RESUMEN
BACKGROUND: Immunotherapy, specifically immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (anti-PD1), has recently received clinical approval for the treatment of adult hepatocellular carcinoma (HCC). However, the safety and efficacy of ICIs prior to solid organ transplant are unknown, especially in pediatrics. Safety reports are variable in adults, with some series describing subsequent allograft rejection and loss while others report successful transplants without allograft rejection.As ICIs stimulate the immune system by blocking the interaction between PD1 and the ligand-receptor pair programmed cell death-ligand 1 (PDL1), the downstream effects of T-cell activation increase the risk of graft rejection. METHODS: Here, we present a case of an adolescent with moderately differentiated non-fibrolamellar HCC treated with pembrolizumab, an anti-PD1 therapy, who subsequently underwent successful orthotopic liver transplantation (OLT). RESULTS: Our patient received an OLT 138 days from the last pembrolizumab dose with graft preservation. The patient has no evidence of recurrent disease or any episode of allograft rejection 48 months post OLT. Staining of tumor and normal tissues from longitudinal specimens finds PDL1 positive Kupffer cells present in normal liver and peritumoral areas with no changes post anti-PD1 therapy. In contrast, tumor cells were negative for PDL1. CONCLUSION: This case represents a basis for optimism in potential use of anti-PD1 therapy in liver transplant candidates and supports further investigation of immune checkpoint inhibitors use in this unique patient population.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Adolescente , Adulto , Carcinoma Hepatocelular/cirugía , Niño , Humanos , Inhibidores de Puntos de Control Inmunológico , Ligandos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugíaRESUMEN
Pigmented epithelioid melanocytoma (PEM) is an intermediate-grade melanocytic tumor with considerable histologic overlap with other melanocytic neoplasms such as epithelioid blue nevus (EBN), which is associated with the neoplastic syndrome Carney complex (CC). Next-generation sequencing is a valuable tool for identifying the primary drivers of melanocytic neoplasms and differentiating them from one another. While germline variants in the protein kinase cAMP-dependent regulatory type 1 alpha (PRKAR1A) gene have been associated with EBN and CC, fusions in protein kinase C-alpha (PRKCA) have been shown as sporadic drivers of PEM. Herein, we report the diagnosis and workup of a case of pigmented epithelioid melanocytoma with a novel protein kinase C-beta (PRKCB) fusion.
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Nevo Azul , Neoplasias Cutáneas , Humanos , Nevo Azul/diagnóstico , Nevo Azul/genética , Nevo Azul/patología , Proteína Quinasa C beta , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/cirugía , Tetraspanina 30RESUMEN
We report a case of disseminated Trichosporon asahii in a patient on systemic antifungal therapy who presented with multiple cutaneous nodules suggestive of fungal infection. Histologic features resembled neutrophilic eccrine hidradenitis but staining with periodic acid-Schiff and Gomori methenamine silver confirmed the clinical diagnosis. This case highlights the importance of maintaining suspicion for trichosporonosis and contextualizing histologic findings within the underlying clinical picture.
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Dermatomicosis , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tricosporonosis , Adolescente , Dermatomicosis/diagnóstico , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/patología , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Tricosporonosis/diagnóstico , Tricosporonosis/tratamiento farmacológico , Tricosporonosis/patologíaRESUMEN
Indications for everolimus and other drugs within the mammalian target of rapamycin inhibitor class have recently expanded to include tuberous sclerosis complex. Everolimus is generally well tolerated, but it is important for physicians to identify and manage associated cutaneous adverse effects. We report the first case of a child developing erythema nodosum while undergoing everolimus therapy.
