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OBJECTIVE: To determine the impact of nodal basin ultrasound (US) surveillance versus completion lymph node dissection (CLND) in children and adolescents with sentinel lymph node (SLN) positive melanoma. BACKGROUND: Treatment for children and adolescents with melanoma are extrapolated from adult trials. However, there is increasing evidence that important clinical and biological differences exist between pediatric and adult melanoma. METHODS: Patients ≤18 years diagnosed with cutaneous melanoma between 2010 and 2020 from 14 pediatric hospitals were included. Data extracted included demographics, histopathology, nodal basin strategies, surveillance intervals, and survival information. RESULTS: Of 252 patients, 90.1% (n=227) underwent SLN biopsy (SLNB), 50.9% (n=115) had at least 1 positive node. A total of 67 patients underwent CLND with 97.0% (n=65/67) performed after a positive SLNB. In contrast, 46 total patients underwent US observation of nodal basins with 78.3% (n=36/46) of these occurring after positive SLNB. Younger patients were more likely to undergo US surveillance (median age 8.5 y) than CLND (median age 11.3 y; P =0.0103). Overall, 8.9% (n=21/235) experienced disease recurrence: 6 primary, 6 nodal, and 9 distant. There was no difference in recurrence (11.1% vs 18.8%; P =0.28) or death from disease (2.2% vs 9.7%; P =0.36) for those who underwent US versus CLND, respectively. CONCLUSIONS: Children and adolescents with cutaneous melanoma frequently have nodal metastases identified by SLN. Recurrence was more common among patients with thicker primary lesions and positive SLN. No significant differences in oncologic outcomes were observed with US surveillance and CLND following the identification of a positive SLN.
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Melanoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Adulto , Humanos , Adolescente , Niño , Melanoma/diagnóstico por imagen , Melanoma/cirugía , Melanoma/patología , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/cirugía , Ganglio Linfático Centinela/patología , Recurrencia Local de Neoplasia/patología , Escisión del Ganglio Linfático , Biopsia del Ganglio Linfático Centinela , Estudios RetrospectivosRESUMEN
PURPOSE: Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non-RCR). PATIENTS AND METHODS: This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups. Kaplan-Meier curves were generated for OS and pulmonary relapse. RESULTS: Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five-year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR (p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17-0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16-0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p = .14). Five-year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non-RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). DISCUSSION: Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.
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Neoplasias Óseas , Neoplasias Pulmonares , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Sarcoma de Ewing/patología , Femenino , Masculino , Niño , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/secundario , Estudios Retrospectivos , Adolescente , Neoplasias Óseas/mortalidad , Neoplasias Óseas/terapia , Neoplasias Óseas/secundario , Neoplasias Óseas/patología , Preescolar , Tasa de Supervivencia , Pronóstico , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto Joven , Inducción de Remisión , Lactante , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Quimioterapia de InducciónRESUMEN
BACKGROUND: Clearing all pulmonary metastases is essential for curing pediatric solid tumors. However, intraoperative localization of such pulmonary nodules can be challenging. Therefore, an intraoperative tool that localizes pulmonary metastases is needed to improve diagnostic and therapeutic resections. Indocyanine green (ICG) real-time fluorescence imaging is used for this purpose in adult solid tumors, but its utility in pediatric solid tumors has not been determined. METHODS: A single-center, open-label, nonrandomized, prospective clinical trial (NCT04084067) was conducted to assess the ability of ICG to localize pulmonary metastases of pediatric solid tumors. Patients with pulmonary lesions who required resection, either for therapeutic or diagnostic intent, were included. Patients received a 15-minute intravenous infusion of ICG (1.5 mg/kg), and pulmonary metastasectomy was performed the following day. A near-infrared spectroscopy iridium system was optimized to detect ICG, and all procedures were photo-documented and recorded. RESULTS: ICG-guided pulmonary metastasectomies were performed in 12 patients (median age: 10.5 years). A total of 79 nodules were visualized, 13 of which were not detected by preoperative imaging. Histologic examination confirmed the following histologies: hepatoblastoma (n = 3), osteosarcoma (n = 2), and one each of rhabdomyosarcoma, Ewing sarcoma, inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, and papillary thyroid carcinoma. ICG guidance failed to localize pulmonary metastases in five (42%) patients who had inflammatory myofibroblastic tumor, atypical cartilaginous tumor, neuroblastoma, adrenocortical carcinoma, or papillary thyroid carcinoma. CONCLUSIONS: ICG-guided identification of pulmonary nodules is not feasible for all pediatric solid tumors. However, it may localize most metastatic hepatic tumors and high-grade sarcomas in children.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Neuroblastoma , Neoplasias de la Tiroides , Adulto , Humanos , Niño , Verde de Indocianina , Estudios Prospectivos , Cáncer Papilar Tiroideo , Estudios de Factibilidad , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulos Pulmonares Múltiples/cirugía , Nódulos Pulmonares Múltiples/patología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Espectroscopía Infrarroja CortaRESUMEN
Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.
