Dr. Steffner specializes in the evaluation, diagnosis, and treatment of bone and soft tissue tumors in pediatric and adult patients. This includes primary bone and soft tissue sarcomas, locally active conditions such as giant cell tumor, aneurysmal bone cyst, and chondroblastoma, as well as impending and pathologic fractures from metastatic carcinoma, multiple myeloma, and lymphoma. He works closely with the multidisciplinary sarcoma group at the Stanford Cancer Center to provide coordinated, highly specialized treatment strategies.

Research interests include circulating tumor DNA in bone and soft tissue sarcomas, local drug delivery, establishment of a national bone and soft tissue registry, and collaborative clinical studies on imaging and soft tissue management.

Clinical Focus

  • Soft Tissue Sarcoma
  • Bone Sarcoma
  • Pediatric Sarcoma
  • Orthopaedic Surgery

Academic Appointments

Boards, Advisory Committees, Professional Organizations

  • Board Certified, American Board of Orthopaedic Surgery (ABOS) (2015 - Present)
  • Fellow, American Academy of Orthopaedic Surgeons (AAOS) (2015 - Present)
  • Member, Children’s Oncology Group (COG) (2015 - Present)
  • Faculty Member, AO Trauma (2013 - Present)
  • Member, Musculoskeletal Tumor Society (MSTS) (2013 - Present)

Professional Education

  • Board Certification: American Board of Orthopaedic Surgery, Orthopaedic Surgery (2015)
  • Oncology Fellowship, University of Chicago, Chicago IL, Department of Orthopaedic Surgery (2013)
  • Trauma Fellowship, University of California-Davis, Sacramento CA, Department of Orthopaedic Surgery (2012)
  • Residency, University of Chicago, Chicago IL, Department of Orthopaedic Surgery (2011)
  • Doctor of Medicine, Wayne State School of Medicine, Detroit MI, Medicine (2006)

Clinical Trials

  • Phase 1/2a Study of SQ3370 in Patients With Advanced Solid Tumors Recruiting

    The purpose of this study is to evaluate the safety, tolerability, and preliminary activity of SQ3370 in patients with advanced solid tumors.

    View full details

Graduate and Fellowship Programs

  • Oncology (Fellowship Program)

All Publications

  • MRI of Soft-Tissue Tumors: What to Include in the Report. Radiographics : a review publication of the Radiological Society of North America, Inc Riley, G. M., Steffner, R., Kwong, S., Chin, A., Boutin, R. D. 2024; 44 (6): e230086


    MRI serves as a critical step in the workup, local staging, and treatment planning of extremity soft-tissue masses. For the radiologist to meaningfully contribute to the management of soft-tissue masses, they need to provide a detailed list of descriptors of the lesion outlined in an organized report. While it is occasionally possible to use MRI to provide a diagnosis for patients with a mass, it is more often used to help with determining the differential diagnosis and planning of biopsies, surgery, radiation treatment, and chemotherapy (when provided). Each descriptor on the list outlined in this article is specifically aimed to assist in one or more facets of the overall approach to soft-tissue masses. This applies to all masses, but in particular sarcomas. Those descriptors are useful to help narrow the differential diagnosis and ensure concordance with a pathologic diagnosis and its accompanying grade assignment of soft-tissue sarcomas. These include a lesion's borders and shape, signal characteristics, and contrast enhancement pattern; the presence of peritumoral edema and peritumoral enhancement; and the presence of lymph nodes. The items most helpful in assisting surgical planning include a lesion's anatomic location, site of origin, size, location relative to a landmark, relationship to adjacent structures, and vascularity including feeding and draining vessels. The authors provide some background information on soft-tissue sarcomas, including their diagnosis and treatment, for the general radiologist and as a refresher for radiologists who are more experienced in tumor imaging. ©RSNA, 2024 See the invited commentary by Murphey in this issue.

    View details for DOI 10.1148/rg.230086

    View details for PubMedID 38696323

  • Sarcoma microenvironment cell states and ecosystems are associated with prognosis and predict response to immunotherapy. Nature cancer Subramanian, A., Nemat-Gorgani, N., Ellis-Caleo, T. J., van IJzendoorn, D. G., Sears, T. J., Somani, A., Luca, B. A., Zhou, M. Y., Bradic, M., Torres, I. A., Oladipo, E., New, C., Kenney, D. E., Avedian, R. S., Steffner, R. J., Binkley, M. S., Mohler, D. G., Tap, W. D., D'Angelo, S. P., van de Rijn, M., Ganjoo, K. N., Bui, N. Q., Charville, G. W., Newman, A. M., Moding, E. J. 2024


    Characterization of the diverse malignant and stromal cell states that make up soft tissue sarcomas and their correlation with patient outcomes has proven difficult using fixed clinical specimens. Here, we employed EcoTyper, a machine-learning framework, to identify the fundamental cell states and cellular ecosystems that make up sarcomas on a large scale using bulk transcriptomes with clinical annotations. We identified and validated 23 sarcoma-specific, transcriptionally defined cell states, many of which were highly prognostic of patient outcomes across independent datasets. We discovered three conserved cellular communities or ecotypes associated with underlying genomic alterations and distinct clinical outcomes. We show that one ecotype defined by tumor-associated macrophages and epithelial-like malignant cells predicts response to immune-checkpoint inhibition but not chemotherapy and validate our findings in an independent cohort. Our results may enable identification of patients with soft tissue sarcomas who could benefit from immunotherapy and help develop new therapeutic strategies.

