Extraskeletal Ewing sarcoma in children, adolescents, and young adults. An analysis of three prospective studies of the Cooperative Weichteilsarkomstudiengruppe (CWS).

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.

[Diagnosis and therapy of tumors with NTRK gene fusion]. / Diagnostik und Therapie von Tumoren mit NTRK-Genfusionen.

NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.

Malignant peripheral nerve sheath tumors in children, adolescents, and young adults: Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

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.

Dermatofibrosarcoma protuberans in children and adolescents: Primary and Relapsed disease-Experience of the Cooperative Weichteilsarkomstudiengruppe (CWS).

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare low-grade tumor. Little is known about best treatment of primary and relapsed disease (RD). METHODS: Treatment and outcome of 40 patients with DFSP prospectively registered within the CWS-96 and -2002P trials and the registry SoTiSaR (1996-2016) were analysed. RESULTS: Median age was 8 years (range, 0.64-17.77). Fluorescence in situ hybridization analysis to detect COL1A1-PDGFB fusion genes was positive in 86% (12/14) of evaluated patients. Primary resection was performed in all patients. Patients had IRS group I (n = 28), II (n = 9), and III (n = 2); not available (n = 1). To achieve complete remission (CR), a secondary resection was performed in 18 patients resulting in microscopically complete (R0, n = 34/40) and microscopically incomplete (R1, n = 5/40) resection. All patients achieved CR. The 5-year event-free survival (EFS) and overall survival was 86% (±12; CI, 95%) and 100% (±0; CI, 95%), respectively. R0 resection/IRS I was significantly favorable for the 5-year EFS. Local relapse occurred after a median time of 1.1 years (range, 0.04-5.1) in 15% (6/40) after CR. All patients with RD underwent resection and achieved CR. Three patients had fibrosarcomatous DFSP, two were alive after R0 resection. CONCLUSION: Complete surgical resection is mandatory to prevent relapse of DFSP.

Undifferentiated sarcoma of the liver: Multicenter international experience of the Cooperative Soft-Tissue Sarcoma Group and Polish Paediatric Solid Tumor Group.

BACKGROUND: Undifferentiated embryonal sarcomas of the liver (UESL) are extremely rare and continue to pose a diagnostic and therapeutic challenge. The aim of the study was to present a multicenter experience of the German CWS and Polish PPSTG groups in the treatment of UESL in children. PROCEDURE: Twenty-five patients were treated according to the CWS-96, CWS-2002, and CYVADIC protocols. Distant metastases were observed in four cases (16%). In four cases, an initial disease presentation mimicked other entities. A pure cystic appearance of liver mass led to misdiagnosis of hydatid cyst in three cases. In one case, laparotomy was performed due to the signs of appendicitis, and bleeding from ruptured liver tumor was found. All these patients were finally diagnosed as UESL. RESULTS: Thirteen patients received preoperative chemotherapy. Partial response was observed in 10 cases. Tumor resection was performed in 20 patients (primary resections, 12; delayed resections-, 8). In five patients, the primary tumor never became operable. The macroscopically complete resection rate was 95% (19/20). Postoperative chemotherapy was given to 20 children. Local radiotherapy was used in three children. After a median follow-up time of 136 months, 17 patients (68%) were alive with no evidence of disease. All children with unresectable tumor and three out of four patients with distant metastases died. The five-year overall survival (OS) rate was 72%. CONCLUSIONS: In summary, a complete tumor excision plays the central role in the treatment of UESL. A cystic presentation of the liver lesion on imaging does not exclude the diagnosis of malignant tumor.

Low-grade fibromyxoid sarcoma: A report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue tumor with benign histologic appearance, though fully malignant behavior is possible. METHODS: Patients with LGFMS <21 years registered in Cooperative Weichteilsarkom Studiengruppe trials until 2017 were analyzed. Firstline treatment consisted of complete surgical resection whenever possible. RESULTS: Median age of 31 patients was 10.9 years (first month to 17.1 years). Twenty-six tumors were confirmed to the tissue of origin (T1), four invaded contiguous structures (T2), one was TX. Eight were >5 cm. The best surgical result was resection with free margins (R0) in 24 and microscopic residuals (R1) in seven. Five-year event-free (EFS), 5-year local-relapse-free (LRFS), and 5-year overall-survival were 71 ± 18.6% confidence interval (CI) 95%, 76 ± 17.6% CI 95%, and 100%, respectively. Six patients suffered local relapse in a median of 1 year, one combined within 1.3 year and one metastatic relapse with lesions in the lung, back muscles, and thigh discovered in whole-body imaging 6 years after the first diagnosis. In univariate analysis, T status correlated with EFS (T1 79.6 ± 18.6%, T2 50.0 ± 49.0%, P = .038). Resection with free margins tends to be associated with better LRFS (R0 82.4 ± 18.6%, R1 53.6 ± 39.4%, P = .053). Among 24 patients with R0 resection, five (21%) suffered relapse, thereof three local, one metastatic, and one combined. Among seven patients with R1-resection, three (43%) suffered local relapse. CONCLUSION: Special caution is advisable in T2 tumors. The metastatic potential with lesions in unusual sites indicates that affected patients need to be informed. If long-term follow-up with whole-body imaging is beneficial, it may be addressed in larger intergroup analyses. Further research in disease biology is essential for optimal treatment and follow-up care.

