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BACKGROUND: Trauma is the leading cause of pediatric and adolescent morbidity and mortality. Firearm-related injuries and deaths contribute substantially to the overall disease burden. This study described the intent, location, demographics, and outcomes of a nationally representative pediatric population with firearm injuries. We hypothesized that younger patients would have a higher percentage of unintentional and self-inflicted injuries with associated higher mortality rates. MATERIALS AND METHODS: The National Trauma Data Bank, maintained by the American College of Surgeons, from 2010 to 2016 was utilized. All pediatric patients (0-19 y) with firearm injuries who had complete data were analyzed for mechanism, location, demographics, and outcomes. Basic descriptive statistics were used to compare subgroups. Multivariable logistic regression analysis was applied to investigate risk factors for firearm injury-caused mortality. RESULTS: In the study period, 46,039 pediatric patients sustained firearm injuries (median age = 17 y). Males, Blacks, ages 15-19, and the Southern region were the most common injured demographics. However, subgroup analysis showed the demographics differ for self-inflicted and unintentional firearm injuries, which had significantly higher White patients (66.6% and 47.9%, respectively; P < 0.001). Nearly 76% of injuries were related to assaults, 14% were unintentional, 5% were self-inflicted, and 5% were undetermined. The overall mortality was nearly 12%. The youngest population had higher proportion of unintentional injuries and highest mortality rate when compared with other classifications of intent (P < 0.001). CONCLUSIONS: Pediatric firearm injuries have high mortality, especially in the youngest populations. Age-tailored prevention strategies, such as strict child access prevention laws and enforced gun storage violations, may help in reducing firearm injuries and improving health outcomes.
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Heridas por Arma de Fuego/epidemiología , Adolescente , Niño , Preescolar , Bases de Datos Factuales , Femenino , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Masculino , Suicidio/estadística & datos numéricos , Factores de Tiempo , Heridas por Arma de Fuego/etnología , Heridas por Arma de Fuego/mortalidad , Adulto JovenRESUMEN
BACKGROUND: Hepatoblastoma and Wilms tumor are the most common primary liver and kidney tumor in children, respectively, and little is documented about patient outcomes in the immediate perioperative period. The aim of this study was to analyze the short-term outcomes of pediatric patients after surgical resection for hepatoblastoma and Wilms tumor. METHODS: We queried the 2012-2016 ACS National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database for patients with hepatoblastoma who underwent liver resection and patients with Wilms tumor who underwent a partial or total nephrectomy. Patient demographics, preoperative, intraoperative, and postoperative characteristics were analyzed. Multivariate logistic regression was used to determine independent risk factors for unplanned reoperations. RESULTS: There were a total of 189 patients with hepatoblastoma and 586 patients with Wilms in National Surgical Quality Improvement Program-Pediatric. The mean age of patients with hepatoblastoma was 3.1 y and 4.2 y in the Wilms group. Nine percent (n = 17) of patients underwent an unplanned reoperation after hepatectomy, and 4.1% (n = 24) of patients with Wilms experienced an unplanned reoperation. Over half of patients with hepatoblastoma (59.8%, n = 113) and 29.7% (n = 174) patients with Wilms tumor received a blood transfusion in the perioperative period. Patients in both groups demonstrated low rates of surgical site infections, but 6.3% (n = 12) of hepatoblastoma patients showed evidence of sepsis. CONCLUSIONS: This study will allow providers to more effectively counsel families of the common morbidities in the associated perioperative period following surgical resection of either solid tumor type including the substantial risk of blood transfusion.
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Hepatoblastoma/cirugía , Neoplasias Renales/cirugía , Neoplasias Hepáticas/cirugía , Tumor de Wilms/cirugía , Niño , Preescolar , Femenino , Humanos , Modelos Logísticos , Masculino , Mejoramiento de la Calidad , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND: Solid pseudopapillary neoplasms (SPPNs) comprise the majority of pediatric pancreatic neoplasms. We queried the National Cancer Database to compare pediatric and adult patients with SSPNs to examine differences in demographics, tumor characteristics, treatment, and overall survival. We aimed to determine if survival differences existed between adult and pediatric patients with SPPN. METHODS: The National Cancer Database (2004-2014) was reviewed, and patients were stratified by age at diagnosis: pediatric (≤21 y) and adult (≥22 y). Demographics, comorbidities, tumor characteristics, diagnostic periods, treatments, and survival rates were compared using pooled variance t-tests and chi-square, followed by multivariate Cox proportional hazard model (α = 0.05). Log-rank test was used to compare survival. RESULTS: A total of 468 patients were analyzed and categorized according to age group. Four hundred and fourteen patients were included in the survival analysis. The pediatric patients were primarily female, Caucasian, had no comorbidities, and presented with stage I disease. Race/ethnicity, gender, socioeconomic status, comorbidities, and disease stage at presentation were similar between the groups. There was no difference in time to initiation of therapy or to surgical intervention. No significant difference was found in type of surgical resection, chemotherapy, or radiotherapy utilization. Despite the similarities between groups, comparison of overall survival demonstrated improved survival of pediatric SPPN compared with adult SPPN in every pathologic stage. CONCLUSIONS: These results suggest that pediatric and adult SPPNs are similar with regards to demographics, tumor characteristics, and treatment modalities. However, survival was better in children with SPPNs, which may be due to differences in tumor biology and may serve for risk stratification of prognosis.
