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Genomic instability disorders are characterized by DNA or chromosomal instability, resulting in various clinical manifestations, including developmental anomalies, immunodeficiency, and increased risk of developing cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop, where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article discusses childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, xeroderma pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anticancer therapy., (©2024 American Association for Cancer Research.)

The Children's Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli-derived asparaginases. Each pegylated Escherichia coli asparaginase dose remaining in a patient's treatment plan was replaced by intramuscular (IM) or intravenous (IV) JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n=33; 1b [37.5 mg/m2 MWF], n=83; 1c [25/25/50 mg/m2 MWF], n=51) and 1 IV cohort (25/25/50 mg/m2 MWF, n=62) were evaluated. The proportion (95% confidence interval) of patients maintaining nadir serum asparaginase activity (NSAA) levels ≥0.1 IU/mL at the last 72 (primary endpoint) and 48 hours during course 1 was 90% (81, 98) and 96% (90, 100) in IM cohort 1c, respectively, and 40% (26, 54) and 90% (82, 98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed administration of IM and IV (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% due to treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on a combination of observed and modeled data with a safety profile consistent with other asparaginases. Clinicaltrials.gov Identifier: NCT04145531., (Copyright © 2024 American Society of Hematology.)

Children harboring certain germline gene variants have an increased risk of developing myelodysplastic syndrome (MDS) and other hematopoietic malignancies (HM), such as leukemias and lymphomas. Recent studies have identified an expanding number of these predisposition genes, with variants most prevalent in children with MDS but also found in children with other HM. For some hematopoietic malignancy predispositions (HMP), specifically those with a high risk of MDS, early intervention through hematopoietic stem cell transplantation can favorably impact overall survival, providing a rationale for rigorous surveillance. A multidisciplinary panel of experts at the 2023 AACR Childhood Cancer Predisposition Workshop reviewed the latest advances in the field and updated prior 2017 surveillance recommendations for children with HMP. In addition to general guidance for all children with HMP, which includes annual physical examination, education about the signs and symptoms of HM, consultation with experienced providers, and early assessment by a hematopoietic stem cell transplantation specialist, the panel provided specific recommendations for individuals with a higher risk of MDS based on the affected gene. These recommendations include periodic and comprehensive surveillance for individuals with those syndromes associated with higher risk of MDS, including serial bone marrow examinations to monitor for morphologic changes and deep sequencing for somatic changes in genes associated with HM progression. This approach enables close monitoring of disease evolution based on the individual's genetic profile. As more HMP-related genes are discovered and the disorders' natural histories are better defined, these personalized recommendations will serve as a foundation for future guidelines in managing these conditions., (©2024 American Association for Cancer Research.)

Opinion Statement: Pathogenic germline variants in the setting of several associated cancer predisposition syndromes (CPS) may lead to the development of sarcoma. We would consider testing for a CPS in patients with a strong family history of cancer, multiple primary malignancies, and/or pediatric/adolescent/young adult patients diagnosed with other malignancies strongly associated with CPS. When a CPS is diagnosed in a patient with sarcoma, additional treatment considerations and imaging options for those patients are required. This applies particularly to the use of radiation therapy, ionizing radiation with diagnostic imaging, and the use of alkylating chemotherapy. As data and guidelines are currently lacking for many of these scenarios, we have adopted a shared decision-making process with patients and their families. If the best chance for cure in a patient with CPS requires utilization of radiation therapy or alkylating chemotherapy, we discuss the risks with the patient but do not omit these modalities. However, if there are treatment options that yield equivalent survival rates, yet avoid these modalities, we elect for those options. Considering staging imaging and post-therapy evaluation for sarcoma recurrence, we avoid surveillance techniques that utilize ionizing radiation when possible but do not completely omit them when their use is indicated., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Li-Fraumeni syndrome (LFS) is an inherited cancer predisposition syndrome with an estimated prevalence of 1 in 3,000-5,000 individuals. LFS poses a significant cancer risk throughout the lifespan, with notable cancer susceptibility in childhood. Despite being predominantly inherited, up to 20% of cases arise de novo . Surveillance protocols facilitate the reduction of mortality and morbidity through early cancer detection. While newborn screening (NBS) has proven effective in identifying newborns with rare genetic conditions, even those occurring as rarely as 1 in 185,000, its potential for detecting inherited cancer predispositions remains largely unexplored., Methods: This survey-based study investigates perspectives toward NBS for LFS among individuals with and parents of children with LFS receiving care at single comprehensive cancer center in the U.S., Results: All participants unanimously supported NBS for LFS (n = 24). Reasons included empowerment (83.3%), control (66.7%), and peace of mind (54.2%), albeit with concerns about anxiety (62.5%) and devastation (50%) related to receiving positive results. Participants endorsed NBS as beneficial for cancer detection and prevention (91.7%), research efforts (87.5%), and family planning (79.2%) but voiced apprehensions about the financial cost of cancer surveillance (62.5%), emotional burdens (62.5%), and insurance coverage and discrimination (54.2%). Approximately 83% of respondents believed that parental consent should be required to screen newborns for LFS., Conclusion: This study revealed strong support for NBS for LFS despite the recognition of various perceived benefits and risks. These findings underscore the complex interplay between clinical, psychosocial, and ethical factors in considering NBS for LFS from the perspective of the LFS community., Competing Interests: Competing Interests: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice., Background: The Children's Oncology Group (COG) AALL1331 trial demonstrated improved survival and less toxicity in children with high-/intermediate-risk relapsed ALL receiving blinatumomab compared with intensive chemotherapy before hematopoietic stem-cell transplant (HSCT). The low-risk arm of AALL1331 compared addition of three cycles of blinatumomab to chemotherapy alone, but a survival improvement was not noted. Secondary analyses showed improvement in disease-free survival (DFS) and overall survival (OS) of low-risk patients with bone marrow disease ± extramedullary (EM) involvement (4-year DFS 72.7% ± 5.8% v 53.7% ± 6.7%; 4-year OS 97.1% ± 2.1% v 84.8% ± 4.8%), but failed to show an advantage with blinatumomab for patients with isolated EM relapse. Of note, DFS of isolated CNS (iCNS) relapse was worse than previous studies at 24% on both arms, likely because of decreases in CNS-intensive therapy compared with previous approaches and inadequacy of blinatumomab for controlling CNS disease., Case: Our case of late isolated CNS B-cell ALL relapse outlines challenges for clinicians attempting to decrease toxicity and avoid HSCT: (1) defining of low risk appropriately, (2) attempting to reduce the treatment burden of past protocols, and (3) understanding approach and timing of cranial irradiation., Approach: Although AALL1331 therapy without blinatumomab leads to excellent survival in patients with isolated testicular relapse, we recommend a modified AALL02P2 backbone of chemotherapy with 1,800 cGy cranial radiotherapy for patients with late iCNS relapse. Future studies integrating chimeric antigen receptor T cells, which have better CNS penetration, may help decrease the intensive treatment burden for patients with late iCNS recurrence.

