Charles A Enke

The Nebraska Medical Center , Omaha, Nebraska, United States

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Publications (68)178.64 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of ven occlusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.
    International journal of radiation oncology, biology, physics 12/2013; · 4.59 Impact Factor
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    ABSTRACT: The immunogenicity of a cellular immunotherapy using genetically modified vaccines to express α(1,3)galactosyl epitopes (αGal) was evaluated in advanced prostate cancer (PC) patients. In this dose escalation phase I study, we report safety, feasibility, and immunologic data of an immunotherapy composed of 2 human PC cell lines engineered to express αGal epitopes (HyperAcute-Prostate, HAP, NewLink Genetics). Eight patients received up to 12 biweekly vaccinations with HAP. Enrolled patients (aged range, 53-85 y) had American Joint Committee on Cancer stage IV, any T, any N, M1, Eastern Cooperative Oncology Group PS≤2, at least 1 prior hormonal treatment and <3 prior chemotherapies, adequate bone marrow and organ function, and albumin ≥3.0 g/dL. Serum IgG antibodies to synthetic peptides overexpressed in PC were determined by enzyme-linked immunosorbent assay. Results indicate that HAP immunotherapy induced humoral immune responses to autoantigens in 2 of 8 patients. These patients developed IgG antibody to multiple epitopes overexpressed in PC after immunization. These responding patients received higher doses of the immunotherapy suggesting a dose response. Two immunogenic proteins (prostate-specific membrane antigen, hepsin) belong to the extracellular molecules family participating in malignant cell invasion. Median overall survival for patients was 25.1 months with 1 patient surviving over 70 months with stable PSA and bone metastasis before expiring of other causes. Three of 8 patients showed PSA stabilization (>100 d). In conclusion, HAP immunotherapy induces IgG responses to epitopes from autoantigens overexpressed in PC suggesting dose-dependent effect. HAP represents a viable immunotherapy approach to induce immune responses against tumor cells and may provide clinical benefit with minimal toxicity.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 11/2012; · 3.20 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate the standard outpatient dose of 131-Iodine tositumomab (75 cGy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell rescue for the treatment of chemotherapy-sensitive relapsed or refractory, or high-risk first complete remission (CR) patients with diffuse large B cell non-Hodgkin's lymphoma (DLBCL). Forty patients with chemotherapy-sensitive persistent or relapsed or high/intermediate or high international prognostic index DLCBL were treated in a phase II trial combining 75 cGy 131-Iodine tositumomab with high-dose BEAM followed by autologous stem cell transplantation. The CR rate after transplantation was 78%, and the overall response rate was 80%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 6 years (range, 3-10 years), the 5-year overall survival (OS) was 72% (95% confidence interval [CI], 55%-83%), and the 5-year progression-free survival (PFS) rate was 70% (95% CI, 53%-82%). The PFS and OS were encouraging in this group of chemotherapy-sensitive persistent, relapsed, or high-risk patients with DLBCL. A follow-up phase III trial with 131-Iodine tositumomab/BEAM vs rituximab/BEAM was planned based on this information.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 08/2012; · 3.15 Impact Factor
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    ABSTRACT: The purpose of this work is to determine appropriate radiation therapy beam margins to account for intrafraction prostate translations for use with real-time electromagnetic position monitoring and correction strategies. Motion was measured continuously in 35 patients over 1157 fractions at 5 institutions. This data was studied using van Herk's formula of (αΣ + γσ') for situations ranging from no electromagnetic guidance to automated real-time corrections. Without electromagnetic guidance, margins of over 10 mm are necessary to ensure 95% dosimetric coverage while automated electromagnetic guidance allows the margins necessary for intrafraction translations to be reduced to submillimeter levels. Factors such as prostate deformation and rotation, which are not included in this analysis, will become the dominant concerns as margins are reduced. Continuous electromagnetic monitoring and automated correction have the potential to reduce prostate margins to 2-3 mm, while ensuring that a higher percentage of patients (99% versus 90%) receive a greater percentage (99% versus 95%) of the prescription dose.
    Prostate cancer. 01/2012; 2012:130579.
