Eben Rosenthal is a surgeon-scientist and academic leader. He is currently serving as the John and Ann Doerr Medical Director of the Stanford Cancer Center, a position he has held since July 2015. He works collaboratively with the Stanford Cancer Institute and Stanford Health Care leaders to set the strategy for the clinical delivery of cancer care across Stanford Medicine and growing cancer networks.

Before coming to Stanford, he learned his surgical skills in otolaryngology from the University of Michigan and traveled west for further training in facial plastic and reconstructive surgery at the Oregon Health and Science University. He joined the faculty at University of Alabama at Birmingham where he started as an Assistant Professor of Surgery within the Division of Otolaryngology. In 2012, Dr. Rosenthal became Division Director of Otolaryngology – Head and Neck Surgery and the holder of the John S. Odess Endowed Chair at the University of Alabama at Birmingham. He moved to Stanford in 2015 to become the Ann and John Doerr Medical Director of the Stanford Cancer Center.

Dr. Rosenthal is certified by the American Board of Otolaryngology and is a Diplomat of the American Board of Facial Plastic and Reconstructive Surgery. He specializes in the treatment and reconstruction of head and neck cancer patients. He has a strong interest in development of new strategies to surgically repair complex head and neck defects to improve functional and cosmetic outcomes.

He has published over 160 peer-reviewed scientific manuscripts, authored many book chapters and published a book on optical imaging in cancer. He is on the editorial board of Head & Neck and The Laryngoscope and is also a charter member of the NIH Developmental Therapeutics Study Section. Dr. Rosenthal has performed preclinical and clinical research on the role of targeted therapies for use to treat cancer alone and in combination with conventional therapy. He has served as principal investigator on several early phase investigator-initiated and industry sponsored clinical trials in molecular oncology. He has received grant funding from the American Cancer Society, NIH/NCI and NIH/NIDCR to study the role of targeted therapy and novel imaging strategies in cancer.

Dr. Rosenthal has conducted bench to bedside development of optical contrast agents to identify cancer in the operating room. He led a multidisciplinary team of scientists through successful IND application to allow testing of fluorescently labeled antibodies in the clinic and operating room. These early phase clinical trials have demonstrated that this technique can visualize microscopic cancer in the operating room and may significantly improve clinical outcomes.

Clinical Focus

  • Otolaryngology

Academic Appointments

Administrative Appointments

  • Ann and John Doerr Medical Director, Stanford Cancer Center (2015 - Present)
  • Associate Director of Clinical Care, Stanford Cancer Institute (2015 - Present)

Boards, Advisory Committees, Professional Organizations

  • Member, American Academy of Otolaryngology (1995 - Present)
  • Microvascular Committee, American Academy of Otolaryngology (2002 - 2014)
  • Member, Society of University Otolaryngologists - Head and Neck Surgeons (2002 - Present)
  • Fellow, American College of Surgeons (2003 - Present)
  • Member, North American Craniomaxillofacial Education Committee (2004 - 2007)
  • Research Education Committee, American Academy of Otolaryngology (2004 - 2007)
  • Centralized Otolaryngology Research Efforts (CORE) Grant Review Comm Program, American Academy of Otolaryngology (2004 - 2011)
  • Member, American Association for Cancer Research (2004 - Present)
  • Member, American Head and Neck Society (2006 - Present)
  • Member, Triological Society (2006 - Present)
  • Associate Editor, Head & Neck (2007 - Present)
  • Editorial Board Member, The Laryngoscope (2007 - Present)
  • Member, World Molecular Imaging Society (2010 - Present)
  • Chair, Program Advisory Committee, American Academy of Otolaryngology (2011 - Present)
  • Editorial Board Member, World Journal of Clinical Oncology (2015 - Present)
  • Editorial Board Member, Laryngoscope (2015 - Present)

Professional Education

  • Residency:University of Michigan
  • Internship:University of MichiganMI
  • Board Certification: Otolaryngology, American Board of Otolaryngology (2001)
  • Medical Education:University of Michigan (1994) MI
  • Fellowship:Oregon Health and Sciences UniversityOR
  • BA, Haverford College (1988)
  • MD, University of Michigan Medical School (1994)

Clinical Trials

  • Panitumumab-IRDye800 in Detecting Cancer in Participants With Lung Cancer During Surgery Recruiting

    This phase I/II trial studies the best dose and timing of panitumumab-IRDye800 in detecting cancer in participants with lung cancer during the surgery. Panitumumab-IRDye800 is a combination of the antibody drug panitumumab and IRDye800CW, an investigational dye that can be seen using a special camera. Panitumumab-IRDye800 may attach to tumor cells and make them more visible during surgery in patients with lung cancer.

