W G Kraybill

The Ohio State University, Columbus, OH, United States

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Publications (96)303.56 Total impact

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    ABSTRACT: In sarcoma, the activity of NF-κB (nuclear factor κB) reduces the abundance of the microRNA (miRNA) miR-29. The tumor suppressor A20 [also known as TNFAIP3 (tumor necrosis factor-α-induced protein 3)] inhibits an upstream activator of NF-κB and is often mutated in lymphomas. In a panel of human sarcoma cell lines, we found that the activation of NF-κB was increased and, although the abundance of A20 protein and mRNA was decreased, the gene encoding A20 was rarely mutated. The 3' untranslated region (UTR) of A20 mRNA has conserved binding sites for both of the miRNAs miR-29 and miR-125. Whereas the expression of miR-125 was increased in human sarcoma tissue, that of miR-29 was decreased in most samples. Overexpression of miR-125 decreased the abundance of A20 mRNA, whereas reconstituting miR-29 in sarcoma cell lines increased the abundance of A20 mRNA and protein. By interacting directly with the RNA binding protein HuR (human antigen R; also known as ELAVL1), miR-29 prevented HuR from binding to the A20 3'UTR and recruiting the RNA degradation complex RISC (RNA-induced silencing complex), suggesting that miR-29 can act as a decoy for HuR, thus protecting A20 transcripts. Decreased miR-29 and A20 abundance in sarcomas correlated with increased activity of NF-κB and decreased expression of genes associated with differentiation. Together, the findings reveal a unique role of miR-29 and suggest that its absence may contribute to sarcoma tumorigenesis.
    Science Signaling 01/2013; 6(286):ra63. · 7.65 Impact Factor
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    ABSTRACT: Liposarcomas are a heterogenous group of fat-derived sarcomas, and surgery with or without chemoradiation therapy remains the main stay of treatment. NY-ESO-1 is a cancer-testis antigen expressed in various cancers where it can induce both cellular and humoral immunity. Immunotherapy has shown promise in clinical trials involving NY-ESO-1-expressing tumors. Gene expression studies have shown upregulation of the gene for NY-ESO-1, CTAG1B, in myxoid and round cell liposarcomas. Herein, we evaluated the expression of NY-ESO-1 among liposarcoma subtypes by quantitative real-time PCR, western blot analysis, and immunohistochemistry. Frozen tissue for quantitative real-time PCR and western blot analysis was obtained for the following liposarcoma subtypes (n=15): myxoid and round cell (n=8); well-differentiated (n=4), and dedifferentiated (n=3). Formalin-fixed paraffin-embedded blocks were obtained for the following liposarcoma subtypes (n=44): myxoid and round cell (n=18); well-differentiated (n=10); dedifferentiated (n=10); and pleomorphic (n=6). Full sections were stained with monoclonal antibody NY-ESO-1, and staining was assessed for intensity (1-3+), percentage of tumor positivity, and location. In all, 7/8 (88%) and 16/18 (89%) myxoid and round cell expressed CTAG1B and NY-ESO-1 by quantitative real-time PCR and immunohistochemistry, respectively. Western blot correlated with mRNA expression levels. By immunohistochemistry, 94% (15/16) of positive cases stained homogenously with 2-3+ intensity. Also, 3/6 (50%) pleomorphic liposarcomas demonstrated a range of staining: 1+ intensity in 50% of cells; 2+ intensity in 5% of cells; and 3+ intensity in 90% of cells. One case of dedifferentiated liposarcoma showed strong, diffuse staining (3+ intensity in 75% of cells). Our study shows that both CTAG1B mRNA and protein are overexpressed with high frequency in myxoid and round cell liposarcoma, enabling the potential use of targeted immunotherapy in the treatment of this malignancy.Modern Pathology advance online publication, 31 August 2012; doi:10.1038/modpathol.2012.133.