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Neoplasias Renales , Derrame Pleural Maligno , Derrame Pleural , Oncología Quirúrgica , Tumor de Wilms , Niño , Humanos , Incidencia , Neoplasias Renales/epidemiología , Neoplasias Renales/cirugía , Derrame Pleural/epidemiología , Derrame Pleural/etiología , Derrame Pleural Maligno/epidemiología , Derrame Pleural Maligno/etiología , Derrame Pleural Maligno/cirugía , Estudios Retrospectivos , Tumor de Wilms/epidemiología , Tumor de Wilms/cirugíaRESUMEN
PURPOSE: Placement of a central venous catheter (CVC) is the most commonly performed pediatric procedure. This study aims to develop simple formulas to calculate intravascular length of CVCs prior to insertion to minimize reliance on fluoroscopic and radiographic imaging, which may not be uniformly available. METHODS: We performed a single-institution, retrospective review of 115 pediatric patients who received both CVC placement and computed tomography (CT) imaging of the chest within 3 months of the procedure. Using measurements from the CT imaging, formulas calculating the length of the intravascular component of the CVC based on height and insertion laterality were developed and compared to previously published formulas. These formulas were then trialed prospectively to validate reliability and application. RESULTS: Formulas were developed for right-sided and left subclavian insertion. The right-side formula accurately predicted CVC length in 52.6% of patients, compared to 47.4% by the Andropoulos formula. The left subclavian formula accurately estimated 62.5%, compared to 34.5% by the Stroud formula. CONCLUSIONS: The optimal intravascular length of central venous catheters may be determined by simple formulas based on patient height and insertion site. LEVEL OF EVIDENCE: III.
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Cateterismo Venoso Central , Catéteres Venosos Centrales , Cateterismo Venoso Central/métodos , Niño , Humanos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Minimally invasive surgery (MIS) has been widely adopted for common operations in pediatric surgery; however, its role in childhood tumors is limited by concerns about oncologic outcomes. We compared open and MIS approaches for pediatric neuroblastoma and Wilms tumor (WT) using a national database. METHODS: The National Cancer Data Base from 2010 to 2012 was queried for cases of neuroblastoma and WT in children ≤21 years old. Children were classified as receiving open or MIS surgery for definitive resection, with clinical outcomes compared using a propensity matching methodology (two open:one MIS). RESULTS: For children with neuroblastoma, 17% (98 of 579) underwent MIS, while only 5% of children with WT (35 of 695) had an MIS approach for tumor resection. After propensity matching, there was no difference between open and MIS surgery for either tumor for 30-day mortality, readmissions, surgical margin status, and 1- and 3-year survival. However, in both tumors, open surgery more often evaluated lymph nodes and had larger lymph node harvest. CONCLUSION: Our retrospective review suggests that the use of MIS appears to be a safe method of oncologic resection for select children with neuroblastoma and WT. Further research should clarify which children are the optimal candidates for this approach.
