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BACKGROUND: Many parents of children with advanced cancer report curative goals and continue intensive therapies that can compound symptoms and suffering. Factors that influence parents to choose palliation as the primary treatment goal are not well understood. The objective of this study was to examine experiences impacting parents' report of palliative goals adjusted for time. The authors hypothesized that awareness of poor prognosis, recall of oncologists' prognostic disclosure, intensive treatments, and burdensome symptoms and suffering would influence palliative goal-setting. METHODS: The authors collected prospective, longitudinal surveys from parents of children with relapsed/refractory neuroblastoma at nine pediatric cancer centers across the United States, beginning at relapse and continuing every 3 months for 18 months or until death. Hypothesized covariates were examined for possible associations with parental report of palliative goals. Generalized linear mixed models were used to evaluate factors associated with parents' report of palliative goals at different time points. RESULTS: A total of 96 parents completed surveys. Parents were more likely to report a primary goal of palliation when they recalled communication about prognosis by their child's oncologist (odds ratio [OR], 52.48; p = .010). Treatment intensity and previous ineffective therapeutic regimens were not associated with parents' report of palliative goals adjusted for time. A parent who reported new suffering for their child was less likely to report palliative goals (OR, 0.13; p = .008). CONCLUSIONS: Parents of children with poor prognosis cancer may not report palliative goals spontaneously in the setting of treatment-related suffering. Prognostic communication, however, does influence palliative goal-setting. Evidence-based interventions are needed to encourage timely, person-centered prognostic disclosure in the setting of advanced pediatric cancer. PLAIN LANGUAGE SUMMARY: Many parents of children with poor-prognosis cancer continue to pursue curative treatments that may worsen symptoms and suffering. Little is known about which factors influence parents to choose palliative care as their child's main treatment goal. To explore this question, we asked parents of children with advanced neuroblastoma across the United States to complete multiple surveys over time. We found that the intensity of treatment, number of treatments, and suffering from treatment did not influence parents to choose palliative goals. However, when parents remembered their child's oncologist talking about prognosis, they were more likely to choose palliative goals of care.
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Neuroblastoma , Cuidados Paliativos , Niño , Humanos , Objetivos , Estudios Prospectivos , Recurrencia Local de Neoplasia/terapia , Neuroblastoma/terapia , Padres , Encuestas y Cuestionarios , Estudios LongitudinalesRESUMEN
BACKGROUND: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib. METHODS: Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response. RESULTS: Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed. CONCLUSION: Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual. CLINICALTRIALS.GOV IDENTIFIER: NCT03233204. IRB approved: initial July 24, 2017.
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Reparación del ADN , Neoplasias , Ftalazinas , Piperazinas , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Adulto Joven , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Mutación de Línea Germinal , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Ftalazinas/uso terapéutico , Ftalazinas/efectos adversos , Ftalazinas/administración & dosificación , Piperazinas/uso terapéutico , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversosRESUMEN
OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. METHODS: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. RESULTS: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85). CONCLUSION: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.
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ARN Helicasas DEAD-box , Neoplasias Ováricas , Blastoma Pulmonar , Sistema de Registros , Ribonucleasa III , Tumor de Células de Sertoli-Leydig , Humanos , Tumor de Células de Sertoli-Leydig/patología , Tumor de Células de Sertoli-Leydig/cirugía , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , ARN Helicasas DEAD-box/genética , Blastoma Pulmonar/patología , Adulto , Ribonucleasa III/genética , Persona de Mediana Edad , Adulto Joven , Anciano , Masculino , Adolescente , Quimioterapia Adyuvante , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Tumores de los Cordones Sexuales y Estroma de las Gónadas/cirugía , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugíaRESUMEN
Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.