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    ABSTRACT: We report a rare presentation of a 66-year-old female with diffuse metastatic adenocarcinoma of unknown primary involving liver, lymphatic system and bone metastases. The neoplastic cells were positive for CK7 and OC125, while negative for CK20, thyroid transcription factor 1, CDX2, BRST-2, chromogranin, synaptophysin, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu). Fluorescence in situ hybridization showed no amplification of the HER2/neu gene. Molecular profiling reported a breast cancer origin with a very high confidence score of 98%. The absence of immunohistochemistry staining for ER, PR, and HER2/neu further classified her cancer as triple-negative breast cancer. Additional studies revealed high expression levels of topoisomerase (Topo) I, androgen receptor, and ribonucleoside-diphosphate reductase large subunit; the results were negative for thymidylate synthase, Topo II-a and O6-methylguanine-DNA methyltransferase. The patient was initially treated with a combination regimen of cisplatin and etoposide, and she experienced a rapid resolution of cancer-related symptoms. Unfortunately, her therapy was complicated by a cerebrovascular accident (CVA), which was thought to be related to cisplatin and high serum mucin. After recovery from the CVA, the patient was successfully treated with second-line chemotherapy based on her tumor expression profile. We highlight the role of molecular profiling in the diagnosis and management of this patient and the implication of personalized chemotherapy in this challenging disease.
    Case Reports in Oncology 01/2012; 5(1):9-16.
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    ABSTRACT: To compare the dosimetric parameters of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in patients with intermediate-risk rhabdomyosarcoma and to analyze their effect on locoregional control and failure-free survival (FFS). The study population consisted of 375 patients enrolled in the Children's Oncology Group protocol D9803 study, receiving IMRT or 3D-CRT. Dosimetric data were collected from 179 patients with an available composite plan. The chi-square test or Fisher's exact test was used to compare the patient characteristics and radiotherapy parameters between the two groups. The interval-to-event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards regression analysis was used to examine the effect of the treatment technique on FFS after adjusting for primary site and risk group. The median follow-up time was 5.7 and 4.2 years for patients receiving 3D-CRT and IMRT, respectively. No differences in the 5-year failure of locoregional control (18% vs. 15%) or FFS (72% vs. 76%) rates were noted between the two groups. Multivariate analysis revealed no association between the two techniques and FFS. Patients with primary tumors in parameningeal sites were more likely to receive IMRT than 3D-CRT. IMRT became more common during the later years of the study. Patients receiving IMRT were more likely to receive >50 Gy, photon energy of ≤6 MV, and >5 radiation fields than those who received 3D-CRT. The coverage of the IMRT planning target volume by the prescription dose was improved compared with the coverage using 3D-CRT with similar target dose heterogeneity. IMRT improved the target dose coverage compared with 3D-CRT, although an improvement in locoregional control or FFS could not be demonstrated in this population. Future studies comparing the integral dose to nontarget tissue and late radiation toxicity between the two groups are warranted.
    International journal of radiation oncology, biology, physics 04/2011; 82(5):1764-70. · 4.59 Impact Factor
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    ABSTRACT: Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment- and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy.
    Cancers. 01/2011; 3(2):2501-15.
  • Philip J Bierman, Charles A Enke
    Oncology (Williston Park, N.Y.) 11/2010; 24(13):1213-4. · 3.19 Impact Factor
  • Charles A Enke
    Oncology (Williston Park, N.Y.) 05/2010; 24(6):507-8. · 3.19 Impact Factor
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    ABSTRACT: The aim of this study is to compare two methodologies of prostate localization in a large cohort of patients. Daily prostate localization using B-mode ultrasound has been performed at the Nebraska Medical Center since 2000. More recently, a technology using electromagnetic transponders implanted within the prostate was introduced into our clinic (Calypso(R)). With each technology, patients were localized initially using skin marks. Localization error distributions were determined from offsets between the initial setup positions and those determined by ultrasound or Calypso. Ultrasound localization data was summarized from 16619 imaging sessions spanning 7 years; Calypso localization data consists of 1524 fractions in 41 prostate patients treated in the course of a clinical trial at five institutions and 640 localizations from the first 16 patients treated with our clinical system. Ultrasound and Calypso patients treated between March and September 2007 at the Nebraska Medical Center were analyzed and compared, allowing a single institutional comparison of the two technologies. In this group of patients, the isocenter determined by ultrasound-based localization is on average 5.3 mm posterior to that determined by Calypso, while the systematic and random errors and PTV margins calculated from the ultrasound localizations were 3 - 4 times smaller than those calculated from the Calypso localizations. Our study finds that there are systematic differences between Calypso and ultrasound for prostate localization.
