University of Wisconsin–Madison
Andrew Baschnagel, MD Headshot

Andrew Baschnagel, MD

Assistant Professor

Department of Human Oncology

I am an assistant professor in the Department of Human Oncology at the University of Wisconsin School of Medicine and Public Health, where I treat patients and perform translational research. In my clinical practice, I specialize in treating patients with lung, esophageal and other thoracic malignancies. In addition, I have expertise in performing stereotactic body radiotherapy and intracranial stereotactic radiosurgery for the treatment of brain, spine and liver metastases. I am a member of the UW Multidisciplinary Thoracic Program and work closely with thoracic surgeons, medical oncologists, pulmonologists and radiologists to best meet the needs of my patients. I also serve as the department’s director of clinical trials.

I am actively involved in translational and clinical research. I work closely with basic scientists, physicists and clinicians with the goal of fostering new ideas and translating research findings into the clinic. I have experience studying combinations of radiation and novel radiosensitizers and biomarkers of treatment response in patients and in preclinical models. My current work focuses on improving treatment of non-small cell lung cancer, esophageal cancer, head and neck cancer and pancreas cancer. I am actively involved at the regional and national level, and I am site PI for multiple national clinical studies here at UW. In addition to my clinical and research activities, I train medical students, medical residents and fellows. This includes mentoring students and residents in the clinic and with research.

Education

Resident, William Beaumont Hospital, Radiation Oncology (2014)

Intern, William Beaumont Hospital, (2010)

Research Fellow, National Institutes of Health, Clinical Research (2008)

MD, State University of New York at Buffalo, Medicine (2009)

BS, State University of New York at Buffalo, Biophysical Sciences (2004)

Academic Appointments

Assistant Professor, Human Oncology (2014)

Selected Honors and Awards

UW Paul P. Carbone Young Investigator Award, UW Carbone Cancer Center (2017)

Travel Grant Award, ASTRO Multidisciplinary Head and Neck Cancer Symposium (2014)

First Place, Resident and Fellow Michigan State Medical Society Annual Research Forum (2013)

First Place, Poster Presentation, 43rd Annual Beaumont Research Forum (2013)

First Place, Michigan Radiological Society Radiation Oncology Research Award (2013)

Baccelli Award for Most Outstanding Research, SUNY at Buffalo (2009)

First Honors, Annual Medical Student Research Forum, SUNY at Buffalo (2009)

University at Buffalo School of Medicine Alumni Scholarship (2004–2009)

Outstanding Underuraduate Award, Biophysics Department SUNY at Buffalo (2004)

Academic Excellence Scholarship, SUNY at Buffalo (2000–2004)

Boards, Advisory Committees and Professional Organizations

Member of Lung Cancer Working Group, Big Ten Cancer Research Consortium (2017–pres.)

Clinical Translational and Basic Science Advisory Committee Member, ASTRO Clinical (2016–pres.)

Quality Control Committee Chair, UWCCC Department of Human Oncology (2016–pres.)

Peer Review Committee Member, UW Hospital and Clinics, (2016–pres.)

Policy and Procedures Committee, UWCCC Department of Human Oncology (2016–pres.)

Abstract reviewer, ASTRO Annual Meeting Lung Committee Member (2015–pres.)

Protocol Review and Monitoring Committee Member, UWCCC (2014–pres.)

Thoracic and Sarcoma Site Moderator, themednet.org (2014-2017)

Residents Affairs Committee, Michigan Radiologic Society (2013–2014)

Admissions Committee Member, University at Buffalo School of Medicine (2005–2006)

Research Focus

Translational Research, Stereotactic Body Radiotherapy, Intracranial Stereotactic Radiosurgery, Novel Radiosensitizers

My research objective is to translate novel findings from the laboratory into the clinic with the goal of improving treatment for cancer patients.

Precision medicine in radiation oncology involves individually optimizing and tailoring radiation treatments to improve outcomes and decrease side effects. This can be done by selectively combining molecular targeted drugs with radiation to improve the therapeutic ratio and using biomarkers to predict radiation tumor and normal tissue response. These are areas that my research focuses on.

Non-small cell lung cancer brain metastases

Approximately 30 percent of patients with non-small cell lung cancer (NSCLC) will develop brain metastases during the course of their disease. Brain metastases from NSCLC remain a significant challenge to treat and unfortunately lead to the death of many patients. Standard treatments for brain metastases are surgical resection and stereotactic radiosurgery for limited lesions or whole brain irradiation for multiple metastases. Whole brain irradiation has significant toxicity, and chemotherapy has a limited role due to its inability to cross the blood-brain barrier. A limited number of patients with alterations in EGFR or ALK may derive some benefit from molecular targeted therapy, but overall there are limited therapeutic options for these patients. Novel treatment approaches are desperately needed to help this patient population.

 

Understanding the biology of brain metastases may shed some light on how they develop and provide novel targets for therapeutics. We currently have an ongoing project examining the genomics differences between patient matched NSCLC pulmonary tumors and their brain metastasis. The goal is to determine molecular differences that might drive the development of brain metastases.

 

One of the major barriers to improving outcomes and developing novel treatments is the lack of robust preclinical brain metastases models. We currently have established patient-derived xenografts from NSCLC brain metastases and are using them to test novel radiosensitizing agents. These are established in mice directly from patient tumor samples. Patient-derived xenografts can provide an excellent model system to study preclinical therapies as they allow a better representation of the biology of their human source than cells grown in plastic tissue culture dishes. These models will be used to validate molecular targets identified in our genomics endeavor and will be used to test combinations of drugs and radiation.

Molecular modulation of radiation response

This research area focuses on studying molecular targeted agents that can enhance the effect of radiation. This includes preclinical testing of molecular target agents in combination with radiation. Previous work involved studying vorinostat (SAHA), a histone deacetylase inhibitor, in combination with radiation in a breast cancer brain metastatic model; crizotinib, a c-MET inhibitor, with radiation in head and neck cancer and Trk receptor in pancreatic cancer. Our current work at Wisconsin involves the study of fibroblast growth receptors (FGRR1 and FGFR2) as targets for radiosensitization in lung and head and neck cancers. Both squamous cell carcinoma of the lung and head and neck have a high rate of FGFR1 and FGFR2 amplification, making it an ideal target to study. We are currently investigating use of the novel pan-FGFR inhibitor, AZD4547, in combination with radiation.

 

Relevant Publications:

  • Baschnagel A, Russo A, Burgan WE, Carter D, Beam K, Palmieri D, Steeg PS, Tofilon P, Camphausen K. Vorinostat enhances the radiosensitivity of a breast cancer brain metastatic cell line grown in vitro and as intracranial xenografts. Mol Cancer Ther. 2009 Jun;8(6):1589-95. PubMed PMID: 19509253; PubMed Central PMCID: PMC3393105.
  • Baschnagel AM, Galoforo S, Thibodeau BJ, Ahmed S, Nirmal S, Akervall J, Wilson GD. Crizotinib Fails to Enhance the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Xenografts. Anticancer Res. 2015 Nov;35(11):5973-82. PubMed PMID: 26504020.
  • Johnson MD, Stone B, Thibodeau BJ, Baschnagel AM, Galoforo S, Fortier LE, Ketelsen B, Ahmed S, Kelley Z, Hana A, Wilson TG, Robertson JM, Jury RP, Wilson GD. The significance of Trk receptors in pancreatic cancer. Tumour Biol. 2017 Feb;39(2):1010428317692256. PubMed PMID: 28218045
  • Baschnagel AM, Chunrong L, Morgan A, Brennan S, Russo K, Iyer G, Harari PM. Combining the pan-FGFR inhibitor AZD4547 with radiation in lung and head and neck squamous cell carcinoma. American Association of Cancer Research 2017 Annual Meeting, Washington, DC, April 2017.