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS., (© 2023 Wiley Periodicals LLC.)

Pathogenic variants (PVs) in the SDHD gene increase risk for paragangliomas (PGL)/pheochromocytomas, renal cell carcinomas, and gastrointestinal stromal tumors. Penetrance in individuals with SDHD PVs varies in reported research from 40-70%, and there is limited evidence of specific genotype risks. This study aims to characterize a multi-generational family with SDHD p.Trp43* PVs and potential genotype-phenotype considerations for surveillance. Individuals with a paternally inherited SDHD p.Trp43*(c.129G > A) PV were identified. Genetic, medical and family histories were abstracted, including clinical characteristics, tumor histories, and treatment approaches. Eleven individuals with the SDHD PV in the same kindred were diagnosed with 41 SDHx-related tumors across all family members. Eight individuals developed 27 head and neck PGL of varying origins, and seven individuals developed tumors outside of the head and neck region. Many individuals had multiple tumors, and age of first tumor diagnosis ranged from age 10 to age 45 years old. Individuals with SDHD p.Trp43* variants may have higher risks for SDHx related tumors than other SDHD variants. Prioritizing identification of at-risk individuals and initiating surveillance tailored to family history is recommended given the rate of multiple tumors found in one familial branch of individuals under 18 years old. Individuals with strong family histories of PGL at young ages with this PV will benefit from tailored surveillance recommendations., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Osteosarcoma risk stratification, on the basis of the presence of metastatic disease at diagnosis and histologic response to chemotherapy, has remained unchanged for four decades, does not include genomic features, and has not facilitated treatment advances. We report on the genomic features of advanced osteosarcoma and provide evidence that genomic alterations can be used for risk stratification., Materials and Methods: In a primary analytic patient cohort, 113 tumor and 69 normal samples from 92 patients with high-grade osteosarcoma were sequenced with OncoPanel, a targeted next-generation sequencing assay. In this primary cohort, we assessed the genomic landscape of advanced disease and evaluated the correlation between recurrent genomic events and outcome. We assessed whether prognostic associations identified in the primary cohort were maintained in a validation cohort of 86 patients with localized osteosarcoma tested with MSK-IMPACT., Results: In the primary cohort, 3-year overall survival (OS) was 65%. Metastatic disease, present in 33% of patients at diagnosis, was associated with poor OS ( P = .04). The most frequently altered genes in the primary cohort were TP 53, RB1, MYC, CCNE1, CCND3, CDKN2A/B, and ATRX . Mutational signature 3 was present in 28% of samples. MYC amplification was associated with a worse 3-year OS in both the primary cohort ( P = .015) and the validation cohort ( P = .012)., Conclusion: The most frequently occurring genomic events in advanced osteosarcoma were similar to those described in prior reports. MYC amplification, detected with clinical targeted next-generation sequencing panel tests, is associated with poorer outcomes in two independent cohorts.

AALL1931, a phase 2/3 study conducted in collaboration with the Children's Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli-derived asparaginases. Each dose of a pegylated E coli-derived asparaginase remaining in patients' treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations ( FGFR1-4 ) in pediatric cancers to inform future clinical trial design., Methods: Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed., Results: We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions ( FGFR3 :: TACC3 [n = 3], FGFR1 :: TACC1 [n = 1], FGFR1 :: EBF2 [n = 1], FGFR1 :: CLIP2 [n = 1], and FGFR2 :: CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor., Conclusion: In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.

Germline pathogenic variants in cancer susceptibility genes are identified in up to 18% of all children with cancer. Because pediatric cancer predisposition syndromes (CPS) themselves are rare and underrecognized, there are limited data to guide the diagnosis and management of affected children and at-risk relatives. Furthermore, the care of affected children requires distinct considerations given the early onset of cancers, lifelong risks of additional cancers, and potential late effects of therapy. Herein, we discuss efforts to leverage existing infrastructure, organize experts, and develop a new consortium to optimize care and advance research for children with CPS. A 2016 workshop organized by the American Association for Cancer Research united many experts in childhood cancer predisposition and resulted in publication of multiple consensus guidelines for tumor surveillance. More recently, several of these authors established the Consortium for Childhood Cancer Predisposition (C3P), a multi-institutional collaboration that provides a structure for systematic research in cancer predisposition, screening, and prevention in children. The Consortium intends to work with other cooperative groups to merge longitudinal data from children with CPS throughout the continuum of the cancer risk period, as well as cancer treatment and survivorship care, to optimize overall outcomes., (©2022 American Association for Cancer Research.)

