Clinical Focus


  • Radiation Oncology

Academic Appointments


Administrative Appointments


  • Director of Head and Neck Radiation Oncology, Stanford University (2017 - Present)

Honors & Awards


  • International Journal of Radiation Oncology, Biology, and Physics Outstanding Reviewer, International Journal of Radiation Oncology, Biology, and Physics (2013)
  • AAWR Research and Education Foundation Professional Leadership Award, American Association for Women Radiologists (AAWR) (2012)
  • HICARE Travel Grant and Ambassadorship, Hiroshima International Council for Health Care of the Radiation-Exposed (HICARE) (2012)
  • AAWR Eleanor Montague Distinguished Resident Award for Radiation Oncology, American Association for Women Radiologists (AAWR) (2008)
  • AAWR Member-In-Training Outstanding ASTRO Presentation Award, American Association for Women Radiologists (AAWR) (2008)
  • ASTRO Translational Advances in Radiation Oncology and Cancer Imaging Symposium Travel Grant, American Society for Radiation Oncology (ASTRO) (2008)
  • American Radium Society Young Oncologist Essay Award, American Radium Society (2008)
  • RSNA Roentgen Resident/Fellow Research Award, Radiological Society of North America (RSNA) (2008)
  • University of Texas MD Anderson Department of Radiation Oncology Eleanor Montague Research Award, University of Texas MD Anderson Cancer Center (2008)
  • ASTRO Residents/Fellows in Radiation Oncology Research Seed Grant, American Society for Radiation Oncology (ASTRO) (2007)

Boards, Advisory Committees, Professional Organizations


  • Scientific Program Chair of the 2018 Annual Meeting, American Radium Society (ARS) (2017 - Present)
  • Previously Untreated Locally Advanced (PULA) Head and Neck Steering Committee Task Force Member, National Cancer Institute (NCI) (2016 - Present)
  • Membership and Credentials Committee Member, American Radium Society (ARS) (2016 - Present)
  • Expert Panel on Osteonecrosis of the Jaw Member, American Society of Clinical Oncology (ASCO) (2016 - Present)
  • Payment Reform Working Group Member, American Society for Radiation Oncology (ASTRO) (2014 - Present)
  • Vice-Chair of the Head and Neck Cancer Track, American Society for Radiation Oncology (ASTRO) (2014 - Present)
  • Member-at-Large of the Executive Committee, American Radium Society (ARS) (2014 - 2016)
  • Radiation and Cancer Biology Teaching and Curriculum Committee Member, American Society for Radiation Oncology (ASTRO) (2012 - 2016)

Professional Education


  • BA, Northwestern University College of Arts and Sciences, Chemistry (1996)
  • PhD, Northwestern University Graduate School, Biophysics and Structural Biology (2002)
  • Residency:University of Texas MD Anderson Cancer Center (2009) TX
  • MD, Northwestern University Feinberg School of Medicine (2004)
  • Internship:McGaw Medical Center - Northwestern University (2005) IL
  • Internship, McGaw Medical Center of Northwestern University, Surgery (2005)
  • Medical Education:Northwestern University Feinberg School of Medicine (2004) IL
  • Residency, University of Texas MD Anderson Cancer Center, Radiation Oncology (2009)
  • Board Certification, American Board of Radiology (ABR), Radiation Oncology (2011)

Community and International Work


  • The Radiation Planning Assistant (RPA) for Radiation Therapy in Low and Middle-Income Countries

    Topic

    Global oncology

    Populations Served

    Low and middle income countries

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

All Publications


  • Reduced feeding tube duration with intensity-modulated radiation therapy for head and neck cancer: A Surveillance, Epidemiology, and End Results-Medicare Analysis. Cancer Beadle, B. M., Liao, K., Giordano, S. H., Garden, A. S., Hutcheson, K. A., Lai, S. Y., Guadagnolo, B. A. 2016

    Abstract

    Intensity-modulated radiation therapy (IMRT) is a technologically advanced and resource-intensive method of delivering radiation therapy (RT) and is used to minimize toxicity for patients with head and neck cancer (HNC). Dependence on feeding tubes is a significant marker of toxicity of RT. The objective of this analysis was to compare the placement and duration of feeding tube use among patients with HNC from 1999 through 2011.The cohort, demographics, and cancer-related variables were determined using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, and claims data were used to analyze treatment details.In total, 2993 patients were identified. At a median follow-up of 47 months, 54.4% of patients had ever had a feeding tube placed. The median duration from feeding tube placement to removal was 277 days. On zero-inflated negative binomial regression, patients who received IMRT and 3-dimensional RT (3DRT) (non-IMRT) had similar rates of feeding tube placement (odds ratio, 1.10; P = .35); however, patients who received 3DRT had a feeding tube in place 1.18 times longer than those who received IMRT (P = .03). The difference was only observed among patients who received definitive RT; patients who underwent surgery and also received adjuvant RT had no statistically significant difference in feeding tube placement or duration.Patients with HNC who received definitive IMRT had a significantly shorter duration of feeding tube placement than those who received 3DRT. These data suggest that there may be significant quality-of-life benefits to IMRT with respect to long-term swallowing function in patients with HNC. Cancer 2017;123:283-293. © 2016 American Cancer Society.

    View details for DOI 10.1002/cncr.30350

    View details for PubMedID 27662641

  • The Influence of Diabetes Mellitus and Metformin on Distant Metastases in Oropharyngeal Cancer: A Multicenter Study INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Spratt, D. E., Beadle, B. M., Zumsteg, Z. S., Rivera, A., Skinner, H. D., Osborne, J. R., Garden, A. S., Lee, N. Y. 2016; 94 (3): 523-531

    Abstract

    Local control in oropharyngeal cancer has improved to unprecedented rates with combined modality therapy; as a result, distant metastases are becoming a principal challenge. We aimed to determine the impact of diabetes mellitus and metformin use on clinical outcomes in a large population of oropharyngeal cancer patients treated in the modern era.We identified 1745 consecutive patients with oropharyngeal cancer treated at 2 large cancer centers with external beam radiation therapy from 1998 to 2011. A total of 184 patients had diabetes mellitus at the time of diagnosis, of whom 102 were taking metformin. The outcomes assessed included local failure-free survival (LFFS), regional failure-free survival (RFFS), distant metastasis-free survival (DMFS), and overall survival (OS).The median follow-up time was 4.3 years. The 5-year actuarial rates of DMFS were 89.6% for nondiabetic patients and 78.7% for diabetic nonmetformin users (P=.011) and of OS were 83.0% for nondiabetic patients and 70.7% for diabetic nonmetformin users (P=.048). Diabetic metformin users had 5-year DMFS (90.1%) and OS (89.6%) similar to those of nondiabetic patients. Multivariate analysis (diabetic nonmetformin users as reference) demonstrated improved DMFS for nondiabetic patients (adjusted hazard ratio 0.54; 95% confidence interval 0.32-0.93; P=.03) and a trend toward improved DMFS with metformin use (adjusted hazard ratio 0.46; 95% confidence interval 0.20-1.04; P=.06). LFFS and RFFS were high in all groups and were not significantly different by diabetic status or metformin use.Diabetic patients not using metformin independently have significantly higher rates of distant metastases than do nondiabetic patients, whereas metformin users have rates of distant metastases similar to those of nondiabetic patients. Further prospective investigation is warranted to validate the benefit of metformin in oropharyngeal cancer.

    View details for DOI 10.1016/j.ijrobp.2015.11.007

    View details for Web of Science ID 000370816500013

    View details for PubMedID 26867881

  • Improved survival using intensity-modulated radiation therapy in head and neck cancers: a SEER-Medicare analysis. Cancer Beadle, B. M., Liao, K., Elting, L. S., Buchholz, T. A., Ang, K. K., Garden, A. S., Guadagnolo, B. A. 2014; 120 (5): 702-710

    Abstract

    Intensity-modulated radiation therapy (IMRT) is a technologically advanced, and more expensive, method of delivering radiation therapy with a goal of minimizing toxicity. It has been widely adopted for head and neck cancers; however, its comparative impact on cancer control and survival remains unknown. The goal of this analysis was to compare the cause-specific survival (CSS) for patients with head and neck cancers treated with IMRT versus non-IMRT from 1999 to 2007.CSS was determined using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database and analyzed regarding treatment details, including the use of IMRT versus non-IMRT, using claims data. Hazard ratios (HRs) were estimated by the frailty model with a propensity score matching cohort and instrumental variable analysis.A total of 3172 patients were identified. With a median follow-up of 40 months, patients treated with IMRT had a statistically significant improvement in CSS compared with those treated with non-IMRT (84.1% versus 66.0%; P < .001). When each anatomic subsite was analyzed separately, all respective subgroups of patients treated with IMRT had better CSS than those treated with non-IMRT. In multivariable survival analyses, patients treated with IMRT were associated with better CSS (HR = 0.72, 95% confidence interval = 0.59 to 0.90 for propensity score matching; HR = 0.60, 95% confidence interval = 0.41 to 0.88 for instrumental variable analysis).Patients with head and neck cancers who were treated with IMRT experienced significant improvements in CSS compared with patients treated with non-IMRT techniques. This suggests there may be benefits to IMRT in cancer outcomes, in addition to toxicity reduction, for this patient population.

    View details for DOI 10.1002/cncr.28372

    View details for PubMedID 24421077

  • Identifying early dehydration risk with home-based sensors during radiation treatment: a feasibility study on patients with head and neck cancer. Journal of the National Cancer Institute. Monographs Peterson, S. K., Shinn, E. H., Basen-Engquist, K., Demark-Wahnefried, W., Prokhorov, A. V., Baru, C., Krueger, I. H., Farcas, E., Rios, P., Garden, A. S., Beadle, B. M., Lin, K., Yan, Y., Martch, S. L., Patrick, K. 2013; 2013 (47): 162-168

    Abstract

    Systems that enable remote monitoring of patients' symptoms and other health-related outcomes may optimize cancer care outside of the clinic setting. CYCORE (CYberinfrastructure for COmparative effectiveness REsearch) is a software-based prototype for a user-friendly cyberinfrastructure supporting the comprehensive collection and analyses of data from multiple domains using a suite of home-based and mobile sensors. This study evaluated the feasibility of using CYCORE to address early at-home identification of dehydration risk in head and neck cancer patients undergoing radiation therapy.Head and neck cancer patients used home-based sensors to capture weight, blood pressure, pulse, and patient-reported outcomes for two 5-day periods during radiation therapy. Data were sent to the radiation oncologist of each head and neck cancer patient, who viewed them online via a Web-based interface. Feasibility outcomes included study completion rate, acceptability and perceived usefulness of the intervention, and adherence to the monitoring protocol. We also evaluated whether sensor data could identify dehydration-related events.Fifty patients consented to participate, and 48 (96%) completed the study. More than 90% of patients rated their ease, self-efficacy, and satisfaction regarding use of the sensor suite as extremely favorable, with minimal concerns expressed regarding data privacy issues. Patients highly valued the ability to have immediate access to objective, self-monitoring data related to personal risk for dehydration. Clinician assessments indicated a high degree of satisfaction with the ease of using the CYCORE system and the resulting ability to monitor their patients remotely.Implementing CYCORE in a clinical oncology care setting is feasible and highly acceptable to both patients and providers.

    View details for DOI 10.1093/jncimonographs/lgt016

    View details for PubMedID 24395986

  • p16 Expression in cutaneous squamous carcinomas with neck metastases: A potential pitfall in identifying unknown primaries of the head and neck HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Beadle, B. M., William, W. N., McLemore, M. S., Sturgis, E. M., Williams, M. D. 2013; 35 (11): 1527-1533

    Abstract

    Human papillomavirus (HPV) positivity (+) has been used to identify oropharyngeal squamous carcinomas (SCCs) presenting as unknown primaries in the neck. p16 overexpression correlates with HPV+ in the oropharynx; however, the use of p16 alone as a surrogate marker of oropharyngeal HPV+ tumors has not been validated.We immunohistochemically analyzed p16 expression in surgically resected aggressive cutaneous head and neck SCC primaries and their nodal metastases from 24 patients to determine the potential overlap of p16 expression outside of the oropharynx.Five of 24 primary tumors (20.8%) and 3 lymph node metastases (12.5%) in levels II, III, and V, and the periparotid region diffusely expressed p16. HPV (high-risk types by in situ hybridization) was negative.p16 expression is relatively common in lymph node-positive cutaneous head and neck SCCs; thus, p16 expression as an independent biomarker and mechanism to determine the oropharyngeal source of an unknown primary is not advised.

    View details for DOI 10.1002/hed.23188

    View details for Web of Science ID 000325986200010

    View details for PubMedID 23108906

  • Evaluating the impact of patient, tumor, and treatment characteristics on the development of jaw complications in patients treated for oral cancers: A SEER-Medicare analysis HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Beadle, B. M., Liao, K., Chambers, M. S., Elting, L. S., Buchholz, T. A., Ang, K. K., Garden, A. S., Guadagnolo, B. A. 2013; 35 (11): 1599-1605

    Abstract

    Jaw complications, including osteoradionecrosis, are significant sequelae of radiation therapy (RT) for oral cancers. This study identifies the impact of patient, tumor, and treatment characteristics on the development of jaw complications in patients treated with RT.The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify patients treated with RT for oral cancers from 1999 to 2007. Jaw complications were identified by International Classification of Diseases 9th revision (ICD-9) diagnosis codes and/or related procedures using Current Procedural Terminology (CPT) and ICD-9 codes.A total of 1848 patients were identified. With a median follow-up of 2.5 years, 297 patients (16.1%) developed jaw complications: 226 patients had a diagnosis, 41 patients had a procedure, and 30 patients had both. On multivariate analysis, female sex, lack of chemotherapy use, and fewer comorbidities were associated with a statistically significant increase in jaw complications.Even with modern techniques, jaw complications are a notable and potentially devastating side effect of RT for oral cancers.

    View details for DOI 10.1002/hed.23205

    View details for Web of Science ID 000325986200019

    View details for PubMedID 23150453

  • Integrative Analysis Identifies a Novel AXL-PI3 Kinase-PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Skinner, H. D., Giri, U., Yang, L. P., Kumar, M., Liu, Y., Story, M. D., Pickering, C. R., Byers, L. A., Williams, M. D., Wang, J., Shen, L., Yoo, S. Y., Fan, Y. H., Molkentine, D. P., Beadle, B. M., Meyn, R. E., Myers, J. N., Heymach, J. V. 2017; 23 (11): 2713-2722

    Abstract

    Purpose: The primary cause of death due to head and neck squamous cell carcinoma (HNSCC) is local treatment failure. The goal of this study was to examine this phenomenon using an unbiased approach.Experimental Design: We utilized human papilloma virus (HPV)-negative cell lines rendered radiation-resistant (RR) via repeated exposure to radiation, a panel of HPV-negative HNSCC cell lines and three cohorts of HPV-negative HNSCC tumors (n = 68, 97, and 114) from patients treated with radiotherapy and subjected to genomic, transcriptomic, and proteomic analysis.Results: RR cell lines exhibited upregulation of several proteins compared with controls, including increased activation of Axl and PI3 kinase signaling as well as increased expression of PD-L1. Additionally, inhibition of either Axl or PI3 kinase led to decreased PD-L1 expression. When clinical samples were subjected to RPPA and mRNA expression analysis, PD-L1 was correlated with both Axl and PI3K signaling as well as dramatically associated with local failure following radiotherapy. This finding was confirmed examining a third cohort using immunohistochemistry. Indeed, tumors with high expression of PD-L1 had failure rates following radiotherapy of 60%, 70%, and 50% compared with 20%, 25%, and 20% in the PD-L1-low expression group (P = 0.01, 1.9 × 10(-3), and 9 × 10(-4), respectively). This finding remained significant on multivariate analysis in all groups. Additionally, patients with PD-L1 low/CD8(+) tumor-infiltrating lymphocytes high had no local failure or death due to disease (P = 5 × 10(-4) and P = 4 × 10(-4), respectively).Conclusions: Taken together, our data point to a targetable Axl-PI3 kinase-PD-L1 axis that is highly associated with radiation resistance. Clin Cancer Res; 23(11); 2713-22. ©2017 AACR.

    View details for DOI 10.1158/1078-0432.CCR-16-2586

    View details for PubMedID 28476872

  • Quantitative pretreatment CT volumetry: Association with oncologic outcomes in patients with T4a squamous carcinoma of the larynx. Head & neck Shiao, J. C., Mohamed, A. S., Messer, J. A., Hutcheson, K. A., Johnson, J. M., Enderling, H., Kamal, M., Warren, B. W., Pham, B., Morrison, W. H., Zafereo, M. E., Hessel, A. C., Lai, S. Y., Kies, M. S., Ferrarotto, R., Garden, A. S., Schomer, D. F., Gunn, G. B., Phan, J., Frank, S. J., Beadle, B. M., Weber, R. S., Lewin, J. S., Rosenthal, D. I., Fuller, C. D. 2017

    Abstract

    The purpose of this study was to determine the impact of CT-determined pretreatment primary tumor volume on survival and disease control in T4a laryngeal squamous cell carcinoma (SCC).We retrospectively reviewed 124 patients with T4a laryngeal cancer from 2000-2011. Tumor volume measurements were collected and correlated with outcomes.Five-year overall survival (OS) for patients with tumor volume ≥21 cm(3) treated with larynx preservation (n = 26 of 41) was significantly inferior compared to <21 cm(3) (42% vs 64%, respectively; P = .003). Five-year OS for patients with tumor volumes ≥21 cm(3) in the cohort treated with total laryngectomy followed by radiotherapy (RT; n = 42 of 83) was not statistically significant when compared to <21 cm(3) (50% vs 63%, respectively; P = .058). On multivariate analysis, tumor volume ≥21 cm(3) was a significant independent correlate of worse disease-specific survival (DSS; P = .004), event-free survival (P = .005), recurrence-free survival (RFS; P = .04), noncancer cause-specific survival (P = .02), and OS (P = .0002).Pretreatment CT-based tumor volume is an independent prognostic factor of outcomes in T4a laryngeal cancer.

