Recent Advances in Neuroblastoma Maris, John M
New England journal of medicine/The New England journal of medicine,
06/2010, Volume:
362, Issue:
23
Journal Article
Peer reviewed
Open access
Neuroblastoma, an embryonal cancer of the autonomic nervous system, is the most common cancer diagnosed during the first year of life. Although neuroblastoma accounts for disproportionately high ...morbidity and mortality among childhood cancers, it has one of the highest rates of spontaneous and complete regression. The author discusses recent advances in our understanding of neuroblastoma.
Neuroblastoma, an embryonal cancer of the autonomic nervous system, is the most common cancer diagnosed during the first year of life. The author discusses recent advances in our understanding of neuroblastoma.
Neuroblastoma is an embryonal tumor of the autonomic nervous system, meaning that the cell of origin is thought to be a developing and incompletely committed precursor cell derived from neural-crest tissues.
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As may be expected with a disease of developing tissues, neuroblastomas generally occur in very young children; the median age at diagnosis is 17 months.
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The tumors arise in tissues of the sympathetic nervous system, typically in the adrenal medulla or paraspinal ganglia, and thus can present as mass lesions in the neck, chest, abdomen, or pelvis. The clinical presentation is highly variable, ranging from a mass that causes . . .
In memoriam: Dr. Audrey E. Evans Maris, John M.
Pediatric blood & cancer,
March 2023, 2023-Mar, 2023-03-00, 20230301, Volume:
70, Issue:
3
Journal Article
Peer reviewed
Open access
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Neuroblastoma is characterized by a relative paucity of recurrent somatic mutations at diagnosis. However, recent studies have shown that the mutational burden increases at relapse, likely as a ...result of clonal evolution of mutation-carrying cells during primary treatment. To inform the development of personalized therapies, we sought to further define the frequency of potentially actionable mutations in neuroblastoma, both at diagnosis and after chemotherapy. We performed a retrospective study to determine mutation frequency, the only inclusion criterion being availability of cancer gene panel sequencing data from Foundation Medicine. We analyzed 151 neuroblastoma tumor samples: 44 obtained at diagnosis, 42 at second look surgery or biopsy for stable disease after chemotherapy, and 59 at relapse (6 were obtained at unknown time points). Nine patients had multiple tumor biopsies. ALK was the most commonly mutated gene in this cohort, and we observed a higher frequency of suspected oncogenic ALK mutations in relapsed disease than at diagnosis. Patients with relapsed disease had, on average, a greater number of mutations reported to be recurrent in cancer, and a greater number of mutations in genes that are potentially targetable with available therapeutics. We also observed an enrichment of reported recurrent RAS/MAPK pathway mutations in tumors obtained after chemotherapy. Our data support recent evidence suggesting that neuroblastomas undergo substantial mutational evolution during therapy, and that relapsed disease is more likely to be driven by a targetable oncogenic pathway, highlighting that it is critical to base treatment decisions on the molecular profile of the tumor at the time of treatment. However, it will be necessary to conduct prospective clinical trials that match sequencing results to targeted therapeutic intervention to determine if cancer genomic profiling improves patient outcomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by ...the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker.
Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor
status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2).
Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with
amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2
nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months (
) or 12-18 months (
, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively.
A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.
The MYC oncogene encodes MYC, a transcription factor that binds the genome through sites termed E-boxes (5′-CACGTG-3′), which are identical to the binding sites of the heterodimeric CLOCK-BMAL1 ...master circadian transcription factor. Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-driven components of the circadian network in cancer cells. We report here that deregulated expression of MYC or N-MYC disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression and oscillation of BMAL1, and this could be rescued by knockdown of REV-ERB. REV-ERBα expression predicts poor clinical outcome for N-MYC-driven human neuroblastomas that have diminished BMAL1 expression, and re-expression of ectopic BMAL1 in neuroblastoma cell lines suppresses their clonogenicity. Further, ectopic MYC profoundly alters oscillation of glucose metabolism and perturbs glutaminolysis. Our results demonstrate an unsuspected link between oncogenic transformation and circadian and metabolic dysrhythmia, which we surmise to be advantageous for cancer.
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•The MYC and MYCN oncogenes disrupt the circadian molecular clock•MYC directly activates negative regulators of BMAL1-CLOCK•Constitutive activation of negative regulators, REV-ERBs, suspends the clock•Clock suspension is associated with disruption of circadian metabolic oscillation
Altman et al. show that oncogenic MYC disrupts the molecular clock and alters circadian glucose metabolism and glutaminolysis in favor of growth-related biosynthesis in cancer cells. Both MYC and N-MYC upregulate REV-ERBα, which suppresses BMAL1 expression and oscillations. High REV-ERBα or low BMAL1 predicts poor clinical outcome in N-MYC-driven human neuroblastomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neuroblastoma Maris, John M, MD; Hogarty, Michael D, MD; Bagatell, Rochelle, MD ...
The Lancet (British edition),
06/2007, Volume:
369, Issue:
9579
Journal Article
Peer reviewed
Summary The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of cure varying widely according to age at diagnosis, extent of disease, and tumour biology. A subset of tumours ...will undergo spontaneous regression while others show relentless progression. Around half of all cases are currently classified as high-risk for disease relapse, with overall survival rates less than 40% despite intensive multimodal therapy. This Seminar focuses on recent advances in our understanding of the biology of this complex paediatric solid tumour. We outline plans for the development of a uniform International Neuroblastoma Risk Group (INRG) classification system, and summarise strategies for risk-based therapies. We also update readers on new discoveries related to the underlying molecular pathogenesis of this tumour, with special emphasis on advances that are translatable to the clinic. Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Carcinogen-induced cancers typically have high mutation burdens and an inflamed microenvironment and thus are poised to respond to immune checkpoint inhibitors (ICIs). However, cancers with ...loss-of-function mutations in the SWI/SNF complex have few additional mutations yet also have an inflamed immunophenotype and should respond to ICI therapy.