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Carcinoma Papilar/epidemiología , Neoplasias Pancreáticas/epidemiología , Adolescente , Adulto , Distribución por Edad , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma Papilar/patología , Carcinoma Papilar/terapia , Quimioterapia Adyuvante/estadística & datos numéricos , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Páncreas/patología , Páncreas/cirugía , Pancreatectomía/estadística & datos numéricos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Pronóstico , Radioterapia Adyuvante/estadística & datos numéricos , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Factores Sexuales , Factores Socioeconómicos , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: While patients with early-stage rhabdomyosarcoma (RMS) have seen steady improvement in prognosis over the last 50 y, those with advanced-stage or high-grade disease continue to have a dismal prognosis. Retinoids have been shown to cause growth suppression and terminal differentiation in RMS cells, but the toxicities associated with retinoic acid limit its use. Rexinoids provide an alternative treatment approach to retinoic acid. Rexinoids primarily bind the retinoid X receptor with minimal retinoic acid receptor binding, the entity responsible for many of the toxicities of retinoid therapies. UAB30 is a novel rexinoid with limited toxicities. We hypothesized that UAB30 would lead to decreased cell survival in RMS. MATERIALS AND METHODS: Two RMS cell lines, one embryonal (RD) subtype and one alveolar (St. Jude Cancer Research Hospital 30) subtype, were used. Cells were treated with UAB30, and cytotoxicity, proliferation, mobility, and apoptosis were evaluated. RESULTS: UAB30 significantly decreased RMS tumor cell viability and proliferation. Invasion, migration, and attachment-independent growth were reduced following UAB30 treatment. UAB30 also resulted in apoptosis and G1 cell cycle arrest. UAB30 affected both the alveolar and embryonal RMS cell lines in a similar fashion. CONCLUSIONS: The results of these studies suggest a potential therapeutic role for the low-toxicity synthetic retinoid X receptor selective agonist, UAB30, in RMS treatment.
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Antineoplásicos/farmacología , Ácidos Grasos Insaturados/farmacología , Naftalenos/farmacología , Receptores X Retinoide/agonistas , Rabdomiosarcoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ácidos Grasos Insaturados/uso terapéutico , Humanos , Naftalenos/uso terapéuticoRESUMEN
BACKGROUND: Foreign body ingestion remains a common reason for emergency room visits and operative interventions in the pediatric population. Rare earth magnet ingestion represents a low percentage of all foreign bodies swallowed by children; however, magnets swallowed in multiplicity can result in severe injuries. MATERIALS AND METHODS: Pediatric surgeons with membership in the Surgical Section of the American Academy of Pediatrics were surveyed to determine the magnitude and consequences of magnet ingestions in the pediatric population. RESULTS: About 100 (16%) participant responses reported on 99 magnet ingestions. The median age at ingestion was 3.7 y, and the majority of ingestions (71%) occurred after year 2010. Thirty-two children underwent endoscopy with successful removal in 70% of cases, and multiple magnets were found in 65% of these patients. Seventy-three children required either laparotomy (51) or laparoscopy (22) for magnet removal, and 90% of these children were discovered to have ingested more than one magnet. In addition, 17% of the children were found to have at least one perforation or fistula, and 34% of the children had multiple perforations or fistulae. Nine children required long-term care for their injuries including repeat endoscopies. One child died after hemorrhage from an esophago-aortic fistula. CONCLUSIONS: These results demonstrated the increasing need for magnet regulations and public awareness to prevent potentially serious complications.
