RESUMO
Vascular malformations of the head and neck represent a spectrum of complex vascular anomalies, requiring a multidisciplinary approach toward diagnosis and treatment. Several intralesional therapeutic agents have been devised and pioneered over the years, some of which are now primary and standard of care for the management of these lesions. In this article, the authors discuss the currently available intralesional therapeutic agents for the management of vascular malformations in the head and neck region.
Assuntos
Escleroterapia , Malformações Vasculares , Humanos , Pescoço/patologia , Cabeça/irrigação sanguínea , Cabeça/patologia , Malformações Vasculares/tratamento farmacológico , Malformações Vasculares/patologia , Resultado do TratamentoRESUMO
Lower-extremity ischemia is a significant complication in children on femoral venoarterial extracorporeal membrane oxygenation (VA ECMO). Our institution currently routinely uses distal perfusion catheters (DPCs) in all femoral arterial cannulations in attempts to reduce ischemia. We performed a single-center, retrospective review of pediatric patients supported with femoral VA ECMO from January 2005 to November 2015. The outcomes of patients with prophylactic DPC placement at cannulation (prophylactic DPC) were compared to a historical group with DPCs placed in response only to clinically evident ischemic changes (reactive DPC). Ischemic complication requiring invasive intervention (fasciotomy or amputation) was the primary outcome. Twenty-nine patients underwent a total of 31 femoral arterial cannulations, 17 with prophylactic DPC and 14 with reactive DPC. Ischemic complications requiring invasive intervention developed in 2 of 17 (12%) prophylactic DPC patients versus 4 of 14 (29%) reactive DPC. In the reactive DPC group, 7 of 14 (50%) had ischemic changes postcannulation, six underwent DPC placement, and three out of six of these patients still required invasive intervention. One of the seven patients had ischemic changes, did not undergo DPC, and required amputation. While a greater percentage of patients in the prophylactic group was cannulated during extracorporeal cardiopulmonary resuscitation (ECPR), statistical significance was not otherwise demonstrated. We demonstrate feasibility of superficial femoral artery (SFA) access in pediatric patients. We note fewer ischemic complications with prophylactic DPC placement, and observe that salvaging a limb with a reactive DPC was only successful 50% of the time. Although there was no statistical difference in the primary outcome between the two groups, limitations and confounding factors include small sample size and a greater percentage of patients in the prophylactic DPC group cannulated with ECPR in progress.
Assuntos
Cateterismo Periférico/métodos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Artéria Femoral/cirurgia , Isquemia/etiologia , Isquemia/prevenção & controle , Perna (Membro)/irrigação sanguínea , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Isquemia/terapia , Masculino , Perfusão/métodos , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disorder characterized by oculocutaneous albinism, a hemorrhagic diathesis due to platelet dysfunction, and lysosomal ceroid accumulation that can cause a Crohn's-like granulomatous colitis and pulmonary fibrosis. We report peristomal and vulvar cutaneous involvement of the granulomatous colitis in HPS.
Assuntos
Doença de Crohn/etiologia , Doença de Crohn/patologia , Síndrome de Hermanski-Pudlak/complicações , Síndrome de Hermanski-Pudlak/patologia , Úlcera Cutânea/etiologia , Úlcera Cutânea/patologia , Biópsia , Criança , Feminino , Humanos , Pele/patologia , Vulva/patologiaRESUMO
We present a case of a large congenital hemangioma (CH) on the neck causing cardiac failure and thrombocytopenia in a female neonate. A trial of medical therapy with corticosteroids and propranolol was attempted, but the patient ultimately underwent definitive treatment with embolization and surgical resection with a positive outcome. A review of the English language literature revealed 16 previously reported cases of CHs complicated by congestive heart failure. This series supports known demographic features of CHs, including a lack of gender discrepancy and a predilection to affect the head and neck. These CHs are rarely diagnosed in utero; most patients present with a mass at birth. Cardiac failure is identified prenatally or in the first days of life. A mild to moderate thrombocytopenia and coagulopathy, which is likely transient and distinct from classic Kasabach-Merritt phenomenon, accompanies many of these cases. There is a 30% associated mortality rate. Both medical and interventional treatment modalities have been reported. Steroids are the most commonly used medication, but without any clear benefit. We hypothesize that, based on its possible mechanisms of action,propranolol may be a more effective treatment for CHs requiring treatment. As surgical intervention may be necessary, we recommend a multidisciplinary approach to treating patients with problematic CHs.