Molecular and genomic markers of radiation response and prognosis

Biomarkers that can predict the response to radiation therapy have not made their way into the clinic. Such markers could help clinicians personalize radiation treatment and help monitor disease status. Such biomarkers can be tumor or blood based. My past work has focused on expression of c-MET, CD44, EGFR, p16, GLUT1 and HK in primary tumors of patients with head and neck cancer. In addition, we have performed gene expression profiling of irradiated tumors to identify genes involved in radiation resistance. Currently, we are studying circulating tumor DNA as a way to monitor treatment response and disease progression in patients undergoing radiotherapy.

 

Relevant Publications:

  • Baschnagel AM, Williams L, Hanna A, Chen PY, Krauss DJ, Pruetz BL, Akervall J, Wilson GD. c-Met expression is a marker of poor prognosis in patients with locally advanced head and neck squamous cell carcinoma treated with chemoradiation. Int J Radiat Oncol Biol Phys. 2014 Mar 1;88(3):701-7. PubMed PMID: 24521684.
  • Baschnagel AM, Tonlaar N, Eskandari M, Kumar T, Williams L, Hanna A, Pruetz BL, Wilson GD. Combined CD44, c-MET, and EGFR expression in p16-positive and p16-negative head and neck squamous cell carcinomas. J Oral Pathol Med. 2017 Mar;46(3):208-213. PubMed PMID: 27442811.
  • Baschnagel AM, Wobb JL, Dilworth JT, Williams L, Eskandari M, Wu D, Pruetz BL, Wilson GD. The association of (18)F-FDG PET and glucose metabolism biomarkers GLUT1 and HK2 in p16 positive and negative head and neck squamous cell carcinomas. Radiother Oncol. 2015 Oct;117(1):118-24. PubMed PMID: 26328941.
  • Wilson GD, Thibodeau BJ, Fortier LE, Pruetz BL, Galoforo S, Baschnagel AM, Chunta J, Oliver Wong CY, Yan D, Marples B, Huang J. Glucose metabolism gene expression patterns and tumor uptake of ¹⁸F-fluorodeoxyglucose after radiation treatment. Int J Radiat Oncol Biol Phys. 2014 Nov 1;90(3):620-7. PubMed PMID: 25304950.

Improving patient care

In addition to the above, I have been involved in many clinical radiation oncology studies that have helped improve patient care. These include studies focused on non-small cell lung cancer, esophageal cancer and head and neck cancers. I have expertise in analyzing large data sets, including data from the National Cancer Database, to answer important clinical questions.

 

Relevant Publications:

  • Pointer K, Brower JV, Ko C, Witek ME, Kimple RJ, Harai PM; Baschnagel, AM. Small cell carcinoma of the head and neck: Analysis of the National Cancer Database. Oral Oncology. 2017 Jun;69:92-98. PubMed PMID: 28559027.
  • Brower JV, Chen S, Bassetti MF, Yu M, Harari PM, Ritter MA, Baschnagel AM. Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012. Int J Radiat Oncol Biol Phys. 2016 Dec 1;96(5):985-993. PubMed PMID: 27869098.
  • Brower JV, Amini A, Chen S, Hullett CR, Kimple RJ, Wojcieszynski AP, Bassetti M, Witek ME, Yu M, Harari PM, Baschnagel AM. Improved survival with dose-escalated radiotherapy in stage III non-small-cell lung cancer: analysis of the National Cancer Database. Ann Oncol. 2016 Oct;27(10):1887-94. PubMed PMID: 27502703.
  • Baschnagel AM, Yadav S, Marina O, Parzuchowski A, Lanni TB Jr, Warner JN, Parzuchowski JS, Ignatius RT, Akervall J, Chen PY, Krauss DJ. Toxicities and costs of placing prophylactic and reactive percutaneous gastrostomy tubes in patients with locally advanced head and neck cancers treated with chemoradiotherapy. Head Neck. 2014 Aug;36(8):1155-61. PubMed PMID: 23852670.

 

I specialize in treating patients with thoracic malignancies. I have expertise in intracranial stereotactic radiosurgery and stereotactic body radiotherapy. I am actively involved in the UW Thoracic Disease Oriented Team and lead multiple clinical trials.  At UW we offer a variety of promising clinical trials, including national studies, studies using novel molecular agents in combination with radiation, studies utilizing new technologies and studies examining biomarkers. Our ultimate goal is provide the best treatment for our patients.

Clinical expertise:

  • External beam radiation therapy including 3D conformal, Intensity Modulated Radiotherapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT)
  • Frame-based and frameless intracranial stereotactic radiosurgery
  • Stereotactic body radiotherapy: lung, adrenal, liver, spine, bone
  • Image guided radiotherapy (IGRT) including cone-beam CT, PET/CT, MRI/CT and
    4D image guidance/treatment planning
  • ViewRay® real time MRI-guided radiotherapy
  • Adaptive radiotherapy treatment planning techniques

Clinical Trials

UW studies:

UW17019: Collection of blood and saliva for biomarker analysis of patients undergoing radiotherapy. PI

 

UW16037: Improving Pulmonary Function Following Radiation Therapy. Co-PI


National Studies open at UW:

RTOG 3505: Cisplatin and Etoposide Plus Radiation Followed By Nivolumab/Placebo For Locally Advanced NSCLC


RTOG 0538: CALGB 30610/Endorsed Study: Phase III Comparison of Thoracic Radiotherapy Regimens in Patients with Limited Small Cell Lung Cancer Also Receiving Cisplatin and Etoposide

 

NRGCC003: Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Treating Patients With Limited Stage or Extensive Stage Small Cell Lung Cancer

 

  • HPV impacts survival of stage IVC non-oropharyngeal HNSCC cancer patients. Otorhinolaryngol Head Neck Surg
    Burr AR, Harari PM, Ko HC, Chen S, Yu M, Baschnagel AM, Kimple RJ, Witek ME
    2018; 3 (1):
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      Objectives: Human papillomavirus (HPV) status is a favorable prognostic marker for patients with oropharyngeal squamous cell carcinoma (OPSCC) and non-metastatic head and neck non-OPSCC. We evaluated the impact of HPV status on overall survival (OS) for patients with Stage IVC non-OPSCC.

      Materials and methods: Patients diagnosed with Stage IVC non-OPSCC and known HPV status between 2010-2013 were identified in the National Cancer Database. Univariate and multivariate analyses were performed to determine factors associated with OS. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in OS analyses. Multiple imputation method was used for sensitivity analysis.

      Results: We identified 708 patients with Stage IVC non-OPSCC with 30% being HPV-positive. Unadjusted median survival was 10.3 months for HPV-negative patients and 21.4 months for HPV-positive patients (p<0.0001). Age ≥ 65 and tumor diameter were associated with worse OS (p<0.05) while treatment versus no treatment and HPV-positive status were associated with improved OS on multivariate analysis (p<0.001). Adjusted median survival for patients with HPV-negative and HPV-positive disease was 11.1 months and 23.8 months, respectively (p<0.001). On unadjusted subgroup analysis, patients with HPV-positive oral cavity disease exhibited improved outcomes (p<0.0001) while HPV-positive hypopharynx (p<0.06) and larynx (p<0.12) patients exhibited a trend for improved OS compared to HPV-negative patients. The survival advantage associated with HPV positivity was maintained on sensitivity analysis (p<0.01).

      Conclusion: These data demonstrate a clinically meaningful association between HPV status and OS in patients with non-OSPCC presenting with Stage IVC disease. In the absence of randomized data, these findings support active consideration of HPV status in clinical decision making, clinical trial design, and patient counseling regarding prognosis.

