Inv(3) Acute Myeloid Leukemia in a Young Adult and Review of the Literature.

Acute myeloid leukemia (AML) with the high-risk variant inv(3)/t(3;3) or t(3;3)(q21;26.2) is rarely seen in the pediatric and young adult population. It is associated with poor outcomes with ineffective therapeutic options. Here, we present a case of an 18-year-old female with treatment refractory inv(3) AML in whom remission was unable to be obtained. Better treatment options are needed given the increased resistance to traditional therapy this subtype portrays. Here, we review the literature on pediatric and young adult inv(3) AML along with newer therapeutic options.

Pediatric Central Nervous System Tumor Overview and Emerging Treatment Considerations.

Pediatric central nervous system (CNS) tumors are the most common solid tumor in children, with the majority being glial in origin. These tumors are classified by the World Health Organization (WHO) as either being low grade (WHO grade 1 and 2) or high grade (WHO grade 3 and 4). Our knowledge of the molecular landscape of pediatric brain tumors has advanced over the last decade, which has led to newer categorizations along with an expansion of therapeutic targets and options. In this review, we will give an overview of common CNS tumors seen in children along with a focus on treatment options and future considerations.

Concurrent high-grade glioma with cavernous malformations and pathogenic variants in PDCD10 and SMARCA4.

The co-occurrence of multiple disease processes can pose diagnostic challenges. We report an unusual case of a patient found to have co-occurrences of an IDH1-mutant high-grade glioma along with cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. Somatic testing was done on the tumor and identified a SMARCA4 and two TP53 variants. Within the literature, little is known about the association of high-grade gliomas with these germline variants. Such findings furthermore not only inform complex diagnoses, but have the potential to play a crucial role in the ongoing care of a patient.

Hemangioblastoma and mosaic von Hippel Lindau disease: rare presentation and review of the literature.

Hemangioblastomas are benign vascular tumors that can occur throughout the central nervous system (CNS) sporadically or in association with von Hippel-Lindau (VHL) disease. We present a case of an 11-year-old girl with a hemangioblastoma that tested negative for germline mutation of VHL disease at the time of diagnosis. Our patient went on to have multiple recurrences and further areas of concern for disease within the CNS. Repeat VHL testing was pursued many years later and remained negative for germline mutations. However, next-generation sequencing (NGS) testing on prior tumor tissue returned positive for VHL somatic mutations. The diagnosis of VHL mosaicism has important implications on management and risk of recurrence of hemangioblastoma, along with the need for close follow-up with surveillance imaging.

Indolent presentation of a diffuse midline glioma, H3 K27-altered.

Diffuse midline glioma (DMG), H3 K27-altered, are aggressive central nervous system tumors which are universally fatal, with a median survival of 8-12 months after diagnosis. Here, we present a patient who was incidentally found to have a lesion, concerning for tumor, within the right thalamus on brain magnetic resonance imaging at 2 years of age. Twelve years later, subsequent imaging showed that the lesion had enlarged, with biopsy consistent with DMG harboring an H3 K27M mutation. This case illustrates an unusual presentation of a DMG, H3 K27-altered, with an indolent course. Such findings highlight the fact that more research is needed to understand what factors may contribute to these tumors' malignant course.

Expenditures in Young Adults with Hodgkin Lymphoma: NCI-Designated Comprehensive Cancer Centers versus Other Sites.