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Antineoplásicos/efectos adversos , Eritema Nudoso/inducido químicamente , Everolimus/efectos adversos , Esclerosis Tuberosa/tratamiento farmacológico , Adolescente , Antineoplásicos/uso terapéutico , Everolimus/uso terapéutico , Femenino , Humanos , Piel/patologíaRESUMEN
Preventing neuronal death is a priority for treating neurological diseases. However, therapies that inhibit pathological neuron loss could promote tumorigenesis by preventing the physiological death of cancerous cells. To avert this, we targeted the transcriptional upregulation of p21(waf1/cip1) (p21), an endogenous tumor suppressor with neuroprotective and pro-regenerative activity. We identified potential p21 indcuers by screening a FDA-approved drug and natural product small molecule library against hippocampal HT22 cells stably expressing a luciferase reporter driven by the proximal 60bp of the p21 promoter, and tested them for neuroprotection from glutathione depletion mediated oxidative stress, and cytotoxicity to cancer cell lines (DLD-1, Neuro-2A, SH-SY5Y, NGP, CHLA15, CHP212, and SK-N-SH) in vitro. Of the p21 inducers identified, only ciclopirox, a hypoxia-inducible factor prolyl-4-hydroxylase (HIF-PHD) inhibitor, simultaneously protected neurons from glutathione depletion and decreased cancer cell proliferation at concentrations that were not basally toxic to neurons. We found that other structurally distinct HIF-PHD inhibitors (desferrioxamine, 3,4-dihydroxybenzoate, and dimethyloxalyl glycine) also protected neurons at concentrations that killed cancer cells. HIF-PHD inhibitors stabilize HIF transcription factors, mediating genetic adaptation to hypoxia. While augmenting HIF stability is believed to promote tumorigenesis, we found that chronic HIF-PHD inhibition killed cancer cells, suggesting a protumorigenic role for these enzymes. Moreover, our findings suggest that PHD inhibitors can be used to treat neurological disease without significant concern for cell-autonomous tumor promotion.
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Antineoplásicos/farmacología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fármacos Neuroprotectores/farmacología , Inhibidores de Prolil-Hidroxilasa/farmacología , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Células PC12 , Ratas , Bibliotecas de Moléculas PequeñasRESUMEN
MYCN-amplified neuroblastoma often presents as a highly aggressive metastatic disease with a poor prognosis. Activating transcription factor 5 (ATF5) is implicated in neural cell differentiation and cancer cell survival. Here, we show that ATF5 is highly expressed in patients with stage 4 high-risk neuroblastoma, with increased expression correlating with a poorer prognosis. We demonstrated that ATF5 promotes the metastasis of neuroblastoma cell lines in vivo. Functionally, ATF5 depletion significantly reduced xenograft tumor growth and metastasis of neuroblastoma cells to the bone marrow and liver. Mechanistically, ATF5 endows tumor cells with resistance to anoikis, thereby increasing their survival in systemic circulation and facilitating metastasis. We identified the proapoptotic BCL-2 modifying factor (BMF) as a critical player in ATF5-regulated neuroblastoma anoikis. ATF5 suppresses BMF under suspension conditions at the transcriptional level, promoting anoikis resistance, whereas BMF knockdown significantly prevents ATF5 depletion-induced anoikis. Therapeutically, we showed that a cell-penetrating dominant-negative ATF5 peptide, CP-d/n-ATF5, inhibits neuroblastoma metastasis to the bone marrow and liver by inducing anoikis sensitivity in circulating tumor cells. Our study identified ATF5 as a metastasis promoter and CP-d/n-ATF5 as a potential antimetastatic therapeutic agent for neuroblastoma. SIGNIFICANCE: This study shows that resistance to anoikis in neuroblastoma is mediated by ATF5 and offers a rationale for targeting ATF5 to treat metastatic neuroblastoma.
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Antineoplásicos , Neuroblastoma , Humanos , Anoicis/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Neuroblastoma/tratamiento farmacológico , Antineoplásicos/farmacología , Factores de Transcripción ActivadoresRESUMEN
Purpose: The mortality in patients with MYCN-amplified high-risk neuroblastoma remains greater than 50% despite advances in multimodal therapy. Novel therapies are urgently needed that requires preclinical evaluation in appropriate mice models. Combinatorial treatment with high-dose radiotherapy (HDRT) and immunotherapy has emerged as an effective treatment option in a variety of cancers. Current models of neuroblastoma do not recapitulate the anatomic and immune environment in which multimodal therapies can be effectively tested, and there is a need for an appropriate syngeneic neuroblastoma mice model to study interaction of immunotherapy with host immune cells. Here, we develop a novel syngeneic mouse model of MYCN-amplified neuroblastoma and report the relevance and opportunities of this model to study radiotherapy and immunotherapy. Materials and methods: A syngeneic allograft tumor model was developed using the murine neuroblastoma cell line 9464D derived a tumor from TH-MYCN transgenic mouse. Tumors were generated by transplanting 1 mm3 portions of 9464D flank tumors into the left kidney of C57Bl/6 mice. We investigated the effect of combining HDRT with anti-PD1 antibody on tumor growth and tumor microenvironment. HDRT (8 Gy x 3) was delivered by the small animal radiation research platform (SARRP). Tumor growth was monitored by ultrasound. To assess the effect on immune cells tumors sections were co-imuunostained for six biomarkers using the Vectra multispectral imaging platform. Results: Tumor growth was uniform and confined to the kidney in 100% of transplanted tumors. HDRT was largely restricted to the tumor region with minimal scattered out-of-field dose. Combinatorial treatment with HDRT and PD-1 blockade significantly inhibited tumor growth and prolonged mice survival. We observed augmented T-lymphocyte infiltration, especially CD3+CD8+ lymphocytes, in tumors of mice which received combination treatment. Conclusion: We have developed a novel syngeneic mouse model of MYCN amplified high-risk neuroblastoma. We have utilized this model to show that combining immunotherapy with HDRT inhibits tumor growth and prolongs mice survival.
