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 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.
We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).
...Eligible patients aged ≥6 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo + five cycles of IVA, ±bevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide + vinorelbine, ±bevacizumab). The primary objective was event-free survival (EFS) evaluated by an independent radiological review committee.
One hundred and fifty-four patients were randomised to receive chemotherapy alone (n = 80) or with bevacizumab (n = 74). At the data cut-off for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval CI: 10.8–35.9) with chemotherapy and 20.6 months (95% CI: 15.2–24.9) with bevacizumab plus chemotherapy (stratified hazard ratio HR = 0.93; 95% CI: 0.61–1.41; P = 0.72). The HR for EFS in patients with RMS (n = 103) was 1.24 (95% CI: 0.73–2.09) versus 0.64 (95% CI: 0.32–1.26) for those with NRSTS (n = 49). Objective response rate was 36.0% (95% CI: 25.2–47.9) with chemotherapy and 54.0% (95% CI: 40.9–66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6–35.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab.
The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement.
Trial registration: ClinicalTrials.gov, NCT00643565.
•BERNIE evaluated the role of bevacizumab in childhood/adolescent metastatic soft tissue sarcoma.•The addition of bevacizumab to the chemotherapy backbone appeared tolerable.•The primary end-point of event-free survival did not show statistically significant improvement.•These data do not support the use of bevacizumab in metastatic RMS.
Abstract Introduction Neuroblastoma (NBL) accounts for 10% of the paediatric malignancies and is responsible for 15% of the paediatric cancer-related deaths. Vanillylmandelic acid (VMA) and ...homovanillic acid (HVA) are most commonly analysed in urine of NBL patients. However, their diagnostic sensitivity is suboptimal (82%). Therefore, we performed in-depth analysis of the diagnostic sensitivity of a panel of urinary catecholamine metabolites. Patients and methods Retrospective study of a panel of 8 urinary catecholamine metabolites (VMA, HVA, 3-methoxytyramine 3MT, dopamine, epinephrine, metanephrine, norepinephrine and normetanephrine NMN) from 301 NBL patients at diagnosis. Special attention was given to subgroups, metaiodobenzylguanidine (MIBG) non-avid tumours and VMA/HVA negative patients. Results Elevated catecholamine metabolites, especially 3MT, correlated with nine out of 12 NBL characteristics such as stage, age, MYCN amplification, loss of heterozygosity for 1p and bone-marrow invasion. The combination of the classical markers VMA and HVA had a diagnostic sensitivity of 84%. NMN was the most sensitive single diagnostic metabolite with overall sensitivity of 89%. When all 8 metabolites were combined, a diagnostic sensitivity of 95% was achieved. Among the VMA and HVA negative patients, were also 29% with stage 4 disease, which usually had elevation of other catecholamine metabolites (93%). Diagnostic sensitivity for patients with MIBG non-avid tumour was improved from 33% (VMA and/or HVA) to 89% by measuring the panel. Conclusions Our study demonstrates that analysis of a urinary catecholamine metabolite panel, comprising 8 metabolites, ensures the highest sensitivity to diagnose NBL patients.
Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1–2/million. Inter/intra-tumour heterogeneity raise ...challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS.
•Review molecular methods and data for childhood and adolescent rhabdomyosarcoma.•The use of germline and somatic genetic abnormalities plus gene expression signatures.•A consensus view of priorities for analyses within and across rhabdomyosarcoma clinical trials.•Priorities include fusion genes, MYOD1 and TP53 mutations and liquid biopsies.•A coordinated approach may more rapidly lead to better management and treatments.
Computed tomography (CT), a strong diagnostic tool, delivers higher radiation doses than most imaging modalities. As CT use has increased rapidly, radiation protection is important, particularly ...among children. We evaluate leukemia and brain tumor risk following exposure to low-dose ionizing radiation from CT scans in childhood.
For a nationwide retrospective cohort of 168 394 children who received one or more CT scans in a Dutch hospital between 1979 and 2012 who were younger than age 18 years, we obtained cancer incidence, vital status, and confounder information by record linkage with external registries. Standardized incidence ratios were calculated using cancer incidence rates from the general Dutch population. Excess relative risks (ERRs) per 100 mGy organ dose were calculated with Poisson regression. All statistical tests were two-sided.
Standardized incidence ratios were elevated for all cancer sites. Mean cumulative bone marrow doses were 9.5 mGy at the end of follow-up, and leukemia risk (excluding myelodysplastic syndrome) was not associated with cumulative bone marrow dose (44 cases). Cumulative brain dose was on average 38.5 mGy and was statistically significantly associated with risk for malignant and nonmalignant brain tumors combined (ERR/100 mGy: 0.86, 95% confidence interval = 0.20 to 2.22, P = .002, 84 cases). Excluding tuberous sclerosis complex patients did not substantially change the risk.
We found evidence that CT-related radiation exposure increases brain tumor risk. No association was observed for leukemia. Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings.
Paediatric rhabdomyosarcoma (RMS) is a soft tissue malignancy of mesenchymal origin that is thought to arise as a consequence of derailed myogenic differentiation. Despite intensive treatment ...regimens, the prognosis for high-risk patients remains dismal. The cellular differentiation states underlying RMS and how these relate to patient outcomes remain largely elusive. Here, we use single-cell mRNA sequencing to generate a transcriptomic atlas of RMS. Analysis of the RMS tumour niche reveals evidence of an immunosuppressive microenvironment. We also identify a putative interaction between NECTIN3 and TIGIT, specific to the more aggressive fusion-positive (FP) RMS subtype, as a potential cause of tumour-induced T-cell dysfunction. In malignant RMS cells, we define transcriptional programs reflective of normal myogenic differentiation and show that these cellular differentiation states are predictive of patient outcomes in both FP RMS and the less aggressive fusion-negative subtype. Our study reveals the potential of therapies targeting the immune microenvironment of RMS and suggests that assessing tumour differentiation states may enable a more refined risk stratification.
Purpose
This study assessed cardiorespiratory fitness (CRF), physical activity (PA), and sedentary behavior (SB), as well as factors associated with these outcomes in children during or shortly after ...cancer treatment.
Methods
Cross-sectionally, CRF data, obtained by the cardiopulmonary exercise test, and PA and SB data, obtained by an accelerometer, were assessed in children with cancer (8–18 years old). Linear regression models were used to determine associations between CRF, PA, or SB and patient characteristics.
Results
Among 60 children with cancer, mean age 12.6 years, 35 boys, 28 % were during cancer treatment. CRF, reported as the
z
score of VO
2peak
, showed that 32 children had a VO
2peak
z
score which was −2 below the predicted value. CRF was significantly associated with PA and SB: each additional activity count per minute resulted in 0.05 ml/kg/min VO
2peak
increase and each additional minute sedentary reduced VO
2peak
by 0.06 ml/kg/min. Multiple linear regression models of PA and SB showed that decreased activity was significantly associated with higher age, being fatigued, being during childhood cancer treatment (
p
< 0.001), or having a higher percentage of fat mass. The multiple linear regression model showed that lower CRF was significantly associated with increased fatigue, being during cancer treatment, having a higher percentage of fat mass, and lower belief of own athletic competence (
p
< 0.001).
Conclusion
This study revealed that children during or shortly after cancer treatment have low CRF scores. The most inactive children had a higher fat mass, were fatigued, older, and during childhood cancer treatment. Unexpectedly, treatment-related factors showed no significant association with activity behavior.
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