      View details for PubMedID 30271885
  • A New Era of Image Guidance with Magnetic Resonance-guided Radiation Therapy for Abdominal and Thoracic Malignancies. Cureus
    Mittauer K, Paliwal B, Hill P, Bayouth JE, Geurts MW, Baschnagel AM, Bradley KA, Harari PM, Rosenberg S, Brower JV, Wojcieszynski AP, Hullett C, Bayliss RA, Labby ZE, Bassetti MF
    2018 Apr 04; 10 (4): e2422
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      Magnetic resonance-guided radiation therapy (MRgRT) offers advantages for image guidance for radiotherapy treatments as compared to conventional computed tomography (CT)-based modalities. The superior soft tissue contrast of magnetic resonance (MR) enables an improved visualization of the gross tumor and adjacent normal tissues in the treatment of abdominal and thoracic malignancies. Online adaptive capabilities, coupled with advanced motion management of real-time tracking of the tumor, directly allow for high-precision inter-/intrafraction localization. The primary aim of this case series is to describe MR-based interventions for localizing targets not well-visualized with conventional image-guided technologies. The abdominal and thoracic sites of the lung, kidney, liver, and gastric targets are described to illustrate the technological advancement of MR-guidance in radiotherapy.

      View details for PubMedID 29872602
  • Impact of HPV Status on the Prognostic Potential of the AJCC Staging System for Larynx Cancer. Otolaryngol Head Neck Surg
    Davidson SM, Ko HC, Harari PM, Wieland AM, Chen S, Baschnagel AM, Kimple RJ, Witek AME
    2018 Apr 01; : 194599818766035
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      Objective We evaluated the ability of the American Joint Committee on Cancer (AJCC) seventh edition staging system to prognosticate the overall survival of patients with human papillomavirus (HPV)-positive laryngeal squamous cell carcinoma. Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods Patients diagnosed with laryngeal squamous cell carcinoma who were treated with curative intent were identified in the National Cancer Database. Multivariate analysis was utilized to determine factors correlated with overall survival in the HPV-negative and HPV-positive cohorts. Unadjusted and propensity score-weighted Kaplan-Meier estimation was used to determine overall survival of HPV-negative and HPV-positive patients across AJCC stage groupings. Results We identified 3238 patients with laryngeal squamous cell carcinoma, of which 2812 were HPV negative and 426 were HPV positive. Overall survival adjusted for age, sex, and comorbidity status confirmed significant differences among all consecutive stage groupings (I vs II, P < .001; II vs III, P < .05; III vs IVA, P < .001; IVA vs IVB, P < .05) in the HPV-negative cohort, whereas only stages IVAs and IVB ( P < .01) exhibited a significant difference in overall survival for HPV-positive patients. Conclusion The current AJCC staging system does not accurately distinguish risk of mortality for patients with HPV-positive disease. These data support the consideration of HPV status in estimating prognosis as well as clinical trial design and clinical decision making for patients with laryngeal squamous cell carcinoma.

      View details for PubMedID 29611770
  • Survival Outcomes for Patients With T3N0M0 Squamous Cell Carcinoma of the Glottic Larynx. JAMA Otolaryngol Head Neck Surg
    Ko HC, Harari PM, Chen S, Wieland AM, Yu M, Baschnagel AM, Kimple RJ, Witek ME
    2017 Nov 01; 143 (11): 1126-1133
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      Importance: Radiotherapy (RT)-based organ preservation approaches for patients with advanced laryngeal cancer have been established stepwise through prospective randomized clinical trials. However, broad adoption of these approaches has stimulated discussion about long-term results challenging their applicability in a heterogeneous patient population, most recently for patients with T3 disease.

      Objective: To define outcomes in patients with clinical T3N0M0 glottic laryngeal cancer treated with definitive surgical and RT-based approaches.

      Design, Setting, and Participants: This retrospective cohort study included patients treated from January 1, 2004, through December 31, 2013, with a median follow-up time of 58 months (range, 0-126.6 months) in the National Cancer Database. Of the 4003 patients with T3N0M0 disease, 2622 received definitive therapy defined by the study protocol. Data were obtained from the clinical oncology database sourced from hospital registry data that are collected from more than 1500 Commission on Cancer-accredited facilities. Data were analyzed from September 14, 2016, through April 24, 2017.

      Interventions: Radiotherapy, chemoradiotherapy, surgery, surgery and RT, or surgery and chemoradiotherapy.

      Main Outcomes and Measures: Five-year overall survival (OS).

      Results: A total of 2622 patients (2251 men [85.9%] and 371 women [14.1%]; median age, 64 years [range, 19-90 years]) were included in the analytic cohort. In the overall patient cohort, the adjusted 5-year survival probability was 53%. No statistical differences were observed between the primary surgery (53%; 95% CI, 48%-57%) and primary RT (54%; 95% CI, 52%-57%) cohorts. In multivariate analysis, patient factors associated with decreased OS included age (hazard ratio [HR], 1.04; 95% CI, 1.03-1.04), insurance status (HR, 1.26; 95% CI, 1.06-1.50), and increasing comorbidity (HR, 1.20; 95% CI, 1.02-1.42).

      Conclusions and Relevance: Current management of T3N0M0 glottic laryngeal cancer relies largely on RT-based organ preservation approaches. The present study substantiates randomized clinical trial data supporting the use of RT-based organ preservation approaches for patients with T3N0M0 glottic laryngeal cancer without compromising OS.

      View details for PubMedID 29049434
  • Precision Oncology and Genomically Guided Radiation Therapy: A Report From the American Society for Radiation Oncology/American Association of Physicists in Medicine/National Cancer Institute Precision Medicine Conference. Int J Radiat Oncol Biol Phys
    Hall WA, Bergom C, Thompson RF, Baschnagel AM, Vijayakumar S, Willers H, Li XA, Schultz CJ, Wilson GD, West CML, Capala J, Coleman CN, Torres-Roca JF, Weidhaas J, Feng FY
    2017 Jun 09; :
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      PURPOSE: To summarize important talking points from a 2016 symposium focusing on real-world challenges to advancing precision medicine in radiation oncology, and to help radiation oncologists navigate the practical challenges of precision, radiation oncology.

      METHODS AND MATERIALS: The American Society for Radiation Oncology, American Association of Physicists in Medicine, and National Cancer Institute cosponsored a meeting on precision medicine in radiation oncology. In June 2016 numerous scientists, clinicians, and physicists convened at the National Institutes of Health to discuss challenges and future directions toward personalized radiation therapy. Various breakout sessions were held to discuss particular components and approaches to the implementation of personalized radiation oncology. This article summarizes the genomically guided radiation therapy breakout session.

      RESULTS: A summary of existing genomic data enabling personalized radiation therapy, ongoing clinical trials, current challenges, and future directions was collected. The group attempted to provide both a current overview of data that radiation oncologists could use to personalize therapy, along with data that are anticipated in the coming years. It seems apparent from the provided review that a considerable opportunity exists to truly bring genomically guided radiation therapy into clinical reality.

      CONCLUSIONS: Genomically guided radiation therapy is a necessity that must be embraced in the coming years. Incorporating these data into treatment recommendations will provide radiation oncologists with a substantial opportunity to improve outcomes for numerous cancer patients. More research focused on this topic is needed to bring genomic signatures into routine standard of care.

      View details for PubMedID 28964588
  • Prognostic implications of human papillomavirus status for patients with non-oropharyngeal head and neck squamous cell carcinomas. J Cancer Res Clin Oncol
    Ko HC, Harari PM, Sacotte RM, Chen S, Wieland AM, Yu M, Baschnagel AM, Bruce JY, Kimple RJ, Witek ME
    2017 Nov; 143 (11): 2341-2350
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      PURPOSE: We examined overall survival in a large cohort of patients with human papillomavirus (HPV)-positive and HPV-negative non-oropharyngeal squamous cell carcinoma of the head and neck (non-OPSCC).

      METHODS: Patients diagnosed with non-OPSCC and known HPV status were identified in the National Cancer Database (NCDB). Multivariate logistic regression was applied to examine factors associated with HPV status. Multivariate analysis was utilized to determine factors correlated with overall survival. Propensity score-weighted Kaplan-Meier estimation was used to adjust for confounders in survival analyses. Multiple imputation method was used for sensitivity analysis.

