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The Oncofertility Consortium Pediatric Initiative Network has published recommendations about the risks of infertility due to gonadotoxic therapy. We abstracted gonadotoxic therapies from central nervous system (CNS) Children's Oncology Group (COG) protocols between 2000 and 2022. We assigned them as unknown, minimal, significant, or high levels of increased risk for gonadal dysfunction/infertility. Seven of 11 CNS protocols placed patients at a high level of risk in at least one treatment arm. Males (7/11) were most commonly at a high level of risk, followed by pubertal females (6/11) and prepubertal females (5/11), highlighting the importance of pre-treatment counseling regarding fertility preservation interventions in this population.
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Pediatric low-grade gliomas (pLGGs) are the most common brain tumor types affecting children. Although gross-total resection remains the treatment of choice, many tumors are not amenable to complete removal, because they either involve midline structures, such as the optic chiasm or hypothalamus, and are not conducive to aggressive resection, or have diffuse biological features and blend with the surrounding brain. Historically, radiation therapy was used as the second-line option for disease control, but with the recognition that this often led to adverse long-term sequelae, particularly in young children, conventional chemotherapy assumed a greater role in initial therapy for unresectable tumors. A variety of agents demonstrated activity, but long-term disease control was suboptimal, with more than 50% of tumors exhibiting disease progression within 5 years. More recently, it has been recognized that a high percentage of these tumors in children exhibit constitutive activation of the mitogen-activated protein kinase (MAPK) pathway because of BRAF translocations or mutations, NFI mutations, or a host of other anomalies that converged on MAPK. This led to phase 1, 2, and 3 trials that explored the activity of blocking this signaling pathway, and the efficacy of this approach compared to conventional chemotherapy. Despite initial promise of these strategies, not all children tolerate this therapy, and many tumors resume growth once MAPK inhibition is stopped, raising concern that long-term and potentially life-long treatment will be required to maintain tumor control, even among responders. This observation has led to interest in other treatments, such as immunotherapy, that may delay or avoid the need for additional treatments. This chapter will summarize the place of immunotherapy in the current armamentarium for these tumors and discuss prior results and future options to improve disease control, with a focus on our prior efforts and experience in this field.
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Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is associated with various specific cytogenetic and molecular markers that significantly influence treatment and prognosis. Intrachromosomal amplification of chromosome 21 (iAMP21) defines a rare distinct cytogenetic subgroup of childhood B-ALL, which is characterized by amplification of region 21q22.12 comprising the RUNX1 gene. Constitutional structural chromosomal abnormalities involving chromosome 21 confer an increased risk for B-ALL with iAMP21. Here, we report the development of B-ALL with iAMP21 in a 9-year-old child with a constitutional ring chromosome 21, r(21)c, uncovered after B-ALL diagnosis. Cytogenetic and microarray analysis of the post-therapy sample revealed an abnormal chromosome 21 lacking a satellite and having a deletion of the terminal 22q22.3 region, consistent with a constitutional ring chromosome 21, r(21)(p11.2q22). On a retrospective analysis, this ring chromosome was observed in the normal cells in the pre-treatment diagnostic specimen. Constitutional ring chromosome 21 may remain undetected in patients with mild or no neurodevelopmental phenotype, posing an unknown lifelong risk of developing B-ALL with iAMP21. Individuals with constitutional structural chromosome 21 rearrangements such as ring 21 require a close surveillance and long-term follow-up studies to establish their risk of B-ALL relapse and possibility of developing other malignancies. Germline analysis is recommended to all pediatric patients with iAMP21-related B-ALL to rule out structural chromosome 21 rearrangements and to elucidate molecular mechanisms of iAMP21 formation.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Cromosomas en Anillo , Humanos , Cromosomas Humanos Par 21 , Estudios Retrospectivos , Aberraciones Cromosómicas , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
BACKGROUND: Despite widespread use, little is known about how adolescents and young adults (AYA) with cancer use social media (SM). This research characterized use and self-reported SM experiences among AYA with cancer. PROCEDURE: AYA, aged 12-26 years, receiving cancer care completed a mixed-methods survey regarding SM experiences. Clinical information was obtained from the electronic medical record. Data were analyzed with descriptive statistics, t tests, and qualitative content analysis. RESULTS: Thirty-nine AYA with average age 16 (SD = 3.2) years participated. Most were Caucasian (92%) males (54%). Participants had leukemia/lymphoma (56%), solid tumors (33%), and brain tumors (10%). Nearly all (97%) used SM, with YouTube, Snapchat, and Instagram being the most popular. AYA self-reported lower SM use than their smartphone data indicated (2.8 hours/day, SD = 1.2 vs 3.4 hours/day, SD = 1.3; P < 0.001). Participants used SM to obtain information about their cancer (45%), post about cancer (47%), and read about others' cancer experience (50%). One-third made a friend with cancer through SM (32%). Qualitative results indicated that AYA had positive cancer-related SM experiences, including feelings of support (54%), community (27%), distraction (8%), and inspiration (8%). Most denied negative experiences (78%); however, 17% reported cyberbullying related to cancer. CONCLUSIONS: AYA with cancer avidly use SM, noting it provides a sense of support and community. However, one-sixth reported cancer-related cyberbullying. AYA oncology providers have an opportunity to enhance positive and blunt negative SM interactions by addressing and guiding SM use in AYA patients.