Endothelial cell malignancies in infants, children and adolescents: Treatment results of three Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

BACKGROUND: Endothelial cell malignancies are extremely rare in childhood. New identification of genetic abnormalities (WWTR1:CAMTA1 translocation) helps to recognize potential therapeutic targets. Little is known about treatment and outcome of these patients. METHODS: Clinical course, treatment, and outcome in patients with endothelial cell malignancies treated within the Cooperative Weichteilsarkom Studiengruppe (CWS) trials CWS-91, -96, -2002P, and the Soft-Tissue Sarcoma Registry (SoTiSaR) were analyzed (1991-2019). RESULTS: Patients had angiosarcoma (AS) (n = 12), malignant epithelioid hemangioendothelioma (EHE) (n = 16), and kaposiform hemangioendothelioma (KHE) (n = 13). The median age was 5.39 years (range, 0.8-17.34); 33 patients had localized disease (LD), and 8 patients had metastatic disease. Therapy consisted of chemotherapy (CHT) (AS n = 8, EHE n = 9, KHE n = 5), interferon or new agent therapy (EHE n = 5, 2 KHE n = 2), microscopically or macroscopically complete resection (AS n = 3, EHE n = 6, KHE n = 3), and radiotherapy (AS n = 6, EHE n = 2, KHE n = 1). Two patients (KHE) had watch-and-wait strategy resulting in stable disease. Complete remission (CR) was achieved in AS (10/12; 83%), EHE (10/16; 63%), and KHE (5/13; 38%). The five-year EFS and OS for patients with AS was 64% (± 29 CI 95%) and 80% (± 25, CI 95%), with EHE 62% (± 24, CI 95%) and 78% (± 23, CI 95%), with KHE 33% (± 34, CI 95%) and 92% (± 15, CI 95%), respectively. Complete resection was a significant prognostic factor for AS, LD for EHE. CONCLUSIONS: Endothelial cell malignancies in childhood have a fair outcome with multimodal treatment. New treatment options are needed for metastic disease.

Localized synovial sarcoma of the foot or ankle: A series of 32 Cooperative Weichteilsarkom Study Group patients.

BACKGROUND: Synovial sarcoma of the foot/ankle is rare. Mutilating surgery is often discussed. METHODS: Patients registered from 1981 to 2013 were analyzed. Cooperative Weichteilsarkom Studiengruppe (CWS) protocols recommend chemotherapy for all synovial sarcoma patients. RESULTS: Thirty-two of 330 patients with localized synovial sarcoma had their tumor at the foot/ankle. Eleven of thirty-two tumors were >5 cm. Twenty were T1, 11 T2, and one TX, respectively. Eight (25%) patients underwent primary complete resection with free margins (Intergroup Rhabdomyosarcoma Study [IRS] I), 12 of 32 (38%) primary complete resection with positive margins (IRS II), and 12 of 32 (38%) had macroscopic residuals (IRS III). The best surgical result at any time was R0 in 19, R1 in 10 and R2 in one patient, and missing in two. Mutilation was documented in 14 of 32 (44%). Radiotherapy was conducted in 20 patients. All patients achieved a first complete remission. Five-year-event-free survival and overall survival rates were 80% and 86%, respectively. Four patients suffered local and four other metastatic recurrences. IRS and the best surgical result at any time did not correlate with survival. There was no prognostic difference between R0- and R1-resection. CONCLUSION: Survival expectancies for patients with localized synovial sarcomas of the foot/ankle compare favorably to that of those with other affected sites. DISCUSSION: Further studies are needed to set the limits of minimally required aggressiveness of local therapies.