    View details for DOI 10.1038/s43018-024-00743-y

    View details for PubMedID 38429415

    View details for PubMedCentralID 4486342

  • Patterns of local recurrence and risk of skin recurrence in soft tissue sarcomas after surgical resection. Practical radiation oncology Ewongwo, A., Oladipo, E. D., Hui, C., Avedian, R. S., Steffner, R. J., Mohler, D. G., Kalbasi, A., Chin, A. L., Million, L., Hiniker, S. M., Moding, E. J. 2023


    Although there is a theoretical risk of skin seeding during surgical resection of soft tissues sarcomas (STSs), current consensus guidelines recommend against routine use of bolus during RT. However, the risk of skin recurrence has not been systematically assessed. We aimed to assess the patterns of local recurrence (LR) in patients with STS treated with surgery with or without RT.We performed a retrospective analysis of adults with STSs evaluated at our institution between 2007-2021. For patients who developed LR, the depth was evaluated. Progression free survival (PFS) and overall survival (OS) were analyzed from time of first LR using Kaplan-Meier method. Cumulative incidence of distant metastasis (CIDM) was calculated with competing risk analysis from date of LR.Of the 206 patients evaluated, 20 had LR (9.7%). Among patients with LR, five patients (25.0%) were treated with surgery alone and 15 patients (75.0%) with surgery and RT. In patients treated with RT, 46.7% had pre-operative RT, 53.3% had post operative RT, and bolus was used in 46.7%. Surgical margins were close (<1mm) in 4 patients (20.0%) and positive in 10 patients (50.0%). LR occurred in the deep subfascial tissue in 9 patients (45%), subcutaneous tissue in 10 patients (50.0%), and skin in 1 patient (5.0%). The patient with a skin recurrence was treated with surgery alone and the tumor involved the skin at presentation. In patients treated with RT, LR occurred within RT field in 13 patients (86.7%). At 1 year after LR, PFS was 70.3%, OS was 81.7%, and CIDM was 5.9%.Skin recurrences were rare after surgical resection of STSs, and only occurred in a tumor that involved the skin at initial presentation. These findings support current recommendations against routine use of bolus in STSs not involving the skin at presentation.

    View details for DOI 10.1016/j.prro.2023.09.006

    View details for PubMedID 37804883

  • Assessment of the Interval to Diagnosis in Pediatric Bone Sarcoma. Pediatric emergency care Kha, S. T., Sharma, J., Kenney, D., Daldrup-Link, H., Steffner, R. 2023


    The timely diagnosis of primary bone malignancies in pediatric patients is critical to clinical outcomes. The purpose of this study is to investigate the initial presentation of pediatric bone sarcoma patients to an academic health care system and assess the current interval to diagnosis.We conducted a retrospective review of pediatric patients (aged 1-18) with biopsy-proven diagnosis of osteosarcoma or Ewing sarcoma presenting between 2004 and 2020. All living patients had 1 year or more of follow-up. Primary outcomes were interval to diagnosis, clinical features on initial presentation, percent of patients with negative radiographic workup at initial presentation, and number of health care encounters before diagnosis.Seventy-one patients (osteosarcoma, 51; Ewing sarcoma, 20) were included. Average age at presentation was 13.1 ± 3.3 years (range, 4.4-18.3). Average symptom duration was 5.4 ± 13.9 months (range, 0.1-84). Clinical features at initial presentation included limb/back pain (91.5% of patients), activity modification/pain medication use (78.9%), palpable mass (40.8%), night pain (35.2%), limp (25.4%), limb disuse (18.3%), and recent fever history (2.8%). Fourteen of 71 patients (19.7%) had negative radiographs at initial presentation. Average number of health care encounters before diagnosis was 1.9 ± 0.6 (range, 1.0-4.0), with most in the outpatient pediatrician clinics (81.2%) and emergency department (18.3%). Average time to diagnosis from initial presentation was 19.5 ± 65 days (range, 0-493); the 14 patients with initial negative radiographs had a statistically significant prolonged interval to diagnosis of 54 ± 134 days (range, 0-493; P = 0.018).We found pediatric patients with primary bone sarcoma present with an average interval to diagnosis of 20 days. Twenty percent of patients had a significantly prolonged interval to diagnosis of 54 days. Clinical features suggest night pain is not a sensitive indicator. In patients of appropriate age with persistent unilateral pain in suspicious locations, early advanced imaging with magnetic resonance imaging should be considered.

    View details for DOI 10.1097/PEC.0000000000003031

    View details for PubMedID 37567167

  • Combining Shelf Osteotomy With Proximal Femoral Reconstruction After Oncologic Resection TECHNIQUES IN ORTHOPAEDICS Zhou, J. Y., Lai, C., Pun, S. Y., Richey, A., Leshikar, H. B., Avedian, R., Steffner, R. 2023; 38 (2): 85-89
  • Outcomes of Pediatric and Adolescent Patients with Metastatic Sarcoma Treated with Surgical Resection or Stereotactic Ablative Radiation Therapy (SABR) Oh, J., Gutkin, P., Donaldson, S., Steffner, R., Bruzoni, M., Avedian, R., Spunt, S., Pribnow, A., Hiniker, S. LIPPINCOTT WILLIAMS & WILKINS. 2022: S42
  • Interactions in CSF1-driven Tenosynovial Giant Cell Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research van IJzendoorn, D. G., Matusiak, M., Charville, G. W., Spierenburg, G., Varma, S., Colburg, D. R., van de Sande, M. A., van Langevelde, K., Mohler, D. G., Ganjoo, K. N., Bui, N. Q., Avedian, R. S., Bovee, J. V., Steffner, R., West, R. B., van de Rijn, M. 2022


    A major component of cells in Tenosynovial Giant Cell Tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here we use single cell RNA sequencing to investigate cellular interactions in TGCT.A total of 18,788 single cells from three TGCT and two Giant Cell Tumor of Bone (GCTB) samples underwent singe cell RNAseq. The three TGCTs were additionally analyzed using long read RNA sequencing. Immunofluorescence and immunohistochemistry for a range of markers was used to validate and extend the scRNAseq findings.Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to non-neoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping features between the giant cells in TGCT and GCTB.The neoplastic cells in TGCT are highly similar non-neoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the PDGF receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.

    View details for DOI 10.1158/1078-0432.CCR-22-1898

    View details for PubMedID 36007098

  • Management of Patients with Newly Diagnosed Desmoid Tumors in a First-Line Setting. Cancers Testa, S., Bui, N. Q., Charville, G. W., Avedian, R. S., Steffner, R., Ghanouni, P., Mohler, D. G., Ganjoo, K. N. 2022; 14 (16)


    The initial management of desmoid tumors (DTs) is shifting from surgery towards active surveillance, with systemic and locally ablative treatments reserved for enlarging and/or symptomatic disease. However, it remains unclear which patients would benefit most from an initial conservative rather than interventional approach. To answer this question, we retrospectively analyzed adult and pediatric patients with DTs treated at a tertiary academic cancer center between 1992 and 2022. Outcomes measured were progression-free survival (PFS) and time to next treatment (TTNT) after first-line therapy. A total of 262 treatment-naïve patients were eligible for analysis with a median age of 36.5 years (range, 0-87 years). The 5-year PFS and the median TTNT (months) after first-line treatment were, respectively: 50.6% and 69.1 mo for surgery; 64.9% and 149.5 mo for surgery plus adjuvant radiotherapy; 57.1% and 44.7 mo for surgery plus adjuvant systemic therapy; 24.9% and 4.4 mo for chemotherapy; 26.7% and 5.3 mo for hormonal therapy; 41.3% and 29.6 mo for tyrosine kinase inhibitors (TKIs); 44.4% and 8.9 mo for cryoablation and high intensity focused ultrasound; and 43.1% and 32.7 mo for active surveillance. Age ≤ 40 years (p < 0.001), DTs involving the extremities (p < 0.001), a maximum tumor diameter > 60 mm (p = 0.04), and hormonal therapy (p = 0.03) predicted a higher risk of progression. Overall, our results suggest that active surveillance should be considered initially for patients with smaller asymptomatic DTs, while upfront TKIs, local ablation, and surgery achieve similar outcomes in those with more aggressive disease.