    Journal of Applied Clinical Medical Physics 01/2010; 11(1):2924. · 0.96 Impact Factor
  • Fuel and Energy Abstracts 01/2010; 78(3).
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    ABSTRACT: Preoperative (preop) chemoradiation therapy improves local control and reduces toxicity for stage II/III rectal cancer better than postoperative (postop) chemoradiation therapy. We examined the temporal and regional variations in the use of preop radiotherapy (RT) across the United States. Patients with stage II/III rectal cancer diagnosed between 1998 and 2005 who had a primary site resection were identified from the SEER database. The rate of preop RT use over time was plotted. Regression models were used to analyze regional variations. From 1998 to 2005, an increase of 1.7 in the ratio of preop RT/postoperative RT was noted, whereas the ratio of RT/no RT increased only by 0.7. The ratio of preop RT/postop RT increased from 0.5 to 1 in 5 years (1998-2003) but from 1 to 1.5 in 2 years (2003-2005). Multivariate regression analysis showed: patients with stage II disease were more likely than those with stage III disease, younger patients were more likely than older patients, and males were more likely than females to receive preop RT. Whites were more likely to receive preop RT than nonwhites for stage III disease only. Patients treated in the San Francisco region, Hawaii, New Mexico, Seattle, and Los Angeles were more likely to receive preop RT than were patients in the Connecticut, Detroit, Iowa, Utah, Atlanta, and San Jose/Monterey regions. The increasing use of preop RT varies across US regions and patient subgroups. Further studies should evaluate potentially modifiable factors contributing to these variations.
    American journal of clinical oncology 11/2009; 33(5):443-7. · 2.21 Impact Factor
  • S. Li, S. Zhou, W. Zhen, C. Enke
    Medical Physics - MED PHYS. 01/2009; 36(6).
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    ABSTRACT: One-hundred and thirteen patients between the ages of 15 and 88 years with biopsy proven, untreated Hodgkin lymphoma were treated by physicians in the Nebraska Lymphoma Study Group using the Stanford V regimen (bleomycin, doxorubicin, etoposide, mechlorethamine, prednisone, vinblastine and vincristine) between January 1997 and January 2006. With a median follow-up of all surviving patients of 63 months, the 5-year overall survival (OS) was 84% and the 5-year progression-free survival (PFS) was 74%. Age >60 years, other than nodular sclerosing histological subtype, Ann Arbor Stage III/IV, and the presence of B-symptoms significantly predicted treatment outcome. Patients with 0-2 of these factors had a 5-year PFS and OS of 80% and 89% vs. 20% and 40% for patients with 3 or 4 factors. Patients who received radiotherapy had a superior 5-year PFS (86% vs. 42%) and OS (96% vs. 53%). Patients with 0-2 adverse risk factors who received radiotherapy had an excellent treatment outcome with 5-year PFS of 88% and a 5-year OS of 97%. The Stanford V chemotherapy regimen has an excellent treatment outcome for good prognosis patients with Hodgkin lymphoma. The results are compromised when radiotherapy is not utilized.
    British Journal of Haematology 12/2008; 144(4):531-7. · 4.94 Impact Factor
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    ABSTRACT: To evaluate whether pre- and post-treatment imaging (immediately before and after a radiation therapy treatment fraction) and intermittent imaging (at intervals during a treatment fraction) are accurate predictors of prostate motion during the delivery of radiation. The Calypso 4D Localization System was used to continuously track the prostate during radiation delivery in 35 prostate cancer patients, for a total of 1,157 fractions (28-45 per patient). Predictions of prostate motion away from isocenter were modeled for a pre- and post-treatment imaging schedule and for multiple intermittent intrafraction imaging schedules and compared with the actual continuous tracking data. The endpoint was drift of the prostate beyond a certain radial displacement for a duration of more than 30 s, 1 min, and 2 min. Results were used to evaluate the sensitivity and specificity of these models as an evaluation of intrafraction prostate motion. The sensitivity of pre- and post-treatment imaging in determining 30 s of intrafraction prostate motion greater than 3, 5, or 7 mm for all fractions was low, with values of 53%, 49%, and 39%, respectively. The specificity of pre- and post-treatment imaging was high for all displacements. The sensitivity of intermittent imaging improved with increasing sampling rate. These results suggest that pre- and post-treatment imaging is not a sensitive method of assessing intrafraction prostate motion, and that intermittent imaging is sufficiently sensitive only at a high sampling rate. These findings support the value of continuous, real-time tracking in prostate cancer radiation therapy.