Carcinogen-induced cancers typically have high mutation burdens and an inflamed microenvironment and thus are poised to respond to immune checkpoint inhibitors (ICIs). However, cancers with loss-of-function mutations in the SWI/SNF complex have few additional mutations yet also have an inflamed immunophenotype and should respond to ICI therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide has activity in these patients, and its acceptable ...toxicity profile makes it an excellent backbone for study of new agents. We aimed to test the addition of temsirolimus or dinutuximab to irinotecan–temozolomide in patients with relapsed or refractory neuroblastoma. Methods For this open-label, randomised, phase 2 selection design trial of the Children's Oncology Group (COG; ANBL1221), patients had to have histological verification of neuroblastoma or ganglioneuroblastoma at diagnosis or have tumour cells in bone marrow with increased urinary catecholamine concentrations at diagnosis. Patients of any age were eligible at first designation of relapse or progression, or first designation of refractory disease, provided organ function requirements were met. Patients previously treated for refractory or relapsed disease were ineligible. Computer-based randomisation with sequence generation defined by permuted block randomisation (block size two) was used to randomly assign patients (1:1) to irinotecan and temozolomide plus either temsirolimus or dinutuximab, stratified by disease category, previous exposure to anti-GD2 antibody therapy, and tumour MYCN amplification status. Patients in both groups received oral temozolomide (100 mg/m2 per dose) and intravenous irinotecan (50 mg/m2 per dose) on days 1–5 of 21-day cycles. Patients in the temsirolimus group also received intravenous temsirolimus (35 mg/m2 per dose) on days 1 and 8, whereas those in the dinutuximab group received intravenous dinutuximab (17·5 mg/m2 per day or 25 mg/m2 per day) on days 2–5 plus granulocyte macrophage colony-stimulating factor (250 μg/m2 per dose) subcutaneously on days 6–12. Patients were given up to a maximum of 17 cycles of treatment. The primary endpoint was the proportion of patients achieving an objective (complete or partial) response by central review after six cycles of treatment, analysed by intention to treat. Patients, families, and those administering treatment were aware of group assignment. This study is registered with ClinicalTrials.gov , number NCT01767194 , and follow-up of the initial cohort is ongoing. Findings Between Feb 22, 2013, and March 23, 2015, 36 patients from 27 COG member institutions were enrolled on this groupwide study. One patient was ineligible (alanine aminotransferase concentration was above the required range). Of the remaining 35 patients, 18 were randomly assigned to irinotecan–temozolomide–temsirolimus and 17 to irinotecan–temozolomide–dinutuximab. Median follow-up was 1·26 years (IQR 0·68–1·61) among all eligible participants. Of the 18 patients assigned to irinotecan–temozolomide–temsirolimus, one patient (6%; 95% CI 0·0–16·1) achieved a partial response. Of the 17 patients assigned to irinotecan–temozolomide–dinutuximab, nine (53%; 95% CI 29·2–76·7) had objective responses, including four partial responses and five complete responses. The most common grade 3 or worse adverse events in the temsirolimus group were neutropenia (eight 44% of 18 patients), anaemia (six 33%), thrombocytopenia (five 28%), increased alanine aminotransferase (five 28%), and hypokalaemia (four 22%). One of the 17 patients assigned to the dinutuximab group refused treatment after randomisation; the most common grade 3 or worse adverse events in the remaining 16 patients evaluable for safety were pain (seven 44% of 16), hypokalaemia (six 38%), neutropenia (four 25%), thrombocytopenia (four 25%), anaemia (four 25%), fever and infection (four 25%), and hypoxia (four 25%); one patient had grade 4 hypoxia related to therapy that met protocol-defined criteria for unacceptable toxicity. No deaths attributed to protocol therapy occurred. Interpretation Irinotecan–temozolomide–dinutuximab met protocol-defined criteria for selection as the combination meriting further study whereas irinotecan–temozolomide–temsirolimus did not. Irinotecan–temozolomide–dinutuximab shows notable anti-tumour activity in patients with relapsed or refractory neuroblastoma. Further evaluation of biomarkers in a larger cohort of patients might identify those most likely to respond to this chemoimmunotherapeutic regimen. Funding National Cancer Institute.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Purpose More than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. ...However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not previously widely available. The National Cancer Institute sponsored a clinical trials planning meeting in 2012 to update and refine response criteria for patients with neuroblastoma. Methods Multidisciplinary investigators from 13 countries reviewed data from published trials performed through cooperative groups, consortia, and single institutions. Data from both prospective and retrospective trials were used to refine the INRC. Monthly international conference calls were held from 2011 to 2015, and consensus was reached through review by working group leadership and the National Cancer Institute Clinical Trials Planning Meeting leadership council. Results Overall response in the revised INRC will integrate tumor response in the primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine-123 (
I) -metaiodobenzylguanidine (MIBG) scans or
Ffluorodeoxyglucose-positron emission tomography scans if the tumor is MIBG nonavid.
I-MIBG scans, or
Ffluorodeoxyglucose-positron emission tomography scans for MIBG-nonavid disease, replace technetium-99m diphosphonate bone scintigraphy for osteomedullary metastasis assessment. Bone marrow will be assessed by histology or immunohistochemistry and cytology or immunocytology. Bone marrow with ≤ 5% tumor involvement will be classified as minimal disease. Urinary catecholamine levels will not be included in response assessment. Overall response will be defined as complete response, partial response, minor response, stable disease, or progressive disease. Conclusion These revised criteria will provide a uniform assessment of disease response, improve the interpretability of clinical trial results, and facilitate collaborative trial designs.
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