Assuntos
Insuficiência Cardíaca/etiologia , Hemangioma/congênito , Hemangioma/complicações , Neoplasias Cutâneas/congênito , Neoplasias Cutâneas/complicações , Cardiomegalia/etiologia , Feminino , Doenças Fetais/patologia , Hemangioma/cirurgia , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Neoplasias Cutâneas/cirurgiaRESUMO
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.
Assuntos
Antineoplásicos , Neuroblastoma , Humanos , Anoikis/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Neuroblastoma/tratamento farmacológico , Antineoplásicos/farmacologia , Fatores Ativadores da TranscriçãoRESUMO
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.
RESUMO
We present the case of a 16-year-old girl who was sexually assaulted with transanal forearm penetration resulting in rectal perforation. She required a sigmoid colostomy that was later reversed. The patient's history and physical examination was complicated by multiple factors: she was intoxicated at the time of presentation as well as during the assault; her presentation fluctuated over time, she was obese, and she carried a psychiatric diagnosis. This case report documents a rare injury caused by sexual assault in the adolescent population and also serves as a platform to discuss the evaluation and management of pediatric victims of sexual assault. We support a collaborative model of care including qualified sexual assault pediatricians, sexual assault nurse (or forensic) examiners, medical specialists, and the criminal justice system. The importance of developing updated sexual assault protocols, ensuring their implementation, and maintaining continuous quality assurance cannot be overemphasized.
Assuntos
Perfuração Intestinal/cirurgia , Estupro/diagnóstico , Reto/lesões , Reto/cirurgia , Adolescente , Intoxicação Alcoólica/complicações , Braço , Colonoscopia/métodos , Colostomia/métodos , Serviço Hospitalar de Emergência , Feminino , Seguimentos , Humanos , Escala de Gravidade do Ferimento , Perfuração Intestinal/etiologia , Laparotomia/métodos , Notificação de Abuso , Transtornos Mentais/complicações , Cidade de Nova Iorque , Obesidade/complicações , Cuidados Pós-Operatórios/reabilitação , Reoperação/métodos , Medição de Risco , Delitos Sexuais , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVE: Early presentation and prompt diagnosis of acute appendicitis are necessary to prevent progression of disease leading to complicated appendicitis. We hypothesize that patients had a delayed presentation of acute appendicitis during the COVID-19 pandemic, which affected severity of disease on presentation and outcomes. PATIENTS AND METHODS: We conducted a retrospective review of all patients who were treated for acute appendicitis at Morgan Stanley Children's Hospital (MSCH) between March 1, 2020 and May 31, 2020 when the COVID-19 pandemic was at its peak in New York City (NYC). For comparison, we reviewed patients treated from March 1, 2019 to May 31, 2019, prior to the pandemic. Demographics and baseline patient characteristics were analyzed for potential confounding variables. Outcomes were collected and grouped into those quantifying severity of illness on presentation to our ED, type of treatment, and associated post-treatment outcomes. Fisher's Exact Test and Kruskal-Wallis Test were used for univariate analysis while cox regression with calculation of hazard ratios was used for multivariate analysis. RESULTS: A total of 89 patients were included in this study, 41 patients were treated for appendicitis from March 1 to May 31 of 2019 (non-pandemic) and 48 were treated during the same time period in 2020 (pandemic). Duration of symptoms prior to presentation to the ED was significantly longer in patients treated in 2020, with a median of 2â¯days compared to 1â¯day (pâ¯=â¯0.003). Additionally, these patients were more likely to present with reported fever (52.1% vs 24.4%, pâ¯=â¯0.009) and had a higher heart rate on presentation with a median of 101 beats per minute (bpm) compared to 91â¯bpm (pâ¯=â¯0.040). Findings of complicated appendicitis on radiographic imaging including suspicion of perforation (41.7% vs 9.8%, pâ¯<â¯0.001) and intra-abdominal abscess (27.1% vs 7.3%, pâ¯=â¯0.025) were higher in patients presenting in 2020. Patients treated during the pandemic had higher rates of non-operative treatment (25.0% vs 7.3%, pâ¯=â¯0.044) requiring increased antibiotic use and image-guided percutaneous drain placement. They also had longer hospital length of stay by a median of 1â¯day (pâ¯=â¯0.001) and longer duration until symptom resolution by a median of 1â¯day (pâ¯=â¯0.004). Type of treatment was not a predictor of LOS (HRâ¯=â¯0.565, 95% CIâ¯=â¯0.357-0.894, pâ¯=â¯0.015) or duration until symptom resolution (HRâ¯=â¯0.630, 95% CIâ¯=â¯0.405-0.979, pâ¯=â¯0.040). CONCLUSION: Patients treated for acute appendicitis at our children's hospital during the peak of the COVID-19 pandemic presented with more severe disease and experienced suboptimal outcomes compared to those who presented during the same time period in 2019. LEVEL OF EVIDENCE: III.
