University of Wisconsin–Madison
Matthew Witek, MD

Matthew Witek, MD

Assistant Professor

Department of Human Oncology

I am an assistant professor in the Department of Human Oncology. I specialize in the management of patients with head and neck cancer and currently manage the vast majority of patients with head and neck cancer undergoing definitive, adjuvant and palliative radiotherapy at the University of Wisconsin. I have been active in resident teaching and recently received the Association of Residents in Radiation Oncology Educator of the Year Award at the University of Wisconsin. I am a member of the American Society of Radiation Oncology’s (ASTRO) head and neck education committee and review radiotherapy treatment plans for the Radiation Therapy Oncology Group national trials 1016 and 1216. At the local level, I coordinate the Head and Neck Cancer Resident Clinical Research Meeting. As for national leadership roles, I serve on the National Comprehensive Cancer Network (NCCN) head and neck steering committee. My research is aimed at exploiting tumor heterogeneity through biomarkers, treatment response and imaging characteristics to identify patients who may benefit from either therapy intensification or de-intensification. In addition, I am invested in evaluating the current standards of care regarding elective and non-elective treatment volumes for head and neck patients receiving radiotherapy. This research will possibly enable reduction in treatment volumes, thereby decreasing toxicity while maintaining similar cure rates.

Education

Resident, Thomas Jefferson University Hospital, Radiation Oncology (2014)

Intern, Lankenau Hospital, (2010)

MD, Jefferson Medical College, (2009)

MS, Thomas Jefferson University, Clinical Pharmacology (2004)

BS, Villanova University, Comprehensive Science (2001)

Academic Appointments

Assistant Clinical Professor, Human Oncology (2014)

Selected Honors and Awards

Educator of the Year Award, University of Wisconsin-Madison, Association of Residents in Radiation Oncology (2016)

Best Paper Award, American Association of Physicists in Medicine Annual Meeting (2015)

Roentgen Resident Research Award, Jefferson Medical College, Department of Radiation Oncology (2014)

Invitation to the AACR/ASCO Workshop on Methods in Clinical Cancer Research (2012)

Second Place, the Eastern-Atlantic Research Forum hosted by the University of Miami (2008)

Best Poster Presentation Medical Division, Sigma Xi Student Research Competition, Thomas Jefferson University (2006)

Best Poster Presentation Master’s Division, Sigma Xi Student Research Competition, Thomas Jefferson University (2004)

Top Abstract at the National Meeting for the American Society of Clinical Pharmacology and Therapeutics (2004)

Boards, Advisory Committees and Professional Organizations

Member, European Society of Radiation Oncology (ESTRO) (2017–pres.)

National Comprehensive Cancer Network (NCCN) Advisory Committee for the Head and Neck Cancer Section (2016–pres.)

Medical Physics Oversight Committee, University of Wisconsin–Madison (2016–pres.)

University of Wisconsin Medical Physics Steering Committee (2016–pres.)

ASTRO Education Committee, Head and Neck Section (2015–pres.)

Department of Human Oncology Clinical Trials Committee (2015–pres.)

Member, Radiological Society of North America (RSNA) (2015–pres.)

Member, NRG Oncology (2015–pres.)

Member, American Society of Radiation Oncology (ASTRO) (2010–pres.)

Member, American Society of Clinical Pharmacology and Therapeutics (ASCPT) (2002–2004)

Member, Sigma Xi Research Society (2002–2004)

  • 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):
    • More

      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
  • Results From a Free Oral Cancer Screening Clinic at a Major Academic Health Center: 10 Years of Free Oral Cancer Screening at an Academic Medical Center. Int J Radiat Oncol Biol Phys
    Blitzer GC, Rosenberg SA, Anderson BM, McCulloch TM, Wieland AM, Hartig GK, Bruce JY, Witek ME, Kimple RJ, Harari PM
    2018 Jul 03; :
  • NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018. J Natl Compr Canc Netw
    Colevas AD, Yom SS, Pfister DG, Spencer S, Adelstein D, Adkins D, Brizel DM, Burtness B, Busse PM, Caudell JJ, Cmelak AJ, Eisele DW, Fenton M, Foote RL, Gilbert J, Gillison ML, Haddad RI, Hicks WL, Hitchcock YJ, Jimeno A, Leizman D, Maghami E, Mell LK, Mittal BB, Pinto HA, Ridge JA, Rocco J, Rodriguez CP, Shah JP, Weber RS, Witek M, Worden F, Zhen W, Burns JL, Darlow SD
    2018 May; 16 (5): 479-490
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      The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