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Endoscopía Gastrointestinal/estadística & datos numéricos , Cuerpos Extraños/cirugía , Laparoscopía/estadística & datos numéricos , Laparotomía/estadística & datos numéricos , Imanes , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adolescente , Niño , Preescolar , Ingestión de Alimentos , Femenino , Cuerpos Extraños/complicaciones , Cuerpos Extraños/diagnóstico , Cuerpos Extraños/epidemiología , Humanos , Lactante , Masculino , Estudios Retrospectivos , Encuestas y Cuestionarios , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of neuroblastoma tumor development and progression. The p53 oncogene, although wild type in most neuroblastomas, lacks significant function as a tumor suppressor in these tumors. Recent reports have found that FAK and p53 interact in some tumor types. We have hypothesized FAK and p53 coordinately control each other's expression and also interact in neuroblastoma. In the present study, we showed that not only do FAK and p53 interact but each one controls the expression of the other. In addition, we also examined the effects of FAK inhibition combined with p53 activation in neuroblastoma and showed that these two, in combination, had a synergistic effect on neuroblastoma cell survival. The findings from this present study help to further our understanding of the regulation of neuroblastoma tumorigenesis and may provide novel therapeutic strategies and targets for neuroblastoma and other pediatric solid tumors.
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Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Neuroblastoma/enzimología , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Supervivencia Celular , HumanosRESUMEN
BACKGROUND: The benefit of targeting high ratio fresh frozen plasma (FFP)/red blood cell (RBC) transfusion in pediatric trauma resuscitation is unclear as existing studies are limited to patients who retrospectively met criteria for massive transfusion. The purpose of this study is to evaluate the use of high ratio FFP/RBC transfusion and the association with outcomes in children presenting in shock. METHODS: A post hoc analysis of a 24-institution prospective observational study (April 2018 to September 2019) of injured children younger than 18 years with elevated age-adjusted shock index was performed. Patients transfused within 24 hours were stratified into cohorts of low (<1:2) or high (≥1:2) ratio FFP/RBC. Nonparametric Kruskal-Wallis and χ 2 were used to compare characteristics and mortality. Competing risks analysis was used to compare extended (≥75th percentile) ventilator, intensive care, and hospital days while accounting for early deaths. RESULTS: Of 135 children with median (interquartile range) age 10 (5-14) years and weight 40 (20-64) kg, 85 (63%) received low ratio transfusion and 50 (37%) high ratio despite similar activation of institutional massive transfusion protocols (low-38%, high-46%, p = 0.34). Most patients sustained blunt injuries (70%). Median injury severity score was greater in high ratio patients (low-25, high-33, p = 0.01); however, hospital mortality was similar (low-24%, high-20%, p = 0.65) as was the risk of extended ventilator, intensive care unit, and hospital days (all p > 0.05). CONCLUSION: Despite increased injury severity, patients who received a high ratio of FFP/RBC had comparable rates of mortality. These data suggest high ratio FFP/RBC resuscitation is not associated with worst outcomes in children who present in shock. Massive transfusion protocol activation was not associated with receipt of high ratio transfusion, suggesting variability in MTP between centers. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.
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Transfusión de Eritrocitos , Plasma , Resucitación , Humanos , Niño , Adolescente , Femenino , Masculino , Preescolar , Transfusión de Eritrocitos/estadística & datos numéricos , Transfusión de Eritrocitos/métodos , Resucitación/métodos , Estudios Prospectivos , Heridas y Lesiones/terapia , Heridas y Lesiones/mortalidad , Heridas y Lesiones/complicaciones , Puntaje de Gravedad del Traumatismo , Transfusión de Componentes Sanguíneos/estadística & datos numéricos , Transfusión de Componentes Sanguíneos/métodos , Resultado del Tratamiento , PrevalenciaRESUMEN
INTRODUCTION: Constipation in pediatrics remains a common problem. Antegrade continence enema (ACE) procedures have been shown to decrease the distress of daily therapy. Patients are able to administer more aggressive washouts in the outpatient setting. Therefore, we hypothesize that patients following an ACE procedure would have reduced admissions for constipation. METHODS: Patients who underwent an ACE procedure at a large children's hospital from 2015 to 2018 were included. Demographics, diagnosis, procedure, and preoperative/postoperative hospital admissions were analyzed. RESULTS: Forty-eight patients were included in the study. Over half were diagnosed with idiopathic constipation. Majority of patients underwent an appendicostomy (88%, n = 42). Preoperatively, 26 patients were admitted for a combined total of 63 times for constipation. Postoperatively, 4 patients were admitted for a total of 5 visits (P = .021). Twenty-eight patients required a nonscheduled appendicostomy tube replacement. CONCLUSION: This study demonstrates ACE procedures can improve constipation-related symptoms in children and are associated with decrease hospital admissions.