Assuntos
Apendicite , COVID-19 , Apendicectomia , Apendicite/diagnóstico , Apendicite/epidemiologia , Apendicite/cirurgia , Criança , Humanos , Tempo de Internação , Cidade de Nova Iorque , Pandemias , Estudos Retrospectivos , SARS-CoV-2RESUMO
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.
Assuntos
Neovascularização Patológica/metabolismo , Doses de Radiação , Receptor Notch1/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Transição Epitelial-Mesenquimal/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Proteína Jagged-1/metabolismo , Camundongos , Camundongos Nus , Neovascularização Patológica/patologia , Neovascularização Patológica/radioterapia , Dosagem Radioterapêutica , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos da radiaçãoRESUMO
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.
Assuntos
Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Colágeno/metabolismo , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Ativação Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Glucuronidase/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Hepatoblastoma/irrigação sanguínea , Hepatoblastoma/enzimologia , Hepatoblastoma/genética , Hepatoblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Modelos Biológicos , Estadiamento de Neoplasias , Neoplasias/irrigação sanguínea , Neoplasias/enzimologia , Neoplasias/patologia , Neovascularização Patológica/genética , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Indução de Remissão , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Neovascularização Patológica/patologia , Neuroblastoma/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Divisão Celular , Hipóxia Celular , Feminino , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Proto-Oncogene Mas , Transplante Heterólogo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
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.
Assuntos
Angiopoietina-1/genética , Regulação da Expressão Gênica/fisiologia , Neoplasias Renais/irrigação sanguínea , Neovascularização Patológica/patologia , Receptor TIE-2/genética , Sarcoma de Ewing/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Western Blotting , Hipóxia Celular , Linhagem Celular Tumoral , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoprecipitação , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Fosforilação , Reação em Cadeia da Polimerase , Sarcoma de Ewing/patologia , Transfecção , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
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.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/patologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/deficiência , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Camundongos , Proteínas de Ligação a RNAAssuntos
Apendicite , COVID-19 , Apendicite/cirurgia , Criança , Abrigo de Emergência , Hospitais , Humanos , New York , Pandemias , SARS-CoV-2RESUMO
PURPOSE: To characterize the effects of high-dose radiation therapy (HDRT) on neuroblastoma tumor vasculature, including the endothelial cell (EC)-pericyte interaction as a potential target for combined treatment with antiangiogenic agents. METHODS AND MATERIALS: The vascular effects of radiation therapy were examined in a xenograft model of high-risk neuroblastoma. In vivo 3-dimensional contrast-enhanced ultrasonography (3D-CEUS) imaging and immunohistochemistry (IHC) were performed. RESULTS: HDRT significantly reduced tumor blood volume 6 hours after irradiation compared with the lower doses used in conventionally fractionated radiation. There was a 63% decrease in tumor blood volume after 12-Gy radiation compared with a 24% decrease after 2 Gy. Analysis of tumor vasculature by lectin angiography showed a significant loss of small vessel ends at 6 hours. IHC revealed a significant loss of ECs at 6 and 72 hours after HDRT, with an accompanying loss of immature and mature pericytes at 72 hours. CONCLUSIONS: HDRT affects tumor vasculature in a manner not observed at lower doses. The main observation was an early reduction in tumor perfusion resulting from a reduction of small vessel ends with a corresponding loss of endothelial cells and pericytes.