      View details for PubMedID 29752322
  • Survival Outcomes for Patients With T3N0M0 Squamous Cell Carcinoma of the Glottic Larynx-Reply. JAMA Otolaryngol Head Neck Surg
    Witek ME, Hartig GK, Harari PM
    2018 Apr 05; :
  • Are All Head and Neck Squamous Cell Carcinomas Created Equal? Int J Radiat Oncol Biol Phys
    Witek ME
    2017 12 01; 99 (5): 1059-1060
  • 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
  • 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
  • NCCN Guidelines Insights: Head and Neck Cancers, Version 2.2017. J Natl Compr Canc Netw
    Adelstein D, Gillison ML, Pfister DG, Spencer S, Adkins D, Brizel DM, Burtness B, Busse PM, Caudell JJ, Cmelak AJ, Colevas AD, Eisele DW, Fenton M, Foote RL, Gilbert J, Haddad RI, Hicks WL, Hitchcock YJ, Jimeno A, Leizman D, Lydiatt WM, Maghami E, Mell LK, Mittal BB, Pinto HA, Ridge JA, Rocco J, Rodriguez CP, Shah JP, Weber RS, Witek M, Worden F, Yom SS, Zhen W, Burns JL, Darlow SD
    2017 Jun; 15 (6): 761-770
    • More

      The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

      View details for PubMedID 28596256
  • 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
  • Pancreatic cancer planning: Complex conformal vs modulated therapies. Med Dosim
    Chapman KL, Witek ME, Chen H, Showalter TN, Bar-Ad V, Harrison AS
    2016; 41 (2): 100-4
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      To compare the roles of intensity-modulated radiation therapy (IMRT) and volumetric- modulated arc therapy (VMAT) therapy as compared to simple and complex 3-dimensional chemoradiotherpy (3DCRT) planning for resectable and borderline resectable pancreatic cancer. In all, 12 patients who received postoperative radiotherapy (8) or neoadjuvant concurrent chemoradiotherapy (4) were evaluated retrospectively. Radiotherapy planning was performed for 4 treatment techniques: simple 4-field box, complex 5-field 3DCRT, 5 to 6-field IMRT, and single-arc VMAT. All volumes were approved by a single observer in accordance with Radiation Therapy Oncology Group (RTOG) Pancreas Contouring Atlas. Plans included tumor/tumor bed and regional lymph nodes to 45Gy; with tumor/tumor bed boosted to 50.4Gy, at least 95% of planning target volume (PTV) received the prescription dose. Dose-volume histograms (DVH) for multiple end points, treatment planning, and delivery time were assessed. Complex 3DCRT, IMRT, and VMAT plans significantly (p < 0.05) decreased mean kidney dose, mean liver dose, liver (V30, V35), stomach (D10%), stomach (V45), mean right kidney dose, and right kidney (V15) as compared with the simple 4-field plans that are most commonly reported in the literature. IMRT plans resulted in decreased mean liver dose, liver (V35), and left kidney (V15, V18, V20). VMAT plans decreased small bowel (D10%, D15%), small bowel (V35, V45), stomach (D10%, D15%), stomach (V35, V45), mean liver dose, liver (V35), left kidney (V15, V18, V20), and right kidney (V18, V20). VMAT plans significantly decreased small bowel (D10%, D15%), left kidney (V20), and stomach (V45) as compared with IMRT plans. Treatment planning and delivery times were most efficient for simple 4-field box and VMAT. Excluding patient setup and imaging, average treatment delivery was within 10minutes for simple and complex 3DCRT, IMRT, and VMAT treatments. This article shows significant improvements in 3D plan performance with complex planning over the more frequently compared 3- or 4-field simple 3D planning techniques. VMAT plans continue to demonstrate potential for the most organ sparing. However, further studies are required to identify if dosimetric benefits associated with inverse optimized planning can be translated into clinical benefits and if these treatment techniques are value-added therapies for this group of patients with cancer.