    View details for DOI 10.3390/cancers14163907

    View details for PubMedID 36010900

  • Health Literacy and Patient Participation in Shared Decision-Making in Orthopedic Surgery ORTHOPEDICS Mertz, K., Eppler, S., Shah, R., Yao, J., Steffner, R., Safran, M., Hu, S., Chou, L., Amanatullah, D. F., Kamal, R. N. 2022; 45 (4): 227-232


    The influence of health literacy on involvement in decision-making in orthopedic surgery has not been analyzed and could inform processes to engage patients. The goal of this study was to determine the relationship between health literacy and the patient's preferred involvement in decision-making. We conducted a cross-sectional observational study of patients presenting to a multispecialty orthopedic clinic. Patients completed the Literacy in Musculoskeletal Problems (LiMP) survey to evaluate their health literacy and the Control Preferences Scale (CPS) survey to evaluate their preferred level of involvement in decision-making. Statistical analysis was performed with Pearson's correlation and multivariable logistic regression. Thirty-seven percent of patients had limited health literacy (LiMP score <6). Forty-eight percent of patients preferred to share decision-making with their physician equally (CPS score=3), whereas 38% preferred to have a more active role in decision-making (CPS score≤2). There was no statistically significant correlation between health literacy and patient preference for involvement in decision-making (r=0.130; P=.150). Among patients with orthopedic conditions, there is no significant relationship between health literacy and preferred involvement in decision-making. Results from studies in other specialties that suggest that limited health literacy is associated with a preference for less involvement in decision-making are not generalizable to orthopedic surgery. Efforts to engage patients to be informed and participatory in decision-making through the use of decision aids and preference elicitation tools should be directed toward variation in preference for involvement in decision-making, but not toward patient health literacy. [Orthopedics. 2022;45(4):227-232.].

    View details for DOI 10.3928/01477447-20220401-04

    View details for Web of Science ID 000831125900015

    View details for PubMedID 35394383

  • Local control outcomes using stereotactic body radiotherapy or surgical resection for metastatic sarcoma. International journal of radiation oncology, biology, physics Gutkin, P. M., von Eyben, R., Chin, A., Donaldson, S. S., Oh, J., Jiang, A., Ganjoo, K. N., Avedian, R. S., Bruzoni, M., Steffner, R. J., Moding, E. J., Hiniker, S. M. 2022


    Traditional management of metastatic sarcoma primarily relies on systemic therapy, with surgery often used for tumor control. We analyzed the rates of recurrence, overall survival, and treatment complications in patients undergoing either surgical resection or stereotactic body radiotherapy (SBRT) for metastatic sarcoma of the bone and/or soft tissue.The records of patients with metastatic sarcoma between 2009-2020 were reviewed. Local recurrence (LR) was defined as tumor growth or recurrence at the tumor site. Cumulative local recurrence incidence was analyzed accounting for the competing risk of death, and groups were compared using the Gray test. Overall survival (OS) was assessed using the Kaplan Meier method and log-rank test. Hazard ratios were determined using Cox proportional test.A total of 525 metastatic lesions in 217 patients were analyzed. Mean age was 57 years (range 4-88). The lung was the predominant site treated (50%), followed by intra-abdominal (13%), and soft-tissue (11%). Two-year cumulative incidences of LR for surgery and SBRT were 14.8% (95% confidence interval [CI], 11.6-18.5) and 1.7% (95% CI, 0.1-8.2), respectively (p=0.003). LR occurred in 72/437 (16.5%) tumors treated with surgery and 2/88 (2.3%) tumors treated with SBRT. Adjusted hazard ratio for LR of lesions treated surgically was 11.5 (p=0.026) when controlled for tumor size and tumor site. Median OS was 29.8 months (95% CI, 25.6-40.9). There were 47 surgical complications of a total of 275 procedures (18%). Of 58 radiation treatment courses, radiation-related toxicity was reported during the treatment of 7 lesions (12%), and none were higher than grade 2.We observed excellent local control among patients selected for treatment with SBRT for metastatic sarcoma, with no evidence of increase in LR following SBRT when compared to surgical management. Further investigation is necessary to better define the most appropriate local control strategies for metastatic sarcoma.

    View details for DOI 10.1016/j.ijrobp.2022.05.017

    View details for PubMedID 35643255

  • MR Imaging of Benign Soft Tissue Tumors: Highlights for the Practicing Radiologist. Radiologic clinics of North America Riley, G. M., Kwong, S., Steffner, R., Boutin, R. D. 2022; 60 (2): 263-281


    The overwhelming majority of soft tissue masses encountered on routine imaging are incidental and benign. When incidental, the radiologist is usually limited to routine MR imaging sequences, often without contrast. In these situations, there are typical imaging features pointing to a single diagnosis or limited differential diagnosis. Although these imaging features can be helpful, many lesions are nonspecific and may require contrast administration, evaluation with other imaging modalities, follow-up imaging, or biopsy for diagnosis. This article will provide an overview of the most commonly encountered benign soft tissue masses along with some of their characteristic MR imaging features.