      RESULTS: We identified 19,993 non-OPSCC patients with 5070 being positive for HPV in the NCDB. Median follow-up was 23.5 months. HPV-positive patients were more commonly male, white, with a lower comorbidity index score, presenting with T-stage <2, and N-stage ≥1. Unadjusted 3-year overall survival was 62% and 80% for HPV-negative and HPV-positive patients, respectively (p < 0.0001). On multivariate analysis, mortality was reduced for HPV-positive patients with early stage (HR = 0.68) and locally advanced disease (HR = 0.46). Adjusted 3-year overall survival was 65% for HPV-negative and 76% for HPV-positive patients (p < 0.0001). The survival advantage of HPV was maintained in all subsites and robust on sensitivity analysis.

      CONCLUSIONS: Patients with HPV-positive non-OPSCC exhibit similar characteristics as HPV-positive OPSCC. Overall survival was significantly higher for patients with HPV-positive versus HPV-negative non-OPSCC. These data reveal that HPV-positive non-OPSCC represent a favorable cohort that warrants recognition in the design of future clinical trial investigation.

      View details for PubMedID 28752235
  • Clinical outcomes for patients presenting with N3 head and neck squamous cell carcinoma: Analysis of the National Cancer Database. Head Neck
    Ko HC, Chen S, Wieland AM, Yu M, Baschnagel AM, Hartig GK, Harari PM, Witek ME
    2017 Nov; 39 (11): 2159-2170
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      BACKGROUND: There is a paucity of data regarding head and neck squamous cell carcinomas (HNSCCs) and N3 nodal disease.

      METHODS: Retrospective analysis of patients with N3 HNSCC identified in the National Cancer Database (NCDB) was performed.

      RESULTS: We identified 4867 patients with N3 HNSCC treated with primary surgery or chemoradiotherapy (CRT). Propensity-adjusted median survival was 54.2 and 44.8 months for surgery and CRT, respectively (P = .06). Oropharyngeal primary subsite demonstrated a survival advantage with surgery versus CRT with propensity-adjusted median survivals of 86.0 and 61.9 months, respectively (P < .05).

      CONCLUSION: Management of N3 HNSCC relies largely on CRT. Patients with N3 nodal disease with nonoropharyngeal primary tumors exhibit 5-year overall survival approaching 30% independent of initial treatment modality. Patients with oropharyngeal primaries exhibit improved outcomes with surgery largely influenced by the human papillomavirus (HPV)-negative subset. These data represent the most comprehensive analysis of N3 HNSCC outcomes and serves as a foundation for future research and clinical management.

      View details for PubMedID 28737019
  • Small cell carcinoma of the head and neck: An analysis of the National Cancer Database. Oral Oncol
    Pointer KB, Ko HC, Brower JV, Witek ME, Kimple RJ, Lloyd RV, Harari PM, Baschnagel AM
    2017 Jun; 69: 92-98
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      PURPOSE/OBJECTIVE(S): To evaluate treatment trends and overall survival of patients with small cell carcinoma of the head and neck region.

      MATERIALS/METHODS: Patients from 2004 to 2012 were identified from the National Cancer Database. Patient demographics and overall survival were analyzed. Multivariable analysis was used to identify predictors of survival.

      RESULTS: Among 347,252 head and neck patients a total of 1042 (0.3%) patients with small cell carcinoma were identified. 17% of patients were diagnosed as stage I/II, 61% as stage III/IVA/IVB and 22% as stage IVC disease. The distribution by anatomic site was 9% oral cavity, 12% oropharynx, 35% larynx, 4% hypopharynx, 10% nasopharynx and 30% nasal cavity and paranasal sinuses. The median overall survival by anatomical site was 20.8months for oral cavity, 23.7months for oropharynx, 17.9months for larynx/hypopharynx, 15.1months for nasopharynx and 36.4months for nasal cavity primary tumors. On multivariable analysis across stage, patients with nasal cavity and paranasal sinuses tumors had the best survival and patients with nasopharynx primaries had the worst survival. In stage I/II patients, type of treatment delivered resulted in no overall survival difference (p=0.78). In patients with locally advanced disease, there was no difference in survival between those treated with combined surgery, radiotherapy and chemotherapy compared to those treated only with radiotherapy and chemotherapy (p=0.46). The addition of radiotherapy to chemotherapy in the metastatic setting did not result in improved survival (p=0.14).

      CONCLUSIONS: Small cell carcinoma of the head and neck is a rare malignancy with a poor prognosis. The addition of surgery to radiotherapy and chemotherapy did not improve survival in patients with locally advanced disease.

      View details for PubMedID 28559027
  • In Reply to Fang et al. Int J Radiat Oncol Biol Phys
    Brower JV, Baschnagel AM
    2017 Apr 01; 97 (5): 1106-1107
  • The significance of Trk receptors in pancreatic cancer. Tumour Biol
    Johnson MD, Stone B, Thibodeau BJ, Baschnagel AM, Galoforo S, Fortier LE, Ketelsen B, Ahmed S, Kelley Z, Hana A, Wilson TG, Robertson JM, Jury RP, Wilson GD
    2017 Feb; 39 (2): 1010428317692256
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      This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity. A specific inhibitor of TrkA, B, and C, AstraZeneca 1332, was investigated in vitro and in vivo in combination with radiation. A tissue microarray was constructed from 77 pancreatic ductal adenocarcinoma patients who had undergone neoadjuvant chemoradiation and the Trk receptor, and neurogenic differentiation 1 expression was assessed and correlated with overall survival. A total of 99 genes were identified that were differentially expressed in the chemoradiation patients with neuroendocrine genes and pathways, in particular the neurogenic differentiation 1 and Trk receptor family, being prominent. Fractionated radiation upregulated the expression of neuroendocrine genes, and AstraZeneca 1332 treatment in vitro enhanced radiosensitivity. No added effect of AstraZeneca 1332 was observed in vivo. Trk receptor expression varied between isoforms but did not correlate significantly with clinical outcome. Radiation treatment upregulated neuroendocrine gene expression but the Trk receptor family does not appear to be a promising treatment target.

      View details for PubMedID 28218045
  • Dosimetric Comparison of Real-Time MRI-Guided Tri-Cobalt-60 Versus Linear Accelerator-Based Stereotactic Body Radiation Therapy Lung Cancer Plans. Technol Cancer Res Treat
    Wojcieszynski AP, Hill PM, Rosenberg SA, Hullett CR, Labby ZE, Paliwal B, Geurts MW, Bayliss RA, Bayouth JE, Harari PM, Bassetti MF, Baschnagel AM
    2017 Jun; 16 (3): 366-372
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      PURPOSE: Magnetic resonance imaging-guided radiation therapy has entered clinical practice at several major treatment centers. Treatment of early-stage non-small cell lung cancer with stereotactic body radiation therapy is one potential application of this modality, as some form of respiratory motion management is important to address. We hypothesize that magnetic resonance imaging-guided tri-cobalt-60 radiation therapy can be used to generate clinically acceptable stereotactic body radiation therapy treatment plans. Here, we report on a dosimetric comparison between magnetic resonance imaging-guided radiation therapy plans and internal target volume-based plans utilizing volumetric-modulated arc therapy.

      MATERIALS AND METHODS: Ten patients with early-stage non-small cell lung cancer who underwent radiation therapy planning and treatment were studied. Following 4-dimensional computed tomography, patient images were used to generate clinically deliverable plans. For volumetric-modulated arc therapy plans, the planning tumor volume was defined as an internal target volume + 0.5 cm. For magnetic resonance imaging-guided plans, a single mid-inspiratory cycle was used to define a gross tumor volume, then expanded 0.3 cm to the planning tumor volume. Treatment plan parameters were compared.