RESUMEN
Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers.
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Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adolescente , Antineoplásicos/uso terapéutico , Niño , Femenino , Humanos , Masculino , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: The biological mechanisms underlying cancer cell motility and invasiveness remain unclear, although it has been hypothesized that they involve some type of epithelial-mesenchymal transition (EMT). METHODS: We used xenograft models of human cancer cells in immunocompromised mice, profiling the harvested tumors separately with species-specific probes and computationally analyzing the results. RESULTS: Here we show that human cancer cells express in vivo a precise multi-cancer invasion-associated gene expression signature that prominently includes many EMT markers, among them the transcription factor Slug, fibronectin, and α-SMA. We found that human, but not mouse, cells express the signature and Slug is the only upregulated EMT-inducing transcription factor. The signature is also present in samples from many publicly available cancer gene expression datasets, suggesting that it is produced by the cancer cells themselves in multiple cancer types, including nonepithelial cancers such as neuroblastoma. Furthermore, we found that the presence of the signature in human xenografted cells was associated with a downregulation of adipocyte markers in the mouse tissue adjacent to the invasive tumor, suggesting that the signature is triggered by contextual microenvironmental interactions when the cancer cells encounter adipocytes, as previously reported. CONCLUSIONS: The known, precise and consistent gene composition of this cancer mesenchymal transition signature, particularly when combined with simultaneous analysis of the adjacent microenvironment, provides unique opportunities for shedding light on the underlying mechanisms of cancer invasiveness as well as identifying potential diagnostic markers and targets for metastasis-inhibiting therapeutics.
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Transición Epitelial-Mesenquimal/genética , Neoplasias/metabolismo , Factores de Transcripción/metabolismo , Animales , Línea Celular Tumoral , Colágeno Tipo XI/metabolismo , Perfilación de la Expresión Génica , Humanos , Ratones , Análisis por Micromatrices , Invasividad Neoplásica/genética , Neoplasias/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factores de Transcripción de la Familia Snail , Especificidad de la EspecieRESUMEN
Cancer of the colon is the second most common visceral cancer in the United States (lung cancer is the first). It is usually diagnosed in patients older than 40 years, with a peak incidence at 70 years of age. Rarely, are cases seen in the pediatric population. In this study, we report a case of a 13-year-old girl with an 11-month history of intermittent abdominal pain whose diagnosis was delayed due to vague symptoms and a low index of suspicion for this condition.
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Dolor Abdominal/diagnóstico por imagen , Adenocarcinoma/diagnóstico por imagen , Carcinoma de Células en Anillo de Sello/diagnóstico por imagen , Neoplasias Retroperitoneales/diagnóstico por imagen , Dolor Abdominal/patología , Dolor Abdominal/cirugía , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adolescente , Carcinoma de Células en Anillo de Sello/patología , Carcinoma de Células en Anillo de Sello/cirugía , Resultado Fatal , Femenino , Humanos , Estadificación de Neoplasias , Neoplasias Retroperitoneales/patología , Neoplasias Retroperitoneales/cirugía , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: The aim of this study is to characterize the effects of high-dose radiation therapy (HDRT) on Notch signaling components of the tumor vasculature. METHODS AND MATERIALS: Human umbilical vein endothelial cells monolayers were exposed to different single fraction doses of irradiation; ribonucleic acid RNA was isolated and polymerase chain reaction was performed for Notch signaling components. The vascular response to radiation therapy was examined in a xenograft model of neuroblastoma. Tumors were treated with 0 Gy, 2 Gy, and 12 Gy single fraction doses and analyzed by double immunofluorescence staining for Notch1, Notch ligands Jagged1 and Dll4, and the endothelial cell (EC) marker endomucin. To assess the role of Notch in vivo, NGP xenograft tumors expressing Fc or Notch1-1-24-decoy (a novel Notch inhibitor) were treated with 0 Gy and 12 Gy. Immunofluorescence staining for endomucin and endomucin/αSMA was performed to analyze the effect of combination treatment on tumor EC and endothelial-to-mesenchymal-transition (EndMT), respectively. RESULTS: In human umbilical vein endothelial cells monolayers doses ≥8 Gy increased expression of NOTCH1, JAG1, and Notch target genes HEY1 and HEY2 as early as 6 hours after irradiation. In vivo, 12 Gy significantly increased Notch1 and Jagged1 in tumor ECs compared with 0 Gy or 2 Gy after 72 hours. Combining HDRT with Notch inhibition using the Notch1-1-24-decoy resulted in a greater loss of EC coverage of tumor vessels than HDRT alone at 6 hours and 72 hours post treatment. Notch inhibition reduced EndMT induced by HDRT, as indicated by diminished αSMA staining in ECs. CONCLUSIONS: HDRT induced Notch1 expression and increased Notch1 signaling in the endothelial component of tumor vasculature, which was not observed with lower doses. This increase in Notch1 activation might protect tumor vessels from HDRT induced damage and regulate EndMT process.