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Proteínas de Ciclo Celular/genética , Receptor con Dominio Discoidina 2/genética , Fibrosarcoma/diagnóstico , Neoplasias Renales/diagnóstico , Proteínas Asociadas a Microtúbulos/genética , Recurrencia Local de Neoplasia/genética , Nefroma Mesoblástico/diagnóstico , Proteínas de Fusión Oncogénica/genética , Serina Endopeptidasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Carcinoma/genética , Preescolar , Femenino , Fibrosarcoma/genética , Pruebas Genéticas , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Neoplasias Renales/congénito , Neoplasias Renales/genética , Masculino , Persona de Mediana Edad , Nefroma Mesoblástico/congénito , Nefroma Mesoblástico/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Análisis de Secuencia de ARN , Proteína ETS de Variante de Translocación 6RESUMEN
BACKGROUND: Vorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD. METHODS: Isotretinoin (cis-13-retinoic acid) 80 mg/m2 /dose was administered by mouth twice daily on days 1-14 in combination with escalating doses of daily vorinostat up to 430 mg/m2 /dose (days 1-4; 8-11) in each 28-day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed. RESULTS: Twenty-nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1-15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose-limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2 /day, days 1-4; 8-11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen. CONCLUSIONS: Increased dose vorinostat (430 mg/m2 /day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Isotretinoína/administración & dosificación , Masculino , Dosis Máxima Tolerada , Recurrencia Local de Neoplasia/patología , Neuroblastoma/patología , Pronóstico , Tasa de Supervivencia , Vorinostat/administración & dosificación , Adulto JovenRESUMEN
More than half of all sarcomas occur in adolescents and young adults (AYAs) aged 15 to 39 years. After the publication of the AYA series in the April 1, 2016 issue of Cancer, several leaders in the field of sarcoma across disciplines gathered to discuss the status of sarcoma clinical research in AYAs. They determined that a focused effort to include the underrepresented and understudied AYA population in current and future sarcoma clinical trials is overdue. Trial enrichment for AYA-aged sarcoma patients will produce more meaningful results that better represent the disease's biology, epidemiology, and treatment environment. To address the current deficit, this commentary outlines changes believed to be necessary to expediently achieve an increase in the enrollment of AYAs in sarcoma clinical trials. Cancer 2017;123:3434-40. © 2017 American Cancer Society.
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Neoplasias Óseas/terapia , Ensayos Clínicos como Asunto , Osteosarcoma/terapia , Selección de Paciente , Adolescente , Adulto , Factores de Edad , American Cancer Society , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Femenino , Humanos , Masculino , Osteosarcoma/mortalidad , Osteosarcoma/patología , Evaluación de Resultado en la Atención de Salud , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/patología , Sarcoma de Ewing/terapia , Análisis de Supervivencia , Estados Unidos , Adulto JovenRESUMEN
Secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) is a rare but devastating complication of solid tumor treatment involving high-dose topoisomerase II inhibitor and alkylator chemotherapy. For relapsed or elderly MDS and AML patients ineligible for hematopoietic stem cell transplantation, epigenetic therapies, including DNA methyltransferase inhibitors and histone deacetylase inhibitors, have been utilized as palliative therapy, offering a well-tolerated approach to disease stabilization, prolonged survival, and quality of life. Literature on the use of epigenetic therapies for both primary and relapsed disease is scarce in the pediatric population. Here, we report 2 pediatric patients with secondary AML and MDS, respectively, due to prior therapy for metastatic solid tumors. Both patients were ineligible for hematopoietic stem cell transplantation due to concurrent solid tumor relapse, but were treated with the epigenetic combination therapy, decitabine and vorinostat, and achieved stabilization of marrow disease, outpatient palliation, and family-reported reasonable quality of life.
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Azacitidina/análogos & derivados , Ácidos Hidroxámicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Adolescente , Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Decitabina , Quimioterapia Combinada/métodos , Epigénesis Genética , Femenino , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Cuidados Paliativos , Calidad de Vida , VorinostatRESUMEN
BACKGROUND: Alveolar soft part sarcoma is a rare soft tissue sarcoma that is characterized by a pattern of slow growth with metastases to the lung, bone, and brain that is not responsive to conventional cytotoxic chemotherapy. OBSERVATIONS: We describe 2 patients, with a combined 19 years of treatment experience including multiple different chemotherapeutic and targeted therapy regimens, surgery, and radiotherapy. We also present a review of the literature regarding treatment options to highlight recent findings. CONCLUSIONS: Alveolar soft part sarcoma is an indolent, but persistently progressive disease. Novel therapeutic agents hold promise in its management.