Assuntos
Neuroblastoma/radioterapia , Fluxo Sanguíneo Regional/efeitos da radiação , Angiografia/métodos , Animais , Apoptose , Comunicação Celular , Linhagem Celular Tumoral , Endotélio Vascular/citologia , Endotélio Vascular/efeitos da radiação , Xenoenxertos , Humanos , Lectinas , Camundongos Nus , Neuroblastoma/irrigação sanguínea , Neuroblastoma/diagnóstico por imagem , Pericitos/citologia , Pericitos/efeitos da radiação , Dosagem Radioterapêutica , Distribuição Aleatória , Fatores de Tempo , UltrassonografiaRESUMO
The Notch pathway plays multiple key roles in tumorigenesis, and its signaling components have therefore aroused great interest as targets for emerging therapies. Here, we show that inhibition of Notch, using a soluble receptor Notch1 decoy, unexpectedly caused a remarkable increase in liver metastases from neuroblastoma and breast cancer cells. Increased liver metastases were also seen after treatment with the γ-secretase inhibitor PF-03084014. Transgenic mice with heterozygous loss of Notch1 demonstrated a marked increase in hepatic metastases, indicating that Notch1 signaling acts as metastatic suppressor in the liver microenvironment. Inhibition of DLL1/4 with ligand-specific Notch1 decoys increased sprouting of sinusoidal endothelial cells into micrometastases, thereby supporting early metastatic angiogenic growth. Inhibition of tumor-derived JAG1 signaling activated hepatic stellate cells, increasing their recruitment to vasculature of micrometastases, thereby supporting progression to macrometastases. These results demonstrate that inhibition of Notch causes pathologic activation of liver stromal cells, promoting angiogenesis and growth of hepatic metastases. Our findings have potentially serious implications for Notch inhibition therapy.
Assuntos
Neoplasias da Mama/patologia , Neoplasias Hepáticas/secundário , Neovascularização Patológica/genética , Neuroblastoma/patologia , Receptor Notch1/fisiologia , Animais , Neoplasias da Mama/genética , Células Cultivadas , Progressão da Doença , Regulação para Baixo , Feminino , Humanos , Neoplasias Hepáticas/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Neuroblastoma/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We describe the clinical course of a recurrent case of congenital fibrosarcoma diagnosed in a 9-mo-old boy with a history of hemimelia. Following complete surgical resection of the primary tumor, the patient subsequently presented with bulky bilateral pulmonary metastases 6 mo following surgery. Molecular characterization of the tumor revealed the absence of the prototypical ETV6-NTRK3 translocation. However, tumor characterization incorporating cytogenetic, array comparative genomic hybridization, and RNA sequencing analyses, revealed a somatic t(2;15)(2p21;15q25) translocation resulting in the novel fusion of EML4 with NTRK3. Cloning and expression of EML4-NTRK3 in murine fibroblast NIH 3T3 cells revealed a potent tumorigenic phenotype as assessed in vitro and in vivo. These results demonstrate that multiple fusion partners targeting NTRK3 can contribute to the development of congenital fibrosarcoma.
RESUMO
Thalidomide has previously been shown to have anti-angiogenic properties. More recently, clinical efficacy of this agent has been demonstrated in multiple myeloma and prostate cancer. Neuroblastoma is the most frequent solid tumor of the abdomen of childhood, yet children with this disease frequently have metastases at presentation. Such patients have a very poor prognosis with current therapies. Thus, new approaches are needed. We have previously shown that VEGF antagonists can inhibit neoangiogenesis and tumor growth in experimental neuroblastoma. In this study, we investigated the anti-angiogenic and anti-tumor properties of thalidomide in a xenograft model of human neuroblastoma. Tumors were induced in athymic mice using the human neuroblastoma cell line NGP. Intraperitoneal thalidomide (100 mg/kg/dose) or vehicle was administered beginning one week after implantation, and animals euthanized at six weeks. Thalidomide treatment did not significantly alter tumor growth as compared with controls. However, thalidomide suppressed angiogenesis, as demonstrated both by fluorescein angiography and immunohistochemical staining, and induced apoptosis of endothelial cells in neuroblastoma xenografts. Quantification of microvessel density demonstrated a significant reduction of vasculature in treated tumors (p<0.004). Thalidomide induced co-option of host vasculature, an effect noted previously after VEGF blockade. This study demonstrates that thalidomide has anti-angiogenic properties in experimental neuroblastoma.
