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Approximately 1400 children in England are diagnosed with cancer each year and in these children an abdominal mass is a common finding, particularly in those under 5 years of age. Here we present an initial diagnostic framework and suggested management plan for children presenting with an abdominal mass, with short summaries of the most common malignant paediatric pathologies. Initial assessment should begin with a thorough history and examination, followed by blood and urine tests in addition to radiological imaging. Management should first be directed at acute concerns requiring immediate attention and then to supportive care, including analgesic, blood product and fluid requirements. Early communication with the local tertiary oncology unit is encouraged to obtain advice on any acute issues and also to plan for transfer and further investigation. Open and honest communication with the family is essential to develop a trusting relationship and prepare them for transfer to an oncology ward environment. [ABSTRACT FROM AUTHOR]

We report the clinical findings and results of treatment in the cohort of patients with inflammatory myofibroblastic tumor (IMT) managed according to the European pediatric Soft Tissue Sarcoma Study Group (EpSSG) protocol from 2005 to 2016. Patients (<25 years old) with IMT from 9 countries were prospectively registered via a web-based system. Their histology was reviewed by a national/international pathology panel. Immunohistochemistry for ALK assessment was mandatory. No adjuvant therapy was suggested for initially resected tumors. No specific systemic therapy was recommended for cases of unresectable disease. Among 80 cases of IMT registered, 20 were excluded because pathology review led to a revised diagnosis. Of the remaining 60 patients (median age 9.5 years), 59 had localized, and 1 had multifocal/metastatic disease. The lung was the primary site in 14 cases. IMT developed as a second tumor in 2 cases. Forty cases were ALK-positive, and 20 were ALK-negative. Five-year event-free survival (EFS) and overall survival (OS) were 82.9% and 98.1%, respectively. No clinical variables correlated statistically with the outcome: survival was the same for ALK-positive and ALK-negative cases. The overall response to systemic therapy was 64%: 8/10 cases responded to vinblastine-methotrexate chemotherapy, and 5/5 to ALK-inhibitors. This study demonstrated a good overall prognosis for IMT, even for initially unresectable disease and in ALK-negative cases. Chemotherapy is still a valid option for advanced disease. Larger studies involving both pediatric and adult patients are needed to clarify the role of ALK inhibitors. • Pediatric inflammatory myofibroblastic tumors have good prognosis, even in initially unresectable and ALK-negative cases. • High response to chemotherapy (especially the minimal-morbidity therapy vinblastine and low-dose methotrexate) were observed. • The efficacy of targeted inhibitors seems to point to their use as the standard of care, but larger studies are needed. [ABSTRACT FROM AUTHOR]

Background The role of postoperative radiotherapy (PORT) in Ewing sarcoma (ES) is unclear. We assessed the impact of PORT on local control in patients with localised ES and good histological response to chemotherapy (<10% cells). Patients and methods All randomised patients in the EE99-R1 trial (comparing two consolidation chemotherapy regimens) undergoing surgery after induction chemotherapy were included. Local relapse (LR) cumulative incidence was estimated using a competing risk approach. Impact of PORT was assessed in multivariable models, adjusted for country, age, tumour site and volume, quality of resection and histological response. We also evaluated the heterogeneity of PORT effect by patient and tumour characteristics. Results One hundred forty-two (24%) of the 599 patients included from 1999 to 2009 received PORT (median dose: 45 Grays). With median follow-up of 6.2 years, 67 patients had an LR (with concomitant metastases in 28), leading to an 8-year LR-incidence = 11.9% (standard error [se] = 1.4%). Overall survival (OS) = 21% (se = 5%) 3 years after LR (31% in isolated LR). Controlling for possible confounders, we observed a statistically significant reduction of LR in patients treated by surgery + PORT compared to surgery alone (subdistribution-hazard ratio = 0.43, 95% confidence interval, 0.21–0.88, p = 0.02). The benefit of PORT was particularly marked for tumours larger than 200 ml at diagnosis and 100% necrosis. We observed a non-significant trend for benefit associated with PORT for disease-free, event-free and OS. Conclusion Radiotherapy appears to improve local control. We now recommend PORT in case of incomplete removal of the tissues involved by the pre-chemotherapy tumour volume. Further studies are required to assess the balance between benefit and risks. [ABSTRACT FROM AUTHOR]

