Publications by authors named "Susan L Cohn"

154 Publications

Pediatric Cancer Data Commons: Federating and Democratizing Data for Childhood Cancer Research.

JCO Clin Cancer Inform 2021 Sep;5:1034-1043

Department of Pediatrics, University of Chicago, Chicago, IL.

The international pediatric oncology community has a long history of research collaboration. In the United States, the 2019 launch of the Children's Cancer Data Initiative puts the focus on developing a rich and robust data ecosystem for pediatric oncology. In this spirit, we present here our experience in constructing the Pediatric Cancer Data Commons (PCDC) to highlight the significance of this effort in fighting pediatric cancer and improving outcomes and to provide essential information to those creating resources in other disease areas. The University of Chicago's PCDC team has worked with the international research community since 2015 to build data commons for children's cancers. We identified six critical features of successful data commons design and implementation: (1) establish the need for a data commons, (2) develop and deploy the technical infrastructure, (3) establish and implement governance, (4) make the data commons platform easy and intuitive for researchers, (5) socialize the data commons and create working knowledge and expertise in the research community, and (6) plan for longevity and sustainability. Data commons are critical to conducting research on large patient cohorts that will ultimately lead to improved outcomes for children with cancer. There is value in connecting high-quality clinical and phenotype data to external sources of data such as genomic, proteomics, and imaging data. Next steps for the PCDC include creating an informed and invested data-sharing culture, developing sustainable methods of data collection and sharing, standardizing genetic biomarker reporting, incorporating radiologic and molecular analysis data, and building models for electronic patient consent. The methods and processes described here can be extended to any clinical area and provide a blueprint for others wishing to develop similar resources.
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http://dx.doi.org/10.1200/CCI.21.00075DOI Listing
September 2021

Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group.

J Clin Oncol 2021 Oct 28;39(29):3229-3241. Epub 2021 Jul 28.

Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Purpose: 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.

Methods: 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).

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1200/JCO.21.00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500606PMC
October 2021

Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma.

J Immunother Cancer 2021 07;9(7)

Department of Pediatrics, The University of Chicago, Chicago, Illinois, USA

Background: Tumor-infiltrating CD8 T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion.

Methods: A defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, amplification, and survival were analyzed by Cox proportional hazards models. Additional survival analysis was conducted after integrating neoantigen load predicted from somatic mutations. Pathways activated in non-T cell-inflamed relative to T cell-inflamed tumors were analyzed using causal network analysis.

Results: Patients with T cell-inflamed high-risk tumors showed improved overall survival compared with those with non-T cell-inflamed tumors (p<0.05), independent of amplification status, in both TARGET and GMKF cohorts. Higher neoantigen load was also associated with better event-free and overall survival (p<0.005) and was independent of the T cell-inflamed signature. Activation of and transcriptional programs was inversely correlated with the T cell-inflamed signature in both cohorts.

Conclusions: Our results indicate that tumors from children with high-risk neuroblastoma harboring a strong T cell-inflamed signature have a more favorable clinical outcome, and neoantigen load is a prognosis predictor, independent of T cell inflammation. Strategies to target SOX11 and other signaling pathways associated with non-T cell-inflamed tumors should be pursued as potential immune-potentiating interventions.
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http://dx.doi.org/10.1136/jitc-2021-002417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287618PMC
July 2021

Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium.

J Clin Oncol 2021 Jul 16:JCO2100703. Epub 2021 Jul 16.

Department of Pediatrics, UCSF Benioff Children's Hospital and UCSF School of Medicine, San Francisco, CA.

Purpose: I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate.

Patients And Methods: Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected.

Results: One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%.

Conclusion: Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.
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http://dx.doi.org/10.1200/JCO.21.00703DOI Listing
July 2021

Association Between Participation in Clinical Trials and Overall Survival Among Children With Intermediate- or High-risk Neuroblastoma.

JAMA Netw Open 2021 Jul 1;4(7):e2116248. Epub 2021 Jul 1.

Department of Pediatrics, University of Chicago, Chicago, Illinois.

Importance: Participants in clinical trials may experience benefits associated with new therapeutic strategies as well as tight adherence to best supportive care practices.

Objectives: To investigate whether participation in a clinical trial is associated with improved survival among children with neuroblastoma and investigate potential recruitment bias of patients in clinical trials.

Design, Setting, And Participants: This cohort study included pediatric patients with intermediate- or high-risk neuroblastoma in North American studies who were included in the International Neuroblastoma Risk Group Data Commons and who received a diagnosis between January 1, 1991, and March 1, 2020.

Exposure: Enrollment in a clinical trial.

Main Outcomes And Measures: Event-free survival and overall survival (OS) of patients with intermediate- or high-risk neuroblastoma enrolled in an up-front Children's Oncology Group (COG) clinical trial vs a biology study alone were analyzed using log-rank tests and Cox proportional hazards regression models. The racial/ethnic composition and the demographic characteristics of the patients in both groups were compared.

Results: The cohort included 3058 children with intermediate-risk neuroblastoma (1533 boys [50.1%]; mean [SD] age, 10.7 [14.7] months) and 6029 children with high-risk neuroblastoma (3493 boys [57.9%]; mean [SD] age, 45.8 [37.4] months) who were enrolled in a Children's Oncology Group or legacy group neuroblastoma biology study between 1991 and 2020. A total of 1513 patients with intermediate-risk neuroblastoma (49.5%) and 2473 patients with high-risk neuroblastoma (41.0%) were also enrolled in a clinical trial, for a cohort total of 3986 of 9087 children (43.9%) enrolled in a clinical trial. The prevalence of prognostic markers for the clinical trial and non-clinical trial cohorts differed, although representation of patients from racial/ethnic minority groups was similar in both cohorts. Among patients with intermediate-risk neuroblastoma, OS was higher among those who participated in a clinical trial compared with those enrolled only in a biology study (OS, 95% [95% CI, 94%-96%] vs 91% [95% CI, 89%-94%]; P = .01). Among patients with high-risk neuroblastoma, participation in a clinical trial was not associated with OS (OS, 38% [95% CI, 35%-41%] in the clinical trial group vs 41% [95% CI, 38%-44%] in the biology study group; P = .23).