    View details for DOI 10.1016/j.rcl.2021.11.006

    View details for PubMedID 35236593

  • Metastatic Pattern of Truncal and Extremity Leiomyosarcoma: Retrospective Analysis of Predictors, Outcomes, and Detection. Journal of personalized medicine Tigchelaar, S. S., Frey, C., Sivaraj, D., Segovia, N. A., Mohler, D. G., Steffner, R. J., Avedian, R. S. 2022; 12 (3)


    Leiomyosarcomas (LMS) are a heterogenous group of malignant mesenchymal neoplasms with smooth muscle origin and are classified as either non-uterine (NULMS) or uterine (ULMS). Metastatic pattern, prognostic factors, and ideal staging/surveillance studies for truncal and extremity LMS have not been defined. A retrospective analysis of patients diagnosed with histopathology-confirmed truncal or extremity LMS between 2009 and 2019 was conducted. Data collected included demographics, tumor characteristics, staging, surveillance, and survival endpoints. The primary site was defined as: (1) extremity, (2) flank/Pelvis, or (3) chest wall/Spine. We identified 73 patients, 23.3% of which had metastatic LMS at primary diagnosis, while 68.5% developed metastatic disease at any point. The mean metastatic-free survival from primary diagnosis of localized LMS was 3.0 ± 2.8 years. Analysis of prognostic factors revealed that greater age (≥50 years) at initial diagnosis (OR = 3.74, p = 0.0003), higher tumor differentiation scores (OR = 12.09, p = 0.002), and higher tumor necrosis scores (OR = 3.65, p = 0.026) were significantly associated with metastases. Older patients (≥50 years, OR = 4.76, p = 0.017), patients with larger tumors (≥5 cm or ≥10 cm, OR = 2.12, p = 0.02, OR = 1.92, p = 0.029, respectively), higher differentiation scores (OR = 15.92, p = 0.013), and higher necrosis scores (OR = 4.68, p = 0.044) show worse survival outcomes. Analysis of imaging modality during initial staging and during surveillance showed greater tumor detection frequency when PET imaging was employed, compared to CT imaging (p < 0.0001). In conclusion, truncal and peripheral extremity LMS is an aggressive tumor with high metastatic potential and mortality. While there is a significant risk of metastases to lungs, extra-pulmonary tumors are relatively frequent, and broad surveillance may be warranted.

    View details for DOI 10.3390/jpm12030345

    View details for PubMedID 35330345

  • Phase 1 trial of SQ3370 in solid tumors. Guminski, A., Wang, D., Bui, N., Bhadri, V., De Silva, M., Steffner, R., Yee, N. A., Srinivasan, S., Oneto, J., Saville, M., Subbiah, V. AMER ASSOC CANCER RESEARCH. 2021
  • Ferumoxytol magnetic resonance imaging detects joint and pleural infiltration of bone sarcomas in pediatric and young adult patients. Pediatric radiology Theruvath, A. J., Rashidi, A., Nyalakonda, R. R., Avedian, R. S., Steffner, R. J., Spunt, S. L., Daldrup-Link, H. E. 2021


    The diagnosis of joint infiltration by a malignant bone tumor affects surgical management. The specificity of standard magnetic resonance imaging (MRI) for diagnosing joint infiltration is limited. During our MRI evaluations with ferumoxytol nanoparticles of pediatric and young adult patients with bone sarcomas, we observed a surprising marked T1 enhancement of joint and pleural effusions in some patients but not in others.To evaluate if nanoparticle extravasation differed between joints and pleura with and without tumor infiltration.We retrospectively identified 15 pediatric and young adult patients (mean age: 16±4 years) with bone sarcomas who underwent 18 MRI scans at 1 h (n=7) or 24 h (n=11) after intravenous ferumoxytol infusion. Twelve patients also received a gadolinium-enhanced MRI. We determined tumor invasion into the joint or pleural space based on histology (n=11) and imaging findings (n=4). We compared the signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) of the joint or pleural fluid for tumors with and without invasion using a Mann-Whitney U test.MRI scans 24 h after intravenous ferumoxytol infusion demonstrated a positive T1 enhancement of the effusion in all joints and pleural spaces with tumor infiltration and no joint or pleural space without infiltration. Corresponding SNR (P=0.004) and CNR (P=0.004) values were significantly higher for joints and pleural spaces with tumor infiltration than without. By contrast, unenhanced MRI, gadolinium-enhanced MRI and 1-h post-contrast ferumoxytol MRI did not show any enhancement of the joint or pleural effusion, with or without tumor infiltration.This pilot study suggests that 24-h post-contrast ferumoxytol MRI scans can noninvasively differentiate between joints with and without tumor infiltration.

    View details for DOI 10.1007/s00247-021-05156-y

    View details for PubMedID 34410452

  • National Metrics Improved Timeliness of Antibiotic Administration for Open Extremity Fractures. Journal of orthopaedic trauma Shieh, A. K., Lucas, J. F., Shelton, T. J., Wright, A. J., Steffner, R. J., Wolinsky, P. R. 2020


    INTRODUCTION: Antibiotics have been shown to be an essential component in the treatment of open extremity fractures. The American College of Surgeons' Trauma Quality Improvement Program, based on a committee of physician leaders including orthopedic trauma surgeons, publishes best-practice guidelines for the management of open fractures. Accordingly, it established the tracking of antibiotic timing as a metric with a plan to use that metric prior to trauma center site reviews. Our hypothesis was that this physician-led effort at the national level would provide the necessary incentive to effect change within our institution.METHODS: A retrospective review of all patients treated at our institution for open extremity fractures was performed over three time periods separated by two quality initiatives. The first initiative was an institution-driven effort to increase awareness and educate specific departments about the importance of prompt antibiotic administration. The second initiative was the tracking of antibiotic order and administration times with quarterly audits following newly published guidelines.RESULTS: Neither antibiotic order placement within one hour nor administration within one hour improved following our first institution-specific initiative. Both outcome measures significantly improved following the second quality initiative, as did median times from arrival to antibiotic order and administration.CONCLUSION: Metrics developed and measured by a physician-led national organization led to practice changes at our hospital. Tracking of antibiotic timing for open fracture treatment was more effective than institutional education of healthcare providers alone. This study suggests that nationally published guidelines, developed and measured by physician leaders, will be found to be relevant by other physicians and can be a powerful tool to drive change.LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

    View details for DOI 10.1097/BOT.0000000000002027

    View details for PubMedID 33278206

  • SQ3370-001 IS A MULTI-CENTER OPEN-LABEL PHASE I DOSE-ESCALATION STUDY TO TEST A NOVEL INTRATUMORAL AND SYSTEMIC APPROACH TO TREAT ADVANCED SOLID TUMORS Bhadri, V., Bui, N., Guminski, A., Oneto, J., Murthy, R., Sankhala, K., Saville, M., Srinivasan, S., Steffner, R., Subbiah, V., Wang, D., Yee, N. BMJ PUBLISHING GROUP. 2020: A253–A254
  • The Importance of Concordance Between Patients and Their Subspecialists ORTHOPEDICS Shah, R. F., Mertz, K., Gil, J. A., Eppler, S. L., Amanatullah, D., Yao, J., Chou, L., Steffner, R., Safran, M., Hu, S. S., Kamal, R. N. 2020; 43 (5): 315-+


