐rank p = .09.
Conclusion
Our analysis provides interesting information on the treatment and specificities of EES, which can be useful for a better understanding of this rare entity and should be considered in the development of future clinical trials for Ewing sarcoma defined as FET–ETS fusion positive tumors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Pediatric tumors frequently arise from embryonal cells, often displaying a stem cell-like ("small round blue") morphology in tissue sections. Because recently "stemness" has been associated with a ...poor immune response in tumors, we investigated the association of prognostic gene expression, stemness and the immune microenvironment systematically using transcriptomes of 4068 tumors occurring mostly at the pediatric and young adult age. While the prognostic landscape of gene expression (PRECOG) and infiltrating immune cell types (CIBERSORT) is similar to that of tumor entities occurring mainly in adults, the patterns are distinct for each diagnostic entity. A high stemness score (mRNAsi) correlates with clinical and morphologic subtype in Wilms tumors, neuroblastomas, synovial sarcomas, atypical teratoid rhabdoid tumors and germ cell tumors. In neuroblastomas, a high mRNAsi is associated with shortened overall survival. In Wilms tumors a high mRNAsi correlates with blastemal morphology, whereas tumors with predominant epithelial or stromal differentiation have a low mRNAsi and a high percentage of M2 type macrophages. This could be validated in Wilms tumor tissue (
= 78). Here, blastemal areas are low in M2 macrophage infiltrates, while nearby stromal differentiated areas contain abundant M2 macrophages, suggesting local microanatomic regulation of the immune response.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We report here the results of the prospective, non-randomized, historically controlled CWS-2002P study in patients ≤ 21 years with localized RMS developed with the aim to improve the long-term ...outcome by adapting the burden of therapy to risk profile and to investigate the feasibility and relation to the outcome of maintenance therapy (MT) in the high-risk groups. Patients were allocated into low-risk (LR), standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. Chemotherapy consisted of vincristine (VCR) and dactinomycin (ACTO-D) for all patients with the addition of ifosfamide (IFO) in the SR, HR, and VHR and doxorubicin (DOX) in the HR and VHR groups. Low-dose cyclophosphamide and vinblastine maintenance therapy (MT) over 6 months was recommended in the HR and VHR groups. A total of 444 patients have been included in this analysis. With a median follow-up of 9·6 years (IQR 7·6-10·9) for patients alive, the 5-year EFS and OS for the whole group was 73% (95% CI 69-77) and 80% (95% CI 76-84), respectively. The 5-year EFS by risk group was 100% in the LR, 79% (95% CI 72-84) in the SR, 69% (95% CI 63-75) in the HR, and 42% (95% CI 23-61) in the VHR (log-rank
= 0.000). The 5-year EFS was 77% (95% CI 70-84) for 155 patients in the HR group who received MT as compared to 63% (95% CI 50-76) for 49 patients who did not (log-rank
= 0.015). Neither the reduction in the IFO dose in the SR nor the increased dose intensity of DOX in HR groups influenced the outcome when compared to the previous CWS and other European studies. MT was feasible, seemed to have an impact on prognosis, and should be studied in a well-controlled prospective trial in this patient population. The weighting of risk factors used for therapy stratification needs to be reevaluated.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Prognostic factors for localized synovial sarcoma are well defined. However, few data exist regarding patients with metastases at diagnosis. Poor outcome is described but the optimal ...therapeutic regimen remains unclear. Our aim was to assess the outcome, identify prognostic factors, and analyze treatment strategies.
Methods
Patients <21 years with synovial sarcoma and primary distant metastases treated in the consecutive prospective European Cooperative Weichteilsarkom Studiengruppe trials 1980–2010 were analyzed.
Results
Twenty‐nine of 296 patients had primary metastases. Twenty‐seven could be included. Median age was 16.7 years. Primaries were mainly located in the limbs (78%) and 74% were ≥10 cm. Metastases involved the lungs in all patients. Two patients presented with synchronous bone metastases. Sixty‐three percent of patients achieved a first remission, whereas only 26% maintained it. Relapses were metastatic with pulmonary metastases in nearly all patients. Five‐year event‐free survival and overall survival (OS) rates were 26% and 30%, respectively. Prognosis was best for patients with oligometastatic lung metastases (5‐year OS probability 85%). Prognosis was worse for patients with multiple bilateral lung metastases (5‐year OS 13%) and even poorer for those with concurrent bone metastases. Treatment elements associated with superior survival were adequate local therapy of the primary tumor and, if feasible, for metastases, chemotherapy with an ifosfamide/doxorubicin‐based regimen. The use of whole lung irradiation was not correlated with better outcomes.
Conclusions
The overall prognosis of primary metastatic synovial sarcoma is poor. However, individuals with oligometastatic lung metastases had very good chance for long‐term survival when treated with adequate multimodal therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background and Objectives
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that present as large, invasive tumors. Our aim was to assess outcomes, identify ...prognostic factors, and analyze treatment strategies in a prospectively collected pediatric cohort.
Methods
Patients less than 21 years with MPNST treated in the consecutive prospective European Cooperative Weichteilsarkom Studiengruppe (CWS)‐trials (1981‐2009) and the CWS‐SoTiSaR registry (2009‐2015) were analyzed.
Results
A total of 159 patients were analyzed. Neurofibromatosis type I (NF1) was reported in thirty‐eight patients (24%). Most were adolescents (67%) with large (>10 cm, 65%) tumors located at extremities (42%). Nodal involvement was documented in 15 (9%) and distant metastases in 15 (9%) upon diagnosis. Overall, event‐free survival (EFS) was 40.5% at 5 and 36.3% at 10 years, and overall survival (OS) was 54.6% at 5 and 47.1% at 10 years. Age, NF1 status, tumor site, tumor size, Intergroup Rhabdomyosarcoma Study (IRS) group, metastatic disease, and achieving first complete remission (CR1) were identified as prognostic factors for EFS and/or OS in the univariate analysis.
Conclusions
Prognostic factors were identified and research questions for future clinical trials were addressed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
(1) Background: Vena cava thrombus (VCT) is rare in Wilms tumor (WT) (4−10%). The aim of this study is to identify factors for an outcome to improve treatment for better survival. (2) Methods: ...148/3015 patients with WT (aged < 18 years) and VCT, prospectively enrolled over a period of 32 years (1989−2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH), are retrospectively analyzed to describe clinical features, response to preoperative chemotherapy (PC) (142 patients) and surgical interventions and to evaluate risk factors for overall survival (OS). (3) Results: 14 VCT regressed completely with PC and another 12 in parts. The thrombus was completely removed in 111 (85.4%), incompletely in 16 (12.3%), and not removed in 3 (2.3%). The type of removal is unknown in four patients. Patients without VCT have a significantly (p < 0.001) better OS (97.8%) than those with VCT (90.1%). OS after complete resection is (89.9%), after incomplete (93.8%) and with no resection (100%). Patients with anaplasia or stage IV without complete remission (CR) after PC had a significantly worse OS compared to the remaining patients with VCT (77.1% vs. 94.4%; p = 0.002). (4) Conclusions: As a result of our study, two risk factors for poor outcomes in WT patients with VCT emerge: diffuse anaplasia and metastatic disease, especially those with non-CR after PC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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