RESUMEN
We present 4 children (diagnosed between 1 and 8 y, 3 females and 1 male) with molecularly distinct tectal gliomas (2 KRAS mutant, 1 EGFR mutant, 1 SRGAP3-RAF-1 fusion) that contributes to the growing literature of this uncommonly biopsied tumor. The patient with EGFR R222C mutation had a more severe course, earlier diagnosis, subsequent leptomeningeal metastatic disease, required more aggressive therapies, and died 9 years after diagnosis. Patients with KRAS mutations and SRGAP3-RAF-1 fusion had a more indolent course. Our series expands the molecular phenotype of tectal glioma with the potential for leptomeningeal dissemination. Future studies on establishing genotypic/phenotypic correlation from those who undergo biopsy are needed.
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Neoplasias Encefálicas , Neoplasias del Tronco Encefálico , Glioma , Femenino , Masculino , Humanos , Glioma/genética , Glioma/patología , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/diagnóstico , Neoplasias del Tronco Encefálico/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptores ErbB/genética , Mutación , Neoplasias Encefálicas/genéticaRESUMEN
PURPOSE: To highlight the clinical, neuroradiographic, neuropathologic, and molecular features of histologically identified neurocytoma in a pediatric cohort and highlight the evolving use methylation profiling in providing diagnostic clarity in difficult to diagnosis pediatric brain tumors. METHODS: Five consecutive children (ages 9-13, 2 girls 3 boys) were histologically diagnosed with neurocytoma at Rady Children's Hospital San Diego from 2012 to 2018. Clinical and molecular features were analyzed with regards to treatment course and outcome. RESULTS: Presenting symptoms included seizures (n = 2), syncope (n = 1), headache (n = 2), visual disturbances (n = 2) and emesis (n = 2). Tumor location included intraventricular (n = 2), intraventricular with parenchymal spread (n = 1), and extraventricular (n = 2). Magnetic resonance imaging demonstrated reduced diffusivity (2/5), signal abnormality on susceptibility-weighted sequences (3/5), and varying degrees of contrast enhancement (4/5). All patients underwent surgical resection alone. Recurrence occurred in four children that were treated with surgery (4/4), adjuvant radiation (2/4), and chemoradiation (1/4). Neuropathologic features included positivity for GFAP (4/5), synaptophysin (4/5), NSE (2/2), NeuN (4/4), and variable Ki-67 (< 1% to 15%). Next generation sequencing (3/5) and microarray (3/5) collectively were abnormal in four of five tumors. Methylation profiling was successfully performed on four of five samples which led to modification of diagnosis in two patients and the others were either unclassifiable or confirmatory with the histologic diagnosis. Mean time to follow up was 77 months (range 44-112 months). Mean progression free survival and overall survival were 24 months (range 6 to 52 months) and 100% respectively. CONCLUSION: Neurocytomas are a rare clinical entity that warrants further investigation into molecular and pathologic prognosticating features. Methylation profiling may aid in differentiation of neurocytoma from other difficult to diagnose tumors who share similar histologic features.
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Neoplasias Encefálicas , Neurocitoma , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Niño , Femenino , Humanos , Antígeno Ki-67 , Imagen por Resonancia Magnética , Masculino , Metilación , Neurocitoma/patología , SinaptofisinaRESUMEN
Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genodermatosis characterized by benign cutaneous tumors (fibrofolliculomas, trichodiscomas, and acrochordons), basal lung cysts, pneumothoraces, and a 20% to 30% lifetime risk for renal cancer. There are isolated cases of other cancers in BHDS reported in the literature, including oncocytoma, rhabdomyoma, melanoma, thyroid cancer, meningioma, colon cancer, and breast cancer, but only the increased renal cancer risk has been substantiated. This is the case of a 9-year-old girl who presented with a leiomyosarcoma whose tumor genetic analysis showed FLCN c.365_372del, p.Arg122Leufs*8. She was diagnosed with BHDS when the same mutation was confirmed in her germline lymphocytes. This is the second known reported case of leiomyosarcoma in BHDS.