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Cecostomía , Incontinencia Fecal , Cecostomía/métodos , Niño , Colostomía/métodos , Estreñimiento/cirugía , Enema/métodos , Incontinencia Fecal/etiología , Humanos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Although most children with cancer can be cured of their disease, a subset of patients with adverse tumor types or biological features, and those with relapsed or refractory disease have significantly worse prognosis. Furthermore, current cytotoxic therapy is associated with significant late effects. Precision oncology, using molecular therapeutics targeted against unique genetic features of the patient's tumor, offers the potential to transform the multimodal therapy for these patients. Potentiated by advances in sequencing technology and molecular therapeutic development, and accelerated by large-scale multi-institutional basket trials, the field of pediatric precision oncology has entered the mainstream. These novel therapeutics have important implications for surgical decision making, as well as pre- and postoperative care. This review summarizes the current state of precision medicine in pediatric oncology including the active North American and European precision oncology clinical trials. LEVEL OF EVIDENCE: Treatment study Level V.
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Neoplasias/terapia , Medicina de Precisión , Cirujanos , Niño , Humanos , Oncología Médica , Pediatría , Guías de Práctica Clínica como AsuntoRESUMEN
As the most common and deadly of primary brain tumors, malignant gliomas have earned their place within one of the most multifaceted and heavily-funded realms of medical research. Numerous avenues of pre-clinical investigation continue to provide valuable insight, but modeling the complex evolution and behavior of these tumors within a host under simulated circumstances may pose challenges to extrapolation of data. Remarkably, certain breeds of pet dogs spontaneously and sporadically develop high grade gliomas that follow similar incidence, treatment, and outcome patterns as their human glioma counterparts. The most malignant of these tumors have been refractory to limited treatment options despite aggressive treatment; outcomes are dismal with median survivals of just over 1 year in humans and 2 months in dogs. Novel treatments are greatly needed and combination therapies appear to hold promise. This clinical protocol, a dose-escalating phase I study in dogs with sporadic malignant glioma, represents a first in comparative oncology and combination immunotherapy. The trial will evaluate M032, an Interleukin-12 expressing Herpes Simplex virus, alone and combined with a checkpoint inhibitor, Indoximod. Extensive pre-clinical work has demonstrated safety of intracranial M032 administration in mice and non-human primates. M032 is currently being tested in humans with high-grade malignant gliomas. Thus, in a novel fashion, both canine and human trials will proceed concurrently allowing a direct "head-to-head" comparison of safety and efficacy. We expect this viral oncolytic therapy to be as safe as it is in human patients and M032 to (a) infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; (b) provide an adjuvant effect due to liberation of viral DNA, which is rich in unmethylated CpG sequences that "toggle" TLR-9 receptors; and (c) express IL-12 locally, stimulating induction of TH1 lymphocytes. The resultant immune-mediated anti-viral responses should, through cross-epitope spreading, translate into a strong response to tumor antigens. The ability to compare human and dog responses in real time affords the most stringent test of suitability of the dog as an informative model of human brain tumors. Subsequent studies will allow canine trials to properly inform the design of human trials.
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BACKGROUND: The purpose of this study was to determine the relationship between timing and volume of crystalloid before blood products and mortality, hypothesizing that earlier transfusion and decreased crystalloid before transfusion would be associated with improved outcomes. METHODS: A multi-institutional prospective observational study of pediatric trauma patients younger than 18 years, transported from the scene of injury with elevated age-adjusted shock index on arrival, was performed from April 2018 to September 2019. Volume and timing of prehospital, emergency department, and initial admission resuscitation were assessed including calculation of 20 ± 10 mL/kg crystalloid boluses overall and before transfusion. Multivariable Cox proportional hazards and logistic regression models identified factors associated with mortality and extended intensive care, ventilator, and hospital days. RESULTS: In 712 children at 24 trauma centers, mean age was 7.6 years, median (interquartile range) Injury Severity Score was 9 (2-20), and in-hospital mortality was 5.3% (n = 38). There were 311 patients(43.7%) who received at least one crystalloid bolus and 149 (20.9%) who received blood including 65 (9.6%) with massive transfusion activation. Half (53.3%) of patients who received greater than one crystalloid bolus required transfusion. Patients who received blood first (n = 41) had shorter median time to transfusion (19.8 vs. 78.0 minutes, p = 0.005) and less total fluid volume (50.4 vs. 86.6 mL/kg, p = 0.033) than those who received crystalloid first despite similar Injury Severity Score (median, 22 vs. 27, p = 0.40). On multivariable analysis, there was no association with mortality (p = 0.51); however, each crystalloid bolus after the first was incrementally associated with increased odds of extended ventilator, intensive care unit, and hospital days (all p < 0.05). Longer time to transfusion was associated with extended ventilator duration (odds ratio, 1.11; p = 0.04). CONCLUSION: Resuscitation with greater than one crystalloid bolus was associated with increased need for transfusion and worse outcomes including extended duration of mechanical ventilation and hospitalization in this prospective study. These data support a crystalloid-sparing, early transfusion approach for resuscitation of injured children. LEVEL OF EVIDENCE: Therapeutic, level IV.