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Neovascularización Patológica/metabolismo , Dosis de Radiación , Receptor Notch1/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica , Transición Epitelial-Mesenquimal/efectos de la radiación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de la radiación , Humanos , Proteína Jagged-1/metabolismo , Ratones , Ratones Desnudos , Neovascularización Patológica/patología , Neovascularización Patológica/radioterapia , Dosificación Radioterapéutica , Proteínas Represoras/metabolismo , Transducción de Señal/efectos de la radiaciónRESUMEN
Vascular endothelial growth factor (VEGF) blockade has been validated clinically as a treatment for human cancers, yet virtually all patients eventually develop progressive disease during therapy. In order to dissect this phenomenon, we examined the effect of sustained VEGF blockade in a model of advanced pediatric cancer. Treatment of late-stage hepatoblastoma xenografts resulted in the initial collapse of the vasculature and significant tumor regression. However, during sustained treatment, vessels recovered, concurrent with a striking increase in tumor expression of perlecan, a heparan sulfate proteoglycan. Whereas VEGF mRNA was expressed at the periphery of surviving clusters of tumor cells, both secreted VEGF and perlecan accumulated circumferential to central vessels. Vascular expression of heparanase, VEGF receptor-2 ligand binding, and receptor activation were concurrently maintained despite circulating unbound VEGF Trap. Endothelial survival signaling via Akt persisted. These findings provide a novel mechanism for vascular survival during sustained VEGF blockade and indicate a role for extracellular matrix molecules that sequester and release biologically active VEGF.
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Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Colágeno/metabolismo , Células Endoteliales/enzimología , Células Endoteliales/metabolismo , Activación Enzimática , Femenino , Regulación Neoplásica de la Expresión Génica , Glucuronidasa/metabolismo , Proteoglicanos de Heparán Sulfato/metabolismo , Hepatoblastoma/irrigación sanguínea , Hepatoblastoma/enzimología , Hepatoblastoma/genética , Hepatoblastoma/patología , Humanos , Ratones , Ratones Desnudos , Modelos Biológicos , Estadificación de Neoplasias , Neoplasias/irrigación sanguínea , Neoplasias/enzimología , Neoplasias/patología , Neovascularización Patológica/genética , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Inducción de Remisión , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Most children with neuroblastoma presenting after infancy have metastatic, chemoresistant disease. Amplification of the MYCN proto-oncogene is a significant marker of these poor-prognosis neuroblastoma tumors. Recent studies suggest that MYCN may function in part by promoting angiogenesis via vascular endothelial growth factor (VEGF). VEGF blockade has been validated as a therapeutic strategy in adult cancers. In these studies, we asked whether inhibition of VEGF signaling via VEGFR2 blockade in established MYCN-amplified neuroblastoma xenografts would: 1) restrict tumor growth; 2) induce hypoxia; and 3) alter tumor vasculature. The MYCN-amplified neuroblastoma human cell line NGP was implanted intrarenally in athymic female mice. After 5 weeks, mice with established tumors were selected, a cohort euthanized to provide day 0 controls, and the rest assigned to receive biweekly injections of DC101 (anti-murine VEGFR2 antibody) or vehicle. DC101 treatment did not inhibit progressive tumor growth in established NGP xenografts. Although tumor vasculature was not significantly disrupted, a modest increase in tumor hypoxia was demonstrated by pimonidazole staining, and expression of a previously described hypoxia metagene was increased by gene set enrichment analysis (GSEA) in DC101-treated tumors. DC101 treatment elicited increased: 1) expression of VEGFR1 and its ligand placental growth factor; and 2) increased Notch activation in tumor vasculature concurrent with expression of the Notch ligand Jagged1. This result suggests that established MYCN-amplified neuroblastoma tumors are relatively VEGF-independent, and display the ability to rapidly up-regulate hypoxia-responsive alternative proangiogenic mechanisms that may stabilize vasculature when VEGF is deficient.