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Síndrome de Birt-Hogg-Dubé/complicaciones , Mutación de Línea Germinal , Leiomiosarcoma/diagnóstico , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , Síndrome de Birt-Hogg-Dubé/genética , Niño , Femenino , Humanos , Leiomiosarcoma/etiología , Leiomiosarcoma/patología , PronósticoRESUMEN
Successful use of immune checkpoint inhibitors in a variety of cancers has generated interest in using this approach in pediatric brain tumors. We performed a retrospective review of 10 consecutive children (6 boys, 4 girls; ages, 2 to 17 y), with recurrent or refractory pediatric brain tumors (5 high-grade glioma, 1 low-grade glioma, pineoblastoma, medulloblastoma, ependymoma, and CNS embryonal tumor, NOS) treated at Rady Children's Hospital San Diego from 2015 to 2017 with the immune checkpoint inhibitor nivolumab (3 mg/kg every 2 wk). Eight of 10 patients received prior chemotherapy and 9 radiation therapy. Nine patients had radiographic disease progression (median, 2.5 doses). Median time to progression was 5.5 weeks (1.6 to 24 wk). Three patients (2 with high-grade glioma, 1 with CNS embryonal tumor NOS) showed a partial response to treatment at the primary tumor site and 2 of 3 had progression of metastatic disease. Grade 2 toxicities were observed without dose limiting side effects. Tumor mutation burden (TMB) was low to intermediate (median, 1.3; range, 0 to 6.3). Median survival for PD-L1 positive patients was 13.7 weeks versus 4.2 weeks for PD-L1 negative patients (ρ=0.08) nivolumab was well tolerated in our series of pediatric recurrent brain tumors with some transient partial responses in patients with positive PD-L1 expression and higher TMB. Our findings suggest that the use of immune checkpoint inhibitors in pediatric brain tumor patients should be limited to those with elevated PD-L1 expression and TMB.
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Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nivolumab/uso terapéutico , Adolescente , Neoplasias Encefálicas/patología , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
INTRODUCTION: Bevacizumab-based therapy has been demonstrated to be effective in the treatment of refractory or recurrent pediatric low-grade glioma (LGG); however its efficacy as a single agent is less understood. METHODS: We report our experience with single-agent bevacizumab for the treatment of recurrent or refractory LGG treated with either standard 2 week dosing (10 mg/kg/dose every 2 weeks) or with a standard 2 week dosing followed by an increased interval dosing (10 mg/kg/dose every 4 weeks). RESULTS: From 2012 to 2017, 15 patients (five males and 10 females) with recurrent/refractory LGG (nine suprasellar, three thalamic, two brainstem, and one intramedullary spinal cord) were treated with a total of 156 doses of bevacizumab (115 every 2 week dosing, 41 every 4 week dosing, median 10 doses). Patients were refractory to a median of one nonsurgical therapy (range 0-3) prior to treatment with bevacizumab. Twelve of 15 demonstrated radiographic response (three complete, nine partial, and three stable disease). Significant clinical responses including improved visual fields (four), cranial neuropathy (three3), strength (seven), and gait (two) were observed. Bevacizumab was discontinued in 12 patients (resolution, one; disease stability, seven; progression, two; toxicity, one; and other, one) and three patients continue to receive monthly bevacizumab. Eleven patients eventually had radiographic progression (median 5 months, range 0.5-31) without clinical progression, and four of five receiving bevacizumab rechallenge had lpartial response. CONCLUSION: Single-agent bevacizumab is efficacious in the management of recurrent or refractory pediatric LGG with radiographic and clinical responses similar to those reported for bevacizumab-based therapies.
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Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias del Tronco Encefálico/diagnóstico por imagen , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Niño , Preescolar , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Glioma/diagnóstico por imagen , Glioma/secundario , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroimagen , Supervivencia sin Progresión , Estudios Retrospectivos , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/tratamiento farmacológico , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers. PATIENTS AND METHODS: Patients, age 3-21 years, with progressive/recurrent pLGG received everolimus orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy. RESULTS: Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median follow-up of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P = .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P < .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients. CONCLUSION: Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.