      View details for PubMedID 26831922
  • Is financial literacy necessary for radiation oncology residents? Int J Radiat Oncol Biol Phys
    Witek M, Siglin J, Malatesta T, Snook A, Gressen E, Rudoler S, Bar-Ad V, Fisher S
    2014 Dec 01; 90 (5): 986-7
  • Optimizing patient positioning for intensity modulated radiation therapy in hippocampal-sparing whole brain radiation therapy. Pract Radiat Oncol
    Siglin J, Champ CE, Vakhnenko Y, Witek ME, Peng C, Zaorsky NG, Harrison AS, Shi W
    2014 Nov-Dec; 4 (6): 378-83
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      PURPOSE: Sparing the hippocampus during whole brain radiation therapy (WBRT) offers potential neurocognitive benefits. However, previously reported intensity modulated radiation therapy (IMRT) plans use multiple noncoplanar beams for treatment delivery. An optimized coplanar IMRT template for hippocampal-sparing WBRT would assist in clinical workflow and minimize resource utilization. In this study, we sought to determine the optimal patient position to facilitate coplanar treatment planning and delivery of hippocampal-sparing WBRT using IMRT.

      METHODS AND MATERIALS: A variable angle, inclined board was utilized for patient positioning. An anthropomorphic phantom underwent computed tomography simulation at various head angles. The IMRT goals were designed to achieve target coverage of the brain while maintaining hippocampal dose-volume constraints designed to conform to the Radiation Therapy Oncology Group 0933 protocol. Optimal head angle was then verified using data from 8 patients comparing coplanar and noncoplanar WBRT IMRT plans.

      RESULTS: Hippocampal, hippocampal avoidance region, and whole brain mean volumes were 1.1 cm(3), 12.5 cm(3), and 1185.1 cm(3), respectively. The hippocampal avoidance region occupied 1.1% of the whole brain planning volume. For the 30-degree head angle, a 7-field coplanar IMRT plan was generated, sparing the hippocampus to a maximum dose of 14.7 Gy; D100% of the hippocampus was 7.4 Gy and mean hippocampal dose was 9.3 Gy. In comparison, for flat head positioning the hippocampal Dmax was 22.9 Gy with a D100% of 9.2 Gy and mean dose of 11.7 Gy. Target coverage and dose homogeneity was comparable with previously published noncoplanar IMRT plans.

      CONCLUSIONS: Compared with conventional supine positioning, an inclined head board at 30 degrees optimizes coplanar whole brain IMRT treatment planning. Clinically acceptable hippocampal-sparing WBRT dosimetry can be obtained using a simplified coplanar plan at a 30-degree head angle, thus obviating the need for complex and time consuming noncoplanar IMRT plans.

      View details for PubMedID 25407858
  • A novel CDX2 isoform regulates alternative splicing. PLoS One
    Witek ME, Snook AE, Lin JE, Blomain ES, Xiang B, Magee MS, Magee M, Waldman SA
    2014; 9 (8): e104293
    • More

      Gene expression is a dynamic and coordinated process coupling transcription with pre-mRNA processing. This regulation enables tissue-specific transcription factors to induce expression of specific transcripts that are subsequently amplified by alternative splicing allowing for increased proteome complexity and functional diversity. The intestine-specific transcription factor CDX2 regulates development and maintenance of the intestinal epithelium by inducing expression of genes characteristic of the mature enterocyte phenotype. Here, sequence analysis of CDX2 mRNA from colonic mucosa-derived tissues revealed an alternatively spliced transcript (CDX2/AS) that encodes a protein with a truncated homeodomain and a novel carboxy-terminal domain enriched in serine and arginine residues (RS domain). CDX2 and CDX2/AS exhibited distinct nuclear expression patterns with minimal areas of co-localization. CDX2/AS did not activate the CDX2-dependent promoter of guanylyl cyclase C nor inhibit transcriptional activity of CDX2. Unlike CDX2, CDX2/AS co-localized with the putative splicing factors ASF/SF2 and SC35. CDX2/AS altered splicing patterns of CD44v5 and Tra2-β1 minigenes in Lovo colon cancer cells independent of CDX2 expression. These data demonstrate unique dual functions of the CDX2 gene enabling it to regulate gene expression through both transcription (CDX2) and pre-mRNA processing (CDX2/AS).

