Publications (26)110.89 Total impact
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Article: Autologous Tumor Lysate-pulsed Dendritic Cell Immunotherapy for Pediatric Patients with Newly Diagnosed or Recurrent High-grade Gliomas.
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ABSTRACT: Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1×10(6) cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required.Anticancer research 05/2013; 33(5):2047-56. · 1.73 Impact Factor -
Article: Transplantation for congenital bone marrow failure syndromes.
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ABSTRACT: Congenital bone marrow failure syndromes (BMFSs) are relatively rare disorders characterized by aberrant development in one or more hematopoietic lineages. Genetic alterations have now been identified in most of these disorders although the exact role of the molecular defects has yet to be elucidated. Most of these diseases are successfully managed with supportive care, however, treatment refractoriness and disease progression-often involving malignant transformation-may necessitate curative treatment with hematopoietic stem cell transplantation. Due to the underlying molecular defects, the outcome of transplantation for BMFS may be dramatically different than those associated with transplantation for more common diseases, including leukemia. Given recent improvements in survival and molecular diagnosis of bone marrow failure syndrome patients presenting at adult ages without physical stigmata, it is important for both pediatric and adult hematologists to be aware of the possible diagnosis of BMF syndromes and the unique approaches required in treating such patients.Bone marrow research. 01/2011; 2011:849387. -
Article: High-dose chemotherapy with autologous hematopoietic stem-cell rescue for pediatric brain tumor patients: a single institution experience from UCLA.
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ABSTRACT: Background. Dose-dependent response makes certain pediatric brain tumors appropriate targets for high-dose chemotherapy with autologous hematopoietic stem-cell rescue (HDCT-AHSCR). Methods. The clinical outcomes and toxicities were analyzed retrospectively for 18 consecutive patients ≤19 y/o treated with HDCT-AHSCR at UCLA (1999-2009). Results. Patients' median age was 2.3 years. Fourteen had primary and 4 recurrent tumors: 12 neural/embryonal (7 medulloblastomas, 4 primitive neuroectodermal tumors, and a pineoblastoma), 3 glial/mixed, and 3 germ cell tumors. Eight patients had initial gross-total and seven subtotal resections. HDCT mostly consisted of carboplatin and/or thiotepa ± etoposide (n = 16). Nine patients underwent a single AHSCR and nine ≥3 tandems. Three-year progression-free and overall survival probabilities were 60.5% ± 16 and 69.3% ± 11.5. Ten patients with pre-AHSCR complete remissions were alive/disease-free, whereas 5 of 8 with measurable disease were deceased (median followup: 2.3 yrs). Nine of 13 survivors avoided radiation. Single AHSCR regimens had greater toxicity than ≥3 AHSCR (P < .01). Conclusion. HDCT-AHSCR has a definitive, though limited role for selected pediatric brain tumors with poor prognosis and pretransplant complete/partial remissions.Journal of Transplantation 01/2011; 2011:740673. -
Article: Clinical outcome in pediatric glial and embryonal brain tumors correlates with in vitro multi‐passageable neurosphere formation
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ABSTRACT: Background Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown.Methods Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere formation and clinical outcome were analyzed retrospectively.ResultsThirty-seven percent of all samples formed renewable neurospheres. Analysis of available clinical outcome data from 51 patients demonstrated significantly increased hazard ratios (HR) for both disease progression (HR = 9.9, P < 0.001) and death (HR = 16.6, P < 0.01) in the neurosphere forming group. Furthermore, neurosphere formation correlated with adverse progression free survival (PFS) in glial and embryonal tumors, but not in mixed glioneuronal tumors. Overall survival (OS) was significantly worse for neurosphere-forming patients with embryonal tumors, as a group and amongst the subgroup with medulloblastoma, but not in the glial group. Multivariate analysis showed that neurosphere formation was associated with diminished PFS and OS independent of age, gender, or treatment. Neurosphere formation was an independent predictor of diminished PFS of glial tumors after adjusting for grade. Multivariate analysis, adjusting for both Ki67 staining and neurosphere formation, demonstrated that neurosphere formation remained predictive of progression whereas Ki67 did not.Conclusions Neurosphere formation is more predictive of pediatric brain tumor progression than semi-quantitative Ki67 staining. Pediatric brain tumor derived neurospheres may provide a predictive model for preclinical explorations. Pediatr Blood Cancer. 2010;55:644–651. © 2010 Wiley-Liss, Inc.Pediatric Blood & Cancer 09/2010; 55(4):644 - 651. · 1.89 Impact Factor -
Article: Efficacy of high-dose chemotherapy and autologous stem cell transplant for recurrent Wilms' tumor: a meta-analysis.