BACKGROUND: Outcomes among Hodgkin lymphoma (HL) patients diagnosed between 22 and 39 years are worse than among those diagnosed <21 years, and have not seen the same improvement over time. Treatment at an NCI-designated Comprehensive Cancer Center (CCC) mitigates outcome disparities, but may be associated with higher expenditures. METHODS: We examined cancer-related expenditures among 22- to 39-year-old HL patients diagnosed between 2001 and 2016 using deidentified administrative claims data (OptumLabs Data Warehouse; CCC: n = 1,154; non-CCC: n = 643). Adjusting for sociodemographics, clinical characteristics, and months enrolled, multivariable general linear models modeled average monthly health-plan paid (HPP) expenditures, and incidence rate ratios compared CCC/non-CCC monthly visit rates. RESULTS: In the year following diagnosis, CCC patients had higher HPP expenditures ($12,869 vs. $10,688, P = 0.001), driven by higher monthly rates of CCC nontreatment outpatient hospital visits (P = 0.001) and per-visit expenditures for outpatient hospital chemotherapy ($632 vs. $259); higher CCC inpatient expenditures ($1,813 vs. $1,091, P = 0.001) were driven by 3.1 times higher rates of chemotherapy admissions (P = 0.001). Out-of-pocket expenditures were comparable (P = 0.3). CONCLUSIONS: Young adults with HL at CCCs saw higher health-plan expenditures, but comparable out-of-pocket expenditures. Drivers of CCC expenditures included outpatient hospital utilization (monthly rates of non-therapy visits and per-visit expenditures for chemotherapy). IMPACT: Higher HPP expenditures at CCCs in the year following HL diagnosis likely reflect differences in facility structure and comprehensive care. For young adults, it is plausible to consider incentivizing CCC care to achieve superior outcomes while developing approaches to achieve long-term savings.

Disparities in Female Pediatric, Adolescent and Young Adult Oncofertility: A Needs Assessment.

Advancements in cancer screening and implementation of targeted treatments have significantly improved survival rates to 85% for pediatric and AYA survivors. Greater than 75% of survivors will live to experience the long-term adverse outcomes of cancer therapies, termed late effects (LE), that disrupt quality of life (QoL). Infertility and poor reproductive outcomes are significant disruptors of QoL in survivorship, affecting 12-88% of survivors who receive at-risk therapies. To mitigate risk, fertility preservation (FP) counseling is recommended as standard of care prior to gonadotoxic therapy. However, disparities in FP counseling, implementation of FP interventions, and screening for gynecologic late effects in survivorship persist. Barriers to care include a lack of provider and patient knowledge of the safety and breadth of current FP options, misconceptions about the duration of time required to implement FP therapies, cost, and health care team bias. Developing strategies to address barriers and implement established guidelines are necessary to ensure equity and improve quality of care across populations.

Expenditures among young adults with acute lymphoblastic leukemia by site of care.

BACKGROUND: Individuals diagnosed with acute lymphoblastic leukemia (ALL) between the ages of 22 and 39 years experience worse outcomes than those diagnosed when they are 21 years old or younger. Treatment at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) mitigates these disparities but may be associated with higher expenditures. METHODS: Using deidentified administrative claims data (OptumLabs Data Warehouse), the cancer-related expenditures were examined among patients with ALL diagnosed between 2001 and 2014. Multivariable generalized linear model with log-link modeled average monthly health-plan-paid (HPP) expenditures and amount owed by the patient (out-of-pocket [OOP]). Cost ratios were used to calculate excess expenditures (CCC vs non-CCC). Incidence rate ratios (IRRs) compared CCC and non-CCC monthly visit rates. Models adjusted for sociodemographics, comorbidities, adverse events, and months enrolled. RESULTS: Clinical and sociodemographic characteristics were comparable between CCC (n = 160) and non-CCC (n = 139) patients. Higher monthly outpatient expenditures in CCC patients ($15,792 vs $6404; P < .001) were driven by outpatient hospital HPP expenditures. Monthly visit rates and per visit expenditures for nonchemotherapy visits (IRR = 1.6; P = .001; CCC = $8247, non-CCC = $1191) drove higher outpatient hospital expenditures among CCCs. Monthly OOP expenditures were higher at CCCs for outpatient care (P = .02). Inpatient HPP expenditures were significantly higher at CCCs ($25,918 vs $13,881; ꞵ = 0.9; P < .001) before accounting for adverse events but were no longer significant after adjusting for adverse events (ꞵ = 0.4; P = .1). Hospitalizations and length of stay were comparable. CONCLUSIONS: Young adults with ALL at CCCs have higher expenditures, likely reflecting differences in facility structure, billing practices, and comprehensive patient care. It would be reasonable to consider CCCs comparable to the oncology care model and incentivize the framework to achieve superior outcomes and long-term cost savings. LAY SUMMARY: Health care expenditures in young adults (aged 22-39 years) with acute lymphoblastic leukemia (ALL) are higher among patients at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) than those at non-CCCs. The CCC/non-CCC differences are significant among outpatient expenditures, which are driven by higher rates of outpatient hospital visits and outpatient hospital expenditures per visit at CCCs. Higher expenditures and visit rates of outpatient hospital visits among CCCs may also reflect how facility structure and billing patterns influence spending or comprehensive care. Young adults at CCCs face higher inpatient HPP expenditures; these are driven by serious adverse events.

