Background
Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer and cases with fusion PAX3–FOXO1 and PAX7–FOXO1 seem to have a poor prognosis. The aim is to evaluate whether PAX–FOXO1 ...alterations influence clinical outcome in childhood and adolescence population with ARMS.
Procedure
A population‐based study was conducted between 2011 and 2016 in patients less than 17 years with a diagnosis of ARMS. Overall survival (OS) depending on fusion status with clinical factors was analyzed.
Results
Out of 111 ARMS patients recorded in the French National Childhood Cancer Registry during the 2011–2016 period, 61% expressed PAX3–FOXO1, 15% expressed PAX7–FOXO1, 13% were FOXO1 fusion‐positive without PAX specification, and 7% were PAX–FOXO1 negative (n = 4 missing data). Compared to patients with PAX7–FOXO1 positive ARMS, those with PAX3–FOXO1 positive tumor were significantly older (10–17 years: 57.4% vs. 29.4%), and had more often a metastatic disease (54.4% vs. 23.5%). Poorer 5‐year OS for patients with PAX3–FOXO1 and PAX not specified FOXO1‐positive tumor were observed (44.0% 32.0–55.4 and 35.7% 13.1–59.4, respectively). After adjustment for stage at diagnosis, patients with positive tumor for PAX3–FOXO1 were 3.6‐fold more likely to die than those with positive tumor for PAX7–FOXO1.
Conclusion
At the population level, PAX3–FOXO1 was associated with a significant higher risk of death compared to PAX7–FOXO1‐positive and PAX–FOXO1‐negative tumors, and could explain poorer 5‐year OS observed in adolescence population diagnosed with ARMS. A continuous risk score derived from the combination of clinical parameters with PAX3–FOXO1 fusion status represents a robust approach to improving current risk‐adapted therapy for ARMS.
Background
After the completion of therapy, patients with localized rhabdomyosarcoma (RMS) are subjected to intensive radiological tumor surveillance. However, the clinical benefit of this ...surveillance is unclear. This study retrospectively analyzed the value of off‐therapy surveillance by comparing the survival of patients in whom relapse was detected by routine imaging (the imaging group) and patients in whom relapse was first suspected by symptoms (the symptom group).
Methods
This study included patients with relapsed RMS after the completion of therapy for localized RMS who were treated in large pediatric oncology hospitals in France, the United Kingdom, Italy, and the Netherlands and who were enrolled in the International Society of Paediatric Oncology Malignant Mesenchymal Tumor 95 (1995‐2004) study, the Italian Paediatric Soft Tissue Sarcoma Committee Rhabdomyosarcoma 96 (1996‐2004) study, or the European Paediatric Soft Tissue Sarcoma Study Group Rhabdomyosarcoma 2005 (2005‐2013) study. The survival times after relapse were compared with a log‐rank test between patients in the imaging group and patients in the symptom group.
Results
In total, 199 patients with relapsed RMS were included: 78 patients (39.2%) in the imaging group and 121 patients (60.8%) in the symptom group. The median follow‐up time after relapse was 7.4 years (interquartile range, 3.9‐11.5 years) for survivors (n = 86); the 3‐year postrelapse survival rate was 50% (95% confidence interval CI, 38%‐61%) for the imaging group and 46% (95% CI, 37%‐55%) for the symptom group (P = .7).
Conclusions
Although systematic routine imaging is the standard of care after RMS therapy, the majority of relapses were detected as a result of clinical symptoms. This study found no survival advantage for patients whose relapse was detected before the emergence of clinical symptoms. These results show that the value of off‐therapy surveillance is controversial, particularly because repeated imaging may also entail potential harm.
This study assesses the clinical value of radiological surveillance imaging in pediatric patients with rhabdomyosarcoma, which is routinely performed after the completion of therapy. In the majority of patients, relapse is detected because of symptoms, and there is no evidence that early detection by imaging results in improved survival.
Neuroblastoma (NB) is the most common extra‐cranial tumour in children. Little is known about the aetiology of NB. The early age at onset and the embryonic nature suggest a role for perinatal ...exposures. We conducted a pooled analysis of two French national population‐based case–control studies to explore whether there was an association between parental smoking and alcohol consumption and the risk of NB. The mothers of 357 NB cases and 1,783 controls from general population, frequency matched by age and sex, were interviewed on demographic, socioeconomic and perinatal characteristics, maternal reproductive story, and life‐style and childhood environment. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. A meta‐analysis of our findings with those of previous studies was also conducted. Maternal smoking during pregnancy was slightly more often reported for the cases (24.1%) than for the controls (19.7%) (OR 1.3 95% CI 0.9–1.7; summary OR from meta‐analysis 1.1 95% CI 1.0–1.3. Paternal smoking in the year before child's birth were not associated with NB as independent exposure (OR 1.1 95% CI 0.9–1.4 but the association was stronger when both parents reported having smoked during pregnancy (OR 1.5 95% CI 1.1–2.1. No association was observed with maternal alcohol intake during pregnancy (OR 1.0 95% CI 0.8–1.4, summary OR from meta‐analysis 1.0 95% CI 0.9–1.2. Our findings provide some evidence of an association between maternal smoking during pregnancy and NB and add another reason to recommend that women refrain from smoking during pregnancy.