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ABSTRACT: SUMMARY: Long-term survival of relapsed Wilms' tumor patients is about 40% to 70%. Modern second-line treatment consists of either (a) salvage chemotherapy+/-radiation therapy (CT) or (b) chemotherapy followed by high-dose chemotherapy and autologous hematopoietic stem cell rescue (ASCR). Here, we conduct an individual patient data meta-analysis on 100 patients collected from 6 studies to determine characteristics that predict survival in relapsed patients who received ASCR therapy. We compare these results with survival data on 118 CT treated patients from 2 recently published studies. Four year overall survival among the combined ASCR treated patients was 54.1% (95% CI: 42.8-64.1%). The ASCR patients who only relapsed in the lungs had higher 4-years survival rates 77.7% (58.6% to 88.8%) than those who relapsed in other locations and/or suffered multiple relapses 41.6% (24.8% to 57.6%). Although lung-only relapse is considered a favorable prognostic factor, there was no clear advantage for the patients treated with salvage chemotherapy. Four-year survival rates among stage I-II patients were about 30% higher with CT than ASCR, but the 2 were comparable for stage III-IV patients. These findings suggest salvage chemotherapy is typically the better choice for relapsed Wilms' tumor patients, ASCR could be considered for stage III-IV patients with a lung-only relapse.Journal of Pediatric Hematology/Oncology 08/2010; 32(6):454-61. · 1.16 Impact Factor -
Article: Graft-versus-leukemia effect on infant lymphoblastic leukemia relapsed after sibling hematopoietic stem cell transplantation.
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ABSTRACT: Infant acute lymphoblastic leukemia (ALL) is considered a high-risk entity. Patients diagnosed in the first 3 months of life have especially high mortality. By morphology, infant ALL is classified as a lymphoid lineage leukemia; however, its physiologic behavior has brought many to consider it a pathologic hybrid between lymphoid leukemia and myeloid leukemias. As such, standard of care currently employs the use of chemotherapeutic agents used commonly in ALL protocols and agents typically reserved for the treatment of myelogenous lineage leukemias. The role of hematopoietic stem cell transplantation and graft-versus-leukemia effect in these patients has not been well studied. An earlier healthy 9-week-old Hispanic male diagnosed with precursor B-cell lymphoblastic leukemia was treated with protocol P9407 and matched sibling hematopoietic stem cell transplantation. Relapse was noted on posttransplant day +114 with blasts on peripheral blood smear. The sole antigraft-versus-host disease (GVHD) agent, cyclosporine, was discontinued. Blast clearance from the peripheral blood was obtained by posttransplant day +128 with the appearance of skin and liver GVHD at posttransplant day +181. Bone marrow examination on posttransplant day +205 revealed normal marrow with no evidence of leukemic cells. He remains disease free more than 2 years posttransplant. Traditionally, graft-versus-leukemia effect was thought to contribute therapeutically little to the treatment of ALL by hematopoietic stem cell transplantation (HSCT). The effects of graft-versus-leukemia immunologic phenomenon in our patient with infant acute lymphoblastic leukemia underscore the potential that infant ALL may not be entirely the same biologic entity as standard pediatric ALL and may be more responsive than understood earlier. Therapeutic response and appearance of GVHD after the withdrawal of immunosuppression in this patient provides evidence that graft-versus-leukemia effect may play a role in disease control in infant ALL after HSCT. Patients who relapse after the HSCT may be salvaged with the withdrawal of immunosuppression. This suggests that other immunotherapeutic interventions in the context of relapse may offer potential clinical benefit in this disease.Journal of Pediatric Hematology/Oncology 02/2010; 32(2):e57-60. · 1.16 Impact Factor -
Article: Evaluating pharmacokinetics and pharmacodynamics of intravenous busulfan in pediatric patients receiving bone marrow transplantation.