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  • Panitumumab-IRDye800 in Diagnosing Participants With Malignant Glioma Undergoing Surgery Recruiting

    The phase I/II trial studies the side effects and best dose of panitumumab-IRDye800 in diagnosing participants with malignant glioma who undergo surgery. Panitumumab-IRDye800 can attach to tumor cells and make them more visible using a special camera during surgery, which may help surgeons better distinguish tumor cells from normal brain tissue and identify small tumors that cannot be seen using current imaging methods.

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  • Panitumumab-IRDye800 in Patients With Pancreatic Cancer Undergoing Surgery Recruiting

    This phase I/II trial studies the side effects and best dose of panitumumab-IRDye800 and to see how well it works in finding cancer in patients with pancreatic cancer who are undergoing surgery. Panitumumab-IRDye800 is a combination of the antibody drug panitumumab and IRDye800CW, an investigational dye that can be seen using a special camera. Panitumumab-IRDye800 may attach to tumor cells and make them more visible during surgery in patients with pancreatic cancer.

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  • Phase I Panitumumab IRDye800 Optical Imaging Study Recruiting

    Phase I trial to evaluate the safety of escalating dose levels of conjugated panitumumab-IRDye800 in subjects with head and neck squamous cell carcinoma (HNSCC) that undergo surgery with curative intent.

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  • Cetuximab IRDye800 Study as an Optical Imaging Agent to Detect Cancer During Surgical Procedures Not Recruiting

    This study is an open label, single institution, Phase 1 dose-escalation study to determine the safety profile of cetuximab-IRDye800 used in subjects with head and neck squamous cell carcinoma (HNSCC) that undergo surgery with curative intent. Participants will be given a dose of an approved head and neck cancer drug (Cetuximab) along with an investigational study drug called Cetuximab-IRDye800. Cetuximab-IRDye800 is a drug that is given prior to surgery that attaches to cancer cells and appears to make them visible to the doctor when he uses a special camera during the operation. The investigators are evaluating whether or not the use of the study drug along with the special camera will better identify the cancer while patients are in the operating room.

    Stanford is currently not accepting patients for this trial. For more information, please contact Alifia Hasan, 650-721-4088.

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  • Cetuximab-IRDye 800CW and Intraoperative Imaging in Finding Pancreatic Cancer in Patients Undergoing Surgery Not Recruiting

    This phase 1-2 trial studies the side effects and best dose of cetuximab-IRDye 800CW when used with intraoperative imaging and to see how well they work in finding pancreatic cancer in patients undergoing surgery. Cetuximab-IRDye 800CW may help doctors better identify cancer in the operating room by making the cancer visible when viewed through a special imaging device.

    Stanford is currently not accepting patients for this trial. For more information, please contact Alifia Hasan, 650-721-4088.

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  • Cetuximab-IRDye 800CW in Detecting Tumors in Patients With Malignant Glioma Undergoing Surgery Not Recruiting

    This study is a phase 1-2 trial that evaluates the best dose of cetuximab-IRDye 800CW and how well it works in detecting tumors in patients with malignant glioma who are undergoing surgery. Cetuximab-IRDye 800CW is an optical imaging agent that may help detect tumor cells when a special camera is used.

    Stanford is currently not accepting patients for this trial. For more information, please contact Alifia Hasan, 650-721-4088.

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  • Panitumumab-IRDye800 Compared to Sentinel Node Biopsy and (Selective) Neck Dissection in Identifying Metastatic Lymph Nodes in Patients With Head and Neck Cancer Not Recruiting

    This phase II trial studies how well panitumumab-IRDye800 works in identifying head and neck cancer that has spread to the lymph nodes in patients with head and neck cancer. Panitumumab-IRDye800 may help surgeons to identify metastatic lymph nodes during surgical removal of the primary tumor and/or lymph nodes of the neck with equal or better accuracy than the current methods.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nick Oberhelman, 650-724-3866.