What's new?
Neuroblastoma strikes early in life, which suggests an influence from risk factors that occur before birth. Here, the authors looked at parental smoking and alcohol drinking in a large population sample in France. Cases were collected by a nationwide registry, so the sample was very complete, and included 357 cases of neuroblastoma. The analysis revealed no association between maternal alcohol drinking and the cancer, nor between neuroblastoma and paternal smoking. They did identify a slight positive association with maternal smoking, and the effect was stronger if both parents smoked.
Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm that affects typically young children. Signs related to advanced upper‐abdominal tumor accompanied by elevated serum α‐fetoprotein ...levels in a young child suggest PBL, however histopathological confirmation is mandatory. The mainstay of the treatment is a complete surgical resection. Unresectable and/or metastatic PBL may become amenable to complete delayed surgery after neoadjuvant chemotherapy. This manuscript presents the international consensus recommendations for the diagnosis and treatment of children with PBL, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU‐funded PARTNER (Paediatric Rare Tumors Network – European Registry) project.
Purpose
Neuroblastoma management in children is multimodal and depends on multiple factors, including the possibility of complete surgical resection. Image‐defined risk factors (IDRFs) are used to ...assess the feasibility of primary surgery. We studied the changes in IDRFs after neoadjuvant chemotherapy for thoracic neurogenic tumors.
Methods
We performed a multicenter review of 27 patients presenting with unresectable thoracic neurogenic tumors. Patients received neoadjuvant chemotherapy, according to their risk group. IDRF at diagnosis and before surgery were retrospectively analyzed by a radiologist and a surgeon, blind to the initial assessment. Surgical and oncologic outcomes were reviewed.
Results
None of the patients presented MYCN amplification, and 78 IDRFs were identified at diagnosis. Vascular IDRFs were the most frequent, with 28 vascular IDRFs detected in 18 patients, 22 of which disappeared after chemotherapy. Reductions of tumor volume were associated with a regression of IDRFs. Patients undergoing minimally invasive surgery had smaller tumor volumes than those undergoing open surgery, and no vascular IDRF. Two patients received two additional courses of chemotherapy to reduce tumor volume sufficiently for surgery. One patient with ganglioneuroblastoma underwent early surgery due to a lack of response to initial chemotherapy.
Conclusion
Tumor volume reduction with neoadjuvant chemotherapy eliminates most IDRF in thoracic neurogenic tumors. Vascular IDRF are rapidly resolved at this site, making surgical resection and minimally invasive surgery possible.
In neuroblastoma (NB), genetic alterations in chromatin remodeling (CRGs) and epigenetic modifier genes (EMGs) have been described. We sought to determine their frequency and clinical impact. Whole ...exome (WES)/whole genome sequencing (WGS) data and targeted sequencing (TSCA®) of exonic regions of 33 CRGs/EMGs were analyzed in tumor samples from 283 NB patients, with constitutional material available for 55 patients. The frequency of CRG/EMG variations in NB cases was then compared to the Genome Aggregation Database (gnomAD). The sequencing revealed SNVs/small InDels or focal CNAs of CRGs/EMGs in 20% (56/283) of all cases, occurring at a somatic level in 4 (7.2%), at a germline level in 12 (22%) cases, whereas for the remaining cases, only tumor material could be analyzed. The most frequently altered genes were ATRX (5%), SMARCA4 (2.5%), MLL3 (2.5%) and ARID1B (2.5%). Double events (SNVs/small InDels/CNAs associated with LOH) were observed in SMARCA4 (n = 3), ATRX (n = 1) and PBRM1 (n = 1). Among the 60 variations, 24 (8.4%) targeted domains of functional importance for chromatin remodeling or highly conserved domains but of unknown function. Variations in SMARCA4 and ATRX occurred more frequently in the NB as compared to the gnomAD control cohort (OR = 4.49, 95%CI: 1.63–9.97, p = 0.038; OR 3.44, 95%CI: 1.46–6.91, p = 0.043, respectively). Cases with CRG/EMG variations showed a poorer overall survival compared to cases without variations. Genetic variations of CRGs/EMGs with likely functional impact were observed in 8.4% (24/283) of NB. Our case–control approach suggests a role of SMARCA4 as a player of NB oncogenesis.
What's new?
Mutations that affect chromatin remodeling can lead to cancer. In this paper, the authors investigated the impact of variations in chromatin remodeling genes and epigenetic modifier genes on neuroblastoma patients. They compared the frequency of these variations in NB cases with data from the Genome Aggregation Database (gnomAD). Neuroblastoma cases had a higher frequency of SMARCA4 and ATRX gene variations than the general population. Furthermore, NB patients with CRG/EMG mutations had poorer overall survival than NB cases without such mutations. These findings highlight the importance of chromatin remodeling in neuroblastoma as an avenue for new therapeutics.
Background
Esthesioneuroblastoma (ENB) is a rare neuroectodermal tumor that seldom occurs during childhood. Multimodal treatments are currently proposed, but the place of each therapy is still in ...debate. Our objective is to describe clinical evolution, especially the pattern of relapses and determine contributors to tumor progression.
Procedure
Medical charts of all children (≤18 years) affected by ENB treated in France from January 1990 to December 2015 were retrospectively analyzed.
Results
Eighteen patients were selected (10 males). Median age at diagnosis was 12.2 years (0.9‐18). Tumor extension was Kadish stage A (n = 1), B (n = 3), C (n = 10), and D (n = 4). Hyams histological grades were I (n = 1), II (n = 3), III (n = 6), and IV (n = 6) (in two cases not defined). Initial cervical nodal spread was assessed by magnetic resonance imaging (n = 15), computed tomography scan (n = 16), fluorodeoxyglucose‐positron emission tomography‐computed tomography (n = 7), and cytological/histological analysis (n = 2). N1 stage was confirmed by imaging in two of 18 cases and one of two cases had cervical node dissection with neck irradiation (58 Gy). After a median follow‐up of survivors of 7.6 years (3.8‐17.9), 10 patients developed neuromeningeal progression, whereas no cervical nodal relapse occurred and only eight survived. Both 5‐year overall and event‐free survival rates were 44.4% (±11.7%).
Conclusions
The poor prognosis is mainly related to neuromeningeal dissemination that should be considered during treatment strategy. However, cervical lymph node relapse is rare.
Neuroblastoma (NB), an embryonic tumour arising from neural crest cells, is the most common malignancy among infants. The aetiology of NB is largely unknown. We conducted a pooled analysis to explore ...whether there is an association between NB and preconception and perinatal factors using data from two French national population‐based case‐control studies. The mothers of 357 NB cases and 1783 controls younger than 6 years, frequency‐matched by age and gender, responded to a telephone interview that focused on demographic, socioeconomic and perinatal characteristics, childhood environment, life‐style and maternal reproductive history. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. After controlling for matching variables, study of origin and potential confounders, being born either small (OR 1.4 95% CI 1.0‐2.0) or large (OR 1.5 95% CI 1.1–2.2) for gestational age and, among children younger than 18 months, having congenital malformations (OR 3.6 95% CI 1.3–8.9), were significantly associated with NB. Inverse associations were observed with breastfeeding (OR 0.7 95% CI 0.5–1.0) and maternal use of any supplements containing folic acid, vitamins or minerals (OR 0.5 95% CI 0.3–0.9) during the preconception period. Our findings reinforce the hypothesis that fetal growth anomalies and congenital malformations may be associated with an increased risk of NB. Further investigations are needed in order to clarify the role of folic acid supplementation and breastfeeding, given their potential importance in NB prevention.
What's New?
Neuroblastoma is the most common extracranial solid tumor in children, yet little is known about its etiology. The vast majority of neuroblastomas are not inherited, suggesting that neuroblastoma risk is influenced by other factors, particularly certain preconception or perinatal factors. Here, in a population'based case'control study of 357 neuroblastoma patients, congenital malformations and small or large size for gestational age were associated with increased neuroblastoma risk. By contrast, breastfeeding and preconception supplementation with vitamins or minerals were inversely associated with risk. The findings confirm previous links between neuroblastoma, abnormal fetal growth, and congenital malformations while highlighting potential protective factors.
Adolescent and young adult (AYA) patients with cancer are poorly recruited to molecularly targeted trials and have not witnessed the advances in cancer treatment and survival seen in other age ...groups. We report here a pan-European proof-of-concept study to identify actionable alterations in some of the worst prognosis AYA cancers: bone and soft tissue sarcomas.
Patients aged 12–29 years with newly diagnosed or recurrent, intermediate or high-grade bone and soft tissue sarcomas were recruited from six European countries. Pathological diagnoses were centrally reviewed. Formalin-fixed tissues were analysed by whole exome sequencing, methylation profiling and RNA sequencing and were discussed in a multidisciplinary, international molecular tumour board.
Of 71 patients recruited, 48 (median 20 years, range 12–28) met eligibility criteria. Central pathological review confirmed, modified and re-classified the diagnosis in 41, 3, and 4 cases, respectively. Median turnaround time to discussion at molecular tumour board was 8.4 weeks. whole exome sequencing (n = 48), methylation profiling (n = 44, 85%) and RNA sequencing (n = 24, 50%) led to therapeutic recommendations for 81% patients, including 4 with germ line alterations. The most common were for agents targeted towards tyrosine kinases (n = 20 recommendations), DNA repair (n = 18) and the PI3K/mTOR/AKT pathway (n = 15). Recommendations were generally based on weak evidence such as activity in a different tumour type (n = 68, 61%), reflecting the dearth of relevant molecular clinical trial data in the same tumour type.
We demonstrate here that comprehensive molecular profiling of AYA patients' samples is feasible and deliverable in a European programme.
•AYA cancers have been neglected by molecular profiling initiatives.•Most AYA sarcomas of adequate sample quality have identifiable actionable mutations.•Clinical evidence to support personalised treatment for AYAs is weak or absent.•International molecular profiling is feasible and necessary to fill research gaps.•More effort is needed to enable AYA patients' access to molecularly focused trials.
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