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Neoplasias Renales/cirugía , Neuroblastoma/cirugía , Tumor de Wilms/cirugía , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Neoplasias Renales/mortalidad , Masculino , Procedimientos Quirúrgicos Mínimamente Invasivos , Neuroblastoma/mortalidad , Sistema de Registros , Estudios Retrospectivos , Tumor de Wilms/mortalidadRESUMEN
PURPOSE: Clinical efficacy of CAR T cells against pediatric osteosarcoma (OS) has been limited. One strategy to improve efficacy may be to drive chemokine-mediated homing of CAR T cells to tumors. We investigated the primary chemokines secreted by OS and evaluated efficacy of B7-H3.CAR T cells expressing the cognate receptors. EXPERIMENTAL DESIGN: We developed a pipeline to identify chemokines secreted by OS by correlating RNA-seq data with chemokines detected in media from fresh surgical specimens. We identified CXCR2 and CXCR6 as promising receptors for enhancing CAR T cell homing against OS. We evaluated the homing kinetics and efficiency of CXCR2- and CXCR6.T cells and homing, cytokine production, and antitumor activity of CXCR2- and CXCR6.B7-H3.CAR T cells in vitro and in vivo. RESULTS: T cells transgenically expressing CXCR2 or CXCR6 exhibited ligand-specific enhanced migration over T cells modified with nonfunctional receptors. Differential homing kinetics were observed, with CXCR2.T cells homing quickly and plateauing early, while CXCR6.T cells homed more slowly but achieved a similar plateau. When expressed in B7-H3.CAR T cells, CXCR2- and CXCR6 modification conferred enhanced homing towards OS in vitro and in vivo. CXCR2- and CXCR6-B7-H3.CAR treated mice experienced prolonged survival in a metastatic model compared to B7-H3.CAR T cell treated mice. CONCLUSIONS: Our patient-based pipeline identified targets for chemokine receptor modification of CAR T cells targeting OS. CXCR2 and CXCR6 expression enhanced homing and anti-OS activity of B7-H3.CAR T cells. These findings support clinical evaluation of CXCR-modified CAR T cells to improve adoptive cell therapy for OS patients.
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BACKGROUND: Limb-sparing surgery is the standard of care for primary bone tumors. However, such procedures are associated with high rates of wound complications, specifically in lower-extremity surgeries. Therefore, identifying and implementing interventions to minimize the likelihood of wound complications after limb-sparing resection of the lower extremity is crucial. METHODS: Patients who underwent limb-sparing osteosarcoma or Ewing sarcoma resection during a 7-year period at a single institution were retrospectively reviewed. Data were collected on 39 patients who underwent limb-sparing resection of the femur. Patient demographics, tumor characteristics, and perioperative and postoperative data were extracted and analyzed. Patients who underwent resection before April 2017 received conventional postoperative incision dressings. Starting in April 2017, patients received vacuum-assisted closure (VAC) with the 3 M™ Prevena VAC system after surgical closure. Eighteen patients received conventional postoperative incision dressing, and 21 received incisional wound VAC. A wound complication was defined as any Clavien-Dindo classification greater than 0 within a 28-day postoperative period. RESULTS: Patients who received postoperative incisional wound VAC had lower rates of wound complications than those who received conventional incision dressings (14% vs. 50%; p = 0.035). Additionally, patients in whom wound complications developed had a longer average hospital stay than those without wound complications (5 days vs. 4 days; p = 0.029). CONCLUSIONS: Wound complications prolong the hospital stay and can delay adjuvant chemotherapy for bone tumors. The use of postoperative incisional wound VAC is associated with less likelihood of wound complications and should be considered in any high-risk surgical closure. LEVEL OF EVIDENCE: Level III Treatment Study.
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Terapia de Presión Negativa para Heridas , Osteosarcoma , Sarcoma de Ewing , Humanos , Terapia de Presión Negativa para Heridas/métodos , Masculino , Estudios Retrospectivos , Femenino , Niño , Adolescente , Osteosarcoma/cirugía , Sarcoma de Ewing/cirugía , Infección de la Herida Quirúrgica/prevención & control , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/etiología , Neoplasias Femorales/cirugía , Neoplasias Óseas/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Tiempo de Internación/estadística & datos numéricos , Fémur/cirugía , Recuperación del Miembro/métodos , PreescolarRESUMEN
Chimeric antigen receptor (CAR) technologies have been clinically implemented for the treatment of hematological malignancies; however, solid tumors remain resilient to CAR therapeutics. Natural killer (NK) cells may provide an optimal class of immune cells for CAR-based approaches due to their inherent anti-tumor functionality. In this study, we sought to tune CAR immune synapses by adding an intracellular scaffolding protein binding site to the CAR. We employ a PDZ binding motif (PDZbm) that enables additional scaffolding crosslinks that enhance synapse formation and NK CAR cell polarization. Combined effects of this CAR design result in increased effector cell functionality in vitro and in vivo. Additionally, we used T cells and observed similar global enhancements in effector function. Synapse-tuned CAR immune cells exhibit amplified synaptic strength, number and abundance of secreted cytokines, enhanced killing of tumor cells and prolonged survival in numerous different tumor models, including solid tumors.
