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Paired-like homeobox 2B (PHOX2B) is a highly sensitive and specific biomarker for diagnosing neuroblastoma, as well as detecting minimal residual disease in neuroblastoma. The clinical significance...

Introduction. The long-term event-free survival of patients with high-risk neuroblastoma (NB) receiving intensive complex therapy according to current russian standard do not exceed 40 %. Also, there is no standard tactics in patients with primary resistant and relapsed disease, most of them die due to disease progression. While, anti-GD2 immunotherapy (IT) proved to be effective in patients with high-risk NB, in Russian Federation this method is not generally available. There are currently two pilot studies ongoing in Raisa Gorbacheva Memorial Institute aimed to evaluate the effectiveness of anti-GD2 antibodies in high-risk NB patients.Aim of the study – describing a single-center experience of anti-GD2 IT in primary high-risk NB patients and patients with primary resistant and relapsed disease.Materials and methods. A total of 20 patients received anti-GD2 antibodies, 16 of them were included into pilot trials. The median age at IT initiation was 5 (3–17) years. In 13 cases the therapy was initiated in patients with high-risk disease after auto-HSCT, in 3 cases – in patients with 1st systemic relapse of primary resistant disease after 2nd-line therapy and haplo-HSCT, in 1 case – in patient with 2nd chemosensitive relapse after haplo-HSCT. Also, 3 patients with progressive chemoresistant disease received anti-GD2 antibodies as monotherapy (n = 1) or in combination with chemotherapy (n = 2) as salvage regimen.Results. Patients receiving anti-GD2 antibodies after auto-HSCT retain response to therapy in 11 of 13 cases with a median follow-up period of 15 (6–27) months, in 2 cases there was disease progression during or immediately after IT cessation. Both patients with disease progression responded well to salvage therapy. Two of 3 haplo-HSCT recipients with prior good response to 2nd-line therapy are currently in remission 16 and 36 months past haplo-HSCT, one patient progressed 55 months after transplantation. A patient with 2nd late relapse after haplo-HSCT currently maintains remission on IT. Both patients with chemorefractory progressive disease did not respond to IT and died due to disease progression. IT was characterized by acceptable toxicity. In most cases it was complicated by Gr 1–2 fever, rash or neuropathic pain effectively controlled by supportive therapy. However, three patients had signs of neurotoxicity requiring therapy termination in one case.Conclusion. Dinutuximab beta IT is characterized by acceptable toxicity. With a median follow-up of 18 (6–59) months the majority (14 of 17) patients receiving anti-GD2 antibodies as maintenance therapy after auto- or allogeneic HSCT retain response. However, we did not observe any response in patients with progressive chemorefractory disease.

Background More than 50% children with high-risk neuroblastoma (HR-NBL) experience disease progression, which we hypothesise is due to non-response of primary tumour to treatment. Current imaging techniques are unable to characterise response in primary tumour (necrotic versus viable tissue) at diagnosis or follow-up. Objectives Compare clinico-histological characteristics between primary 123ImIBG-avid tumours that became entirely 123ImIBG-non-avid (responders) after induction chemotherapy (IC) versus primary 123ImIBG-avid tumour that remained 123ImIBG-avid (non-responders). Methods Retrospective review of clinico-radiological data of children diagnosed with 123ImIBG-avid HR-NBL at our centre (2005-2016). Patients received Rapid COJEC IC and two additional courses of TVD if metastatic response was inadequate. Primary tumour 123ImIBG response was assessed qualitatively as positive, negative or intermediate at diagnosis and after IC. Post-surgical histopathology slices were marked considering percentage of viable tissue. Results Sixteen of 61 patients showed complete primary tumour 123ImIBG response, 20 partial response, while 25 no response. There was no statistically significant difference between clinical demographics of complete responders and group of non- or partial responders. Mean percentage of viable tumour cells was higher in non-responders than in complete responders (44.6% vs 20.6%; p = 0.05). Five-year EFS was significantly higher in complete responders than non-responders (43 ± 15% vs 7 ± 6%; p Conclusions 123ImIBG response in primary HR-NBL correlates with amount of necrotic tissue, skeletal metastatic 123ImIBG response and outcome. An entirely 123ImIBG non-avid tumour can still harbour viable tumour cells. Therefore, our findings do not support utility of primary tumour 123ImIBG response in decision making regarding residual tumour surgery. Combining both, primary and metastatic 123ImIBG response will improve interpretability of clinical trial results.

Monoclonal antibodies (mAbs) are part of the standard of care for the treatment of many adult solid tumors. Until recently none have been approved for use in children with solid tumors. Neuroblastoma (NB) is the most common extracranial solid tumor in children. Those with high-risk disease, despite treatment with very intensive multimodal therapy, still have poor overall survival. Results of treatment with an immunotherapy regimen using a chimeric (human/mouse) mAb against a cell surface disialoganglioside (GD2) have changed the standard of care for these children and resulted in the first approval of a mAb for use in children with solid tumors. This article will review the use of the various anti-GD2 mAbs in children with NB, methods that have been or are being evaluated for enhancing their efficacy, as well as review other promising antigenic targets for the therapeutic use of mAbs in children with NB.

Neuroblastoma (NB) is the most common extracranial solid embryonic tumor in children. The age of patient, the prevalence of the tumor process and the molecular genetic profile formed the basis of risk-adapted therapy protocols. High-risk patients receive complex treatment, including various combinations of chemotherapy drugs, surgical removal of the tumor, radiation and radioisotope therapy. Since the end of the 90s of the last century, immunotherapy has been introduced into clinical practice as a post-consolidation phase with the aim of affecting the minimal residual tumour mass. GD2-targeted drugs are used as a therapeutic agent for immunotherapy. An important aspect is the study of the early and late toxicity of this therapeutic method. The main side effects include fever, neuropathic pain, allergic reactions, and capillary leak syndrome. The article presents the analysis of literature data on toxic effects arising from immunotherapy (dinutuximab beta), as well and a description of clinical case report of rare specific pathology – ophthalmic complications, which include mydriasis and accommodation disorder up to paresis. The pathogenesis of these disorders is described in the literature as a parasympathetic deficiency, realized through exposure to anti-GD2 drugs, and is leveled after the end of treatment. Given the reversible nature of the disorders, the occurrence of ophthalmic complications does not require the abolition of immunotherapy, however, careful ophthalmological monitoring of the dynamics of pathological manifestations and timely symptomatic correction of the revealed changes are necessary. This information is very important not only for pediatric oncologists/hematologists, but also for ophthalmologists and pediatricians.