    View details for DOI 10.1002/hed.24804

    View details for PubMedID 28464542

  • Recurrent oral cavity cancer: Patterns of failure after salvage multimodality therapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Quinlan-Davidson, S. R., Morrison, W. H., Myers, J. N., Gunn, G. B., William, W. N., Beadle, B. M., Skinner, H. D., Gillenwater, A. M., Frank, S. J., Phan, J., Johnson, F. M., Fuller, C. D., Zafereo, M. E., Rosenthal, D. I., Garden, A. S. 2017; 39 (4): 633-638

    View details for DOI 10.1002/hed.24666

    View details for Web of Science ID 000397856000004

  • Predicting two-year longitudinal MD Anderson Dysphagia Inventory outcomes after intensity modulated radiotherapy for locoregionally advanced oropharyngeal carcinoma LARYNGOSCOPE Goepfert, R. P., Lewin, J. S., Barrow, M. P., Fuller, C. D., Lai, S. Y., Song, J., Hobbs, B. P., Gunn, G. B., Beadle, B. M., Rosenthal, D. I., Garden, A. S., Kies, M. S., Papadimitrakopoulou, V. A., Schwartz, D. L., Hutcheson, K. A. 2017; 127 (4): 842-848

    View details for DOI 10.1002/lary.26153

    View details for Web of Science ID 000397572700020

  • Long-Term, Prospective Performance of the MD Anderson Dysphagia Inventory in "Low-Intermediate Risk" Oropharyngeal Carcinoma After Intensity Modulated Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Goepfert, R. P., Lewin, J. S., Barrow, M. P., Gunn, G. B., Fuller, C. D., Beadle, B. M., Garden, A. S., Rosenthal, D. I., Kies, M. S., Papadimitrakopoulou, V., Lai, S. Y., Gross, N. D., Schwartz, D. L., Hutcheson, K. A. 2017; 97 (4): 700-708
  • Conditional Survival Analysis of Patients With Locally Advanced Laryngeal Cancer: Construction of a Dynamic Risk Model and Clinical Nomogram SCIENTIFIC REPORTS Sheu, T., Vock, D. M., Mohamed, A. S., Gross, N., Mulcahy, C., Zafereo, M., Gunn, G. B., Garden, A. S., Sevak, P., Phan, J., Lewin, J. S., Frank, S. J., Beadle, B. M., Morrison, W. H., Lai, S. Y., Hutcheson, K., Marai, G. E., Canahuate, G. M., Kies, M., El-Naggar, A., Weber, R. S., Rosenthal, D. I., Fuller, C. D. 2017; 7

    Abstract

    Conditional survival (CS), the survival beyond a pre-defined time interval, can identify periods of higher mortality risk for patients with locally advanced laryngeal cancer who face treatment-related toxicity and comorbidities related to alcohol and smoking in the survivorship setting. Using Weibull regression modeling, we analyzed retrospectively abstracted data from 638 records of patients who received radiation to identify prognostic factors for overall survival (OS) and recurrence free survival (RFS) for the first 3 years of survival and for OS conditional upon 3 years of survival. The CS was iteratively calculated, stratifying on variables that were statistically significant on multivariate regression. Predictive nomograms were generated. The median total follow up time was 175 months. The 3- and 6- year actuarial overall survival (OS) was 68% (95% confidence interval [CI] 65-72%) and 49% (CI 45-53%). The 3-year conditional overall survival (COS) at 3 years was 72% (CI 65-74%). Black patients had worse COS over time. Nodal disease was significantly associated with recurrence, but after 3 years, the 3-year conditional RFS converged for all nodal groups. In conclusion, the CS analysis in this patient cohort identified subgroups and time intervals that may represent opportunities for intervention.

    View details for DOI 10.1038/srep43928

    View details for Web of Science ID 000395799900001

    View details for PubMedID 28276466

  • Symptom burden and dysphagia associated with osteoradionecrosis in long-term oropharynx cancer survivors: A cohort analysis. Oral oncology Wong, A. T., Lai, S. Y., Gunn, G. B., Beadle, B. M., Fuller, C. D., Barrow, M. P., Hofstede, T. M., Chambers, M. S., Sturgis, E. M., Mohamed, A. S., Lewin, J. S., Hutcheson, K. A. 2017; 66: 75-80

    Abstract

    The purpose is to examine the relationship between mandibular osteoradionecrosis (ORN) and chronic dysphagia in long-term oropharynx cancer (OPC) survivors, and to determine the perceived symptom burden associated with ORN.Medical records of 349 OPC patients treated with bilateral IMRT and systemic therapy were reviewed. ORN was graded using a published 4-point classification schema. Patients were considered to have chronic dysphagia if they had aspiration pneumonia, stricture or aspiration detected by fluoroscopy or endoscopy, and/or feeding tube dependence in long-term follow-up ⩾1year following radiotherapy. MD Anderson Symptom Inventory - Head and Neck Module (MDASI-HN) scores were analyzed in a nested cross-sectional survey sample of 118 patients.34 (9.7%, 95% CI: 6.8-13.3%) patients developed ORN and 45 (12.9%, 95% CI: 9.6-16.9%) patients developed chronic dysphagia. Prevalence of chronic dysphagia was significantly higher in ORN cases (12/34, 35%) compared to those who did not develop ORN (33/315, 11%, p<0.001). ORN grade was also significantly associated with prevalence of dysphagia (p<0.001); the majority of patients with grade 4 ORN requiring major surgery (6 patients, 75%) were found to have chronic dysphagia. Summary MDASI-HN symptom scores did not significantly differ by ORN grade. Significantly higher symptom burden was reported, however, among ORN cases compared to those without ORN for MDASI-HN swallowing (p=0.033), problems with teeth and/or gums (p=0.016) and change in activity (p=0.015) item scores.ORN is associated with excess burden of chronic dysphagia and higher symptom severity related to swallowing, dentition and activity limitations.

    View details for DOI 10.1016/j.oraloncology.2017.01.006

    View details for PubMedID 28249651

    View details for PubMedCentralID PMC5336132

  • The impact of HPV testing for oropharyngeal cancers: Why the addendum matters. Cancer Beadle, B. M. 2017

    View details for DOI 10.1002/cncy.21842

    View details for PubMedID 28241100

  • Reduced Feeding Tube Duration With Intensity-Modulated Radiation Therapy for Head and Neck Cancer: A Surveillance, Epidemiology, and End Results-Medicare Analysis CANCER Beadle, B. M., Liao, K., Giordano, S. H., Garden, A. S., Hutcheson, K. A., Lai, S. Y., Guadagnolo, B. A. 2017; 123 (2): 283-293

    View details for DOI 10.1002/cncr.30350

    View details for Web of Science ID 000394719200015

  • The feasibility of endoscopy-CT image registration in the head and neck without prospective endoscope tracking. PloS one Ingram, W. S., Yang, J., Beadle, B. M., Wendt, R., Rao, A., Wang, X. A., Court, L. E. 2017; 12 (5)

    Abstract

    Endoscopic examinations are frequently-used procedures for patients with head and neck cancer undergoing radiotherapy, but radiation treatment plans are created on computed tomography (CT) scans. Image registration between endoscopic video and CT could be used to improve treatment planning and analysis of radiation-related normal tissue toxicity. The purpose of this study was to explore the feasibility of endoscopy-CT image registration without prospective physical tracking of the endoscope during the examination.A novel registration technique called Location Search was developed. This technique uses physical constraints on the endoscope's view direction to search for the virtual endoscope coordinates that maximize the similarity between the endoscopic video frame and the virtual endoscopic image. Its performance was tested on phantom and patient images and compared to an established registration technique, Frame-To-Frame Tracking.In phantoms, Location Search had average registration errors of 0.55 ± 0.60 cm for point measurements and 0.29 ± 0.15 cm for object surface measurements. Frame-To-Frame Tracking achieved similar results on some frames, but it failed on others due to the virtual endoscope becoming lost. This weakness was more pronounced in patients, where Frame-To-Frame tracking could not make it through the nasal cavity. On successful patient video frames, Location Search was able to find endoscope positions with an average distance of 0.98 ± 0.53 cm away from the ground truth positions. However, it failed on many frames due to false similarity matches caused by anatomical structural differences between the endoscopic video and the virtual endoscopic images.Endoscopy-CT image registration without prospective physical tracking of the endoscope is possible, but more development is required to achieve an accuracy suitable for clinical translation.

    View details for DOI 10.1371/journal.pone.0177886

    View details for PubMedID 28542331

  • Reproducibility of patient setup in the seated treatment position: A novel treatment chair design JOURNAL OF APPLIED CLINICAL MEDICAL PHYSICS McCarroll, R. E., Beadle, B. M., Fullen, D., Balter, P. A., Followill, D. S., Stingo, F. C., Yang, J., Court, L. E. 2017; 18 (1): 223-229

    View details for DOI 10.1002/acm2.12024

    View details for Web of Science ID 000393176200028

  • Recurrent oral cavity cancer: Patterns of failure after salvage multimodality therapy. Head & neck Quinlan-Davidson, S. R., Morrison, W. H., Myers, J. N., Gunn, G. B., William, W. N., Beadle, B. M., Skinner, H. D., Gillenwater, A. M., Frank, S. J., Phan, J., Johnson, F. M., Fuller, C. D., Zafereo, M. E., Rosenthal, D. I., Garden, A. S. 2016

    Abstract

    We focused on a cohort of radiation naïve patients who had recurrent oral cavity cancer (recurrent OCC) to assess their outcomes with salvage multimodal therapy.A retrospective single institutional study was performed of patients with recurrent OCC. Disease recurrence and survival outcomes were assessed.Seventy-eight patients were analyzed. All patients had salvage surgery and intensity-modulated radiotherapy (IMRT) and 74% had chemotherapy. Five-year overall survival, recurrence-free survival, and locoregional control rates were 59%, 60%, and 74%, respectively.Outcomes of radiation naïve patients with recurrent OCC are fair, and seem similar with patients with locally advanced nonrecurrent OCC treated with multimodal therapy. © 2016 Wiley Periodicals, Inc. Head Neck, 2016.

    View details for DOI 10.1002/hed.24666

    View details for PubMedID 28006086

  • Prospective Qualitative and Quantitative Analysis of Real-Time Peer Review Quality Assurance Rounds Incorporating Direct Physical Examination for Head and Neck Cancer Radiation Therapy. International journal of radiation oncology, biology, physics Cardenas, C. E., Mohamed, A. S., Tao, R., Wong, A. J., Awan, M. J., Kuruvila, S., Aristophanous, M., Gunn, G. B., Phan, J., Beadle, B. M., Frank, S. J., Garden, A. S., Morrison, W. H., Fuller, C. D., Rosenthal, D. I. 2016

    Abstract

    Our department has a long-established comprehensive quality assurance (QA) planning clinic for patients undergoing radiation therapy (RT) for head and neck cancer. Our aim is to assess the impact of a real-time peer review QA process on the quantitative and qualitative radiation therapy plan changes in the era of intensity modulated RT (IMRT).Prospective data for 85 patients undergoing head and neck IMRT who presented at a biweekly QA clinic after simulation and contouring were collected. A standard data collection form was used to document alterations made during this process. The original pre-QA clinical target volumes (CTVs) approved by the treating-attending physicians were saved before QA and compared with post-QA consensus CTVs. Qualitative assessment was done according to predefined criteria. Dice similarity coefficients (DSC) and other volume overlap metrics were calculated for each CTV level and were used for quantitative comparison. Changes are categorized as major, minor, and trivial according to the degree of overlap. Patterns of failure were analyzed and correlated to plan changes.All 85 patients were examined by at least 1 head and neck subspecialist radiation oncologist who was not the treating-attending physician; 80 (94%) were examined by ≥3 faculty members. New clinical findings on physical examination were found in 12 patients (14%) leading to major plan changes. Quantitative DSC analysis revealed significantly better agreement in CTV1 (0.94 ± 0.10) contours than in CTV2 (0.82 ± 0.25) and CTV3 (0.86 ± 0.2) contours (P=.0002 and P=.03, respectively; matched-pair Wilcoxon test). The experience of the treating-attending radiation oncologist significantly affected DSC values when all CTV levels were considered (P=.012; matched-pair Wilcoxon text). After a median follow-up time of 38 months, only 10 patients (12%) had local recurrence, regional recurrence, or both, mostly in central high-dose areas.Comprehensive peer review planning clinic is an essential component of IMRT QA that led to major changes in one-third of the study population. This process ensured safety related to target definition and led to favorable disease control profiles, with no identifiable recurrences attributable to geometric misses or delineation errors.

    View details for DOI 10.1016/j.ijrobp.2016.11.019

    View details for PubMedID 28258898

  • Proteomic Profiling Identifies PTK2/FAK as a Driver of Radioresistance in HPV-negative Head and Neck Cancer CLINICAL CANCER RESEARCH Skinner, H. D., Giri, U., Yang, L., Woo, S. H., Story, M. D., Pickering, C. R., Byers, L. A., Williams, M. D., El-Naggar, A., Wang, J., Diao, L., Shen, L., Fan, Y. H., Molkentine, D. P., Beadle, B. M., Meyn, R. E., Myers, J. N., Heymach, J. V. 2016; 22 (18): 4643-4650

    Abstract

    Head and neck squamous cell carcinoma (HNSCC) is commonly treated with radiotherapy, and local failure after treatment remains the major cause of disease-related mortality. To date, human papillomavirus (HPV) is the only known clinically validated, targetable biomarkers of response to radiation in HNSCC.We performed proteomic and transcriptomic analysis of targetable biomarkers of radioresistance in HPV-negative HNSCC cell lines in vitro, and tested whether pharmacologic blockade of candidate biomarkers sensitized cells to radiotherapy. Candidate biomarkers were then investigated in several independent cohorts of patients with HNSCC.Increased expression of several targets was associated with radioresistance, including FGFR, ERK1, EGFR, and focal adhesion kinase (FAK), also known as PTK2. Chemical inhibition of PTK2/FAK, but not FGFR, led to significant radiosensitization with increased G2-M arrest and potentiated DNA damage. PTK2/FAK overexpression was associated with gene amplification in HPV-negative HNSCC cell lines and clinical tumors. In two independent cohorts of patients with locally advanced HPV-negative HNSCC, PTK2/FAK amplification was highly associated with poorer disease-free survival (DFS; P = 0.012 and 0.034). PTK2/FAK mRNA expression was also associated with worse DFS (P = 0.03). Moreover, both PTK2/FAK mRNA (P = 0.021) and copy number (P = 0.063) were associated with DFS in the Head and Neck Cancer subgroup of The Cancer Genome Atlas.Proteomic analysis identified PTK2/FAK overexpression is a biomarker of radioresistance in locally advanced HNSCC, and PTK2/FAK inhibition radiosensitized HNSCC cells. Combinations of PTK2/FAK inhibition with radiotherapy merit further evaluation as a therapeutic strategy for improving local control in HPV-negative HNSCC. Clin Cancer Res; 22(18); 4643-50. ©2016 AACR.

    View details for DOI 10.1158/1078-0432.CCR-15-2785

    View details for Web of Science ID 000383359000015

    View details for PubMedID 27036135

  • Reirradiation of Head and Neck Cancers With Proton Therapy: Outcomes and Analyses INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Phan, J., Sio, T. T., Nguyen, T. P., Takiar, V., Gunn, G. B., Garden, A. S., Rosenthal, D. I., Fuller, C. D., Morrison, W. H., Beadle, B., Ma, D., Zafereo, M. E., Hutcheson, K. A., Kupferman, M. E., William, W. N., Frank, S. J. 2016; 96 (1): 30-41

    Abstract

    Reirradiation of head and neck (H&N) cancer is a clinical challenge. Proton radiation therapy (PRT) offers dosimetric advantages for normal tissue sparing and may benefit previously irradiated patients. Here, we report our initial experience with the use of PRT for H&N reirradiation, with focus on clinical outcomes and toxicity.We retrospectively reviewed the records of patients who received H&N reirradiation with PRT from April 2011 through June 2015. Patients reirradiated with palliative intent or without prior documentation of H&N radiation therapy were excluded. Radiation-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events Version 4.0.The conditions of 60 patients were evaluated, with a median follow-up time of 13.6 months. Fifteen patients (25%) received passive scatter proton therapy (PSPT), and 45 (75%) received intensity modulated proton therapy (IMPT). Thirty-five patients (58%) received upfront surgery, and 44 (73%) received concurrent chemotherapy. The 1-year rates of locoregional failure-free survival, overall survival, progression-free survival, and distant metastasis-free survival were 68.4%, 83.8%, 60.1%, and 74.9%, respectively. Eighteen patients (30%) experienced acute grade 3 (G3) toxicity, and 13 (22%) required a feeding tube at the end of PRT. The 1-year rates of late G3 toxicity and feeding tube independence were 16.7% and 2.0%, respectively. Three patients may have died of reirradiation-related effects (1 acute and 2 late).Proton beam therapy can be a safe and effective curative reirradiation strategy, with acceptable rates of toxicity and durable disease control.

    View details for DOI 10.1016/j.ijrobp.2016.03.053

    View details for Web of Science ID 000381087300006

    View details for PubMedID 27325480

  • Long-term outcomes after multidisciplinary management of T3 laryngeal squamous cell carcinomas: Improved functional outcomes and survival with modern therapeutic approaches. Head & neck Fuller, C. D., Mohamed, A. S., Garden, A. S., Gunn, G. B., Mulcahy, C. F., Zafereo, M., Phan, J., Lai, S. Y., Lewin, J. S., Hutcheson, K. A., Frank, S. J., Beadle, B. M., Morrison, W. H., El-Naggar, A. K., Kocak-Uzel, E., Ginsberg, L. E., Kies, M. S., Weber, R. S., Rosenthal, D. I. 2016

    Abstract

    The purpose of this study was to evaluate the long-term outcomes after initial definitive or adjuvant radiotherapy (RT) for T3 laryngeal cancers.We reviewed 412 patients treated for T3 laryngeal squamous cell cancer from 1985 to 2011.The 10-year overall survival (OS) was 35%; disease-specific-survival (DSS) was 61%; locoregional control was 76%; and freedom from distant metastasis was 83%. Chemotherapy, age, performance status <2, node-negative status, and glottic subsite were associated with improved survival (all p < .03). Larynx preservation with induction and/or concurrent chemoradiotherapy (LP-CRT) had better laryngectomy-free survival than RT alone (LP-RT; hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.47-0.81; p = .0005); 10-year laryngectomy-free survival rates of the LP-CRT cohort (37%) were higher than those of the LP-RT cohort (18%). The 5-year DSS and OS rates of the LP-CRT cohort (79% and 67%) were better after total laryngectomy with postoperative RT (TL-PORT; 61% and 50%) and LP-RT (64% and 46%; p < .006 for all).In patients with T3 laryngeal cancers, LP-CRT provides better functional, oncologic, and survival outcomes than historical TL-PORT or LP-RT does. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1739-1751, 2016.