      View details for PubMedID 25101906
  • Molecular markers to predict clinical outcome and radiation induced toxicity in lung cancer. J Thorac Dis
    Palmer JD, Zaorsky NG, Witek M, Lu B
    2014 Apr; 6 (4): 387-98
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      The elucidation of driver mutations involved in the molecular pathogenesis of cancer has led to a surge in the application of novel targeted therapeutics in lung cancer. Novel oncologic research continues to lead investigators towards targeting personalized tumor characteristics rather than applying targeted therapy to broad patient populations. Several driver genes, in particular epidermal growth factor receptor (EGFR) and ALK fusions, are the earliest to have made their way into clinical trials. The avant-garde role of genomic profiling has led to important clinical challenges when adapting current standard treatments to personalized oncologic care. This new frontier of medicine requires newer biomarkers for toxicity that will identify patients at risk, as well as, new molecular markers to predict and assess clinical outcomes. Thus far, several signature genes have been developed to predict outcome as well as genetic factors related to inflammation to predict toxicity.

      View details for PubMedID 24688783
  • Tumor radiation therapy creates therapeutic vaccine responses to the colorectal cancer antigen GUCY2C. Int J Radiat Oncol Biol Phys
    Witek M, Blomain ES, Magee MS, Xiang B, Waldman SA, Snook AE
    2014 Apr 01; 88 (5): 1188-95
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      PURPOSE: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined.

      METHODS AND MATERIALS: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence.

      RESULTS: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells.

      CONCLUSIONS: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance of modality sequence optimization before the initiation of clinical trials of RT and IT to maximize immune and antitumor responses.

      View details for PubMedID 24661671
  • Treatment-related acute esophagitis for patients with locoregionally advanced non-small cell lung cancer treated with involved-field radiotherapy and concurrent chemotherapy. Am J Clin Oncol
    Bar-Ad V, Leiby B, Witek M, Xiao Y, Cui Y, Dai Y, Cao J, Axelrod R, Campling B, Both S, Werner-Wasik M
    2014 Oct; 37 (5): 433-7
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      PURPOSE: To explore the incidence and risk factors for treatment-related acute esophagitis associated with involved-field radiation therapy (RT) delivered concurrently with chemotherapy for patients with locoregionally advanced non-small cell lung cancer.

      MATERIALS AND METHODS: Forty-nine consecutive patients diagnosed with locoregionally advanced non-small cell lung cancer were treated using involved-field RT. Radiotherapy target volumes included the primary lung tumor and involved mediastinal lymphadenopathy as defined on imaging studies including computed tomography of the chest and fluorodeoxyglucose-positron emission tomography/computed tomography. The patients were treated to a median total dose of 63 Gy (range, 55.8 to 74 Gy) using daily fractions of 1.8 or 2.0 Gy. No elective radiotherapy of mediastinal lymph nodes was used. Concurrent platinum-based chemotherapy was delivered to all patients. Treatment-related toxicity was evaluated during the course of RT and subsequent follow-up visits.

      RESULTS: Thirty-one (63%) patients were female and 18 (37%) were male. Median age at the time of diagnosis was 68 years (range, 36 to 83 y). Thirty-one patients (63%) developed treatment-related acute esophagitis: 24 patients (49%) grade 2 and 7 (14%) patients grade 3 esophagitis, with the peak occurring during the seventh week of radiotherapy. No grade ≥ 4 esophagitis was seen in this cohort. Eighteen patients (37%) did not develop radiation-induced esophagitis associated with their course of chemoradiotherapy. In the univariate analysis, age at the time of diagnosis, radiation dose per fraction, and total volume of the esophagus were significantly associated with the risk of acute esophagitis. Increasing age reduced the risk of acute esophagitis (odds ratio [OR] for 10-y increase = 0.40) as did increasing total esophagus volume (OR for 10-U increase = 0.27). Dose per fraction of 1.8 Gy was associated with lower risk of acute esophagitis when compared with dose per fraction of 2 Gy (OR = 0.19). Marginal associations were observed for all of the volume variables. Higher volume variable values had a nonsignificant association with an increase in risk of acute esophagitis. However, only the total volume of the esophagus (P = 0.0032) and larger dose per fraction (2 vs. 1.8 Gy) (P = 0.011) remained significantly associated with higher risk of developing grade ≥ 2 acute esophagitis in the multivariate analysis.