Conclusions And Relevance: Approximately 44% of patients in this large cohort of patients with neuroblastoma were enrolled in up-front clinical trials. Compared with children not enrolled in clinical trials, a higher prevalence of favorable prognostic markers was identified among patients with intermediate-risk neuroblastoma enrolled in clinical trials, and unfavorable features were more prevalent among patients with high-risk neuroblastoma enrolled in clinical trials. No evidence of recruitment bias according to race/ethnicity was observed. Participation in a clinical trial was not associated with OS in this cohort, likely reflecting the common practice of treating nontrial participants with therapeutic and supportive care regimens used in a previous therapeutic trial.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.16248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267607PMC
July 2021

Stage 4S Neuroblastoma: Molecular, Histologic, and Immunohistochemical Characteristics and Presence of 2 Distinct Patterns of MYCN Protein Overexpression-A Report From the Children's Oncology Group.

Am J Surg Pathol 2021 08;45(8):1075-1081

Departments of Pathology.

Stage 4S neuroblastoma (4SNB) is associated with spontaneous tumor regression and an excellent prognosis. However, a small group of the patients have a poor prognosis. One hundred eighty-five stage 4SNB cases filed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory were studied. MYCN oncogene status [non-amplified (NA) vs. Amplified (A)] determined by fluorescence in situ hybridization, MYC-family (MYCN/MYC) protein expression [no-overexpression(-)/(+/-) vs. overexpression(+)] by immunohistochemistry and histopathology by International Neuroblastoma Pathology Classification [Favorable Histology (FH) vs. Unfavorable Histology (UH)] with particular attention to nucleolar hypertrophy [NH(-) vs. (+)] were assessed with patient survival. One hundred forty-seven (79.5%) tumors were MYCN-NA, FH, MYC-family protein(-)/(+/-), and NH(-) with a good prognosis [88.5±3.1% 3-y event-free survival (EFS); 94.1±2.3% 3-y overall survival (OS)]. Among MYCN-NA tumors, 11 demonstrated MYCN protein(+) with a moderate and uniform (M/U) staining pattern: they were FH(10/11), NH(-), 1 showed MYC protein(+) simultaneously, and all patients are alive. Also found were 5 MYC protein(+) and MYCN(-)/(+/-) tumors; they were FH without NH (4/5), and all patients are alive. Among MYCN-A tumors, 18 had MYCN protein(+) with a strong and heterogeneous (S/H) staining pattern, 9 had UH (44.4±23.4% EFS/OS) and 9 had FH (68.6±19.2% EFS/OS), and 15 showed NH(+). Two tumors had MYCN protein(-)/(+/-) despite MYCN-A; both were FH and NH(-), and 1 patient died. S/H staining pattern of MYCN protein overexpression by immunohistochemistry was associated with MYCN amplification, NH(+) and a poor prognosis. In contrast, the M/U staining pattern was associated with MYCN nonamplification and NH(-), and had no adverse prognostic effects for the stage 4SNB patients.
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http://dx.doi.org/10.1097/PAS.0000000000001647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217390PMC
August 2021

Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032.

Clin Cancer Res 2021 Apr 27;27(8):2179-2189. Epub 2021 Jan 27.

University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.

Purpose: Previously our randomized phase III trial demonstrated that immunotherapy including dinutuximab, a chimeric anti-GD2 mAb, GM-CSF, and IL2 improved survival for children with high-risk neuroblastoma that had responded to induction and consolidation therapy. These results served as the basis for FDA approval of dinutuximab. We now present long-term follow-up results and evaluation of predictive biomarkers.

Patients And Methods: Patients recieved six cycles of isotretinoin with or without five cycles of immunotherapy which consists of dinutuximab with GM-CSF alternating with IL2. Accrual was discontinued early due to meeting the protocol-defined stopping rule for efficacy, as assessed by 2-year event-free survival (EFS). Plasma levels of dinutuximab, soluble IL2 receptor (sIL2R), and human anti-chimeric antibody (HACA) were assessed by ELISA. Fcγ receptor 2A and 3A genotypes were determined by PCR and direct sequencing.

Results: For 226 eligible randomized patients, 5-year EFS was 56.6 ± 4.7% for patients randomized to immunotherapy ( = 114) versus 46.1 ± 5.1% for those randomized to isotretinoin only ( = 112; = 0.042). Five-year overall survival (OS) was 73.2 ± 4.2% versus 56.6 ± 5.1% for immunotherapy and isotretinoin only patients, respectively ( = 0.045). Thirteen of 122 patients receiving dinutuximab developed HACA. Plasma levels of dinutuximab, HACA, and sIL2R did not correlate with EFS/OS, or clinically significant toxicity. Fcγ receptor 2A and 3A genotypes did not correlate with EFS/OS.

Conclusions: Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample size than originally planned, yet clinically significant long-term differences in survival were observed.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046731PMC
April 2021

A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project.

Pediatr Blood Cancer 2021 03 18;68(3):e28794. Epub 2020 Nov 18.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1002/pbc.28794DOI Listing
March 2021

Tailoring Therapy for Children With Neuroblastoma on the Basis of Risk Group Classification: Past, Present, and Future.

JCO Clin Cancer Inform 2020 10;4:895-905

Department of Pediatrics and Comer Children's Hospital, University of Chicago, Chicago, IL.

