Jason W Denbo

St. Jude Children's Research Hospital, Memphis, Tennessee, United States

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Publications (10)28.36 Total impact

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    ABSTRACT: Background Complete resection of lung metastases improves survival in patients with osteosarcoma. We evaluated the long-term effect of metastasectomy on pulmonary function of patients treated for osteosarcoma during childhood. Study Design We reviewed the medical records of patients who had pulmonary function tests (PFTs) following metastasectomy for osteosarcoma. Patient, tumor, and treatment variables were abstracted along with PFTs. PFTs were recorded as a percentage of predicted value and were classified as abnormal for FVC <80%, FEV1 <80%, TLC <75%, and DLCOcorr <75%. Results Twenty-one patients had PFTs performed during follow-up. Mean age at diagnosis of osteosarcoma was 13.2±4.7 years. Fifteen patients had a single thoracotomy, and 6 patients had ≥2 thoracotomies (range, 2-6). Eighty lesions were resected. Nine patients had ≤2 lesions resected and 12 patients had >2 lesions (range, 3-12) resected. Mean time from the last surgical procedure to measurement of PFTs was 20.3±9.0years. TLC was abnormal for 28.6%, DLCOcorr for 47.4%, FVC for 40%, and FEV1 for 47.6% of the cohort members. Individual PFTs were abnormal in 13.3% (TLC) to 46.7% (DLCOcorr) of patients who had one thoracotomy and in 50.0% (DLCOcorr) to 66.7% (FEV1, TLC) of patients with ≥two thoracotomies. The number of thoracotomies was associated with abnormal TLC (p=0.03). Conclusions Patients who underwent pulmonary metastasectomy for osteosarcoma as children often had abnormal PFTs on long-term follow up, but the reduction in lung volumes and DLCOcorr was relatively mild. Multiple thoracotomies predicted greater impairment of pulmonary function.
    Journal of the American College of Surgeons 01/2014; · 4.50 Impact Factor
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    Annals of Surgical Oncology 05/2013; · 4.12 Impact Factor
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    ABSTRACT: Ionizing radiation (IR) is an essential component of therapy for alveolar rhabdomyosarcoma. Nuclear factor-kappaB (NF-κΒ) transcription factors are upregulated by IR and have been implicated in radioresistance. We evaluated the ability of curcumin, a putative NF-κΒ inhibitor, and cells expressing genetic NF- κΒ inhibitors (IκBα and p100 super-repressor constructs) to function as a radiosensitizer. Ionizing radiation induced NF-κΒ activity in the ARMS cells in vitro in a dose- and time-dependent manner, and upregulated expression of NF-κΒ target proteins. Pretreatment of the cells with curcumin inhibited radiation-induced NF-κΒ activity and target protein expression. In vivo, the combination of curcumin and IR had synergistic antitumor activity against Rh30 and Rh41 ARMS xenografts. The greatest effect occurred when tumor-bearing mice were treated with curcumin prior to IR. Immunohistochemistry revealed that combination therapy significantly decreased tumor cell proliferation and endothelial cell count, and increased tumor cell apoptosis. Stable expression of the super-repressor, SR-IκBα, that blocks the classical NF-κB pathway, increased sensitivity to IR, while expression of SR-p100, that blocks the alternative pathway, did not. Our results demonstrate that curcumin can potentiate the antitumor activity of IR in ARMS xenografts by suppressing a classical NF-κΒ activation pathway induced by ionizing radiation. These data support testing of curcumin as a radiosensitizer for the clinical treatment of alveolar rhabdomyosarcoma. IMPACT OF WORK: The NF-κΒ protein complex has been linked to radioresistance in several cancers. In this study, we have demonstrated that inhibiting radiation-induced NF-κΒ activity by either pharmacologic (curcumin) or genetic (SR-IκBα) means significantly enhanced the efficacy of radiation therapy in the treatment of alveolar rhabdomyosarcoma cells and xenografts. These data suggest that preventing the radiation-induced activation of the NF-κΒ pathway is a promising way to improve the antitumor efficacy of ionizing radiation and warrants clinical trials.
    PLoS ONE 01/2013; 8(2):e51309. · 3.53 Impact Factor