Background: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors., Methods: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D., Results: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4)., Conclusions: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Pediatric Acute Lymphoblastic Leukemia (ALL) cure rates have improved exponentially over the past five decades with now over 90% of children achieving long-term survival. A direct contributor to this remarkable feat is the development and expanded understanding of combination chemotherapy. Asparaginase is the most recent addition to the ALL chemotherapy backbone and has now become a hallmark of therapy. It is generally accepted that the therapeutic effects of asparaginase is due to depletion of the essential amino acid asparagine, thus occupying a unique space within the therapeutic landscape of ALL. Pharmacokinetic and pharmacodynamic profiling have allowed a detailed and accessible insight into the biochemical effects of asparaginase resulting in regular clinical use of therapeutic drug monitoring (TDM). Asparaginase's derivation from bacteria, and in some cases conjugation with a polyethylene glycol (PEG) moiety, have contributed to a unique toxicity profile with hypersensitivity reactions being the most salient. Hypersensitivity, along with several other toxicities, has limited the use of asparaginase in some populations of ALL patients. Both TDM and toxicities have contributed to the variety of approaches to the incorporation of asparaginase into the treatment of ALL. Regardless of the approach to asparagine depletion, it has continually demonstrated to be among the most important components of ALL therapy. Despite regular use over the past 50 years, and its incorporation into the standard of care treatment for ALL, there remains much yet to be discovered and ample room for improvement within the utilization of asparaginase therapy., Competing Interests: LM served on advisory board and speakers bureau for Jazz Pharmaceuticals. RR served on advisory board for Jazz Pharmaceuticals and Servier Pharmaceuticals., (Copyright © 2022 Maese and Rau.)

Background: Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53., Objective: To determine whether gTP53 predisposes to prostate cancer., Design, Setting, and Participants: This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort., Outcome Measurements and Statistical Analysis: We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer., Results and Limitations: We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis., Conclusions: Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing., Patient Summary: Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Given the locally destructive osteolytic nature of primary B-cell lymphoblastic lymphoma (B-LBL) of the spine, careful attention is needed to identify clinical signs and symptoms as well as radiological findings of spinal instability because these lesions may warrant resection, decompression, and instrumentation with posterolateral fusion. Our objective was to summarize the presenting symptoms, clinical features, potential treatment modalities, and clinical outcome of cases described in the literature., Methods: We undertook a systematic literature review to identify all relevant cases and case series describing primary manifestations B-LBL of the spine using Pubmed/Medline. We summarized the findings in accordance with the PRISMA guidelines. We also present a case illustration., Results: Together with our case, 9 cases of primary B-LBL of the spine were identified in 6 male and 3 female patients (age 8-58 years, median 31 years). Back pain was the most common symptom, and five patients also had neurological signs of spinal cord compression. T1-weighted MRI contrast enhancement was seen in 5 cases. Surgery was performed in 5 patients with progression of neurological deficits. Steroid treatment was also given in 3 patients preoperatively. Seven patients had chemotherapy after diagnosis. During follow-up of 1 month to 1 year, 2 cases of recurrence and 4 cases of complete remission were noted; however, with the short follow-up time, patient prognosis overall remains unclear., Conclusions: Primary B-LBL of the spine represents a rare clinical entity whose management mandates a multidisciplinary approach. Careful attention must be paid to the neurological status of the patient, as well as to imaging that may highlight potential local instability of the spine., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.