    Concordance, the concept of patients having shared demographic/socioeconomic characteristics with their physicians, has been associated with improved patient satisfaction and outcomes in primary care but has not been studied in subspecialty care. The objective of this study was to investigate whether patients value concordance with their specialty physicians. The authors assessed the importance of concordance in subspecialist care in 2 cohorts of participants. The first cohort consisted of patients seeking care at a multispecialty orthopedic clinic. The second cohort consisted of volunteer participants recruited from an online platform. Each participant completed a survey scored on an ordinal scale which characteristics of their physicians they find important for their primary care physician (PCP) and a specialist. The characteristics included age, sex, ethnicity, sexual orientation, primary language spoken, and religion. The difference in concordance scores for PCPs and specialists were compared with paired t tests with a Bonferroni correction. A total of 118 patients were recruited in clinic, and a total of 982 volunteers were recruited online. In the clinic cohort, the level of importance for patient-physician concordance of age, ethnicity, language, and religion was not significantly different between PCPs and specialists. In the volunteer cohort, the level of importance for concordance of age, sex, national origin, language, and religion was not significantly different between PCPs and specialists. The volunteers recruited online had significantly higher concordance scores than the patients recruited in clinic for most variables. Patients find patient-physician concordance as important in specialty care as they do in primary care. This may have similar effects on patient outcomes in specialty care. [Orthopedics. 2020;43(5):315-319.].

    View details for DOI 10.3928/01477447-20200818-01

    View details for Web of Science ID 000608158400032

    View details for PubMedID 32931591

  • Soft tissue pathology for the radiologist: a tumor board primer with 2020 WHO classification update. Skeletal radiology Kuhn, K. J., Cloutier, J. M., Boutin, R. D., Steffner, R., Riley, G. 2020


    Radiologists serve an important role in the diagnosis and staging of soft tissue tumors, often through participation in multidisciplinary tumor board teams. While an important function of the radiologist is to review pertinent imaging and assist in the differential diagnosis, a critical role is to ensure that there is concordance between the imaging and the pathologic diagnosis. This requires a basic understanding of the pathology of soft tissue tumors, particularly in the case of diagnostic dilemmas or incongruent imaging and histologic features. This work is intended to provide an overview of soft tissue pathology for the radiologist to optimize participation in multidisciplinary orthopedic oncology tumor boards, allowing for contribution to management decisions with expertise beyond image interpretation.

    View details for DOI 10.1007/s00256-020-03567-w

    View details for PubMedID 32743671

  • Anti-rotation pins for the compress implant do not increase risk of mechanical failure or impair osseointegration ANNALS OF JOINT Campbell, S. T., Steffner, R. J., Finlay, A., Mohler, D. G., Avedian, R. S. 2019; 4 (8)
  • Motor-sparing high-thoracic erector spinae plane block for proximal humerus surgery and total shoulder arthroplasty surgery: clinical evidence for differential peripheral nerve block? Canadian journal of anaesthesia = Journal canadien d'anesthesie Ma, W., Sun, L., Ngai, L., Costouros, J. G., Steffner, R., Boublik, J., Tsui, B. C. 2019

    View details for DOI 10.1007/s12630-019-01442-4

    View details for PubMedID 31290120

  • The Association of Financial Distress With Disability in Orthopaedic Surgery. The Journal of the American Academy of Orthopaedic Surgeons Mertz, K., Eppler, S. L., Thomas, K., Alokozai, A., Yao, J., Amanatullah, D. F., Chou, L., Wood, K. B., Safran, M., Steffner, R., Gardner, M., Kamal, R. N. 2019; 27 (11): e522–e528


    INTRODUCTION: Increased out-of-pocket costs have led to patients bearing more of the financial burden for their care. Previous work has shown that financial burden and distress can affect outcomes, symptoms, satisfaction, and adherence to treatment. We asked the following questions: (1) Does patients' financial distress correlate with disability in patients with nonacute orthopaedic conditions? (2) Do patient demographic factors affect this correlation?METHODS: We conducted a cross-sectional, observational study of new patients presenting to a multispecialty orthopaedic clinic with a nonacute orthopaedic complication. Patients completed a demographics questionnaire, the InCharge Financial Distress/Financial Well-Being Scale, and the Health Assessment Questionnaire Disability Index. Statistical analysis was done using Pearson's correlation.RESULTS: The mean score for financial distress was 4.10 (SD, 2.09; scale 1 [low distress] to 10 [high distress]; range, 1.13 to 10.0), and the mean disability score was 0.54 (SD, 0.65; scale 0 to 3; range, 0 to 2.75). A moderate positive correlation exists between financial distress and disability (r = 0.43; P < 0.01). Financial distress and disability were highest for poor, uneducated, Medicare patients.CONCLUSIONS: A moderate correlation exists between financial distress and disability in patients with nonacute orthopaedic conditions, particularly in patients with low socioeconomic status. Orthopaedic surgeons may benefit from identifying patients in financial distress and discussing the cost of treatment because of its association with disability and potentially inferior outcomes. Further investigation is needed to test whether decreasing financial distress decreases disability.LEVEL OF EVIDENCE: Level III prospective cohort.