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    ABSTRACT: In 2005 the International Study Group for Pancreatic Fistula (ISGPF) created a definition and grading system for pancreatic fistulae (PF) in which grade C denotes the most severe and potentially life-threatening type. Factors and outcomes associated with grade C fistulae have been ill defined. Systematic searches of PubMed and EMBASE were conducted by two independent reviewers utilizing the keywords 'pancreaticoduodenectomy' (PD) and 'pancreatic fistula'. Inclusion criteria were: (i) a sample of ≥100 patients; (ii) consecutive accrual of all pathologies, and (iii) use of the ISGPF definition and grading system. Quality appraisal and data extraction were performed using pilot-tested templates. Fourteen articles describing a total of 2706 PDs met the study entrance criteria. Pancreatic fistulae occurred in 479 patients (18%) and included 71 grade C PF that were directly responsible for 25 deaths (35% mortality rate). Only two studies analysed risk factors; these found soft pancreatic texture and histology other than adenocarcinoma to be the most common risk factors. Ten studies reported management strategies and indicated that 51% of patients required reoperation. Grade C PF: (i) accounts for 15% of fistulae following PD and has an associated mortality rate of 35%; (ii) occurs most commonly in pathology associated with a soft remnant, and (iii) requires reoperation in approximately one half of patients. The published literature incompletely describes grade C PF.
    HPB 09/2012; 14(9):589-93. · 1.94 Impact Factor
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    ABSTRACT: Ewing sarcoma (ES) is the most common chest wall malignancy in adolescents. Current therapy incorporates chemotherapy to treat systemic disease and radiotherapy to assist with local control. We sought to evaluate the timing of surgery and role of adjuvant radiotherapy. We reviewed the St. Jude Children's Research Hospital chest wall ES experience from 1979 to 2009. Patient demographics, tumor characteristics, treatment variables, and outcomes were analyzed with respect to timing of surgery and use of adjuvant radiotherapy. Our cohort consisted of 36 patients with chest wall ES; median follow-up was 14.2 years, and 15-year estimate of overall survival was 66 %. In patients with localized disease, the timing of surgery (up-front vs. delayed) did not impact margin negativity or the use of adjuvant radiotherapy, but it did decrease the extent of chest wall resection. When considering radiotherapy in patients with localized disease, we found that patients who did not receive radiotherapy had smaller tumor size (median 6 vs. 10 cm) (p = 0.04) and were more likely to have had negative margins (p = 0.01) than patients who received adjuvant radiotherapy. One patient in each group developed a locoregional recurrence. The 15-year estimated of overall survival for patients who received adjuvant radiotherapy was 80 versus 100 % for those who did not. Delayed surgery decreased the extent of chest wall resection and helped define a patient population with favorable tumor biology. Patients with complete pathologic responses to chemotherapy, and those with tumors <8 cm and negative surgical margins may be spared adjuvant radiotherapy without any decrement in overall survival.
    Annals of Surgical Oncology 07/2012; 19(12):3809-15. · 4.12 Impact Factor
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    ABSTRACT: Nuclear factor-κB (NF-κB) has been implicated in tumor cell proliferation and survival and in tumor angiogenesis. We sought to evaluate the effects of curcumin, an inhibitor of NF-κB, on a xenograft model of disseminated neuroblastoma. For in vitro studies, neuroblastoma cell lines NB1691, CHLA-20, and SK-N-AS were treated with various doses of liposomal curcumin. Disseminated neuroblastoma was established in vivo by tail vein injection of NB1691-luc cells into SCID mice, which were then treated with 50 mg/kg/day of liposomal curcumin 5 days/week intraperitoneally. Curcumin suppressed NF-κB activation and proliferation of all neuroblastoma cell lines in vitro. In vivo, curcumin treatment resulted in a significant decrease in disseminated tumor burden. Curcumin-treated tumors had decreased NF-κB activity and an associated significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis, as well as a decrease in tumor vascular endothelial growth factor levels and microvessel density. Liposomal curcumin suppressed neuroblastoma growth, with treated tumors showing a decrease in NF-κB activity. Our results suggest that liposomal curcumin may be a viable option for the treatment of neuroblastoma that works via inhibiting the NF-κB pathway.
    Surgery 01/2012; 151(5):736-44. · 3.37 Impact Factor