Purpose: Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks., Materials and Methods: Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation., Results: One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events., Conclusion: A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition., Competing Interests: Alanna J. Church Honoraria: The Jackson Laboratory Consulting or Advisory Role: AlphaSights, The Jackson Laboratory, Bayer Travel, Accommodations, Expenses: Bayer Laura B. Corson Employment: Sema4 Stock and Other Ownership Interests: Alnylam, Inovio Pharmaceuticals, Agios Consulting or Advisory Role: Biomatics Patents, Royalties, Other Intellectual Property: Patent from work done at H3 Biomedicine before 2016 Brennan Decker Employment: Foundation Medicine Stock and Other Ownership Interests: Avidea Technologies, Roche Consulting or Advisory Role: Foundation Medicine, Avidea Technologies Catherine M. Clinton Employment: Helix OpCo LLC Mark A. Applebaum Consulting or Advisory Role: Fennec Pharma Rochelle Bagatell Uncompensated Relationships: Ymabs Therapeutics Inc Steven G. DuBois Consulting or Advisory Role: Bayer, Amgen Research Funding: Merck (Inst), Roche/Genentech (Inst), Lilly (Inst), Curis (Inst), Loxo (Inst), BMS (Inst), Eisai (Inst), Pfizer (Inst), Turning Point Therapeutics (Inst), Bayer (Inst), Salarius Pharmaceuticals (Inst) Travel, Accommodations, Expenses: Roche/Genentech, Salarius Pharmaceuticals Uncompensated Relationships: Ymabs Therapeutics Inc Julia L. Glade-Bender Research Funding: Eisai (Inst), Lilly (Inst), Loxo (Inst), Roche/Genentech (Inst), Bayer (Inst) Patents, Royalties, Other Intellectual Property: Patent on a T lympboblastic lymphoma cell line, CUTLL1 Travel, Accommodations, Expenses: Amgen (Inst) Uncompensated Relationships: SpringWorks Therapeutics, Bristol Myers Squibb, Merck, Eisai Open Payments Link: https://openpaymentsdata.cms.gov/physician/708514 AeRang Kim Research Funding: Esai (Inst); AstraZeneca (Inst); Oncternal (Inst); Ascentage (Inst); BioAlta (Inst). Theodore W. Laetsch Consulting or Advisory Role: Novartis, Bayer, Cellectis, Aptitude Health, Clinical Education Alliance, Deciphera, Jumo Health, Massive Bio, Med Learning Group, Medscape, Physicans' Education Resource, Y-mAbs Therapeutics Research Funding: Pfizer (Inst), Novartis (Inst), Bayer (Inst), AbbVie (Inst), Amgen (Inst), Atara Biotherapeutics (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Epizyme (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Jubilant Pharmaceuticals (Inst), Novella Clinical (Inst), Servier (Inst), Foundation Medicine (Inst), Merck Sharp & Dohme (Inst) Margaret E. Macy Stock and Other Ownership Interests: Johnson & Johnson, GE Healthcare, Varian Medical Systems Consulting or Advisory Role: Ymabs Therapeutics Inc Research Funding: Bayer (Inst), Ignyta (Inst), Roche (Inst), Lilly (Inst), Merck (Inst), Oncternal Therapeutics Inc (Inst), AbbVie (Inst), Jubilant DraxImage (Inst), Actuate Therapeutics (Inst) Patents, Royalties, Other Intellectual Property: Patent for non-invasive methods of leukemia cell detection with MRI/MRS—Patent No. 8894975 Luke Maese Honoraria: Jazz Pharmaceuticals Consulting or Advisory Role: Jazz Pharmaceuticals Amit J. Sabnis Consulting or Advisory Role: Cardinal Health Joshua D. Schiffman Employment: PEEL Therapeutics Leadership: PEEL Therapeutics Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics Honoraria: Affymetrix Consulting or Advisory Role: N-of-One, Fabric Genomics Samuel L. Volchenboum Stock and Other Ownership Interests: Litmus Health Consulting or Advisory Role: Accordant Travel, Accommodations, Expenses: Sanford Health Daniel A. Weiser Consulting or Advisory Role: Illumina Radiopharmaceuticals Jonathan A. Nowak Research Funding: NanoString Technologies, Illumina Katherine A. Janeway Honoraria: Foundation Medicine, Takeda Consulting or Advisory Role: Bayer, Ipsen Travel, Accommodations, Expenses: Bayer Brian D. Crompton Employment: Acceleron Pharma (I) Stock and Other Ownership Interests: Acceleron Pharma (I) Research Funding: Gradalis Junne Kamihara Stock and Other Ownership Interests: PanTher Therapeutics (I), ROME Therapeutics (I), TellBio (I) Honoraria: Pfizer (I), NanoString Technologies (I), Foundation Medicine (I), Ikena Oncology (I) Consulting or Advisory Role: ROME Therapeutics (I), Third Rock Ventures (I), Tekla Capital Management (I) Research Funding: PureTech (I), Ribon Therapeutics (I), ACD Biotechne (I) Patents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics (I), Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics (I), Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc (I) No other potential conflicts of interest were reported. Alanna J. Church Honoraria: The Jackson Laboratory Consulting or Advisory Role: AlphaSights, The Jackson Laboratory, Bayer Travel, Accommodations, Expenses: Bayer Laura B. Corson Employment: Sema4 Stock and Other Ownership Interests: Alnylam, Inovio Pharmaceuticals, Agios Consulting or Advisory Role: Biomatics Patents, Royalties, Other Intellectual Property: Patent from work done at H3 Biomedicine before 2016 Brennan Decker Employment: Foundation Medicine Stock and Other Ownership Interests: Avidea Technologies, Roche Consulting or Advisory Role: Foundation Medicine, Avidea Technologies Catherine M. Clinton Employment: Helix OpCo LLC Mark A. Applebaum Consulting or Advisory Role: Fennec Pharma Rochelle Bagatell Uncompensated Relationships: Ymabs Therapeutics Inc Steven G. DuBois Consulting or Advisory Role: Bayer, Amgen Research Funding: Merck (Inst), Roche/Genentech (Inst), Lilly (Inst), Curis (Inst), Loxo (Inst), BMS (Inst), Eisai (Inst), Pfizer (Inst), Turning Point Therapeutics (Inst), Bayer (Inst), Salarius Pharmaceuticals (Inst) Travel, Accommodations, Expenses: Roche/Genentech, Salarius Pharmaceuticals Uncompensated Relationships: Ymabs Therapeutics Inc Julia L. Glade-Bender Research Funding: Eisai (Inst), Lilly (Inst), Loxo (Inst), Roche/Genentech (Inst), Bayer (Inst) Patents, Royalties, Other Intellectual Property: Patent on a T lympboblastic lymphoma cell line, CUTLL1 Travel, Accommodations, Expenses: Amgen (Inst) Uncompensated Relationships: SpringWorks Therapeutics, Bristol Myers Squibb, Merck, Eisai Open Payments Link: https://openpaymentsdata.cms.gov/physician/708514 AeRang Kim Research Funding: Esai (Inst); AstraZeneca (Inst); Oncternal (Inst); Ascentage (Inst); BioAlta (Inst). Theodore W. Laetsch Consulting or Advisory Role: Novartis, Bayer, Cellectis, Aptitude Health, Clinical Education Alliance, Deciphera, Jumo Health, Massive Bio, Med Learning Group, Medscape, Physicans' Education Resource, Y-mAbs Therapeutics Research Funding: Pfizer (Inst), Novartis (Inst), Bayer (Inst), AbbVie (Inst), Amgen (Inst), Atara Biotherapeutics (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Epizyme (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Jubilant Pharmaceuticals (Inst), Novella Clinical (Inst), Servier (Inst), Foundation Medicine (Inst), Merck Sharp & Dohme (Inst) Margaret E. Macy Stock and Other Ownership Interests: Johnson & Johnson, GE Healthcare, Varian Medical Systems Consulting or Advisory Role: Ymabs Therapeutics Inc Research Funding: Bayer (Inst), Ignyta (Inst), Roche (Inst), Lilly (Inst), Merck (Inst), Oncternal Therapeutics Inc (Inst), AbbVie (Inst), Jubilant DraxImage (Inst), Actuate Therapeutics (Inst) Patents, Royalties, Other Intellectual Property: Patent for non-invasive methods of leukemia cell detection with MRI/MRS—Patent No. 8894975 Luke Maese Honoraria: Jazz Pharmaceuticals Consulting or Advisory Role: Jazz Pharmaceuticals Amit J. Sabnis Consulting or Advisory Role: Cardinal Health Joshua D. Schiffman Employment: PEEL Therapeutics Leadership: PEEL Therapeutics Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics Honoraria: Affymetrix Consulting or Advisory Role: N-of-One, Fabric Genomics Samuel L. Volchenboum Stock and Other Ownership Interests: Litmus Health Consulting or Advisory Role: Accordant Travel, Accommodations, Expenses: Sanford Health Daniel A. Weiser Consulting or Advisory Role: Illumina Radiopharmaceuticals Jonathan A. Nowak Research Funding: NanoString Technologies, Illumina Katherine A. Janeway Honoraria: Foundation Medicine, Takeda Consulting or Advisory Role: Bayer, Ipsen Travel, Accommodations, Expenses: Bayer Brian D. Crompton Employment: Acceleron Pharma (I) Stock and Other Ownership Interests: Acceleron Pharma (I) Research Funding: Gradalis Junne Kamihara Stock and Other Ownership Interests: PanTher Therapeutics (I), ROME Therapeutics (I), TellBio (I) Honoraria: Pfizer (I), NanoString Technologies (I), Foundation Medicine (I), Ikena Oncology (I) Consulting or Advisory Role: ROME Therapeutics (I), Third Rock Ventures (I), Tekla Capital Management (I) Research Funding: PureTech (I), Ribon Therapeutics (I), ACD Biotechne (I) Patents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics (I), Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics (I), Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc (I) No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Competing Interests: Luke MaeseHonoraria: Jazz PharmaceuticalsConsulting or Advisory Role: Jazz Pharmaceuticals Jennie VagherConsulting or Advisory Role: InVitae Samuel H. CheshierPatents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/020905 Entitled: Treatment of Pediatric Brain Tumors with Targeting of CD47 Pathway. First Named Inventor: Sharareh Gholamin, Your Ref.: S17-082, Our Ref.: STAN-1400WO; US Application Serial No. 15/912,447 Entitled: Treatment of Pediatric Brain Tumors with Targeting of CD47 Pathway. First Named Inventor: Sharareh Gholamin, Your Ref.: S17-082, Our Ref.: STAN-1400; International Patent Application No. PCT/US2018/020905 Entitled: Treatment of Pediatric Brain Tumors with Targeting of CD47 Pathway. First Named Inventor: Sharareh Gholamin, Your Ref.: S17-082, Our Ref.: STAN-1400WO; US Application Serial No. 15/912,447 Entitled: Treatment of Pediatric Brain Tumors with Targeting of CD47 Pathway. First Named Inventor: Sharareh Gholamin, Your Ref.: S17-082, Our Ref.: STAN-1400No other potential conflicts of interest were reported.