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Neoplasias , Medios de Comunicación Sociales , Adolescente , Femenino , Humanos , Masculino , Neoplasias/terapia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Polymerase chain reaction (PCR) respiratory viral panel (RVP) testing is often used in evaluation of pediatric cancer patients with febrile neutropenia (FN), but correlation with adverse outcomes has not been well characterized. PROCEDURE: A retrospective cohort of all children ages 0-21 years with cancer admitted to Children's Healthcare of Atlanta for FN from January 2013 to June 2016 was identified. Patient demographic and clinical variables such as age, RVP results, length of stay (LOS), and deaths were abstracted. Relationship between RVP testing and positivity and LOS, highest temperature (Tmax), hypotension and intensive care unit (ICU) admission were compared using Wilcoxon rank sums, chi-square, or Fisher's exact tests adjusting for age, sex, bacteremia, and diagnosis. RESULTS: The 404 patients identified had 787 total FN admissions. RVPs were sent in 38% of admissions and were positive in 59%. Patients with RVPs sent were younger (median 5.5 vs 8.0 years, P < .0001) with higher Tmax (39.2° vs 39.1°, P = .016). The most common virus identified was rhinovirus/Enterovirus (61%). There were no significant differences in highest temperature or lowest blood pressure based on RVP positivity. Patients admitted to the ICU were more likely to have RVPs sent (odds ratio [OR] = 3.19, P < .002); however, neither having RVP testing nor RVP positivity were significantly associated with increased LOS or death. Coinfection with bacteremia and a respiratory virus was identified in 9.1% of patients. CONCLUSIONS: These data raise the question of the utility of sending potentially costly RVP testing as RVP positivity during febrile neutropenia does not impact LOS, degree of hypotension, or ICU admission.
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ADN Viral/análisis , Fiebre/virología , Neoplasias/complicaciones , Neutropenia/virología , Infecciones del Sistema Respiratorio/virología , Virosis/diagnóstico , Virus/aislamiento & purificación , Adolescente , Adulto , Niño , Preescolar , ADN Viral/genética , Femenino , Fiebre/epidemiología , Estudios de Seguimiento , Georgia/epidemiología , Hospitalización , Humanos , Lactante , Recién Nacido , Tiempo de Internación , Masculino , Neutropenia/epidemiología , Reacción en Cadena de la Polimerasa , Pronóstico , Infecciones del Sistema Respiratorio/epidemiología , Estudios Retrospectivos , Virosis/epidemiología , Virosis/virología , Virus/genética , Adulto JovenRESUMEN
Surgical treatment of deep or difficult to access lesions represents a unique and significant challenge for pediatric neurosurgeons. The introduction of stereotactic magnetic resonance-guided laser interstitial thermal therapy (LITT) over the last decade has had a dramatic impact on the landscape of pediatric neurosurgery. LITT provides a safe and effective option for children with epilepsy from hypothalamic hamartoma that represents a ground-breaking new therapy for a condition which was historically very difficult to treat with previous neurosurgical techniques. LITT has also been used as an alternative surgical technique for mesial temporal sclerosis, focal cortical dysplasia, MR-negative epilepsy, cavernoma-related epilepsy, insular epilepsy, and corpus callosotomy among other epilepsy etiologies. In some cases, LITT has been associated with improved cognitive outcomes compared to standard techniques, as in mesial temporal lobe epilepsy. Initial experiences with LITT for neuro-oncologic processes are also promising. LITT is often attractive to patients and providers as a minimally invasive approach, but the differences in safety and clinical outcome between LITT and traditional approaches are still being studied. In this review, we examine the emerging indications and clinical evidence for LITT in pediatric neurosurgery.