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2018-19 Courses

Stanford Advisees

All Publications

  • Regionalization of Head and Neck Cancer Surgery May Fragment Care and Impact Overall Survival. The Laryngoscope Chen, M. M., Megwalu, U. C., Liew, J., Sirjani, D., Rosenthal, E. L., Divi, V. 2018


    OBJECTIVE: While surgical treatment concentrates in tertiary care centers, an increasing number of patients request postoperative radiation therapy (PORT) at a separate center closer to home. Our goal was to determine whether fragmentation of surgery and PORT were associated with poorer oncologic outcomes.METHODS: We conducted a retrospective cohort study of 32,813 head and neck cancer patients treated with surgery and PORT in the National Cancer Data Base. Our main outcome was overall survival (OS). Statistical analysis included chi2 , t tests, Kaplan-Meier, and Cox regression analysis.RESULTS: Fragmented care was independently associated with increased risk of mortality (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.03-1.13), whereas distance to surgical center>30 miles (HR, 0.92; 95% CI, 0.87-0.97) was associated with improved OS. On subgroup analysis, fragmented care was associated with decreased OS only among patients who had surgery at an academic center (HR, 1.10; 95% CI, 1.04-1.17). Within academic centers, greater distance from the surgical center was associated with improved survival only in patients who received PORT at the same facility (HR, 0.85; 95% CI, 0.78-0.93), but this effect was negated among patients who had fragmented care (HR, 0.97; 95% CI, 0.85-1.11).CONCLUSION: When cancer care is fragmented, there is no longer a survival benefit for patients to travel for surgical care at academic medical centers. Fragmented care is independently associated with worse survival, and further research is needed to evaluate the causes of this difference in survival to determine if improving care coordination can mitigate this survival difference.LEVEL OF EVIDENCE: NA. Laryngoscope, 2018.

    View details for DOI 10.1002/lary.27440

    View details for PubMedID 30152007

  • Intraoperative Pancreatic Cancer Detection using Tumor-Specific Multimodality Molecular Imaging. Annals of surgical oncology Tummers, W. S., Miller, S. E., Teraphongphom, N. T., Gomez, A., Steinberg, I., Huland, D. M., Hong, S., Kothapalli, S., Hasan, A., Ertsey, R., Bonsing, B. A., Vahrmeijer, A. L., Swijnenburg, R., Longacre, T. A., Fisher, G. A., Gambhir, S. S., Poultsides, G. A., Rosenthal, E. L. 2018; 25 (7): 1880–88


    BACKGROUND: Operative management of pancreatic ductal adenocarcinoma (PDAC) is complicated by several key decisions during the procedure. Identification of metastatic disease at the outset and, when none is found, complete (R0) resection of primary tumor are key to optimizing clinical outcomes. The use of tumor-targeted molecular imaging, based on photoacoustic and fluorescence optical imaging, can provide crucial information to the surgeon. The first-in-human use of multimodality molecular imaging for intraoperative detection of pancreatic cancer is reported using cetuximab-IRDye800, a near-infrared fluorescent agent that binds to epidermal growth factor receptor.METHODS: A dose-escalation study was performed to assess safety and feasibility of targeting and identifying PDAC in a tumor-specific manner using cetuximab-IRDye800 in patients undergoing surgical resection for pancreatic cancer. Patients received a loading dose of 100mg of unlabeled cetuximab before infusion of cetuximab-IRDye800 (50mg or 100mg). Multi-instrument fluorescence imaging was performed throughout the surgery in addition to fluorescence and photoacoustic imaging ex vivo.RESULTS: Seven patients with resectable pancreatic masses suspected to be PDAC were enrolled in this study. Fluorescence imaging successfully identified tumor with a significantly higher mean fluorescence intensity in the tumor (0.09±0.06) versus surrounding normal pancreatic tissue (0.02±0.01), and pancreatitis (0.04±0.01; p<0.001), with a sensitivity of 96.1% and specificity of 67.0%. The mean photoacoustic signal in the tumor site was 3.7-fold higher than surrounding tissue.CONCLUSIONS: The safety and feasibilty of intraoperative, tumor-specific detection of PDAC using cetuximab-IRDye800 with multimodal molecular imaging of the primary tumor and metastases was demonstrated.