    International journal of radiation oncology, biology, physics 09/2008; 73(3):692-8. · 4.59 Impact Factor
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    ABSTRACT: Engraftment of donor hepatocytes is a critical step that determines the success of hepatocyte transplantation. Rapid and efficient integration of donor cells would enable prompt liver repopulation of these cells in response to selective proliferative stimuli offered by a preparative regimen. We have earlier demonstrated that hepatic irradiation (HIR) in combination with a variety of hepatotrophic growth signals, such as partial hepatectomy and hepatocyte growth factor, can be used as a preparative regimen for liver repopulation of transplanted hepatocytes. In this study, we investigated the effects of HIR on engraftment of transplanted dipeptidyl peptidase IV (DPPIV)-positive hepatocytes in congeneic DPPIV-deficient rats. HIR-induced apoptosis of hepatic sinusoidal endothelial cells (SEC) within 6 hours of HIR resulted in dehiscence of the SEC lining in 24 hours. Although there was no change of the number of Kupffer cells after HIR, colloidal carbon clearance decreased 24 hours post HIR, indicating a suppression of phagocytic function. DPPIV+ donor cells were transplanted 24 hours after HIR (0-50 Gy). There was an HIR dose-dependent increase in the donor hepatocyte mass engrafted in the liver parenchyma. The number of viable transplanted hepatocytes present in hepatic sinusoids or integrated in the parenchyma was greater in the HIR-treated group at 3 and 7 days after transplantation compared with the sham controls. Finally, we validated these rodent studies in cynomolgus monkeys, demonstrating that a single 10-Gy dose of HIR was sufficient to enhance engraftment of donor porcine hepatocytes. These data indicate that transient disruption of the SEC barrier and inhibition of the phagocytic function of Kupffer cells by HIR enhances hepatocyte engraftment and the integrated donor cell mass. Thus, preparative HIR could be potentially useful to augment hepatocyte transplantation.
    Hepatology 09/2008; 49(1):258-67. · 12.00 Impact Factor
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    ABSTRACT: To analyze characteristics of intrafraction prostate motion, monitored using the Calypso system, and investigate dosimetric consequences of the motion for different clinical target volume (CTV) to planning target volume (PTV) margins. Motion characteristics were analyzed for 1,267 tracking sessions and 35 patients. Using prostate-PTV margins of 0, 1, 2, 3, and 5 mm, dose metrics for the prostate gland, bladder, and rectum were evaluated for scenarios including patient population, individual patients showing the greatest motion during the course of treatment, and the individual session with the largest overall movement. Composite dose distributions incorporating motion blurring were calculated by convolving static intensity-modulated radiotherapy plans with corresponding motion probability functions. For prostate-PTV margins of 2 mm or greater, intrafraction motion did not compromise prostate dose coverage for either the patient population or individual patients. For the patient showing the largest overall movement, the prostate equivalent uniform dose was reduced by only 17.4 cGy (0.23%), and the minimum prostate dose remained greater than 95% of the nominal dose. For margins less than 2 mm, the prostate dose-volume histogram in the same patient was slightly compromised, and the equivalent uniform dose was reduced by 38.5 cGy (0.51%). Sparing of the bladder and rectum was improved substantially by reducing margins. Although significant motion can be observed during individual fractions, the dosimetric consequences are insignificant during a typical course of radiotherapy (30-40 fractions) with CTV-PTV margins of 2 mm or greater provided that the Calypso system is applied for pretreatment localization. Further reduction of the margin is possible if intrafraction realignment is performed.
    International Journal of Radiation OncologyBiologyPhysics 08/2008; 71(3):801-12. · 4.52 Impact Factor
  • Journal of Urology - J UROL. 01/2008; 179(4):230-230.