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Transfusión de Componentes Sanguíneos , Soluciones Cristaloides/uso terapéutico , Resucitación/métodos , Tiempo de Tratamiento , Heridas y Lesiones/terapia , Adolescente , Niño , Preescolar , Femenino , Mortalidad Hospitalaria , Humanos , Lactante , Puntaje de Gravedad del Traumatismo , Masculino , Estudios Prospectivos , Estados Unidos , Heridas y Lesiones/mortalidad , Adulto JovenRESUMEN
High-risk neuroblastoma continues to carry a poor prognosis. Nearly 50% of these tumors relapse following extensive treatment regimens. Protein phosphatase 2A (PP2A), a tumor suppressor, has been shown to be downregulated in many human cancers via multiple mechanisms including upregulation of its endogenous inhibitors, I2PP2A or CIP2A. We hypothesized that inhibition of the endogenous PP2A inhibitors or activation of PP2A would decrease tumorigenicity in human neuroblastoma cells. Four human neuroblastoma cell lines were utilized. Expression of PP2A and its endogenous inhibitors I2PP2A and CIP2A was confirmed by immunoblotting. PP2A activation was measured via phosphatase activation assay. Multiple parallel methods including siRNA inhibition of the endogenous PP2A inhibitors and pharmacologic activation of PP2A were utilized. Cell viability, proliferation, migration, and invasion assays were performed. In vivo studies were utilized to determine the effects of PP2A activation on neuroblastoma tumor growth. Inhibition of the endogenous inhibitors of PP2A or pharmacologic activation of PP2A with the PP2A activator FTY720 led to decreased neuroblastoma cell viability, proliferation, migration, and invasion. Treatment of mice bearing SK-N-AS or SK-N-BE(2) neuroblastoma tumors with FTY720 resulted in a significant decrease in tumor growth compared to vehicle-treated animals. In conclusion, activation of PP2A may provide a novel therapeutic target for neuroblastoma.
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BACKGROUND: Pancreatic islet cell tumors are rare in adolescents, and most studies published to date focus on older patients. We utilized a national database to describe the histology and clinical pattern of pancreatic islet cell tumors in adolescent and young adult (AYA) patients, and to compare AYAs to older adults. We hypothesized that AYAs with pancreatic islet cell tumors would have better overall survival. METHODS: The National Cancer Data Base (NCDB, 1998-2012) was queried for AYA patients (15-39â¯years) with a pancreatic islet cell tumor diagnosis. Demographics, tumor characteristics, treatment modalities, and outcomes were abstracted and compared to adults (≥40â¯years). RESULTS: 383 patients (56.4% female, 65% non-Hispanic Whites) were identified, with a median age of 27 (IQR 16-34) years. Islet cell carcinoma was the most common histology. Of patients with known stage of disease, 49% presented with early stage (I or II). Seventy percent of patients underwent surgical resection, including local excision 44%, Whipple procedure 37.5%, or total pancreatectomy 19%. Chemotherapy was utilized in 27% and radiotherapy in 7%. All-cause mortality was 36%. AYA patients underwent more extensive resections (pâ¯=â¯0.001) and had lower mortality rates (pâ¯<â¯0.001), with no differences in tumor stage or use of adjuvant therapies, when compared to adults. CONCLUSIONS: AYA patients with pancreatic islet cell tumors had comparable utilization of adjuvant therapies but underwent more extensive resections and demonstrated a higher overall survival rate than adult counterparts. Further investigation into approaches to earlier diagnosis and tailoring of multimodality therapy of these neoplasms in the AYA population is needed. LEVELS OF EVIDENCE: Prognostic Study, Level II - retrospective study.