    Modern Pathology 08/2012; · 5.25 Impact Factor
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    ABSTRACT: Our objective was to evaluate the effectiveness of follow-up tests for detecting first local and distant recurrences in patients with primary extremity soft tissue sarcoma. We retrospectively analyzed all adult cases of primary extremity soft tissue sarcoma (n = 174) treated between 1982 and 1992. Patients were observed every 3 months for 2 years, every 4 months the third year, every 6 months the next 2 years, and annually, thereafter. Each visit consisted of taking the patient's history, a physical examination, a complete blood count, a blood chemistry panel, and a chest x-ray. For high-grade tumors, the primary site was imaged annually when clinically appropriate. Of 141 patients who were assessable, 29 patients developed local recurrence and 57 developed distant recurrence. All but one of the local recurrences was detected on the basis of an abnormal physical examination. Of the 29 patients who developed local recurrence, 25 were resected. Distant metastases were detected because of symptoms in 21 cases. Of the 36 asymptomatic lung recurrences, 30 were detected by follow-up chest x-ray. Of the 36 asymptomatic lung recurrences, 24 patients underwent metastasectomy. The positive and negative predictive values of surveillance chest x-ray were 92% and 97%, respectively. Laboratory testing never led to the detection of recurrence. Close surveillance by clinical assessment and chest x-ray is appropriate for follow-up observation of patients with primary extremity soft tissue sarcoma.
    Annals of Surgical Oncology 04/2012; 7(1):9-14. · 4.12 Impact Factor
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    ABSTRACT: Soft tissue sarcoma (STS) staging is a constantly evolving process. Grading is still of utmost importance and has been adapted into a three-tier system. The STS most difficult to categorize are those with uncertain malignant potential, such as solitary fibrous tumors, gastrointestinal stromal tumors, and glomus tumors, some of which have developed completely separate staging systems and may not even be considered sarcomas. Beyond the current TNM staging system, a multitude of prognostic factors for STS will continue to be discovered and ultimately incorporated into future revisions of the staging system.
    Surgical Oncology Clinics of North America 04/2012; 21(2):187-200. · 1.22 Impact Factor
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    ABSTRACT: Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL) to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs) and to preoperative radiation (XRT) for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A): >5 cm, low grade (cohort B). Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day)/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7). Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE) events: 40% cohort A (1 catheter thrombus and 5 DVT or PE) versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.
    Sarcoma 01/2012; 2012:659485.
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    ABSTRACT: About 1% of all cancers are soft tissue sarcomas (STS); about 60% of these occur in the extremities. Post-treatment surveillance programs are designed to identify recurrence, new primary cancers, and complications of therapy early enough to increase survival duration and quality of life. The intensity of surveillance varies among surgeons. We hypothesized that geographic factors would account for much of this variation. The 1,592 members of the Society of Surgical Oncology were surveyed regarding their personal postoperative STS surveillance strategy using standardized clinical vignettes and a questionnaire based on the vignettes. Practice patterns were analyzed by US Census Region, Metropolitan Statistical Area (MSA), and managed care organization (MCO) penetration rate, using repeated measures analysis of variance. The study end-point was surveillance intensity. Mean follow-up intensity for the 12 surveillance modalities on the questionnaire was highly correlated with tumor size, grade, and year post surgery. Controlling for tumor stage, grade, and year post surgery, the practice location of the surgeon infrequently impacted surveillance intensity. MSA was a significant (p<0.05) predictor only of office visit frequency. MCO penetration rate significantly predicted only the frequency of urinalysis and tumor-site MRI. US Census Region significantly predicted only the frequency of LFTs. Geographic factors do not generally predict self-reported surveillance practice patterns for patients after curative-intent STS surgery. The overall variation in follow-up intensity appears to reflect factors not evaluated, such as the absence of high-quality evidence supporting any particular strategy and the quality of patients' insurance.
    International Journal of Oncology 01/2011; 38(1):233-9. · 2.66 Impact Factor
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    ABSTRACT: The use of neoadjuvant and adjuvant chemotherapy in soft tissue sarcomas is controversial. This is a report of long-term (≥5 years) follow-up in patients with high-grade, high-risk soft tissue sarcomas treated with neoadjuvant chemotherapy, preoperative radiotherapy (RT), and adjuvant chemotherapy. Patients with high-grade soft tissue sarcoma≥8 cm in diameter of the extremities and body wall received 3 cycles of neoadjuvant chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine) and preoperative RT (44 grays administered in split courses), and 3 cycles of postoperative chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine). Sixty-four of 66 patients were analyzed. After chemotherapy and RT, 61 patients had surgery; 58 had R0 resections (5 amputations), and 3 had R1 resections. Ninety-seven percent experienced grade 3 or higher toxicity, including 3 deaths. These toxicities were short term. With a median follow-up of 7.7 years in surviving patients, the 5-year rates of locoregional failure (including amputation), and distant metastasis were 22.2% (95% confidence interval [CI], 11.8-32.6) and 28.1% (95% CI, 17.0-39.2). The most common site of metastasis was lung. Estimated 5-year rates of disease-free survival, distant disease-free survival, and overall survival were 56.1% (95% CI, 43.9-68.3), 64.1% (95% CI, 52.3-75.8), and 71.2% (95% CI, 60.0-82.5), respectively. Although the toxicity was significant, it was limited in its course and for the most part resolved by 1 year. The long-term outcome was better than might be expected in such high-risk tumors.