Background Extracranial malignant rhabdoid tumours (MRT) are rare lethal childhood cancers that often occur in infants and have a characteristic genetic mutation in the SMARCB1 gene. The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) conducted a multinational prospective study of registered cases of extracranial MRT to test an intensive multimodal approach of treatment for children with newly diagnosed extracranial MRT. Methods Between December 2005 and June 2014, we prospectively registered 100 patients from 12 countries with a diagnosis of MRT tumour at an extracranial site on the EpSSG Non-Rhabdomyosarcoma Soft Tissue Sarcoma 2005 Study (NRSTS 2005). They were all treated on a standard multimodal protocol of surgery, radiotherapy, and chemotherapy over 30 weeks as follows: vincristine, cyclophosphamide, and doxorubicin (VDCy) at weeks 1, 10, 13, 22, and 28; vincristine was also given alone on weeks 2, 3, 11, 12, 14, 15, 23, 24, 29, and 30. Cyclophosphamide, carboplatin, and etoposide (Cy*CE) was given at weeks 4, 7, 16, 19, and 25. Radiotherapy was recommended for all primary tumour sites and all sites of metastatic disease. Results Forty-three patients completed the protocol treatment. Median follow-up for alive patients of the complete cohort was 44.6 months (range 11.5–84.6). For the whole cohort, the 3-year event-free survival (EFS) was 32.3% (95% confidence interval [CI] 23.2–41.6%) with a 3-year overall survival (OS) of 38.4% (95% CI 28.8–47.9%). For localised disease, the 4-year EFS was 39.3% (95% CI 28.2–50.1%) with a 4-year OS of 40.1% (95% CI 28.4–51.5%). For metastatic disease, the 2-year EFS was 8.7% (95% CI 1.5–24.2%) with a 2-year OS of 13.0% (95% CI 3.3–29.7%). Multivariable analysis disclosed that all patients ≤1 year of age were associated with at higher risk of death (hazard ratio [HR]: 2.6; 95% CI 1.0–6.8; p-value = 0.0094). Risk of death was also related with gender in metastatic patients (HR for males: 2.9, 95% CI 1.0–8.0; p-value = 0.0077). Conclusions The EpSSG NRSTS 2005 protocol of intensive therapy can be delivered to extracranial MRT patients, with a possible improvement in outcome. The outcome, however, remains poor for patients who progress or with metastatic disease. [ABSTRACT FROM AUTHOR]

Background Infantile fibrosarcoma (IFS) is a very rare disease occurring in young infants characterised by a high local aggressiveness but overall with a favourable survival. To try to reduce the total burden of therapy, the European pediatric Soft tissue sarcoma Study Group has developed conservative therapeutic recommendations according to initial resectability. Material and methods Between 2005 and 2012, children with localised IFS were prospectively registered. Initial surgery was suggested only if possible without mutilation. Patients with initial complete (IRS-group I/R0) or microscopic incomplete (group II/R1) resection had no further therapy. Patients with initial inoperable tumour (group III/R2) received first-line vincristine-actinomycin-D chemotherapy (VA). Delayed conservative surgery was planned after tumour reduction. Aggressive local therapy (mutilating surgery or external radiotherapy) was discouraged. Results A total of 50 infants (median age 1.4 months), were included in the study. ETV6-NTRK3 transcript was present in 87.2% of patients where investigation was performed. According to initial surgery, 11 patients were classified as group I, 8 as group II and 31 as group III. VA chemotherapy was first delivered to 25 children with IRS-III/R2 and one with IRS-II/R1 disease. Response rate to VA was 68.0%. Mutilating surgery was only performed in three cases. After a median follow-up of 4.7 years (range 1.9–9.0), 3-year event-free survival and overall survival were respectively 84.0% (95% confidence interval [CI] 70.5–91.7) and 94.0% (95% CI 82.5–98.0). Conclusions Conservative therapy is possible in IFS as only three children required mutilating surgery, and alkylating or anthracycline based chemotherapy was avoided in 71.0% of patients needing chemotherapy. VA regimen should be first line therapy in order to reduce long term effects. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pleuropulmonary blastoma (PPB) is an aggressive embryonal malignancy presenting in early childhood, presumably arising from pleuropulmonary mesenchyme. The European Cooperative Study Group for Paediatric Rare Tumours (EXPeRT) analysed its data on this tumour. Methods: This analysis concerns patients aged 0–17years with histologically-confirmed PPB registered up to 2008 in national databases in Italy, France and the United Kingdom and Poland. Lesions were classified as type I, II or III according to Dehner’s classification. Findings: Sixty-five patients were considered (13 type I, 24 type II and 28 type III). Most tumours were large (91% >5cm) and invaded the parietal pleura (29), mediastinum (10), major vessels (four) or pericardium (three). Regional nodes were involved in two cases, and three had metastases. The median follow-up was 5years (0.6–22). For type I patients, 5-year progression free survival (PFS) was 83.3% and overall survival 91.7%; six patients received no further treatment after surgery, but two relapsed. All type II/III PPB had chemotherapy (CT) and their 5-year PFS was 42.9% (27.7–57.2). On univariate analysis, favourable prognostic factors were: complete tumour resection at diagnosis (p =0.008); and absence of invasiveness (p =0.02); for type II/III tumours, type of CT was also a significant factor (patients given doxorubicin fared better, with a 5-year PFS of 70% versus 31.3% [p =0.01]). Interpretations: Type I PPB patients’ outcome was satisfactory. Complete resection at diagnosis seems important but rarely feasible for type II/III tumours, who benefited from doxorubicin-containing CT regimens. These results will inform the EXPeRT group’s PPB treatment guidelines. [Copyright &y& Elsevier]