The majority of patients with high-risk neuroblastoma (HR-NB) in low- and middle-income countries (LMIC) do not have access to autologous stem cell transplant (ASCT) and dinutuximab. Consolidation with nonmyeloablative chemotherapy is not well-defined, and the outcomes are variable. We report a single-center outcome of patients with HR-NB, treated with nonmyeloablative consolidation. A tabulated compilation of similar reports is included. A retrospective chart review of patients with HR-NB was performed from January 2009 till June 2016. Patients were treated on the backbone of HR-NBL1/SIOPEN protocol. Treatment included induction with rapid-COJEC, surgery, followed by consolidation. Consolidation involved 4 cycles of topotecan, vincristine, and doxorubicin (TVD) instead of ASCT. Infusion of vincristine and doxorubicin were modified for ease and to enable administration in the clinic. Subsequent treatment included radiotherapy to the primary tumor and differentiation therapy with isotretinoin. Over 7½ years, 28 patients with HR-NB were treated. Two (7%) patients had therapy-related mortality. A relapse or disease progression occurred in 11 (39%) patients at a median duration of 17 months (IQR: 5, 18). Treatment abandonment was observed in 4 (14%) patients. The median follow-up of disease-free patients was 49 months (IQR: 45, 79). Patients with relapse were not treated further. A 4-year EFS of 29.3% was observed when 4-cycles of TVD were administered instead of ASCT in patients with HR-NB. The study and the review will aid decision-making for care of patients in LMIC while considering the options of treatment for HR-NB if access to ACST and dinutuximab is lacking.

Survival in high-risk neuroblastoma (HR-NB) patients remains poor despite multimodal treatment. We aimed to identify HR-NB patients with worse outcomes by analyzing the genomic instability derived from segmental chromosomal aberrations. We calculated 3 genomic instability indexes for primary tumor SNP array profiles from 127 HR-NB patients: (1) Copy number aberration burden (%gainslength+%losseslength), (2) copy number load (CNL) (%gainslength-%losseslength) and (3) net genomic load (NGL) (%gainsamount-%lossesamount). Tumors were classified according to positive or negative CNL and NGL genomic subtypes. The impact of the genomic instability indexes on overall survival (OS) was assessed with Cox regression. We identified 38% of HR-NB patients with poor 5-year OS. A negative CNL genomic background was related to poor prognosis in patients =18 months showing tumors with homogeneous MYCN amplification (9.5% survival probability, P < 0.05) and patients with non-MYCN amplified NB (18.8% survival probability related to >2.4% CNL, P < 0.01). A positive CNL genomic background was associated with worse outcome in patients with heterogeneous MYCN amplification (22.5% survival probability, P < 0.05). We conclude that characterizing a tumor genomic background according to predominance of genome gained or lost contributes toward improved outcome prediction and brings greater insight into the tumor biology of HR-NB patients.

Introduction: Neuroblastoma is a tumor of the developing sympathetic nervous system. Low and intermediate-risk patients usually have good treatment outcomes, whereas high-risk cases have poorer sur...

INTRODUCTION: Neuroblastoma (NB) is the prime cancer of infancy, and accounts for 9% of pediatric cancer deaths. While children diagnosed with clinically stable NB experience a complete cure, those with high-risk disease (HR-NB) do not recover, despite intensive therapeutic strategies. Development of novel and effective targeted therapies is needed to counter disease progression, and to benefit long-term survival of children with HR-NB. AREAS COVERED: Recent studies (2017–2020) pertinent to NB evolution are selectively reviewed to recognize novel and effective therapeutic targets. The prospective and promising therapeutic targets/strategies for HR-NB are categorized into (a) targeting oncogene-like and/or reinforcing tumor suppressor (TS)-like lncRNAs; (b) targeting oncogene-like microRNAs (miRs) and/or mimicking TS-miRs; (c) targets for immunotherapy; (d) targeting epithelial-to-mesenchymal transition and cancer stem cells; (e) novel and beneficial combination approaches; and (f) repurposing drugs and other strategies in development. EXPERT OPINION: It is highly unlikely that agents targeting a single candidate or signaling will be beneficial for an HR-NB cure. We must develop efficient drug deliverables for functional targets, which could be integrated and advance clinical therapy. Fittingly, the looming evidence indicated an aggressive evolution of promising novel and integrative targets, development of efficient drugs, and improvised strategies for HR-NB treatment.

PURPOSE A primary objective of the Children’s Oncology Group (COG) ANBL0532 phase III study was to assess the effect of increasing local dose of radiation to a residual primary tumor on the cumulative incidence of local progression (CILP) in patients with high-risk neuroblastoma. PATIENTS AND METHODS Newly diagnosed patients with high-risk neuroblastoma were randomly assigned or assigned to receive single or tandem autologous stem-cell transplantation (SCT) after induction chemotherapy. Local control consisted of surgical resection during induction chemotherapy and radiotherapy after last SCT. Patients received 21.6 Gy to the preoperative primary tumor volume. For patients with incomplete surgical resection, an additional boost of 14.4 Gy was delivered to the gross residual tumor, for a total dose of 36 Gy. CILP (primary end point) and event-free (EFS) and overall survival (OS; secondary end points) were compared with the COG A3973 historical cohort, in which all patients received single SCT and 21.6 Gy without a boost. RESULTS For all patients in ANBL0532 receiving radiotherapy (n = 323), 5-year CILP, EFS, and OS rates were 11.2% ± 1.8%, 56.2% ± 3.4%, and 68.4% ± 3.2% compared with 7.1% ± 1.4% ( P = .0590), 47.0% ± 3.5% ( P = .0090), and 57.4% ± 3.5% ( P = .0088) for all patients in A3973 receiving radiotherapy (n = 328), respectively. Five-year CILP, EFS, and OS rates for patients in A3973 with incomplete resection and radiotherapy (n = 47) were 10.6% ± 4.6%, 48.9% ± 10.1%, and 56.9% ± 10.0%, respectively. In comparison, 5-year CILP, EFS, and OS rates for patients in ANBL0532 who were randomly assigned or assigned to single SCT and received boost radiotherapy (n = 74) were 16.3% ± 4.3% ( P = .4126), 50.9% ± 7.0% ( P = .5084), and 68.1% ± 6.7% ( P = .2835), respectively. CONCLUSION Boost radiotherapy to gross residual tumor present at the end of induction did not significantly improve 5-year CILP. These results highlight the need for new strategies to decrease the risk of locoregional failure.

Introduction Neuroblastoma is the most common extracranial solid tumor in pediatrics but is considerably uncommon in adults, with approximately 1 case per 10 million diagnosed per year and is associated with poor prognosis. There are no standard treatment protocols for adult-onset neuroblastomas and there are only a few published case reports on neuroblastoma in adults. Case report We report our treatment experience in a 41-year-old female diagnosed with high-risk, poorly differentiated neuroblastoma. Management and outcome Our patient received two cycles of dinutuximab adapted from the Children’s Oncology Group ANBL1221 protocol. The patient experienced pain, neuropathy, pruritus, and infusion reactions which were managed with supportive care. Due to the lack of tumor regression, dinutuximab was omitted from future treatments. Currently, the patient is asymptomatic from her disease and remains off of all therapy and pain medication. Discussion While dinutuximab has produced promising outcomes in pediatric patients, it is not without potentially severe adverse effects. Serious reactions of capillary leak syndrome, infusion reactions, pain, and neuropathy have been reported. Clinicians must be cognizant of the treatment-related toxicities associated with dinutuximab therapy, ranging from pain, neuropathy, pruritus, and infusion reactions as explored in this patient case.