    View details for DOI 10.5435/JAAOS-D-18-00252

    View details for PubMedID 31125323

  • Ferumoxytol Does Not Impact Standardized Uptake Values on PET/MR Scans. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Muehe, A. M., Yerneni, K. n., Theruvath, A. J., Thakor, A. S., Pribnow, A. n., Avedian, R. n., Steffner, R. n., Rosenberg, J. n., Hawk, K. E., Daldrup-Link, H. E. 2019


    Tumor response assessments on positron emission tomography (PET)/magnetic resonance imaging (MRI) scans require correct quantification of radiotracer uptake in tumors and normal organs. Historically, MRI scans have been enhanced with gadolinium (Gd)-based contrast agents, which are now controversial due to brain deposition. Recently, ferumoxytol nanoparticles have been identified as an alternative to Gd-based contrast agents because they provide strong tissue enhancement on MR images but are not deposited in the brain. However, it is not known if the strong T1- and T2-contrast obtained with iron oxide nanoparticles such as ferumoxytol could affect MR-based attenuation correction of PET data. The purpose of our study was to investigate if ferumoxytol administration prior to a 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG PET/MR scan would change standardized uptake values (SUV) of normal organs.Thirty pediatric patients (6-18 years) with malignant tumors underwent [18F]FDG-PET/MR scans (dose 3 MBq/kg). Fifteen patients received an intravenous ferumoxytol injection (5 mg Fe/kg) prior to the [18F]FDG-PET/MR scans (group 1). Fifteen additional age- and sex-matched patients received unenhanced [18F]FDG-PET/MR scans (group 2). For attenuation correction of PET data, we used a Dixon-based gradient echo sequence (TR 4.2 ms, TE 1.1, 2.3 ms, FA 5), which accounted for soft tissue, lung, fat, and background air. We used a mixed linear effects model to compare the tissue MRI enhancement, quantified as the signal-to-noise ratio (SNR), as well as tissue radiotracer signal, quantified as SUVmean and SUVmax, between group 1 and group 2. Alpha was assumed at 0.05.The MRI enhancement of the blood and solid extra-cerebral organs, quantified as SNR, was significantly higher on ferumoxytol-enhanced MRI scans compared to unenhanced scans (p < 0.001). However, SUVmean and SUVmax values, corrected based on the patients' body weight or body surface area, were not significantly different between the two groups (p > 0.05).Ferumoxytol administration prior to a [18F]FDG PET/MR scan did not change standardized uptake values (SUV) of solid extra-cerebral organs. This is important, because it allows injection of ferumoxytol contrast prior to a PET/MRI procedure and, thereby, significantly accelerates image acquisition times.

    View details for DOI 10.1007/s11307-019-01409-3

    View details for PubMedID 31325083

  • Outcomes for pediatric patients with osteosarcoma treated with palliative radiotherapy. Pediatric blood & cancer Chen, E. L., Yoo, C. H., Gutkin, P. M., Merriott, D. J., Avedian, R. S., Steffner, R. J., Spunt, S. L., Pribnow, A. K., Million, L. n., Donaldson, S. S., Hiniker, S. M. 2019: e27967


    Few studies have addressed the efficacy of palliative radiotherapy (RT) for pediatric osteosarcoma (OS), a disease generally considered to be radioresistant. We describe symptom relief, local control, and toxicity associated with palliative RT among children with OS.Patients diagnosed with OS at age 18 and under and treated with RT for palliation of symptomatic metastases or local recurrence at the primary site from 1997 to 2017 were included. We retrospectively reviewed details of RT, symptom improvement, local control, survival, and toxicity.Thirty-two courses of palliative RT were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. The median equivalent dose in 2 Gy fractions (EQD2) was 40.0 Gy (range, 20.0-60.4). The median number of fractions per course was 15 (range, 5-39). Symptom improvement occurred in 24 (75%) courses of RT at a median time of 15.5 days (range, 3-43). In nine courses (37.5%), symptoms recurred after a median duration of symptom relief of 140 days (range, 1-882). Higher EQD2 correlated with longer duration of response (r = 0.39, P = 0.0003). Imaging revealed local failure in 3 of 14 courses followed with surveillance imaging studies (21.4%). The median time to progression was 12.9 months (range, 4.4-21.8). The median follow-up time following the first course of palliative RT was 17.5 months (range, 1.74-102.24), and median time to overall survival was 19.4 months. Toxicity was mild, with grade 2 toxicity occurring in one course (3.1%).RT is an effective method of symptom palliation for patients with recurrent or metastatic OS, with higher delivered dose correlating with longer symptom relief and with little associated toxicity.

    View details for DOI 10.1002/pbc.27967

    View details for PubMedID 31407520

  • Patient Perceptions Correlate Weakly With Observed Patient Involvement in Decision-making in Orthopaedic Surgery CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Mertz, K., Eppler, S., Yao, J., Amanatullah, D. F., Chou, L., Wood, K. B., Safran, M., Steffner, R., Gardner, M., Kamal, R. 2018; 476 (9): 1859–65
  • Staging of Bone and Soft-tissue Sarcomas JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS Steffner, R. J., Jang, E. S. 2018; 26 (13): E269–E278
  • Patient Perceptions Correlate Weakly With Observed Patient Involvement in Decision-making in Orthopaedic Surgery. Clinical orthopaedics and related research Mertz, K., Eppler, S., Yao, J., Amanatullah, D. F., Chou, L., Wood, K. B., Safran, M., Steffner, R., Gardner, M., Kamal, R. 2018


    BACKGROUND: Shared decision-making between patients and physicians involves educating the patient, providing options, eliciting patient preferences, and reaching agreement on a decision. There are different ways to measure shared decision-making, including patient involvement, but there is no consensus on the best approach. In other fields, there have been varying relationships between patient-perceived involvement and observed patient involvement in shared decision-making. The relationship between observed and patient-perceived patient involvement in decision-making has not been studied in orthopaedic surgery.QUESTIONS/PURPOSES: (1) Does patient-perceived involvement correlate with observed measurements of patient involvement in decision-making in orthopaedic surgery? (2) Are patient demographics associated with perceived and observed measurements of patient involvement in decision-making?METHODS: We performed a prospective, observational study to compare observed and perceived patient involvement in new patient consultations for eight orthopaedic surgeons in subspecialties including hand/upper extremity, total joint arthroplasty, spine, sports, trauma, foot and ankle, and tumor. We enrolled 117 English-literate patients 18 years or older over an enrollment period of 2 months. A member of the research team assessed observed patient involvement during a consultation with the Observing Patient Involvement in Decision-Making (OPTION) instrument (scaled 1-100 with higher scores representing greater involvement). After the consultation, we asked patients to complete a questionnaire with demographic information including age, sex, race, education, income, marital status, employment status, and injury type. Patients also completed the Perceived Involvement in Care Scale (PICS), which measures patient-perceived involvement (scaled 1-13 with higher scores representing greater involvement). Both instruments are validated in multiple studies in various specialties and the physicians were blinded to the instruments used. We assessed the correlation between observed and patient-perceived involvement as well as tested the association between patient demographics and patient involvement scores.RESULTS: There was weak correlation between observed involvement (OPTION) and patient-perceived involvement (PICS) (r = 0.37, p < 0.01) in decision-making (mean OPTION, 28.7, SD 7.7; mean PICS, 8.43, SD 2.3). We found a low degree of observed patient involvement despite a moderate to high degree of perceived involvement. No patient demographic factor had a significant association with patient involvement.CONCLUSIONS: Further work is needed to identify the best method for evaluating patient involvement in decision-making in the setting of discordance between observed and patient-perceived measurements. Knowing whether it is necessary for (1) actual observable patient involvement to occur; or (2) a patient to simply believe they are involved in their care can inform physicians on the best way to improve shared decision-making in their practice.LEVEL OF EVIDENCE: Level II, therapeutic study.