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Although survival for many pediatric cancers has improved with advances in conventional chemotherapeutic regimens and surgical techniques in the last several decades, it remains a leading cause of disease-related death in children. Outcomes in patients with recurrent, refractory, or metastatic disease are especially poor. Recently, the advent of alternative classes of therapies, including immunotherapies, have revolutionized systemic treatment for pediatric malignancies. Several classes of immunotherapies, including chimeric antigen receptor (CAR) T cell therapy, transgenic T-cell receptor (TCR)-T cell therapy, bispecific T-cell engagers, and monoclonal antibody checkpoint inhibitors have been FDA-approved or entered early-phase clinical trials in children and young adults. The pediatric surgeon is likely to encounter these therapies during the care of children with malignancies and should be familiar with the classes of therapy, indications, adverse events, and potential need for surgical intervention in these cases. This review from the APSA Cancer Committee offers a brief discussion of the three most encountered classes of immunotherapy in children and young adults and discusses surgical relevance. LEVEL OF EVIDENCE: IV.
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Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly by NTRK fusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. The NTRK fusion acts as a driver for tumor formation, which can be targeted by first- and second-generation TRK inhibitors. Although NTRK gatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy and TRK inhibition that developed metastatic, progressive disease with multiple acquired mutations, including TP53, SUFU, and an NTRK F617L gatekeeper mutation. Alterations in pathways of SUFU and TP53 have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response to TRK inhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma with ETV6::NTRK3 and acquired SUFU, TP53, and NTRK F617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes.
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Fibrosarcoma , Neoplasias Primarias Secundarias , Sarcoma , Niño , Humanos , Fibrosarcoma/genética , Mutación , Inhibidores de Proteínas Quinasas , Progresión de la EnfermedadRESUMEN
OBJECTIVE: To determine the efficacy of osteopontin (OPN) targeting in hepatocellular cancer (HCC). SUMMARY/BACKGROUND: OPN is associated with HCC growth and metastasis and represents a unique therapeutic target. METHODS: OPN and epithelial-mesenchymal transition (EMT) markers, α-smooth muscle actin (SMA), vimentin, and tenascin-c, were measured in archived human HCC tissues from metastatic (n = 4) and nonmetastatic (n = 4) settings. Additional studies utilized human Sk-Hep-1 (high OPN expression) and Hep3b (low OPN expression) HCC cells. An RNA aptamer (APT) that avidly binds (Kd = 18 nM; t1/2 = 7 hours) and ablates OPN binding was developed. Adhesion, migration/invasion, and EMT markers were determined with APT or a mutant control aptamer (Mu-APT). RFP-Luc-Sk-Hep-1 were implanted into NOD-scid mice livers and followed by using bioluminescence imaging. After verification of tumor growth, at week 3, APT (0.5 mg/kg; n = 4) or Mu-APT (0.5 mg/kg; n = 4) was injected q48h. When mice were killed at week 8, tumor cells were reisolated and assayed for EMT markers. RESULTS: OPN and EMT markers were significantly increased in the metastatic cohort. APT inhibited Sk-Hep-1 adhesion and migration/invasion by 5- and 4-fold, respectively. APT significantly decreased EMT protein markers, SMA, vimentin, and tenascin-c. In contrast, APT did not alter Hep3B adhesion, or migration/invasion. EMT markers were slightly decreased. In the in vivo model, at weeks 6 to 8, APT inhibited HCC growth by more than 10-fold. SMA, vimentin, and tenascin-c mRNAs were decreased by 60%, 40%, and 49%, respectively, in RFP-positive Sk-Hep-1 recovered by fluorescence-activated cell sorting (P < 0.04 vs Mu-APT for all). CONCLUSIONS: APT targeting of OPN significantly decreases EMT and tumor growth of HCC.
