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.

Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults.

PURPOSE: To improve risk-adapted therapy for localized childhood soft tissue sarcoma within an international multicenter setting. PATIENTS AND METHODS: Four hundred forty-one patients younger than 21 years with localized rhabdomyosarcoma and rhabdomyosarcoma-like tumors (ie, extraosseous tumors of the Ewing family, synovial sarcoma, and undifferentiated sarcoma) were eligible. Therapy was stratified according to postsurgical stage, histology, and tumor site. In unresectable tumors, treatment was further adapted depending on response to induction chemotherapy, TN classification, tumor size and second-look surgery. A novel five-drug combination of etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin (EVAIA) was evaluated for high-risk patients, but cumulative chemotherapy dosage and treatment duration were reduced for the remaining individuals as compared with that of the previous trial CWS-86. Hyperfractionated accelerated radiotherapy (HART) was recommended at doses of either 32 or 48 Gy. RESULTS: At a median follow-up of 8 years, 5-year event-free survival (EFS) and overall (OS) survival for the entire cohort was 63% +/- 4% and 73% +/- 4%, respectively (all survival rates in this abstract are calculated and displayed with +/-95% CI). EFS/OS rates by histology were 60% +/- 5%/72% +/- 5% in rhabdomyosarcoma, 62% +/- 10%/69% +/- 10% for Ewing tumors of soft tissues, 84% +/- 12%/90% +/- 10% for synovial sarcoma, and 67% +/- 38%/83% +/- 30% for undifferentiated sarcoma, respectively. Response to one cycle of the five-drug combination EVAIA was similar to that of the four-drug combination VAIA used in CWS-86. Two hundred twelve patients with rhabdomyosarcoma underwent radiation (EFS, 66% +/- 6%); 53 of those patients had a favorable risk profile and received 32 Gy of HART (EFS, 73% +/- 12%). TN classification, tumor site, tumor size, histology, and age were prognostic in univariate analysis. CONCLUSION: Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.

Initial patient characteristics can predict pattern and risk of relapse in localized rhabdomyosarcoma.

PURPOSE: Evaluation of primary tumor-, treatment-, and patient-related factors predicting relapse pattern, risk, and survival after relapse with the aim to design a risk-adapted, tumor-directed surveillance program for patients with localized rhabdomyosarcoma (RMS). PATIENTS AND METHODS: One thousand one hundred sixty-four patients with nonmetastatic RMS achieved complete remission at the end of multimodal therapy in the consecutive trials of the Cooperative Weichteilsarkom Studiengruppe (CWS)-81, CWS-86, CWS-91, and CWS-96 between 1980 and 2002 (median follow-up, 5 years). Three hundred thirty-seven of these individuals developed either locoregional, metastatic, or combined relapses. Predictive factors for relapse, its pattern, and postrelapse survival were analyzed. RESULTS: Age, histology, tumor size, tumor site, postsurgical stage, and omission of radiotherapy were identified as factors associated with an increased relapse risk in multivariate analyses. Relapse rates did not differ among the CWS trials. Median time to relapse was 1.43 years from first diagnosis (range, 0.13 to 13.5 years). There were 217 locoregional, 72 metastatic, and 48 combined recurrences. Only two patients developed metastases more than 4 years after diagnosis, and both had combined recurrences. Five-year postrelapse survival was 24%. Patient subsets with consistent relapse pattern, risk, and postrelapse survival rates were identified on the basis of histologic subtype and tumor size. CONCLUSION: Initial patient and tumor characteristics predict pattern and risk of relapse and also correlate with postrelapse survival probabilities. In localized RMS, tumor-directed follow-up should focus on the primary site. Screening for metastatic relapse may not be necessary more than 4 years after diagnosis. The identification of subgroups with distinctive pattern and risk of relapse may be used to develop risk-adapted, tumor-directed guidance for detection of recurrent disease in localized RMS.

The role of adjuvant chemotherapy in children and adolescents with surgically resected, high-risk adult-type soft tissue sarcomas.

PURPOSE: This analysis evaluates whether adjuvant chemotherapy can be recommended for high-risk, surgically-resected, adult-type non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) within the new European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) protocol. The Italian and German Cooperative Groups reviewed their data-bases, analyzing patients classified as group I-II, with high-grade tumor (G3) larger than 5 cm in size. METHODS: The analysis included 36 patients, and compared the clinical features and outcome of the group of 21 patients who received chemotherapy versus the group of 15 patients treated with local therapies only. RESULTS: For the series as a whole, 5-year event-free survival (EFS), metastasis-free survival (MFS), and overall survival (OS) were 26.2%, 34.0%, and 37.5%, respectively. In patients treated with chemotherapy, MFS and OS were 49.5% and 41.5% (median time to relapse: 13 months). In patients who did not receive chemotherapy, MFS and OS were 0% and 23.8% (median time to relapse: 3 months). CONCLUSION: The role of adjuvant chemotherapy in NRSTS is still uncertain, however, the current retrospective analysis showed that: (1) despite the globally good prognosis of grossly-resected cases, patients with G3 and large-size have a high-risk of metastatic spread, and (2) MFS appears to be better in patients who had chemotherapy. Based in part on these results, and in accordance with recent suggestions coming from the literature on adult sarcomas, the EpSSG NRSTS protocol will recommend adjuvant chemotherapy in high-risk surgically-resected patients.

Inhaled nitric oxide inhibits platelet-leukocyte interactions in patients with acute respiratory distress syndrome.

INTRODUCTION: In addition to its effects on platelet function, recent studies suggest that inhaled nitric oxide (NO) also influences the function of circulating leukocytes. Therefore, the aim of this work was to investigate the formation of platelet-leukocyte aggregates (PLAs) and platelet and leukocyte cell surface receptor expression during NO therapy in patients with acute respiratory distress syndrome. METHODS: In 16 patients responding to NO therapy with an improvement in oxygenation (NO group) and in four nonresponders (control), platelet P-selectin expression, platelet fibrinogen binding, the expression CD11a on leukocytes, and the formation of PLAs were investigated at 0, 60, 120, and 180 mins of therapy or at corresponding time points by means of flow cytometry. In addition, PLA was investigated in 30 healthy volunteers during NO inhalation, in five mechanically ventilated patients without acute respiratory distress syndrome and without NO inhalation, and during NO incubation in platelet-rich plasma of ten healthy volunteers in vitro. RESULTS: NO therapy inhibited PLA formation at 60 (13% +/- 4% in the NO group vs. 19% +/- 7% in the control group, p <.01) and 120 mins (14% +/- 4% vs. 18% +/- 7%, p <.05) and slightly decreased CD11a expression at 60 mins (152 +/- 22 arbitrary units vs. 187 +/- 36 arbitrary units, p <.05). Furthermore, besides inhibiting platelet fibrinogen binding, NO also led to a significant inhibition of P-selectin expression at 120 (38% +/- 4% vs. 43% +/- 5%, p <.05) and 180 mins (34% +/- 5% vs. 43% +/- 6%, p <.01), demonstrating a significant correlation between changes in P-selectin expression and PLA formation. In contrast, PLA formation was not influenced by mechanical ventilation in patients without acute respiratory distress syndrome. These results were further supported by additional studies showing inhibition of PLA formation in healthy volunteers as well. CONCLUSIONS: NO-dependent inhibition of PLA formation in patients with acute respiratory distress syndrome can be explained by the inhibition in platelet P-selectin expression. Thus, this study provides rational evidence of systemic antileukocytic and antiplatelet properties of NO therapy in the clinical setting.