    View details for DOI 10.1002/hed.24532

    View details for PubMedID 27466789

  • Methodology for analysis and reporting patterns of failure in the Era of IMRT: head and neck cancer applications RADIATION ONCOLOGY Mohamed, A. S., Rosenthal, D. I., Awan, M. J., Garden, A. S., Kocak-Uzel, E., Belal, A. M., El-Gowily, A. G., Phan, J., Beadle, B. M., Gunn, G. B., Fuller, C. D. 2016; 11

    Abstract

    The aim of this study is to develop a methodology to standardize the analysis and reporting of the patterns of loco-regional failure after IMRT of head and neck cancer.Twenty-one patients with evidence of local and/or regional failure following IMRT for head-and-neck cancer were retrospectively reviewed under approved IRB protocol. Manually delineated recurrent gross disease (rGTV) on the diagnostic CT documenting recurrence (rCT) was co-registered with the original planning CT (pCT) using both deformable (DIR) and rigid (RIR) image registration software. Subsequently, mapped rGTVs were compared relative to original planning target volumes (TVs) and dose using a centroid-based approaches. Failures were then classified into five types based on combined spatial and dosimetric criteria; A (central high dose), B (peripheral high dose), C (central elective dose), D (peripheral elective dose), and E (extraneous dose).A total of 26 recurrences were identified. Using DIR, recurrences were assigned to more central TVs compared to RIR as detected using the spatial centroid-based method (p = 0.0002). rGTVs mapped using DIR had statistically significant higher mean doses when compared to rGTVs mapped rigidly (mean dose 70 vs. 69 Gy, p = 0.03). According to the proposed classification 22 out of 26 failures were of type A (central high dose) as assessed by DIR method compared to 18 out of 26 for the RIR because of the tendencey of RIR to assign failures more peripherally.RIR tends to assigns failures more peripherally. DIR-based methods showed that the vast majority of failures originated in the high dose target volumes and received full prescribed doses suggesting biological rather than technology-related causes of failure. Validated DIR-based registration is recommended for accurate failure characterization and a novel typology-indicative taxonomy is recommended for failure reporting in the IMRT era.

    View details for DOI 10.1186/s13014-016-0678-7

    View details for Web of Science ID 000380232900003

    View details for PubMedID 27460585

  • Predicting two-year longitudinal MD Anderson Dysphagia Inventory outcomes after intensity modulated radiotherapy for locoregionally advanced oropharyngeal carcinoma. Laryngoscope Goepfert, R. P., Lewin, J. S., Barrow, M. P., Fuller, C. D., Lai, S. Y., Song, J., Hobbs, B. P., Gunn, G. B., Beadle, B. M., Rosenthal, D. I., Garden, A. S., Kies, M. S., Papadimitrakopoulou, V. A., Schwartz, D. L., Hutcheson, K. A. 2016

    Abstract

    To determine the factors associated with longitudinal patient-reported dysphagia as measured by the MD Anderson Dysphagia Inventory (MDADI) in locoregionally advanced oropharyngeal carcinoma (OPC) survivors treated with split-field intensity modulated radiotherapy (IMRT).Retrospective patient analysis.A retrospective analysis combined data from three single-institution clinical trials for stage III/IV head and neck carcinoma. According to trial protocols, patients had prospectively collected MDADI at baseline, 6, 12, and 24 months after treatment. OPC patients with baseline and at least one post-treatment MDADI were included. Longitudinal analysis was completed with multivariate linear mixed effects modeling.There were 116 patients who met inclusion criteria. Mean baseline MDADI composite was 88.3, dropping to 73.8 at 6 months, and rising to 78.6 and 83.3 by 12 and 24 months, respectively (compared to baseline, all P < .0001). Tumor stage and smoking status were significant predictors of longitudinal MDADI composite scores. Patients with T1, T2, and T3 tumors had 15.9 (P = .0001), 10.9 (P = .0049), and 7.5 (P = .0615), respectively, higher mean MDADI composite than those with T4 tumors, and current smokers had a 9.4 (P = .0007) lower mean MDADI composite than never smokers.Patients report clinically meaningful dysphagia early after split-field IMRT for locoregionally advanced OPC that remains apparent 6 months after treatment. MDADI scores recover slowly thereafter, but remain depressed at 24 months compared to baseline. Higher tumor stage and smoking status are important markers of patient-reported function through the course of treatment, suggesting these are important groups for heightened surveillance and more intensive interventions to optimize swallowing outcomes.4 Laryngoscope, 2016.

    View details for DOI 10.1002/lary.26153

    View details for PubMedID 27440393

  • Reirradiation of Head and Neck Cancers With Intensity Modulated Radiation Therapy: Outcomes and Analyses INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Takiar, V., Garden, A. S., Ma, D., Morrison, W. H., Edson, M., Zafereo, M. E., Gunn, G. B., Fuller, C. D., Beadle, B., Frank, S. J., William, W. N., Kies, M., El-Naggar, A. K., Weber, R., Rosenthal, D. I., Jack Phan, J. 2016; 95 (4): 1117-1131

    Abstract

    To review our 15-year institutional experience using intensity modulated radiation therapy (IMRT) to reirradiate patients with head and neck squamous cell carcinomas (HNSCC) and identify predictors of outcomes and toxicity.We retrospectively reviewed the records of 227 patients who received head and neck reirradiation using IMRT from 1999 to 2014. Patients treated with noncurative intent were excluded. Radiation-related acute and late toxicities were recorded. Prognostic variables included performance status, disease site, disease-free interval, chemotherapy, and RT dose and volume. Correlative analyses were performed separately for surgery and nonsurgery patients.Two hundred six patients (91%) were retreated with curative intent, and 173 had HNSCC histology; 104 (50%) underwent salvage resection, and 135 (66%) received chemotherapy. Median follow-up after reirradiation was 24.7 months. Clinical outcomes were worse for HNSCC patients, with 5-year locoregional control, progression-free survival, and overall survival rates of 53%, 22%, and 32%, respectively, compared with 74%, 59%, and 79%, respectively, for non-HNSCC patients. On multivariate analysis, concurrent chemotherapy and retreatment site were associated with tumor control, whereas performance status was associated with survival. Favorable prognostic factors specific to surgery patients were neck retreatment and lack of extracapsular extension, whereas for nonsurgery patients, these were a nasopharynx subsite and complete response to induction chemotherapy. Actuarial rates of grade ≥3 toxicity were 32% at 2 years and 48% at 5 years, with dysphagia or odynophagia being most common. Increased grade ≥3 toxicity was associated with retreatment volume >50 cm(3) and concurrent chemotherapy.Reirradiation with IMRT either definitively or after salvage surgery can produce promising local control and survival in selected patients with head and neck cancers. Treatment-related toxicity remains significant. Prognostic factors are emerging to guide multidisciplinary treatment approaches and clinical trial design.

    View details for DOI 10.1016/j.ijrobp.2016.03.015

    View details for Web of Science ID 000378207000007

    View details for PubMedID 27354127

  • The role of elective nodal irradiation for esthesioneuroblastoma patients with clinically negative neck. Practical radiation oncology Jiang, W., Mohamed, A. S., Fuller, C. D., Kim, B. Y., Tang, C., Gunn, G. B., Hanna, E. Y., Frank, S. J., Su, S. Y., Diaz, E., Kupferman, M. E., Beadle, B. M., Morrison, W. H., Skinner, H., Lai, S. Y., El-Naggar, A. K., DeMonte, F., Rosenthal, D. I., Garden, A. S., Phan, J. 2016; 6 (4): 241-247

    Abstract

    Although adjuvant radiation to the tumor bed has been reported to improve the clinic outcomes of esthesioneuroblastoma (ENB) patients, the role of elective neck irradiation (ENI) in clinically node-negative (N0) patients remains controversial. Here, we evaluated the effects of ENI on neck nodal relapse risk in ENB patients treated with radiation therapy as a component of multimodality treatment.Seventy-one N0 ENB patients irradiated at the University of Texas MD Anderson Cancer Center between 1970 and 2013 were identified. ENI was performed on 22 of these patients (31%). Survival analysis was performed with focus on comparative outcomes of those patients who did and did not receive ENI.The median follow-up time for our cohort is 80.8 months (range, 6-350 months). Among N0 patients, 13 (18.3%) developed neck nodal relapses, with a median time to progression of 62.5 months. None of these 13 patients received prophylactic neck irradiation. ENI was associated with significantly improved regional nodal control at 5 years (regional control rate of 100% for ENI vs 82%, P < .001), but not overall survival or disease-free survival. Eleven patients without ENI developed isolated neck recurrences. All had further treatment for their neck disease, including neck dissection (n = 10), radiation (n = 10), or chemotherapy (n = 5). Six of these 11 patients (54.5%) demonstrated no evidence of further recurrence with a median follow-up of 55.5 months.ENI significantly reduces the risk of cervical nodal recurrence in ENB patients with clinically N0 neck, but this did not translate to a survival benefit. Multimodality treatment for isolated neck recurrence provides a reasonable salvage rate. The greatest benefit for ENI appeared to be among younger patients who presented with Kadish C disease. Further studies are needed to confirm these findings.

    View details for DOI 10.1016/j.prro.2015.10.023

    View details for PubMedID 26979544

  • Long-Term, Prospective Performance of the MD Anderson Dysphagia Inventory in "Low-Intermediate Risk" Oropharyngeal Carcinoma After Intensity Modulated Radiation Therapy. International journal of radiation oncology, biology, physics Goepfert, R. P., Lewin, J. S., Barrow, M. P., Gunn, G. B., Fuller, C. D., Beadle, B. M., Garden, A. S., Rosenthal, D. I., Kies, M. S., Papadimitrakopoulou, V., Lai, S. Y., Gross, N. D., Schwartz, D. L., Hutcheson, K. A. 2016

    Abstract

    To characterize long-term MD Anderson Dysphagia Inventory (MDADI) results after primary intensity modulated radiation therapy (IMRT) for oropharyngeal carcinoma (OPC) among patients with "low-intermediate risk" OPC who would be eligible for current trials (eg, ECOG 3311, NRG HN002, CRUK PATHOS).A retrospective pooled analysis combined data from 3 single-institution clinical trials for advanced-stage head and neck carcinoma. Inclusion criteria were clinical stage III/IV OPC (T1-2/N1-2b, T3/N0-2b) treated with definitive split-field IMRT and prospectively collected MDADI at baseline and at least 1 posttreatment interval available in trial databases. Patients were sampled to represent likely human papillomavirus (HPV)-associated disease (HPV(+)/p16(+) or <10 pack-years if HPV/p16 unknown). The MDADI composite scores were collected at baseline and 6, 12, and 24 months after treatment. Pairwise tests were Bonferroni corrected for multiple comparisons.Forty-six patients were included. All received bilateral neck irradiation with a median dose of 70 Gy and systemic therapy (57% concurrent, 43% induction only). Overall the mean baseline MDADI composite score was 90.1, dropping to 74.6 at 6 months (P<.0001) and rising to 78.5 (P<.0001) and 83.1 (P=.002) by 12 and 24 months relative to baseline, respectively, representing a clinically meaningful drop in MDADI scores at 6 months that partially recovers by 24 months (6 vs 24 months, P=.05). Poor MDADI scores (composite <60) were reported in 4%, 11%, 15%, and 9% of patients at baseline and 6, 12, and 24 months, respectively. Fifteen percent of patients had a persistently depressed composite score by at least 20 points at the 24-month interval."Low-intermediate risk" patients with OPC treated with laryngeal/esophageal inlet dose-optimized split-field IMRT are highly likely to report recovery of acceptable swallowing function in long-term follow-up. Only 15% report poor swallowing function and/or persistently depressed MDADI at 12 months or more after IMRT. These data serve as a benchmark future trial design and endpoint interpretation.

    View details for DOI 10.1016/j.ijrobp.2016.06.010

    View details for PubMedID 27485284

  • Osteoradionecrosis in patients with salivary gland malignancies ORAL ONCOLOGY Tucker, J. R., Xu, L., Sturgis, E. M., Mohamed, A. S., Hofstede, T. M., Chambers, M. S., Lai, S. Y., Fuller, C. D., Beadle, B., Gunn, G. B., Hutcheson, K. A. 2016; 57: 1-5

    Abstract

    The present study was undertaken to evaluate osteoradionecrosis (ORN) in patients with salivary gland malignancies (SGM) after treatment with radiation therapy.The medical records of 172 patients treated with radiation therapy for SGM during a 12-year period (August 2001 to November 2013) were reviewed. Incidence, time to event, staging and management of ORN were analyzed.Of the 172 patients, 7 patients (4%) developed ORN (median latency: 19months, range: 4-72months). Of those 7 patients, 4 required major surgery, 1 required hyperbaric oxygen therapy (HBO), one required minor debridement, and one required conservative management. Total prescribed radiation dose varied from 50Gy (1 case) to 70Gy (1 case) among those patients who developed ORN, and radiotherapy was delivered postoperatively after osseous resection in 4 of 7 cases. Three of the 7 cases of ORN occurred after traumatic injury to the bone. Of the 7 patients who developed ORN, 3 had SGM of the major glands, 3 had other sites of the oral cavity, and 1 had a sinonasal location.While the rate of ORN after radiotherapy for SGM was somewhat lower (4%) than previously published data on patients with squamous cell carcinomas of the head and neck treated with radiation therapy (8-14%), ORN necessitating major surgery remains a clinically significant, possible late effect of radiotherapy in SGM survivors. Location of SGM is very important, with cases that developed ORN disproportionally having primary disease arising in the oral cavity.

    View details for DOI 10.1016/j.oraloncology.2016.03.006

    View details for Web of Science ID 000376084500006

    View details for PubMedID 27208837

  • Radiation Therapy (With or Without Neck Surgery) for Phenotypic Human Papillomavirus-Associated Oropharyngeal Cancer CANCER Garden, A. S., Fuller, C. D., Rosenthal, D. I., William, W. N., Gunn, G. B., Beadle, B. M., Johnson, F. M., Morrison, W. H., Phan, J., Frank, S. J., Kies, M. S., Sturgis, E. M. 2016; 122 (11): 1702-1707

    Abstract

    Favorable outcomes for human papillomavirus-associated oropharyngeal cancer have led to interest in identifying a subgroup of patients with the lowest risk of disease recurrence after therapy. De-intensification of therapy for this group may result in survival outcomes that are similar to those associated with current therapy but with less toxicity. To advance this effort, this study analyzed the outcomes of oropharyngeal cancer patients treated with or without systemic therapy.This was a retrospective study of patients with oropharyngeal cancer treated between 1985 and 2012. The criteria for inclusion were ≤10 pack-years of cigarette smoking and stage III/IVA cancer limited to T1-3, N1-N2b, and T3N0 disease. A survival analysis was performed with the primary endpoint of progression-free survival (PFS).The cohort included 857 patients. Systemic therapy was given to 439 patients (51%). The median survival was 80 months. The 2-year PFS rate was 91%. When the analysis was limited to 324 patients irradiated without systemic therapy, the 2- and 5-year PFS rates were 90% and 85%, respectively. Furthermore, for these 324 patients, the 5-year PFS rates for T1, T2, and T3 disease were 90%, 83%, and 70%, respectively. The 5-year PFS rate for patients treated with systemic therapy for T3 disease was 77% (P = .07).According to the low-risk definition currently established in cooperative trials, the patients had a 2-year PFS rate approximating 90%. When patients who were treated with radiation alone were evaluated, no compromise was observed in this high rate of PFS, which is higher than the 2-year PFS thresholds used in current cooperative trials. Cancer 2016;122:1702-7. © 2016 American Cancer Society.

    View details for DOI 10.1002/cncr.29965

    View details for Web of Science ID 000378402900012

    View details for PubMedID 27019396

  • Association of Body Composition With Survival and Locoregional Control of Radiotherapy-Treated Head and Neck Squamous Cell Carcinoma. JAMA oncology Grossberg, A. J., Chamchod, S., Fuller, C. D., Mohamed, A. S., Heukelom, J., Eichelberger, H., Kantor, M. E., Hutcheson, K. A., Gunn, G. B., Garden, A. S., Frank, S., Phan, J., Beadle, B., Skinner, H. D., Morrison, W. H., Rosenthal, D. I. 2016; 2 (6): 782-789

    Abstract

    Major weight loss is common in patients with head and neck squamous cell carcinoma (HNSCC) who undergo radiotherapy (RT). How baseline and posttreatment body composition affects outcome is unknown.To determine whether lean body mass before and after RT for HNSCC predicts survival and locoregional control.Retrospective study of 2840 patients with pathologically proven HNSCC undergoing curative RT at a single academic cancer referral center from October 1, 2003, to August 31, 2013. One hundred ninety patients had computed tomographic (CT) scans available for analysis of skeletal muscle (SM). The effect of pre-RT and post-RT SM depletion (defined as a CT-measured L3 SM index of less than 52.4 cm2/m2 for men and less than 38.5 cm2/m2 for women) on survival and disease control was evaluated. Final follow-up was completed on September 27, 2014, and data were analyzed from October 1, 2014, to November 29, 2015.Primary outcomes were overall and disease-specific survival and locoregional control. Secondary analyses included the influence of pre-RT body mass index (BMI) and interscan weight loss on survival and recurrence.Among the 2840 consecutive patients who underwent screening, 190 had whole-body positron emission tomography-CT or abdominal CT scans before and after RT and were included for analysis. Of these, 160 (84.2%) were men and 30 (15.8%) were women; their mean (SD) age was 57.7 (9.4) years. Median follow up was 68.6 months. Skeletal muscle depletion was detected in 67 patients (35.3%) before RT and an additional 58 patients (30.5%) after RT. Decreased overall survival was predicted by SM depletion before RT (hazard ratio [HR], 1.92; 95% CI, 1.19-3.11; P = .007) and after RT (HR, 2.03; 95% CI, 1.02-4.24; P = .04). Increased BMI was associated with significantly improved survival (HR per 1-U increase in BMI, 0.91; 95% CI, 0.87-0.96; P < .001). Weight loss without SM depletion did not affect outcomes. Post-RT SM depletion was more substantive in competing multivariate models of mortality risk than weight loss-based metrics (Bayesian information criteria difference, 7.9), but pre-RT BMI demonstrated the greatest prognostic value.Diminished SM mass assessed by CT imaging or BMI can predict oncologic outcomes for patients with HNSCC, whereas weight loss after RT initiation does not predict SM loss or survival.