    View details for PubMedID 29965894

  • Staging of Bone and Soft-tissue Sarcomas. The Journal of the American Academy of Orthopaedic Surgeons Steffner, R. J., Jang, E. S. 2018


    The purpose of staging in orthopaedic oncology is to provide a framework for classifying tumors based on their risk of local recurrence and distant metastasis to guide treatment decisions. Two separate systems are commonly used to categorize bone and soft-tissue sarcomas. The Musculoskeletal Tumor Society system for bone sarcomas and the Enneking system for soft-tissue sarcomas are the original staging systems developed by orthopaedic surgeons. The American Joint Committee on Cancer staging systems for bone and soft-tissue sarcomas are periodically updated based on new data, and they are currently on their eighth edition.

    View details for PubMedID 29781819

  • LYMPHOMA OF BONE JBJS REVIEWS Steffner, R. J., Jang, E. S., Danford, N. C. 2018; 6 (1): e1

    View details for PubMedID 29298179

  • Conservative management of desmoid tumors is safe and effective. journal of surgical research Park, J. S., Nakache, Y., Katz, J., Boutin, R. D., Steffner, R. J., Monjazeb, A. M., Canter, R. J. 2016; 205 (1): 115-120


    Surgical resection of desmoid tumors has traditionally been the mainstay of therapy, but this is a potentially morbid approach with high rates of recurrence. Given increasing reports of active surveillance in this disease, we sought to evaluate our experience with conservative management hypothesizing this would be an effective strategy.Using a prospectively maintained database of sarcoma patients from 2008 to 2015, we identified 47 patients with a diagnosis of desmoid tumor from all anatomic sites. Data points were abstracted on clinical and pathologic factors, disease stability or progression, and follow-up time. Main outcome measurements were tumor recurrence after surgical resection versus tumor progression with conservative management.In our cohort, 20 patients were managed with surveillance, 24 patients with surgery, and three patients with other approaches. Clinical and tumor characteristics between treatment groups were not significantly different. With a median follow-up of 35.7 mo, there was one complete regression, five partial regressions, and 13 stable diseases among the surveillance group. Only one patient under observation progressed, crossing over to surgical resection. Among 24 patients managed with surgery, 13 patients developed local recurrence. Kaplan-Meier analysis revealed a statistically superior progression-free survival in the surveillance group (P = 0.001).This retrospective analysis adds to the growing body of evidence that observation of desmoid tumors is safe and effective with high rates of stable disease. These data further support an initial conservative approach to desmoid tumors that may spare patients the morbidity and risk of recurrence that accompanies potentially extensive operations.

    View details for DOI 10.1016/j.jss.2016.06.028

    View details for PubMedID 27621007

  • Emerging Concepts in Upper Extremity Trauma Humeral Shaft Fractures ORTHOPEDIC CLINICS OF NORTH AMERICA Steffner, R. J., Lee, M. A. 2013; 44 (1): 21-?


    Fractures of the humeral shaft are common in low-energy and high-energy trauma, and optimal clinical management remains controversial. Nonsurgical management has been supported as the preferred treatment based on high union rates and minimal functional deficit due to a rich vascular supply from overlying muscle and the wide motion available at the glenohumeral joint. Recent studies of nonoperative management have challenged surgeons' understanding of these fractures and the perception of favorable outcomes. Current considerations support expanded operative indications with traditional open-plate fixation and with the use of minimally invasive techniques, implants, and a reconsideration of intramedullary nailing.

    View details for DOI 10.1016/j.ocl.2012.08.005

    View details for Web of Science ID 000313135100004

    View details for PubMedID 23174323

  • Case series of sural island flaps used for soft-tissue defects of the distal-third lower extremity JOURNAL OF WOUND CARE Steffner, R. J., Spiguel, A., Ranieri, J., Suk, M., Yoo, B. J. 2012; 21 (10): 469-475


    To establish the sural island fasciocutaneous flap as an initial consideration for distal third lower-extremity soft tissue coverage and to provide non-plastic surgeons with a procedure they can perform on their own.Literature on reverse sural island fasciocutaneous flaps was reviewed and summarised. We then assessed our care series of sural island flaps from 2008-2011 and looked to provide our operative technique and patient outcomes.Nine patients, aged 12-70 years old, with greater than 1 year follow-up, were reviewed. Five patients had diabetes, peripheral vascular disease, or smoked tobacco. All patients healed their soft tissue coverage with minimal complication and were able to accommodate normal footwear.Reverse sural island flaps are resilient flaps that should be considered as an alternative to free muscle transfer, for distal third lower extremity coverage.There were no external sources of funding for this study. The authors have no conflicts of interest to declare.

    View details for Web of Science ID 000309466600002

    View details for PubMedID 23103480

  • Humeral shaft fractures. Current reviews in musculoskeletal medicine Spiguel, A. R., Steffner, R. J. 2012; 5 (3): 177-183


    Management of humeral shaft fractures has historically been largely conservative. A significant body of literature, dating back to the 1970s, has shown that functional bracing may achieve greater than 90 % union rates and acceptable functional outcomes. More recently, however, with the advent of new surgical techniques and implant options, less tolerance for acceptable deformity and functional deficits, and less patience with conservative management, many treating orthopaedic surgeons are increasingly likely to consider surgical intervention. This article reviews the current recommendations for treatment of humeral shaft fractures, including both nonoperative and operative intervention. It also discusses the current thinking and operative trends in humeral shaft fracture fixation.