    Cancer 10/2010; 116(19):4613-21. · 5.20 Impact Factor
  • Fuel and Energy Abstracts 01/2010; 78(3).
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    ABSTRACT: Dermatofibrosarcoma protuberans (DFSP) is a spindle cell tumor with a high local recurrence rate. Wide excision (WE) has been the standard treatment, but ideal margin width is poorly defined and Mohs micrographic surgery (MMS) has emerged as an alternative procedure. This study examines the use of WE versus MMS for the treatment of primary DFSP at a single institution. Retrospective review of 48 primary DFSP cases treated from 1971 to 2006. Patient demographics, tumor features, surgical modality (WE vs. MMS), final pathology, and clinical outcome were evaluated. Twenty-eight patients underwent WE versus 20 patients for MMS. Median age was 40 years. Median WE margin width was 2 cm. For MMS, the median number of layers required to clear the tumor was 2. Median maximal defect size was 10 cm for WE versus 9.4 cm for MMS. Advanced closure techniques were required for 18% WE versus 65% MMS (P = 0.001). Median operative time was significantly lower for WE at 77 minutes versus 257 minutes for MMS (P < 0.001). Positive margins were present in 21.4% (6/28) WE versus 0% MMS (P = 0.01). At a median follow-up of 49.9 months for WE and 40.4 months for MMS, local recurrence rates were 3.6% (1/28) and 0%, respectively (P = 1.0). From a surgical standpoint, WE was faster than MMS and resulted in a less complex defect/closure. Although positive margin resection was more common with WE, local control was ultimately similar for the 2 surgical modalities. The choice of WE versus MMS should be based on individualized patients/tumor characteristics and institutional expertise in these modalities.
    American journal of clinical oncology 10/2009; 33(3):300-3. · 2.21 Impact Factor
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    ABSTRACT: The objective of this study was to evaluate the impact of adjuvant radiation therapy (RT) on regional recurrence and survival after therapeutic lymphadenectomy (TL) for clinically advanced, lymph node-metastatic melanoma. Six hundred fifteen patients who had clinically advanced, regional lymph node-metastatic disease underwent TL. All patients were appropriate potential candidates for adjuvant RT (enlarged or multiple positive lymph nodes, extracapsular extension) because of a high risk for regional recurrence regardless of whether or not they received RT. Patient-related, tumor-related, and treatment-related variables that were associated with recurrence, survival, and treatment-related morbidity with and without RT were analyzed. The median follow-up was 5 years. The actuarial 5-year regional lymph node basin control rate was 81%. On multivariate analysis, the number of positive lymph nodes, the number of lymph nodes removed, and the use of adjuvant RT were associated with improved regional control. Treatment-related morbidity, particularly lymphedema, was increased with the use of adjuvant RT and an inguinal site of lymph node metastases. At last follow-up, 268 patients were alive with actuarial 5-year distant metastasis-free survival (DMFS) and disease-specific survival (DSS) rates of 40% and 48%, respectively. On multivariate analysis, DMFS and DSS both were influenced by the number of positive lymph nodes and the number of lymph nodes removed. In addition, DSS was influenced by primary tumor thickness and the receipt of adjuvant RT. Adjuvant RT was associated with improved regional lymph node basin control compared with TL alone in patients with high-risk, clinically advanced, lymph node-metastatic melanoma. Although it is a regional therapy, adjuvant RT also may have an impact on DSS.
    Cancer 09/2009; 115(24):5836-44. · 5.20 Impact Factor
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    ABSTRACT: This article reviews the current state of diagnosis and treatment of soft tissue sarcomas. Etiology, staging, imaging, tissue sampling, and current treatment are all reviewed using updated references. Current standards for surgical treatment are emphasized and the future directions of treatment addressed.