    View details for DOI 10.1001/jamaoncol.2015.6339

    View details for PubMedID 26891703

  • Impact of selective neck dissection on chronic dysphagia after chemo-intensity-modulated radiotherapy for oropharyngeal carcinoma HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Hutcheson, K. A., Abualsamh, A. R., Sosa, A., Weber, R. S., Beadle, B. M., Sturgis, E. M., Lewin, J. S. 2016; 38 (6): 886-893

    Abstract

    Conflicting results are reported regarding the impact of neck dissection on radiation-associated dysphagia. The purpose of this study was to reexamine this question specific to oropharyngeal intensity-modulated radiotherapy (IMRT).Three hundred forty-nine patients with oropharyngeal cancer treated with bilateral IMRT with systemic therapy (induction and/or concurrent) were reviewed. Chronic dysphagia was defined by aspiration, stricture, pneumonia, and/or gastrostomy dependence ≥12 months post-IMRT.Selective neck dissection was performed after IMRT in 75 patients (21%). Overall, 41 patients (12%) developed chronic dysphagia. Neck dissection did not increase the rate of chronic dysphagia (9% neck dissection; 12% no neck dissection; p = .464) or gastrostomy duration (p = .482). On multivariate analysis, age (odds ratio [OR] per 5-year = 1.25; 95% confidence interval [CI] = 1.04-1.51), baseline abnormal diet (OR = 2.78; 95% CI = 1.31-5.88), and IMRT dose (OR per 5-Gy = 5.11; 95% CI = 1.77-14.81) significantly predicted dysphagia.In the setting of selective neck dissection for residual adenopathy after IMRT, neck dissection did not impact dysphagia. © 2015 Wiley Periodicals, Inc. Head Neck 38: 886-893, 2016.

    View details for DOI 10.1002/hed.24195

    View details for Web of Science ID 000379939900015

    View details for PubMedID 26339764

  • A Multidisciplinary Orbit-Sparing Treatment Approach That Includes Proton Therapy for Epithelial Tumors of the Orbit and Ocular Adnexa INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Holliday, E. B., Esmaeli, B., Pinckard, J., Garden, A. S., Rosenthal, D. I., Morrison, W. H., Kies, M. S., Gunn, G. B., Fuller, C. D., Phan, J., Beadle, B. M., Zhu, X. R., Zhang, X., Frank, S. J. 2016; 95 (1): 344-352

    Abstract

    Postoperative radiation is often indicated in the treatment of malignant epithelial tumors of the orbit and ocular adnexa. We present details of radiation technique and toxicity data after orbit-sparing surgery followed by adjuvant proton radiation therapy.Twenty patients underwent orbit-sparing surgery followed by proton therapy for newly diagnosed malignant epithelial tumors of the lacrimal gland (n=7), lacrimal sac/nasolacrimal duct (n=10), or eyelid (n=3). Tumor characteristics, treatment details, and visual outcomes were obtained from medical records. Acute and chronic toxicity were prospectively scored using Common Terminology Criteria for Adverse Events version 4.0.The median radiation dose was 60 Gy(RBE) (relative biological effectiveness; [range 50-70 Gy]); 11 patients received concurrent chemotherapy. Dose to ipsilateral anterior optic structures was reduced in 13 patients by having them gaze away from the target during treatment. At a median follow-up time of 27.1 months (range 2.6-77.2 months), no patient had experienced local recurrence; 1 had regional and 1 had distant recurrence. Three patients developed chronic grade 3 epiphora, and 3 developed grade 3 exposure keratopathy. Four patients experienced a decrease in visual acuity from baseline but maintained vision sufficient to perform all activities of daily living without difficulty. Patients with grade ≥3 chronic ocular toxicity had higher maximum dose to the ipsilateral cornea (median 46.3 Gy[RBE], range 36.6-52.7 Gy[RBE] vs median 37.4 Gy[RBE], range 9.0-47.3 Gy(RBE); P=.017).Orbit-sparing surgery for epithelial tumors of the orbit and ocular adnexa followed by proton therapy successfully achieved disease control and was well tolerated. No patient required orbital exenteration or enucleation. Chronic grade 3 toxicity was associated with high maximum dose to the cornea. An eye-deviation technique can be used to limit the maximum corneal dose to <35 Gy(RBE).

    View details for DOI 10.1016/j.ijrobp.2015.08.008

    View details for Web of Science ID 000375419500051

    View details for PubMedID 26454680

  • Outcomes and complications of osseointegrated hearing aids in irradiated temporal bones LARYNGOSCOPE Nader, M., Beadle, B. M., Roberts, D. B., Gidley, P. W. 2016; 126 (5): 1187-1192

    Abstract

    To compare the complication rate for osseointegrated hearing aids (OIHA) in patients with or without irradiation.Retrospective case review.We studied patients with OIHAs implanted between January 1, 2005, and July 15, 2013 in a tertiary university center with a referral otology and neurotology practice. Demographics, history of oncologic surgery, follow-up length after OIHA implantation, radiation history and dosage, postoperative complications, and chronologic relationship between oncologic resection, OIHA implantation, and irradiation were reviewed to collect information. Soft tissue complications were graded according to a modified Holgers classification.The study included 48 patients. Twenty-nine patients (32 implants) did not undergo radiotherapy and 19 patients (19 implants) did. In the radiotherapy group, six patients had OIHAs implanted before radiotherapy, and 13 had OIHAs implanted in irradiated bone. Of these 13 patients, one had OIHA implanted during primary oncologic surgery; 11 had OIHA implanted during secondary surgery; and one patient did not have oncologic surgery. Patients with both OIHA implantation and radiotherapy had more complications than patients without radiotherapy (31.6% vs. 24.1%, P > 0.05) and more major complications than patients without radiotherapy (26.3% vs. 3.4%, P > 0.05). Patients with OIHAs implanted before radiotherapy did not have any complications. There were significantly fewer and less severe complications in patients with OIHAs implanted during primary oncologic resection than in patients with OIHAs implanted secondarily (0/8 vs. 8/11, P < 0.05).The rate and severity of complications of OIHAs can be minimized by implanting the device before irradiation, ideally at the time of primary oncologic surgery.4. Laryngoscope, 126:1187-1192, 2016.

    View details for DOI 10.1002/lary.25592

    View details for Web of Science ID 000374769400037

    View details for PubMedID 26371776

  • Clinical Outcomes and Patterns of Disease Recurrence After Intensity Modulated Proton Therapy for Oropharyngeal Squamous Carcinoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Gunn, G. B., Blanchard, P., Garden, A. S., Zhu, X. R., Fuller, C. D., Mohamed, A. S., Morrison, W. H., Phan, J., Beadle, B. M., Skinner, H. D., Sturgis, E. M., Kies, M. S., Hutcheson, K. A., Rosenthal, D. I., Mohan, R., Gillin, M. T., Frank, S. J. 2016; 95 (1): 360-367

    Abstract

    A single-institution prospective study was conducted to assess disease control and toxicity of proton therapy for patients with head and neck cancer.Disease control, toxicity, functional outcomes, and patterns of failure for the initial cohort of patients with oropharyngeal squamous carcinoma (OPC) treated with intensity modulated proton therapy (IMPT) were prospectively collected in 2 registry studies at a single institution. Locoregional failures were analyzed by using deformable image registration.Fifty patients with OPC treated from March 3, 2011, to July 2014 formed the cohort. Eighty-four percent were male, 50% had never smoked, 98% had stage III/IV disease, 64% received concurrent therapy, and 35% received induction chemotherapy. Forty-four of 45 tumors (98%) tested for p16 were positive. All patients received IMPT (multifield optimization to n=46; single-field optimization to n=4). No Common Terminology Criteria for Adverse Events grade 4 or 5 toxicities were observed. The most common grade 3 toxicities were acute mucositis in 58% of patients and late dysphagia in 12%. Eleven patients had a gastrostomy (feeding) tube placed during therapy, but none had a feeding tube at last follow-up. At a median follow-up time of 29 months, 5 patients had disease recurrence: local in 1, local and regional in 1, regional in 2, and distant in 1. The 2-year actuarial overall and progression-free survival rates were 94.5% and 88.6%.The oncologic, toxicity, and functional outcomes after IMPT for OPC are encouraging and provide the basis for ongoing and future clinical studies.

    View details for DOI 10.1016/j.ijrobp.2016.02.021

    View details for Web of Science ID 000375419500053

    View details for PubMedID 27084653

  • Comparison of systemic therapies used concurrently with radiation for the treatment of human papillomavirus-associated oropharyngeal cancer HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Nien, H., Sturgis, E. M., Kies, M. S., El-Naggar, A. K., Morrison, W. H., Beadle, B. M., Johnson, F. M., Gunn, G. B., Fuller, C. D., Phan, J., Gold, K. A., Frank, S. J., Skinner, H., Rosenthal, D. I., Garden, A. S. 2016; 38: E1554-E1561

    Abstract

    This was a retrospective study of patients with human papillomavirus (HPV)-associated oropharyngeal cancer treated with concurrent systemic therapy and radiation.Data were extracted through chart review, and statistical analyses included frequency tabulation, chi-square, and Kaplan-Meier tests.Three hundred thirty-nine patients were analyzed; 166 received neoadjuvant chemotherapy. One hundred thirty-six patients were treated with cisplatin, 123 with cetuximab, and 59 with carboplatin. The 2-, 3-, and 5-year actuarial overall survival rates were 92%, 88%, and 78%, respectively. There were no significant differences in survival or disease control when analyzed by systemic agent. Platin-treated patients had greater hematologic toxicity, and required more intravenous hydration. The incidence of confluent mucositis was highest among patients treated with cetuximab.Platin and cetuximab seem to have similar efficacy when delivered concurrently with radiation in our retrospective population study. Although platin did cause greater hematologic toxicity, radiation-specific side effects seemed relatively comparable. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1554-E1561, 2016.

    View details for DOI 10.1002/hed.24278

    View details for Web of Science ID 000375116400200

    View details for PubMedID 26595157

  • Outcomes for hypopharyngeal carcinoma treated with organ-preservation therapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Edson, M. A., Garden, A. S., Takiar, V., Glisson, B. S., Fuller, C. D., Gunn, G. B., Beadle, B. M., Morrison, W. H., Frank, S. J., Shah, S. J., Tao, R., William, W. N., Weber, R. S., Rosenthal, D. I., Phan, J. 2016; 38: E2091-E2099

    Abstract

    This study assessed outcomes of patients with hypopharyngeal carcinoma treated with organ-preservation therapy utilizing intensity-modulated radiation therapy (IMRT).The medical records of 98 patients treated with definitive IMRT +/- chemotherapy from 2001 to 2013 for nonmetastatic hypopharyngeal cancer were retrospectively reviewed.Patients were treated to doses of 66 to 72 Gy. Eighty-three patients (85%) received chemotherapy. With median follow-up of 35 months, 2-year overall survival (OS), locoregional control, progression-free survival (PFS), and laryngectomy-free survival rates were 74%, 77%, 67%, and 65%, respectively. Functional laryngeal preservation rate was 76% at 2 years. N3 disease correlated with worse OS (p < .01). Concurrent chemotherapy correlated with improved locoregional control (p = .03) and complete response to induction chemotherapy correlated with improved OS and PFS (p = .02). Actuarial 2-year and 5-year grade 3 treatment toxicities were 17% and 21%, respectively.Favorable disease outcomes and functional laryngeal preservation rates can be achieved with IMRT for patients with hypopharyngeal cancer. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2091-E2099, 2016.

    View details for DOI 10.1002/hed.24387

    View details for Web of Science ID 000375116400273

    View details for PubMedID 26920665

  • Orbital carcinomas treated with adjuvant intensity-modulated radiation therapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Tao, R., Ma, D., Takiar, V., Frank, S. J., Fuller, C. D., Gunn, G. B., Beadle, B. M., Morrison, W. H., Rosenthal, D. I., Edson, M. A., Esmaeli, B., Kupferman, M. E., Hanna, E. Y., Garden, A. S., Phan, J. 2016; 38: E580-E587

    Abstract

    The purpose of this study was to assess outcomes of patients with orbital carcinomas treated with orbital exenteration and intensity-modulated radiation therapy (IMRT).Twenty-nine patients were treated with orbital exenteration and postoperative IMRT between 2002 through 2011; their medical records were retrospectively reviewed.Adenoid cystic carcinoma represented the most common histology (41%) followed by squamous cell carcinoma (21%). Perineural invasion (PNI) was identified in 22 patients (76%). The median radiation dose was 60 Gy (range, 60-70). Seven patients (24%) received neck radiation. The median follow-up was 43 months (range, 5-102 months). Five-year local control, overall survival (OS), and disease-free survival rates were 83%, 60%, and 55%, respectively. PNI (p = .01) and especially involvement of a named nerve (p = .001) significantly correlated with worse OS.Favorable disease control rates for orbital carcinomas are achievable with IMRT after orbital exenteration even for patients with advanced disease. Toxicity for the contralateral eye was minimal. © 2015 Wiley Periodicals, Inc. Head Neck 38: E580-E587, 2016.

    View details for DOI 10.1002/hed.24044

    View details for Web of Science ID 000375116400064

    View details for PubMedID 25782700

  • Prognostic value of p16 expression in Epstein-Barr virus-positive nasopharyngeal carcinomas HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Jiang, W., Chamberlain, P. D., Garden, A. S., Kim, B. Y., Ma, D., Lo, E. J., Bell, D., Gunn, G. B., Fuller, C. D., Rosenthal, D. I., Beadle, B. M., Frank, S. J., Morrison, W. H., El-Naggar, A. K., Glisson, B. S., Sturgis, E. M., Phan, J. 2016; 38: E1459-E1466

    Abstract

    Overexpression of p16 is associated with improved outcomes among patients with oropharyngeal carcinoma. However, its role in the outcomes of patients with nasopharyngeal cancer (NPC) remains unclear.Eighty-six patients with NPC treated at MD Anderson Cancer Center from 2000 to 2014 were identified. Epstein-Barr virus (EBV) and human papillomavirus (HPV) status were determined by in situ hybridization (ISH) and p16 by immunohistochemical staining.EBV positivity was associated with extended overall survival (OS; median, 95.0 vs 44.9 months; p < .004), progression-free survival (PFS; median, 80.4 vs 28.1 months; p < .013), and locoregional control (median, 104.4 vs 65.5 months; p < .043). In patients with EBV-positive tumors, p16 overexpression correlated with improved PFS (median, 106.3 vs 27.1 months; p < .02) and locoregional control (median, 93.6 vs 64.5 months; p < .02).P16 overexpression is associated with improved PFS and locoregional control in patients with EBV-positive NPC. P16 expression may complement EBV status in predicting treatment outcomes for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1459-E1466, 2016.

    View details for DOI 10.1002/hed.24258

    View details for Web of Science ID 000375116400187

    View details for PubMedID 26560893

  • Merkel cell carcinoma of the head and neck: Favorable outcomes with radiotherapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Bishop, A. J., Garden, A. S., Gunn, G. B., Rosenthal, D. I., Beadle, B. M., Fuller, C. D., Levy, L. B., Gillenwater, A. M., Kies, M. S., Esmaeli, B., Frank, S. J., Phan, J., Morrison, W. H. 2016; 38: E452-E458

    Abstract

    The purpose of this study was to report the outcomes of patients with Merkel cell carcinoma (MCC) of the head and neck using a radiation-based treatment approach.We reviewed records of 106 consecutive patients with MCC of the head and neck treated with radiation therapy (RT) at our institution between 1988 and 2011. The Kaplan-Meier method was used to estimate outcomes and hazard ratios (HRs) were calculated.The 5-year actuarial local and regional control rates were 96% and 96%, respectively. There were no regional recurrences in 22 patients treated with RT to gross nodal disease without neck dissection. The 5-year cause-specific survival rate was 76%. Lymphadenopathy at presentation impacted distant metastatic-free survival outcomes (p < .001). Treatment was well tolerated with only 5 patients having grade ≥3 toxicities.For MCC of the head and neck, a management strategy that includes RT offers excellent locoregional control. Gross nodal disease can be successfully treated with RT. © 2015 Wiley Periodicals, Inc. Head Neck 38: E452-E458, 2016.

    View details for DOI 10.1002/hed.24017

    View details for Web of Science ID 000375116400047

    View details for PubMedID 25645649

  • Disease control and toxicity outcomes for T4 carcinoma of the nasopharynx treated with intensity-modulated radiotherapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Takiar, V., Ma, D., Garden, A. S., Li, J., Rosenthal, D. I., Beadle, B. M., Frank, S. J., Fuller, C. D., Gunn, G. B., Morrison, W. H., Hutcheson, K., El-Naggar, A. K., Gold, K. A., Kupferman, M. E., Phan, J. 2016; 38: E925-E933

    Abstract

    Treatment of T4 nasopharyngeal carcinoma (NPC) is challenging because of the proximity of the tumor to the central nervous system. The purpose of this study was to present our evaluation of disease control and toxicity outcomes for patients with T4 NPC treated with intensity-modulated radiation therapy (IMRT) and chemotherapy.The medical records of 66 patients with T4 NPC treated from 2002 to 2012 with IMRT were reviewed. Endpoints included tumor control and toxicity outcomes (Common Terminology Criteria for Adverse Events [CTCAE v4.0]).Median follow-up was 38 months. Five-year rates of locoregional control, distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS) were 80%, 62%, 57%, and 69%, respectively. Nodal involvement was associated with worse PFS (p = .015). Gross target volume (GTV) volume >100 cm and planning target volume (PTV) volume >400 cm were associated with worse OS (p = .038 and p = .004, respectively). Four patients had significant cognitive impairment, and 9 had MRI evidence of brain necrosis.For patients with T4 NPC treated with IMRT and chemotherapy, survival and locoregional disease control rates have improved; however, late treatment toxicity remains a concern. © 2015 Wiley Periodicals, Inc. Head Neck 38: E925-E933, 2016.