    View details for DOI 10.1245/s10434-018-6453-2

    View details for PubMedID 29667116

  • Outcomes in Head and Neck Resections That Require Multiple-Flap Reconstructions: A Systematic Review. JAMA otolaryngology-- head & neck surgery Gao, R. W., Nuyen, B. A., Divi, V., Sirjani, D., Rosenthal, E. L. 2018


    Complex head and neck cancer defects that require multiflap reconstructions are technically feasible, but the morbidity and patient outcomes of such large-scale head and neck operations have yet to be systematically reviewed.To systematically review existing literature to characterize the outcomes of large-scale head and neck resections that require multiple-flap reconstructions (defined as defects that require >1 flap [free, pedicled, or combinations thereof]).Two authors independently searched PubMed, Embase, and the Cochrane Review databases for English-only texts published on any date. Included studies examined patients who underwent complex head and neck surgical resections that required multiple simultaneous flaps for reconstruction. Included studies reported results on at least one of the following outcomes: functional and aesthetic, patient survival, or cost (estimated by operating room time, length of stay, and/or complications). Methodological Index for Non-Randomized Studies (MINORS) criteria for bias and modified Oxford Centre for Evidence-Based Medicine recommendations were used to assess study quality.Twenty-four studies published from November 1, 1992, through September 1, 2016, met the final inclusion criteria, with a total of 487 patients (370 male [79.4%]; mean [SD] weighted age, 55.1 [4.1] years). Sixty-two of 250 patients (24.8%) were partially or fully dependent on feeding tubes at follow-up. Twenty-two of 75 patients (29.3%) had poor postoperative oral competence, causing moderate to severe drooling. Nineteen of 108 patients (17.6%) had unintelligible speech. Nine of 64 patients (14.1%) were unsatisfied with their aesthetic outcome. The mean (SD) reported survival was 2.36 (1.39) years. The mean (SD) length of stay was 24.5 (12.2) days in 219 patients. Eighty-eight minor complications (eg, partial flap necrosis, donor site complications) and 185 major complications (eg, surgical reexplorations, flap loss, or cardiopulmonary complications) were reported in 380 patients. Mean (SD) MINORS scores were 16.0 (3.2) for comparison studies and 11.4 (1.8) for noncomparison studies.Because of limited patient life expectancies, modest functional and aesthetic outcomes, and significant associated costs, surgeons should weigh the curative potential and palliative benefits for individual patients with a comprehensive view of the overall outcomes of extensive head and neck resections and reconstructions. Realistic expectations should be emphasized during preoperative discussions with patients.

    View details for DOI 10.1001/jamaoto.2018.0835

    View details for PubMedID 29978196

  • First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800. Journal of neuro-oncology Miller, S. E., Tummers, W. S., Teraphongphom, N., van den Berg, N. S., Hasan, A., Ertsey, R. D., Nagpal, S., Recht, L. D., Plowey, E. D., Vogel, H., Harsh, G. R., Grant, G. A., Li, G. H., Rosenthal, E. L. 2018


    Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection.Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue.The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence.This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.

    View details for DOI 10.1007/s11060-018-2854-0

    View details for PubMedID 29623552

  • Regulatory Aspects of Optical Methods and Exogenous Targets for Cancer Detection CANCER RESEARCH Tummers, W. S., Warram, J. M., Tipirneni, K. E., Fengler, J., Jacobs, P., Shankar, L., Henderson, L., Ballard, B., Pogue, B. W., Weichert, J. P., Bouvet, M., Sorger, J., Contag, C. H., Frangioni, J. V., Tweedle, M. F., Basilion, J. P., Gambhir, S. S., Rosenthal, E. L. 2017; 77 (9): 2197-2206


    Considerable advances in cancer-specific optical imaging have improved the precision of tumor resection. In comparison to traditional imaging modalities, this technology is unique in its ability to provide real-time feedback to the operating surgeon. Given the significant clinical implications of optical imaging, there is an urgent need to standardize surgical navigation tools and contrast agents to facilitate swift regulatory approval. Because fluorescence-enhanced surgery requires a combination of both device and drug, each may be developed in conjunction, or separately, which are important considerations in the approval process. This report is the result of a one-day meeting held on May 4, 2016 with officials from the National Cancer Institute, the FDA, members of the American Society of Image-Guided Surgery, and members of the World Molecular Imaging Society, which discussed consensus methods for FDA-directed human testing and approval of investigational optical imaging devices as well as contrast agents for surgical applications. The goal of this workshop was to discuss FDA approval requirements and the expectations for approval of these novel drugs and devices, packaged separately or in combination, within the context of optical surgical navigation. In addition, the workshop acted to provide clarity to the research community on data collection and trial design. Reported here are the specific discussion items and recommendations from this critical and timely meeting. Cancer Res; 77(9); 2197-206. ©2017 AACR.