Epithelioid sarcoma in children, adolescents, and young adults: Localized, primary metastatic and relapsed disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

BACKGROUND: Epithelioid sarcoma (ES) is a rare malignant soft-tissue tumor. Little is known about the optimal treatment of primary localized (LD), metastatic (MD), and relapsed disease (RD). METHODS: Characteristics, treatment, and outcome of 67 patients registered within the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, -2002P trials and the registry SoTiSaR were analyzed (1981-2016). RESULTS: The median age was 14 years (range, 0.7-26.9); 53 patients had localized disease (LD) and 14 metastatic disease (MD). A total of 58 of 67 patients were treated with primary resection. Resection was microscopically complete (R0) in 35, microscopically incomplete (R1) in 12, macroscopically incomplete (R2) in 20 patients. Radiotherapy (RT) was administered to 33 of 67 patients and 49 of 67 patients received chemotherapy (CHT). Complete remission (CR) was achieved in 45 of 53 (85%) patients with LD. Twenty-seven of 53 patients relapsed after a median time of 0.9 years (range, 0.1-2.3). Relapse therapy consisted of resection (n = 19/27), RT (n = 10/27), CHT (n = 12/27), and limb perfusion (n = 3/27). The five-year event-free survival and overall survival of patients with LD, MD, and RD was 35% (± 12, CI 95%) and 58% (± 14, CI 95%), 7% (± 14, CI 95%), and 9% (± 16, CI 95%), 24% (± 17, CI 95%), and 40% (± 20, CI 95%), respectively. Tumor size, IRS group, tumor invasiveness, nodal status, and best resection correlated with a favorable prognosis in patients with LD while best resection was the only significant factor in patients with RD. CONCLUSIONS: Complete tumor resection correlates with long-term survival in patients with ES.

Rhabdomyosarcoma diagnosed in the first year of life: Localized, metastatic, and relapsed disease. Outcome data from five trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Rhabdomyosarcoma (RMS) diagnosed during the first year of life is reported to have poor outcome. Little is known about treatment and outcome data of relapsed disease (RD). METHODS: Characteristics, treatment, and outcome of 155 patients ≤ 12 months registered within the Cooperative Weichteilsarkom Studiengruppe (CWS) between 1981 and 2016 were evaluated. RESULTS: Localized disease (LD) was diagnosed in 144 patients and metastatic disease (MD) in 11. The histological diagnosis was alveolar (RMA) (n = 38, 23/25 examined patients PAX7/3:FOXO1-positive), embryonal (RME) (n = 100), botryoid (n = 10), anaplastic (n = 1), and spindle-cell RMS (n = 6). Multimodal treatment including conventional (age-adjusted) chemotherapy (CHT) (n = 150), resection (n = 137), and radiotherapy (RT) (n = 37) was administered. Complete remission was achieved in 129 of 144 patients with LD. RD occurred in 51 infants at a median age of 1.7 years (range, 0.3-8.8). Sixty-three percent of patients with RMA suffered RD, in contrast to 28% of patients with RME. Relapse treatment consisted of conventional CHT (n = 48), resection (n = 28), and RT (n = 21). The pattern of relapse and best resection were significant prognostic factors for patients with RD (P = 0.000 and P = 0.002). Late effects occurred as secondary malignancies in 6%, long-term toxicity in 21%, and resection-related impairment in 33% of the 105 surviving patients. The 5-year event-free survival and overall survival for infants with initial LD were 51% and 69%, 14% and 14% for patients with initial MD and 39% and 41% for relapsed patients, respectively. CONCLUSION: Multimodal treatment including microscopically complete resection is strongly recommended to achieve a good prognosis in LD and RD of infants with RMS.

Inflammatory myofibroblastic tumors-A retrospective analysis of the Cooperative Weichteilsarkom Studiengruppe.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are a rare subgroup of soft tissue tumors. The outcome of patients with IMT has been reported as favorable when the tumor is completely resected. If surgical resection is not possible, systemic therapy has to be considered. However, the best systemic treatment and response rates are currently unclear. METHODS: Thirty-eight patients under the age of 21, who were registered between 2000 and 2014 with a primary diagnosis of IMT, were analyzed. RESULTS: IMT was typically localized intra-abdominally or in the pelvis. In 20 patients, the tumor was resected without further therapy; 17 patients were in complete remission at last evaluation and two patients were in partial remission. Eighteen patients received systemic therapy, 15 of whom had macroscopically incomplete resection. Systemic therapy most commonly consisted of regimens with dactinomycin, ifosfamide or cyclophosphamide, and vincristine, with or without doxorubicin, and it seemed to reduce tumor extension in individual cases. Five-year event-free survival was 74 ± 14% and 5-year overall survival was 91 ± 10% for all patients. The patients who died due to the disease were those with incomplete resection (n = 3). CONCLUSIONS: Surgery without further systemic therapy was a feasible and acceptable therapeutic option for every second patient with IMT. Standard chemotherapy for pediatric soft tissue sarcoma produced favorable results in individual cases and was able to shrink the tumor enough to enable resection. Superior efficacy of new targeted therapies such as anaplastic lymphoma kinase-inhibitors compared to standard chemotherapy has to be proven in the future.