    View details for DOI 10.1002/hed.24128

    View details for Web of Science ID 000375116400113

    View details for PubMedID 25994561

  • Beyond mean pharyngeal constrictor dose for beam path toxicity in non-target swallowing muscles: Dose-volume correlates of chronic radiation-associated dysphagia (RAD) after oropharyngeal intensity modulated radiotherapy RADIOTHERAPY AND ONCOLOGY Dale, T., Hutcheson, K., Mohamed, A. S., Lewin, J. S., Gunn, G. B., Rao, A. U., Kalpathy-Cramer, J., Frank, S. J., Garden, A. S., Messer, J. A., Warren, B., Lai, S. Y., Beadle, B. M., Morrison, W. H., Phan, J., Skinner, H., Gross, N., Ferrarotto, R., Weber, R. S., Rosenthal, D. I., Fuller, C. D. 2016; 118 (2): 304-314
  • Favorable patient reported outcomes following IMRT for early carcinomas of the tonsillar fossa: Results from a symptom assessment study RADIOTHERAPY AND ONCOLOGY Gunn, G. B., Hansen, C. C., Garden, A. S., Fuller, C. D., Mohamed, A. S., Morrison, W. H., Frank, S. J., Beadle, B. M., Phan, J., Chronowski, G. M., Sturgis, E. M., Lewis, C. M., Lu, C., Hutcheson, K. A., Mendoza, T. R., Cleeland, C. S., Rosenthal, D. I. 2015; 117 (1): 132-138

    Abstract

    A questionnaire-based study was conducted to assess long-term patient reported outcomes (PROs) following definitive IMRT-based treatment for early stage carcinomas of the tonsillar fossa.Participants had received IMRT with or without systemic therapy for squamous carcinoma of the tonsillar fossa (T1-2 and N0-2b) with a minimum follow-up of 2years. Patients completed a validated head and neck cancer-specific PRO instrument, the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). Symptoms were compared between treatment groups of interest and overall symptom burden was evaluated.Of 139 participants analyzed, 51% had received ipsilateral neck IMRT, and 62% single modality IMRT alone (no systemic therapy). There were no differences in mean severity ratings for the top-ranked individual symptoms or symptom interference for those treated with bilateral versus ipsilateral neck IMRT alone. However, 40% of those treated with bilateral versus 25% of those treated with ipsilateral neck RT alone reported moderate-to-severe levels of dry mouth (p=0.03). Fatigue, numbness/tingling, and constipation were rated more severe for those who had received systemic therapy (p<0.05 for each), but absolute differences were small. Overall, 51% had no more than mild symptom ratings across all 22 symptoms assessed.The long-term patient reported symptom profile in this cohort of tonsil cancer survivors treated with definitive IMRT-based treatment showed a majority of patients with no more than mild symptoms, low symptom interference, and provides an opportunity for future comparison studies with other treatment approaches.

    View details for DOI 10.1016/j.radonc.2015.09.007

    View details for Web of Science ID 000364247700021

    View details for PubMedID 26403258

  • A multimodality segmentation framework for automatic target delineation in head and neck radiotherapy MEDICAL PHYSICS Yang, J., Beadle, B. M., Garden, A. S., Schwartz, D. L., Aristophanous, M. 2015; 42 (9): 5310-5320

    Abstract

    To develop an automatic segmentation algorithm integrating imaging information from computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) to delineate target volume in head and neck cancer radiotherapy.Eleven patients with unresectable disease at the tonsil or base of tongue who underwent MRI, CT, and PET/CT within two months before the start of radiotherapy or chemoradiotherapy were recruited for the study. For each patient, PET/CT and T1-weighted contrast MRI scans were first registered to the planning CT using deformable and rigid registration, respectively, to resample the PET and magnetic resonance (MR) images to the planning CT space. A binary mask was manually defined to identify the tumor area. The resampled PET and MR images, the planning CT image, and the binary mask were fed into the automatic segmentation algorithm for target delineation. The algorithm was based on a multichannel Gaussian mixture model and solved using an expectation-maximization algorithm with Markov random fields. To evaluate the algorithm, we compared the multichannel autosegmentation with an autosegmentation method using only PET images. The physician-defined gross tumor volume (GTV) was used as the "ground truth" for quantitative evaluation.The median multichannel segmented GTV of the primary tumor was 15.7 cm(3) (range, 6.6-44.3 cm(3)), while the PET segmented GTV was 10.2 cm(3) (range, 2.8-45.1 cm(3)). The median physician-defined GTV was 22.1 cm(3) (range, 4.2-38.4 cm(3)). The median difference between the multichannel segmented and physician-defined GTVs was -10.7%, not showing a statistically significant difference (p-value = 0.43). However, the median difference between the PET segmented and physician-defined GTVs was -19.2%, showing a statistically significant difference (p-value =0.0037). The median Dice similarity coefficient between the multichannel segmented and physician-defined GTVs was 0.75 (range, 0.55-0.84), and the median sensitivity and positive predictive value between them were 0.76 and 0.81, respectively.The authors developed an automated multimodality segmentation algorithm for tumor volume delineation and validated this algorithm for head and neck cancer radiotherapy. The multichannel segmented GTV agreed well with the physician-defined GTV. The authors expect that their algorithm will improve the accuracy and consistency in target definition for radiotherapy.

    View details for DOI 10.1118/1.4928485

    View details for Web of Science ID 000360645000031

    View details for PubMedID 26328980

  • A choice of radionuclide: Comparative outcomes and toxicity of ruthenium-106 and iodine-125 in the definitive treatment of uveal melanoma. Practical radiation oncology Takiar, V., Voong, K. R., Gombos, D. S., Mourtada, F., Rechner, L. A., Lawyer, A. A., Morrison, W. H., Garden, A. S., Beadle, B. M. 2015; 5 (3): e169-76

    Abstract

    Both iodine-125 ((125)I) Collaborative Ocular Melanoma Study and ruthenium-106 ((106)Ru) eye plaques can achieve excellent tumor control in patients diagnosed with uveal melanoma. We analyzed our single institutional experience in the management of ocular melanoma treated with either (125)I or (106)Ru plaque brachytherapy.The records of 107 patients with uveal melanoma treated with either (106)Ru (n = 40) or (125)I (n = 67) plaque brachytherapy between 2000 and 2008 were retrospectively reviewed. Tumor control parameters and toxicity were assessed.Actuarial 5-year rates of local control, progression-free survival, and overall survival with (106)Ru were 97%, 94%, and 92%, respectively. For (125)I, these values were 83%, 65%, and 80%. In the subset of patients with tumor apex height ≤5 mm (36 (125)I and 40 (106)Ru), there was no difference in overall survival; however, progression-free survival was significantly improved with (106)Ru (P = .02). Enucleation-free survival was significantly different between the 2 subsets, with no enucleations in the (106)Ru cohort (P = .02). Patients treated with (106)Ru experienced reduced retinopathy (P = .03) and cataracts (P < .01).Both (125)I and (106)Ru eye plaque brachytherapy treatment result in encouraging tumor control for patients with uveal melanoma. We demonstrate that (106)Ru offers these benefits with reduced toxicity in patients treated for uveal melanomas ≤5 mm in apical height.

    View details for DOI 10.1016/j.prro.2014.09.005

    View details for PubMedID 25423888

  • Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer CANCER RESEARCH Neskey, D. M., Osman, A. A., Ow, T. J., Katsonis, P., McDonald, T., Hicks, S. C., Hsu, T., Pickering, C. R., Ward, A., Patel, A., Yordy, J. S., Skinner, H. D., Giri, U., Sano, D., Story, M. D., Beadlel, B. M., El-Naggar, A. K., Kies, M. S., William, W. N., Caulin, C., Frederick, M., Kimmel, M., Myers, J. N., Lichtarge, O. 2015; 75 (7): 1527-1536

    Abstract

    TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations.

    View details for DOI 10.1158/0008-5472.CAN-14-2735

    View details for Web of Science ID 000351948900037

    View details for PubMedID 25634208

  • Characteristics and kinetics of cervical lymph node regression after radiation therapy for human papillomavirus-associated oropharyngeal carcinoma: Quantitative image analysis of post-radiotherapy response ORAL ONCOLOGY Tang, C., Fuller, C. D., Garden, A. S., Awan, M. J., Colen, R. R., Morrison, W. H., Frank, S. J., Beadle, B. M., Phan, J., Sturgis, E. M., Zafereo, M. E., Weber, R. S., Rosenthal, D. I., Gunn, G. B. 2015; 51 (2): 195-201

    Abstract

    We sought to characterize the pattern of lymph node regression and morphology following definitive radiation therapy (RT) for human papilloma virus (HPV)-associated oropharyngeal carcinoma in patients with disease control.Radiographically positive cervical lymph nodes from patients treated with definitive RT for HPV-associated oropharyngeal carcinoma were segmented on initial pre- and subsequent post-RT contrast enhanced CT images. Pre-specified quantitative nodal parameters were calculated. Initial nodal parameter correlates of final nodal size, final nodal volume, and time to <1 cm short-axis diameter were determined.Sixty-six radiographically positive lymph node were analyzed in 36 patients. Lymph nodes exhibited initial volume decreases with size stabilization at ∼4 months. Fifteen nodes (23%) underwent complete radiographic response (median 6.4 months following RT; range 2.9-25.6 months). On multivariate time-to-event analysis, initial hypodense/fat component, nodal volume, and short-axis diameter exhibited inverse association, while higher HU standard deviation exhibited a positive association, with reaching <1 cm short-axis diameter (all p<0.05).Our results showed a substantial decrease in nodal volume within the first 1-2 months following RT. These findings support our current nodal imaging paradigm, propose a quantitative methodology, and describe a reference dataset for further validation and comparison studies.

    View details for DOI 10.1016/j.oraloncology.2014.11.001

    View details for Web of Science ID 000347901800019

    View details for PubMedID 25444304

  • Sleep-Related Breathing Disorders in Patients With Tumors in the Head and Neck Region ONCOLOGIST Faiz, S. A., Balachandran, A., Hessel, A. C., Lei, X., Beadle, B. M., William, D. N., Bashoura, L. 2014; 19 (11): 1200-1206

    Abstract

    Sleep disturbance is a prominent complaint of cancer patients. Most studies have focused on insomnia and cancer-related fatigue. Obstructive sleep apnea (OSA) has been reported in small studies and case reports.In a retrospective review of patients who underwent formal sleep evaluation and polysomnography (PSG) from 2006 to 2011, 56 patients with tumors in the head and neck region were identified. Clinical characteristics, sleep-related history, and PSG data were reviewed.Most patients had active cancer (80%), and the majority had squamous pathology (68%). Prominent symptoms included daytime fatigue (93%), daytime sleepiness (89%), and snoring (82%). Comorbid conditions primarily included hypertension (46%) and hypothyroidism (34%). Significant sleep-related breathing disorder was noted in 93% of patients, and 84% met clinical criteria for OSA. A male predominance (77%) was noted, and patients were not obese (body mass index <30 kg/m(2) in 52%). The majority of patients (79%) underwent radiation prior to sleep study, of which 88% had OSA, and in the group without prior radiation, 67% had OSA. Adherence to positive airway pressure (PAP) therapy was slightly better when compared with the general population. A subset of patients with persistent hypoxia despite advanced forms of PAP required tracheostomy. Multivariate analysis revealed that patients with active disease and radiation prior to PSG were more likely to have OSA.Sleep-related breathing disorder was common in patients with tumors in the head and neck region referred for evaluation of sleep disruption, and most met clinical criteria for OSA. Daytime fatigue and sleepiness were the most common complaints. OSA was prevalent in male patients, and most with OSA were not obese. Architectural distortion from the malignancy and/or treatment may predispose these patients to OSA by altering anatomic and neural factors. A heightened clinical suspicion for sleep-related breathing disorder and referral to a sleep specialist would be beneficial for patients with these complaints.

    View details for DOI 10.1634/theoncologist.2014-0176

    View details for Web of Science ID 000346601600017

    View details for PubMedID 25273079

  • Nomogram for Predicting Symptom Severity during Radiation Therapy for Head and Neck Cancer OTOLARYNGOLOGY-HEAD AND NECK SURGERY Sheu, T., Fuller, C. D., Mendoza, T. R., Garden, A. S., Morrison, W. H., Beadle, B. M., Phan, J., Frank, S. J., Hanna, E. Y., Lu, C., Cleeland, C. S., Rosenthal, D. I., Gunn, G. B. 2014; 151 (4): 619-626

    Abstract

    Radiation therapy (RT), with or without chemotherapy, can cause significant acute toxicity among patients treated for head and neck cancer (HNC), but predicting, before treatment, who will experience a particular toxicity or symptom is difficult. We created and evaluated 2 multivariate models and generated a nomogram to predict symptom severity during RT based on a patient-reported outcome (PRO) instrument, the MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN).This was a prospective, longitudinal, questionnaire-based study.Tertiary cancer care center.Subjects were 264 patients with HNC (mostly oropharyngeal) who had completed the MDASI-HN before and during therapy. Pretreatment variables were correlated with MDASI-HN symptom scores during therapy with multivariate modeling and then were correlated with the composite MDASI-HN score during week 5 of therapy.A multivariate model incorporating pretreatment PROs better predicted MDASI-HN symptom scores during treatment than did a model based on clinical variables and physician-rated patient performance status alone (Akaike information criterion = 1442.5 vs 1459.9). In the most parsimonious model, pretreatment MDASI-HN symptom severity (P < .001), concurrent chemotherapy (P = .006), primary tumor site (P = .016), and receipt of definitive (rather than adjuvant) RT (P = .044) correlated with MDASI-HN symptom scores during week 5. That model was used to construct a nomogram.Our model demonstrates the value of incorporating baseline PROs, in addition to disease and treatment characteristics, to predict patient symptom burden during therapy. Although additional investigation and validation are required, PRO-inclusive prediction tools can be useful for improving symptom interventions and expectations for patients being treated for HNC.

    View details for DOI 10.1177/0194599814545746

    View details for Web of Science ID 000342982900015

    View details for PubMedID 25104816

  • Management of the Lymph Node-Positive Neck in the Patient With Human Papillomavirus-Associated Oropharyngeal Cancer CANCER Garden, A. S., Gunn, G. B., Hessel, A., Beadle, B. M., Ahmed, S., El-Naggar, A. K., Fuller, C. D., Byers, L. A., Phan, J., Frank, S. J., Morrison, W. H., Kies, M. S., Rosenthal, D. I., Sturgis, E. M. 2014; 120 (19): 3082-3088

    Abstract

    The goal of the current study was to assess the rates of recurrence in the neck for patients with lymph node-positive human papillomavirus-associated cancer of the oropharynx who were treated with definitive radiotherapy (with or without chemotherapy).This is a single-institution retrospective study. Methodology included database search, and statistical testing including frequency analysis, Kaplan-Meier tests, and comparative tests including chi-square, logistic regression, and log-rank.The cohort consisted of 401 patients with lymph node-positive disease who underwent radiotherapy between January 2006 and June 2012. A total of 388 patients had computed tomography restaging, and 251 had positron emission tomography and/or ultrasound as a component of their postradiation staging. Eighty patients (20%) underwent neck dissection, and 21 patients (26%) had a positive specimen. The rate of neck dissection increased with increasing lymph node stage, and was lower in patients who had positron emission tomography scans or ultrasound in addition to computed tomography restaging. The median follow-up was 30 months. The 2-year actuarial neck recurrence rate was 7% and 5%, respectively, in all patients and those with local control. Lymph node recurrence rates were greater in current smokers (P = .008). There was no difference in lymph node recurrence rates noted between patients who did and those who did not undergo a neck dissection (P = .4) CONCLUSIONS: A treatment strategy of (chemo)radiation with neck dissection performed based on response resulted in high rates of regional disease control in patients with human papillomavirus-associated oropharyngeal cancer.

    View details for DOI 10.1002/cncr.28831

    View details for Web of Science ID 000342630000022

    View details for PubMedID 24898672

  • Forecasting longitudinal changes in oropharyngeal tumor morphology throughout the course of head and neck radiation therapy. Medical physics Yock, A. D., Rao, A., Dong, L., Beadle, B. M., Garden, A. S., Kudchadker, R. J., Court, L. E. 2014; 41 (8): 081708-?

    Abstract

    To create models that forecast longitudinal trends in changing tumor morphology and to evaluate and compare their predictive potential throughout the course of radiation therapy.Two morphology feature vectors were used to describe 35 gross tumor volumes (GTVs) throughout the course of intensity-modulated radiation therapy for oropharyngeal tumors. The feature vectors comprised the coordinates of the GTV centroids and a description of GTV shape using either interlandmark distances or a spherical harmonic decomposition of these distances. The change in the morphology feature vector observed at 33 time points throughout the course of treatment was described using static, linear, and mean models. Models were adjusted at 0, 1, 2, 3, or 5 different time points (adjustment points) to improve prediction accuracy. The potential of these models to forecast GTV morphology was evaluated using leave-one-out cross-validation, and the accuracy of the models was compared using Wilcoxon signed-rank tests.Adding a single adjustment point to the static model without any adjustment points decreased the median error in forecasting the position of GTV surface landmarks by the largest amount (1.2 mm). Additional adjustment points further decreased the forecast error by about 0.4 mm each. Selection of the linear model decreased the forecast error for both the distance-based and spherical harmonic morphology descriptors (0.2 mm), while the mean model decreased the forecast error for the distance-based descriptor only (0.2 mm). The magnitude and statistical significance of these improvements decreased with each additional adjustment point, and the effect from model selection was not as large as that from adding the initial points.The authors present models that anticipate longitudinal changes in tumor morphology using various models and model adjustment schemes. The accuracy of these models depended on their form, and the utility of these models includes the characterization of patient-specific response with implications for treatment management and research study design.