    View details for DOI 10.1158/0008-5472.CAN-16-3217

    View details for Web of Science ID 000400270100004

    View details for PubMedID 28428283

  • Sensitivity and Specificity of Cetuximab-IRDye800CW to Identify Regional Metastatic Disease in Head and Neck Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Rosenthal, E., Moore, L., Tipirneni, K., de Boer, E., Stevens, T. M., Hartman, Y. E., Carroll, W. R., Zinn, K. R., Warram, J. M. 2017


    Purpose: Comprehensive cervical lymphadenectomy can be associated with significant morbidity and poor quality of life. This study evaluated the sensitivity and specificity of cetuximab-IRDye800CW to identify metastatic disease in patients with head and neck cancer.Experimental Design: Consenting patients scheduled for curative resection were enrolled in a clinical trial to evaluate the safety and specificity of cetuximab-IRDye800CW. Patients (n = 12) received escalating doses of the study drug. Where indicated, cervical lymphadenectomy accompanied primary tumor resection, which occurred 3 to 7 days following intravenous infusion of cetuximab-IRDye800CW. All 471 dissected lymph nodes were imaged with a closed-field, near-infrared imaging device during gross processing of the fresh specimens. Intraoperative imaging of exposed neck levels was performed with an open-field fluorescence imaging device. Blinded assessments of the fluorescence data were compared to histopathology to calculate sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).Results: Of the 35 nodes diagnosed pathologically positive, 34 were correctly identified with fluorescence imaging, yielding a sensitivity of 97.2%. Of the 435 pathologically negative nodes, 401 were correctly assessed using fluorescence imaging, yielding a specificity of 92.7%. The NPV was determined to be 99.7%, and the PPV was 50.7%. When 37 fluorescently false-positive nodes were sectioned deeper (1 mm) into their respective blocks, metastatic cancer was found in 8.1% of the recut nodal specimens, which altered staging in two of those cases.Conclusions: Fluorescence imaging of lymph nodes after systemic cetuximab-IRDye800CW administration demonstrated high sensitivity and was capable of identifying additional positive nodes on deep sectioning. Clin Cancer Res; 1-9. ©2017 AACR.

    View details for DOI 10.1158/1078-0432.CCR-16-2968

    View details for PubMedID 28446503

  • Characterizing the Utility and Limitations of Repurposing an Open-Field Optical Imaging Device for Fluorescence-Guided Surgery in Head and Neck Cancer Patients JOURNAL OF NUCLEAR MEDICINE Moore, L. S., Rosenthal, E. L., Chung, T. K., de Boer, E., Patel, N., Prince, A. C., Korb, M. L., Walsh, E. M., Young, E. S., Stevens, T. M., Withrow, K. P., Morlandt, A. B., Richman, J. S., Carroll, W. R., Zinn, K. R., Warram, J. M. 2017; 58 (2): 246-251


    The purpose of this study was to assess the potential of U.S. Food and Drug Administration-cleared devices designed for indocyanine green-based perfusion imaging to identify cancer-specific bioconjugates with overlapping excitation and emission wavelengths. Recent clinical trials have demonstrated potential for fluorescence-guided surgery, but the time and cost of the approval process may impede clinical translation. To expedite this translation, we explored the feasibility of repurposing existing optical imaging devices for fluorescence-guided surgery.Consenting patients (n = 15) scheduled for curative resection were enrolled in a clinical trial evaluating the safety and specificity of cetuximab-IRDye800 (NCT01987375). Open-field fluorescence imaging was performed preoperatively and during the surgical resection. Fluorescence intensity was quantified using integrated instrument software, and the tumor-to-background ratio characterized fluorescence contrast.In the preoperative clinic, the open-field device demonstrated potential to guide preoperative mapping of tumor borders, optimize the day of surgery, and identify occult lesions. Intraoperatively, the device demonstrated robust potential to guide surgical resections, as all peak tumor-to-background ratios were greater than 2 (range, 2.2-14.1). Postresection wound bed fluorescence was significantly less than preresection tumor fluorescence (P < 0.001). The repurposed device also successfully identified positive margins.The open-field imaging device was successfully repurposed to distinguish cancer from normal tissue in the preoperative clinic and throughout surgical resection. This study illuminated the potential for existing open-field optical imaging devices with overlapping excitation and emission spectra to be used for fluorescence-guided surgery.