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Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Neoplasias Hepáticas/metabolismo , Osteopontina/metabolismo , Adulto , Animales , Aptámeros de Nucleótidos , Western Blotting , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Trasplante de Neoplasias , Reacción en Cadena en Tiempo Real de la Polimerasa , Técnica SELEX de Producción de AptámerosRESUMEN
Pediatric osteosarcomas (OS) exhibit extensive genomic instability that has complicated the identification of new targeted therapies. We found the vast majority of 108 patient tumor samples and patient-derived xenografts (PDXs), which display an unusually dilated endoplasmic reticulum (ER), have reduced expression of four COPII vesicle components that trigger aberrant accumulation of procollagen-I protein within the ER. CRISPR activation technology was used to increase the expression of two of these, SAR1A and SEC24D, to physiological levels. This was sufficient to resolve the dilated ER morphology, restore collagen-I secretion, and enhance secretion of some extracellular matrix (ECM) proteins. However, orthotopic xenograft growth was not adversely affected by restoration of only SAR1A and SEC24D. Our studies reveal the mechanism responsible for the dilated ER that is a hallmark characteristic of OS and identify a highly conserved molecular signature for this genetically unstable tumor. Possible relationships of this phenotype to tumorigenesis are discussed.
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PURPOSE: We sought to identify clinical features associated with difficult subcutaneous port removals in children. METHODS: Ports placed between April 2014 and September 2017 at our institution were prospectively tracked for difficult removals. A case-control analysis was performed. Patients with ports that were difficult to remove (stuck; cases) were compared to biological sex and age-matched controls in a ratio of 1:3. Logistic regression determined the association between case/control status and clinical features adjusting for biological sex and age as covariates. A multivariable analysis was performed to identify independent associations. RESULTS: 57 stuck ports (28 extreme [10 endovascular intervention] and 29 moderate) and 171 controls were analyzed. Stuck ports were associated with a diagnosis of acute lymphoblastic leukemia (86% cases versus 22.2% controls; p < 0.001) and a longer placement duration (median 2.6 years [interquartile range (IQR) 2.5-2.6] versus 0.8 years [IQR 0.5-1.4]; p < 0.001). On univariate analysis, procedural and device features associated with stuck ports included subclavian access (71.9% cases versus 48.5% controls; p = 0.0126), a polyurethane versus silicone catheter (96.5% cases versus 79.9% controls; p = 0.001), and a rough catheter appearance at removal (92.6% cases versus 9.4% controls; p < 0.0001). A diagnosis of ALL and duration of line placement were associated with having a stuck port on multivariate analysis. CONCLUSION: Polyurethane central venous catheters placed for the two-year treatment of acute lymphoblastic leukemia may become difficult to remove. This constellation of factors warrants more extensive preoperative discussion of risk, endovascular backup availability, and scheduling for longer operating room time.
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Cateterismo Venoso Central , Catéteres Venosos Centrales , Leucemia-Linfoma Linfoblástico de Células Precursoras , Estudios de Casos y Controles , Catéteres de Permanencia , Niño , Humanos , Poliuretanos , Estudios RetrospectivosRESUMEN
The interaction between cancer and its local microenvironment can determine properties of growth and metastasis. A critical component of the tumor microenvironment in this context is the cancer-associated fibroblast (CAF), which can promote tumor growth, angiogenesis and metastasis. It has been hypothesized that CAF may be derived from mesenchymal stromal cells (MSC), derived from local or distant sources. However, the signaling mechanisms by which tumors and MSCs interact to promote CAF-dependent cancer growth are largely unknown. In this study with in vitro and in vivo models using MDA-MB231 human breast cancer cells, we demonstrate that tumor-derived osteopontin (OPN) induces MSC production of CCL5; the mechanism involves OPN binding to integrin cell surface receptors and activator protein-1 c-jun homodimer transactivation. In a murine xenograft model, concomitant inoculation of MSC with MDA-MB231 cells induces: (i) significantly increased growth and metastasis of MB231 cells and (ii) increased MSC migration to metastatic sites in lung and liver; this mechanism is both OPN and CCL5 dependent. MSCs retrieved from sites of metastases exhibit OPN-dependent expression of the CAF markers, α-smooth muscle actin, tenascin-c, CXCL12 (or stromal cell-derived factor 1) and fibroblast-specific protein-1 and the matrix metalloproteinases (MMP)-2 and MMP-9. Based upon these results, we propose that tumor-derived OPN promotes tumor progression via the transformation of MSC into CAF.