Acromegaly is an endocrine disorder characterized by sustained hypersecretion of growth hormone (GH) with concomitant elevation of insulin-like growth factor I (IGF-I) associated with premature mortality from cardiopulmonary diseases and certain malignancies. In particular, there is a two-fold increased risk of developing colorectal cancer. Possible mechanisms underlying this association include elevated levels of circulating GH and IGF-I, but several other plausible processes may be relevant. In a parallel literature, there has been debate whether GH replacement therapy is associated with increased cancer risk in three scenarios: (1) tumour recurrence in children with previously treated cancer; (2) second neoplasms (SNs) in survivors of childhood cancer treated with GH; and (3) de-novo cancer in non-cancer patients treated with GH. The general evidence suggests no increased risk in scenario 1. Through a maze of complex study designs, there is inconclusive evidence of a very modest increase in cancer risk in treated GH-deficiency patients in scenarios 2 and 3, but it is likely that the cumulative risk equates to that of the general population. This emphasizes the need for patient selection balanced against the known morbidity of untreated GH deficiency. [Copyright &y& Elsevier]

Ewing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials. We included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12–17 years, 18–24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models. The analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group. The excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups. • We compared toxicity after BuMel high-dose regimen vs VAI conventional chemotherapy • Severe acute toxicity (haemato, GI, liver, infection) is more frequent after BuMel. • Haemato-toxicity and lower general condition are more frequent in younger patients. • Excess risk of severe toxicity of BuMel / VAI appears homogeneous across age groups • This suggests the feasibility of BuMel whatever the age of patients up to 50 years. [ABSTRACT FROM AUTHOR]

Summary: Extracranial rhabdoid tumours are rare, and often occur in infants. Although the kidney is the most common site, they can occur anywhere in the body. Most contain a biallelic inactivating mutation in SMARCB1, which is part of the chromatin remodelling complex SWI/SNF, and functions as a classic tumour suppressor gene. Despite multimodal therapy, outcome in rhabdoid tumours remains poor with only 31% of patients surviving to 1 year. The young age of patients limits use of radiotherapy, which, along with age, is an important prognostic factor. Because the tumours are rare, no standard therapeutic pathway exists, and no randomised trials have examined the role of new therapeutic approaches. Improved understanding of the biology and role of SMARCB1 has enabled identification of new targets for small molecule inhibitors to combine with chemotherapy backbones that we might establish from the current EpSSG and COG studies. [Copyright &y& Elsevier]

Abstract: Hemostatic matrices are a part of the surgeon''s armamentarium against profuse intraoperative bleeding. Granular deposits may form after the use of a liquid hemostat which can be mistaken for tumor recurrence or metastatic disease in the setting of neoplasia. We present two cases that highlight the importance of full knowledge of product usage during previous operations and the need for histological examination of these lesions. [Copyright &y& Elsevier]