Alveolar soft-part sarcoma: Primary metastatic disease and metastatic relapse occurring during long-term follow-up: Treatment results of four Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

BACKGROUND: Patients with metastatic alveolar soft-part sarcoma (ASPS) are known to have a very poor prognosis. Little is known about best treatment of primary metastatic disease (MD) or relapsed metastatic disease (rMD). PATIENTS AND METHODS: Patients with localized disease (LD), primary MD, and metastatic recurrence after complete remission (CR) treated within the CWS-86, -91, -96, -2002P trials and the recent registry SoTiSaR (1985-2016) were analyzed. RESULTS: Fifteen of 61 patients had primary metastases at initial diagnosis at the age of 14.6 years (range, 7.8-19.7). Nine of 46 patients with initial LD suffered of rMD at a median age of 9.9 years (range, 3.5-30), 3.75 years (0.75-21) after CR of primary disease. Complete resection (microscopically or macroscopically) was possible in 2 of 15 patients with MD and in 5 of 9 with rMD. RT was administered in 4 of 15 MD and 1 of 9 rMD. Chemotherapy was administered to 11 of 15 MD and 3 of 9 rMD, targeted therapy to 3 of 15 MD and 1 of 9 rMD. Median time to progression of patients treated with targeted therapy (n = 4), CHT (n = 14), and resection only (n = 6) was 56, 17, and 23 months, respectively. The 5-year event-free survival and overall survival (OS) rates were 19.8% and 61%, respectively, for patients with MD compared with 79% and 98% for patients with LD. The 5-year progression-free survival and OS were 67% and 100% for patients with rMD. CONCLUSIONS: Complete tumor resection correlates with long-term survival in patients with primary and relapsed MD.

Systemic therapy of aggressive fibromatosis in children and adolescents: Report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Treatment algorithms for patients with aggressive fibromatosis (AF) are challenging. There are limited data available about the use of systemic therapy (ST) in pediatric patients with AF. METHODS: Patient-, tumor-, and treatment-related factors of 90 children and adolescents with AF treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (1981-2015) were analyzed with focus on response and outcome of ST. RESULTS: Median age was 9.48 years (0.02-18.05). Primary resection was performed in 54 patients and ST was administered in 29 of 54 patients because of disease progression or relapse. In 35 patients, ST was the initial treatment modality. A secondary resection was performed in 21 of 35 patients after ST. A total of 64 patients received ST, mainly methotrexate and vinblastine (40%) with a median duration of 380 days. The most frequent radiological response to ST was stable disease at 3 months (39%) and partial response at 6 months (53%). Radiotherapy was administered to 15 of 90 patients. One patient remained on observation only. The 5-year overall survival was 100% and the 5-year event-free survival (EFS) was 44%. Patients who had a primary resection showed a 5-year EFS of 35% versus 59% in patients who had received primary ST (P = 0.08). Functional deficiencies as long-term sequelae following resection occurred in 11 patients. At a median follow-up of 5.05 years (0.25-14.88), complete remission was achieved in 51 patients and partial remission in 28 patients. CONCLUSIONS: ST seems appropriate if a primary complete resection is not feasible and at relapse/progression after resection.

Importance of whole-body imaging with complete coverage of hands and feet in alveolar rhabdomyosarcoma staging.