      RESULTS: Planning tumor volumes trended larger for volumetric-modulated arc therapy-based plans, with a mean planning tumor volume of 47.4 mL versus 24.8 mL for magnetic resonance imaging-guided plans ( P = .08). Clinically acceptable plans were achievable via both methods, with bilateral lung V20, 3.9% versus 4.8% ( P = .62). The volume of chest wall receiving greater than 30 Gy was also similar, 22.1 versus 19.8 mL ( P = .78), as were all other parameters commonly used for lung stereotactic body radiation therapy. The ratio of the 50% isodose volume to planning tumor volume was lower in volumetric-modulated arc therapy plans, 4.19 versus 10.0 ( P < .001). Heterogeneity index was comparable between plans, 1.25 versus 1.25 ( P = .98).

      CONCLUSION: Magnetic resonance imaging-guided tri-cobalt-60 radiation therapy is capable of delivering lung high-quality stereotactic body radiation therapy plans that are clinically acceptable as compared to volumetric-modulated arc therapy-based plans. Real-time magnetic resonance imaging provides the unique capacity to directly observe tumor motion during treatment for purposes of motion management.

      View details for PubMedID 28168936
  • Strategies for Translating Evidence-Based Medicine in Lung Cancer into Community Practice. Curr Oncol Rep
    Rosenberg SA, Baschnagel AM, Bagley SJ, Housri N
    2017 Jan; 19 (1): 5
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      The landscape of non-small cell lung cancer (NSCLC) treatment has rapidly evolved over the past decade. This is exemplified by the use of molecular targeted agents, immunotherapies, and newer technologies such as stereotactic body radiotherapy (SBRT). As the translation of preclinical discoveries into clinical practice continues, the effective dissemination and implementation of evidence-based treatment of NSCLC will remain a foremost challenge for oncologists. To further extend evidence-based medicine into the community setting, community oncologists are being engaged on multiple fronts including leadership and participation in national clinical trials and utilization of internet-based resources.

      View details for PubMedID 28168606
  • Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012. Int J Radiat Oncol Biol Phys
    Brower JV, Chen S, Bassetti MF, Yu M, Harari PM, Ritter MA, Baschnagel AM
    2016 Dec 01; 96 (5): 985-993
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      PURPOSE: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy.

      METHODS AND MATERIALS: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching.

      RESULTS: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses).

      CONCLUSIONS: In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer.

      View details for PubMedID 27869098
  • Improved survival with dose-escalated radiotherapy in stage III non-small-cell lung cancer: analysis of the National Cancer Database. Ann Oncol
    Brower JV, Amini A, Chen S, Hullett CR, Kimple RJ, Wojcieszynski AP, Bassetti M, Witek ME, Yu M, Harari PM, Baschnagel AM
    2016 Oct; 27 (10): 1887-94
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      BACKGROUND: Concurrent chemoradiation is the standard of care in non-operable stage III non-small-cell lung cancer (NSCLC). Data have suggested a benefit of dose escalation; however, results from the randomized dose-escalation trial RTOG 0617 revealed a lower survival rate with high-dose radiation. To evaluate the impact of dose escalation on overall survival (OS) in stage III NSCLC treated with chemoradiotherapy outside the controlled setting of a randomized trial, we carried out an observational, population-based investigation of the National Cancer Database (NCDB).

      PATIENTS AND METHODS: A total of 33 566 patients with stage III NSCLC treated with chemoradiation from 2004 to 2012 and radiation doses between 59.4 and 85 Gy were included. The primary end point was OS, with median survival calculated via Kaplan-Meier. Univariate, multivariable and propensity-score matching analyses were carried out.

      RESULTS: Patients were stratified by dose with median OS of: 18.8, 19.8 and 21.6 months for cohorts receiving 59.4-60, 61-69 and ≥70 Gy, respectively (P < 0.001). Granular dose analyses were carried out demonstrating increased OS with increasing radiation dose: median survival of 18.8, 21.1, 22.0 and 21.0 months for 59.4-60, 66, 70 and ≥71 Gy, respectively. While 66, 70 and ≥71 Gy resulted in increased OS in comparison with 59.4-60 Gy, no significant difference in OS was observed when comparing 66 with ≥71 Gy (P = 0.38).

      CONCLUSIONS: Dose escalation above 60 Gy was associated with improved OS in this cohort of stage III NSCLC patients treated with chemoradiotherapy. A plateau of benefit was observed, with no additional improvement in OS with increased dose (≥71 Gy) compared with 66-70 Gy. With evidence suggesting worse OS and quality of life with increased dose, these data support investigation of the role of intermediate-dose radiation, and in the absence of randomized evidence, may be leveraged to justify utilization of intermediate-dose radiation.

      View details for PubMedID 27502703
  • Combined CD44, c-MET, and EGFR expression in p16-positive and p16-negative head and neck squamous cell carcinomas. J Oral Pathol Med
    Baschnagel AM, Tonlaar N, Eskandari M, Kumar T, Williams L, Hanna A, Pruetz BL, Wilson GD
    2017 Mar; 46 (3): 208-213
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      PURPOSE/OBJECTIVE(S): To examine the association between CD44 and c-MET expression in relation to p16 and EGFR in patients with head and neck squamous cell carcinoma (HNSCC).

      MATERIALS/METHODS: Immunohistochemical staining of CD44, p16, EGFR, and c-MET was performed on 105 locally advanced HNSCC patients treated with chemoradiation. CD44 expression was correlated with c-MET, EGFR, and p16, locoregional control (LRC), distant metastases (DM), disease-free survival (DFS) and overall survival (OS).

      RESULTS: High CD44 expression was present in 33% of patients and was associated with non-oropharynx primaries (P < 0.001), high c-MET expression (P < 0.001), p16-negative (P < 0.001) and EGFR-positive tumors (P < 0.001). Fifty-seven percent of CD44 high expressing tumors had high c-MET expression compared to 21% of CD44 low expressing tumors (P < 0.001). High CD44 expression predicted for worse LRC (HR: 2.44; 95% CI: 1.16-5.13; P = 0.018), DFS (HR: 2.61; 95% CI: 1.46-4.67; P = 0.001), and OS (HR: 2.52; 95% CI: 1.30-4.92; P = 0.007) but not DM (P = 0.57) on univariate analysis. Patients with both high CD44 and c-MET expression had a poor prognosis with a 2-year DFS of 30% compared to 70% in the rest of the cohort (P = 0.003). On multivariable analysis, after adjusting for site, T-stage, smoking history, and EGFR status, high c-MET (P = 0.039) and negative p16 status (P = 0.034) predicted for worse DFS, while high CD44 expression did not (P = 0.43).

      CONCLUSIONS: High CD44 expression is associated with high c-MET expression, p16-negative tumors, and EGFR-positive tumors. The combination of these markers predicts for poor prognosis in HNSCC patients treated with chemoradiation.

      View details for PubMedID 27442811
  • Cancer Stem Cell Signaling during Repopulation in Head and Neck Cancer. Stem Cells Int
    Wilson GD, Thibodeau BJ, Fortier LE, Pruetz BL, Galoforo S, Marples B, Baschnagel AM, Akervall J, Huang J
    2016; 2016: 1894782
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      The aim of the study was to investigate cancer stem signaling during the repopulation response of a head and neck squamous cell cancer (HNSCC) xenograft after radiation treatment. Xenografts were generated from low passage HNSCC cells and were treated with either sham radiation or 15 Gy in one fraction. At different time points, days 0, 3, and 10 for controls and days 4, 7, 12, and 21, after irradiation, 3 tumors per group were harvested for global gene expression, pathway analysis, and immunohistochemical evaluation. 316 genes were identified that were associated with a series of stem cell-related genes and were differentially expressed (p ≤ 0.01 and 1.5-fold) at a minimum of one time point in UT-SCC-14 xenografts after radiation. The largest network of genes that showed significant changes after irradiation was associated with CD44, NOTCH1, and MET. c-MET and ALDH1A3 staining correlated with the changes in gene expression. A clear pattern emerged that was consistent with the growth inhibition data in that genes associated with stem cell pathways were most active at day 7 and day 12 after irradiation. The MET/CD44 axis seemed to be an important component of the repopulation response.

