Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) computed tomography (CT) for the detection of bone, lung, and lymph node metastases in rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma and can emerge throughout the whole body. For patients with newly diagnosed RMS, prognosis for survival depends on multiple factors such as histology, tumour site, and extent of the disease. Patients with metastatic disease at diagnosis have impaired prognosis compared to those with localised disease. Appropriate staging at diagnosis therefore plays an important role in choosing the right treatment regimen for an individual patient. Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is a functional molecular imaging technique that uses the increased glycolysis of cancer cells to visualise both structural information and metabolic activity. 18F-FDG-PET combined with computed tomography (CT) could help to accurately stage the extent of disease in patients with newly diagnosed RMS. In this review we aimed to evaluate whether 18F-FDG-PET could replace other imaging modalities for the staging of distant metastases in RMS. OBJECTIVES: To determine the diagnostic accuracy of 18F-FDG-PET/CT imaging for the detection of bone, lung, and lymph node metastases in RMS patients at first diagnosis. SEARCH METHODS: We searched MEDLINE in PubMed (from 1966 to 23 December 2020) and Embase in Ovid (from 1980 to 23 December 2020) for potentially relevant studies. We also checked the reference lists of relevant studies and review articles; scanned conference proceedings; and contacted the authors of included studies and other experts in the field of RMS for information about any ongoing or unpublished studies. We did not impose any language restrictions. SELECTION CRITERIA: We included cross-sectional studies involving patients with newly diagnosed proven RMS, either prospective or retrospective, if they reported the diagnostic accuracy of 18F-FDG-PET/CT in diagnosing lymph node involvement or bone metastases or lung metastases or a combination of these metastases. We included studies that compared the results of the 18F-FDG-PET/CT imaging with those of histology or with evaluation by a multidisciplinary tumour board as reference standard. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and methodological quality assessement according to Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). We analysed data for the three outcomes (nodal involvement and lung and bone metastases) separately. We used data from the 2 × 2 tables (consisting of true positives, false positives, true negatives, and false negatives) to calculate sensitivity and specificity in each study and corresponding 95% confidence intervals. We did not consider a formal meta-analysis to be relevant because of the small number of studies and substantial heterogeneity between studies. MAIN RESULTS: Two studies met our inclusion criteria. The diagnostic accuracy of 18F-FDG-PET/CT was reported in both studies, which included a total of 36 participants. We considered both studies to be at high risk of bias for the domain reference standard. We considered one study to be at high risk of bias for the domain index test and flow and timing. Sensitivity and specificity of 18F-FDG-PET/CT for the detection of bone metastases was 100% in both studies (95% confidence interval (CI) for sensitivity was 29% to 100% in study one and 40% to 100% in study two; 95% CI for specificity was 83% to 100% in study one and 66% to 100% in study two). The reported sensitivity of 18F-FDG-PET/CT for the detection of lung metastases was not calculated since only two participants in study two showed lung metastases, of which one was detected by 18F-FDG-PET/CT. Reported specificity was 96% in study one (95% CI 78% to 100%) and 100% (95% CI 72% to 100%) in study two. The reported sensitivity for the detection of nodal involvement was 100% (95% CI 63% to 100% in study one and 40% to 100% in study two); the reported specificity was 100% (95% CI 78% to 100%) in study one and 89% (95% CI 52% to 100%) in study two. AUTHORS' CONCLUSIONS: The diagnostic accuracy of 18F-FDG-PET/CT for the detection of bone, lung, and lymph node metastases was reported in only two studies including a total of only 36 participants with newly diagnosed RMS. Because of the small number of studies (and participants), there is currently insufficient evidence to reliably determine the diagnostic accuracy of 18F-FDG-PET/CT in the detection of distant metastases. Larger series evaluating the diagnostic accuracy of 18F-FDG-PET/CT for the detection of metastases in patients with RMS are necessary.

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with primary metastatic Ewing sarcoma.