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    ABSTRACT: To report the clinical experience with an electromagnetic treatment target positioning and continuous monitoring system in patients with localized prostate cancer receiving external beam radiotherapy. The Calypso System is a target positioning device that continuously monitors the location of three implanted electromagnetic transponders at a rate of 10 Hz. The system was used at five centers to position 41 patients over a full course of therapy. Electromagnetic positioning was compared to setup using skin marks and to stereoscopic X-ray localization of the transponders. Continuous monitoring was performed in 35 patients. The difference between skin mark vs. the Calypso System alignment was found to be >5 mm in vector length in more than 75% of fractions. Comparisons between the Calypso System and X-ray localization showed good agreement. Qualitatively, the continuous motion was unpredictable and varied from persistent drift to transient rapid movements. Displacements > or =3 and > or =5 mm for cumulative durations of at least 30 s were observed during 41% and 15% of sessions. In individual patients, the number of fractions with displacements > or =3 mm ranged from 3% to 87%; whereas the number of fractions with displacements > or =5 mm ranged from 0% to 56%. The Calypso System is a clinically efficient and objective localization method for positioning prostate patients undergoing radiotherapy. Initial treatment setup can be performed rapidly, accurately, and objectively before radiation delivery. The extent and frequency of prostate motion during radiotherapy delivery can be easily monitored and used for motion management.
    International Journal of Radiation OncologyBiologyPhysics 03/2007; 67(4):1088-98. · 4.52 Impact Factor
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    ABSTRACT: Thus far, the therapy of pancreatic cancer remains an insurmountable challenge. Not a solitary therapeutic modality in the battery of available therapeutic options is capable to cure or, at the very least, stop the progression of this disease in any meaningful way. The purpose of reported here studies was to implement a multimodality approach to radioimmunotherapy of pancreatic cancer and, ultimately, to develop a course of therapy with the clinical value. Animal model was NCr-nu/nu mouse bearing s.c. xenografts of SW1990 pancreatic adenocarcinoma. Radioimmunotherapy based on (131)ICC49, a TAG-72-targeting monoclonal antibody, was augmented with imatinib, a potent inhibitor of platelet-derived growth factor receptor-beta. The postulated interactions between these two modalities depended on the imatinib-induced drop in the tumor interstitial fluid pressure and the subsequent increase of (131)ICC49 uptake into the tumor, resulting in improved tumor responses to radioimmunotherapy. Biodistribution studies revealed a 50% improvement in the tumor uptake of (131)ICC49 in mice treated with imatinib. Tumor development was practically arrested for approximately 3 weeks in response to the treatment composed of (131)ICC49 and imatinib with tumor quadrupling time (T(Q)) of 40.8 days. (131)ICC49 alone and imatinib alone also delayed the tumor growth to T(Q) of 30.2 and 31.2 days, respectively. Unanticipated was the significant response of SW1990 to a brief treatment with imatinib given i.p. at 100 mg/kg b.i.d. for 3 days. Xenografts in control mice receiving injection of PBS had T(Q) of 23 days. The inclusion of imatinib in the radioimmunotherapy regimen is beneficial and it does not produce any overt side effects. The improved responses of pancreatic cancer xenografts to the multimodality treatment comprising radioimmunotherapy and platelet-derived growth factor receptor-beta inhibition suggest that this approach to therapy of pancreatic cancer may also be successful in patients.
    Clinical Cancer Research 02/2007; 13(1):299-306. · 7.84 Impact Factor

Publication Stats

638 Citations
178.64 Total Impact Points

Institutions

  • 2006–2012
    • The Nebraska Medical Center
      Omaha, Nebraska, United States
  • 2001–2012
    • University of Nebraska at Omaha
      • • Division of Oncology and Hematology
      • • Department of Radiation Oncology
      Omaha, NE, United States
  • 2011
    • Minamata City General Hospital and Medical Center
      Mizumata, Kumamoto Prefecture, Japan
  • 2001–2011
    • University of Nebraska Medical Center
      • • Department of Biostatistics
      • • Department of Radiation Oncology
      Omaha, Nebraska, United States
  • 2008
    • Creighton University
      Omaha, Nebraska, United States