    Surgical Clinics of North America 03/2009; 89(1):235-47, x. · 2.02 Impact Factor
  • Robert Kenney, Richard Cheney, William Kraybill
    Journal of Surgical Oncology 05/2008; 97(5):374-5. · 2.64 Impact Factor
  • Journal of Surgical Research - J SURG RES. 01/2008; 144(2):284-285.
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    ABSTRACT: Two major questions were addressed: (1) Can fever-range whole body hyperthermia (FR-WBH) affect the number of perfused tumor blood vessels? (2) Can pre-treatment with FR-WBH improve accumulation or anti-tumor efficacy of doxorubicin or DOXIL (liposomal doxorubicin)? Perfused blood vessels were visualized by intravenous injection of the fluorescent dye (DiOC7(3)) and the number of labeled vessels in tumors and normal organs of unheated mice and those previously heated to 39.5 degrees C for 6 hours were compared. Using three animal tumor models (one syngeneic murine model and two human tumor xenografts in SCID mice) we also compared tumor growth and amount of intratumoral doxorubicin (given as free drug or as DOXIL) in control mice or those given pre-treatment with FR-WBH. FR-WBH had no effect on the number of CD-31 labeled blood vessels. However, in tumors, but not in normal organs of the same animals, FR-WBH resulted in a significant increase in those blood vessels which could take up dye over a prolonged period of time after heating. There was also an increase in DOXIL uptake in the tumors of mice given FR-WBH prior to drug injection as well as enhanced therapeutic efficacy in all three tumor models. FR-WBH increases the number of perfused blood vessels in tumors over a prolonged period following FR-WBH and thus may be useful for improving tumor targeting of cancer therapeutics. We discuss these data in relation to long-conserved thermoregulatory features in normal vasculature, which may be deficient in tumor vasculature.
    International Journal of Hyperthermia 10/2007; 23(6):513-27. · 2.59 Impact Factor
  • Journal of the National Comprehensive Cancer Network: JNCCN 05/2007; 5(4):364-99. · 5.11 Impact Factor
  • Michael Schlieman, Richard Smith, William G Kraybill
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    ABSTRACT: Extremity soft tissue sarcomas (STS) represent a rare, heterogeneous malignancy. Surgery is the primary treatment for patients with no evidence of metastatic disease, and for small low-grade superficial tumors in which adequate margins can be obtained, it may be the only therapy indicated. For large, deep tumors or tumors that are close to important neurovascular structures or bone, the addition of radiotherapy to resection has improved local control and increased limb salvage without affecting overall survival. Adjuvant chemotherapy has been an issue of considerable debate. Because 50% of patients with high-risk tumors will develop metastatic disease, effective systemic treatment with chemotherapy is needed. Unfortunately, studies have shown minimal improvement in overall survival when chemotherapy is added to the local treatment of high-risk extremity STS. More recently, a few trials of neoadjuvant chemotherapy consisting of mesna, doxorubicin, ifosfamide, and dacarbazine and high-dose doxorubicin and ifosfamide have shown some early promising results, but at the price of increased toxicity. Targeted therapy has shown some of its best results with gastrointestinal stromal tumors, but so far there has been little success in treating extremity STS. At this time, high-dose adjuvant or neoadjuvant chemotherapy should be given in the setting of a clinical trial to patients with high-risk tumors who can tolerate a potentially toxic chemotherapeutic regimen. The goal of these trials should be to assess new combination therapies, possibly including targeted therapies, for the management of large high-grade, high-risk soft tissue sarcomas.
    Current Treatment Options in Oncology 12/2006; 7(6):456-63. · 2.42 Impact Factor
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    ABSTRACT: To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-alpha) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma. Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-alpha during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status. The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-alpha arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-alpha arm, and one disease progression-related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-alpha arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-alpha arm (P = .435 and P = .890, respectively). In locally advanced extremity melanoma treated with HILP, the addition of TNF-alpha to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-alpha plus melphalan was associated with a higher complication rate.
    Journal of Clinical Oncology 10/2006; 24(25):4196-201. · 18.04 Impact Factor
  • Article: Melanoma.