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Hipertermia Inducida , Enfermedades Hipotalámicas , Terapia por Láser , Procedimientos Neuroquirúrgicos/tendencias , Niño , Humanos , Enfermedades Hipotalámicas/cirugía , Rayos Láser , Imagen por Resonancia Magnética , Resultado del TratamientoRESUMEN
Coagulopathy in pediatric leukemia patients is typically associated with acute promyelocytic leukemia or after asparaginase use in acute lymphoblastic leukemia. Rarely seen in acute lymphoblastic leukemia, we report 2 patients who presented with normal coagulation markers, but subsequently developed severe hypofibrinogenemia and bleeding in induction before administration of asparaginase. In both cases, cryoprecipitate was administered as initial treatment for bleeding associated with the hypofibrinogenemia. One patient was refractory to cryoprecipitate replacement and required treatment with human fibrinogen concentrate due to the persistence of hypofibrinogenemia with significant bleeding. The hypofibrinogenemia was transient in both cases and resolved within a few weeks.
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Afibrinogenemia/etiología , Quimioterapia de Inducción/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Asparaginasa/uso terapéutico , Niño , Factor VIII/uso terapéutico , Femenino , Fibrinógeno/uso terapéutico , Hemorragia/etiología , Hemorragia/terapia , Humanos , Quimioterapia de Inducción/métodos , Masculino , Resultado del TratamientoRESUMEN
Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.
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Glioma , Histonas , Animales , Niño , Humanos , Ratones , Quinasas MAP Reguladas por Señal Extracelular , Glioma/genética , Glucólisis , Histonas/genética , Fosfofructoquinasa-2 , Monoéster Fosfórico Hidrolasas , Transducción de SeñalRESUMEN
OBJECTIVE: Social media (SM) is ubiquitous in modern society. How SM provides information, advice, and community to families coping with childhood brain tumors is poorly understood. We sought to understand how caregivers of children with brain tumors use and are affected by SM. METHODS: A survey was administered to caregivers of children who were receiving or within the last 5 years received chemotherapy for pediatric brain tumors. Differences in variables across groups were evaluated using nonparametric tests and chi-square tests. RESULTS: Thirty-five of 36 caregivers acknowledged use of SM. Facebook was the most used platform (86%). Fifty-eight percent and 47% used SM to read and share information about their child's cancer, respectively. Thirty-four percent were comforted while 40% were bothered by cancer-related information on SM. Eleven participants (31%) sought a second opinion based on information from SM. Caregivers of children with a poor prognosis were more likely to use a treatment from SM that was not initially recommended by their oncologist (p = 0.043). CONCLUSION: SM is commonly used by caregivers to obtain and share care-related information. Many noted positive and negative effects of SM on emotional wellness. SM influenced treatment decisions, and this effect was stronger with poorer prognosis. Our results demonstrate the dichotomous impact of SM in medicine-it is a source of both solace and anxiety, a place to confirm treatment decisions and to create doubt in the treatment decisions of the oncologist. This illustrates the importance of discussing SM with caregivers of children with brain tumors.
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Neoplasias Encefálicas , Medios de Comunicación Sociales , Adaptación Psicológica , Neoplasias Encefálicas/terapia , Cuidadores/psicología , Niño , Humanos , Padres/psicologíaRESUMEN
Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.
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Neoplasias Encefálicas , Glioma , Metionina Adenosiltransferasa/metabolismo , Animales , Neoplasias Encefálicas/genética , Epigenoma , Glioma/genética , Histonas/genética , Metionina/genética , RatonesRESUMEN
INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is an almost universally fatal pediatric brain cancer. There has been no improvement in event-free survival (EFS) or overall survival (OS) despite immense effort through a multitude of clinical trials to find a cure. Recently, there has been a surge in the knowledge of DIPG biology, including the discovery of a recurrent H3F3A mutation in over 80% of these tumors. AREAS COVERED: The authors review the most recent approaches to diagnosis and treatment of DIPG including chemotherapy, biologics, surgical approaches, and immunotherapy. EXPERT OPINION: The authors propose four main opportunities to improve long-term survival. First, patients should be enrolled in scientifically sound clinical trials that include molecularly profiling either via stereotactic biopsy or liquid biopsy. Second, clinical trials should include more innovative endpoints other than traditional EFS and OS such as MRI/PET imaging findings combined with surrogates of activity (e.g. serial liquid biopsies) to better ascertain biologically active treatments. Third, innovative clinical trial approaches are needed to help allow for the rapid development of combination therapies to be tested. Finally, effort should be concentrated on reversing the effects of the histone mutation, as this malfunctioning development program seems to be key to DIPG relentlessness.