BACKGROUND: Alveolar rhabdomyosarcoma commonly arises in the extremities and is characterized by aggressive biology and high frequency of metastases. Whole-body imaging is increasingly employed in pediatric oncology but not recommended as standard in the staging of soft-tissue sarcomas. OBJECTIVE: After observing patients with a large symptomatic alveolar rhabdomyosarcoma lesion and a smaller silent lesion in the more distal part of an extremity we sought to estimate the frequency of this constellation. MATERIALS AND METHODS: We retrospectively evaluated the data of prospectively registered paediatric patients (age <21 years) with alveolar rhabdomyosarcoma in the SoTiSaR (Soft Tissue Sarcoma Registry) of the Cooperative Weichteilsarkom Studiengruppe (CWS) 09/2011-04/2015 with regard to whole-body imaging. RESULTS: Seventy-five patients were eligible. Images of 57 patients had been submitted for reference consultation, including 80 whole-body examinations in 36 patients. Among them were 5 patients (14%, 95% confidence interval 3-25%) who had been diagnosed because of a symptomatic lesion while an additional silent lesion in the distal part of an extremity had remained unnoticed and had only been detected by later whole-body imaging. It is noteworthy that in 42 (53%) of all 80 whole-body examinations, the hands and feet had been only partially covered or completely excluded. CONCLUSION: In alveolar rhabdomyosarcoma silent lesions can be overlooked when the distal parts of the limbs are not thoroughly examined and not completely covered by imaging. Missing them influences treatment decisions and prognosis. Our results should be considered when evaluating the potential role of whole-body imaging in rhabdomyosarcoma.

The impact of local control in the treatment of type II/III pleuropulmonary blastoma. Experience of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND AND OBJECTIVES: This study aims at examining the potential survival benefits of primary versus secondary surgery in the management of children diagnosed with pleuropulmonary blastoma (PPB) type II/III. PATIENTS AND METHODS: Disease characteristics, treatment, and survival of 29 children with localized PPB type II/III, treated in six prospective Cooperative Weichteilsarkom Studiengruppe (CWS) trials, were reviewed retrospectively. RESULTS: Five year event free survival (EFS) and overall survival (OS) of children treated according to CWS protocols was 72%. Patients with tumors ≤10 cm had a 5 year OS of 91% versus 57% in patients with tumors >10 cm (P = 0.025). Five year OS of patients with macroscopically incomplete upfront resections was 44% as opposed to 68% in patients with delayed/secondary microscopically or macroscopically complete resection after an initial biopsy (P = 0.476). Ten patients died of disease, one patient died of second malignancy. Tumor size and complete tumor resection at any time were significant prognostic factors (P = 0.025/0.003) for EFS. EFS for microscopically complete, microscopically incomplete, and macroscopically incomplete resection at any time was 91%, 90%, and 25%, respectively (P = 0.01). CONCLUSIONS: Primary or secondary microscopically/macroscopically complete tumor resections in combination with chemotherapy correlates with long term survival in children with PPB. J. Surg. Oncol. 2017;115:164-172. © 2017 Wiley Periodicals, Inc.

The prognostic impact of SYT-SSX fusion type and histological grade in pediatric patients with synovial sarcoma treated according to the CWS (Cooperative Weichteilsarkom Studie) trials.

BACKGROUND: The aim of our analysis was the evaluation of the prognostic impact of SYT-SSX fusion status and histological grading in synovial sarcoma (SS) of children and adolescents in the context of the consistent multimodal treatment strategy of the CWS (Cooperative Weichteilsarkom Studie; Cooperative Soft Tissue Sarcoma Study Group) and in comparison with other risk factors. PROCEDURE: Between 1986 and 2006, out of 243 patients with SS, tumor samples from 84 patients with localized disease were available for RT-PCR analysis. Outcome depending on fusion status in the context with known clinical risk factors was analyzed. RESULTS: No prognostic significance was shown for SYT-SSX fusion status and for histological grade. Highest significance of negative prognostic impact was found for large tumor size in uni- and multivariate analysis (P < 0.01). Furthermore, male gender was shown to be an adverse prognostic factor in multivariate analysis (P = 0.01). CONCLUSIONS: Based on our results, neither histological grading nor SYT-SSX fusion status seems to be suitable for outcome prediction and risk stratification in localized SS treated according to the CWS. This is in contrast to several other publications concerning more heterogeneous age groups including children and adults, and this indicates that prognostic factors should not be interpreted apart from the particular study population and the therapeutic context.