      CONCLUSIONS: Higher risk of grade ≥ 2 treatment-related esophagitis was associated with lower total esophageal volume and higher radiotherapy dose per fraction and should be taken into consideration during patient treatment planning. Inclusion of total esophageal volume and dose per fraction into future clinical protocols may further help our understanding of treatment-related esophagitis and enable the development of novel preventative approaches.

      View details for PubMedID 23388558
  • Fractionated stereotactic radiation therapy improves cranial neuropathies in patients with skull base meningiomas: a retrospective cohort study. Radiat Oncol
    Shen X, Andrews DW, Sergott RC, Evans JJ, Curran WJ, Machtay M, Fragoso R, Eldredge H, Champ CE, Witek M, Mishra MV, Dicker AP, Werner-Wasik M
    2012 Dec 28; 7: 225
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      BACKGROUND: Skull base meningiomas commonly present with cranial neuropathies. Fractionated stereotactic radiation therapy (FSRT) has been used to treat these tumors with excellent local control, but rates of improvement in cranial neuropathies have not been well defined. We review the experience at Thomas Jefferson University using FSRT in the management of these patients with a focus on symptom outcomes.

      METHODS: We identified 225 cases of skull base meningiomas treated with FSRT at Thomas Jefferson University from 1994 through 2009. The target volume was the enhancing tumor, treated to a standard prescription dose of 54 Gy. Symptoms at the time of RT were classified based on the cranial nerve affected. Logistic regression was performed to determine predictors of symptom improvement after FSRT.

      RESULTS: The median follow-up time was 4.4 years. In 92% of cases, patients were symptomatic at the time of RT; the most common were impaired visual field/acuity (58%) or extraocular movements (34%). After FSRT, durable improvement of at least one symptom occurred in 57% of cases, including 40% of visual acuity/visual field deficits, and 40% of diplopia/ptosis deficits. Of all symptomatic patients, 27% experienced improvement of at least one symptom within 2 months of the end of RT.

      CONCLUSIONS: FSRT is very effective in achieving improvement of cranial neuropathies from skull base meningiomas, particularly visual symptoms. Over half of treated patients experience a durable improvement of at least one symptom, frequently within 2 months from the end of RT.

      View details for PubMedID 23270432
  • The transcription factor encyclopedia. Genome Biol
    Yusuf D, Butland SL, Swanson MI, Bolotin E, Ticoll A, Cheung WA, Zhang XY, Dickman CT, Fulton DL, Lim JS, Schnabl JM, Ramos OH, Vasseur-Cognet M, de Leeuw CN, Simpson EM, Ryffel GU, Lam EW, Kist R, Wilson MS, Marco-Ferreres R, Brosens JJ, Beccari LL, Bovolenta P, Benayoun BA, Monteiro LJ, Schwenen HD, Grontved L, Wederell E, Mandrup S, Veitia RA, Chakravarthy H, Hoodless PA, Mancarelli MM, Torbett BE, Banham AH, Reddy SP, Cullum RL, Liedtke M, Tschan MP, Vaz M, Rizzino A, Zannini M, Frietze S, Farnham PJ, Eijkelenboom A, Brown PJ, Laperrière D, Leprince D, de Cristofaro T, Prince KL, Putker M, del Peso L, Camenisch G, Wenger RH, Mikula M, Rozendaal M, Mader S, Ostrowski J, Rhodes SJ, Van Rechem C, Boulay G, Olechnowicz SW, Breslin MB, Lan MS, Nanan KK, Wegner M, Hou J, Mullen RD, Colvin SC, Noy PJ, Webb CF, Witek ME, Ferrell S, Daniel JM, Park J, Waldman SA, Peet DJ, Taggart M, Jayaraman PS, Karrich JJ, Blom B, Vesuna F, O'Geen H, Sun Y, Gronostajski RM, Woodcroft MW, Hough MR, Chen E, Europe-Finner GN, Karolczak-Bayatti M, Bailey J, Hankinson O, Raman V, LeBrun DP, Biswal S, Harvey CJ, DeBruyne JP, Hogenesch JB, Hevner RF, Héligon C, Luo XM, Blank MC, Millen KJ, Sharlin DS, Forrest D, Dahlman-Wright K, Zhao C, Mishima Y, Sinha S, Chakrabarti R, Portales-Casamar E, Sladek FM, Bradley PH, Wasserman WW
    2012; 13 (3): R24
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      Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