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Neoplasias del Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/terapia , Neoplasias del Tronco Encefálico/diagnóstico , Neoplasias del Tronco Encefálico/mortalidad , Niño , Glioma Pontino Intrínseco Difuso/diagnóstico , Glioma Pontino Intrínseco Difuso/mortalidad , HumanosRESUMEN
Familial cerebral cavernous malformation syndromes are most commonly caused by mutations in one of three genes. The overlap of these genetic malformations with other acquired neoplastic lesions and congenital malformations is still under investigation. To the best of our knowledge, the concurrent occurrence of familial cavernous malformations and ependymoma has not been previously reported in the literature. Herein, we describe a patient with familial cerebral cavernous malformation syndrome and posterior fossa ependymoma. A 17-year-old asymptomatic male was referred to our outpatient neurosurgery clinic after genetic testing identified a familial KRIT1 (CCM1) mutation. The patient's sister had presented with a seizure disorder previously; multiple cavernous malformations were discovered, and a symptomatic large cavernous malformation required a craniotomy for resection. Two years later, she was diagnosed with follicular thyroid cancer due to HRAS (c.182A>G) mutation. The patient and his sister were found to have a novel germline KRIT1 disease-causing variant (c.1739deletion, p.ASN580Ilefs*2) and a variant of uncertain significance, potentially pathogenic (c.1988 A>G, p.Asn663Ser) in cis in CCM1 (KRIT1), of paternal inheritance. Due to the presence of genetic abnormalities, the patient underwent screening imaging of his neuraxis. Multiple cavernous malformations were identified, as was an incidental fourth ventricular mass. Resection of the fourth ventricular lesion was performed, and histopathological examination was consistent with ependymoma. We report a unique case of posterior fossa ependymoma in an individual with a familial cerebral cavernous malformation syndrome and a novel genetic abnormality in KRIT1. The association of these two findings may be valuable in determining a potential genetic association between the two pathologies and elucidating the pathogenesis of both cavernous malformations and ependymomas.
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Neoplasias del Ventrículo Cerebral/patología , Ependimoma/patología , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Adolescente , Neoplasias del Ventrículo Cerebral/complicaciones , Ependimoma/complicaciones , Femenino , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Humanos , Proteína KRIT1/genética , Masculino , Mutación , Linaje , Pronóstico , SíndromeRESUMEN
Diffuse intrinsic pontine gliomas (DIPG) are incurable brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for patients with DIPG, who have a median survival time of less than one year. Most DIPG cells harbor mutations in genes encoding histone H3 (H3K27M) proteins, resulting in a global reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. Here we show that the H3K27M mutations contribute to RAS pathway signaling, which is augmented by additional RAS activators including PDGFRA. H3K27M mutation led to increased expression of receptor tyrosine kinases (RTK). A RAS pathway functional screen identified ERK5, but not ERK1/2, as a RAS pathway effector important for DIPG growth. Suppression of ERK5 decreased DIPG cell proliferation and induced apoptosis in vitro and in vivo. In addition, depletion or inhibition of ERK5 significantly increased survival of mice intracranially engrafted with DIPG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Collectively, our data demonstrate an underappreciated role of H3K27M in RAS activation and reveal novel therapeutic targets for treating DIPG tumors. SIGNIFICANCE: These findings identify the H3K27M mutation as an enhancer of RAS activation in DIPG and ERK5 as a novel, immediately actionable molecular target. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4026/F1.large.jpg.
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Neoplasias del Tronco Encefálico/metabolismo , Glioma Pontino Intrínseco Difuso/metabolismo , Mutación , Proteínas ras/metabolismo , Compuestos de Anilina/farmacología , Animales , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/patología , Línea Celular Tumoral , Proliferación Celular/genética , Glioma Pontino Intrínseco Difuso/tratamiento farmacológico , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Genes myc , Histonas/genética , Histonas/metabolismo , Humanos , Indoles/farmacología , Lisina/genética , Lisina/metabolismo , Masculino , Ratones SCID , Proteína Quinasa 7 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 7 Activada por Mitógenos/genética , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Células-Madre Neurales/metabolismo , Proto-Oncogenes Mas , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteínas ras/genéticaAsunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Animales , Barrera Hematoencefálica , Xenoinjertos , RatonesRESUMEN
Prolactinomas are a rare subset of brain tumors in pediatrics. We report a child with a prolactin secreting macroadenoma which was refractory to initial treatment with a dopamine antagonist. Given the location of her tumor she was ineligible for surgical resection. Temozolomide (200 mg/m2×5 days each month) was administered with a dramatic and prolonged response in tumor size, prolactin level, and symptoms, with no side effects from treatment. We demonstrate the benefit of temozolomide in the treatment of a pediatric patient with prolactinoma.