    Journal of the National Comprehensive Cancer Network: JNCCN 09/2006; 4(7):666-84. · 5.11 Impact Factor
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    ABSTRACT: A significant proportion of newly diagnosed melanomas are thin lesions (< or = 1.00 mm). Because tumor thickness correlates with the risk for nodal metastases, sentinel lymph node (SLN) biopsy in this subset is controversial. Incorporating other prognostic factors (Clark level and ulceration), we evaluated the 6th edition American Joint Committee on Cancer (AJCC) clinical stage as a simple and widely applicable guideline for offering SLN biopsy for thin melanoma. This study was a review of a prospective melanoma SLN database from 1993 to 2003 with emphasis on SLN positivity rates based on the 6th edition AJCC primary tumor thickness intervals and clinical stage. Three hundred five patients underwent SLN biopsy, with an overall positivity rate of 17.7%. By the 6th edition AJCC, lesions < or = 1.00 mm had an SLN positivity rate of 6.6%. By 6th edition clinical stage, SLN positivity rates were 4.9% for stage IA and 10.4% for stage IB. By using stage IA as the criterion for not offering SLN biopsy, this procedure would have been avoided in 46% (39 of 85) of < or = 1.00-mm melanoma patients with a negative SLN. Sixth edition AJCC clinical stage IB as a selection criterion for performing SLN biopsy in thin melanoma identifies most patients with a positive SLN while also avoiding a negative SLN biopsy in many patients. Until additional widely accepted and validated selection criteria are available, SLN biopsy for clinical stage IB, but not stage IA, thin melanomas is a reasonable approach.
    Annals of Surgical Oncology 03/2006; 13(2):198-204. · 4.12 Impact Factor
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    ABSTRACT: On the basis of a positive reported single-institution pilot study, the Radiation Therapy Oncology Group initiated phase II trial 9514 to evaluate its neoadjuvant regimen in a multi-institutional Intergroup setting. Eligibility included a high-grade soft tissue sarcoma > or = 8 cm in diameter of the extremities and body wall. Patients received three cycles of neoadjuvant chemotherapy (CT; modified mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]), interdigitated preoperative radiation therapy (RT; 44 Gy administered in split courses), and three cycles of postoperative CT (modified MAID). Sixty-six patients were enrolled, of whom 64 were analyzed. Seventy-nine percent of patients completed their preoperative CT and 59% completed all planned CT. Three patients (5%) experienced fatal grade 5 toxicities (myelodysplasias, two patients; infection, one patient). Another 53 patients (83%) experienced grade 4 toxicities; 78% experienced grade 4 hematologic toxicity and 19% experienced grade 4 nonhematologic toxicity. Sixty-one patients underwent surgery. Fifty-eight of these were R0 resections, of which five were amputations. There were three R1 resections. The estimated 3-year rate for local-regional failure is 17.6% if amputation is considered a failure and 10.1% if not. Estimated 3-year rates for disease-free, distant-disease-free, and overall survival are 56.6%, 64.5%, and 75.1%, respectively. This combined-modality treatment can be delivered successfully in a multi-institutional setting. Efficacy results are consistent with previous single-institution results.
    Journal of Clinical Oncology 02/2006; 24(4):619-25. · 18.04 Impact Factor

Publication Stats

2k Citations
303.56 Total Impact Points

Institutions

  • 2010–2012
    • The Ohio State University
      • Department of Surgery
      Columbus, OH, United States
  • 1999–2012
    • University at Buffalo, The State University of New York
      • Roswell Park Cancer Institute
      Buffalo, NY, United States
  • 1993–2011
    • St Louis University Hospital
      • Department of Surgery
      San Luis, Missouri, United States
  • 2009
    • St. Luke's Hospital (MO, USA)
      Saint Louis, Michigan, United States
  • 2008–2009
    • University of Missouri - Kansas City
      • Department of Surgery
      Kansas City, MO, United States
  • 1997–2006
    • Roswell Park Cancer Institute
      • • Roswell Park Cancer Institute, Elm and Carlton Streets
      • • Department of Surgical Oncology
      • • Department of Cancer Control and Epidemiology
      Buffalo, New York, United States
  • 2005
    • Texas Tech University Health Sciences Center
      • Department of Surgery
      Lubbock, TX, United States
  • 1990–2004
    • University of Washington Seattle
      • • Division of General Internal Medicine
      • • Department of Surgery
      Seattle, WA, United States
  • 2000
    • Geisinger Medical Center
      Danville, Pennsylvania, United States
  • 1995
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 1986–1994
    • Washington University in St. Louis
      • Department of Surgery
      San Luis, Missouri, United States
  • 1984
    • University of Missouri
      • Department of Surgery
      Columbia, Missouri, United States