Necrotizing myositis in a rectus muscle arising in the setting of long-standing Langerhans cell histiocystosis and recent dabrafenib treatment.

PURPOSE: to describe an unusual case of necrotizing myositis in a rectus muscle, possibly related to BRAF inhibitor therapy. OBSERVATIONS: An 18-year old man with neurodegenerative Langerhans cell histiocytosis (LCH), recently started on the BRAF inhibitor dabrafenib, presented with right eye pain. Magnetic resonance imaging (MRI) orbits revealed a rectus muscle mass concerning for LCH recurrence or malignancy. Dabrafenib was stopped, and incisional biopsy of the mass was performed. The mass was absent on post-operative MRI, so no further treatment was pursued. Histopathologic evaluation was initially concerning for sarcoma, but on further analysis, appeared more consistent with necrotizing myositis. The mass did not recur, nor did the patient develop other signs or symptoms concerning for myositis or malignancy over a 24-month follow-up period. CONCLUSIONS: Necrotizing myositis has not been previously described in a rectus muscle or with BRAF inhibitor use, though myalgias and malignancies are established side effects. Necrotizing myositis may masquerade as sarcoma and should be on the differential diagnosis for a new mass in the setting of dabrafenib therapy.

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

Isobaric Labeling Strategy Utilizing 4-Plex N,N-Dimethyl Leucine (DiLeu) Tags Reveals Proteomic Changes Induced by Chemotherapy in Cerebrospinal Fluid of Children with B-Cell Acute Lymphoblastic Leukemia.

The use of mass spectrometry for protein identification and quantification in cerebrospinal fluid (CSF) is at the forefront of research efforts to identify and explore biomarkers for the early diagnosis and prognosis of neurologic disorders. Here we implemented a 4-plex N,N-dimethyl leucine (DiLeu) isobaric labeling strategy in a longitudinal study aiming to investigate protein dynamics in children with B-cell acute lymphoblastic leukemia (B-cell ALL) undergoing chemotherapy. The temporal profile of CSF proteome during chemotherapy treatment at weeks 5, 10-14, and 24-28 highlighted many differentially expressed proteins, such as neural cell adhesion molecule, neuronal growth regulator 1, and secretogranin-3, all of which play important roles in neurodegenerative diseases. A total of 63 proteins were significantly altered across all of the time points investigated. The most over-represented biological processes from gene ontology analysis included platelet degranulation, complement activation, cell adhesion, fibrinolysis, neuron projection, regeneration, and regulation of neuron death. We expect that results from this and future studies will provide a means to monitor neurotoxicity and develop strategies to prevent central nervous system injury in response to chemotherapy in children.

Quantitative Glycomic Analysis by Mass-Defect-Based Dimethyl Pyrimidinyl Ornithine (DiPyrO) Tags and High-Resolution Mass Spectrometry.