Extracranial malignant rhabdoid tumours are tumours that mainly affect young children and have a poor prognosis. In 2014, the European Paediatric Soft-tissue sarcoma Study Group developed treatment recommendations consisting in intensive dose chemotherapy every 2 weeks using vincristine-doxorubicin-cyclophosphamide (VDCy) and ifosfamide-etoposide (IE) associated with early surgery and irradiation of tumour sites. A retrospective study was conducted on children treated in France by these new recommendations up to January 2019. Thirty-five patients were identified. The primary tumour was in miscellaneous soft parts for 18 patients, in the kidney for 11 and in the liver for six. The median age at diagnosis was 17.5 months (range 1.2–198.2). Distant locations (metastatic or synchronous tumours) were present in 37.1% at diagnosis. SMARCB1 germline pathogenic variant was detected in 17.1% of patients. Overall tolerance was good, with 87–97% of theoretical chemotherapy cumulative doses actually delivered. The median interval between two courses was 18 days. Surgical resection was performed in 83% (19 R0, 7 R1 and 3 R2) and local radiotherapy in 49% of patients. After a median follow-up of 50.4 months (range 16.5–134.1), the 2-year overall and event-free survivals were 47.6% (95% confidence interval [CI] 30.2–63.1) and 42.9% (95% [CI] 26.5–58.3), respectively. On univariate analyses, localised disease and gross total resection were significantly associated with favourable outcomes. Intensive dose chemotherapy with VDCy/IE can be administrated with no remarkable short-term toxicity, including in infants. However, the outcome remains poor for patients without gross total resection and with metastatic or multifocal disease. These patients could be stratified into a high-risk group that requires a new immediate therapeutic approach such as targeted agents combined with multimodal therapy. • Dose-intensity chemotherapy can be safely administered to paediatric patients. • Metastatic status and gross total resection are significant prognostic factors. • Dose-intense strategy appears at least equivalent to recent studies in treatment of extracranial maligant rhabdoid tumour. • Next trials may aim at combining targeted therapies with this backbone. [ABSTRACT FROM AUTHOR]

We analysed the cohort of paediatric patients with metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated in the BERNIE protocol, i.e. open-label, multicentre, randomised phase II study evaluating the role of bevacizumab (BO20924/ITCC-006; ClinicalTrials.gov: NCT00643565). Eligible patients were randomised 1:1 to add or not add bevacizumab to nine courses of intensive multi-drug chemotherapy, followed by 12-month maintenance chemotherapy (plus surgery and radiotherapy). The primary end-point was event-free survival (EFS); secondary objectives were objective response rate (ORR) and overall survival (OS). From 2008 and 2013, 49 NRSTS patients (out of 154 cases) were treated, 26 in the standard arm and 23 in the bevacizumab arm. ORR was seen in 10 out of 36 evaluable cases (27.7%), i.e. 4/18 standard arm cases and 6/18 bevacizumab arm cases. Two-year EFS was 27.3% (95% confidence interval [CI] 13.9–42.5) for all NRSTS patients, i.e. 34.9% (95% CI 14.6–56.2) for bevacizumab arm and 22.9% (95% CI 7.1–43.9) for standard arm (p -value = 0.19). Three-year OS (median follow-up 48.6 months) was 35.2%, with no differences in the two arms. Time to event and time to death were 16.3 and 17.2 months for bevacizumab arm and 2.1 and 7.6 months for standard arm, respectively. Patients not receiving any local treatment on primary disease had a worse outcome as compared to others. Treatment results were better for patients receiving surgical resection and worse for those who did not receive any specific treatment. The addition of the anti-angiogenic agent to the standard chemotherapy did not show statistically significant improvement in survival in metastatic NRSTS. • This is the first series of paediatric metastatic NRSTS treated in a randomised phase II trial including a biologic agent. • The addition of the anti-angiogenic agent to the standard chemotherapy did not show significant improvement in survival. • This series may be considered benchmark for this disease category for developing future investigational studies. [ABSTRACT FROM AUTHOR]