      View details for PubMedID 26880935
  • Surgical Resection of Brain Metastases and the Risk of Leptomeningeal Recurrence in Patients Treated With Stereotactic Radiosurgery. Int J Radiat Oncol Biol Phys
    Johnson MD, Avkshtol V, Baschnagel AM, Meyer K, Ye H, Grills IS, Chen PY, Maitz A, Olson RE, Pieper DR, Krauss DJ
    2016 Mar 01; 94 (3): 537-43
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      PURPOSE: Recent prospective data have shown that patients with solitary or oligometastatic disease to the brain may be treated with upfront stereotactic radiosurgery (SRS) with deferral of whole-brain radiation therapy (WBRT). This has been extrapolated to the treatment of patients with resected lesions. The aim of this study was to assess the risk of leptomeningeal disease (LMD) in patients treated with SRS to the postsurgical resection cavity for brain metastases compared with patients treated with SRS to intact metastases.

      METHODS AND MATERIALS: Four hundred sixty-five patients treated with SRS without upfront WBRT at a single institution were identified; 330 of these with at least 3 months' follow-up were included in this analysis. One hundred twelve patients had undergone surgical resection of at least 1 lesion before SRS compared with 218 treated for intact metastases. Time to LMD and overall survival (OS) time were estimated from date of radiosurgery, and LMD was analyzed by the use of cumulative incidence method with death as a competing risk. Univariate and multivariate analyses were performed with competing risk regression to determine whether various clinical factors predicted for LMD.

      RESULTS: With a median follow-up time of 9.0 months, 39 patients (12%) experienced LMD at a median of 6.0 months after SRS. At 1 year, the cumulative incidence of LMD, with death as a competing risk, was 5.2% for the patients without surgical resection versus 16.9% for those treated with surgery (Gray test, P<.01). On multivariate analysis, prior surgical resection (P<.01) and breast cancer primary (P=.03) were significant predictors of LMD development. The median OS times for patients undergoing surgery compared with SRS alone were 12.9 and 10.6 months, respectively (log-rank P=.06).

      CONCLUSIONS: In patients undergoing SRS with deferral of upfront WBRT for intracranial metastatic disease, prior surgical resection and breast cancer primary are associated with an increased risk for the development of LMD.

      View details for PubMedID 26867883
  • Crizotinib Fails to Enhance the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Xenografts. Anticancer Res
    Baschnagel AM, Galoforo S, Thibodeau BJ, Ahmed S, Nirmal S, Akervall J, Wilson GD
    2015 Nov; 35 (11): 5973-82
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      AIM: Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model.

      MATERIALS AND METHODS: Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth-delay experiments with UT-SCC-14 and UT-SCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity.

      RESULTS: All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in vivo. Crizotinib alone inhibited phosphorylation of MET and inhibited cell growth in vitro but did not inhibit phosphorylation of downstream signaling proteins: MAPK, AKT or c-SRC. When combined with radiation in vitro, crizotinib demonstrated radiation enhancement in only one cell line. Crizotinib did not enhance the effect of radiation in either UT-SCC-14 or UT-SCC-15 tumors grown as xenografts.

      CONCLUSION: MET is overexpressed in HNSCC cell lines, however, crizotinib failed to enhance the radiation response and failed to inhibit MET downstream signaling proteins in this HNSCC model.

      View details for PubMedID 26504020
  • The association of (18)F-FDG PET and glucose metabolism biomarkers GLUT1 and HK2 in p16 positive and negative head and neck squamous cell carcinomas. Radiother Oncol
    Baschnagel AM, Wobb JL, Dilworth JT, Williams L, Eskandari M, Wu D, Pruetz BL, Wilson GD
    2015 Oct; 117 (1): 118-24
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      OBJECTIVES: To investigate the relationship between FDG-PET maximum standard uptake value (SUVmax), p16, EGFR, GLUT1 and HK2 expression in head and neck squamous cell carcinomas (HNSCC).

      MATERIALS AND METHODS: Immunohistochemical staining of p16, EGFR, GLUT1 and HK2 was performed on primary tumor tissue from 97 locally advanced HNSCC patients treated with definitive chemoradiation. SUVmax along with p16, EGFR, GLUT1 and HK2 expression were analyzed for associations including local control, locoregional control and disease free survival.

      RESULTS: Pretreatment SUVmax in primary tumors did not differ when stratified by p16, EGFR or GLUT1 expression but SUVmax was significantly higher in HK2 expressing tumors (p=0.021) and in tumors with higher T-stage (p=0.022). GLUT1 expression was significantly higher in p16 negative (p<0.001) and EGFR positive tumors (p<0.01). HK2 expressing tumors were associated with EGFR positive tumors (p=0.022) but not with p16 or GLUT1 expression. EGFR positive, p16 negative and high GLUT1 expressing tumors were associated with worse local control and disease free survival on univariate analyses. After adjusting for patient and treatment characteristics p16 status was the only factor that predicted for outcome on multivariate analysis.

      CONCLUSIONS: High GLUT1 expression was associated with EGFR positive and p16 negative HNSCC tumors. GLUT1 maybe an important biomarker in HNSCC but its expression appears dependent on p16 status.

      View details for PubMedID 26328941
  • Glucose metabolism gene expression patterns and tumor uptake of ¹⁸F-fluorodeoxyglucose after radiation treatment. Int J Radiat Oncol Biol Phys
    Wilson GD, Thibodeau BJ, Fortier LE, Pruetz BL, Galoforo S, Baschnagel AM, Chunta J, Oliver Wong CY, Yan D, Marples B, Huang J
    2014 Nov 01; 90 (3): 620-7
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      PURPOSE: To investigate whether radiation treatment influences the expression of glucose metabolism genes and compromises the potential use of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a tool to monitor the early response of head and neck cancer xenografts to radiation therapy (RT).

      METHODS AND MATERIALS: Low passage head and neck squamous cancer cells (UT14) were injected to the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm(3) they were treated with either sham RT or 15 Gy in 1 fraction. At different time points, days 3, 9, and 16 for controls and days 4, 7, 12, 21, 30, and 40 after irradiation, 2 to 3 mice were assessed with dynamic FDG-PET acquisition over 2 hours. Immediately after the FDG-PET the tumors were harvested for global gene expression analysis and immunohistochemical evaluation of GLUT1 and HK2. Different analytic parameters were used to process the dynamic PET data.

      RESULTS: Radiation had no effect on key genes involved in FDG uptake and metabolism but did alter other genes in the HIF1α and glucose transport-related pathways. In contrast to the lack of effect on gene expression, changes in the protein expression patterns of the key genes GLUT1/SLC2A1 and HK2 were observed after radiation treatment. The changes in GLUT1 protein expression showed some correlation with dynamic FDG-PET parameters, such as the kinetic index.

      CONCLUSION: (18)F-fluorodeoxyglucose positron emission tomography changes after RT would seem to represent an altered metabolic state and not a direct effect on the key genes regulating FDG uptake and metabolism.

      View details for PubMedID 25304950
  • c-Met expression is a marker of poor prognosis in patients with locally advanced head and neck squamous cell carcinoma treated with chemoradiation. Int J Radiat Oncol Biol Phys
    Baschnagel AM, Williams L, Hanna A, Chen PY, Krauss DJ, Pruetz BL, Akervall J, Wilson GD
    2014 Mar 01; 88 (3): 701-7
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      PURPOSE: To examine the prognostic significance of c-Met expression in relation to p16 and epidermal growth factor receptor (EGFR) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with definitive concurrent chemoradiation.