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Everolimus , Glioma , Humanos , Niño , Femenino , Preescolar , Adolescente , Adulto Joven , Adulto , Masculino , Everolimus/efectos adversos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt , Fosfatidilinositol 3-Quinasas , Glioma/tratamiento farmacológico , Glioma/genética , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/uso terapéutico , BiomarcadoresRESUMEN
OBJECTIVE: We describe our single-institutional experience with magnetic resonance-guided stereotactic laser ablation (SLA) for the treatment of newly diagnosed and recurrent pediatric brain tumors. METHODS: Eighteen consecutive ablation procedures were performed in 17 patients from March 2016-April 2020. Patient demographics, indications, procedures, neuroimaging features, and outcomes were reviewed retrospectively. RESULTS: Seventeen patients (mean age of 11.4 years, 11 boys, 6 girls) underwent SLA with a mean follow-up of 24 months (range: 3-45 months). Tumor histologies included pilocytic astrocytoma (n = 5), ganglioglioma (n = 3), low-grade glioma not otherwise specified (n = 4), glioblastoma (n = 2), meningioma (n = 1), medulloblastoma (n = 1), and metastatic malignant peripheral nerve sheath tumor (n = 1). SLA was first-line therapy in 10 patients. Mean procedure duration including anesthesia time was 328 minutes (range: 244-529 minutes), and mean postoperative length of stay was 1.5 days (range 1-5 days). The complication rate was 29%, which included 3 patients who experienced postoperative motor changes, which resolved within several weeks of surgery, 1 patient with self-limited intraoperative bradycardia and hypotension, and 1 patient who died postoperatively due to intracranial hemorrhage from a distant lesion. Twelve of 17 patients had a neuroimaging response after SLA (4 complete responses, 8 partial responses, 1 stable disease). Percentage of tumor shrinkage from baseline ranged from 33%-100% (mean 75%). Patients with low-grade glioma exhibited the best responses to SLA (range 3%-100% decrease; mean 90%; 36% complete response rate). CONCLUSIONS: SLA is a minimally invasive modality for the treatment of newly diagnosed and recurrent low-grade pediatric brain tumors. Low-grade glioma exhibited the best responses. Identification of ideal candidates for SLA, mitigation of perioperative complications, and demonstration of long-term outcomes need to be better defined in a clinical trial setting.
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Neoplasias Encefálicas/cirugía , Terapia por Láser/métodos , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Técnicas Estereotáxicas , Cirugía Asistida por Computador/métodos , Adolescente , Anestesia , Niño , Preescolar , Femenino , Humanos , Complicaciones Intraoperatorias/epidemiología , Tiempo de Internación , Masculino , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: Biopsies of tumors located in deep midline structures require highly accurate stereotaxy to safely obtain lesional tissue suitable for molecular and histological analysis. Versatile platforms are needed to meet a broad range of technical requirements and surgeon preferences. The authors present their institutional experience with the robotic stereotactic assistance (ROSA) system in a series of robot-assisted biopsies of pediatric brainstem and thalamic tumors. METHODS: A retrospective analysis was performed of 22 consecutive patients who underwent 23 stereotactic biopsies of brainstem or thalamic lesions using the ROSA platform at Rady Children's Hospital in San Diego between December 2015 and January 2020. RESULTS: The ROSA platform enabled rapid acquisition of lesional tissue across various combinations of approaches, registration techniques, and positioning. No permanent deficits, major adverse outcomes, or deaths were encountered. One patient experienced temporary cranial neuropathy, and 3 developed small asymptomatic hematomas. The diagnostic success rate of the ROSA system was 91.3%. CONCLUSIONS: Robot-assisted stereotactic biopsy of these lesions may be safely performed using the ROSA platform. This experience comprises the largest clinical series to date dedicated to robot-assisted biopsies of brainstem and diencephalic tumors.