      View details for PubMedID 22458515
  • Bile acids initiate lineage-addicted gastroesophageal tumorigenesis by suppressing the EGF receptor-AKT axis. Clin Transl Sci
    Gong L, Debruyne PR, Witek M, Nielsen K, Snook A, Lin JE, Bombonati A, Palazzo J, Schulz S, Waldman SA
    2009 Aug; 2 (4): 286-93
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      While bile acids are a risk factor for tumorigenesis induced by reflux disease, the mechanisms by which they contribute to neoplasia remain undefined. Here, we reveal that in gastroesophageal junction (GEJ) cells bile acids activate a tissue-specific developmental program defining the intestinal epithelial cell phenotype characterizing GEJ metaplasia. Deoxycholic acid (DCA) inhibited phosphorylation of EGF receptors (EGFRs) suppressing the proto-oncogene AKT. Suppression of EGFRs and AKT by DCA actuated an intestine-specific cascade in which NF-kappaB transactivated the tissue-specific transcription factor CDX2. In turn, CDX2 orchestrated a lineage-specific differentiation program encompassing genes characterizing intestinal epithelial cells. Conversely, progression from metaplasia to invasive carcinoma in patients, universally associated with autonomous activation of EGFRs and/or AKT, was coupled with loss of this intestinal program. Thus, bile acids induce intestinal metaplasia at the GEJ by activating the lineage-specific differentiation program involving suppression of EGFR and AKT, activating the NF-kappaB-CDX2 axis. Induction of this axis provides the context for lineage-addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF-kappaB signaling, amplifying tumorigenic programs.

      View details for PubMedID 20443907
  • A validated quantitative assay to detect occult micrometastases by reverse transcriptase-polymerase chain reaction of guanylyl cyclase C in patients with colorectal cancer. Clin Cancer Res
    Schulz S, Hyslop T, Haaf J, Bonaccorso C, Nielsen K, Witek ME, Birbe R, Palazzo J, Weinberg D, Waldman SA
    2006 Aug 01; 12 (15): 4545-52
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      PURPOSE: Guanylyl cyclase C (GCC), a receptor for bacterial diarrheagenic enterotoxins, may be a prognostic and predictive marker to detect occult micrometastases in patients undergoing staging for colorectal cancer. However, quantification of GCC expression in tissues by the quantitative reverse transcription-PCR (qRT-PCR) has not undergone analytic and clinicopathologic validation.

      EXPERIMENTAL DESIGN: A technique to quantify GCC mRNA in tissues employing RT-PCR was developed and validated employing external calibration standards of RNA complementary to GCC.

      RESULTS: GCC qRT-PCR exhibited reaction efficiencies >92%, coefficients of variations <5%, linearity >6 orders of magnitude, and a limit of quantification of >25 copies of GCC cRNA. This assay confirmed that GCC mRNA was overexpressed by colorectal tumors from 41 patients, which correlated with increased GCC protein quantified by immunohistochemistry. Analyses obtained with 164 lymph nodes from patients free of cancer and 15 nodes harboring metastases established a threshold for metastatic disease of approximately 200 GCC mRNA copies/mug total RNA, with a sensitivity of 93% and specificity of 97%. GCC mRNA above that threshold was detected in 76 of 367 (approximately 21%) nodes free of disease by histopathology from 6 of 23 (26%) patients, suggesting the presence of occult micrometastases.

      CONCLUSIONS: Quantifying GCC mRNA in tissues by RT-PCR employing external calibration standards is analytically robust and reproducible, with high clinicopathologic sensitivity and specificity. This validated assay is being applied to approximately 10,000 lymph nodes in a prospective trial to define the sensitivity of GCC qRT-PCR for staging patients with colorectal cancer.