For children with neuroblastoma, the likelihood of cure varies widely according to age at diagnosis, disease stage, and tumor biology. Treatments are tailored for children with this clinically heterogeneous malignancy on the basis of a combination of markers that are predictive of risk of relapse and death. Sequential risk-based, cooperative-group clinical trials conducted during the past 4 decades have led to improved outcome for children with neuroblastoma. Increasingly accurate risk classification and refinements in treatment stratification strategies have been achieved with the more recent discovery of robust genomic and molecular biomarkers. In this review, we discuss the history of neuroblastoma risk classification in North America and Europe and highlight efforts by the International Neuroblastoma Risk Group (INRG) Task Force to develop a consensus approach for pretreatment stratification using seven risk criteria including an image-based staging system-the INRG Staging System. We also update readers on the current Children's Oncology Group risk classifier and outline plans for the development of a revised 2021 Children's Oncology Group classifier that will incorporate INRG Staging System criteria to facilitate harmonization of risk-based frontline treatment strategies conducted around the globe. In addition, we discuss new approaches to establish increasingly robust, future risk classification algorithms that will further refine treatment stratification using machine learning tools and expanded data from electronic health records and the INRG Data Commons.
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http://dx.doi.org/10.1200/CCI.20.00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608590PMC
October 2020

Reply to K. Beiske et al.

J Clin Oncol 2020 11 15;38(31):3720-3721. Epub 2020 Sep 15.

Elizabeth Sokol, MD, Department of Pediatrics and Lurie Children's Hospital, Northwestern University, Chicago, IL; Ami V. Desai, MD, MSCE, and Mark A. Applebaum, MD, Department of Pediatrics and Comer Children's Hospital, University of Chicago, Chicago, IL; Dominique Valteau-Couanet, MD, PhD, Institute Gustave Roussy, Villejuif, France; Julie R. Park, MD, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA; Andrew D.J. Pearson, MD, Paediatric Drug Development, Children and Young People's Unit, Royal Marsden Hospital, London, UK; Gudrun Schleiermacher, MD, PhD, Department of Pediatric, Adolescents, and Young Adults Oncology and INSERM U830, Institut Curie, Paris, France; Meredith S. Irwin, MD, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Michael Hogarty, MD, Department of Pediatrics, University of Pennsylvania, Philadelphia, PA; Arlene Naranjo, PhD, Department of Biostatistics, Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL; Samuel Volchenboum, MD, PhD, and Susan L. Cohn, MD, Department of Pediatrics and Comer Children's Hospital, University of Chicago, Chicago, IL; and Wendy B. London, PhD, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1200/JCO.20.02147DOI Listing
November 2020

Association between end-induction response according to the revised International Neuroblastoma Response Criteria (INRC) and outcome in high-risk neuroblastoma patients.

Pediatr Blood Cancer 2020 10 25;67(10):e28390. Epub 2020 Jul 25.

Department of Pediatrics, University of Chicago, Chicago, Illinois.

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 (< MXR or < MR). Event-free survival (EFS) and overall survival (OS) for responders versus nonresponders were determined from end induction and stratified by Cox regression. Patients with progressive disease at end induction were eliminated from the EFS analyses but included in the OS analysis.

Results: The 1993 criteria classified 52 of the 60 HR patients as responders, whereas 54 responders were identified using the 2017 criteria (Spearman correlation r = 0.82, P < 0.001). No statistically significant difference in EFS was observed for responders versus nonresponders using either criteria (P = 0.48 and P = 0.08). However, superior OS was observed for responders (P = 0.01) using either criteria. Both criteria were sensitive in identifying responders among those with good outcomes. The specificity to identify nonresponders among those with poor outcomes was poor.

Conclusions: In HR neuroblastoma, end-induction response defined by the 1993 or 2017 INRC is associated with survival. Larger cohorts are needed to determine if the 2017 INRC provides more precise prognostication.
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http://dx.doi.org/10.1002/pbc.28390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722196PMC
October 2020

Paraneoplastic opsoclonus myoclonus syndrome associated with inflammatory myofibroblastic tumor in a pediatric patient.

Pediatr Blood Cancer 2020 08 30;67(8):e28218. Epub 2020 May 30.

Department of Pediatrics, University of Chicago, Chicago, Illinois.

Opsoclonus myoclonus syndrome (OMS) is a rare neurological syndrome caused by a paraneoplastic autoimmune process that affects children with neuroblastic tumors. Treatment includes corticosteroids, intravenous gamma globulin (IVIG), rituximab, and other immunosuppressive therapies. Here, we describe a patient diagnosed with OMS associated with a localized inflammatory myofibroblastic tumor. The patient has no evidence of tumor recurrence following surgical resection with 8-month follow-up. The neurologic symptoms resolved with corticosteroids and IVIG. This case demonstrates that in children, neoplasms other than neuroblastoma may be associated with this paraneoplastic syndrome, and highlights the importance of evaluating patients with OMS for underlying malignancies.
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http://dx.doi.org/10.1002/pbc.28218DOI Listing
August 2020

The prognostic strength of serum LDH and serum ferritin in children with neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

Pediatr Blood Cancer 2020 08 30;67(8):e28359. Epub 2020 May 30.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Purpose: Age, MYCN status, stage, and histology have been used as neuroblastoma (NB) risk factors for decades. Serum lactate dehydrogenase (LDH) and serum ferritin are reproducible, easily obtained, and prognostic, though never used in risk stratification, except one German trial. We analyzed the prognostic strength of LDH and ferritin, overall, within high-risk NB, and by era, using the International Neuroblastoma Risk Group Data Commons.

Patients And Methods: Children with NB (1990-2016) were categorized into LDH (n = 8867) and ferritin (n = 8575) risk groups using EFS. Cox models compared the prognostic strength of LDH and ferritin to age, MYCN status, and INSS stage.