      METHODS AND MATERIALS: Archival tissue from 107 HNSCC patients treated with chemoradiation was retrieved, and a tissue microarray was assembled. Immunohistochemical staining of c-Met, p16, and EGFR was performed. c-Met expression was correlated with p16, EGFR, clinical characteristics, and clinical endpoints including locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS).

      RESULTS: Fifty-one percent of patients were positive for p16, and 53% were positive for EGFR. Both p16-negative (P≤.001) and EGFR-positive (P=.019) status predicted for worse DFS. Ninety-three percent of patients stained positive for c-Met. Patients were divided into low (0, 1, or 2+ intensity) or high (3+ intensity) c-Met expression. On univariate analysis, high c-Met expression predicted for worse LRC (hazard ratio [HR] 2.27; 95% CI, 1.08-4.77; P=.031), DM (HR 4.41; 95% CI, 1.56-12.45; P=.005), DFS (HR 3.00; 95% CI, 1.68-5.38; P<.001), and OS (HR 4.35; 95% CI, 2.13-8.88; P<.001). On multivariate analysis, after adjustment for site, T stage, smoking history, and EGFR status, only high c-Met expression (P=.011) and negative p16 status (P=.003) predicted for worse DFS. High c-Met expression was predictive of worse DFS in both EGFR-positive (P=.032) and -negative (P=.008) patients. In the p16-negative patients, those with high c-Met expression had worse DFS (P=.036) than did those with low c-Met expression. c-Met expression was not associated with any outcome in the p16-positive patients.

      CONCLUSIONS: c-Met is expressed in the majority of locally advanced HNSCC cases, and high c-Met expression predicts for worse clinical outcomes. High c-Met expression predicted for worse DFS in p16-negative patients but not in p16-positive patients. c-Met predicted for worse outcome regardless of EGFR status.

      View details for PubMedID 24521684
  • Trigeminal neuralgia pain relief after gamma knife stereotactic radiosurgery. Clin Neurol Neurosurg
    Baschnagel AM, Cartier JL, Dreyer J, Chen PY, Pieper DR, Olson RE, Krauss DJ, Maitz AH, Grills IS
    2014 Feb; 117: 107-11
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      OBJECTIVES: To report outcomes of patients with medical and/or surgical refractory trigeminal neuralgia (TN) treated with gamma knife stereotactic radiosurgery (GK SRS).

      METHODS: One hundred and forty-nine patients with 152 cases of TN treated with GK SRS were analyzed. All patients, except one, received a dose of 40Gy to the 50% isodose volume. The Barrow Neurological Institute (BNI) pain intensity score was used to grade pain. Actuarial rates of pain relief were calculated. Multiple factors were analyzed for association with pain relief.

      RESULTS: The median follow up was 27 months (4-71 months). Overall 92% of cases achieved a BNI score I-III after GK SRS. Of those who had pain relief after GK SRS, 32% developed pain recurrence defined as a BNI score of IV or V. The actuarial rate of freedom from pain recurrence (BNI scores I-III) of all treated cases at 1, 2 and 3-years was 76%, 69% and 60%, respectively. On univariate analysis age ≥70 was predictive of better pain relief (p=0.046). Type of pain, prior surgery, multiple sclerosis, number of isocenters, treated nerve length, volume and thickness and distance from the root entry zone to the isocenter were not significant for maintaining a BNI score of I-III. Those who achieved a BNI score of I or II were more likely to maintain pain relief compared to those who only achieved a BNI score of III (93% vs 38% at three years, p<0.01). The rate of pain relief of twenty-seven patients who underwent repeat GK SRS was 70% and 62% at 1 and 2 years, respectively. Toxicity after first GK SRS was minimal with 25% of cases experiencing only new or worsening post-treatment numbness.

      CONCLUSION: GK SRS provides acceptable pain relief with limited morbidity in patients with medical and/or surgical refractory TN.

      View details for PubMedID 24438815
  • Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery. J Neurosurg
    Baschnagel AM, Meyer KD, Chen PY, Krauss DJ, Olson RE, Pieper DR, Maitz AH, Ye H, Grills IS
    2013 Nov; 119 (5): 1139-44
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      OBJECT: The aim of this study was to examine tumor volume as a prognostic factor for patients with brain metastases treated with Gamma Knife surgery (GKS).

      METHODS: Two hundred fifty patients with 1-14 brain metastases who had initially undergone GKS alone at a single institution were retrospectively reviewed. Patients who received upfront whole brain radiation therapy were excluded. Survival times were estimated using the Kaplan-Meier method. Univariate and multivariate analyses using Cox proportional hazard regression models were used to determine if various prognostic factors could predict overall survival, distant brain failure, and local control.

      RESULTS: Median overall survival was 7.1 months and the 1-year local control rate was 91.5%. Median time to distant brain failure was 8.0 months. On univariate analysis an increasing total tumor volume was significantly associated with worse survival (p = 0.031) whereas the number of brain metastases, analyzed as a continuous variable, was not (p = 0.082). After adjusting for age, Karnofsky Performance Scale score, and extracranial disease on multivariate analysis, total tumor volume was found to be a better predictor of overall survival (p = 0.046) than number of brain metastases analyzed as a continuous variable (p = 0.098). A total tumor volume cutoff value of ≥ 2 cm(3) (p = 0.008) was a stronger predictor of overall survival than the number of brain metastases (p = 0.098). Larger tumor volume and extracranial disease, but not the number of brain metastases, were predictive of distant brain failure on multivariate analysis. Local tumor control at 1 year was 97% for lesions < 2 cm(3) compared with 75% for lesions ≥ 2 cm(3) (p < 0.001).

      CONCLUSIONS: After adjusting for other factors, a total brain metastasis volume was a strong and independent predictor for overall survival, distant brain failure, and local control, even when considering the number of metastases.

      View details for PubMedID 23971958
  • Toxicities and costs of placing prophylactic and reactive percutaneous gastrostomy tubes in patients with locally advanced head and neck cancers treated with chemoradiotherapy. Head Neck
    Baschnagel AM, Yadav S, Marina O, Parzuchowski A, Lanni TB, Warner JN, Parzuchowski JS, Ignatius RT, Akervall J, Chen PY, Krauss DJ
    2014 Aug; 36 (8): 1155-61
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      BACKGROUND: We compared dependence rates, complications, toxicities, and costs associated with prophylactic versus reactive percutaneous endoscopic gastrostomy (PEG) tube placement.

      METHODS: One hundred ninety-three patients with locally advanced head and neck squamous cell carcinoma treated with concurrent chemoradiotherapy were retrospectively reviewed.

      RESULTS: The 1-year and 2-year actuarial PEG tube dependence rate of the entire cohort was 24% and 13%, respectively. There was no difference in the PEG tube dependence rates between those placed prophylactically versus reactively. Patients who received a PEG tube reactively had a significantly higher stricture rate (p = .03) and aspiration rate (p < .001) compared to the prophylactic group. There were significantly fewer hospitalizations in the prophylactic group compared to the reactive group (p = .003). When accounting for both PEG placement and hospitalizations, the prophylactic approach was found to be more cost effective.

      CONCLUSION: PEG tubes placed prophylactically were associated with lower rates of strictures, aspirations, hospitalizations, and costs compared to those placed reactively.

      View details for PubMedID 23852670
  • A matched-pair comparison of intensity-modulated radiation therapy with cetuximab versus intensity-modulated radiation therapy with platinum-based chemotherapy for locally advanced head neck cancer. Int J Clin Oncol
    Huang J, Baschnagel AM, Chen P, Gustafson G, Jaiyesmi I, Folbe M, Ye H, Akervall J, Krauss D
    2014 Apr; 19 (2): 240-6
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      PURPOSE: We retrospectively compared the efficacy of intensity-modulated radiotherapy (IMRT) and cetuximab (IMRT/cetuximab) versus IMRT and platinum-based chemotherapy (IMRT/platinum) for locally advanced head neck squamous cell carcinoma (LAHNSCC).