BACKGROUND: Ewing sarcomas are solid tumours of the bone and soft tissue, that usually affect children, adolescents, and young adults. The incidence is about three cases per million a year, with a peak incidence at 12 years of age. Metastatic disease is detected in about 20 % to 30% of people, and is typically found in the lungs, bone, bone marrow, or a combination of these. Presence of metastatic disease at diagnosis (primary metastatic disease) is the most important adverse prognostic factor, and is associated with a five-year survival lower than 30%. High-dose chemotherapy (HDC) followed by autologous haematopoietic cell transplantation (AHCT) is used in various solid tumours with unfavourable prognoses in children, adolescents, and young adults. It has also been used as rescue after multifocal radiation of metastases. The hypothesis is that HDC regimens may overcome the resistance to standard multidrug chemotherapy and improve survival rates. OBJECTIVES: To assess the effects of high-dose chemotherapy with autologous haematopoietic cell transplantation compared with conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with primary metastatic Ewing sarcoma, and to determine the toxicity of the treatment. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings from major international cancer-related conferences, and ongoing trial registers until January 2020. We also searched reference lists of included articles and review articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC and AHCT with conventional chemotherapy for children, adolescents, and young adults (younger than 30 years at the date of diagnostic biopsy) with primary metastatic Ewing sarcoma. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified one RCT, which investigated the effects of HDC with AHCT versus conventional chemotherapy with whole lung irradiation (WLI) in people with Ewing sarcoma metastasised to the lungs only at diagnosis. Only a selection of the participants were eligible for our review (N = 267: HDC with AHCT group N = 134; control group N = 133). There may be no difference in event-free survival between the two treatment groups (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.59 to 1.17; low-certainty evidence). We downgraded one level each because of study limitations and imprecision. Overall survival and toxicity were not reported separately for the participants eligible for this review, while quality-adjusted survival and progression-free survival were not reported at all. We did not identify any studies that addressed children, adolescents, and young adults with Ewing sarcoma with metastases to other locations. AUTHORS' CONCLUSIONS: In people with Ewing sarcoma with primary metastases to locations other than the lungs, there is currently no evidence from RCTs or CCTs to determine the efficacy of HDC with AHCT compared to conventional chemotherapy. Based on low-certainty evidence from one study (267 participants), there may be no difference in event-free survival between children, adolescents, and young adults with primary pulmonary metastatic Ewing sarcoma who receive HDC with AHCT and those who receive conventional chemotherapy with WLI. Further high-quality research is needed. Results are anticipated for the EuroEwing 2008R3 study, in which the effects of HDC with treosulfan and melphalan followed by AHCT on survival, in people with Ewing sarcoma with metastatic disease to bone, other sites, or both were explored. Achieving high-quality studies in a selection of people with rare sarcoma requires long-term, multi-centre, international participant inclusion.

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with first recurrence of Ewing sarcoma.

BACKGROUND: Ewing sarcoma is a solid tumour, which is the second most common primary bone malignancy in children, often occurring in the long bones and pelvis. An incidence rate of 4.5 per million a year is reported, with a peak incidence of 11 per million at the age of 12 years. Despite more intensive chemotherapy, 30% to 40% of young people with Ewing sarcoma will have recurrence of the disease. Less than 30% of young people with a recurrence of Ewing sarcoma are alive at 24 months, and less than 10% are alive at 48 months. High-dose chemotherapy (HDC), followed by autologous haematopoietic cell transplantation (AHCT), is used in a variety of paediatric groups with diverse solid tumours. The hypothesis is that HDC regimens may overcome resistance to standard polychemotherapy, and this way may eradicate minimal residual disease, leading to improved survival after a first recurrence of disease. OBJECTIVES: To assess the efficacy of HDC with AHCT versus conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with first recurrence of Ewing sarcoma, and to determine the toxicity of the treatment. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings from the SIOP, ASPHO, CTOS, ASBMT, EBMT, and EMSOS, and two trial registries in January 2020. We also searched reference lists of relevant articles and review articles. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC plus AHCT with conventional chemotherapy for children, adolescents, and young adults (up to 30 years old at the date of diagnostic biopsy) with a first recurrence of Ewing sarcoma. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We did not identify any eligible studies. AUTHORS' CONCLUSIONS: Since we did not identify any eligible studies, we are unable to draw any conclusions about the efficacy and toxicity of HDC with AHCT versus conventional chemotherapy in children, adolescents, and young adults with a first recurrence of Ewing sarcoma. Further high-quality research is urgently needed.

Validation of a clinical screening instrument for tumour predisposition syndromes in patients with childhood cancer (TuPS): protocol for a prospective, observational, multicentre study.

INTRODUCTION: Recognising a tumour predisposition syndrome (TPS) in patients with childhood cancer is of significant clinical relevance, as it affects treatment, prognosis and facilitates genetic counselling. Previous studies revealed that only half of the known TPSs are recognised during standard paediatric cancer care. In current medical practice it is impossible to refer every patient with childhood cancer to a clinical geneticist, due to limited capacity for routine genetic consultation. Therefore, we have developed a screening instrument to identify patients with childhood cancer with a high probability of having a TPS. The aim of this study is to validate the clinical screening instrument for TPS in patients with childhood cancer. METHODS AND ANALYSIS: This study is a prospective nationwide cohort study including all newly diagnosed patients with childhood cancer in the Netherlands. The screening instrument consists of a checklist, two- and three-dimensional photographic series of the patient. 2 independent clinical geneticists will assess the content of the screening instrument. If a TPS is suspected based on the instrument data and thus further evaluation is indicated, the patient will be invited for full genetic consultation. A negative control group consists of 20% of the patients in whom a TPS is not suspected based on the instrument; they will be randomly invited for full genetic consultation. Primary outcome measurement will be sensitivity of the instrument. ETHICS AND DISSEMINATION: The Medical Ethical Committee of the Academic Medical Centre stated that the Medical Research Involving Human Subjects Act does not apply to this study and that official approval of this study by the Committee was not required. The results will be offered for publication in peer-reviewed journals and presented at International Conferences on Oncology and Clinical Genetics. The clinical data gathered in this study will be available for all participating centres. TRIAL REGISTRATION NUMBER: NTR5605.