Results: Higher LDH conferred worse EFS, overall (5-year EFS) (100-899 IU/L: 76 ± 0.6%; 0-99 or 900-1399 IU/L: 60 ± 1.2%; ≥1400 IU/L: 36 ± 1.2%; P < .0001), and in high-risk NB post-2009 (3-year EFS) (117-381 IU/L: 67 ± 8.9%; 382-1334 IU/L: 58 ± 4.4%; 0-116 or ≥1335 IU/L: 46 ± 3.9%; P = .003). Higher ferritin conferred worse EFS, overall (5-year EFS) (1-29 ng/mL: 87 ± 0.9%; 0 or 30-89 ng/mL: 74 ± 0.8%; ≥90 ng/mL: 48 ± 0.9%; P < .0001), and in high-risk NB post-2009 (3-year EFS) (1-53 ng/mL: 71 ± 9.3%; 0 or 54-354 ng/mL: 55 ± 4.7%; ≥355 ng/mL: 34 ± 6.1%; P = .0008). In multivariable analyses adjusting for age, MYCN, and stage, LDH and ferritin maintained independent prognostic ability (P < .0001; adjusted HRs (95% CI): 1.7 (1.5-1.9), 2.3 (2.0-2.7), respectively).

Conclusions: LDH and ferritin are strongly prognostic in NB, overall and within high-risk NB patients treated post-2009 with modern therapy. LDH and ferritin show promise for (a) identifying ultra-high-risk; (b) refining risk stratification; and (c) clinical utility in low-/middle-income countries. Routine collection of LDH and ferritin should be reinitiated for evolving NB risk stratification.
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http://dx.doi.org/10.1002/pbc.28359DOI Listing
August 2020

Racial and Ethnic Differences in Communication and Care for Children With Advanced Cancer.

J Pain Symptom Manage 2020 10 30;60(4):782-789. Epub 2020 Apr 30.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.

Context: Racial and ethnic disparities in end-of-life care are well documented among adults with advanced cancer.

Objectives: To examine the extent to which communication and care differ by race and ethnicity among children with advanced cancer.

Methods: We conducted a prospective cohort study at nine pediatric cancer centers enrolling 95 parents (42% racial/ethnic minorities) of children with poor prognosis cancer (relapsed/refractory high-risk neuroblastoma). Parents were surveyed about whether prognosis was discussed; likelihood of cure; intent of current treatment; and primary goal of care. Medical records were used to identify high-intensity medical care since the most recent recurrence. Logistic regression evaluated differences between white non-Hispanic and minority (black, Hispanic, and Asian/other race) parents.

Results: About 26% of parents recognized the child's low likelihood of cure. Minority parents were less likely to recognize the poor prognosis (odds ratio [OR] = 0.19; 95% CI = 0.06-0.63; P = 0.006) and the fact that current treatment was unlikely to offer cure (OR = 0.07; 95% CI = 0.02-0.27; P < 0.0001). Children of minority parents were more likely to experience high-intensity medical care (OR = 3.01; 95% CI = 1.29-7.02; P = 0.01). After adjustment for understanding of prognosis, race/ethnicity was no longer associated with high-intensity medical care (adjusted odds ratio = 2.14; 95% CI = 0.84-5.46; P = 0.11), although power to detect an association was limited.

Conclusion: Parental understanding of prognosis is limited across racial and ethnic groups; racial and ethnic minorities are disproportionately affected. Perhaps as a result, minority children experience higher rates of high-intensity medical care. Work to improve prognostic understanding should include focused work to meet needs of minority populations.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523916PMC
October 2020

Age, Diagnostic Category, Tumor Grade, and Mitosis-Karyorrhexis Index Are Independently Prognostic in Neuroblastoma: An INRG Project.

J Clin Oncol 2020 06 21;38(17):1906-1918. Epub 2020 Apr 21.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA.

Purpose: The Children's Oncology Group (COG) stratifies the treatment of patients with neuroblastoma on the basis of a combination of biomarkers that include age and tumor histology classified by age-linked International Neuroblastoma Pathology Classification (INPC) criteria. By definition, this leads to a duplication of the prognostic contribution of age. The individual histologic features underlying the INPC have prognostic strength and are incorporated in the International Neuroblastoma Risk Group classification schema. Here, we analyzed data in the International Neuroblastoma Risk Group Data Commons to validate the prognostic strength of the underlying INPC criteria and to determine whether a risk classification devoid of the confounding of age and INPC criteria will identify new prognostic subgroups.

Patients And Methods: Event-free survival of patients diagnosed between 1990 and 2002 (cohort 1; n = 10,104) and between 2003 and 2016 (cohort 2; n = 8,761) was analyzed. Recursive partitioning with univariate Cox models of event-free survival ("survival tree regression") was performed using (1) individual INPC criteria (age at diagnosis, histologic category, mitosis-karyorrhexis index (MKI), grade of differentiation) and (2) factors in (1) plus other COG-risk biomarkers (International Neuroblastoma Staging System [INSS] stage, status, ploidy).

Results: The independent prognostic ability of age, histologic category, MKI, and grade were validated. Four histologic prognostic groups were identified (< 18 months with low high MKI, and ≥ 18 months with differentiating undifferentiated/poorly differentiating tumors). Compared with survival trees generated with established COG risk criteria, an additional prognostic subgroup was identified and validated when individual histologic features were analyzed in lieu of INPC.

Conclusion: Replacing INPC with individual histologic features in the COG risk classification will eliminate confounding, facilitate international harmonization of risk classification, and provide a schema for more precise prognostication and refined therapeutic approaches.
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http://dx.doi.org/10.1200/JCO.19.03285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280049PMC
June 2020

5-Hydroxymethylcytosine Profiles in Circulating Cell-Free DNA Associate with Disease Burden in Children with Neuroblastoma.

Clin Cancer Res 2020 03 18;26(6):1309-1317. Epub 2019 Dec 18.