X-linked lymphoproliferative disease type 1 (XLP1) is a primary immunodeficiency disorder caused by pathogenic variants in the SH2D1A gene (SH2 domain containing protein 1A). Patients with XLP1 may present acutely with fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, and/or B-cell non-Hodgkin lymphoma (B-NHL). We report a boy who developed 2 clonally distinct B-NHL 4 years apart and was found to have previously unrecognized XLP1. The report highlights the importance of clonal analysis and XLP1 testing in males with presumed late recurrences of B-NHL, and the role of allogeneic stem cell transplant (allo-SCT) in XLP1 patients and their affected male relatives., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Alterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-ALL) but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-ALL with IKZF1 alterations., Objective: To determine whether focal deletions within the λ variable chain region in chromosome 22q11.22 were associated with patients with B-ALL with IKZF1 alterations with the highest risk of relapse and/or death., Design, Setting, and Participants: This cohort study included 1310 primarily high-risk pediatric patients with B-ALL who were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts (AALL0232 [2004-2011], P9906 [2000-2003], and patients with Down syndrome who were pooled from national and international studies) and 3 single-institution cohorts (University of Utah [Salt Lake City], Children's Hospital of Philadelphia [Philadelphia, Pennsylvania], and St. Jude Children's Hospital [Memphis, Tennessee]). Data analysis began in 2011 using patients from the older studies first, and data analysis concluded in 2021., Exposures: Focal 22q11.22 deletions., Main Outcomes and Measures: Event-free and overall survival was investigated. The hypothesis that 22q11.22 deletions stratified the prognostic effect of IKZF1 alterations was formulated while investigating nearby deletions in VPREB1 in 2 initial cohorts (n = 270). Four additional cohorts were then obtained to further study this association (n = 1040)., Results: This study of 1310 patients with B-ALL (717 male [56.1%] and 562 female patients [43.9%]) found that focal 22q11.22 deletions are frequent (518 of 1310 [39.5%]) in B-ALL and inconsistent with physiologic V(D)J recombination. A total of 299 of 1310 patients with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, more than half shared concomitant focal 22q11.22 deletions (159 of 299 [53.0%]). Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates, 43.3% vs 68.5%; hazard ratio [HR], 2.18; 95% CI, 1.54-3.07; P < .001; 5-year overall survival rates, 66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001). While 22q11.22 deletions were not prognostic in patients with wild-type IKZF1 , concomitant 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for event-free survival (HR, 2.05; 95% CI, 1.27-3.29; P = .003) and overall survival (HR, 1.83; 95% CI, 1.01-3.34; P = .05)., Conclusions and Relevance: This cohort study suggests that 22q11.22 deletions identify patients with B-ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine B-ALL risk stratification and treatment strategies.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Bacterial L-asparaginase has played an important role in ALL treatment for several decades; however, hypersensitivity reactions to Escherichia coli-derived asparaginases often preclude their use. Inability to receive asparaginase due to hypersensitivities is associated with poor patient outcomes. Erwinia chrysanthemi-derived asparaginase (ERW) is an effective, non-cross-reactive treatment option, but is limited in supply. Consequently, alternative asparaginase preparations are needed to ensure asparaginase availability for patients with hypersensitivities. Recombinant technology can potentially address this unmet need by programming cells to produce recombinant asparaginase. JZP-458, a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform with no immunologic cross-reactivity to E. coli-derived asparaginases, has the same primary amino acid sequence as ERW, with comparable activity based on in vitro measurements. The efficient manufacturing of JZP-458 would provide an additional asparaginase preparation for patients with hypersensitivities., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy representing 25% of all cancers in children less than 15 years of age. Significant improvements in survival and cure rates have been made over the past four decades in pediatric ALL treatment. Asparaginases, derived from Escherichia coli and Erwinia chrysanthemi , have become a critical component of ALL therapy since the 1960s. Asparaginases cause depletion of serum asparagine, leading to deprivation of this critical amino acid for protein synthesis, and hence limit survival of lymphoblasts. Pegaspargase, a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase, has become an integral component of pediatric upfront and relapsed ALL protocols due to its longer half-life and improved immunogenicity profile compared to native asparaginase preparations. Over the past two decades great strides have been made in outcomes for pediatric ALL due to risk stratification, incorporation of multiagent chemotherapy protocols, and central nervous system prophylaxis with pegaspargase having played an important role in this success. However, adolescents and young adults (AYA) with ALL when treated on contemporaneous trials using adult ALL regimens, continue to have poor outcomes. There is increasing realization of adapting pediatric trial regimens for treating AYAs, especially those incorporating higher intensity of chemotherapeutic agents with pegaspargase being one such agent. Dose or treatment-limiting toxicity is observed in 25-30% of patients, most notable being hypersensitivity reactions. Other toxicities include asparaginase-associated pancreatitis, thrombosis, liver dysfunction, osteonecrosis, and dyslipidemia. Discontinuation or subtherapeutic levels of asparaginase are associated with inferior disease-free survival leading to higher risk of relapse, and in cases of relapse, a higher risk for remission failure. This article provides an overview of available evidence for use of pegaspargase in pediatric acute lymphoblastic leukemia., Competing Interests: Anupam Verma, Cynthia Bender and Maria Carter have no conflicts of interest to report in this work. Luke Maese has served as consultant and has received honoraria from Jazz Pharmaceuticals., (© 2021 Bender et al.)