High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Prognosis for patients with metastatic disease has not improved significantly in the past decades. High-dose chemotherapy (HDC) seems to be an attractive option to treat minimal residual disease in metastatic rhabdomyosarcoma patients. OBJECTIVES: The objective of the review was to assess the effectiveness of HDC with stem cell rescue (SRC) versus standard-dose chemotherapy in improving event-free survival (EFS) and overall survival (OS) of children and young adults with metastatic rhabdomyosarcoma. SEARCH STRATEGY: We searched the databases of MEDLINE (1966 to December 2009), EMBASE (1980 to December 2009) and CENTRAL (The Cochrane Library Issue 1, 2009). In addition, we handsearched the reference lists of selected papers and conference proceedings of the SIOP, ASPHO and ASCO meetings (all 2000 to 2009). SELECTION CRITERIA: Randomised controlled trials (RCT), prospective or historical controlled clinical trials (CCT), in which HDC with SCR was compared to conventional chemotherapy and prospective case series (non-controlled clinical trials) including at least 20 naive metastatic rhabdomyosarcoma patients DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, quality assessment and data extraction. MAIN RESULTS: No RCTs could be identified. We identified one prospective CCT, one retrospective CCT and one non-controlled clinical trial. Another CCT has been published as an abstract. All studies have severe methodological limitations, in particular selection bias could not be excluded. One CCT reported a significantly worse OS compared to oral maintenance therapy, however in a subgroup of high-risk patients no difference could be found. The retrospective CCT reported a similar survival for HDC compared to conventional chemotherapy. The non-controlled clinical trial and the CCT reported as a conference proceeding reported survival outcomes comparable to previous studies. Data on toxicity showed more grade 3-4 toxicity in the HDC group. However, there was no difference in the number of toxic deaths. AUTHORS' CONCLUSIONS: Overall, the results of this review do not justify the use of HDC with SCR as a standard therapy for children with metastatic rhabdomyosarcoma. However, all reported studies were possibly subject to significant bias, especially selection bias. This might have underestimated the measured effect of HDC. As a result, a clinically important excess of adverse risk patients in the HDC arms may explain the non-beneficial effect of HDC. Only a large prospective RCT will be able to answer the question of whether HDC with SCR adds to survival or not definitively.

High-resolution molecular cytogenetic analysis of Wilms tumors highlights diagnostic difficulties among small round cell kidney tumors.

Many solid tumors exhibit characteristic gene fusions, which are reflected by balanced translocations at the cytogenetic level. These changes might be useful diagnostic and prognostic tools. In Wilms tumor (WT, nephroblastoma) no fusions genes or recurrent balanced translocations have been described thus far. To screen for cryptic balanced translocations, we have analyzed 17 renal neoplasms, histopathologically classified as WT, by a combination of G-banding, multicolor FISH, and subtelomeric FISH. This approach revealed several submicroscopic chromosomal aberrations and three different seemingly balanced translocations, resulting in a heterozygous deletion of HACE1, an EWSR1/ERG fusion, and an EWSR1/FLI1 fusion, respectively. As EWSR1 rearrangements are known to be a characteristic of Ewing tumors (ET), our findings illustrate the diagnostic problems regarding small cell kidney tumors and strongly argue for the need of adjuvant diagnostic techniques in this group of neoplasms. In summary, our genomic screening approach proved efficient in finding structural chromosomal aberrations. The fact that no recurrent translocations were found in the WTs of this study argues against the presence of a frequent pathognomonic translocation in this disease entity.

Management of tumors of the chest wall in childhood: a review.

Chest wall tumors in childhood are major challenges with respect to diagnostic workup and treatment. Incidence rate is less than 1 per 1,000,000 and various benign and malignant diseases are noted. From the malignant diseases, Ewing tumors and rhabdomyosarcoma tumors are most often seen. Depending on diagnosis, staging, and age, therapy has to be tailored for each patient, which should be discussed in a multidisciplinary team setting. Radical resection is in most cases the major component of treatment. Use of chemotherapy depends on the diagnosis. In soft-tissue tumors, previously considered to be chemotherapy insensitive, favorable results are currently reported. The role of radiotherapy is debated owing to its pronounced late sequelae in children, but should be added when adequate margins cannot be achieved by surgery.