Department of Pediatrics, University of Chicago, Chicago, Illinois.

Purpose: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression. We profiled 5-hmC with Nano-hmC-Seal technology using 10 ng of plasma-derived cell-free DNA (cfDNA) in blood samples from patients with neuroblastoma to determine its utility as a biomarker.

Experimental Design: For the Discovery cohort, 100 5-hmC profiles were generated from 34 well children and 32 patients (27 high-risk, 2 intermediate-risk, and 3 low-risk) at various time points during the course of their disease. An independent Validation cohort encompassed 5-hmC cfDNA profiles ( = 29) generated from 21 patients (20 high-risk and 1 intermediate-risk). Metastatic burden was classified as high, moderate, low, or none per Curie metaiodobenzylguanidine scores and percentage of tumor cells in bone marrow. Genes with differential 5-hmC levels between samples according to metastatic burden were identified using DESeq2.

Results: Hierarchical clustering using 5-hmC levels of 347 genes identified from the Discovery cohort defined four clusters of samples that were confirmed in the Validation cohort and corresponded to high, high-moderate, moderate, and low/no metastatic burden. Samples from patients with increased metastatic burden had increased 5-hmC deposition on genes in neuronal stem cell maintenance and epigenetic regulatory pathways. Further, 5-hmC cfDNA profiles generated with 1,242 neuronal pathway genes were associated with subsequent relapse in the cluster of patients with predominantly low or no metastatic burden (sensitivity 65%, specificity 75.6%).

Conclusions: cfDNA 5-hmC profiles in children with neuroblastoma correlate with metastatic burden and warrants development as a biomarker of treatment response and outcome.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073281PMC
March 2020

Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.

Lancet Oncol 2020 01 4;21(1):121-133. Epub 2019 Dec 4.

Hematology and Oncology, Seattle Children's Hospital, Seattle, WA, USA.

Background: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.

Methods: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.

Findings: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8·6 months (IQR 2·5-16·4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60·0%; 95% CI 32·3-83·7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5·9% (95% CI 2·6-11·3).

Interpretation: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.
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http://dx.doi.org/10.1016/S1470-2045(19)30671-0DOI Listing
January 2020

Unrealistic parental expectations for cure in poor-prognosis childhood cancer.

Cancer 2020 01 4;126(2):416-424. Epub 2019 Oct 4.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Many parents of children with advanced cancer pursue curative goals when cure is no longer possible. To the authors' knowledge, no pediatric studies to date have prospectively evaluated prognosis communication or influences on decision making in poor-prognosis childhood cancer.

Methods: The authors conducted a prospective cohort study at 9 pediatric cancer centers that enrolled 95 parents of children with recurrent or refractory, high-risk neuroblastoma (63% of those who were approached), a condition for which cure rarely is achieved. Parents were surveyed regarding the child's likelihood of cure; their primary goal of care; the child's symptoms, suffering, and quality of life; and regret concerning the last treatment decision. Medical records identified care and treatment decisions.

Results: Only 26% of parents recognized that the chance of cure was <25%. When asked to choose a single most important goal of care, approximately 72% chose cure, 10% chose longer life, and 18% chose quality of life. Parents were more likely to prioritize quality of life when they recognized the child's poor prognosis (P = .002). Approximately 41% of parents expressed regret about the most recent treatment decision. Parents were more likely to experience regret if the child had received higher intensity medical care (odds ratio [OR], 3.14; 95% CI, 1.31-7.51), experienced suffering with limited benefit from the most recent treatment (OR, 4.78; 95% CI, 1.16-19.72), or experienced suffering from symptoms (OR, 2.91; 95% CI, 1.18-7.16).

Conclusions: Parents of children with poor-prognosis cancer frequently make decisions based on unrealistic expectations. New strategies for effective prognosis communication are needed.
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http://dx.doi.org/10.1002/cncr.32553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523918PMC
January 2020

Maintaining Outstanding Outcomes Using Response- and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531.

J Clin Oncol 2019 12 6;37(34):3243-3255. Epub 2019 Aug 6.

The University of Chicago, Chicago, IL.

Purpose: The primary objective of the Children's Oncology Group study ANBL0531 (ClinicalTrials.gov identifier: NCT00499616) was to reduce therapy for subsets of patients with intermediate-risk neuroblastoma using a biology- and response-based algorithm to assign treatment duration while maintaining a 3-year overall survival (OS) of 95% or more for the entire cohort.

Patients And Methods: Children younger than age 12 years with intermediate-risk stage 2A/2B or stage 3 tumors with favorable histology; infants younger than age 365 days with stage 3, 4 or 4S disease; and toddlers from 365 to younger than 547 days with favorable histology, hyperdiploid stage 4, or unfavorable histology stage 3 tumors were eligible. Patients with -amplified tumors were excluded. Patients were assigned to initially receive two (group 2), four (group 3), or eight (group 4) cycles of chemotherapy with or without surgery on the basis of prognostic markers, including allelic status of chromosomes 1p and 11q; ultimate duration of therapy was determined by overall response.

Results: Between 2007 and 2011, 404 evaluable patients were enrolled. Compared with legacy Children's Oncology Group studies, subsets of patients had a reduction in treatment. The 3-year event-free survival and OS rates were 83.2% (95% CI, 79.4% to 87.0%) and 94.9% (95% CI, 92.7% to 97.2%), respectively. Infants with stage 4 tumors with favorable biology (n = 61) had superior 3-year event-free survival compared with patients with one or more unfavorable biologic features (n = 47; 86.9% [95% CI, 78.3% to 95.4%] 66.8% [95% CI, 53.1% to 80.6%]; = .02), with a trend toward OS advantage (95.0% [95% CI, 89.5% to 100%] 86.7% [95% CI, 76.6% to 96.7%], respectively; = .08). OS for patients with localized disease was 100%.