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Neovascularización Patológica/patología , Neuroblastoma/irrigación sanguínea , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , División Celular , Hipoxia de la Célula , Femenino , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Proto-Oncogenes Mas , Trasplante Heterólogo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signaling in tumors induces remodeling in surviving vessels, and link increased expression of angiopoietin-1 (Ang-1) with this process. However, overexpression of Ang-1 in different tumors has yielded divergent results, restricting angiogenesis in some systems while promoting it in others. These data raise the possibility that effects of Ang-1/Tie-2 may be context-dependent. Expression of an Ang-1 construct (Ang1*) did not significantly change tumor growth in our model prior to treatment, although vessels exhibited changes consistent with increased Tie-2 signaling. During inhibition of VEGF, however, both overexpression of Ang1* and administration of an engineered Ang-1 agonist (Bow-Ang1) strikingly protected tumors and vasculature from regression. In this context, Ang-1/Tie-2 activation limited tumor hypoxia, increased vessel caliber, and promoted recruitment of mural cells. Thus, these studies support a model in which activation of Tie-2 is important for tumor and vessel survival when VEGF-dependent vasculature is stressed. Understanding such mechanisms of adaptation to this validated form of therapy may be important in designing regimens that make the best use of this approach.
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Angiopoyetina 1/genética , Regulación de la Expresión Génica/fisiología , Neoplasias Renales/irrigación sanguínea , Neovascularización Patológica/patología , Receptor TIE-2/genética , Sarcoma de Ewing/irrigación sanguínea , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Western Blotting , Hipoxia de la Célula , Línea Celular Tumoral , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoprecipitación , Neoplasias Renales/patología , Ratones , Ratones Desnudos , Fosforilación , Reacción en Cadena de la Polimerasa , Sarcoma de Ewing/patología , Transfección , Trasplante Heterólogo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
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.
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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
An association between neuroblastoma and opsoclonus-myoclonus syndrome (OMS) was described as early as 1927 within the first report on the transformation of malignant neuroblastoma to a benign ganglioneuroma. It was not recognized at that time nor was it appreciated in the subsequent follow-up report on the same patient in 1959. Myoclonic encephalopathy of infancy, an alternative name for OMS, was described by a pediatric neurologist in 1962; however, its connection to neuroblastoma was not known. It was only in 1968 that the association between these two conditions was first reported. The neuroblastoma tumors associated with OMS are almost all small, stage I-II with no associated MYCN amplification or metastases. OMS occurs in 2-3% of patients with neuroblastoma, but neuroblastoma is found in as many as 50% of children who present with OMS. Nearly 100% of the children with neuroblastoma associated with OMS survive, and this has led to speculation that the OMS is a result of an autoimmune process, not metastases. Affected children are treated with steroids, ACTH, or intravenous immunoglobulin, but many have persistent neurologic and developmental deficits. Using the original case reported in 1927, we summarize a century of literature in this review on OMS and its association with neuroblastoma.
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Diagnóstico por Imagen/historia , Neuroblastoma/diagnóstico , Neuroblastoma/historia , Síndrome de Opsoclonía-Mioclonía/diagnóstico , Síndrome de Opsoclonía-Mioclonía/historia , Pediatría/historia , Radiología/historia , Niño , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Estados UnidosRESUMEN
The clinical management of pediatric liver tumors involves stratification into risk groups. One previously defined, high-risk group of hepatoblastomas is the small cell undifferentiated variant. In light of molecular studies showing SMARCB1 deletion in these tumors, it is now recognized that most small cell, undifferentiated liver tumors represent an aggressive unrelated tumor-the malignant rhabdoid tumor (MRT). SMARCB1 is a member of the chromatin remodeling SWI/SNF complex and encodes the INI1 protein. The histologic diagnosis of MRT is currently based on INI1 negative immunoreactivity and the presence of rhabdoid morphology. INI1-negative small cell liver tumors lacking classic rhabdoid morphology are often misclassified as small cell undifferentiated hepatoblastomas (SCUD-HB), according to the current classification. Pediatric liver tumors diagnosed between 2003-2017 as SCUD-HB (four cases) or MRT (two cases) were identified from the Columbia University Pathology Department Archives. All tumors were associated with normal or low serum alpha fetoprotein levels, and showed an absence of immunohistochemical staining of hepatocellular markers (Hep-par1, Arginase) and loss of INI1 staining. Two cases were initially diagnosed as MRT, one with prominent rhabdoid morphology, the other with predominant small cell morphology. The remaining four cases with small cell morphology were classified as SCUD-HB. Ancillary molecular studies confirmed the loss of SMARCB1, supporting the diagnosis of MRT in all cases, proving morphology an unreliable criterion. It is critical to eliminate the term INI1-negative hepatoblastoma from the current classification scheme, and classify INI1-negative tumors as MRT, particularly since high-risk HB-chemotherapy regimens are not effective for treating MRT.