The prognostic value of early radiographic response in children and adolescents with embryonal rhabdomyosarcoma stage IV, metastases confined to the lungs: A report from the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis apart from children with embryonal RMS whose metastases are confined to the lungs (PRME). The prognostic significance of response in patients with metastatic disease is still unknown and optimal treatment remains to be defined. METHODS: Patient-, tumor- and treatment-related factors of patients with PRME treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (CWS) (1981-2013) were analyzed with a focus on response to induction chemotherapy. Response at week 7-10 was based on anatomic imaging and determined (1) for the primary tumor as complete response (CR), good response (GR), partial response (PR) and no response (NR) and (2) for pulmonary metastases as either complete lack of residual lesions (pCR) or no complete response (no-pCR). Event-free (EFS) and overall survival (OS) were the endpoints. RESULTS: EFS and OS of all 53 eligible patients was 41% (±13 confidence interval [CI] 95%) and 52% (±11 CI 95%), respectively. pCR at week 7-10 and maintenance therapy (MT) were favorable prognostic factors. Interestingly, response of primary tumor at week 7-10 and number of metastases were not prognostic factors. The 5-year OS was 68% (±18 CI 95%) for 26 patients in pCR, but only 36% (±18 CI 95%) for 27 patients not in pCR at week 7-10 (P = 0.004) despite achieving pCR under continuation of chemotherapy or local therapy. CONCLUSION: Achievement of pCR at week 7-10 by induction chemotherapy is a prognostic factor.

Synovial Sarcoma Recurrence in Children and Young Adults.

BACKGROUND: Recurrence of synovial sarcoma (SS) has been associated with poor prognosis. Optimal treatment is unknown due to heterogeneous primary therapies with or without chemotherapy. METHODS: Data of patients treated in consecutive prospective European Cooperative Weichteilsarkom Studiengruppe trials 1981-2010 with primary localized SS less than 21 years were analyzed. Chemotherapy had been recommended for all SS patients during primary therapy. RESULTS: Of 220 patients, 52 experienced recurrence a median of 2.5 years (range, 0.3-11.6 years) after their initial diagnosis. Recurrence was local in 22 (42 %), metastatic in 24 (46 %), and combined in 6 (12 %) of the 52 patients. If present, metastases involved the lungs in more than 90 % of the patients. Second remission was achieved by 39 (75 %) of the 52 patients, whereas only 12 (23 %) of the 39 patients maintained it. The median follow-up period for 17 survivors was 6.7 years (range, 3.2-19.6 years). The 5-year post-relapse event-free survival probability was 26 %, and the overall survival probability was 40 %. In the univariable analyses, initial tumor smaller than 3 cm, 2.5 years or longer to recurrence, local relapse only, and R0/R1 resection at relapse correlated with improved survival expectancies. In the multivariable analysis, the only factor retaining significance was R0/R1 resection of the recurrence. No difference between R0 and R1 resections was evident. For the patients with metastatic relapse, maintenance therapy seemed to prolong the time to subsequent recurrences. CONCLUSION: Although 75 % of the patients with first SS recurrence achieved a second remission, only a minority became long-term, disease-free survivors. They had small tumors at initial diagnosis, local relapse as the only site of involvement, and complete resection of their recurrence. Because the majority of patients relapse subsequently, quality-of-life-based treatment approaches prolonging disease-free intervals are needed.

Creatine and creatine pyruvate reduce hypoxia-induced effects on phrenic nerve activity in the juvenile mouse respiratory system.

Adequate concentrations of ATP are required to preserve physiological cell functions and protect tissue from hypoxic damage. Decreased oxygen concentration results in ATP synthesis relying increasingly on the presence of phosphocreatine. The lack of ATP through hypoxic insult to neurons that generate or regulate respiratory function, would lead to the cessation of breathing (apnea). It is not clear whether creatine plays a role in maintaining respiratory phrenic nerve (PN) activity during hypoxic challenge. The aim of the study was to test the effects of exogenously applied creatine or creatine pyruvate in maintaining PN induced respiratory rhythm against the deleterious effects of severe hypoxic insult using Working Heart-Brainstem (WHB) preparations of juvenile Swiss type mice. WHB's were perfused with control perfusate or perfusate containing either creatine [100µM] or creatine pyruvate [100µM] prior to hypoxic challenge and PN activity recorded throughout. Results showed that severe hypoxic challenge resulted in an initial transient increase in PN activity, followed by a reduction in that activity leading to respiratory apnea. The results demonstrated that perfusing the WHB preparation with creatine or creatine pyruvate, significantly reduced the onset of apnea compared to control conditions, with creatine pyruvate being the more effective substance. Overall, creatine and creatine pyruvate each produced time-dependent degrees of protection against severe hypoxic-induced disturbances of PN activity. The underlying protective mechanisms are unknown and need further investigations.

Primary Metastatic Synovial Sarcoma: Experience of the CWS Study Group.

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.