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Biopsia/métodos , Neoplasias del Tronco Encefálico/patología , Tronco Encefálico/patología , Procedimientos Quirúrgicos Robotizados/métodos , Técnicas Estereotáxicas , Enfermedades Talámicas/patología , Tálamo/patología , Adolescente , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Neoplasias del Tronco Encefálico/diagnóstico , Niño , Preescolar , Femenino , Glioma/diagnóstico , Glioma/patología , Hematoma/etiología , Humanos , Imagenología Tridimensional , Masculino , Posicionamiento del Paciente , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Técnicas Estereotáxicas/efectos adversos , Enfermedades Talámicas/diagnóstico , Adulto JovenRESUMEN
Angiomatoid fibrous histiocytoma is a rare soft tissue tumor usually discovered in young individuals. This tumor is often mistaken for a hematoma and typically misdiagnosed. It is commonly found in the extremities and may be associated with a site of recent or previous trauma. Characteristic histology includes nodules of histiocytoid spindle cells with pseudoangiomatoid spaces, fibrous pseudocapsules, and lymphoid cuffing. We describe the case of an 8-year-old girl who presented after incision and drainage of a superficial thigh lesion and experienced subsequent chronic bleeding of her wound. Her initial presentation was concerning for an underlying bleeding disorder, and laboratory analysis uncovered a paraneoplastic platelet function disorder that resolved with therapy of the primary tumor.
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Histiocitoma Fibroso Maligno/complicaciones , Deficiencia de Almacenamiento del Pool Plaquetario/etiología , Neoplasias de los Tejidos Blandos/complicaciones , Niño , Diagnóstico Diferencial , Femenino , Hematoma/diagnóstico , Histiocitoma Fibroso Maligno/cirugía , Humanos , Neoplasias de los Tejidos Blandos/cirugía , Muslo/lesiones , Resultado del TratamientoRESUMEN
For many cancers the use of conventional chemotherapy has been maximized, and further intensification of chemotherapy generally results in excess toxicity with little long-term benefit for cure. Many tumors become resistant to chemotherapy, making the investigation of novel approaches such as immunotherapy of interest. Because the tumor microenvironment is known to promote immune tolerance and down regulate the body's natural defense mechanisms, modulating the immune system with the use of dendritic cell (DC) therapy is an attractive approach. Thousands of patients with diverse tumor types have been treated with DC vaccines. While antigen specific immune responses have been reported, the duration and magnitude of these responses are typically weak, and objective clinical responses have been limited. DC vaccine generation and administration is a multi-step process with opportunities for improvement in source of DC for vaccine, selection of target antigen, and boosting effector cell response via administration of vaccine adjuvant or concomitant pharmacologic immunomodulation. In this review we will discuss recent developments in each of these areas and highlight elements that could be moved into pediatric clinical trials.
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Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Células Dendríticas/inmunología , Neoplasias/terapia , Niño , HumanosRESUMEN
The development of an independent blood supply by a tumor is essential for maintaining growth beyond a certain limited size and for providing a portal for metastatic dissemination. Host-derived endothelial cells (ECs) residing in and compromising the tumor vasculature originate via distinct processes known as sprouting angiogenesis and vasculogenesis. More recently ECs originating directly from the tumor cells themselves have been described although the basis for this phenomenon remains poorly understood. Here we describe in vitro conditions that allow lung and ovarian cancer cells to undergo a rapid and efficient transition into ECs that are indistinguishable from those obtained in vivo. A variety of methods were used to establish that the acquired phenotypes and behaviors of these tumor-derived ECs (TDECs) closely resemble those of authentic ECs. Xenografts arising from co-inoculated in vitro-derived TDECs and tumor cells were also more highly vascularized than control tumors; moreover, their blood vessels were on average larger and frequently contained admixtures of host-derived ECs and TDECs derived from the initial inoculum. These results demonstrate that cancer cells can be manipulated under well-defined in vitro conditions to initiate a tumor cell-to-EC transition that is largely cell-autonomous, highly efficient and closely mimics the in vivo process. These studies provide a suitable means by which to identify and perhaps modify the earliest steps in TDEC generation.