    View details for DOI 10.1118/1.4887815

    View details for PubMedID 25086518

  • Forecasting longitudinal changes in oropharyngeal tumor morphology throughout the course of head and neck radiation therapy MEDICAL PHYSICS Yock, A. D., Rao, A., Dong, L., Beadle, B. M., Garden, A. S., Kudchadker, R. J., Court, L. E. 2014; 41 (8): 119-129

    View details for DOI 10.1118/1.4887815

    View details for Web of Science ID 000341068100010

  • Disease control and toxicity outcomes using ruthenium eye plaque brachytherapy in the treatment of uveal melanoma. Practical radiation oncology Takiar, V., Gombos, D. S., Mourtada, F., Rechner, L. A., Lawyer, A. A., Morrison, W. H., Garden, A. S., Beadle, B. M. 2014; 4 (4): e189-94

    Abstract

    Ruthenium-106 ((106)Ru) eye plaques have the potential to achieve excellent tumor control with acceptable radiation toxicity. We evaluated our experience in the management of uveal melanoma treated with (106)Ru brachytherapy.The records of 40 patients with uveal melanoma treated with brachytherapy using (106)Ru plaques from 2003 to 2007 at University of Texas MD Anderson Cancer Center were reviewed. Endpoints assessed included tumor control and toxicity.Median ophthalmologic follow-up was 67 months. Actuarial 5-year rates of local control (LC), progression-free survival (PFS), and overall survival (OS) were 97%, 94%, and 92%. There were 3 deaths, 2 related to melanoma. Fifteen patients experienced clinically significant visual loss; no patients were diagnosed with neovascular glaucoma, and 1 patient developed a clinically significant radiation-associated cataract. No patient required enucleation.We report the largest published US cohort of patients treated with (106)Ru plaque brachytherapy for uveal melanoma. Tumor control was excellent, and toxicity was acceptably low. These data support the reintroduction of (106)Ru into clinical practice for ocular melanoma.

    View details for DOI 10.1016/j.prro.2013.08.004

    View details for PubMedID 25012839

  • Clinical characteristics of patients with multiple potentially human papillomavirus-related malignancies HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Skinner, H. D., Sturgis, E. M., Klopp, A. H., Ang, K., Rosenthal, D. I., Garden, A. S., Morrison, W. H., Gunn, G. B., Beadle, B. M. 2014; 36 (6): 819-825

    Abstract

    Human papillomavirus (HPV) is a causative factor in squamous cell carcinomas of the anus, penis, vagina, vulva, and head and neck, and adenocarcinoma of the cervix. We examined the demographics, clinical characteristics, and timing of multiple potentially HPV-related cancers in individual patients.One hundred forty-three patients were identified with 300 potentially HPV-related cancers. The median follow-up from index and second cancer was 18.5 years and 3.2 years, respectively.Median age at index and second cancer was 45 and 60.5 years of age, respectively, with a median interval of 11 years. Cervical cancer was the most common initial diagnosis (61.7%), whereas head and neck squamous cell carcinoma (HNSCC) was the most common second cancer (57.6%).These data suggest differential patterns for development of multiple HPV-related cancers based upon clinical characteristics. Prospective longitudinal and population-based studies are warranted to understand the impact of these findings and opportunities for intervention and screening.

    View details for DOI 10.1002/hed.23379

    View details for Web of Science ID 000336493200012

    View details for PubMedID 23720126

  • Predicting oropharyngeal tumor volume throughout the course of radiation therapy from pretreatment computed tomography data using general linear models MEDICAL PHYSICS Yock, A. D., Rao, A., Dong, L., Beadle, B. M., Garden, A. S., Kudchadker, R. J., Court, L. E. 2014; 41 (5)

    Abstract

    The purpose of this work was to develop and evaluate the accuracy of several predictive models of variation in tumor volume throughout the course of radiation therapy.Nineteen patients with oropharyngeal cancers were imaged daily with CT-on-rails for image-guided alignment per an institutional protocol. The daily volumes of 35 tumors in these 19 patients were determined and used to generate (1) a linear model in which tumor volume changed at a constant rate, (2) a general linear model that utilized the power fit relationship between the daily and initial tumor volumes, and (3) a functional general linear model that identified and exploited the primary modes of variation between time series describing the changing tumor volumes. Primary and nodal tumor volumes were examined separately. The accuracy of these models in predicting daily tumor volumes were compared with those of static and linear reference models using leave-one-out cross-validation.In predicting the daily volume of primary tumors, the general linear model and the functional general linear model were more accurate than the static reference model by 9.9% (range: -11.6%-23.8%) and 14.6% (range: -7.3%-27.5%), respectively, and were more accurate than the linear reference model by 14.2% (range: -6.8%-40.3%) and 13.1% (range: -1.5%-52.5%), respectively. In predicting the daily volume of nodal tumors, only the 14.4% (range: -11.1%-20.5%) improvement in accuracy of the functional general linear model compared to the static reference model was statistically significant.A general linear model and a functional general linear model trained on data from a small population of patients can predict the primary tumor volume throughout the course of radiation therapy with greater accuracy than standard reference models. These more accurate models may increase the prognostic value of information about the tumor garnered from pretreatment computed tomography images and facilitate improved treatment management.

    View details for DOI 10.1118/1.4870437

    View details for Web of Science ID 000336053100008

    View details for PubMedID 24784371

  • Beam path toxicity in candidate organs-at-risk: Assessment of radiation emetogenesis for patients receiving head and neck intensity modulated radiotherapy RADIOTHERAPY AND ONCOLOGY Kocak-Uzel, E., Gunn, G. B., Colen, R. R., Kantor, M. E., Mohamed, A. S., Schoultz-Henley, S., Mavroidis, P., Frank, S. J., Garden, A. S., Beadle, B. M., Morrison, W. H., Phan, J., Rosenthal, D. I., Fuller, C. D. 2014; 111 (2): 281-288

    Abstract

    To investigate potential dose-response relationship between radiation-associated nausea and vomiting (RANV) reported during radiotherapy and candidate nausea/vomiting-associated regions of interest (CNV-ROIs) in head and neck (HNC) squamous cell carcinomas.A total of 130 patients treated with IMRT with squamous cell carcinomas of head and neck were evaluated. For each patient, CNV-ROIs were segmented manually on planning CT images. Clinical on-treatment RANV data were reconstructed by a review of the records for all patients. Dosimetric data parameters were recorded from dose-volume histograms. Nausea and vomiting reports were concatenated as a single binary "Any N/V" variable, and as a "CTC-V2+" variable.The mean dose to CNV-ROIs was higher for patients experiencing RANV events. For patients receiving IMRT alone, a dose-response effect was observed with varying degrees of magnitude, at a statistically significant level for the area postrema, brainstem, dorsal vagal complex, medulla oblongata, solitary nucleus, oropharyngeal mucosa and whole brain CNV-ROIs.RANV is a common therapy-related morbidity facing patients receiving HNC radiotherapy, and, for those receiving radiotherapy-alone, is associated with modifiable dose to specific CNS structures.

    View details for DOI 10.1016/j.radonc.2014.02.019

    View details for Web of Science ID 000339150100019

    View details for PubMedID 24746582

  • Improved Survival Using Intensity-Modulated Radiation Therapy in Head and Neck Cancers CANCER Beadle, B. M., Liao, K., Elting, L. S., Buchholz, T. A., Ang, K. K., Garden, A. S., Guadagnolo, B. A. 2014; 120 (5): 702-710
  • Auto-segmentation of low-risk clinical target volume for head and neck radiation therapy. Practical radiation oncology Yang, J., Beadle, B. M., Garden, A. S., Gunn, B., Rosenthal, D., Ang, K., Frank, S., Williamson, R., Balter, P., Court, L., Dong, L. 2014; 4 (1): e31-7

    Abstract

    To investigate atlas-based auto-segmentation methods to improve the quality of the delineation of low-risk clinical target volumes (CTVs) of unilateral tonsil cancers.Sixteen patients received intensity modulated radiation therapy for left tonsil tumors. These patients were treated by a total of 8 oncologists, who delineated all contours manually on the planning CT image. We chose 6 of the patients as atlas cases and used atlas-based auto-segmentation to map each the atlas CTV to the other 10 patients (test patients). For each test patient, the final contour was produced by combining the 6 individual segmentations from the atlases using the simultaneous truth and performance level estimation algorithm. In addition, for each test patient, we identified a single atlas that produced deformed contours best matching the physician's manual contours. The auto-segmented contours were compared with the physician's manual contours using the slice-wise Hausdorff distance (HD), the slice-wise Dice similarity coefficient (DSC), and a total volume overlap index.No single atlas consistently produced good results for all 10 test cases. The multiatlas segmentation achieved a good agreement between auto-segmented contours and manual contours, with a median slice-wise HD of 7.4 ± 1.0 mm, median slice-wise DSC of 80.2% ± 5.9%, and total volume overlap of 77.8% ± 3.3% over the 10 test cases. For radiation oncologists who contoured both the test case and one of the atlas cases, the best atlas for a test case had almost always been contoured by the oncologist who had contoured that test case, indicating that individual physician's practice dominated in target delineation and was an important factor in optimal atlas selection.Multiatlas segmentation may improve the quality of CTV delineation in clinical practice for unilateral tonsil cancers. We also showed that individual physician's practice was an important factor in selecting the optimal atlas for atlas-based auto-segmentation.

    View details for DOI 10.1016/j.prro.2013.03.003

    View details for PubMedID 24621429

  • Anisotropic Margin Expansions in 6 Anatomic Directions for Oropharyngeal Image Guided Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Yock, A. D., Garden, A. S., Court, L. E., Beadle, B. M., Zhang, L., Dong, L. 2013; 87 (3): 596-601

    Abstract

    The purpose of this work was to determine the expansions in 6 anatomic directions that produced optimal margins considering nonrigid setup errors and tissue deformation for patients receiving image-guided radiation therapy (IGRT) of the oropharynx.For 20 patients who had received IGRT to the head and neck, we deformably registered each patient's daily images acquired with a computed tomography (CT)-on-rails system to his or her planning CT. By use of the resulting vector fields, the positions of volume elements within the clinical target volume (CTV) (target voxels) or within a 1-cm shell surrounding the CTV (normal tissue voxels) on the planning CT were identified on each daily CT. We generated a total of 15,625 margins by dilating the CTV by 1, 2, 3, 4, or 5 mm in the posterior, anterior, lateral, medial, inferior, and superior directions. The optimal margins were those that minimized the relative volume of normal tissue voxels positioned within the margin while satisfying 1 of 4 geometric target coverage criteria and 1 of 3 population criteria.Each pair of geometric target coverage and population criteria resulted in a unique, anisotropic, optimal margin. The optimal margin expansions ranged in magnitude from 1 to 5 mm depending on the anatomic direction of the expansion and on the geometric target coverage and population criteria. Typically, the expansions were largest in the medial direction, were smallest in the lateral direction, and increased with the demand of the criteria. The anisotropic margin resulting from the optimal set of expansions always included less normal tissue than did any isotropic margin that satisfied the same pair of criteria.We demonstrated the potential of anisotropic margins to reduce normal tissue exposure without compromising target coverage in IGRT to the head and neck.

    View details for DOI 10.1016/j.ijrobp.2013.06.2036

    View details for Web of Science ID 000325165300034

    View details for PubMedID 23906931

  • Eat and Exercise During Radiotherapy or Chemoradiotherapy for Pharyngeal Cancers Use It or Lose It JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Hutcheson, K. A., Bhayani, M. K., Beadle, B. M., Gold, K. A., Shinn, E. H., Lai, S. Y., Lewin, J. 2013; 139 (11): 1127-1134

    Abstract

    Data support proactive swallowing therapy during radiotherapy (RT) or chemoradiotherapy (CRT) for pharyngeal cancers. The benefits of adherence to a regimen of swallowing exercises and maintaining oral intake throughout treatment are reported, but independent effects are unclear.To evaluate the independent effects of maintaining oral intake throughout radiotherapy and adherence to preventive swallowing exercise.Retrospective observational study.The University of Texas MD Anderson Cancer Center, Houston.The study included 497 patients treated with definitive RT or CRT for pharyngeal cancer (458 oropharynx, 39 hypopharynx) between 2002 and 2008.Swallowing-related end points were final diet after RT or CRT and duration of gastrostomy dependence. Primary independent variables included oral intake status at the end of RT or CRT (no oral intake, partial oral intake, or full oral intake) and adherence to a swallowing exercise regimen. Multiple linear regression and ordered logistic regression models were analyzed.At the conclusion of RT or CRT, 131 patients (26%) had no oral intake and 74% maintained oral intake (167 partial [34%], 199 full [40%]). Fifty-eight percent (286 of 497) reported adherence to swallowing exercises. Maintenance of oral intake during RT or CRT and swallowing exercise adherence were independently associated with better long-term diet after RT or CRT (P = .045 and P < .001, respectively) and shorter duration of gastrostomy dependence (P < .001 and P = .007, respectively) in models adjusted for tumor and treatment burden.The data indicate independent, positive associations of maintenance of oral intake throughout RT or CRT and swallowing exercise adherence with long-term swallowing outcomes. Patients who either eat or exercise fare better than those who do neither. Patients who both eat and exercise have the highest rate of return to a regular diet and shortest duration of gastrostomy dependence.

    View details for DOI 10.1001/jamaoto.2013.4715

    View details for Web of Science ID 000328944900006

    View details for PubMedID 24051544

  • High symptom burden prior to radiation therapy for head and neck cancer: A patient-reported outcomes study HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Gunn, G. B., Mendoza, T. R., Fuller, C. D., Gning, I., Frank, S. J., Beadle, B. M., Hanna, E. Y., Lu, C., Cleeland, C. S., Rosenthal, D. I. 2013; 35 (10): 1490-1498

    Abstract

    As a first step toward developing effective strategies to control symptoms associated with head and neck cancer (HNC) and its treatment, we sought to describe the pattern of symptoms experienced before radiation therapy.Subjects completed the MD Anderson Symptom Inventory-Head and Neck Module before beginning radiation therapy.In all, 270 patients participated. Symptom severity and interference varied between treatment-naïve patients and those with prior treatment. Cluster analyses revealed that 33% of patients had high symptom burden. Symptoms most often rated moderate-to-severe were fatigue, sleep disturbance, distress, pain, and problems chewing and swallowing. Poorer performance status, higher T classification, and receipt of previous treatment correlated with higher symptom burden.A substantial proportion of patients were experiencing high symptom burden. Because few interventions currently exist for several of the most problematic symptoms, research in symptom reduction that targets the pattern of symptoms described here is greatly needed.

    View details for DOI 10.1002/hed.23181

    View details for Web of Science ID 000325091000030

    View details for PubMedID 23169304

  • Residual nodal disease in patients with advanced-stage oropharyngeal squamous cell carcinoma treated with definitive radiation therapy and posttreatment neck dissection: Association with locoregional recurrence, distant metastasis, and decreased survival HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Sandulache, V. C., Ow, T. J., Daram, S. P., Hamilton, J., Skinner, H., Bell, D., Rosenthal, D. I., Beadle, B. M., Ang, K. K., Kies, M. S., Johnson, F. M., El-Naggar, A. K., Myers, J. N. 2013; 35 (10): 1454-1460

    Abstract

    Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in frequency. We reviewed patients with advanced-stage OPSCC treated with chemoradiation to assess the impact of residual neck disease on survival.We reviewed 202 patients with OPSCC between 1990 and 2010 treated with primary chemoradiation followed by neck dissection. Imaging was analyzed using RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria. Survival was evaluated using both univariate and multivariate analyses.Overall survival at 5 years was 89%. Forty-two patients (21%) had residual disease in the neck (pN+). pN+ was associated with greater locoregional recurrence (LRR) and distant metastasis (DM) and decreased survival. No clinicopathologic factors were predictive of pN+. Contrasted posttreatment CT had low sensitivity and specificity.In advanced OPSCC pN+, patients have higher rates of LRR and DM. Neither clinicopathologic factors nor posttreatment imaging was predictive of pN+, although increased use of modern imaging may reduce the rate of negative neck dissections.

    View details for DOI 10.1002/hed.23173

    View details for Web of Science ID 000325091000024

    View details for PubMedID 23018868

  • The impact of radiographic retropharyngeal adenopathy in oropharyngeal cancer CANCER Gunn, G. B., Debnam, J. M., Fuller, C. D., Morrison, W. H., Frank, S. J., Beadle, B. M., Sturgis, E. M., Glisson, B. S., Phan, J., Rosenthal, D. I., Garden, A. S. 2013; 119 (17): 3162-3169

    Abstract

    We performed this study to define the incidence of radiographic retropharyngeal lymph node (RPLN) involvement in oropharyngeal cancer (OPC) and its impact on clinical outcomes, neither of which has been well established to date.Our departmental database was queried for patients irradiated for OPC between 2001 and 2007. Analyzable patients were those with imaging data available for review to determine radiographic RPLN status. Demographic, clinical, and outcome data were retrieved and analyzed.The cohort consisted of 981 patients. The median follow-up was 69 months. The base of the tongue (47%) and the tonsil (46%) were the most common primary sites. The majority of patients had stage T1 to T2 primary tumors (64%), and 94% had stage 3 to 4B disease. Intensity-modulated radiation therapy was used in 77% of patients, and systemic therapy was administered in 58% of patients. The incidence of radiographic RPLN involvement was 10% and was highest for the pharyngeal wall (23%) and lowest for the base of the tongue (6%). RPLN adenopathy correlated with several patient and tumor factors. RPLN involvement was associated with poorer 5-year outcomes on univariate analysis (P<.001 for all) for local control (79% vs 92%), nodal control (80% vs 93%), recurrence-free survival (51% vs 81%), distant metastases-free survival (66% vs 89%), and overall survival (52% vs 82%) and maintained significance on multivariate analysis for local control (P = .023), recurrence-free survival (P = .001), distant metastases-free survival (P = .003), and overall survival (P = .001).In this cohort of nearly 1000 patients investigating [corrected] radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends [corrected] a negative influence on disease recurrence, distant relapse, and survival. In this cohort of nearly 1000 patients investigating radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends a negative influence on disease recurrence, distant relapse, and survival.