131I-meta-iodo-benzyl-guanidine (131I-MIBG) therapy has been used in children with high-risk neuroblastoma, who, in Japan, are cared for by trained nurses. To determine the safety of occupational radiation exposure in nurses, we retrospectively examined radiation exposure during therapy. Sixty-two nurses who received radiation exposure during 131I-MIBG therapy were assessed for the daily percentage of total radiation exposure received using the formula, daily radiation exposure/total radiation dose × 100; self-care score of children was evaluated. Fifty-four 131I-MIBG treatments (592 ± 111 MBq/kg) were performed in neuroblastoma patients (M/F; 27 /27, mean age at 131I-MIBG treatment; 7 ± 2 years), who were isolated for 5 ± 1 days. Average total (0.36 ± 0.18 mSv; range 0.09–0.97 mSv) and daily (0.07 ± 0.05 mSv/day; range 0.02–0.32 mSv/day) radiation exposure to nurses per patient care. The daily percentage of total radiation exposure significantly decreased in 3 days after 131I-MIBG treatment (days 0, 1, and 2 was 38.2 ± 14.7%, 26.9 ± 12.6%, and 15.3 ± 7.1%, respectively), and the average self-care score was 12.2 ± 3.5 (10–27) for all patients. Higher self-care score was significantly related to younger patients’ age and higher daily radiation exposure in nurses. Individual exposure to radiation was well controlled. Nurses who care for pediatric patients needing daily assistance must be aware of the radiation exposure risks, which can be reduced by establishing a care system and monitoring radiation exposure.

The objective of this phase IIa, open-label, single-centre, single-arm, two-stage clinical trial was to evaluate the safety and activity of 177-lutetium DOTATATE (LuDO) molecular radiotherapy in neuroblastoma. Children with relapsed or refractory metastatic high-risk neuroblastoma were treated with up to four courses of LuDO. The administered activity was 75 to 100 MBq kg−1 per course, spaced at 8- to 12-week intervals. Outcomes were assessed by the International Neuroblastoma Response Criteria (primary outcome), progression-free survival (PFS), and overall survival (OS). The trial recruited 21 patients; eight received the planned four courses. There was dose-limiting haematologic toxicity in one case, but no other significant haematologic or renal toxicities. None of 14 evaluable patients had an objective response at 1 month after completion of treatment (Wilson 90% CI 0.0, 0.16; and 95% CI is 0.0, 0.22). The trial did not therefore proceed to the second stage. The median PFS was 2.96 months (95% CI 1.71, 7.66), and the median OS was 13.0 months (95% CI 2.99, 21.52). In the absence of any objective responses, the use of LuDO as a single agent at the dose schedule used in this study is not recommended for the treatment of neuroblastoma. There are several reasons why this treatment schedule may not have resulted in objective responses, and as other studies do show benefit, the treatment should not be regarded as being of no value. Further trials designed to overcome this schedule’s limitations are required. ISRCTN98918118; URL: https://www.isrctn.com/search?q=98918118

To investigate the impact of local therapies on high-risk neuroblastoma (HR-NB) outcomes in South Africa. Data from 295 patients with HR-NB from nine pediatric oncology units between 2000 and 2014 were analysed. All patients received chemotherapy. Five-year overall (OS) and event free survival (EFS) were determined for patients who had received local therapy, either surgery or radiotherapy or both. Surgery was performed in only 35.9% (n = 106/295) patients. Surgical excision was done for 34.8% (n = 85/244) of abdominal primaries, 50.0% (n = 11/22) of thoracic primaries; 22.2% (n = 2/9) neck primaries and 66.7% (n = 8/12) of the paraspinal primaries. Only 15.9% (n = 47/295) of all patients received radiotherapy. Children, who had surgery, had an improved five-year OS of 32.1% versus 5.9% without surgery (p

Monitoring of several sets of neuroblastoma-associated mRNAs (NB-mRNAs) by real-time quantitative PCR (qPCR) can be used to evaluate minimal residual disease in NB patients. Droplet digital PCR (ddPCR) is an adaption of qPCR that potentially provides simpler and more reproducible detection of low levels of mRNAs. However, whether minimal residual disease in NB patients can be monitored by ddPCR using a set of NB-mRNAs is not yet tested. In this study, 208 bone marrow (BM) and 67 peripheral blood samples were retrospectively collected from 20 high-risk NB patients with clinical disease evaluation at two Japanese centers between 2011 and 2018, and level of each NB-mRNA (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was determined by ddPCR. Level of 7NB-mRNAs (defined as the combined signature of each NB-mRNA) was higher in BM than peripheral blood, but correlated significantly with each other. In accordance with disease burden, it varied with disease status (remission, stable, or progression) and collection time point (diagnosis, treatment, post-treatment, or relapse). In 73 post-treatment BM samples, it was significantly higher in 17 relapsed/regrown samples than in 56 nonrelapsed/nonregrown samples. Furthermore, ddPCR had a better prognostic value than qPCR in detecting 7NB-mRNAs in the same 73 post-treatment BM samples. This study suggests that ddPCR detection of 7NB-mRNAs is significantly associated with tumor relapse/regrowth in high-risk NB patients.

Although isolated central nervous system (CNS) relapses are rare, they may become a serious clinical problem in intensively treated patients with high-risk neuroblastoma (NBL). The aim of the study is presentation, assessment of incidence and the clinical course of isolated CNS relapses. Retrospective analysis involved 848 NBL patients treated from 2001 to 2019 at 8 centers of the Polish Pediatric Solid Tumors Study Group (PPSTSG). Group characteristics at diagnosis, treatment and patterns of relapse were analyzed. Observation was completed in December 2020. We analyzed 286 high risk patients, including 16 infants. Isolated CNS relapse, defined as presence of a tumor in brain parenchyma or leptomeningeal involvement, was found in 13 patients (4.5%, 8.4% of all relapses), all of them were stage 4 at diagnosis. Isolated CNS relapses seem to be more common in young patients with stage 4 MYCN amplified NBL, and in this group they may occur early during the first line therapy. The only or the first one symptom may be bleeding into CNS, especially in younger children, even without clear relapse picture on imaging, or the relapse may be clinically asymptomatic and found on routine screening. Although incidence of isolated CNS relapses is not statistically significantly higher in patients after immunotherapy, their occurrence should be carefully monitored, especially in intensively treated infants, with potential disruption of brain-blood barrier.

Introduction In Europe and Northern America, the majority of children with high-risk neuroblastoma survive the disease. Elsewhere, treatment outcomes are poor. Methods A retrospective review of children treated for high-risk neuroblastoma in a single institution in Singapore from 2007 to 2019 was carried out. Treatment consisted of intensive chemotherapy, surgery aimed for gross total resection of residual disease after chemotherapy, consolidation with high-dose therapy followed by autologous stem cell rescue, radiotherapy to the primary and metastatic sites, followed by maintenance treatment with either cis-retinoic acid or anti-disialoganglioside (anti-GD2) monoclonoal antibody therapy. Survival data were examined on certain clinical and laboratory factors. Results There were 57 children with 32 males treated for high-risk neuroblastoma. Their mean age was 3.9 (0.7-14.9) years. The median follow-up time was 5.5 (1.8-13.0) years for the surviving patients. There were 31 survivors with 27 surviving in first remission, and 5-year overall survival and event-free survival rates were 52.5% and 47.4%, respectively. On log-rank testing, only the group of 17 patients who were exclusively treated at our centre had a survival advantage. Their 5-year overall survival rate, compared with others whose initial chemotherapy was done elsewhere, was 81.6% versus 41.1% (p = 0.011), and that of event-free survival was 69.7% versus 36.1% (p = 0.032). Published treatment results were found from four countries in Southeast Asia with 5-year overall survival rates from 13.5%-28.2%. Conclusion Intensified medical and surgical treatment for high-risk neuroblastoma proved to be effective with superior survival rates compared with previous data from Southeast Asia.