Purpose: The therapeutic utility of Cannabis in cancer is a topic of intense interest. Dronabinol is synthetic Δ 9 -tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa , and is approved for treating refractory chemotherapy-induced nausea and vomiting. Little is known about dronabinol prescribing in children and young adults, and no published concentration data are available. This study evaluated national level dronabinol use and assessed concentrations of THC and its primary metabolites in patients with cancer <27 years of age prescribed dronabinol. Methods: Observational review of records from the Pediatric Health Information System (PHIS) and a regional network of hospitals in the Intermountain West, including a tertiary care children's hospital, Primary Children's Hospital (PCH), for inpatients <27 years of age prescribed dronabinol. Prospective blood samples were collected from children with cancer at PCH. Results: Across PHIS institutions, overall dronabinol prescribing aligned with the pharmacy records for those with cancer ( p  < 0.0001), and of these, 10.4% received dronabinol as inpatients. Blood collected within 72 hours of dronabinol administration was available from 10 children with a median age of 12.5 (range 6-17) years. Quantifiable concentrations were found in 4 (13%), 6 (20%), and 1 (3%) samples assayed for THC, 11-nor-9-carboxy-Δ 9 -tetrahydrocannabinol (COOH-THC), and 11-hydroxy-Δ 9 -tetrahydrocannabinol (OH-THC), respectively. THC concentrations ranged between 0.100 and 0.128 ng/mL and were not associated with dose. Conclusion: Dronabinol prescribing appears exclusive to patients diagnosed with cancer, and its use has increased steadily in the past decade. In a small sample of children administered dronabinol, THC and metabolite concentrations were consistently low or undetectable.