    View details for DOI 10.1002/cncr.28195

    View details for Web of Science ID 000323255600010

    View details for PubMedID 23733178

  • Prospective assessment of an atlas-based intervention combined with real-time software feedback in contouring lymph node levels and organs-at-risk in the head and neck: Quantitative assessment of conformance to expert delineation. Practical radiation oncology Awan, M., Kalpathy-Cramer, J., Gunn, G. B., Beadle, B. M., Garden, A. S., Phan, J., Holliday, E., Jones, W. E., Maani, E., Patel, A., Choi, J., Clyburn, V., Tantiwongkosi, B., Rosenthal, D. I., Fuller, C. D. 2013; 3 (3): 186-193

    Abstract

    A number of studies have previously assessed the role of teaching interventions to improve organ-at-risk (OAR) delineation. We present a preliminary study demonstrating the benefit of a combined atlas and real time software-based feedback intervention to aid in contouring of OARs in the head and neck.The study consisted of a baseline evaluation, a real-time feedback intervention, atlas presentation, and a follow-up evaluation. At baseline evaluation, 8 resident observers contoured 26 OARs on a computed tomography scan without intervention or aid. They then received feedback comparing their contours both statistically and graphically to a set of atlas-based expert contours. Additionally, they received access to an atlas to contour these structures. The resident observers were then asked to contour the same 26 OARs on a separate computed tomography scan with atlas access. In addition, 6 experts (5 radiation oncologists specializing in the head and neck, and 1 neuroradiologist) contoured the 26 OARs on both scans. A simultaneous truth and performance level estimation (STAPLE) composite of the expert contours was used as a gold-standard set for analysis of OAR contouring.Of the 8 resident observers who initially participated in the study, 7 completed both phases of the study. Dice similarity coefficients were calculated for each user-drawn structure relative to the expert STAPLE composite for each structure. Mean dice similarity coefficients across all structures increased between phase 1 and phase 2 for each resident observer, demonstrating a statistically significant improvement in overall OAR-contouring ability (P < .01). Additionally, intervention improved contouring in 16/26 delineated organs-at-risk across resident observers at a statistically significant level (P ≤ .05) including all otic structures and suprahyoid lymph node levels of the head and neck.Our data suggest that a combined atlas and real-time feedback-based educational intervention detectably improves contouring of OARs in the head and neck.

    View details for DOI 10.1016/j.prro.2012.11.002

    View details for PubMedID 24674363

  • Pilot study of a computed tomography-compatible shielded intracavitary brachytherapy applicator for treatment of cervical cancer. Practical radiation oncology Klopp, A. H., Mourtada, F., Yu, Z. H., Beadle, B. M., Munsell, M. F., Jhingran, A., Eifel, P. J. 2013; 3 (2): 115-123

    Abstract

    The traditional Fletcher-Williamson tandem and ovoid brachytherapy applicators for treatment of cervical cancer have ovoid shields that reduce the dose to the bladder and rectum. However, these shields produce artifact on computed tomography (CT) that prevents acquisition of high-quality images. To address this limitation, we designed and tested a novel CT-compatible applicator with movable shields, called MDA(3).Fifteen patients with stage IB1-IIB cervical cancer requiring definitive radiation therapy were enrolled in a prospective pilot study to evaluate image quality with the MDA(3). Image quality was assessed by comparing an initial scan obtained with the shields shifted to minimize shield artifact to a second scan obtained with the shields in treatment position. The 2 scans were then compared by a radiation oncologist blinded to the image source. In addition, image quality was assessed by analysis of Hounsfield values in the normal tissues.The MDA(3) was successfully employed for intracavitary brachytherapy in 15 patients. CT images obtained with the shields shifted were superior to CT images obtained with the shields in treatment position in every case as evaluated by the radiation oncologist (P < .0001). The presence of the shields in the treatment position significantly increased the mean Hounsfield values within the bladder (P = .002) and rectum (P = .001) due to high-density image artifact.This novel applicator provides a clinically feasible solution to overcome the limitation of lack of ovoid shields on currently available CT-compatible applicators.

    View details for DOI 10.1016/j.prro.2012.03.014

    View details for PubMedID 24674314

  • Patterns of Disease Recurrence Following Treatment of Oropharyngeal Cancer With Intensity Modulated Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Garden, A. S., Dong, L., Morrison, W. H., Stugis, E. M., Glisson, B. S., Frank, S. J., Beadle, B. M., Gunn, G. B., Schwartz, D. L., Kies, M. S., Weber, R. S., Ang, K. K., Rosenthal, D. I. 2013; 85 (4): 941-947

    Abstract

    To report mature results of a large cohort of patients diagnosed with squamous cell carcinoma of the oropharynx who were treated with intensity modulated radiation therapy (IMRT).The database of patients irradiated at The University of Texas, M.D. Anderson Cancer Center was searched for patients diagnosed with oropharyngeal cancer and treated with IMRT between 2000 and 2007. A retrospective review of outcome data was performed.The cohort consisted of 776 patients. One hundred fifty-nine patients (21%) were current smokers, 279 (36%) former smokers, and 337 (43%) never smokers. T and N categories and American Joint Committee on Cancer group stages were distributed as follows: T1/x, 288 (37%); T2, 288 (37%); T3, 113 (15%); T4, 87 (11%); N0, 88(12%); N1/x, 140 (18%); N2a, 101 (13%); N2b, 269 (35%); N2c, 122 (16%); and N3, 56 (7%); stage I, 18(2%); stage II, 40(5%); stage III, 150(19%); and stage IV, 568(74%). Seventy-one patients (10%) presented with nodes in level IV. Median follow-up was 54 months. The 5-year overall survival, locoregional control, and overall recurrence-free survival rates were 84%, 90%, and 82%, respectively. Primary site recurrence developed in 7% of patients, and neck recurrence with primary site control in 3%. We could only identify 12 patients (2%) who had locoregional recurrence outside the high-dose target volumes. Poorer survival rates were observed in current smokers, patients with larger primary (T) tumors and lower neck disease.Patients with oropharyngeal cancer treated with IMRT have excellent disease control. Locoregional recurrence was uncommon, and most often occurred in the high dose volumes. Parotid sparing was accomplished in nearly all patients without compromising tumor coverage.

    View details for DOI 10.1016/j.ijrobp.2012.08.004

    View details for Web of Science ID 000315809300025

    View details for PubMedID 22975604

  • Outcomes and patterns of care of patients with locally advanced oropharyngeal carcinoma treated in the early 21st century RADIATION ONCOLOGY Garden, A. S., Kies, M. S., Morrison, W. H., Weber, R. S., Frank, S. J., Glisson, B. S., Gunn, G. B., Beadle, B. M., Ang, K. K., Rosenthal, D. I., Sturgis, E. M. 2013; 8

    Abstract

    We performed this study to assess outcomes of patients with oropharyngeal cancer treated with modern therapy approaches.Demographics, treatments and outcomes of patients diagnosed with Stage 3- 4B squamous carcinoma of the oropharynx, between 2000-2007 were tabulated and analyzed.The cohort consisted of 1046 patients. The 5-year actuarial overall survival, recurrence-free survival and local-regional control rates for the entire cohort were 78%, 77% and 87% respectively. More advanced disease, increasing T-stage and smoking were associated with higher rates of local-regional recurrence and poorer survival.Patients with locally advanced oropharyngeal cancer have a relatively high survival rate. Patients' demographics and primary tumor volume were very influential on these favorable outcomes. In particular, patients with small primary tumors did very well even when treatment was not intensified with the addition of chemotherapy.

    View details for DOI 10.1186/1748-717X-8-21

    View details for Web of Science ID 000315408100001

    View details for PubMedID 23360540

  • Oropharynx Cancer CURRENT PROBLEMS IN CANCER Skinner, H. D., Holsinger, F. C., Beadle, B. M. 2012; 36 (6): 334-415
  • Management of Radiation-Induced Severe Anophthalmic Socket Contracture in Patients With Uveal Melanoma OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY Nasser, Q. J., Gombos, D. S., Williams, M. D., Guadagnolo, B. A., Morrison, W. H., Garden, A. S., Beadle, B. M., Canseco, E., Esmaeli, B. 2012; 28 (3): 208-212

    Abstract

    High-dose radiotherapy can cause contracture of the anophthalmic socket, but the incidence of this complication in patients with enucleation for uveal melanoma has not been reported previously. The authors reviewed the surgical management and outcomes in terms of successful prosthesis wear in patients with severe contracture of the anophthalmic socket treated with high-dose radiotherapy for high-risk uveal melanoma, and they estimated the relative risk of this complication.The medical records of all consecutive patients enrolled in a prospective uveal-melanoma tissue-banking protocol at the authors' institution who underwent enucleation between January 2003 and December 2010 were reviewed. Patients who underwent adjuvant radiotherapy of the enucleated socket were further studied.Of the 68 patients enrolled in the prospective tissue-banking protocol, 12 had high-risk histologic features (e.g., extrascleral spread or vortex vein invasion) and were treated with 60 Gy of external beam radiotherapy after enucleation. Five of these patients (41.7%) experienced severe socket contracture precluding prosthesis wear. The median time to onset of contracture following completion of radiotherapy was 20 months. Three patients underwent surgery, which entailed scar tissue release, oral mucous membrane grafting, and socket reconstruction; 2 patients declined surgery. All 3 patients who had surgery experienced significant improvement of socket contracture that enabled patients to wear a prosthesis again.High-dose radiotherapy after enucleation in patients with uveal melanoma caused severe socket contracture and inability to wear a prosthesis in approximately 40% of patients. Surgical repair of the contracted socket using oral mucous membrane grafting can allow resumption of prosthesis wear.

    View details for DOI 10.1097/IOP.0b013e31824dd9b8

    View details for Web of Science ID 000304530700024

    View details for PubMedID 22581085

  • Unilateral Radiotherapy for the Treatment of Tonsil Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chronowski, G. M., Garden, A. S., Morrison, W. H., Frank, S. J., Schwartz, D. L., Shah, S. J., Beadle, B. M., Gunn, G. B., Kupferman, M. E., Ang, K. K., Rosenthal, D. I. 2012; 83 (1): 204-209

    Abstract

    To assess, through a retrospective review, clinical outcomes of patients with squamous cell carcinoma of the tonsil treated at the M. D. Anderson Cancer Center with unilateral radiotherapy techniques that irradiate the involved tonsil region and ipsilateral neck only.Of 901 patients with newly diagnosed squamous cell carcinoma of the tonsil treated with radiotherapy at our institution, we identified 102 that were treated using unilateral radiotherapy techniques. All patients had their primary site of disease restricted to the tonsillar fossa or anterior pillar, with <1 cm involvement of the soft palate. Patients had TX (n = 17 patients), T1 (n = 52), or T2 (n = 33) disease, with Nx (n = 3), N0 (n = 33), N1 (n = 23), N2a (n = 21), or N2b (n = 22) neck disease.Sixty-one patients (60%) underwent diagnostic tonsillectomy before radiotherapy. Twenty-seven patients (26%) underwent excision of a cervical lymph node or neck dissection before radiotherapy. Median follow-up for surviving patients was 38 months. Locoregional control at the primary site and ipsilateral neck was 100%. Two patients experienced contralateral nodal recurrence (2%). The 5-year overall survival and disease-free survival rates were 95% and 96%, respectively. The 5-year freedom from contralateral nodal recurrence rate was 96%. Nine patients required feeding tubes during therapy. Of the 2 patients with contralateral recurrence, 1 experienced an isolated neck recurrence and was salvaged with contralateral neck dissection only and remains alive and free of disease. The other patient presented with a contralateral base of tongue tumor and involved cervical lymph node, which may have represented a second primary tumor, and died of disease.Unilateral radiotherapy for patients with TX-T2, N0-N2b primary tonsil carcinoma results in high rates of disease control, with low rates of contralateral nodal failure and a low incidence of acute toxicity requiring gastrostomy.

    View details for DOI 10.1016/j.ijrobp.2011.06.1975

    View details for Web of Science ID 000302993900052

    View details for PubMedID 22019242

  • TP53 Disruptive Mutations Lead to Head and Neck Cancer Treatment Failure through Inhibition of Radiation-Induced Senescence CLINICAL CANCER RESEARCH Skinner, H. D., Sandulache, V. C., Ow, T. J., Meyn, R. E., Yordy, J. S., Beadle, B. M., Fitzgerald, A. L., Giri, U., Ang, K. K., Myers, J. N. 2012; 18 (1): 290-300

    Abstract

    Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity.Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model.Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P < 0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-β-gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin.Disruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment.

    View details for DOI 10.1158/1078-0432.CCR-11-2260

    View details for Web of Science ID 000298758900031

    View details for PubMedID 22090360

  • The Impact of Age on Outcome in Early-Stage Breast Cancer SEMINARS IN RADIATION ONCOLOGY Beadle, B. M., Woodward, W. A., Buchholz, T. A. 2011; 21 (1): 26-34

    Abstract

    Multiple studies have shown that breast-conserving therapy (BCT) and mastectomy have equivalent outcomes for large populations of women with early-stage breast cancer. For individual treatment decisions, however, it is important to appreciate the heterogeneity of disease. Recent molecular studies have suggested that "breast cancer" includes biologically distinct classes of disease; although these molecular distinctions are important, other patient-related factors also affect outcome and influence prognosis. One of the most important of these patient factors is the age of the patient at diagnosis. Numerous studies have shown very different breast cancer outcomes based on patient age; younger women typically have more aggressive tumors that are more likely to recur both locoregionally and distantly, and older women more commonly have less aggressive disease. The overall disease-specific outcomes, techniques, and doses for adjuvant radiation therapy and toxicity of treatments should be discussed within the context of age because breast cancer is a very different disease based on this factor. Arguments can be made that more aggressive locoregional therapy is warranted in populations of young women with breast cancer and perhaps less aggressive therapy in the elderly.

    View details for DOI 10.1016/j.semradonc.2010.09.001

    View details for Web of Science ID 000285775600005

    View details for PubMedID 21134651

  • PATTERNS OF REGIONAL RECURRENCE AFTER DEFINITIVE RADIOTHERAPY FOR CERVICAL CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Beadle, B. M., Jhingran, A., Yom, S. S., Ramirez, P. T., Eifel, P. J. 2010; 76 (5): 1396-1403

    Abstract

    To determine the patterns of regional recurrence in patients treated with definitive radiotherapy (RT) for cervical cancer.The records of 198 patients treated with definitive RT for cervical cancer between 1980 and 2000 who experienced a regional recurrence without a central or distal vaginal recurrence were reviewed. All patients received a combination of external-beam RT and intracavitary brachytherapy. In the 180 patients with a documented location of regional recurrence, the relationship between the recurrence and the radiation fields was determined.The median time to regional recurrence was 13 months (range, 2-85 months). Of the 180 patients who had an evaluable regional recurrence, 119 (66%) had a component of marginal failure; 71 patients recurred above-the-field, 2 patients occurred in the inguinal nodes, and 2 patients recurred above-the-field and in the inguinal nodes. In addition, 105 patients (58%) had a component of in-field failure; 59 patients recurred in-field only, 39 patients recurred in-field and above-the-field, 2 patients recurred in-field, above-the-field, and in the inguinal nodes, and 5 patients recurred in-field and in the inguinal nodes. The median survival after regional recurrence was 8 months (range, 0-194 months).Most regional recurrences after definitive RT for cervical cancer include a component of marginal failure, usually immediately superior to the radiation field. These recurrences suggest a deficiency in target volume. Recurrences also occur in-field, suggesting a deficiency in dose. Developments in pretreatment staging, field delineation, dose escalation, and posttreatment surveillance may help to improve outcome in these patients.

    View details for DOI 10.1016/j.ijrobp.2009.04.009

    View details for Web of Science ID 000276675300020

    View details for PubMedID 19581056

  • RADIATION THERAPY FIELD EXTENT FOR ADJUVANT TREATMENT OF AXILLARY METASTASES FROM MALIGNANT MELANOMA INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Beadle, B. M., Guadagnolo, B. A., Ballo, M. T., Lee, J. E., Gershenwald, J. E., Cormier, J. N., Mansfield, P. F., Ross, M. I., Zagars, G. K. 2009; 73 (5): 1376-1382

    Abstract

    To compare treatment-related outcomes and toxicity for patients with axillary lymph node metastases from malignant melanoma treated with postoperative radiation therapy (RT) to either the axilla only or both the axilla and supraclavicular fossa (extended field [EF]).The medical records of 200 consecutive patients treated with postoperative RT for axillary lymph node metastases from malignant melanoma were retrospectively reviewed. All patients received postoperative hypofractionated RT for high-risk features; 95 patients (48%) received RT to the axilla only and 105 patients (52%) to the EF.At a median follow-up of 59 months, 111 patients (56%) had sustained relapse, and 99 patients (50%) had died. The 5-year overall survival, disease-free survival, and distant metastasis-free survival rates were 51%, 43%, and 46%, respectively. The 5-year axillary control rate was 88%. There was no difference in axillary control rates on the basis of the treated field (89% for axilla only vs. 86% for EF; p = 0.4). Forty-seven patients (24%) developed treatment-related complications. On both univariate and multivariate analyses, only treatment with EF irradiation was significantly associated with increased treatment-related complications.Adjuvant hypofractionated RT to the axilla only for metastatic malignant melanoma with high-risk features is an effective method to control axillary disease. Limiting the radiation field to the axilla only produced equivalent axillary control rates to EF and resulted in lower treatment-related complication rates.