      View details for PubMedID 16899600
  • Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells. Gastroenterology
    Debruyne PR, Witek M, Gong L, Birbe R, Chervoneva I, Jin T, Domon-Cell C, Palazzo JP, Freund JN, Li P, Pitari GM, Schulz S, Waldman SA
    2006 Apr; 130 (4): 1191-206
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      BACKGROUND & AIMS: Although progression to adenocarcinoma at the gastroesophageal junction reflects exposure to acid and bile acids associated with reflux, mechanisms mediating this transformation remain undefined. Guanylyl cyclase C (GC-C), an intestine-specific tumor suppressor, may represent a mechanism-based marker and target of transformation at the gastroesophageal junction. The present studies examine the expression of GC-C in normal tissues and tumors from esophagus and stomach and mechanisms regulating its expression by acid and bile acids.

      METHODS: Gene expression was examined by reverse-transcription polymerase chain reaction, promoter analysis, immunohistochemistry, immunoblotting, and functional analysis. Promoter transactivation was quantified by using luciferase constructs and mutational analysis. DNA binding of transcription factors was examined by electromobility shift analysis.

      RESULTS: GC-C mRNA and protein were ectopically expressed in approximately 80% of adenocarcinomas arising in, but not in normal, esophagus and stomach. Similarly, in OE19 human esophageal cancer cells, deoxycholate and acid induced expression of GC-C. This was associated with the induction of expression of Cdx2, a transcription factor required for GC-C expression. In turn, induction of Cdx2 expression by deoxycholate was mediated by binding sites in the proximal promoter for nuclear factor kappaB (NF-kappaB). Furthermore, deoxycholate increased NF-kappaB activity, associated with nuclear translocation and Cdx2 promoter binding of the NF-kappaB subunit p50. Moreover, a dominant negative construct for NF-kappaB prevented deoxycholate-induced p50 nuclear translocation and activation of the Cdx2 promoter.

      CONCLUSIONS: Transformation associated with reflux at the gastroesophageal junction reflects activation by bile acid and acid of a transcriptional program involving NF-kappaB and Cdx2, which mediate intestinal metaplasia and ectopic expression of GC-C.

      View details for PubMedID 16618413
  • The putative tumor suppressor Cdx2 is overexpressed by human colorectal adenocarcinomas. Clin Cancer Res
    Witek ME, Nielsen K, Walters R, Hyslop T, Palazzo J, Schulz S, Waldman SA
    2005 Dec 15; 11 (24 Pt 1): 8549-56
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      PURPOSE: The current paradigm suggests that the homeodomain transcription factor Cdx2, which directs the development and maintenance of the intestinal epithelium, is a tumor suppressor in the colon and rectum. Although a cardinal property of tumor suppressors is their inactivation during carcinogenesis, the expression of Cdx2 in colorectal tumors has not been compared with that in normal mucosa. Here, Cdx2 expression and function was quantified in tumors and matched normal mucosa from patients with colorectal cancer.

      EXPERIMENTAL DESIGN: Cdx2 expression was quantified by reverse transcription-PCR, immunoblot analysis, and immunohistochemistry. Transcriptional activity was explored by quantifying expression of an endogenous downstream target of Cdx2, guanylyl cyclase C (GCC), in tissues by quantitative reverse transcription-PCR and expression of exogenous Cdx2-specific luciferase promoter constructs in epithelial cells isolated from tumors and normal mucosa.

      RESULTS: Most (>80%) colorectal tumors overexpressed Cdx2 mRNA and protein compared with normal mucosa, with median fold increases of 3.6 and 1.4, respectively (P<0.002). Concomitantly, immunohistochemistry revealed elevated levels of Cdx2 in nuclei of tumor cells compared with normal epithelial cells. Further, tumors exhibited increased expression of GCC compared with normal mucosa. Moreover, cells isolated from tumors overexpressed a Cdx2-specific luciferase promoter construct compared with normal mucosal cells.

      CONCLUSION: These observations show, for the first time, the structural and functional overexpression of Cdx2 by human colorectal tumors compared with matched normal mucosa. They suggest that loss of Cdx2 expression or transcriptional activity is an infrequent event during tumorigenesis, which does not contribute to molecular mechanisms underlying initiation and progression of most colorectal tumors.

      View details for PubMedID 16361536

 

 

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Matthew Witek, MD

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