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    ABSTRACT: Rapamycin inhibits vascular endothelial growth factor expression. Vascular endothelial growth factor is a tumor-elaborated protein that stimulates neovascularization. This inhibition can cause transient "normalization" of the generally dysfunctional tumor vasculature, resulting in improved tumor perfusion and oxygenation. We hypothesized that this may potentiate the antitumor effects of adjuvant ionizing radiation. Mice bearing orthotopic Rh30 alveolar rhabdomyosarcomas were treated with rapamycin (5 mg/kg intraperitoneally daily ×5). Tumors were then evaluated for changes in intratumoral oxygenation, perfusion, vessel permeability, and microvessel density. Additional tumor-bearing mice were treated with 5 doses of rapamycin, irradiation (4 Gy), or 5 doses of rapamycin with irradiation administered on the first or sixth day of rapamycin treatment. Although tumor vessel permeability changed only minimally, microvessel density decreased (3153 ± 932 vs 20,477 ± 3717.9 pixels per high-power field), whereas intratumoral oxygenation increased significantly (0.0385 ± 0.0141 vs 0.0043 ± 0.0023 mm Hg/mm(3)) after 5 doses of rapamycin. Contrast-enhanced ultrasound demonstrated a significantly increased rate of change of signal intensity after 5 days of rapamycin, suggesting improved intratumoral perfusion. Tumor volume 14 days after treatment was smallest in mice treated with the combination of rapamycin given before irradiation. Combination therapy with rapamycin given before irradiation to normalize the tumor vasculature, thereby improving tumor oxygenation, increased the sensitivity of alveolar rhabdomyosarcoma xenografts to adjuvant irradiation.
    Journal of Pediatric Surgery 01/2012; 47(1):183-9. · 1.38 Impact Factor
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    ABSTRACT: High-grade glioblastomas have immature, leaky tumor blood vessels that impede the efficacy of adjuvant therapy. We assessed the ability of human interferon (hIFN)-β delivered locally via gene transfer to effect vascular stabilization in an orthotopic model of glioblastoma xenograft resection. Xenografts were established by injecting 3 grade IV glioblastoma cell lines (GBM6-luc, MT330-luc, and SJG2-luc) into the cerebral cortex of nude rats. Tumors underwent subtotal resection, and then had gel foam containing an adeno-associated virus vector encoding either hIFN-β or green fluorescence protein (control) placed in the resection cavity. The primary endpoint was stabilization of tumor vasculature, as evidenced by CD34, α-SMA, and CA IX staining. Overall survival was a secondary endpoint. hIFN-β treatment altered the tumor vasculature of GBM6-luc and SJG2-luc xenografts, decreasing the density of endothelial cells, stabilizing vessels with pericytes, and decreasing tumor hypoxia. The mean survival for rats with these neoplasms was not improved, however. In rats with MT330-luc xenografts, hIFN-β resulted in tumor regression with a 6-month survival of 55% (INF-β group) and 9% (control group). The use of AAV hIFN-β in our orthotopic model of glioblastoma resection stabilized tumor vasculature and improved survival in rats with MT330 xenografts.
    Surgery 09/2011; 150(3):497-504. · 3.37 Impact Factor
  • Journal of Surgical Research 02/2011; 165(2):178-178. · 2.02 Impact Factor
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    ABSTRACT: Background—High-grade glioblastomas have immature, leaky tumor blood vessels that impede the efficacy of adjuvant therapy. We assessed the ability of human interferon-beta (hIFN-β) delivered locally via gene transfer to effect vascular stabilization in an orthotopic glioblastoma xenograft resection model. Methods—Xenografts were established by injecting three grade IV glioblastoma cell lines (GBM6-luc, MT330-luc, and SJG2-luc) into the cerebral cortex of nude rats. Tumors underwent subtotal resection, and then had gel foam containing an adeno-associated virus vector encoding either hIFN-β or green fluorescence protein (GFP, control) placed in the resection cavity. The primary end point was stabilization of tumor vasculature, as evidenced by CD34, αSMA, and CA IX staining. Overall survival was a secondary endpoint. Results—hIFN-β treatment altered the tumor vasculature of GBM6-luc and SJG2-luc xenografts, decreasing the density of endothelial cells, stabilizing vessels with pericytes, and decreasing tumor hypoxia. The mean survival for rats with these tumors was not significantly improved, however. In rats with MT330-luc xenografts, hIFN-β resulted in tumor regression, with a 6-month survival of 55% (INF-β group) and 9% (control group). Conclusion—The use of AAV hIFN-β in our orthotopic glioblastoma resection model stabilized
    6th Annual Academic Surgical Congress,, Huntington Beach,; 01/2011

Publication Stats

25 Citations
28.36 Total Impact Points

Institutions

  • 2011–2014
    • St. Jude Children's Research Hospital
      • Department of Surgery
      Memphis, Tennessee, United States
  • 2012–2013
    • The University of Tennessee Health Science Center
      • Department of Surgery
      Memphis, Tennessee, United States