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Metástasis de la Neoplasia/patología , Sarcoma de Parte Blanda Alveolar/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Terapia Combinada/métodos , Femenino , Humanos , Radioterapia , Sarcoma de Parte Blanda Alveolar/patología , Procedimientos Quirúrgicos OperativosRESUMEN
BACKGROUND: Introducing whole genome sequencing (WGS) into pediatric cancer research at diagnosis poses unique challenges related to informed consent. WGS requires tissue obtained prior to initiating treatment, when families may be overwhelmed with uncertainty and fear. Motivation to participate may be high without fully understanding the range of possible results, including secondary findings. Little is known about parental knowledge, attitudes, and beliefs about this type of research. PROCEDURE: A qualitative study was conducted to investigate parental knowledge about genetic concepts and WGS, thoughts about the informed consent process, and preferences for secondary findings. Focus groups were conducted with parents/guardians of children with cancer and semi-structured interviews were conducted in a control group without cancer. All transcripts were analyzed using content analysis. RESULTS: Four focus groups included 15 participants; eight semi-structured interviews included 10 participants. Basic knowledge about genetics was limited to heredity. Some knowledge of genomic analysis was present in 3/15 focus group participants. Major factors related to participation in WGS research were: (i) hope for their child and future children; (ii) no additional procedures; (iii) and protection of privacy. All favored a two-step consent process, first to store extra tissue from a diagnostic biopsy/resection, followed by consenting to WGS research, one-to-two months later. The desire to receive secondary findings was high among both groups, but there were individuals who did not want these results, fearing increased anxiety. CONCLUSIONS: Parents/guardians of children with cancer have limited knowledge about WGS. A two-step consent process may improve their ability to provide meaningful informed consent.
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Mapeo Cromosómico , Conocimientos, Actitudes y Práctica en Salud , Consentimiento Paterno/psicología , Padres/psicología , Análisis de Secuencia de ADN , Investigación Biomédica , Toma de Decisiones , Femenino , Grupos Focales , Genoma Humano/genética , Humanos , Hallazgos Incidentales , Masculino , Padres/educación , Selección de PacienteRESUMEN
Multiple large-scale tumor genomic profiling efforts have been undertaken in osteosarcoma, however, little is known about the spatial and temporal intratumor heterogeneity and how it may drive treatment resistance. We performed whole-genome sequencing of 37 tumor samples from eight patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. We identified subclonal copy number alterations in all but one patient. We observed that in five patients, a subclonal copy number clone from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clone in 6 out of 7 patients with more than one clone. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy number clones. Our study sheds light on intratumor heterogeneity and the potential drivers of treatment resistance in osteosarcoma.
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Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease. SIGNIFICANCE: The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
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Neoplasias Óseas , Osteosarcoma , Humanos , Osteosarcoma/genética , Secuenciación Completa del Genoma , Genómica , Neoplasias Óseas/genética , Recurrencia , Variaciones en el Número de Copia de ADN , MutaciónRESUMEN
Adolescents and young adults (AYAs) require a multidisciplinary approach to cancer care due to their complex biopsychosocial situations and varied developmental maturity. Currently, age and diagnosis determine referral to pediatric or adult oncology, with differing treatment paradigms and service utilization patterns, contributing to suboptimal improvements in outcomes. Understanding the unique perspectives of AYAs is essential to designing patient-centered AYA services. Thus, we conducted six focus groups with AYAs (n = 25) treated by medical or pediatric oncologists to evaluate: (1) the unique experiences of cancer care as an AYA; (2) AYA-specific information needs and communication preferences; and (3) recommendations for service provision, delivery and accommodations for AYAs. Transcripts were analyzed using inductive thematic content analysis and identified six major themes to inform clinically-actionable recommendations and the development of a patient-reported outcome measure: (1) AYAs experience social isolation and loss of independence; (2) AYAs have an uncertain sense of the future and need conversations around survivorship and long-term and late effects; (3) AYAs desire greater control over discussions with their care team; (4) AYAs need additional navigational and social/caregiver supports; (5) AYAs prefer an inclusive AYA space in the hospital; and (6) LGBTQ+ patients experience distinct concerns as AYA cancer patients. These will form the basis for specific and tailored clinical recommendations to improve AYA cancer care delivery.
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The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control and TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations include TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.
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Neoplasias Óseas , Osteosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Genómica , Humanos , Sarcoma/tratamiento farmacológico , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/genéticaRESUMEN
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.
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Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias , Adolescente , Adulto , Biomarcadores de Tumor/genética , Niño , Preescolar , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Lactante , Recién Nacido , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Estudios Prospectivos , Adulto JovenRESUMEN
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.