Assuntos
Inibidores da Angiogênese/farmacologia , Neuroblastoma/tratamento farmacológico , Talidomida/farmacologia , Animais , Linhagem Celular Tumoral , Endotélio Vascular/citologia , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Nus , Músculo Liso/patologia , Transplante de Neoplasias , Neovascularização Patológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossínteseRESUMO
We characterized the effect of potent vascular endothelial growth factor (VEGF) blockade on early-stage Wilms tumor xenograft growth, vasculature and metastasis. VEGF is a key mediator of both physiologic and tumor angiogenesis. We recently described that potent VEGF blockade induces regression of established Wilms tumor xenografts and vessels, also reducing the size but not the incidence of pre-existing metastases. In these studies, we examined the effects of potent VEGF blockade on earlier stages of experimental Wilms tumors, focusing on tumor growth, vasculature and metastasis. Athymic mice received intrarenal human Wilms tumor cell implants. Biweekly treatment with vehicle or the VEGF-Trap, a high-affinity soluble decoy receptor incorporating regions of VEGFR1 and VEGFR2, was begun 1 week later (100 or 500 micrograms/dose, n=20 in each group). Mice were euthanized at week 6 to examine tumor weight, incidence of lung metastases, vascularity and expression of angiogenic factors. A cohort of mice was examined 2 weeks after cessation of treatment. Compared to controls, VEGF-Trap treated tumors were significantly smaller (100 micrograms/dose: 92.7% smaller, p=0.0017; 500 micro g/dose: 99.0% smaller, p=0.0009). The incidence of lung metastasis also decreased significantly (p<0.0055). VEGF-Trap nearly eradicated tumor vasculature. Rare persisting vessels were characterized by large caliber, quiescence (lacking proliferation/apoptosis) and arterialization (both phenotypic and molecular). Potent VEGF blockade caused near-arrest of experimental Wilms tumor growth, resulted in nearly avascular tumors, and also decreased the incidence and size of metastases. Persistent vessels in tumors treated with VEGF-Trap displayed specific morphologic and molecular features, suggestive of arterialization. Future strategies that target these persisting vessels may enhance the efficacy of VEGF blockade therapy.
Assuntos
Neoplasias Renais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tumor de Wilms/tratamento farmacológico , Animais , Apoptose , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Feminino , Neoplasias Renais/irrigação sanguínea , Camundongos , Camundongos Nus , Transplante de Neoplasias , Proteínas Recombinantes de Fusão/farmacologia , Regulação para Cima , Fatores de Crescimento do Endotélio Vascular/genética , Tumor de Wilms/irrigação sanguínea , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Over the last 15 years thoracoscopic lobectomy for congenital and acquired lesions has become an accepted modality in pediatric thoracic surgery. There is still debate about the need to perform a complete lobectomy for some of these lesions, and some advocate observation rather than resection, despite possible long-term complications of untreated lesions. High-resolution computed tomography (CT) scans and physical findings at the time of surgery, along with new advanced techniques, now allow for discrete partial anatomic resections, which may preserve normal lung. This study evaluates the feasibility and early results using these techniques in selected cases. PATIENTS AND METHODS: With institutional review board approval, the records of all patients undergoing thoracoscopic lung resection were reviewed. From January 2006 to December 2012, 23 patients, ranging from 1 month to 16 years of age and weighing 3.8-42 kg, underwent thoracoscopy for planned resection. Pathology was congenital cystic lung disease in 19 patients, bronchiectasis in 3 patients, and arteriovenous malformation in 1 patient. In each case findings on CT scan and at the time of surgery warranted consideration of lung-preserving surgery. Procedures were performed through three ports using single lung ventilation and CO2 insufflation to achieve lung collapse. The LigaSure™ device (Covidien, Norwalk, CT) was the primary instrument used to seal and divide the lung parenchyma and seal vessels. RESULTS: All procedures were completed successfully thoracoscopically. An anatomic segmental resection was achieved in 22 of 23 cases. Operative time ranged from 30 to 300 minutes (mean, 120 minutes). Segmental resections included the left upper lobe apical/posterior (n=4), lingula (n=3), left lower lobe superior (n=5), medial or posterior basal (n=3), right middle lobe medial (n=1), right upper lobe apical (n=1), right lower lobe superior (n=4), and posterior basal (n=2). Two patients had more than one segment excised. Chest tubes were left in for 24 hours in 16 cases, 48 hours in 4 cases, and 5 days in 1 case. Hospital stay ranged from 1 to 6 days (mean, 2 days). Follow-up CT scans obtained at 1-6 years (mean, 28 months) show no residual disease in 20 of 21 patients. One patient underwent a nonanatomic resection and had evidence of recurrent congenital pulmonary airway malformation at the 4-year follow-up. This patient underwent a secondary thoracoscopic resection. CONCLUSIONS: Thoracoscopic lung-conserving therapy is technically feasible and safe in infants and children. The magnification provided by a thoracoscopic approach makes identification of segmental anatomic planes easier, aiding in safe dissection and resection. Anatomic resection appears to be associated with a low morbidity. It may be appropriate in the case of bilateral or extensive disease or in cases where the diseased tissue is clearly limited to an anatomic segment. Continued long-term follow-up is needed.