Bone marrow necrosis (BMN) is a rare pathologic finding, but when encountered is most often associated with malignancy. In adults, its presence correlates with an inferior prognosis, however in children the prognostic implication is unclear. We performed a retrospective review of 3,760 bone marrow specimens in patients ≤18 years over a 10-year period. BMN was identified in less than 1% of specimens and only in patients with leukemia, lymphoma, or neuroblastoma. BMN contributed to a delay in diagnosis; however, advanced medical imaging may serve as a tool to localize nonnecrotic areas for bone marrow sampling, facilitating an expedited diagnosis., (© 2020 Wiley Periodicals LLC.)

Background: Although febrile neutropenia (FN) is a frequent complication in children with cancer receiving chemotherapy, there remains significant variability in selection of route (intravenous [IV] vs oral) and length of therapy. We implemented a guideline with a goal to change practice from using IV antibiotics after hospital discharge to the use of step-down oral therapy with levofloxacin for most children with FN until absolute neutrophil count > 500. The objectives of this study were to determine the impact of this guideline on home IV antibiotic use, and to evaluate the safety of implementation of this guideline., Methods: We performed a quasi-experimental, pre-post study of discharge FN treatment at a stand-alone children's hospital in patients without bacteremia discharged between January 2013 and October 2018. In January 2015, a multidisciplinary team created a guideline to switch most children with FN to oral levofloxacin, which was formally implemented as of September 2017. Discharges during the postintervention period (after September 2017) were compared to discharges in the preintervention period (between January 2013 and December 2014)., Results: In adjusted multivariable regression analyses, the postimplementation period was associated with a decrease in home IV antibiotics (adjusted risk ratio [aRR], 0.07 [95% confidence interval {CI}, .03-.13]) and fewer IV antibiotic initiations within 24 hours of a new healthcare encounter up to 7 days after discharge (aRR, 0.39 [95% CI, .17-.93]) compared to the preintervention time period., Conclusions: Step-down oral levofloxacin for children with FN who are afebrile with an ANC ≤ 500 at discharge is feasible and resulted in similar clinical outcomes compared to home IV antibiotics., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts., Materials and Methods: Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort., Results: We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants ( ATM , CDKN1C ) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with FOXO1 fusion-negative RMS patients versus the patients with FOXO1 fusion-positive RMS. We identified pathogenic germline variants in CSGs previously ( TP53 , NF1 , DICER1 , mismatch repair genes), rarely ( BRCA2 , CBL , CHEK2 , SMARCA4 ), or never ( FGFR4 ) reported in RMS. Numerous genes ( TP53 , BRCA2 , mismatch repair) were on the ACMG Secondary Findings 2.0 list., Conclusion: In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Talia Wegman-OstroskyTravel, Accommodations, Expenses: PfizerDonald A. BarkauskasEmployment: Genentech Stock and Other Ownership Interests: Genentech Patents, Royalties, Other Intellectual Property: U.S. patent based on Ph.D. research in glioblastomaLuke D. MaeseHonoraria: Jazz Pharmaceuticals Consulting or Advisory Role: Jazz PharmaceuticalsSean V. TavtigianPatents, Royalties, Other Intellectual Property: I hold patents on BRCA1, BRCA2, and PTEN. However, the claims in these patents related to genetic testing have been overturned by the US Supreme Court. Continuing claims are irrelevant to the paper. My royalty stream ended more than 2 years ago.Anna GoldenbergResearch Funding: 4UandMeDouglas S. HawkinsResearch Funding: Loxo, Bristol-Myers Squibb, Merck Sharp Dohme, Bayer, Lilly, Eisai, Amgen, Seattle Genetics, Incyte, Jazz Pharmaceuticals Travel, Accommodations, Expenses: Loxo, Bayer, Celgene, AstraZenecaJoshua D. SchiffmanEmployment: PEEL Therapeutics, Inc. Leadership: PEEL Therapeutics, Inc. Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics, Inc. Honoraria: Affymetrix Consulting or Advisory Role: N-of-One, Fabric GenomicsJaved KhanResearch Funding: Lentigen Patents, Royalties, Other Intellectual Property: Monoclonal antibody-based therapeutics targeting fibroblast growth factor receptor 4 (FGFR4) for potential treatment of human cancers expressing FGFR4David MalkinConsulting or Advisory Role: Bayer, CanadaDouglas R. StewartEmployment: Genome Medical, LLC No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Background: Li-Fraumeni Syndrome (LFS) is a rare cancer-predisposing condition caused by germline mutations in TP53. Conventional wisdom and prior work has implied an increased risk of secondary malignancy in LFS patients treated with radiation therapy (RT); however, this risk is not well-characterized. Here we describe the risk of subsequent malignancy and cancer-related death in LFS patients after undergoing RT for a first or second primary cancer., Methods: We reviewed a multi-institutional hereditary cancer registry of patients with germline TP53 mutations who were treated from 2004 to 2017. We assessed the rate of subsequent malignancy and death in the patients who received RT (RT group) as part of their cancer treatment compared to those who did not (non-RT group)., Results: Forty patients with LFS were identified and 14 received RT with curative intent as part of their cancer treatment. The median time to follow-up after RT was 4.5 years. Fifty percent (7/14) of patients in the curative-intent group developed a subsequent malignancy (median time 3.5 years) compared to 46% of patients in the non-RT group (median time 5.0 years). Four of seven subsequent malignancies occurred within a prior radiation field and all shared histology with the primary cancer suggesting recurrence rather than new malignancy., Conclusion: We found that four of14 patients treated with RT developed in-field malignancies. All had the same histology as the primary suggesting local recurrences rather than RT-induced malignancies. We recommend that RT should be considered as part of the treatment algorithm when clinically indicated and after multidisciplinary discussion., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Advancements in technology that enhance our understanding of the biology of the disease, risk-adapted therapy, and enhanced supportive care have contributed to improved survival rates. However, additional clinical management is needed to improve outcomes for patients classified as high risk at presentation (eg, T-ALL, infant ALL) and who experience relapse. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric ALL provide recommendations on the workup, diagnostic evaluation, and treatment of the disease, including guidance on supportive care, hematopoietic stem cell transplantation, and pharmacogenomics. This portion of the NCCN Guidelines focuses on the frontline and relapsed/refractory management of pediatric ALL.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a spectrum of underlying genetic alterations that activate kinase or cytokine receptor signaling. Ph-like ALL occurs at all ages but is most common in adolescents and young adults and is postulated to be a factor in the inferior outcomes in this age group. Ph-like ALL confers a poor prognosis with conventional chemotherapy and the pediatric and adult oncology communities are conducting trials utilizing molecularly targeted approaches. In parallel, the role of immunotherapy is being assessed for this unique and biologically diverse ALL subgroup., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: Patients with germline TP53 pathogenic variants (Li-Fraumeni syndrome [LFS]) are at extremely high lifetime risk of developing cancer. Recent data suggest that tumor surveillance for patients with LFS may improve survival through early cancer detection. The objective of this study was to assess the cost-effectiveness of a cancer surveillance strategy for patients with LFS compared with those whose tumors present clinically., Methods: A Markov decision analytic model was developed from a third-party payer perspective to estimate cost-effectiveness of routine cancer surveillance over a patient's lifetime. The model consisted of four possible health states: no cancer, cancer, post-cancer survivorship, and death. Model outcomes were costs (2015 United States Dollars [USD]), effectiveness (life years [LY] gained), and incremental cost-effectiveness ratio (ICER; change in cost/LY gained). One-way sensitivity analyses and probabilistic sensitivity analyses examined parameter uncertainty., Results: The model showed a mean cost of $46 496 and $117 102 and yielded 23 and 27 LY for the nonsurveillance and surveillance strategies, respectively. The ICER for early cancer surveillance versus no surveillance was $17 125 per additional LY gained. At the commonly accepted willingness to pay threshold of $100 000/life-year gained, surveillance had a 98% probability of being the most cost-effective strategy for early cancer detection in this high-risk population., Conclusions: Presymptomatic cancer surveillance is cost-effective for patients with germline pathogenic variants in TP53. Lack of insurance coverage or reimbursement in this population may have significant consequences and leads to undetected cancers presenting in later stages of disease with worse clinical outcomes., (© 2019 Wiley Periodicals, Inc.)