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Neoplasias de la Mama/patología , Quimiocina CCL5/fisiología , Células Madre Mesenquimatosas/fisiología , Osteopontina/fisiología , Células del Estroma/fisiología , Animales , Línea Celular Tumoral , Técnicas de Cocultivo , Femenino , Humanos , Ratones , Ratones SCID , Metástasis de la Neoplasia , Trasplante de Neoplasias , Trasplante HeterólogoRESUMEN
BACKGROUND: Optimal management of neutropenic appendicitis (NA) in children undergoing cancer therapy remains undefined. Management strategies include upfront appendectomy or initial nonoperative management. We aimed to characterize the effect of management strategy on complications and length of stay (LOS) and describe implications for chemotherapy delay or alteration. METHODS: Sites from the Pediatric Surgery Oncology Research Collaborative performed a retrospective review of children with NA over a 6-year period. RESULTS: Sixty-six children, with a median age of 11 years (range 1-17), were identified with NA while undergoing cancer treatment. The most common cancer diagnoses were leukemia (62%) and brain tumor (12%). Upfront appendectomy was performed in 41% of patients; the remainder had initial nonoperative management. Rates of abscess or perforation at diagnosis were equivalent in the groups (30% vs 24%; P = .23). Of patients who had initial nonoperative management, 46% (17 of 37) underwent delayed appendectomy during the same hospitalization. Delayed appendectomy was due to failure of initial nonoperative management in 65% (n = 11) and count recovery in 35% (n = 6). Cancer therapy was delayed in 35% (n = 23). Initial nonoperative management was associated with a delay in cancer treatment (46% vs. 22%, P = .05) and longer LOS (29 vs 12 days; P = .01). Patients who had initial nonoperative management and delayed appendectomy had a higher rate of postoperative complications (P < .01). CONCLUSIONS: In pediatric patients with NA from oncologic treatment, upfront appendectomy resulted in lower complication rates, reduced LOS, and fewer alterations in chemotherapy regimens compared to initial nonoperative management.
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Apendicectomía/tendencias , Apendicitis/terapia , Neutropenia Febril Inducida por Quimioterapia/terapia , Neoplasias/terapia , Espera Vigilante/tendencias , Adolescente , Apendicitis/diagnóstico , Apendicitis/epidemiología , Neutropenia Febril Inducida por Quimioterapia/diagnóstico , Neutropenia Febril Inducida por Quimioterapia/epidemiología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasias/diagnóstico , Neoplasias/epidemiología , Estudios Retrospectivos , Espera Vigilante/métodosRESUMEN
Accurate measurement of total body surface area (TBSA) burned is a key factor in the care of pediatric patients with burn, especially those with large thermal injuries. There is a paucity of data on the accuracy of these measurements by prehospital, nonburn center, and emergency department (ED) providers, which can have drastic implications for patient management and outcomes. We sought to determine the accuracy of these estimates for large pediatric burns. A retrospective chart review was conducted of patients with TBSA ≥10% admitted to an American Burn Association (ABA)-verified pediatric burn center from 2007 to 2015. Final TBSA was determined by pediatric burn surgeons and compared with prehospital emergency medical service providers, outside hospital physicians for transferred patients, and burn center ED physicians. Statistical significance was determined using a paired t-test with P < 0.05. A total of 139 patients ≤18 years of age met inclusion criteria, with an average TBSA of 18.9 ± 1.1%, weight 23.7 ± 1.6 kg and age of 5.4 ± 0.41 years. When compared in a pairwise fashion to the TBSA values determined by pediatric burn surgeons, estimates of TBSA were higher by: prehospital emergency medical service providers, 40.0% (n = 67, P < 0.0001); outside hospital physicians, 18.7% (n = 46, P = 0.0009), and burn center ED physicians, 7.2% (n = 120, P = 0.0117). TBSA burn estimates for pediatric patients by prehospital, nonburn center, and ED providers are significantly higher than those recorded by burn surgeons at an ABA-verified pediatric burn center. These inaccuracies in TBSA measurement may have profound clinical implications.