Data on the clinical features, optimal treatment and outcomes of paediatric patients with epithelioid sarcoma (ES) are limited and mostly retrospective. A subset analysis of ES patients < 30 years of age enrolled on two international prospective clinical trials conducted between 7/2005 and 11/2015 was performed. Risk-adapted therapy was based on tumour diameter, histologic grade, extent of surgery and presence/absence of metastases and included surgery ± radiotherapy for all patients with the addition of ifosfamide/doxorubicin chemotherapy for intermediate-/high-risk patients. Response to therapy, event-free and overall survival and pattern and predictors of treatment failure were evaluated. Sixty-three ES patients (median age 13.1 years, 52% male) were eligible. Clinical features included the following: 68% extremity, median tumour diameter 3.5 cm, 56% high histologic grade, 14% nodal metastases, 14% distant metastases. Thirty-four low-risk patients underwent surgery (n = 30) or surgery/radiotherapy (n = 4); 16 intermediate-risk and 13 high-risk patients received chemotherapy ± surgery ± radiotherapy. Partial response was observed in 11/22 (50%) patients receiving neoadjuvant therapy. Events were local recurrence (n = 10) and distant recurrence (n = 15); estimated 5-year survival was 86.4%, 63.5% and 0%, respectively, for low-, intermediate- and high-risk patients. Locoregional nodal involvement, invasive tumour, high grade and lesser extent of resection predicted event-free survival in patients without metastases. Most low-risk ES patients who have undergone an adequate resection fare well without adjuvant therapy. Large tumour size, high histologic grade, tumour invasiveness, inadequate tumour resection and metastatic disease predict poorer outcomes in higher risk ES patients, for whom more effective therapies are needed. COG ARST0332: ClinicalTrials.gov Identifier NCT00346164 , EpSSG NRSTS 2005: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31. • Large series of prospectively treated young patients with epithelioid sarcoma. • Most low-risk patients treated with surgery alone fared well. • Half of patients receiving neoadjuvant therapy had a partial tumour response. • Poorer outcome predicted by large tumour size/invasiveness, high FNCLCC grade, metastatic disease and inadequate resection. [ABSTRACT FROM AUTHOR]

Background Multimodal risk-adapted treatment is used in paediatric protocols for synovial sarcoma (SS). Retrospective analyses suggest that low-risk SS patients can be safely treated with surgery alone, but no prospective studies have confirmed the safety of this approach. This analysis pooled data from the two prospective clinical trials to assess outcomes in SS patients treated with a surgery-only approach and to identify predictors of treatment failure. Methods Patients with localised SS enrolled on the European paediatric Soft tissue sarcoma Study Group (EpSSG) NRSTS2005 and on the Children Oncology Group (COG) ARST0332 trials, treated with surgery alone were eligible for this analysis. Patients must have undergone initial complete resection with histologically free margins, with a grade 2 tumour of any size or a grade 3 tumour ≤5 cm. Results Sixty patients under 21 years of age were eligible for the analysis; 36 enrolled in the COG (from 2007 to 2012) and 24 in the EpSSG study (from 2005 to 2012). The 3-year event-free survival was 90% (median follow-up 5.2 years, range 1.9–9.1). All eight events were local tumour recurrence, whereas no metastatic recurrences were seen. All patients with recurrence were effectively salvaged, resulting in 100% overall survival. Conclusion This joint prospective analysis showed that patients with adequately resected ≤5 cm SS, regardless of grade, can be safely treated with a surgery-only approach. Avoiding the use of adjuvant chemotherapy and radiotherapy in this low-risk patient population may decrease both short- and long-term morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma.Methods: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030.Findings: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate.Interpretation: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting.Funding: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre. [ABSTRACT FROM AUTHOR]

Background Based on the randomised Euro-EWING99-R1 trial, vincristine, adriamycin, cyclophosphamide (VAC) may be able to replace vincristine, adriamycin, ifosfamide (VAI) in the treatment of standard-risk Ewing sarcoma. However some heterogeneity of treatment effect by gender was observed. The current exploratory study aimed at investigating the influence of gender on treatment efficacy and acute toxicity. Patients and methods Impact of gender on event-free survival (EFS), acute toxicity by course, switches between treatment arms and cumulative dose of alkylating agents was evaluated in multivariable models adjusted for age including terms to test for heterogeneity of treatment effect by gender. The analysis of the EFS was performed on the intention-to-treat population. Results EFS did not significantly differ between the 509 males and 347 females ( p = 0.33), but an interaction in terms of efficacy was suspected between treatment and gender ( p = 0.058): VAC was associated with poorer EFS than VAI in males, hazard ratio (HR) (VAC/VAI) = 1.37 [95% confidence interval (CI), 0.98–1.90], contrasting with HR = 0.81 [95%CI, 0.53–1.24] in females. Severe toxicity was more frequent in females, whatever the toxicity type. Thirty patients switched from VAI to VAC (9/251 males, 4%, and 21/174 females, 12%) mostly due to renal toxicity, and three from VAC to VAI (2/258 males, 0.8%, and 1/173 females, 0.6%). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% versus 9%, p = 0.005), with no major difference between VAC and VAI (10% versus 13%, p = 0.15). Conclusion Differences of acute toxicity rate and cumulative doses of alkylating agents could not explain the marginal interaction observed in the Euro-EWING99-R1 trial data. Effects of gender-dependent polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide versus cyclophosphamide should be explored. External data are required to further evaluate whether there is heterogeneity of alkylating agent effect by gender. Trial numbers NCT00987636 and EudraCT 2008-003658-13. [ABSTRACT FROM AUTHOR]