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently identified high risk disease subtype characterized by a gene expression profile similar to that observed in Philadelphia chromosome-positive (Ph-positive) ALL, but without an underlying BCR-ABL1 translocation. Adults and children with Ph-like ALL harbor a diversity of alterations that all lead to activated kinase signaling. Outcomes for patients with Ph-like ALL are poor, which has prompted investigation into the role of tyrosine kinase inhibitor (TKI)-based therapies for this disease. Several clinical trials are now ongoing that include screening for the Ph-like signature and treatment of patients with Ph-like ALL with TKI therapy. This review examines how testing for Ph-like ALL is being incorporated into clinical trials., (Copyright © 2017. Published by Elsevier Ltd.)

There is a known association of primary nonseminomatous mediastinal germ cell tumors (NSMGCT) and hematologic malignancy in younger males not linked to treatment. When combined these two rare entities convey a very poor prognosis. Here we report a 16-year-old male with an anterior mediastinal mass diagnosed as a malignant germ cell tumor based on elevation of serologic markers. He was found to have acute leukemia with megakaryocytic differentiation several days later. We focus our report on the pathologic findings, including a review of the literature, and a novel molecular analysis of the germ cell tumor.

Cell fate specification requires precise coordination of transcription factors and their regulators to achieve fidelity and flexibility in lineage allocation. The transcriptional repressor growth factor independence 1 (GFI1) is comprised of conserved Snail/Slug/Gfi1 (SNAG) and zinc finger motifs separated by a linker region poorly conserved with GFI1B, its closest homolog. Moreover, GFI1 and GFI1B coordinate distinct developmental fates in hematopoiesis, suggesting that their functional differences may derive from structures within their linkers. We show a binding interface between the GFI1 linker and the SP-RING domain of PIAS3, an E3-SUMO (small ubiquitin-related modifier) ligase. The PIAS3 binding region in GFI1 contains a conserved type I SUMOylation consensus element, centered on lysine-239 (K239). In silico prediction algorithms identify K239 as the only high-probability site for SUMO modification. We show that GFI1 is modified by SUMO at K239. SUMOylation-resistant derivatives of GFI1 fail to complement Gfi1 depletion phenotypes in zebrafish primitive erythropoiesis and granulocytic differentiation in cultured human cells. LSD1/CoREST recruitment and MYC repression by GFI1 are profoundly impaired for SUMOylation-resistant GFI1 derivatives, while enforced expression of MYC blocks granulocytic differentiation. These findings suggest that SUMOylation within the GFI1 linker favors LSD1/CoREST recruitment and MYC repression to govern hematopoietic differentiation., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)