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ABSTRACT: BU is a commonly used conditioning agent in BMT. However, it is a narrow therapeutic index drug which shows a strong correlation between AUC and both efficacy and toxicity. Studies in pediatric patients have suggested that children less than four yr of age have a greater clearance and thus lower AUC at standard adult doses. The goal of this retrospective analysis was to evaluate any age-related pharmacokinetic and pharmacodynamic differences in pediatric patients who received BU as a conditioning agent. From 2003 to 2006, 21/77 pediatric patients who received BMT were reviewed. There were 15 males and six females with a mean age of six yr old. Diagnoses of leukemia (n = 11), Hodgkin's lymphoma (n = 3), myelodysplastic syndrome (n = 2), and other (n = 5) were included. Sixteen patients received BU + cyclophosphamide while five patients received BU + another agent. There were 20 allogeneic and one autologous transplants among which 16 were human leukocyte antigen matched and five were mismatched. Average BU clearance in patients younger than four yr old (n = 8) was 4.1 +/- 1.0 mL/min/kg vs. 3.1 +/- 0.7 mL/min/kg in patients older than four yr old (n = 13) (p = 0.02). The corresponding averages for AUC were 998 +/- 226 microm x min vs. 1155 +/- 183 microm x min (p = 0.12). No patients younger than four yr old developed VOD while five of the older patients did (p = 0.044). There were no significant differences in terms of engraftment and acute GvHD. There were significant age-related pharmacokinetic differences in pediatric patients less than four yr of age receiving BU for conditioning prior to BMT. There was a decrease in drug toxicity seen in these patients.Pediatric Transplantation 12/2008; 13(8):971-6. · 1.48 Impact Factor -
Article: One year follow-up of children and adolescents with chronic immune thrombocytopenic purpura (ITP) treated with rituximab.
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ABSTRACT: We previously showed in a prospective study that rituximab appears to be effective in some children and adolescents with severe chronic immune thrombocytopenia. Eleven of 36 patients achieved and maintained platelet counts over 50,000/mm(3) within the first 12 weeks. These patients were followed for the next year. Platelet counts were monitored monthly and all subsequent bleeding manifestations and need for further treatment was noted. Eight of the 11 initial responders maintained a platelet count over 150,000/mm(3) without further treatment intervention. Three patients had a late relapse. One initial non-responder achieved a remission after 16 weeks, and two additional patients maintained platelet counts around 50,000/mm(3) without the need for further intervention. Rituximab resulted in sustained efficacy with platelet counts of 50,000/mm(3) or higher in 11 of 36 patients (31%).Pediatric Blood & Cancer 11/2008; 52(2):259-62. · 1.89 Impact Factor -
Article: ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia.
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ABSTRACT: In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3-internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC(50) approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC(50) = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G(0)/G(1) phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)-FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC(50) approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC(50) = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML.Blood 05/2007; 109(8):3400-8. · 9.90 Impact Factor -
Article: National collaborative study groups: structure, benefits gained and potential for rare genetic diseases.
Genetics in Medicine 01/2007; 8(12):793-6. · 4.76 Impact Factor -
Article: Treatment of embryonal rhabdomyosarcoma of the sinus and orbit with chemotherapy, radiation, and endoscopic surgery.
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ABSTRACT: Parameningeal rhabdomyosarcoma in children has a lower survival than rhabdomyosarcoma at other more favorable sites. This report describes the case of a 14-year-old girl who was successfully treated with multimodal therapy including chemotherapy, radiation, and endoscopic surgery.Journal of Pediatric Surgery 07/2006; 41(6):e15-7. · 1.45 Impact Factor -
Article: FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia.