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Neoplasias/genética , Secuenciación Completa del Genoma/normas , Adolescente , Adulto , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Masculino , Medicina de Precisión/métodos , Medicina de Precisión/normas , Medicina de Precisión/tendencias , Secuenciación Completa del Genoma/métodos , Secuenciación Completa del Genoma/estadística & datos numéricosRESUMEN
BACKGROUND: To evaluate the neuropsychological late effects amongst survivors treated on the Head Start II protocol between 1997 and 2003. PROCEDURES: Forty-nine patients (mean age 2.9 years) diagnosed with a malignant brain tumor underwent baseline neuropsychological assessment prior to autologous hematopoietic cell transplantation (AuHCT). Twenty-six survivors were retested after 3 years of follow-up as 20 patients did not survive. Patients were evaluated for intelligence, academic achievement, receptive language, visual-motor integration (VMI), learning/memory, social-emotional and behavioral functioning based upon age at testing. RESULTS: Overall intelligence and VMI at baseline were low average while verbal and non-verbal intelligence, academic achievement, and receptive vocabulary were in average range. Parents reported social-emotional and behavioral functioning within normal limits. Serial testing revealed Full Scale (FSIQ)/Mental Development Index (MDI), Verbal (VIQ), and Performance (PIQ) Intelligence to be generally stable over 3-year follow-up. Group-average analysis at follow-up demonstrated low average intelligence, academic achievement, receptive language, and VMI. Age at diagnosis was positively correlated with internalizing symptoms and visual immediate memory, while time since diagnosis was inversely correlated with FSIQ, VIQ, PIQ, reading and delayed verbal memory. Craniospinal irradiation (CSI) was avoided in two-thirds of patients. CONCLUSION: Induction, with or without intensification using intravenous methotrexate, followed by myeloablative consolidation chemotherapy with AuHCT, may avoid or delay CSI, with possible stabilization of neuropsychological functioning, including those younger at diagnosis. Continued follow-up is necessary to determine the preservation of neuropsychological, academic, social-emotional and behavioral functioning.
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Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/psicología , Trasplante de Células Madre Hematopoyéticas , Inteligencia/efectos de los fármacos , Neoplasias Encefálicas/radioterapia , Niño , Preescolar , Terapia Combinada , Irradiación Craneana/efectos adversos , Irradiación Craneana/métodos , Femenino , Humanos , Masculino , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Pruebas Neuropsicológicas , Desempeño Psicomotor/efectos de los fármacos , SobrevivientesRESUMEN
Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). Hypertension is a well-recognized, common side effect of VEGF blocking agents. The reversible posterior leukoencephalopathy syndrome (RPLS) has been described as a rare but serious consequence of bevacizumab administration. We present a case of a 6-year-old child with refractory hepatoblastoma who developed hypertensive crisis, seizures and MRI changes consistent with RPLS while receiving bevacizumab with gemcitabine and oxaliplatin. Findings completely resolved without neurologic sequelae with stringent blood-pressure control. Better understanding of risk for RPLS, prompt recognition and aggressive management will be required as bevacizumab gains wider use in pediatrics.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia , Síndrome de Leucoencefalopatía Posterior/tratamiento farmacológico , Síndrome de Leucoencefalopatía Posterior/inmunología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Bevacizumab , Presión Sanguínea/efectos de los fármacos , Preescolar , Resultado Fatal , Humanos , Inmunoterapia/efectos adversos , Imagen por Resonancia Magnética , Masculino , Estadificación de Neoplasias , Síndrome de Leucoencefalopatía Posterior/patología , Síndrome de Leucoencefalopatía Posterior/fisiopatologíaRESUMEN
INTRODUCTION: Nutritional status (NS), defined by undernutrition (body mass index [BMI] <5th percentile) or overnutrition (BMI â¯≥â¯85th percentile), is a poor prognostic indicator in pediatric oncology patients. The impact of NS has been primarily studied in hematologic malignancies. This review is intended to summarize literature reporting on the association of NS and treatment-related outcomes in pediatric solid tumors. METHODS: We searched four electronic databases from inception through August 2018 without language restriction, and included studies of children with cancers arising from renal, bone, liver, eye, muscle, vascular, germ cell, and neural crest tissues, reporting on NS as a predictor for toxicity, survival or relapse. Due to data heterogeneity and limited availability of studies, formal statistical analysis was not achievable. Descriptive statistics were summarized in table format. RESULTS: Of 8,991 reports identified, 75 full-text articles were evaluated, 10 of which met inclusion criteria. Up to 62% of patients were over- or undernourished at diagnosis. Abnormal BMI was associated with worse overall survival in Ewing sarcoma (hazard ratio (HR): 3.46, Pâ¯=â¯.022), osteosarcoma (HR: 1.6, P < .005), and a trend toward poorer overall survival in rhabdomyosarcoma (HR: 1.70, Pâ¯=â¯.0596). High BMI in osteosarcoma was associated with increased nephrotoxicity (odds ratio: 2.8, Pâ¯=â¯.01) and postoperative complications. NS was not a significant predictor of outcomes in other included disease categories. CONCLUSIONS: Existing literature supports the prognostic significance of NS in pediatric solid tumor patients and underscores the need for prospective studies to better elucidate underlying physiological changes in this population.