Conclusion: Excellent survival was achieved with this treatment algorithm, with reduction of therapy for subsets of patients. More-effective treatment strategies still are needed for infants with unfavorable biology stage 4 disease.
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http://dx.doi.org/10.1200/JCO.19.00919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881103PMC
December 2019

5-Hydroxymethylcytosine Profiles Are Prognostic of Outcome in Neuroblastoma and Reveal Transcriptional Networks That Correlate With Tumor Phenotype.

JCO Precis Oncol 2019 16;3. Epub 2019 May 16.

University of Chicago, Chicago, IL.

Purpose: Whole-genome profiles of the epigenetic modification 5-hydroxymethylcytosine (5-hmC) are robust diagnostic biomarkers in adult patients with cancer. We investigated if 5-hmC profiles would serve as novel prognostic markers in neuroblastoma, a clinically heterogeneous pediatric cancer. Because this DNA modification facilitates active gene expression, we hypothesized that 5-hmC profiles would identify transcriptomic networks driving the clinical behavior of neuroblastoma.

Patients And Methods: Nano-hmC-Seal sequencing was performed on DNA from Discovery (n = 51), Validation (n = 38), and Children's Oncology Group (n = 20) cohorts of neuroblastoma tumors. RNA was isolated from 48 tumors for RNA sequencing. Genes with differential 5-hmC or expression between clusters were identified using DESeq2. A 5-hmC model predicting outcome in high-risk patients was established using linear discriminant analysis.

Results: Comparison of low- versus high-risk tumors in the Discovery cohort revealed 577 genes with differential 5-hmC. Hierarchical clustering of tumors from the Discovery and Validation cohorts using these genes identified two main clusters highly associated with established prognostic markers, clinical risk group, and outcome. Genes with increased 5-hmC and expression in the favorable cluster were enriched for pathways of neuronal differentiation and KRAS activation, whereas genes involved in inflammation and the PRC2 complex were identified in the unfavorable cluster. The linear discriminant analysis model trained on high-risk Discovery cohort tumors was prognostic of outcome when applied to high-risk tumors from the Validation and Children's Oncology Group cohorts (hazard ratio, 3.8).

Conclusion: 5-hmC profiles may be optimal DNA-based biomarkers in neuroblastoma. Analysis of transcriptional networks regulated by these epigenomic modifications may lead to a deeper understanding of drivers of neuroblastoma phenotype.
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http://dx.doi.org/10.1200/PO.18.00402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553657PMC
May 2019

Role of the extent of prophylactic regional lymph node radiotherapy on survival in high-risk neuroblastoma: A report from the COG A3973 study.

Pediatr Blood Cancer 2019 07 9;66(7):e27736. Epub 2019 Apr 9.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.

Purpose: Neuroblastoma is the most common extracranial solid pediatric malignancy, with poor outcomes in high-risk disease. Standard treatment approaches employ an increasing array of aggressive multimodal therapies, of which local control with surgery and radiotherapy remains a backbone; however, the benefit of broad regional nodal irradiation remains controversial. We analyzed centrally reviewed radiation therapy data from patients enrolled on COG A3973 to evaluate the impact of primary site irradiation and the extent of regional nodal coverage stratified by extent of surgical resection.

Methods: Three hundred thirty high-risk neuroblastoma patients with centrally reviewed radiotherapy plans were analyzed. Outcome was evaluated by the extent of nodal irradiation. For the 171 patients who also underwent surgery (centrally reviewed), outcome was likewise analyzed according to the extent of resection. Overall survival (OS), event-free survival (EFS), and cumulative incidence of local progression (CILP) were examined by Kaplan-Meier, log-rank test (EFS, OS), and Grey test (CILP).

Results: The five-year CILP, EFS, and OS for all 330 patients receiving radiotherapy on A3973 were 8.5% ± 1.5%, 47.2% ± 3.0%, and 59.7% ± 3.0%, respectively. There were no significant differences in outcomes based on the extent of lymph node irradiation regardless of the degree of surgical resection (< 90% or ≥90%).

Conclusion: Although local control remains a significant component of treatment of high-risk neuroblastoma, our results suggest there is no benefit of extensive lymph node irradiation, irrespective of the extent of surgical resection preceding stem cell transplant.
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http://dx.doi.org/10.1002/pbc.27736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281832PMC
July 2019

Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma.

Mol Cancer Ther 2019 03 23;18(3):507-516. Epub 2019 Jan 23.

Department of Pediatrics, University of Chicago, Chicago, Illinois.

Maternal embryonic leucine zipper kinase (MELK) activates pathways that mediate aggressive tumor growth and therapy resistance in many types of adult cancers. Pharmacologic and genomic inhibition of MELK impairs tumor growth and increases sensitivity to radiation and chemotherapy. On the basis of these promising preclinical studies, early-phase adult clinical trials testing the MELK inhibitor OTS167 are ongoing. To investigate whether MELK is also a therapeutic target in neuroblastoma, we analyzed MELK expression in primary tumors and cell lines, and examined the effects of OTS167 on neuroblastoma growth. In primary tumors, high levels of MELK were associated with advanced stage disease and inferior survival. Higher levels of MELK were also detected in tumorigenic versus nontumorigenic neuroblastoma cell lines, and cells with higher levels of MELK expression were more sensitive to OTS167 than low-MELK expressing cells. OTS167 suppressed the growth of neuroblastoma xenografts, and in a preclinical model of minimal residual disease, survival was prolonged with MELK inhibition. OTS167 treatment downregulated MELK and its target enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2) that is known to modulate the DNA damage response. We also show that OTS167 reduced the formation of collapsed replication forks induced by camptothecin or radiation. Taken together, our results indicate that MELK indirectly mediates efficient processing of replication-associated DNA lesions in neuroblastoma, and that OTS167 sensitizes cells to DNA-damaging agents by abrogating this process. Further studies evaluating the activity of combination treatment regimens with OTS167 in neuroblastoma are warranted.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398941PMC
March 2019

Statistical Framework in Support of a Revised Children's Oncology Group Neuroblastoma Risk Classification System.