Purpose: Neuroblastoma is the most common extracranial solid tumor in children, and most patients are at high risk when they are initially diagnosed. The roles of surgery and induction chemotherapy in patients with high-risk neuroblastoma have been a subject of much controversy and debate. The objective of the current study was to assess the roles of surgery in high-risk neuroblastoma.Method: The review protocol was prospectively registered (PROSPEROID: CRD42021253961). The PubMed, Embase, Cochrane, and CNKI databases were searched from inception to January 2020 with no restrictions on language or publication date. Clinical studies comparing the outcomes of different surgical ranges for the treatment of high-risk neuroblastoma were analyzed. The Mantel–Haenszel method and a random effects model was utilized to calculate the hazard ratio (95% CI).Results: Fourteen studies that assessed 1,915 subjects met the full inclusion criteria. Compared with the gross tumor resection (GTR) group, complete tumor resection (CTR) did not significantly improve the 5-year EFS [p = 1.0; HR = 0.95 (95% CI, 0.87–1.05); I2 = 0%], and the 5-year OS [p = 0.76; HR = 1.08 (95% CI, 0.80–1.46); I2 = 0%] of patients. GTR or CTR resection had significantly better 5-year OS [p = 0.45; HR = 0.56 (95% CI, 0.43–0.72); I2 = 0%] and 5-year EFS [p = 0.15; HR = 0.80 (95% CI, 0.71–0.90); I2 = 31%] than subtotal tumor resection (STR) or biopsy only; however, both CTR or GTR showed a trend for more intra and post-operative complications compared with the STR or biopsy only [p = 0.37; OR = 1.54 (95% CI, 1.08–2.20); I2 = 0%]. The EFS of the patients who underwent GTR or CTR at the time of diagnosis and after induction chemotherapy were similar [p = 0.24; HR = 1.53 (95% CI, 0.84–2.77); I2 = 29%].Conclusion: For patients with high-risk neuroblastoma, complete tumor resection and gross tumor resection of the primary tumor were related to improved survival, with very limited effects on reducing intraoperative and postoperative complications. It is necessary to design strong chemotherapy regimens to improve the survival rate of advanced patients.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, PROSPEROID [CRD42021253961].

High-risk neuroblastoma accounts for 4% of newly diagnosed pediatric malignancies, but for 9-10% of pediatric cancer mortality. To reduce the number of (late) recurrences and subsequently improve survival, anti-GD2 monoclonal antibody based immunotherapy has been added to the maintenance phase of treatment. The first randomized study (ANBL0032) was ground breaking, showing a 20% improved event free survival. Subsequently immunotherapy was included in all international high-risk treatment regimens. Randomization will never be repeated. In this article we present additional data from our retrospective cohort to corroborate the ANBL0032 study. Our cohort contains 84 Dutch high-risk neuroblastoma patients. They were treated with GPOH or POG induction, followed by immunotherapy according to original ANBL0032 protocol (immunotherapy group) or single-agent isotretinoin (historical control group). In the complete cohort, 5 year OS was 64 +/- 7% and 49 +/- 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 +/- 7% and 41 +/- 8%, respectively (p = 0.16). In the subgroup of patients +/- 18 months, 5-yr OS was 63 +/- 8% and 39 +/- 9, respectively (p = 0.04) and EFS 54 +/- 8% and 29 +/- 8%, respectively (p = 0.05). Our five year data suggest a role for the immunotherapy in preventing late events, especially in patients >= 18 months old.Background: Anti-GD2 based immunotherapy has improved overall (OS) and event free survival (EFS) for high-risk neuroblastoma (HR-NBL) patients. Here, we evaluate the longterm efficacy of anti-GD2 immunotherapy in combination with isotretinoin, GM-CSF, and IL-2. Methods: Dutch HR-NBL patients treated with immunotherapy according to the COG-ANBL0032 protocol (n = 47) were included and compared to historical controls (n = 37) treated with singleagent isotretinoin maintenance therapy. Survival time was calculated from start of the maintenance therapy.Results: The study and control group were similar concerning baseline characteristics. In the complete cohort, 5 year OS was 64 +/- 7% and 49 +/- 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 +/- 7% and 41 +/- 8%, respectively (p = 0.16). In the subgroup of patients >= 18 months, 5-yr OS was 63 +/- 8% and 39 +/- 9, respectively (p = 0.04) and EFS 54 +/- 8% and 29 +/- 8%, respectively (p = 0.05). Landmark analysis for EFS with landmark point at 6 months after start of maintenance suggests a larger effect on the prevention of late than early events.Conclusions: This study is the first to confirm the results of the COG-ANBL0032 study in a cohort treated with a different induction regimen. Anti-GD2 immunotherapy prevents late events, most significantly in patients older than 18 months of age at diagnosis.

PURPOSE Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]). PATIENTS AND METHODS Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS. RESULTS A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 ( P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 ( P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 ( P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) ( P < .001); infection 35% versus 25% ( P = .011); stomatitis 25% versus 3% ( P < .001); nausea and vomiting 17% versus 7% ( P < .001); and diarrhea 7% versus 3% ( P = .011). CONCLUSION No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.

Childhood cancer survivors (CCSs) from high-grade malignancies, such as high-risk neuroblastoma, have been increased, and second malignant neoplasm, becomes a serious problem for CCSs. However, detailed reports about rare types of second cancer such as gastric cancer remain limited. We herein reported a female patient who developed diffuse type gastric carcinoma after 21 years from completion of treatment to high-risk neuroblastoma. We reviewed the previous cohort studies for second gastrointestinal cancer in CCSs and the case reports with second gastric carcinoma for CCSs. We presumed second gastric cancer was refractory for CCSs as well as for adult cancer survivors.