We recently developed a novel amine-reactive mass-defect-based chemical tag, dimethyl pyrimidinyl ornithine (DiPyrO), for quantitative proteomic analysis at the MS1 level. In this work, we further extend the application of the DiPyrO tag, which provides amine group reactivity, optical detection capability, and improved electrospray sensitivity, to quantify N-linked glycans enzymatically released from glycoproteins in the glycosylamine form. Duplex DiPyrO tags that differ in mass by 45.3 mDa were used to label the glycosylamine moieties of freshly released N-glycosylamines from glycoprotein standards and human serum proteins. We demonstrate that both MALDI-LTQ-Orbitrap and nano-HILIC LC/MS/MS Fusion Lumos Orbitrap platforms are capable of resolving the singly or multiply charged N-glycans labeled with mass-defect DiPyrO tags. Dynamic range of quantification, based on MS1 peak intensities, was evaluated across 2 orders of magnitude. With optimized N-glycan release conditions, glycosylamine labeling conditions, and MS acquisition parameters, the N-glycan profiles and abundances in human serum proteins of cancer patients before and after chemotherapy were compared. Moreover, this study also opens a door for using well-developed amine-reactive tags for relative quantification of glycans, which could be widely applied.

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Evidence to incorporate inclusive reproductive health measures in guidelines for childhood and adolescent cancer survivors.

OBJECTIVE: Female childhood cancer survivors are at an increased risk of reproductive health impairment. We compared reproductive health outcomes with the recommended standard in a cohort of childhood cancer survivors. STUDY DESIGN AND PARTICIPANTS: A retrospective chart review of 222 female childhood cancer survivors aged 21 years or younger that presented to a tertiary referral center between 1997-2008 was initiated. The main outcome measures were the compliance with the American Society of Clinical Oncology guidelines for childhood cancer survivor management of reproductive health. In particular, we evaluated menstrual cycle regularity, fertility preservation counseling, and endocrine profile, as defined by follicle stimulating hormone (FSH) and anti-mullerian hormone (AMH) levels as surrogate markers for ovarian reserve. Secondary outcomes were to study the contribution of survivor clinics in enforcing these guidelines. RESULTS: Of 136 patients older than 13 years at their last visit, 58 patients (43%) had FSH data available and none had AMH data. Patients were stratified into 3 groups according to FSH levels. Forty of 58 patients (69%) have normal ovarian reserve (FSH level < 10), 10 of 58 patients (17%) have decreased ovarian reserve (FSH levels 10-40), and 8 of 58 patients (14%) have premature menopause, defined as FSH > 40. Most patients with amenorrhea have elevated FSH levels indicating primary ovarian insufficiency, while 3 patients (2.2%) have low FSH levels consistent with hypothalamic amenorrhea. None of the patients were counseled on fertility preservation. CONCLUSIONS: Reproductive health follow-up in children with cancer, including FSH and AMH measurement when indicated, should be established and strictly adhered.

Socioeconomic disparities in the quality of life in children with cancer or brain tumors: the mediating role of family factors.

OBJECTIVE: This study aimed to determine if and to what extent (i) socioeconomic disparities exist in the health-related quality of life (QOL) of children with cancer or brain tumors and healthy children; and (ii) family functioning and burden mediate the relationship between socioeconomic status and children's QOL. METHODS: In this cross-sectional study, parents of children ages 2-18 with (n = 71) and without (n = 135) cancer or brain tumors completed in-person interviewer-assisted surveys assessing sociodemographics (including income and parental education), child QOL (measure: PedsQL), family functioning (measure: Family Adaptability and Cohesion Evaluation Scale IV) and burden (measure: Impact on the Family Scale). For children with cancer, clinical characteristics were captured through medical record abstraction. Multiple linear regression was used to determine the relationship between income and child QOL; the interaction between group status and income was assessed. Staged multivariate regression models were used to assess the role of family factors in this relationship among children with cancer. RESULTS: In multivariate analyses, the effect of income differed by cancer status; lower income was associated with worse QOL in children with cancer but not among healthy children. Among children with cancer, this relationship was significantly attenuated by family burden. CONCLUSIONS: Significant socioeconomic disparities exist in the QOL of children with cancer. Family factors partially explain the relationship between low income and poor QOL outcomes among these children. Lower-income families may have fewer resources to cope with their child's cancer. Increased support, monitoring, and referrals to reduce burden for these families may lead to improved QOL in children with cancer.

Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside.

BACKGROUND: Central nervous system (CNS) complications of Langerhans cell histiocytosis (LCH) include mass lesions and a neurodegenerative (ND) syndrome with ataxia, dysarthria, dysmetria, learning and behavior difficulties and/or characteristic changes on brain MRIs. Hydrocephalus has rarely been reported in LCH. LCH lesions of the orbit, mastoid and temporal bones ("CNS-Risk" lesions) and diabetes insipidus predispose patients to ND-CNS-LCH. Treatment options have been limited and only a case series using trans-retinoic acid (ATRA) and intravenous immunoglobulin (IVIG) have been published. METHODS: We have used cytosine arabinoside (ARA-C) with or without vincristine to treat eight patients with ND-CNS LCH. PATIENTS: Seven male children and one young adult male with clinical and radiologic ND-CNS-LCH were treated with a regimen of vincristine 1.5 mg/m(2) on day 1 and ARA-C 100 mg/m(2) daily for 5 days or ARA-C alone monthly for 4-19 months. Seven patients were evaluated with an ataxia rating scale (ARS) and all with serial MRIs of the brain. RESULTS: Five of seven patients had decreases in their ARS scores and/or decreased T2 hyperintense lesions on MRI images. Grade 2 neutropenia was the most frequent adverse event. Vincristine-associated neuropathy occurred in two patients. Hydrocephalus caused symptoms and signs that confounded the diagnosis and management of ND-CNS-LCH in all four patients affected with both. CONCLUSIONS: Subtle changes in neurologic function may be complicated by hydrocephalus. Vcr/ARA-C or ARA-C were an effective therapies for some ND-CNS LCH patients. A clinical trial using this and possibly other modalities such as IVIG or ATRA should be done.

A phase II study of preradiotherapy chemotherapy followed by hyperfractionated radiotherapy for newly diagnosed high-risk medulloblastoma/primitive neuroectodermal tumor: a report from the Children's Oncology Group (CCG 9931).

PURPOSE: To verify feasibility and monitor progression-free survival and overall survival in children with high-risk medulloblastoma and noncerebellar primitive neuroectodermal tumors (PNETs) treated in a Phase II study with preradiotherapy chemotherapy (CHT) followed by high-dose, hyperfractionated craniospinal radiotherapy (CSRT). METHODS AND MATERIALS: Eligibility criteria included age >3 years at diagnosis, medulloblastoma with either high M stage and/or >1.5 cm(2) postoperative residual disease, and all patients with noncerebellar PNET. Treatment was initiated with five alternating monthly cycles of CHT (A [cisplatin, cyclophosphamide, etoposide, and vincristine], B [carboplatin and etoposide], A, B, and A) followed by hyperfractionated CSRT (40 Gy) with a boost to the primary tumor (72 Gy) given in twice-daily 1-Gy fractions. RESULTS: The valid study group consisted of 124 patients whose median age at diagnosis was 7.8 years. Eighty-four patients (68%) completed the entire protocol according to study guidelines (within 9 months), and the median time to complete CSRT was 1.6 months. Major reasons for failure to complete CHT included progressive disease (17%) and toxic death (2.4%). The 5-year progression-free survival and overall survival rates were 43% +/- 5% and 52% +/- 5%, respectively. No significant differences were detected in subset analysis related to response to CHT, site of primary tumor, postoperative residual disease, or M stage. CONCLUSIONS: The feasibility of this intensive multimodality protocol was confirmed, and response to pre-RT CHT did not impact on survival. Survival data from this protocol can not be compared with data from other studies, given the protocol design.

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PURPOSE: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.