      METHODS: Thirty-one IMRT/cetuximab patients were matched 1:2 with 62 IMRT/platinum patients according to primary site and clinical stage. The primary endpoint was locoregional recurrence (LRR), and secondary endpoints included distant metastasis (DM), cause-specific survival (CSS), and overall survival (OS).

      RESULTS: Because of inherent selection bias, the IMRT/cetuximab cohort was significantly older and with a higher Charlson Comorbidity Index. IMRT/cetuximab and IMRT/platinum did not have significantly different LRR and DM (33 vs. 23 % at 2 years, P = 0.22; 17 vs. 11 % at 2 years, P = 0.40; respectively). IMRT/cetuximab had significantly worse CSS and OS (67 vs. 84 %, P = 0.04; 58 vs. 83 %, P = 0.001; respectively). However, for the subset of elderly patients ≥65 years old, there is no difference between the two cohorts for all endpoints (all P = NS).

      CONCLUSION: IMRT/platinum should remain the preferred choice of chemoradiotherapy for LAHNSCC, but IMRT/cetuximab may be a reasonable alternative for elderly patients.

      View details for PubMedID 23479120
  • Lung metastases treated with image-guided stereotactic body radiation therapy. Clin Oncol (R Coll Radiol)
    Baschnagel AM, Mangona VS, Robertson JM, Welsh RJ, Kestin LL, Grills IS
    2013 Apr; 25 (4): 236-41
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      AIMS: To evaluate outcomes after treatment with image-guided stereotactic body radiation therapy (SBRT) using daily online cone beam computed tomography for malignancies metastatic to the lung.

      MATERIALS AND METHODS: Forty-seven lung metastases in 32 patients were treated with volumetrically guided SBRT. The median age was 62 years (21-87). Primaries included colorectal (n = 10), sarcoma (n = 4), head and neck (n = 4), melanoma (n = 3), bladder (n = 2), non-small cell lung cancer (n = 2), renal cell (n = 2), thymoma (n = 2), thyroid (n = 1), endometrial (n = 1) and oesophageal (n = 1). The number of lung metastases per patient ranged from one to three (68% single lesions). SBRT was prescribed to the edge of the target volume to a median dose of 60 Gy (48-65 Gy) in a median of four fractions (four to 10). Most lesions were treated using 12 Gy fractions (92%) to 48 or 60 Gy.

      RESULTS: The median follow-up was 27.6 months (7.6-57.1 months). The 1, 2 and 3 year actuarial local control rates for all treated lesions were 97, 92 and 85%, respectively. Two patients with colorectal primaries (four lesions in total) had local failure. The median overall survival was 40 months. The 1, 2 and 3 year overall survival from the time of SBRT completion was 83, 76 and 63%, respectively. There were no grade 4 or 5 toxicities. Grade 3 toxicities (one instance of each) included pneumonitis, dyspnoea, cough, rib fracture and pain.

      CONCLUSION: SBRT with daily online cone beam computed tomography for lung metastases achieved excellent local tumour control with low toxicity and encouraging 2 and 3 year survival.

      View details for PubMedID 23352916
  • Hearing preservation in patients with vestibular schwannoma treated with Gamma Knife surgery. J Neurosurg
    Baschnagel AM, Chen PY, Bojrab D, Pieper D, Kartush J, Didyuk O, Naumann IC, Maitz A, Grills IS
    2013 Mar; 118 (3): 571-8
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      OBJECT: Hearing loss after Gamma Knife surgery (GKS) in patients with vestibular schwannoma has been associated with radiation dose to the cochlea. The purpose of this study was to evaluate serviceable hearing preservation in patients with VS who were treated with GKS and to determine if serviceable hearing loss can be correlated with the dose to the cochlea.

      METHODS: Forty patients with vestibular schwannoma with serviceable hearing were treated using GKS with a median marginal dose of 12.5 Gy (range 12.5-13 Gy) to the 50% isodose volume. Audiometry was performed prospectively before and after GKS at 1, 3, and 6 months, and then every 6 months thereafter. Hearing preservation was based on pure tone average (PTA) and speech discrimination (SD). Serviceable hearing was defined as PTA less than 50 dB and SD greater than 50%.

      RESULTS: The median cochlear maximum and mean doses were 6.9 Gy (range 1.6-16 Gy) and 2.7 Gy (range 0.7-5.0 Gy), respectively. With a median audiological follow-up of 35 months (range 6-58 months), the 1-, 2-, and 3-year actuarial rates of maintaining serviceable hearing were 93%, 77%, and 74%, respectively. No patient who received a mean cochlear dose less than 2 Gy experienced serviceable hearing loss (p = 0.035). Patients who received a mean cochlear dose less than 3 Gy had a 2-year hearing preservation rate of 91% compared with 59% in those who received a mean cochlear dose of 3 Gy or greater (p = 0.029). Those who had more than 25% of their cochlea receiving 3 Gy or greater had a higher rate of hearing loss (p = 0.030). There was no statistically significant correlation between serviceable hearing loss and age, tumor size, pre-GKS PTA, pre-GKS SD, pre-GKS Gardner-Robertson class, maximum cochlear dose, or the percentage of cochlear volume receiving 5 Gy. On multivariate analysis there was a trend toward significance for serviceable hearing loss with a mean cochlear dose of 3 Gy or greater (p = 0.074). Local control was 100% at 24 months. No patient developed facial or trigeminal nerve dysfunction.

      CONCLUSIONS: With a median mean cochlear dose of 2.7 Gy, the majority of patients with serviceable hearing retained serviceable hearing 3 years after GKS. A mean cochlear dose less than 3 Gy was associated with higher serviceable hearing preservation.

      View details for PubMedID 23216466
  • Failure rate and cosmesis of immediate tissue expander/implant breast reconstruction after postmastectomy irradiation. Clin Breast Cancer
    Baschnagel AM, Shah C, Wilkinson JB, Dekhne N, Arthur DW, Vicini FA
    2012 Dec; 12 (6): 428-32
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      BACKGROUND: This study reports the rate of breast reconstruction failure and cosmetic outcomes after postmastectomy radiation therapy (PMRT) with temporary tissue expanders (TEs) or implants in place.

      PATIENTS AND METHODS: Ninety-four patients underwent mastectomy (93 unilateral, 1 bilateral; 95 cases total) and immediate TE reconstruction followed by PMRT. Ninety TEs and 5 permanent implants were irradiated. All patients received a dose of 5400 cGy given in 180-cGy fractions to the reconstructed breast. Twenty-one patients (22%) received tangents alone and 74 patients (78%) were treated with tangents and a supraclavicular field using a monoisocentric technique. Bolus was used in 91 patients (96%). Eighty-eight patients (93%) received chemotherapy and 78 patients (82%) received endocrine therapy.

      RESULTS: With a median follow-up of 24.1 months, 19 patients (20%) experienced failure of reconstruction. The 1-, 2-, and 3-year actuarial rate of reconstruction failure was 9.7%, 19.3%, and 25.5%, respectively. Infection was the most common cause of failure. Of the 19 failures, 8 patients underwent salvage procedures with flap reconstruction. Univariate analysis was performed examining age, chemotherapy use, hormone therapy use, use of a supraclavicular field, smoking status, diabetes, hypertension, and menopausal status. No risk factors were found to be associated with reconstruction failure. In patients who did not experience reconstruction failure, good/excellent cosmesis was observed in 75% of patients.

      CONCLUSION: In the current series of women with a high risk of locoregional recurrence, PMRT with a TE/implant in place provides good cosmesis in the majority of women, with an acceptable risk of expander or implant loss.

      View details for PubMedID 23062707

Contact Information

Andrew Baschnagel, MD

600 Highland Avenue, L7/B38,
Madison, WI 53792-0001