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ABSTRACT: Ligand-mediated activation of the FMS-like tyrosine kinase 3 (FLT3) receptor is important for normal proliferation of primitive hematopoietic cells. However, activating mutations in FLT3 induce ligand-independent downstream signaling that promotes oncogenesis through pathways involved in proliferation, differentiation, and survival. FLT3 mutations are identified as the most frequent genetic abnormality in acute myeloid leukemia and are also observed in other leukemias. Multiple small-molecule inhibitors are under development to target aberrant FLT3 activity that confers a poor prognosis in patients.Stem Cells 06/2006; 24(5):1174-84. · 7.78 Impact Factor -
Article: Changing outcomes for children requiring intensive care following hematopoietic stem cell transplantation.
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ABSTRACT: Past literature has shown that respiratory failure following hematopoietic stem cell transplant is associated with a universally poor outcome with mortality rates approaching 100%. More recent studies have suggested that patient survival is improving. We report our experience with the patients from our institution, a large children's hospital, who were admitted to the intensive care unit (ICU). Medical records of 183 patients, who received a bone marrow transplant between 1992 and early 2004, who were <20 yr of age, were retrospectively reviewed. Various factors that might influence mortality were examined. Over the course of the study, the ICU survival increased from 18% during the period 1992-1999 to 59% between 2000 and early 2004. In the latter period, 54% of the patients discharged from the ICU were alive at 100 days post-transplant. Factors that were significant predictors of poor outcome were malignancy as the reason for transplant, dialysis during the ICU stay, or extreme respiratory failure with a ratio of arterial oxygen tension (PaO2)/inspired oxygen concentration (FiO2) <300. Analysis of patients who required a high positive end-expiratory pressure or were ventilated with permissive hypercapnia showed that they also had a higher mortality. The impact on survival of factors such as age at time of transplant, graft-vs.-host disease, pneumonia, bacteremia, sepsis, post-transplant days, Pediatric Risk of Mortality III score, engraftment status, or veno-occlusive disease did not reach statistical significance in this cohort. Survival has improved for children who require intensive care following a bone marrow transplant, even for those who require mechanical ventilation. Patients with extreme respiratory failure and those requiring dialysis continue to have poor outcome. Because of an overall improvement in survival, children whose condition following transplant requires intensive care should be treated aggressively.Pediatric Transplantation 05/2006; 10(3):299-303. · 1.48 Impact Factor -
Article: Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura.
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ABSTRACT: We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 x 10(9)/L (50,000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP.Blood 05/2006; 107(7):2639-42. · 9.90 Impact Factor -
Article: FMS‐Like Tyrosine Kinase 3 in Normal Hematopoiesis and Acute Myeloid Leukemia
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ABSTRACT: Ligand-mediated activation of the FMS-like tyrosine kinase 3 (FLT3) receptor is important for normal proliferation of primitive hematopoietic cells. However, activating mutations in FLT3 induce ligand-independent downstream signaling that promotes oncogenesis through pathways involved in proliferation, differentiation, and survival. FLT3 mutations are identified as the most frequent genetic abnormality in acute myeloid leukemia and are also observed in other leukemias. Multiple small-molecule inhibitors are under development to target aberrant FLT3 activity that confers a poor prognosis in patients.Stem Cells 04/2006; 24(5):1174 - 1184. · 7.78 Impact Factor -
Article: The role of CREB as a proto-oncogene in hematopoiesis and in acute myeloid leukemia.
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ABSTRACT: CREB is a transcription factor that functions in glucose homeostasis, growth factor-dependent cell survival, and memory. In this study, we describe a role of CREB in human cancer. CREB overexpression is associated with increased risk of relapse and decreased event-free survival. CREB levels are elevated in blast cells from patients with acute myeloid leukemia. To understand the role of CREB in leukemogenesis, we studied the biological consequences of CREB overexpression in primary human leukemia cells, leukemia cell lines, and transgenic mice. Our results demonstrate that CREB promotes abnormal proliferation and survival of myeloid cells in vitro and in vivo through upregulation of specific target genes. Thus, we report that CREB is implicated in myeloid cell transformation.Cancer Cell 05/2005; 7(4):351-62. · 26.57 Impact Factor -
Article: Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution.