Abstract: Background: European protocols for paediatric synovial sarcoma (SS) require that all children routinely undergo chest computed tomography (CT) scanning and bone scanning as initial staging procedures. This study aims to determine the rate of initial metastases in paediatric SS based on specific clinical characteristics, thereby investigating whether these diagnostic procedures are really necessary in all patients. Methods: Data on 258 previously-untreated SS patients <21years old were pooled from the databases of different European paediatric groups (study period 1988–2005) for this analysis, and the associations between patients’ characteristics and any presence of metastasis were estimated. Results: Fifteen cases (5.8%) had distant metastases at diagnosis (86% pulmonary). The presence of metastases was unassociated with patients’ gender or age, tumour grade or site, but it was influenced by T-status, and especially primary tumour size: the risk of metastases was 32 times higher in cases of tumour >5cm than for tumours ⩽5cm. Conclusions: Our findings suggest that tumour diameter can be used as a variable for identifying patients at greater risk of metastases and warranting more accurate radiological investigations. Chest CT scanning may improve the accuracy of pulmonary staging over X-ray, but requires different ionising radiation exposures that might have carcinogenic potential: it can be omitted for patients with tumours ⩽5cm. Given the very low risk of bone metastases, bone scans may be recommended only in cases with evidence of lung metastases. [Copyright &y& Elsevier]

Abstract: Background: Pancreatoblastoma is a very rare malignant tumour typically occurring in the early years of life. Due to its rarity, standardised diagnostic and therapeutic guidelines are not available for pancreatoblastoma. Methods: The newborn cooperative group denominated EXPeRT – European cooperative study group for paediatric rare tumours – combined in a joint analysis of all cases registered between 2000 and 2009 by the national groups of Italy, France, United Kingdom, Poland and Germany. Results: Twenty patients <18years old (median age 4years) were analysed: nine had distant metastases at diagnosis. Seventeen patients had tumour resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), seven received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58.8% and 79.4%, respectively. Outcome did not correlate with tumour site and size, but was strongly influenced by the feasibility of tumour complete resection. Conclusions: This international study confirms the rarity of the disease, the critical role of surgical resection both as therapy and as a prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centres. Further international cooperation is needed to collect larger series and stimulate biological studies to improve our understanding of the biology and the natural history of PBL. [ABSTRACT FROM AUTHOR]

Abstract: Background: Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with initially unresected tumours represent a particular subset of patients with a poor outcome. Various international research groups pooled their data in a joint study in order to investigate prognostic variables and treatment modalities. Methods: The study population consisted of 304patients <21years old treated between 1980 and 2005 using a multimodality therapeutic strategy. Results: Synovial sarcoma and malignant peripheral nerve sheath tumour (MPNST) were the most frequent histotypes. Most patients received initial chemotherapy: major responses were recorded in 41% and minor in 16% of cases. Overall survival (OS) was 60.0% and 51.5% at 5 and 10years, respectively, and it was significantly associated with patient’s age, histological subtype, tumour site and size, quality of delayed surgical resection, radiotherapy administration and response to induction chemotherapy. MPNST associated to neurofibromatosis type 1 was the tumour type with the worst rate of response to chemotherapy and the worst outcome. Conclusions: In unresected NRSTS patients, radiotherapy and delayed surgery are of crucial importance. Patients who respond to chemotherapy have better chance of survival. However, given the relatively poor prognosis, research on intensive multimodal treatment approaches and novel strategies is warranted. [Copyright &y& Elsevier]

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder resulting from mutations in the NBS1 gene, which encodes for the DNA double strand break repair protein nibrin. NBS is clinically characterized by microcephaly, dysmorphic features, immunodeficiency, and increased susceptibility to malignancy, mainly of lymphoid origin. Here, we describe a 7-year-old girl with NBS who is homozygous for the NBS1 698del4 mutation. She had been diagnosed with perianal rhabdomyosarcoma (RMS) and experienced severe toxicity from chemotherapy. RMS arising perianally is extremely uncommon but has been previously described in two cases with NBS. The strong association of perianal RMS with NBS should, therefore, be considered when confronted with a perianal RMS, as this carries important clinical implications in terms of potential need for therapy modification and follow up investigations. In addition, it suggests a role for the NBS1 gene and the nibrin dependent pathway in the pathogenesis of RMS, especially those arising perianally. [Copyright &y& Elsevier]