    View details for DOI 10.1007/s12178-012-9125-z

    View details for PubMedID 22566083

    View details for PubMedCentralID PMC3535078

  • Surgical Intervention of Nonvertebral Osseous Metastasis CANCER CONTROL Attar, S., Steffner, R. J., Avedian, R., Hussain, W. M. 2012; 19 (2): 113-121


    Nonvertebral osseous metastases can result in pain and disability. The goals of surgical intervention are to reduce pain and to improve function if nonsurgical treatment fails. The indications for proceeding with surgical intervention depend on anatomic location, amount of local destruction, extent of skeletal and visceral disease and, most important, the patient's performance status and life expectancy.This article reviews the evaluation and treatment of metastatic nonvertebral osseous lesions from the perspective of the orthopedic surgeon, based mainly on an assessment of the surgical literature.This article summarizes the approaches to preoperative evaluation, patient selection, and medical optimization. Guidelines for estimating osseous stability and fracture risk are discussed, and surgical implants and their relation to postoperative outcomes are examined. This review also describes less invasive ablative procedures currently available.The surgical management of nonvertebral osseous metastases involves multidisciplinary collaboration. The surgical construct must be a stable, reliable, and durable intervention that is individually tailored and matched to a patient's prognosis and performance status.

    View details for Web of Science ID 000307969100005

    View details for PubMedID 22487973

  • Factors associated with recurrence of primary aneurysmal bone cysts: is argon beam coagulation an effective adjuvant treatment? journal of bone and joint surgery. American volume Steffner, R. J., Liao, C., Stacy, G., Atanda, A., Attar, S., Avedian, R., Peabody, T. D. 2011; 93 (21): e1221-9


    Our goal was to assess the effectiveness and safety of argon beam coagulation as an adjuvant treatment for primary aneurysmal bone cysts, to reevaluate the adjuvant effectiveness of the use of a high-speed burr alone, and, secondarily, to identify predictors of aneurysmal bone cyst recurrence.We retrospectively reviewed the records of ninety-six patients with primary aneurysmal bone cysts who were managed at our institution from January 1, 1983, to December 31, 2008. Forty patients were managed with curettage, a high-speed burr, and argon beam coagulation; thirty-four were managed with curettage and a high-speed burr without argon beam coagulation; and the remaining twenty-two were managed with curettage with argon beam coagulation alone, curettage with no adjuvant treatment, or resection of the entire lesion. Demographic, clinical, and radiographic data were viewed comparatively for possible predictors of recurrence. Kaplan-Meier survival analysis with a log-rank test was performed to measure association and effectiveness.The median age at the time of diagnosis was fifteen years (range, one to sixty-two years). The median duration of follow-up was 29.5 months (range, zero to 300 months). The overall rate of recurrence of aneurysmal bone cyst after surgical treatment was 11.5%. The rate of recurrence was 20.6% after curettage and high-speed-burr treatment alone and 7.5% after curettage and high-speed-burr treatment plus argon beam coagulation. The five-year Kaplan-Meier survival estimate was 92% for patients managed with curettage and adjuvant treatment with a high-speed burr and argon beam coagulation, compared with 73% for patients managed with curettage and a high-speed burr only (p = 0.060).Surgical treatment of aneurysmal bone cyst with curettage and adjuvant argon beam coagulation is effective. Postoperative fracture appears to be a common complication of this treatment and needs to be studied further. Treatment with curettage and high-speed burr alone may not reduce recurrence.

    View details for DOI 10.2106/JBJS.J.01067

    View details for PubMedID 22048101

  • Ascorbic acid recycling by cultured beta cells: Effects of increased glucose metabolism FREE RADICAL BIOLOGY AND MEDICINE Steffner, R. J., Wu, L., Powers, A., May, A. M. 2004; 37 (10): 1612-1621


    Ascorbic acid is necessary for optimal insulin secretion from pancreatic islets. We evaluated ascorbate recycling and whether it is impaired by increased glucose metabolism in the rat beta-cell line INS-1. INS-1 cells, engineered with the potential for overexpression of glucokinase under the control of a tetracycline-inducible gene expression system, took up and reduced dehydroascorbic acid to ascorbate in a concentration-dependent manner that was optimal in the presence of physiologic D-glucose concentrations. Ascorbate uptake did not affect intracellular GSH concentrations. Whereas depletion of GSH in culture to levels about 25% of normal also did not affect the ability of the cells to reduce dehydroascorbic acid, more severe acute GSH depletion to less than 10% of normal levels did impair dehydroascorbic acid reduction. Culture of inducible cells in 11.8 mM D-glucose and doxycycline for 48 h enhanced glucokinase activity, increased glucose utilization, abolished D-glucose-dependent insulin secretion, and increased generation of reactive oxygen species. The latter may have contributed to subsequent decreases in the ability of the cells both to maintain intracellular ascorbate and to recycle it from dehydroascorbic acid. Cultured beta cells have a high capacity to recycle ascorbate, but this is sensitive to oxidant stress generated by increased glucose metabolism due to culture in high glucose concentrations and increased glucokinase expression. Impaired ascorbate recycling as a result of increased glucose metabolism may have implications for the role of ascorbate in insulin secretion in diabetes mellitus and may partially explain glucose toxicity in beta cells.

    View details for DOI 10.1016/j.freeradbiomed.2004.07.032

    View details for Web of Science ID 000224792100010

    View details for PubMedID 15477012

  • Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines JOURNAL OF BIOLOGICAL CHEMISTRY Wu, L., Nicholson, W., Knobel, S. M., Steffner, R. J., May, J. M., Piston, D. W., Powers, A. C. 2004; 279 (13): 12126-12134


    Pancreatic beta cells secrete insulin in response to changes in the extracellular glucose. However, prolonged exposure to elevated glucose exerts toxic effects on beta cells and results in beta cell dysfunction and ultimately beta cell death (glucose toxicity). To investigate the mechanism of how increased extracellular glucose is toxic to beta cells, we used two model systems where glucose metabolism was increased in beta cell lines by enhancing glucokinase (GK) activity and exposing cells to physiologically relevant increases in extracellular glucose (3.3-20 mm). Exposure of cells with enhanced GK activity to 20 mm glucose accelerated glycolysis, but reduced cellular NAD(P)H and ATP, caused accumulation of intracellular reactive oxygen species (ROS) and oxidative damage to mitochondria and DNA, and promoted apoptotic cell death. These changes required both enhanced GK activity and exposure to elevated extracellular glucose. A ROS scavenger partially prevented the toxic effects of increased glucose metabolism. These results indicate that increased glucose metabolism in beta cells generates oxidative stress and impairs cell function and survival; this may be a mechanism of glucose toxicity in beta cells. The level of beta cell GK may also be critical in this process.

    View details for DOI 10.1074/jbc.M307097200

    View details for Web of Science ID 000220334900018

    View details for PubMedID 14688272