Background/Purpose MYCN-amplification in neuroblastoma is associated with an aggressive clinical phenotype. We evaluated the association of MYCN amplification with tumor response to neoadjuvant chemotherapy. Methods Primary tumor response, assessed by percentage volume change on CT scan and degree of tumor resection, assessed by the operating surgeon, were retrospectively compared in 84 high-risk neuroblastoma patients. There were thirty-four (40%) with MYCN-amplified tumors and fifty (60%) with non-amplified tumors treated at our institution from 1999 to 2016. Metastatic disease response was assessed on MIBG scan by change in Curie score. Results MYCN-amplification was associated with a greater mean percentage reduction in primary tumor volume after neoadjuvant chemotherapy (72.27% versus 46.83% [non-amplified tumors], p = 0.001). The percentage of patients with a Curie score > 2 at diagnosis who then had a score ≤ 2 after neoadjuvant chemotherapy was not significantly different (8 [61.5%] and 8 [34.8%], respectively, p = 0.37). Twenty-eight (85.7%) patients with MYCN-amplification had ≥ 90% surgical resection compared to 45 (91.84%) patients with non-amplified tumors (p = 0.303). Conclusions MYCN-amplification in high-risk neuroblastoma was associated with a better response of the primary tumor to neoadjuvant chemotherapy, but not metastatic sites, than in patients with non-amplified tumors. This did not significantly impact the ability to resect ≥ 90% of the primary tumor/locoregional disease. Type of Study Treatment Study Level of Evidence Level III

Although intensive multimodal treatment has improved outcomes for patients with high-risk neuroblastoma, the specific role of primary tumor resection remains controversial. Many studies have been designed to determine whether the extent of surgical resection impacts survival; however, these reports have demonstrated conflicting results. There is also ongoing debate regarding the timing of primary tumor resection, with subtle differences in the approach between the large pediatric oncology cooperative consortia. Most of the published literature to date has been approached from a surgical viewpoint. Although most evidence supports surgery as part of the local control approach for high-risk neuroblastoma, recommendations for timing and extent of surgical resection are not consistent. This review summarizes our current understanding from the perspectives of both the pediatric oncologist and pediatric surgeons and discusses how the objectives of neuroblastoma primary surgical resection are different from that of other malignancies. Furthermore, this commentary will address how retrospective surgical outcome data may be interpreted in the setting of modern era high-risk neuroblastoma treatment.

Despite on using the use of complex treatment, the survival of high risk neuroblastoma patients doesn’t exceed 50 % with relapse as the main cause of death. The bone marrow (BM) lesion and presence of minimal residual disease at various stages of therapy are key factors of poor outcome and high frequency of relapse. Real time PCR is the most promising method for detecting neuroblastoma cells in BM samples due to the high sensitivity and specificity, which achieved by combination of several molecular markers. In this study we developed a method for evaluation TH and PHOX2B expression for monitoring metastatic BM lesion in neuroblastoma patients. This method has high sensitivity (1·10–4) and specificity to tumor cells. Evaluation of TH and PHOX2B gene expression was performed for 67 children with neuroblastoma at the time of diagnosis. We demonstrated that patients with overexpression of these genes has significantly worse overall and relapse-free survival. So, the developed method can be used in clinical practice for evaluation BM lesion degree as well as for risk group stratification in neuroblastoma patients at the time of diagnosis.Real time PCR is the most promising method for detecting neuroblastoma cells in BM samples due to the high sensitivity and specificity, which achieved by combination of several molecular markers. In this study we developed a method for evaluation TH and PHOX2B expression for monitoring metastatic BM lesion in neuroblastoma patients. This method has high sensitivity (1·10–4) and specificity to tumor cells. Evaluation of TH and PHOX2B gene expression was performed for 67 children with neuroblastoma at the time of diagnosis. We demonstrated that patients with overexpression of these genes has significantly worse overall and relapse-free survival. So, the developed method can be used in clinical practice for evaluation BM lesion degree as well as for risk group stratification in neuroblastoma patients at the time of diagnosis.

Induction chemotherapy plays an important role in the management of patients with high-risk neuroblastoma. Predictors of response to induction therapy are largely lacking. We sought to describe clinical and biological features associated with induction response.Patients from four consecutive COG high-risk trials were included. Response was evaluated by the 1993 International Neuroblastoma Response Criteria. The primary end-point was end-induction partial response (PR) or better. Univariate analyses were performed to compare response as a function of clinical or biologic predictors. A multivariate logistic regression model using significant predictors from univariate analyses was constructed to model PR or better.The analytic cohort included 1242 patients. End-induction response ≥PR was significantly associated with higher event-free and overall survival. Baseline factors associated with ≥PR included age18 months (87.4% with ≥PR vs. 78.7% if older; p = 0.0103), International Neuroblastoma Staging System non-stage 4 (89.0% vs. 78.4% if stage 4; p = 0.0016), MYCN amplification (85.5% vs. 77.1% if non-amplified; p = 0.0006), 1p loss of heterozygosity (LOH; 85.6% vs. 76.0% if no LOH; p = 0.0085), no 11q LOH (84.8% vs. 70.9% if 11q LOH; p = 0.0004) and high mitosis-karyorrhexis index (MKI; 84.5% vs. 77.5% if low-intermediate MKI; p = 0.0098). On multivariable analysis (n = 407), the absence of 11q LOH was the only factor that remained significantly associated with ≥PR (odds ratio: 1.962 vs. 11q LOH; 95% confidence interval 1.104-3.487; p = 0.0216).Improved end-induction response in high-risk neuroblastoma is associated with longer survival. Patients with 11q LOH are less likely to respond to induction therapies and should be prioritised for novel approaches in future trials.

The predictive value of Image-Defined Risk Factors (IDRFs) developed by the International Neuroblastoma Risk Group Task Force as it relates to primary-site management is undefined and may aid patient selection for de-escalation of adjuvant radiation therapy to the primary site in high-risk neuroblastoma.Patients (N = 76) with high-risk neuroblastoma treated on prospective trials at our institution from 1997 to 2014 were eligible for inclusion. IDRFs were defined based on pretherapy imaging. Overall survival, progression-free survival, and locoregional failure-free survival (LRFFS) were described using the Kaplan-Meier estimator and tested across strata by using the log-rank test.Twenty of 76 patients (26%) experienced local (n = 6), regional (n = 6), or combined locoregional failure (n = 8) with or without distant failure. Ten (50%) of the locoregional failures had concurrent distant relapse. Of patients who completed all therapy, both those with no IDRFs and those with90% resection had a 3-year LRFFS of 100%, with or without radiation therapy. Patients with either ≥1 IDRF or Gross Total Resection (GTR) or the inability to complete all therapy had inferior 3-year LRFFS of 77.8% and 14.4% with or without radiation therapy, respectively (P .04). Patients treated with a dose ≥30.6 Gy as part of therapy for residual disease had an 83.3% locoregional control rate.Patients with90% tumor resection and no primary site IDRFs at diagnosis may be candidates for de-escalation of adjuvant primary-site radiation therapy, although validation of these findings in future studies is required.

PURPOSE: Image-defined risk factors (IDRFs) are associated with surgical risks in neuroblastoma. We sought to evaluate the impact of neoadjuvant therapy on IDRFs and associated ability to achieve gross total resection of locoregional disease in patients with high-risk neuroblastoma. METHODS: We retrospectively reviewed charts of patients treated on four consecutive high-risk neuroblastoma protocols over a 20-year period at a single institution. The number of IDRFs at diagnosis and just prior to surgery, and the percent decrease of tumor volume from just prior to surgery to the end of induction were determined. RESULTS: Eighty-eight patients were included. There were 438 IDRFs (average 5.0±3.1/patient) at diagnosis and 198 (average 2.3±1.9/patient) after neoadjuvant chemotherapy (p90% GTR at 9.33 (95%CI 3.14–31.5). CONCLUSION: Neoadjuvant chemotherapy reduced the number of IDRFs in the majority of patients with high-risk neuroblastoma. The number of IDRFs present after neoadjuvant therapy correlated with the extent of resection.

Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]).Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged1 year withA total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age withNo difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.

Simple Summary Low-dose metronomic chemotherapy has anti-angiogenic activity and inhibits tumor growth. Therefore, we investigated the benefits of low-dose metronomic maintenance therapy (MT) in high-risk neuroblastoma (NB) patients who are unable to undergo autologous stem cell transplantation (ASCT) or anti-GD2 antibody therapy. A total of 217 high-risk NB patients were enrolled. One hundred and eighty-five (85%) had a complete/very good partial remission/partial remission (CR/VGPR/PR) to treatment, of them, 167 patients with stage 4, that did or did not receive oral metronomic MT, 3 years of event-free survival (EFS) were 42.5% versus 29.4%, and overall survival (OS) was 71.1% versus 59.4%, respectively. Totally, 117 high-risk patients with oral metronomic MT had an EFS rate of 42.7%. The results were similar to those of ASCT from other studies. The toxicities of metronomic MT were lower. Our study showed that oral metronomic MT is an optimal option for high-risk NB patients without ASCT or anti-GD2 antibody therapy. Abstract Despite aggressive treatment, the prognosis of high-risk NB patients is still poor. This retrospective study investigated the benefits of metronomic maintenance treatment (MT) in high-risk NB patients without ASCT or GD2 antibody therapy. Patients aged ≤ 21 years with newly diagnosed high-risk NB were included. Patients with complete/very good partial remission (CR/VGPR/PR) to conventional treatment received, or not, oral metronomic MT for 1 year. Two hundred and seventeen high-risk NB patients were enrolled. One hundred and eighty-five (85%) had a CR/VGPR/PR to conventional treatment, of the patients with stage 4, 106 receiving and 61 not receiving oral metronomic MT, and the 3-year event-free survival (EFS) rate was 42.5 ± 5.1% and 29.6 ± 6%, respectively (p = 0.017), and overall survival (OS) rate was 71.1 ± 4.7% and 59.4 ± 6.4%, respectively (p = 0.022). A total of 117 high-risk patients with oral metronomic MT had EFS rate of 42.7 ± 4.8%. The toxicity of MT was mild. For high-risk NB patients without ASCT or anti-GD2 antibody therapy, stage 4, MYCN amplication and patients with stage 4 not receiving oral metronomic MT after CR/VGPR/PR were independent adverse prognostic factors. Oral metronomic MT can improve survival in high-risk NB patients in CR/VGPR/PR without ASCT or anti-GD2 antibodies therapy.

Background High-risk neuroblastoma, as a lethal pediatric tumor, has unfavorable clinical outcomes, and accounts for ~15% of childhood cancer‐related mortality. However, the biomarkers for treatment prognosis have remained largely elusive. The present study sought to identify potential genes associated with the progression and prognosis of high-risk neuroblastoma. Methods The gene expression profiles of neuroblastoma were downloaded from the Gene Expression omnibus (GEO) database, and samples from GSE62564 and GSE16476 were applied as the training set and validation set, respectively. Bioinformatic analysis were performed by R. Subsequently, the biological functions of key gene were investigated by transwell, western blot, and flow cytometry analysis. miRNA that regulated the expression of key gene were predicted and the bind site were validated by luciferase reporter analysis and Q-PCR in children with high-risk neuroblastoma. Results Analysis shown that 120 differentially expressed genes (DEGs) in the blue module were identified to be significantly related to high-risk neuroblastoma by weighted correlation network analysis (WGCNA). After MCODE and Cytohubba algorithm analyses, 26 genes were recognized as hub genes. Subsequently, univariate COX and LASSO regression analyses identified a six-gene signature (NCAPG, UBE2C, MELK, CCNA2, KIF15, and BIRC5) and constructed a prognostic model. The expression of these six genes in high-risk neuroblastoma children was significantly higher than that in non-high-risk neuroblastoma children. These signature genes and the prognostic model demonstrated strong prognostic capability using Kaplan-Meier (KM) curves. Subsequently, NCAPG was selected as key gene and the results indicated that knockdown NCAPG suppressed the migration and invasion, increased the apoptosis rate and decreased the Bcl-2 level in neuroblastoma cells. In addition, the luciferase reporter analysis method showed that miR-495-3p can negatively regulate the expression of NCAPG. Q-PCR indicated that miR-495-3p highly expressed in children with high-risk neuroblastoma. Conclusion Our findings identified that miR-495-3p/ NCAPG could serve as prognostic biomarkers of high-risk neuroblastoma and may advance the understanding of the molecular pathogenesis.

Purpose: To assess agreement between 123I-metaiodobenzylguanidine (MIBG) and Whole Body Magnetic Resonance Imaging with diffusion-weighted whole-body imaging with background body signal suppression (WB MRI-DWIBS) in High and Low, Intermediate risk neuroblastoma, a retrospective review was performed on MIBG and DWIBS paired scans acquired at diagnosis, response-to-therapy steps, after-surgery, off therapy.Methods: 80 paired MIBG and DWIBS scans were acquired for 31 patients between June 2009 and June 2019 within 30 days, without intercurrent therapy. SIOPEN Semi-quantitative scoring systems for NB with 12 body sections was applied at whole body MIBG and WB MRI-DWIBS acquired to evaluate the disease extent. We evaluated specificity, sensitivity, overall accuracy, positive predictive value (PPV) and negative predictive value (NPV) of WB MRI-DWIBS respect MIBG scintigraphy considered as gold standard, and vice versa.Results: DWIBS and MIBG images were concordant in 890 out of the 960 analyzed segments, with high agreement between the two techniques (kendal =0.85 PConclusions: DWIBS and MIBG images showed very high concordance. WB MRI may represent an alternative in weak-avid MIBG tumors and for follow up assessment. An integrated imaging model is proposed for HR, Low and Intermediate Risk protocols.

Prognosis of high-risk neuroblastoma (HRNB) remains poor despite multimodal therapies. Better prediction of survival could help to refine patient stratification and better tailor treatments. We established a mechanistic model of metastasis in HRNB relying on two processes: growth and dissemination relying on two patient-specific parameters: the dissemination rate μ and the minimal visible lesion size Svis. This model was calibrated using diagnosis values of primary tumor size, lactate dehydrogenase circulating levels, and the meta-iodobenzylguanidine International Society for Paediatric Oncology European (SIOPEN) score from nuclear imaging, using data from 49 metastatic patients. It was able to describe the data of total tumor mass (lactate dehydrogenase, R2 > 0.99) and number of visible metastases (SIOPEN, R2 = 0.96). A prediction model of overall survival (OS) was then developed using Cox regression. Clinical variables alone were not able to generate a model with sufficient OS prognosis ability ( P = .507). The parameter μ was found to be independent of the clinical variables and positively associated with OS ( P = .0739 in multivariable analysis). Critically, addition of this computational biomarker significantly improved prediction of OS with a concordance index increasing from 0.675 (95% CI, 0.663 to 0.688) to 0.733 (95% CI, 0.722 to 0.744, P < .0001), resulting in significant OS prognosis ability ( P = .0422).