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Superficie Corporal , Quemaduras/patología , Servicios Médicos de Urgencia/normas , Examen Físico/normas , Adolescente , Niño , Preescolar , Femenino , Humanos , Puntaje de Gravedad del Traumatismo , Masculino , Estudios RetrospectivosRESUMEN
PURPOSE: Neonates after emergent enterostomy creation frequently require reversal at low weight because of complications including cholestasis, dehydration, dumping, failure to thrive, and failure to achieve enteral independence. We investigated whether stoma reversal at low weight (< 2.5kg) is associated with poor surgical outcomes. METHODS: Patients who underwent enterostomy reversal from 2005 to 2013 at less than 6months old were identified in our institutional database. Only patients who underwent emergent enterostomy creation (i.e. for necrotizing enterocolitis or spontaneous perforation) were included. Demographics, disease process, comorbidities, stoma type, reversal indication, operative details, and complications were examined. Patients were categorized by weight at reversal of less than 2kg, 2.01-2.5kg, 2.51-3.5kg, and greater than 3.5kg. Data were analyzed using univariable and multivariable regression with significance level of p<0.05. The primary outcome examined was major morbidity, defined as the presence of anastomotic leak, obstruction, hernia, EC fistula, perforation, wound infection, sepsis, or death. RESULTS: Eighty-nine patients met inclusion criteria. Demographics (sex, ethnicity, surgical disease process, reversal indication, and ASA score) were similar. The lowest weight group had lower gestational age (p<0.001) and birth weight (p=0.005), and contained a higher proportion of jejunostomies to ileostomies (p=0.013). On univariable analysis, only incisional hernia was significantly different as a complication between weight groups. On multivariable analysis controlling for gestational age and ASA, there was no significant difference in odds of major operative morbidity between groups. CONCLUSIONS: Enterostomy reversal at lower weight may not be associated with increased risk of perioperative complications. Early stoma reversal may be acceptable when required for progression of neonatal care. LEVEL OF EVIDENCE: Level III, Treatment Study (Retrospective comparative study).
Asunto(s)
Peso Corporal , Enterostomía , Reoperación , Estomas Quirúrgicos , Peso al Nacer , Colestasis/etiología , Enterocolitis Necrotizante/cirugía , Enterostomía/efectos adversos , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Perforación Intestinal/cirugía , Masculino , Complicaciones Posoperatorias , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Adrenocortical carcinoma (ACC) is a rare tumor in children with important distinctions from the adult disease. We reviewed the National Cancer Data Base (NCDB) to determine factors associated with long-term survival. METHODS: The NCDB was queried for patients less than 18 years of age who were diagnosed with ACC between 1998 and 2011. Kaplan-Meier analysis was utilized to determine factors significantly associated with overall survival. RESULTS: A total of 111 patients were included (median age: 4 years, 69% female). ACC was more common in the youngest cohort, with 48% of cases occurring in children younger than the age of 3. Median tumor size was 9.5 cm (IQR: 6.5-13.0), and 87% of patients underwent some form of surgical resection. Among children with available data, 19 of 62 presented with metastases. Overall 1- and 3-year survival was 70% and 64%, respectively. Age, tumor size, extension of tumor into surrounding tissue, and metastatic disease were all found to be significantly associated with survival. Among patients who underwent a surgical procedure, margin status was also found to be significantly associated with survival. CONCLUSION: Age, tumor size, extension of tumor, metastatic disease, and margin status are significantly associated with long-term survival in children with adrenocortical carcinoma.