JCO Clin Cancer Inform 2018 12;2:1-15

Arlene Naranjo, University of Florida, Gainesville, FL; Meredith S. Irwin, Hospital for Sick Children, Toronto, ON, Canada; Michael D. Hogarty, University of Pennsylvania, Philadelphia, PA; Susan L. Cohn, The University of Chicago, Chicago, IL; Julie R. Park, University of Washington, Seattle, WA; and Wendy B. London, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA.

Purpose: The International Neuroblastoma Risk Group (INRG) Staging System (INRGSS) was developed through international consensus to provide a presurgical staging system that uses clinical and imaging data at diagnosis. A revised Children's Oncology Group (COG) neuroblastoma (NB) risk classification system is needed to incorporate the INRGSS and within the context of modern therapy. Herein, we provide statistical support for the clinical validity of a revised COG risk classification system.

Patients And Methods: Nine factors were tested for potential statistical and clinical significance in 4,569 patients diagnosed with NB who were enrolled in the COG biology/banking study ANBL00B1 (2006-2016). Recursive partitioning was performed to create a survival-tree regression (STR) analysis of event-free survival (EFS), generating a split by selecting the strongest prognostic factor among those that were statistically significant. The least absolute shrinkage and selection operator (LASSO) was applied to obtain the most parsimonious model for EFS. COG patients were risk classified using STR, LASSO, and per the 2009 INRG classification (generated using an STR analysis of INRG data). Results were descriptively compared among the three classification approaches.

Results: The 3-year EFS and overall survival (± SE) were 72.9% ± 0.9% and 84.5% ± 0.7%, respectively (N = 4,569). In each approach, the most statistically and clinically significant factors were diagnostic category (eg, NB, ganglioneuroblastoma), INRGSS, MYCN status, International Neuroblastoma Pathology Classification, ploidy, and 1p/11q status. The results of the STR analysis were more concordant with those of the INRG classification system than with LASSO, although both methods showed moderate agreement with the INRG system.

Conclusion: These analyses provide a framework to develop a new COG risk classification incorporating the INRGSS. There is statistical evidence to support the clinical validity of each of the three classifications: STR, LASSO, and INRG.
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http://dx.doi.org/10.1200/CCI.17.00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421832PMC
December 2018

The challenge of defining "ultra-high-risk" neuroblastoma.

Pediatr Blood Cancer 2019 04 26;66(4):e27556. Epub 2018 Nov 26.

Hospital for Sick Children and University of Toronto, Toronto, Canada.

Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to determining appropriate treatment. Historically, most patients with high-risk neuroblastoma (HR-NBL) have been treated uniformly without further stratification. Attempts have been made to identify factors that can be used to risk stratify these patients and to characterize an "ultra-high-risk" (UHR) subpopulation with particularly poor outcome. However, among published data, there is a lack of consensus in the definition of the UHR population and heterogeneity in the endpoints and statistical methods used. This review summarizes our current understanding of stratification of HR-NBL and discusses the complex issues in defining UHR neuroblastoma.
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http://dx.doi.org/10.1002/pbc.27556DOI Listing
April 2019

Defining Risk Factors for Chemotherapeutic Intervention in Infants With Stage 4S Neuroblastoma: A Report From Children's Oncology Group Study ANBL0531.

J Clin Oncol 2019 01 16;37(2):115-124. Epub 2018 Nov 16.

6 Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: Infants with stage 4S neuroblastoma usually have favorable outcomes with observation or minimal chemotherapy. However, young infants with symptoms secondary to massive hepatomegaly or with unfavorable tumor biology are at high risk of death. Our aim was to improve outcomes for patients with symptomatic and/or unfavorable biology 4S neuroblastoma with a uniform treatment approach using a biology- and response-based algorithm.

Patients And Methods: The subset of patients with 4S disease with MYCN-not amplified tumors with impaired or impending organ dysfunction, or with unfavorable histology and/or diploid DNA index, were eligible. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of histology, diploid DNA index, chromosome arm 1p or 11q loss of heterozygosity (LOH) status, and symptoms.

Results: Forty-nine eligible patients were enrolled: 41 were symptomatic and 28 had unfavorable biology. Seventeen patients (symptomatic, favorable biology) were assigned two cycles, 21 patients (any unfavorable biologic feature without 1p or 11q LOH) were assigned four cycles, and 11 patients (unfavorable biology including 1p and/or 11q LOH [n = 7] or symptomatic with unknown biology [n = 4]), were assigned eight cycles. The 3-year overall survival was 81.4% ± 5.8%. Eight of nine deaths were in patients younger than 2 months of age at diagnosis (median, 9 days [range, 1 to 68 days]): five acute deaths were a result of hepatomegaly and associated toxicities; two were a result of late relapse in patients with unfavorable biology; and two were a result of treatment complications. No deaths occurred after protocol-mandated pre-emptive treatment of infants younger than 2 months with hepatomegaly, regardless of symptoms. A new scoring algorithm for emergent chemotherapy in patients with 4S disease was developed on the basis of this experience.

Conclusion: The outcome for 4S neuroblastoma can be improved with pre-emptive chemotherapy for evolving hepatomegaly or other baseline comorbidities in infants younger than 2 months of age.
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http://dx.doi.org/10.1200/JCO.18.00419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325354PMC
January 2019

Computer-assisted Curie scoring for metaiodobenzylguanidine (MIBG) scans in patients with neuroblastoma.

Pediatr Blood Cancer 2018 12 10;65(12):e27417. Epub 2018 Sep 10.