Aims: Diagnostic and post-induction I-123-meta-iodobenzylguanidine (I-123-mIBG) scans have prognostic significance in the treatment of neuroblastoma, but data from low-and middle-income countries are limited due to resource constraints. The aim of this study was to determine the association between neuroblastoma-associated tumour markers (lactate dehydrogenase [LDH], ferritin and MYCN amplification) and I-123-mIBG scans (modified Curie scores and metastatic disease patterns) in predicting complete metastatic response rates (mCR) and overall survival. Materials and methods: Two hundred and ninety patients diagnosed with high-risk neuroblastoma in South Africa between January 2000 and May 2018 and a subanalysis of 78 patients with diagnostic I-123-mIBG scans were included. Data collection included LDH, ferritin and MYCN amplification at diagnosis. Two nuclear physicians independently determined the modified Curie scores and pattern of distribution for each diagnostic and post-induction I-123-mIBG scans with high inter-rater agreement (r = 0.952) and reliability (K = 0.805). The cut-off values for the diagnostic and post-induction modified Curie scores of >= 7.0 (P = 0.026) and 3 (P = 0.009), respectively, were generated. The association between the tumour markers and the modified Curie score of the I-123-mIBG scans was determined using post-induction mCR and 2-year overall survival. Results: Diagnostic LDH (P < 0.001), ferritin (P < 0.001) and the diagnostic modified Curie scores (P = 0.019) significantly predicted mCR. Only ferritin correlated with diagnostic modified Curie scores (P = 0.003) but had a low correlation coefficient of 0.353. On multivariable analysis, the only significant covariate for 2 year overall survival at diagnosis was LDH 3.0 (P = 0.484). Conclusion: LDH, ferritin and the diagnostic I-123-mIBG scans significantly predicted mCR, but only LDH predicted 2-year overall survival. Ferritin and the modified Curie scores correlated with each other. MYCN amplification neither correlated with any aspect of the I-123-mIBG scans nor significantly predicted mCR or 2-year overall survival. LDH and ferritin are therefore appropriate neuroblastoma tumour markers to be used in low-and middle-income countries with limited or no access to mIBG scans and/or MYCN amplification studies. (C) 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Although high-risk neuroblastoma (HR-NB) is clinically heterogeneous, it is treated in a similar fashion without additional risk stratification. Based on the 4 copy-number profiles with 556 HR-NB subjects and 14 potential risk factors of neuroblastoma, we develop an interpretable machine learning model with L 0 penalized global AUC summary ( L 0 GAUCS) maximization, and identify 6 and 4 molecular factors associated with overall and event-free survivals (OS and EFS) of HR-NB, respectively. We further construct a six-factor model for OS and a four-factor model for EFS, and categorize HR-NB patients into 4 subtypes (Excellent, Good, Fair, and Poor) for both OS ( P = 1 . 59 e − 11 ) and EFS ( P = 1 . 73 e − 06 ). Particularly, 14.05% and 6.75% HR-NB patients are in the Excellent (I) and Poor subtype (IV) with median OS times of 137. and 14.5 months, respectively. Patients from such distinct subtypes may be assigned to different experimental therapies in future trials. Furthermore, although it is well known that infants (children less than 1 year) has significantly better prognosis in neuroblastoma, we discover that infants with MYCN amplification (MNA+) has unfavorable OS and EFS in HR-NB. Infants with MNA+ have the hazard ratio of 2.9 (95% CI: 1 . 33 − 6 . 34 ) and P value of 3 . 67 e − 06 for OS, and hazard ratio of 2.61 (95% CI: 1 . 05 − 6 . 48 ) and P value of 0.0007 for EFS. The unexpected but important finding that the survival of infants with MNA+ has significantly worse prognosis in HR-NB may have clinical implications.

Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort.A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves.The nomogram, including MYCN status (P 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1).In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children.

Background The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far. Methods Investigators of seven European countries representing national reference or large oncological centers convened in 2016. They agreed to quantitatively assess routine bone marrow smears of the participating institutions and to discuss the discrepant results in joint meetings. Results From 2017 through 2019, three cytology rounds with 24, 28, and 28 bone marrow samples were run evaluating the representativity of the smears (yes/[restricted]/no) and the presence of tumor cells (yes/no and %). The comparison of the reports using κ (Fleiss) and α (Krippendorff) statistics demonstrated no robust reliabilities. The agreement on the representativity was moderate to poor, on the presence of tumor cells moderate to good, and on the percentage of tumor cells slight to moderate. Though the value of cytology is unquestioned to detect even tiny metastatic cells in bone marrow, the investigators unanimously agreed that a reliable quantification of the tumor cell content in bone marrow smears is unrealistic. For the key issue of representativity, a new practical definition was developed. Conclusion For any work with bone marrow aspirates, the representativity of the material is of paramount importance. A practical definition is proposed. A reliable quantitative cytological assessment of tumor cell content in bone marrow aspirates is not feasible in metastatic neuroblastoma. Therefore, its use as response criterion should be reconsidered.

This study aimed to identify the prognostic subgroups of stage 4 high-risk neuroblastoma based on metastatic burden and explore their distinct clinical and genomic features. Patients aged &ge, 18 months with stage 4 and metaiodobenzylguanidine-avid neuroblastoma were enrolled. One hundred and thirty eligible patients were treated under the tandem high-dose chemotherapy scheme. Prognostic significance of metastatic burden measured by the modified Curie score was analyzed using a competing risk approach, and the optimal cut-point was determined. Metastasis-specific subgroups (cut-point: 26) were compared using clinicopathological variables, and differential gene expression analysis and gene set variation analysis (GSVA) were performed using RNA sequencing (RNA-seq). Metastatic burden at diagnosis showed a progressive association with relapse/progression. After applying the cut-point, patients with high metastatic burden showed &gt, 3-fold higher risk of relapse/progression than those with low metastatic burden. Moreover, patients with high metastatic burden showed smaller primary tumors and higher biochemical marker levels than those with low metastatic burden. In the genomic analysis, 51 genes were found to be differentially expressed based on the set criteria. GSVA revealed 55 gene sets, which significantly distinguished patients with high metastatic burden from those with low metastatic burden at a false discovery rate &lt, 0.25. The results indicated the prognostic significance of metastatic burden in stage 4 high-risk neuroblastoma, and we identified the distinct clinicopathological and genomic features based on metastatic burden. This study may aid in the better understanding and risk-stratification of stage 4 high-risk neuroblastoma patients.

BACKGROUND The 1993 International Neuroblastoma Response Criteria (INRC) were revised in 2017 to include modern functional imaging studies and methods for quantifying disease in bone marrow. We hypothesized the 2017 INRC would enable more precise assessment of response to treatment and provide superior prognostic information compared with the 1993 criteria. METHODS High-risk (HR) neuroblastoma patients from two institutions in Chicago diagnosed between 2006 and 2016 were identified. Patients were assessed post induction chemotherapy via the 1993 and 2017 INRC and classified as responder (≥ mixed response [MXR] or ≥ minor response [MR], respectively) or nonresponder (

PURPOSE To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. PATIENTS AND METHODS Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. RESULTS A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; P < .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; P < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04; P = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME ( P < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy ( P = .030 and P = .038). CONCLUSION In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.