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Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/cirugía , Adenoma de Células de los Islotes Pancreáticos , Adolescente , Adulto , Factores de Edad , Anciano , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/patología , Pancreatectomía/estadística & datos numéricos , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pancreaticoduodenectomía/estadística & datos numéricos , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Increasing incidence coupled with poor prognosis and treatments that are virtually unchanged over the past 20 years have made the need for the development of novel therapeutics for hepatoblastoma imperative. PIM kinases have been implicated as drivers of tumorigenesis in multiple cancers, including hepatocellular carcinoma. We hypothesized that PIM kinases, specifically PIM3, would play a role in hepatoblastoma tumorigenesis and that PIM kinase inhibition would affect hepatoblastoma in vitro and in vivo. Parameters including cell survival, proliferation, motility, and apoptosis were assessed in human hepatoblastoma cells following PIM3 knockdown with siRNA or treatment with the PIM inhibitor AZD1208. An in vivo model of human hepatoblastoma was utilized to study the effects of PIM inhibition alone and in combination with cisplatin. PIM kinases were found to be present in the human hepatoblastoma cell line, HuH6, and in a human hepatoblastoma patient-derived xenograft, COA67. PIM3 knockdown or inhibition with AZD1208 decreased cell survival, attachment independent growth, and motility. Additionally, inhibition of tumor growth was observed in a hepatoblastoma xenograft model in mice treated with AZD1208. Combination therapy with AZD1208 and cisplatin resulted in a significant increase in animal survival when compared to either treatment alone. The current studies showed that PIM kinase inhibition decreased human hepatoblastoma tumorigenicity both in vitro and in vivo, implying that PIM inhibitors may be useful as a novel therapeutic for children with hepatoblastoma.
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Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.
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Vectores Genéticos/administración & dosificación , Herpesvirus Humano 1/genética , Viroterapia Oncolítica , Proyectos de Investigación , Neoplasias Supratentoriales/genética , Neoplasias Supratentoriales/radioterapia , Adolescente , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/virología , Niño , Preescolar , Femenino , Terapia Genética , Humanos , Masculino , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/virología , Virus Oncolíticos/genética , Seguridad , Neoplasias Supratentoriales/virologíaRESUMEN
Pediatric solid tumors remain a major health concern, with nearly 16,000 children diagnosed each year. Of those, ~2,000 succumb to their disease, and survivors often suffer from lifelong disability secondary to toxic effects of current treatments. Countless multimodality treatment regimens are being explored to make advances against this deadly disease. One targeted treatment approach is oncolytic virotherapy. Conditionally replicating viruses can infect tumor cells while leaving normal cells unharmed. Four viruses have been advanced to pediatric clinical trials, including herpes simplex virus-1, Seneca Valley virus, reovirus, and vaccinia virus. In this review, we discuss the mechanism of action of each virus, pediatric preclinical studies conducted to date, past and ongoing pediatric clinical trials, and potential future direction for these novel viral therapeutics.
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Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies, such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side-effect profile. In this study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo We successfully demonstrated decreased cellular proliferation, invasion and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should be further investigated as a developing therapeutic in these rare and difficult-to-treat pediatric solid organ tumors. Mol Cancer Ther; 15(5); 911-21. ©2016 AACR.
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Antineoplásicos/farmacología , Ácidos Grasos Insaturados/farmacología , Naftalenos/farmacología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Neoplasias Renales , Neoplasias Hepáticas , Ratones , Ratones Desnudos , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite the tremendous advances in the treatment of childhood solid tumors, rhabdomyosarcoma (RMS) continues to provide a therapeutic challenge. Children with metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumorigenesis. Signaling pathways both upstream and downstream to FAK have been found to be important in sarcoma tumorigenesis, leading us to hypothesize that FAK would be present in RMS and would impact cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric alveolar and embryonal RMS tumor specimens and cell lines. We also examined the effects of FAK inhibition upon two RMS cell lines utilizing parallel approaches including RNAi and small molecule inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Furthermore, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse RMS xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in RMS and may provide desperately needed novel therapeutic strategies for these difficult-to-treat tumors.
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Rhabdomyosarcoma (RMS), a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV), are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS) cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.
RESUMEN
Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell-cycle analysis, migration, and invasion were studied using AlamarBlue assays, FACS, and Transwell assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion, and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment.