Immunotherapy holds great promise for the treatment of pediatric cancers. In neuroblastoma, the recent implementation of anti-GD2 antibody Dinutuximab into the standard of care has improved patient ...outcomes substantially. However, 5-year survival rates are still below 50% in patients with high-risk neuroblastoma, which has sparked investigations into novel immunotherapeutic approaches. T cell-engaging therapies such as immune checkpoint blockade, antibody-mediated therapy and adoptive T cell therapy have proven remarkably successful in a range of adult cancers but still meet challenges in pediatric oncology. In neuroblastoma, their limited success may be due to several factors. Neuroblastoma displays low immunogenicity due to its low mutational load and lack of MHC-I expression. Tumour infiltration by T and NK cells is especially low in high-risk neuroblastoma and is prognostic for survival. Only a small fraction of tumour-infiltrating lymphocytes shows tumour reactivity. Moreover, neuroblastoma tumours employ a variety of immune evasion strategies, including expression of immune checkpoint molecules, induction of immunosuppressive myeloid and stromal cells, as well as secretion of immunoregulatory mediators, which reduce infiltration and reactivity of immune cells. Overcoming these challenges will be key to the successful implementation of novel immunotherapeutic interventions. Combining different immunotherapies, as well as personalised strategies, may be promising approaches. We will discuss the composition, function and prognostic value of tumour-infiltrating lymphocytes (TIL) in neuroblastoma, reflect on challenges for immunotherapy, including a lack of TIL reactivity and tumour immune evasion strategies, and highlight opportunities for immunotherapy and future perspectives with regard to state-of-the-art developments in the tumour immunology space.
•TIL in neuroblastoma include T cells, (i)NKT cells, NK cells and few B cells.•TIL infiltration & cytotoxicity associate with survival, risk stage and MYCN status.•Only a small fraction of TIL show anti-tumour reactivity against neuroblastoma.•Neuroblastoma employs many immune evasion strategies hampering immune reactivity.•Combination therapy is an important consideration to overcome immune resistance.
Whole-genome sequencing detected structural rearrangements of TERT in 17 of 75 high-stage neuroblastomas, with five cases resulting from chromothripsis. Rearrangements were associated with increased ...TERT expression and targeted regions immediately up- and downstream of TERT, positioning a super-enhancer close to the breakpoints in seven cases. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non-overlapping groups of high-stage neuroblastoma, each associated with very poor prognosis.
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.
Neuroblastoma is the most common extracranial solid tumor in children. The chromatin remodeler ATRX is frequently mutated in high‐risk patients with a poor prognosis. Although many studies have ...reported ATRX aberrations and the associated clinical characteristics in neuroblastoma, a comprehensive overview is currently lacking. In this study, we extensively characterize the mutational spectrum of ATRX aberrations in neuroblastoma tumors reported in previous studies and present an overview of patient and tumor characteristics. We collected the data of a total of 127 neuroblastoma patients and three cell lines with ATRX aberrations originating from 20 papers. We subdivide the ATRX aberrations into nonsense, missense, and multiexon deletions (MEDs) and show that 68% of them are MEDs. Of these MEDs, 75% are predicted to be in‐frame. Furthermore, we identify a missense mutational hotspot region in the helicase domain. We also confirm that all three ATRX mutation types are more often identified in patients diagnosed at an older age, but still approximately 40% of the patients are aged 5 years or younger at diagnosis. Surprisingly, we found that 11q deletions are enriched in neuroblastomas with ATRX deletions compared to a reference cohort, but not in neuroblastomas with ATRX point mutations. Taken together, our data emphasizes a distinct ATRX mutation spectrum in neuroblastoma, which should be considered when studying molecular phenotypes and therapeutic strategies.
The ATRX chromatin remodeller is mutated in up to 8.6% of high‐risk neuroblastoma patients. We show that ATRX multiexon deletions (MEDs) are almost unique to neuroblastoma compared to other pediatric cancers and that 75% of these MEDs are predicted to be in‐frame. Additionally, we found a missense mutational hotspot region in the helicase domain and show that 11q deletions, which are associated with poor survival, are strongly enriched in tumors containing ATRX MEDs, but not in tumors containing ATRX point mutations.
Neuroblastoma is an embryonic tumour of childhood that originates in the neural crest. It is the second most common extracranial malignant solid tumour of childhood.Neuroblastoma cells have the ...unique capacity to accumulate Iodine-123-metaiodobenzylguanidine (¹²³I-MIBG), which can be used for imaging the tumour. Moreover, ¹²³I-MIBG scintigraphy is not only important for the diagnosis of neuroblastoma, but also for staging and localization of skeletal lesions. If these are present, MIBG follow-up scans are used to assess the patient's response to therapy. However, the sensitivity and specificity of ¹²³I-MIBG scintigraphy to detect neuroblastoma varies according to the literature.Prognosis, treatment and response to therapy of patients with neuroblastoma are currently based on extension scoring of ¹²³I-MIBG scans. Due to its clinical use and importance, it is necessary to determine the exact diagnostic accuracy of ¹²³I-MIBG scintigraphy. In case the tumour is not MIBG avid, fluorine-18-fluorodeoxy-glucose ((18)F-FDG) positron emission tomography (PET) is often used and the diagnostic accuracy of this test should also be assessed.
1.1 To determine the diagnostic accuracy of ¹²³I-MIBG (single photon emission computed tomography (SPECT), with or without computed tomography (CT)) scintigraphy for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.1.2 To determine the diagnostic accuracy of negative ¹²³I-MIBG scintigraphy in combination with (18)F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old, i.e. an add-on test.
2.1 To determine the diagnostic accuracy of (18)F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old.2.2 To compare the diagnostic accuracy of ¹²³I-MIBG (SPECT-CT) and (18)F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. This was performed within and between included studies. ¹²³I-MIBG (SPECT-CT) scintigraphy was the comparator test in this case.
We searched the databases of MEDLINE/PubMed (1945 to 11 September 2012) and EMBASE/Ovid (1980 to 11 September 2012) for potentially relevant articles. Also we checked the reference lists of relevant articles and review articles, scanned conference proceedings and searched for unpublished studies by contacting researchers involved in this area.
We included studies of a cross-sectional design or cases series of proven neuroblastoma, either retrospective or prospective, if they compared the results of ¹²³I-MIBG (SPECT-CT) scintigraphy or (18)F-FDG-PET(-CT) imaging, or both, with the reference standards or with each other. Studies had to be primary diagnostic and report on children aged between 0 to 18 years old with a neuroblastoma of any stage at first diagnosis or at recurrence.
One review author performed the initial screening of identified references. Two review authors independently performed the study selection, extracted data and assessed the methodological quality.We used data from two-by-two tables, describing at least the number of patients with a true positive test and the number of patients with a false negative test, to calculate the sensitivity, and if possible, the specificity for each included study.If possible, we generated forest plots showing estimates of sensitivity and specificity together with 95% confidence intervals.
Eleven studies met the inclusion criteria. Ten studies reported data on patient level: the scan was positive or negative. One study reported on all single lesions (lesion level). The sensitivity of ¹²³I-MIBG (SPECT-CT) scintigraphy (objective 1.1), determined in 608 of 621 eligible patients included in the 11 studies, varied from 67% to 100%. One study, that reported on a lesion level, provided data to calculate the specificity: 68% in 115 lesions in 22 patients. The sensitivity of ¹²³I-MIBG scintigraphy for detecting metastases separately from the primary tumour in patients with all neuroblastoma stages ranged from 79% to 100% in three studies and the specificity ranged from 33% to 89% for two of these studies.One study reported on the diagnostic accuracy of (18)F-FDG-PET(-CT) imaging (add-on test) in patients with negative ¹²³I-MIBG scintigraphy (objective 1.2). Two of the 24 eligible patients with proven neuroblastoma had a negative ¹²³I-MIBG scan and a positive (18)F-FDG-PET(-CT) scan.The sensitivity of (18)F-FDG-PET(-CT) imaging as a single diagnostic test (objective 2.1) and compared to ¹²³I-MIBG (SPECT-CT) (objective 2.2) was only reported in one study. The sensitivity of (18)F-FDG-PET(-CT) imaging was 100% versus 92% of ¹²³I-MIBG (SPECT-CT) scintigraphy. We could not calculate the specificity for both modalities.
The reported sensitivities of ¹²³-I MIBG scintigraphy for the detection of neuroblastoma and its metastases ranged from 67 to 100% in patients with histologically proven neuroblastoma.Only one study in this review reported on false positive findings. It is important to keep in mind that false positive findings can occur. For example, physiological uptake should be ruled out, by using SPECT-CT scans, although more research is needed before definitive conclusions can be made.As described both in the literature and in this review, in about 10% of the patients with histologically proven neuroblastoma the tumour does not accumulate ¹²³I-MIBG (false negative results). For these patients, it is advisable to perform an additional test for staging and assess response to therapy. Additional tests might for example be (18)F-FDG-PET(-CT), but to be certain of its clinical value, more evidence is needed.The diagnostic accuracy of (18)F-FDG-PET(-CT) imaging in case of a negative ¹²³I-MIBG scintigraphy could not be calculated, because only very limited data were available. Also the detection of the diagnostic accuracy of index test (18)F-FDG-PET(-CT) imaging for detecting a neuroblastoma tumour and its metastases, and to compare this to comparator test ¹²³I-MIBG (SPECT-CT) scintigraphy, could not be calculated because of the limited available data at time of this search.At the start of this project, we did not expect to find only very limited data on specificity. We now consider it would have been more appropriate to use the term "the sensitivity to assess the presence of neuroblastoma" instead of "diagnostic accuracy" for the objectives.
Purpose
Meta
-
18
Ffluorobenzylguanidine (
18
FmFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine ...transporter. This pilot study investigates the feasibility of
18
FmFBG PET-CT for imaging in neuroblastoma.
Methods
In a prospective, single-centre study, we recruited children with neuroblastoma, referred for
meta
-
123
Iiodobenzylguanidine (
123
ImIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of
123
ImIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of
18
FmFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score.
Results
Twenty paired
123
ImIBG and
18
FmFBG scans were performed in 14 patients (median age 4.9 years,
n
= 13 stage 4 disease and
n
= 1 stage 4S).
18
FmFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for
18
FmFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for
123
ImIBG scanning (84.5 min, SD 10.5),
p
< 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection
18
FmFBG PET-CT. Compared to
123
ImIBG scanning,
18
FmFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on
18
FmFBG PET-CT compared to
123
ImIBG scanning.
Conclusion
Results of this study demonstrate feasibility of
18
FmFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on
18
FmFBG PET-CT compared to
123
ImIBG scanning.
18
FmFBG PET-CT shows promise for future staging and response assessment in neuroblastoma.
Trial registration
Dutch Trial Register NL8152.
Cell-free DNA profiling using patient blood is emerging as a non-invasive complementary technique for cancer genomic characterization. Since these liquid biopsies will soon be integrated into ...clinical trial protocols for pediatric cancer treatment, clinicians should be informed about potential applications and advantages but also weaknesses and potential pitfalls. Small retrospective studies comparing genetic alterations detected in liquid biopsies with tumor biopsies for pediatric solid tumor types are encouraging. Molecular detection of tumor markers in cell-free DNA could be used for earlier therapy response monitoring and residual disease detection as well as enabling detection of pathognomonic and therapeutically relevant genomic alterations.
Conclusion
: Existing analyses of liquid biopsies from children with solid tumors increasingly suggest a potential relevance for molecular diagnostics, prognostic assessment, and therapeutic decision-making. Gaps remain in the types of tumors studied and value of detection methods applied. Here we review the current stand of liquid biopsy studies for pediatric solid tumors with a dedicated focus on cell-free DNA analysis. There is legitimate hope that integrating fully validated liquid biopsy–based innovations into the standard of care will advance patient monitoring and personalized treatment of children battling solid cancers.
What is Known:
•
Liquid biopsies are finding their way into routine oncological screening, diagnosis, and disease monitoring in adult cancer types fast.
•
The most widely adopted source for liquid biopsies is blood although other easily accessible body fluids, such as saliva, pleural effusions, urine, or cerebrospinal fluid (CSF) can also serve as sources for liquid biopsies
What is New:
•
Retrospective proof-of-concept studies in small cohorts illustrate that liquid biopsies in pediatric solid tumors yield tremendous potential to be used in diagnostics, for therapy response monitoring and in residual disease detection.
•
Liquid biopsy diagnostics could tackle some long-standing issues in the pediatric oncology field; they can enable accurate genetic diagnostics in previously unbiopsied tumor types like renal tumors or brain stem tumors leading to better treatment strategies
This population-based study is the first to provide a detailed analysis of trends in incidence and survival of children and adolescents diagnosed with renal malignancies in the Netherlands.
Data on ...all renal malignancies diagnosed in paediatric patients (0–18 years) between 1990 and 2014 N = 648, 92% Wilms tumour (WT) were extracted from the Netherlands Cancer Registry. Five-year overall survival (OS) was estimated using the actuarial method. Time trends in incidence were assessed by calculating average annual percentage change. A parametric survival model was used to compare the multivariable-adjusted risk of dying from WT between two diagnostic periods.
The incidence was 8 per million person-years and was constant over time (average annual percentage change -0.8%, p = 0.29). Patients with WT had a favourable outcome in both time periods; 5-year OS was 88% in 1990–2001 and 91% in 2002–2014. Multivariable analysis showed that the risk of dying from WT was not significantly decreased in the latest period (hazard ratio, 95% CI: 0.7, 0.4–1.3). Five-year OS decreased with increasing disease stage, ranging from 95 to 100% for stage I-II and about 80% for stage III–IV to 74% for bilateral disease. Five-year OS were 81% for renal cell carcinoma, 77% for clear cell sarcoma of the kidney and 20% for malignant rhabdoid tumour of the kidney.
Incidence of paediatric renal malignancies in the Netherlands has been stable since the 1990s. Five-year OS of WT reached 91% and was similar to findings for other developed countries. Contrary to the excellent outcome for WT, the outcome of malignant rhabdoid tumour of the kidney remained inferior.
•The incidence of paediatric renal tumours in the Netherlands was stable between 1990 and 2014.•5-year OS of Wilms tumour reached 91% and was similar to rates in other developed countries.•5-year OS were 81% for renal cell carcinoma, 77% for clear cell sarcoma of the kidney and 20% for malignant rhabdoid tumour of the kidney.•Particular attention should be paid to adverse prognostic subgroups, especially malignant rhabdoid tumour of the kidney.
Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk ...stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR.
Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol.
We identified the following 11 rhabdomyosarcoma markers:
, and
. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% 95% confidence interval (CI), 17.5%-53.5% for the 33/99 RNA-positive patients, versus 88.0% (95% CI, 78.9%-97.2%) for the 66/99 RNA-negative patients (
< 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%-73.4%) and 93.7% (95% CI, 86.6%-100.0%), respectively (
< 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23-28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model.
This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.
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