Neuroblastoma is the most frequent extracranial malignant solid tumor in children, and the 5 year OS of high risk neuroblastoma patients was less than 15%. This study aimed to identify biomarkers for risk stratification and prognosis prediction in neuroblastoma.149 low risk samples, 108 intermediate risk samples and 619 high risk samples were included in our study, and NBPF1 gene was found to be significantly correlated with risk levels and OS. Significant negative correlations between NBPF1 and the expression of MYCN and AKT1S1, and positive correlations between NBPF1 and KIF1B expression were found, but only NBPF1 was an independent biomarker based on the construct of PPI for MYCN, NBPF1, KIF1B and AKT1S1 by STRING enrichment.

Background: Metaiodobenzylguanidine (MIBG; iobenguane), a guanethidine derivative, is a substrate for norepinephrine reuptake transporter which is highly expressed on the surface of neuroblastoma cells. AZEDRA® (HSA I-131 MIBG) has been approved by the FDA for the treatment of pheochromocytoma and paraganglioma, in pts 12 years and older with MIBG avid, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. The aim of this study was to establish the maximum tolerated dose in children with neuroblastoma, with secondary aims of assessing overall response and tumor and organ dosimetry. Here we report current long-term survival and toxicity data. Methods: Eligible pts were 1-30 years old with resistant neuroblastoma. A diagnostic dose of HSA I-131 MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. To prevent prolonged myelosuppression, autologous hematopoietic stem cells were infused 14 days after therapy. Response and toxicity were evaluated on day 60. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/µL within 28 days, or platelets to greater than 20,000/µL within 56 days, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: First pt was enrolled in June 2008. 15 pts total were evaluable at 12 (n=5), 15 (n=3), and 18 (n=7) mCi/kg. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight pts had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. MYC-N amplification was present in two of 11 pts with available results. Of the 15 treated pts, 1 had a complete response, 3 had a partial response, 1 had a mixed response and 6 had stable disease. The remaining 4 had progressive disease. Twelve of the 15 evaluable pts received non-protocol therapy after HSA I-131 MIBG, the remaining 3 died due to tumor without further therapy. At 3.6 years of follow-up the overall survival was 26.7% (95% CI, 8.3%-49.6%). As of March 2018, one remaining pt is in long term follow up with an overall survival of 8.4 years. This pt was previously reported to have a secondary malignancy of myelodysplastic syndrome which has been in remission since receiving an allogenic bone marrow transplant in March 2014. Conclusions: HSA I-131 MIBG contributed to long term median survival of two years and was well tolerated. Treatment showed promising activity in the absence of significant nonhematologic toxicity.

High Risk Neuroblastoma (HRNB) is the second most frequent solid tumor in children. Prognosis remains poor despite multimodal therapies. Mathematical models have been developed to describe metastasis, but their prognosis value has yet to be determined and none exists in neuroblastoma.We established such a model for HRNB relying on two coefficients: α(growth) and μ (dissemination). The model was calibrated using diagnosis values of primary tumor size, lactate dehydrogenase circulating levels (LDH) and the meta-iodo-benzyl-guanidine (mIBG) SIOPEN score from nuclear imaging, using data from 49 metastatic patients treated according to the European HR_NBL1 protocol.The model was able to accurately describe the data for both total tumor mass (LDH, R2 > 0.99) and number of visible metastasis (SIOPEN, R2 = 0.96). Statistical analysis revealed significant association of LDH with overall survival (OS, p=0.0268). However, clinical variables alone were not able to generate a Cox-based model with sufficient prognosis ability (p=0.507). The parameter μ was found to be independent of the clinical variables and positively significantly associated with OS (p = 0.0175 in multivariate analysis). Critically, addition of this novel computational biomarker to the clinical data drastically improved the performances of predictive algorithms, with a concordance index in cross-validation going from 0.755 to 0.827. The resulting signature had significant prognosis ability of OS (p=0.0353).Mechanistic modeling was able to describe pathophysiological data of metastatic HRNB and outperformed the predictive value of clinical variables. The physiological substrate underlying these results has yet to be explored, and results should be confirmed in a larger cohort.SignificanceA mechanistic mathematical model of metastasis in high risk neuroblastoma is able to describe clinical data and provides a numerical biomarker with superior predictive power of overall survival than clinical data alone.

Background The majority of patients in low- and middle-income countries (LMIC) are unable to receive optimal therapy, including autologous stem cell transplant (ASCT) for high-risk neuroblastoma. Management is intensive and multidisciplinary; survival is often poor. We report a single-center outcome of high-risk neuroblastoma, with adaptations optimized for LMIC. Procedure The study was retrospective. Patients were treated on the backbone of the high-risk neuroblastoma study-1 of SIOP-Europe (HR-NBL1/SIOPEN) protocol with ASCT. Adaptations incorporated to decrease cost, requirement for inpatient admission, infections, and faster engraftment included (a) optional outpatient administration for rapid-COJEC, (b) two sessions of stem-cell apheresis, (c) storing stem cells at 2-6°C without cryopreservation for up to 7 days, (d) no central lines, (e) no antibacterial/antifungal/antiviral prophylaxis, (f) omitting formal assessment of cardiac/renal/pulmonary functions before ASCT, and (g) administration of pegylated granulocyte colony-stimulating factor on Day +4. Results Over 5 years 9 months, 35 patients with high-risk neuroblastoma were treated. Rapid-COJEC was administered over a median duration of 80 days (interquartile range: 77, 83). Conditioning regimen included melphalan (n = 7), oral busulfan-melphalan (Bu/Mel; n = 6), or intravenous Bu/Mel (n = 22). The median viability of stem cells stored for 6 days (n = 28) was 93% (range: 88-99). Two (5.7%) patients had ASCT-related mortality. The 3-year overall and event-free survival was 41% and 39%, respectively. A relapse occurred in 20 (57%) patients. Treatment abandonment was observed in one (3%) patient. Conclusions Administration of therapy in a disciplined time frame along with low-cost adaptations enables to manage high-risk neuroblastoma with low abandonment and an encouraging survival in LMIC. Stem cells can be stored safely without cryopreservation for up to 7 days.

Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long‐term prognosis for patients with high‐risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event‐free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease‐free after completion of standard upfront therapy and did not receive DFMO. The 2‐ and 5‐year EFS were 86.4% [95% confidence interval (CI) 79.3%‐94.2%] and 85.2% [77.8%‐93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%‐88.3%] and 65.6% [55.5%‐77.5%] for the historical control group. The 2‐ and 5‐year OS were 98.8% [96.4‐100%] and 95.1% [90.5%‐99.9%] vs 94.4% [89.3%‐99.9%] and 81.6% [73.0%‐91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB., What's new? The long‐term prognosis for patients with high‐risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This phase II clinical trial update is the first study to demonstrate statistically and clinically significant improvement in event‐free and overall survival in HRNB patients as a result of DFMO administration following standard upfront therapy relative to a closely matched historical control. The findings support DFMO maintenance as a novel strategy to prevent relapse in a high‐risk population for relapse following frontline treatment.