Department of Pediatrics, The University of Chicago, Chicago, Illinois.

Background: Radiolabeled metaiodobenzylguanidine (MIBG) is sensitive and specific for detecting neuroblastoma. The extent of MIBG-avid disease is assessed using Curie scores. Although Curie scoring is prognostic in patients with high-risk neuroblastoma, there is no standardized method to assess the response of specific sites of disease over time. The goal of this study was to develop approaches for Curie scoring to facilitate the calculation of scores and comparison of specific sites on serial scans.

Procedure: We designed three semiautomated methods for determining Curie scores, each with increasing degrees of computer assistance. Method A was based on visual assessment and tallying of MIBG-avid lesions. For method B, scores were tabulated from a schematic that associated anatomic regions to MIBG-positive lesions. For method C, an anatomic mesh was used to mark MIBG-positive lesions with automatic assignment and tallying of scores. Five imaging physicians experienced in MIBG interpretation scored 38 scans using each method, and the feasibility and utility of the methods were assessed using surveys.

Results: There was good reliability between methods and observers. The user-interface methods required 57 to 110 seconds longer than the visual method. Imaging physicians indicated that it was useful that methods B and C enabled tracking of lesions. Imaging physicians preferred method B to method C because of its efficiency.

Conclusions: We demonstrate the feasibility of semiautomated approaches for Curie score calculation. Although more time was needed for strategies B and C, the ability to track and document individual MIBG-positive lesions over time is a strength of these methods.
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http://dx.doi.org/10.1002/pbc.27417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317352PMC
December 2018

Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma.

Clin Cancer Res 2018 12 9;24(24):6142-6149. Epub 2018 Aug 9.

Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.

Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.

Patients And Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m/dose × 7 days), irinotecan (50 mg/m/dose i.v. × 5 days), and temozolomide (100 mg/m/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.

Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m had significantly higher median and exposure compared with tablets at 60 mg/m. Higher alisertib trough concentration was associated with first cycle DLT, whereas amplification was associated with inferior PFS.

Conclusions: This combination shows antitumor activity, particularly in patients with nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295246PMC
December 2018

MYC-family protein overexpression and prominent nucleolar formation represent prognostic indicators and potential therapeutic targets for aggressive high-MKI neuroblastomas: a report from the children's oncology group.

Oncotarget 2018 Jan 15;9(5):6416-6432. Epub 2017 Dec 15.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.

Neuroblastomas with a high mitosis-karyorrhexis index (High-MKI) are often associated with amplification, MYCN protein overexpression and adverse clinical outcome. However, the prognostic effect of MYC-family protein expression on these neuroblastomas is less understood, especially when is not amplified. To address this, MYCN and MYC protein expression in High-MKI cases (120 amplified and 121 non- amplified) was examined by immunohistochemistry. The majority (101) of -amplified High-MKI tumors were MYCN(+), leaving one MYC(+), 2 both(+), and 16 both(-)/(+/-), whereas non--amplified cases appeared heterogeneous, including 7 MYCN(+), 36 MYC(+), 3 both(+), and 75 both(-)/(+/-) tumors. These MYC-family proteins(+), or MYC-family driven tumors, were most likely to have prominent nucleolar (PN) formation (indicative of augmented rRNA synthesis). High-MKI neuroblastoma patients showed a poor survival irrespective of amplification. However, patients with MYC-family driven High-MKI neuroblastomas had significantly lower survival than those with non-MYC-family driven tumors. MYCN(+), MYC-family protein(+), PN(+), and clinical stage independently predicted poor survival. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and neuroblastoma growth. Together, MYC-family protein overexpression and PN formation should be included in new neuroblastoma risk stratification and considered for potential therapeutic targets.
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http://dx.doi.org/10.18632/oncotarget.23740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814222PMC
January 2018

Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial.

Lancet Child Adolesc Health 2018 01 3;2(1):25-34. Epub 2017 Nov 3.

Department of Pediatrics, University of Chicago, Chicago, IL.

Purpose: No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children's Oncology Group designed a randomized therapeutic trial.

Patient And Methods: Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293).

Results: Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject.

Conclusion: This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG+ constitutes a back-bone upon which to build additional therapy.
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http://dx.doi.org/10.1016/S2352-4642(17)30130-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783315PMC
January 2018

Immune Reconstitution Following Autologous Stem Cell Transplantation in Patients with High-Risk Neuroblastoma at the Time of Immunotherapy.

Biol Blood Marrow Transplant 2018 03 5;24(3):452-459. Epub 2017 Dec 5.

Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation, University of Chicago, Chicago, Illinois. Electronic address:

Outcomes for patients with high-risk neuroblastoma (HR-NBL) are significantly improved with the addition of immunotherapy (dinutuximab + cytokines) following autologous hematopoietic stem cell transplantation (auto-HSCT). We hypothesized that the immune system is not fully reconstituted at the initiation of immunotherapy. To test this hypothesis, we evaluated hematologic and immune subsets in 34 patients with HR-NBL before and after auto-HSCT. We found that absolute T, B, and NK cell counts at the time of immunotherapy were below normal in 80% of patients. Patients with residual disease at the time of transplantation had significantly lower absolute lymphocyte counts (ALC; P = .008), lower CD16 cell counts (P = .009), and an abnormal ratio of cytokine-releasing to cytotoxic NK cells at the time of dinutuximab treatment. In addition, the preparative regimen used for auto-HSCT predicted immune recovery. Finally, higher total white blood cell count (P = .013) and ALC (P = .013) at 3 months after completion of therapy were measured in patients who remained in remission compared with those who relapsed. Our results indicate that most patients with HR-NBL do not have full immune reconstitution at the time of dinutuximab treatment after auto-HSCT, and that immune recovery may correlate with disease-related outcomes in patients with high-risk disease.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.012DOI Listing
March 2018
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