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ABSTRACT: The purpose of this study was to determine the incidence of fungal infections in pediatric hematology and oncology (PHO) patients and to describe variations regarding site of infection, organisms, and mortality. The records of 1,052 patients presenting to the UCLA PHO service with various malignancies from 1991 to 2001 were retrospectively reviewed. No patient received invasive antifungal prophylaxis. Transplant patients were excluded. The 11-year incidence of fungal infections in this pediatric oncology cohort was 4.9%. There was a linear increase in the incidence of fungal infections from 2.9% to 7.8% between 1996 and 2001 (P = 0.001). Patients with acute leukemia represented 36% of the population but had a disproportionate incidence (67%) of fungal infections. Adolescents had twice the expected incidence of infection (P < 0.0001). Overall, Candida sp. was the major pathogen. Over time, a trend of fewer infections caused by Candida and more due to Aspergillus was noted. Blood-borne infections decreased over time, while those in the urinary and respiratory tracts increased (P = 0.04). Sixty-two percent of infections occurred in neutropenic patients. PHO patients had an overall mortality of 21%, but those with fungal infections experienced a 2.6-fold higher mortality that was not attributable to infections alone. Empiric antifungal therapy had no effect on mortality rates. Concurrent nonfungal infections did not increase mortality rates. The incidence of fungal infections increased over time, possibly as a result of advances in antibacterial and chemotherapeutic regimens. Adolescents and patients with leukemia were especially at risk. Fungal infections are a poor prognostic factor, independent of fungal-related mortality. New diagnostic methods allowing for early detection and treatment as well as more effective therapies are needed.Journal of Pediatric Hematology/Oncology 04/2005; 27(3):135-40. · 1.16 Impact Factor -
Article: Topics in pediatric leukemia--hematopoietic stem cell transplantation.
MedGenMed: Medscape general medicine 02/2005; 7(1):19. -
Article: Severe lactic acidosis in a 14-year-old female with metastatic undifferentiated carcinoma of unknown primary.
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ABSTRACT: A 14-year-old girl was found to have a large, non-tender breast mass with anemia and thrombocytopenia. The diagnosis of an undifferentiated carcinoma of unknown primary was made after open breast biopsy of the mass with negative immunohistochemical studies for breast malignancies. Further evaluation showed extensive metastatic disease affecting the bone marrow, ribs, liver, and brain with magnetic resonance imaging evidence of carcinomatous meningitis. Despite 2 months of chemotherapy and intensive supportive care, the patient died of severe lactic acidosis and disseminated intravascular coagulation after exaggerated menstrual bleeding. The association of severe lactic acidosis and undifferentiated carcinoma of unknown primary in an adolescent has not been previously described.Journal of Pediatric Hematology/Oncology 12/2004; 26(11):780-2. · 1.16 Impact Factor -
Article: Megatherapy and stem cell transplantation for Ewing's family of tumors: a critical review of current literature.
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ABSTRACT: Although a multimodal approach consisting of chemotherapy and local control with surgery and/or radiation has improved survival in children with Ewing's sarcoma family of tumors, the prognosis for patients with high-risk disease remains poor. More aggressive treatments with high-dose myeloablative chemotherapy followed by stem cell rescue have been utilized in an attempt to improve survival in these patients. Although many studies have been published, it is difficult to interpret the data since patient populations were heterogeneous with respect to disease stage, prior therapy, conditioning and stem cell source. Furthermore, there was no uniform definition of high risk, the sample sizes were small and most studies lacked appropriate control groups. Assessment of the utility of megatherapy will require prospective controlled studies.Pediatric Transplantation 07/2004; 8 Suppl 5:83-8. · 1.48 Impact Factor
Top co-authors
Top Journals
Institutions
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2011
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Harbor-UCLA Medical Center
Torrance, CA, USA
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2002–2011
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University of California, Los Angeles
- • Department of Pediatrics
- • Division of Hematology and Medical Oncology
Los Angeles, CA, USA -
California Institute of Technology
Pasadena, CA, USA
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2004–2008
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Children's Hospital Los Angeles
- • Department of Pediatrics
- • Division of Hematology-Oncology
Los Angeles, CA, USA
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2005–2006
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Comprehensive Cancer Centers of Nevada
Las Vegas, NV, USA
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