    View details for DOI 10.1016/j.ijrobp.2008.06.1910

    View details for Web of Science ID 000264728000013

    View details for PubMedID 18774657

  • The Impact of Pregnancy on Breast Cancer Outcomes in Women <= 35 Years CANCER Beadle, B. M., Woodward, W. A., Middleton, L. P., Tereffe, W., Strom, E. A., Litton, J. K., Meric-Bernstam, F., Theriault, R. L., Buchholz, T. A., Perkins, G. H. 2009; 115 (6): 1174-1184

    Abstract

    Some evidence suggests that women with pregnancy-associated breast cancers (PABC) have a worse outcome compared with historical controls. However, young age is a worse prognostic factor independently, and women with PABC tend to be young. The purpose of the current study was to compare locoregional recurrence (LRR), distant metastases (DM), and overall survival (OS) in young patients with PABC and non-PABC.Data for 668 breast cancers in 652 patients aged

    View details for DOI 10.1002/cncr.24165

    View details for Web of Science ID 000264148300008

    View details for PubMedID 19204903

  • TEN-YEAR RECURRENCE RATES IN YOUNG WOMEN WITH BREAST CANCER BY LOCOREGIONAL TREATMENT APPROACH INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Beadle, B. M., Woodward, W. A., Tucker, S. L., Outlaw, E. D., Allen, P. K., Oh, J. L., Strom, E. A., Perkins, G. H., Tereffe, W., Yu, T., Meric-Bernstam, F., Litton, J. K., Buchholz, T. A. 2009; 73 (3): 734-744

    Abstract

    Young women with breast cancer have higher locoregional recurrence (LRR) rates than older patients. The goal of this study is to determine the impact of locoregional treatment strategy, breast-conserving therapy (BCT), mastectomy alone (M), or mastectomy with adjuvant radiation (MXRT), on LRR for patients 35 years or younger.Data for 668 breast cancers in 652 young patients with breast cancer were retrospectively reviewed; 197 patients were treated with BCT, 237 with M, and 234 with MXRT.Median follow-up for all living patients was 114 months. In the entire cohort, 10-year actuarial LRR rates varied by locoregional treatment: 19.8% for BCT, 24.1% for M, and 15.1% for MXRT (p = 0.05). In patients with Stage II disease, 10-year actuarial LRR rates by locoregional treatment strategy were 17.7% for BCT, 22.8% for M, and 5.7% for MXRT (p = 0.02). On multivariate analysis, M (hazard ratio, 4.45) and Grade III disease (hazard ratio, 2.24) predicted for increased LRR. In patients with Stage I disease, there was no difference in LRR rates based on locoregional treatment (18.0% for BCT, 19.8% for M; p = 0.56), but chemotherapy use had a statistically significant LRR benefit (13.5% for chemotherapy, 27.9% for none; p = 0.04).Young women have high rates of LRR after breast cancer treatment. For patients with Stage II disease, the best locoregional control rates were achieved with MXRT. For patients with Stage I disease, similar outcomes were achieved with BCT and mastectomy; however, chemotherapy provided a significant benefit to either approach.

    View details for DOI 10.1016/j.ijrobp.2008.04.078

    View details for Web of Science ID 000263440900016

    View details for PubMedID 18707822

  • CERVIX REGRESSION AND MOTION DURING THE COURSE OF EXTERNAL BEAM CHEMORADIATION FOR CERVICAL CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Beadle, B. M., Jhingran, A., Salehpour, M., Sam, M., Iyer, R. B., Eifel, P. I. 2009; 73 (1): 235-241

    Abstract

    To evaluate the magnitude of cervix regression and motion during external beam chemoradiation for cervical cancer.Sixteen patients with cervical cancer underwent computed tomography scanning before, weekly during, and after conventional chemoradiation. Cervix volumes were calculated to determine the extent of cervix regression. Changes in the center of mass and perimeter of the cervix between scans were used to determine the magnitude of cervix motion. Maximum cervix position changes were calculated for each patient, and mean maximum changes were calculated for the group.Mean cervical volumes before and after 45 Gy of external beam irradiation were 97.0 and 31.9 cc, respectively; mean volume reduction was 62.3%. Mean maximum changes in the center of mass of the cervix were 2.1, 1.6, and 0.82 cm in the superior-inferior, anterior-posterior, and right-left lateral dimensions, respectively. Mean maximum changes in the perimeter of the cervix were 2.3 and 1.3 cm in the superior and inferior, 1.7 and 1.8 cm in the anterior and posterior, and 0.76 and 0.94 cm in the right and left lateral directions, respectively.Cervix regression and internal organ motion contribute to marked interfraction variations in the intrapelvic position of the cervical target in patients receiving chemoradiation for cervical cancer. Failure to take these variations into account during the application of highly conformal external beam radiation techniques poses a theoretical risk of underdosing the target or overdosing adjacent critical structures.

    View details for DOI 10.1016/j.ijrobp.2008.03.064

    View details for Web of Science ID 000261820200036

    View details for PubMedID 18513882

  • Surgical patterns of care in operable lung carcinoma treated with radiation JOURNAL OF THORACIC ONCOLOGY Chang, J. Y., Moughan, J., Johnstone, D. W., Komaki, R., Goldberg, M., Langer, C. J., Beadle, B. M., Owen, J., Movsas, B. 2006; 1 (6): 526-531

    Abstract

    To determine the national surgical practice patterns of care for operable lung cancer patients treated with radiation.A nationwide survey of a stratified random sample of institutions was conducted for patients who had non-metastatic lung cancer, Karnofsky Performance Scores (KPS) > or =60, and who had received radiation therapy as definitive or adjuvant treatment. Among 541 patients, representing a weighted sample size of 42,335 patients nationwide, 131 (19.8%) underwent surgery as part of their therapy. Pearson chi statistics were used to analyze characteristics of this subset of patients.Of the 131 patients who underwent surgery, 126 patients who had non-small cell lung cancer (NSCLC) were analyzed. Surgical patients were younger, had less weight loss, higher KPS, and higher forced expiratory volume within 1 second (FEV1) values than those treated without surgery. Surgical patients had more stage I/II (53.5% vs 32.2%; p = 0.0004) and less clinical N2/N3 disease (28.8% vs 47.5%; p = 0.002) than nonsurgical patients. Surgery consisted of lobectomy or bilobectomy in 63.2% of patients, pneumonectomy in 23.5%, and wedge resection in 5.9%. Of the patients, 80.4% received radiation in the adjuvant setting and 9.9% in the neoadjuvant setting.Patients with non-metastatic lung cancer who are treated surgically and with radiation have clinically less advanced disease than those treated with radiation alone. Most radiation therapy in this setting is administrated postoperatively and secondary to hilar and/or mediastinal nodal involvement undetected before surgery. Improved preoperative nodal staging and neoadjuvant approaches may alter these practice patterns.

    View details for Web of Science ID 000239191500005

    View details for PubMedID 17409912

  • Structural basis for imipenem inhibition of class C beta-lactamases ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Beadle, B. M., Shoichet, B. K. 2002; 46 (12): 3978-3980

    Abstract

    To determine how imipenem inhibits the class C beta-lactamase AmpC, the X-ray crystal structure of the acyl-enzyme complex was determined to a resolution of 1.80 A. In the complex, the lactam carbonyl oxygen of imipenem has flipped by approximately 180 degrees compared to its expected position; the electrophilic acyl center is thus displaced from the point of hydrolytic attack. This conformation resembles that of imipenem bound to the class A enzyme TEM-1 but is different from that of moxalactam bound to AmpC.

    View details for DOI 10.1128/AAC.46.12.3978-3980.2002

    View details for Web of Science ID 000179376000041

    View details for PubMedID 12435704

  • Structural bases of stability-function tradeoffs in enzymes JOURNAL OF MOLECULAR BIOLOGY Beadle, B. M., Shoichet, B. K. 2002; 321 (2): 285-296

    Abstract

    The structures of enzymes reflect two tendencies that appear opposed. On one hand, they fold into compact, stable structures; on the other hand, they bind a ligand and catalyze a reaction. To be stable, enzymes fold to maximize favorable interactions, forming a tightly packed hydrophobic core, exposing hydrophilic groups, and optimizing intramolecular hydrogen-bonding. To be functional, enzymes carve out an active site for ligand binding, exposing hydrophobic surface area, clustering like charges, and providing unfulfilled hydrogen bond donors and acceptors. Using AmpC beta-lactamase, an enzyme that is well-characterized structurally and mechanistically, the relationship between enzyme stability and function was investigated by substituting key active-site residues and measuring the changes in stability and activity. Substitutions of catalytic residues Ser64, Lys67, Tyr150, Asn152, and Lys315 decrease the activity of the enzyme by 10(3)-10(5)-fold compared to wild-type. Concomitantly, many of these substitutions increase the stability of the enzyme significantly, by up to 4.7kcal/mol. To determine the structural origins of stabilization, the crystal structures of four mutant enzymes were determined to between 1.90A and 1.50A resolution. These structures revealed several mechanisms by which stability was increased, including mimicry of the substrate by the substituted residue (S64D), relief of steric strain (S64G), relief of electrostatic strain (K67Q), and improved polar complementarity (N152H). These results suggest that the preorganization of functionality characteristic of active sites has come at a considerable cost to enzyme stability. In proteins of unknown function, the presence of such destabilized regions may indicate the presence of a binding site.

    View details for DOI 10.1016/S0022-2836(02)00599-5

    View details for Web of Science ID 000177488000009

    View details for PubMedID 12144785

  • Structural milestones in the reaction pathway of an amide hydrolase: Substrate, acyl, and product complexes of cephalothin with AmpC beta-lactamase STRUCTURE Beadle, B. M., Trehan, I., Focia, P. J., Shoichet, B. K. 2002; 10 (3): 413-424

    Abstract

    Beta-lactamases hydrolyze beta-lactam antibiotics and are the leading cause of bacterial resistance to these drugs. Although beta-lactamases have been extensively studied, structures of the substrate-enzyme and product-enzyme complexes have proven elusive. Here, the structure of a mutant AmpC in complex with the beta-lactam cephalothin in its substrate and product forms was determined by X-ray crystallography to 1.53 A resolution. The acyl-enzyme intermediate between AmpC and cephalothin was determined to 2.06 A resolution. The ligand undergoes a dramatic conformational change as the reaction progresses, with the characteristic six-membered dihydrothiazine ring of cephalothin rotating by 109 degrees. These structures correspond to all three intermediates along the reaction path and provide insight into substrate recognition, catalysis, and product expulsion.

    View details for Web of Science ID 000174409600016

    View details for PubMedID 12005439

  • Inhibition of AmpC beta-lactamase through a destabilizing interaction in the active site BIOCHEMISTRY Trehan, I., Beadle, B. M., Shoichet, B. K. 2001; 40 (27): 7992-7999

    Abstract

    Beta-lactamases hydrolyze beta-lactam antibiotics, including penicillins and cephalosporins; these enzymes are the most widespread resistance mechanism to these drugs and pose a growing threat to public health. beta-Lactams that contain a bulky 6(7)alpha substituent, such as imipenem and moxalactam, actually inhibit serine beta-lactamases and are widely used for this reason. Although mutant serine beta-lactamases have arisen that hydrolyze beta-lactamase resistant beta-lactams (e.g., ceftazidime) or avoid mechanism-based inhibitors (e.g., clavulanate), mutant serine beta-lactamases have not yet arisen in the clinic with imipenemase or moxalactamase activity. Structural and thermodynamic studies suggest that the 6(7)alpha substituents of these inhibitors form destabilizing contacts within the covalent adduct with the conserved Asn152 in class C beta-lactamases (Asn132 in class A beta-lactamases). This unfavorable interaction may be crucial to inhibition. To test this destabilization hypothesis, we replaced Asn152 with Ala in the class C beta-lactamase AmpC from Escherichia coli and examined the mutant enzyme's thermodynamic stability in complex with imipenem and moxalactam. Consistent with the hypothesis, the Asn152 --> Ala substitution relieved 0.44 and 1.10 kcal/mol of strain introduced by imipenem and moxalactam, respectively, relative to the wild-type complexes. However, the kinetic efficiency of AmpC N152A was reduced by 6300-fold relative to that of the wild-type enzyme. To further investigate the inhibitor's interaction with the mutant enzyme, the X-ray crystal structure of moxalactam in complex with N152A was determined to a resolution of 1.83 A. Moxalactam in the mutant complex is significantly displaced from its orientation in the wild-type complex; however, moxalactam does not adopt an orientation that would restore competence for hydrolysis. Although Asn152 forces beta-lactams with 6(7)alpha substituents out of a catalytically competent configuration, making them inhibitors, the residue is essential for orienting beta-lactam substrates and cannot simply be replaced with a much smaller residue to restore catalytic activity. Designing beta-lactam inhibitors that interact unfavorably with this conserved residue when in the covalent adduct merits further investigation.

    View details for DOI 10.1021/bi010641m

    View details for Web of Science ID 000169833400006

    View details for PubMedID 11434768

  • Interaction energies between beta-lactam antibiotics and E-coli penicillin-binding protein 5 by reversible thermal denaturation PROTEIN SCIENCE Beadle, B. M., Nicholas, R. A., Shoichet, B. K. 2001; 10 (6): 1254-1259

    Abstract

    Penicillin-binding proteins (PBPs) catalyze the final stages of bacterial cell wall biosynthesis. PBPs form stable covalent complexes with beta-lactam antibiotics, leading to PBP inactivation and ultimately cell death. To understand more clearly how PBPs recognize beta-lactam antibiotics, it is important to know their energies of interaction. Because beta-lactam antibiotics bind covalently to PBPs, these energies are difficult to measure through binding equilibria. However, the noncovalent interaction energies between beta-lactam antibiotics and a PBP can be determined through reversible denaturation of enzyme-antibiotic complexes. Escherichia coli PBP 5, a D-alanine carboxypeptidase, was reversibly denatured by temperature in an apparently two-state manner with a temperature of melting (T(m)) of 48.5 degrees C and a van't Hoff enthalpy of unfolding (H(VH)) of 193 kcal/mole. The binding of the beta-lactam antibiotics cefoxitin, cloxacillin, moxalactam, and imipenem all stabilized the enzyme significantly, with T(m) values as high as +4.6 degrees C (a noncovalent interaction energy of +2.7 kcal/mole). Interestingly, the noncovalent interaction energies of these ligands did not correlate with their second-order acylation rate constants (k(2)/K'). These rate constants indicate the potency of a covalent inhibitor, but they appear to have little to do with interactions within covalent complexes, which is the state of the enzyme often used for structure-based inhibitor design.

    View details for Web of Science ID 000168914700018

    View details for PubMedID 11369864

  • Functional analyses of AmpC beta-lactamase through differential stability PROTEIN SCIENCE Beadle, B. M., McGovern, S. L., Patera, A., Shoichet, B. K. 1999; 8 (9): 1816-1824

    Abstract

    Despite decades of intense study, the complementarity of beta-lactams for beta-lactamases and penicillin binding proteins is poorly understood. For most of these enzymes, beta-lactam binding involves rapid formation of a covalent intermediate. This makes measuring the equilibrium between bound and free beta-lactam difficult, effectively precluding measurement of the interaction energy between the ligand and the enzyme. Here, we explore the energetic complementarity of beta-lactams for the beta-lactamase AmpC through reversible denaturation of adducts of the enzyme with beta-lactams. AmpC from Escherichia coli was reversibly denatured by temperature in a two-state manner with a temperature of melting (Tm) of 54.6 degrees C and a van't Hoff enthalpy of unfolding (deltaH(VH)) of 182 kcal/mol. Solvent denaturation gave a Gibbs free energy of unfolding in the absence of denaturant (deltaG(u)H2O) of 14.0 kcal/mol. Ligand binding perturbed the stability of the enzyme. The penicillin cloxacillin stabilized AmpC by 3.2 kcal/mol (deltaTm = +5.8 degrees C); the monobactam aztreonam stabilized the enzyme by 2.7 kcal/mol (deltaTm = +4.9 degrees C). Both acylating inhibitors complement the active site. Surprisingly, the oxacephem moxalactam and the carbapenem imipenem both destabilized AmpC, by 1.8 kcal/mol (deltaTm = -3.2 degrees C) and 0.7 kcal/mol (deltaTm = -1.2 degrees C), respectively. These beta-lactams, which share nonhydrogen substituents in the 6(7)alpha position of the beta-lactam ring, make unfavorable noncovalent interactions with the enzyme. Complexes of AmpC with transition state analog inhibitors were also reversibly denatured; both benzo(b)thiophene-2-boronic acid (BZBTH2B) and p-nitrophenyl phenylphosphonate (PNPP) stabilized AmpC. Finally, a catalytically inactive mutant of AmpC, Y150F, was reversibly denatured. It was 0.7 kcal/mol (deltaTm = -1.3 degrees C) less stable than wild-type (WT) by thermal denaturation. Both the cloxacillin and the moxalactam adducts with Y150F were significantly destabilized relative to their WT counterparts, suggesting that this residue plays a role in recognizing the acylated intermediate of the beta-lactamase reaction. Reversible denaturation allows for energetic analyses of the complementarity of AmpC for beta-lactams, through ligand binding, and for itself, through residue substitution. Reversible denaturation may be a useful way to study ligand complementarity to other beta-lactam binding proteins as well.

    View details for Web of Science ID 000082424200011

    View details for PubMedID 10493583

  • Comparing the thermodynamic stabilities of a related thermophilic and mesophilic enzyme BIOCHEMISTRY Beadle, B. M., Baase, W. A., Wilson, D. B., Gilkes, N. R., Shoichet, B. K. 1999; 38 (8): 2570-2576

    Abstract

    Several models have been proposed to explain the high temperatures required to denature enzymes from thermophilic organisms; some involve greater maximum thermodynamic stability for the thermophile, and others do not. To test these models, we reversibly melted two analogous protein domains in a two-state manner. E2cd is the isolated catalytic domain of cellulase E2 from the thermophile Thermomonospora fusca. CenAP30 is the analogous domain of the cellulase CenA from the mesophile Cellulomonas fimi. When reversibly denatured in a common buffer, the thermophilic enzyme E2cd had a temperature of melting (Tm) of 72.2 degrees C, a van't Hoff enthalpy of unfolding (DeltaHVH) of 190 kcal/mol, and an entropy of unfolding (DeltaSu) of 0.55 kcal/(mol*K); the mesophilic enzyme CenAP30 had a Tm of 56.4 degrees C, a DeltaHVH of 107 kcal/mol, and a DeltaSu of 0. 32 kcal/(mol*K). The higher DeltaHVH and DeltaSu values for E2cd suggest that its free energy of unfolding (DeltaGu) has a steeper dependence on temperature at the Tm than CenAP30. This result supports models that predict a greater maximum thermodynamic stability for thermophilic enzymes than for their mesophilic counterparts. This was further explored by urea denaturation. Under reducing conditions at 30 degrees C, E2cd had a concentration of melting (Cm) of 5.2 M and a DeltaGu of 11.2 kcal/mol; CenAP30 had a Cm of 2.6 M and a DeltaGu of 4.3 kcal/mol. Under nonreducing conditions, the Cm and DeltaGu of CenAP30 were increased to 4.5 M and 10.8 kcal/mol at 30 degrees C; the Cm for E2cd was increased to at least 7.4 M at 32 degrees C. We were unable to determine a DeltaGu value for E2cd under nonreducing conditions due to problems with reversibility. These data suggest that E2cd attains its greater thermal stability (DeltaTm = 15.8 degrees C) through a greater thermodynamic stability (DeltaDeltaGu = 6.9 kcal/mol) compared to its mesophilic analogue CenAP30.

    View details for Web of Science ID 000078971300038

    View details for PubMedID 10029552