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Much evidence supports an important role for the inducible enzyme cyclooxygenase-2 (COX-2) in tumor angiogenesis. Previous studies have focused on the role of COX-2 in stimulating endothelial proliferation, with blockade of this enzyme impairing endothelial homeostasis. However, recent data suggest that COX-2 also regulates molecules implicated in endothelial trafficking with pericytes/vascular mural cells (VMC), an interaction crucial to vessel stability. We investigated the role of COX-2 in vascular assembly by testing the effect of the specific COX-2 inhibitor SC-236 in an orthotopic xenograft model of human Wilms' tumor. Tumor growth was significantly suppressed by SC-236 (78% at day 28, 55% at day 35). Perfusion studies and immunostaining showed a marked decrease in vasculature, particularly in small vessels. Specifically, SC-236 inhibited participation of VMC in xenograft vessels. SC-236-treated tumors developed segmentally dilated, architecturally erratic tumor vessels with decreased nascent pericytes and scant mature VMC. Although vascular endothelial growth factor expression was unchanged, expression of the chemokine receptor CXCR4 was decreased in tumor vessels, consistent with defective homing of vascular progenitor cells. Vascular expression of phosphorylated platelet-derived growth factor receptor-beta was also diminished, indicating impaired VMC-endothelial trafficking. Consistent with the key role of this interaction in vessel homeostasis, vascular cells in SC-236-treated tumors displayed markedly diminished phosphorylated Akt, indicating disrupted survival signaling. These results show that SC-236 causes defective vascular assembly by attenuating incorporation of VMC into tumor vessels, impairing endothelial survival, and raise the possibility that blockade of COX-2 may provide therapeutic synergies with antiangiogenic molecules that more selectively target endothelial cells.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/farmacología , Pirazoles/farmacología , Sulfonamidas/farmacología , Tumor de Wilms/irrigación sanguínea , Tumor de Wilms/tratamiento farmacológico , Animales , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/enzimología , Neovascularización Patológica/patología , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores CXCR4/biosíntesis , Receptores CXCR4/deficiencia , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Tumor de Wilms/enzimología , Tumor de Wilms/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite the identification of MYCN amplification as an adverse prognostic marker in neuroblastoma, MYCN inhibitors have yet to be developed. Here, by integrating evidence from a whole-genome shRNA library screen and the computational inference of master regulator proteins, we identify transcription factor activating protein 4 (TFAP4) as a critical effector of MYCN amplification in neuroblastoma, providing a novel synthetic lethal target. We demonstrate that TFAP4 is a direct target of MYCN in neuroblastoma cells, and that its expression and activity strongly negatively correlate with neuroblastoma patient survival. Silencing TFAP4 selectively inhibits MYCN-amplified neuroblastoma cell growth both in vitro and in vivo, in xenograft mouse models. Mechanistically, silencing TFAP4 induces neuroblastoma differentiation, as evidenced by increased neurite outgrowth and upregulation of neuronal markers. Taken together, our results demonstrate that TFAP4 is a key regulator of MYCN-amplified neuroblastoma and may represent a valuable novel therapeutic target.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proteína Proto-Oncogénica N-Myc/metabolismo , Neuroblastoma/patología , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/deficiencia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Proteínas de Unión al ADN , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Humanos , Ratones , Proteínas de Unión al ARNRESUMEN
We report a rare case of an 18-month-old female with autosomal recessive polycystic kidney disease, Caroli syndrome, and pure fetal type hepatoblastoma. The liver tumor was surgically resected with no chemotherapy given. Now 9 years post resection she demonstrates no local or distant recurrence and stable renal function.