    View details for DOI 10.2967/jnumed.115.171413

    View details for Web of Science ID 000393360100017

    View details for PubMedID 27587708

    View details for PubMedCentralID PMC5288741

  • Beyond the margins: real-time detection of cancer using targeted fluorophores. Nature reviews. Clinical oncology Zhang, R. R., Schroeder, A. B., Grudzinski, J. J., Rosenthal, E. L., Warram, J. M., Pinchuk, A. N., Eliceiri, K. W., Kuo, J. S., Weichert, J. P. 2017


    Over the past two decades, synergistic innovations in imaging technology have resulted in a revolution in which a range of biomedical applications are now benefiting from fluorescence imaging. Specifically, advances in fluorophore chemistry and imaging hardware, and the identification of targetable biomarkers have now positioned intraoperative fluorescence as a highly specific real-time detection modality for surgeons in oncology. In particular, the deeper tissue penetration and limited autofluorescence of near-infrared (NIR) fluorescence imaging improves the translational potential of this modality over visible-light fluorescence imaging. Rapid developments in fluorophores with improved characteristics, detection instrumentation, and targeting strategies led to the clinical testing in the early 2010s of the first targeted NIR fluorophores for intraoperative cancer detection. The foundations for the advances that underline this technology continue to be nurtured by the multidisciplinary collaboration of chemists, biologists, engineers, and clinicians. In this Review, we highlight the latest developments in NIR fluorophores, cancer-targeting strategies, and detection instrumentation for intraoperative cancer detection, and consider the unique challenges associated with their effective application in clinical settings.

    View details for DOI 10.1038/nrclinonc.2016.212

    View details for PubMedID 28094261

  • Safety and Tumor Specificity of Cetuximab-IRDye800 for Surgical Navigation in Head and Neck Cancer. Clinical cancer research Rosenthal, E. L., Warram, J. M., de Boer, E., Chung, T. K., Korb, M. L., Brandwein-Gensler, M., Strong, T. V., Schmalbach, C. E., Morlandt, A. B., Agarwal, G., Hartman, Y. E., Carroll, W. R., Richman, J. S., Clemons, L. K., Nabell, L. M., Zinn, K. R. 2015; 21 (16): 3658-3666


    Positive margins dominate clinical outcomes after surgical resections in most solid cancer types, including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that EGFR can be targeted for safe and specific real-time localization of cancer.A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n = 12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days after infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology.There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathologic analysis of tissues ex vivo. Fluorescence levels positively correlated with EGFR levels.We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology.

    View details for DOI 10.1158/1078-0432.CCR-14-3284

    View details for PubMedID 25904751

  • Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors ANNALS OF ONCOLOGY Rosenthal, E. L., Chung, T. K., Parker, W. B., Allan, P. W., Clemons, L., Lowman, D., Hong, J., HUNT, F. R., Richman, J., Conry, R. M., MANNION, K., Carroll, W. R., Nabell, L., Sorscher, E. J. 2015; 26 (7): 1481-1487


    The use of Escherichia coli purine nucleoside phosphorylase (PNP) to activate fludarabine has demonstrated safety and antitumor activity during preclinical analysis and has been approved for clinical investigation.A first-in-human phase I clinical trial (NCT 01310179; IND 14271) was initiated to evaluate safety and efficacy of an intratumoral injection of adenoviral vector expressing E. coli PNP in combination with intravenous fludarabine for the treatment of solid tumors. The study was designed with escalating doses of fludarabine in the first three cohorts (15, 45, and 75 mg/m(2)) and escalating virus in the fourth (10(11)-10(12) viral particles, VP).All 12 study subjects completed therapy without dose-limiting toxicity. Tumor size change from baseline to final measurement demonstrated a dose-dependent response, with 5 of 6 patients in cohorts 3 and 4 achieving significant tumor regression compared with 0 responsive subjects in cohorts 1 and 2. The overall adverse event rate was not dose-dependent. Most common adverse events included pain at the viral injection site (92%), drainage/itching/burning (50%), fatigue (50%), and fever/chills/influenza-like symptoms (42%). Analysis of serum confirmed the lack of systemic exposure to fluoroadenine. Antibody response to adenovirus was detected in two patients, suggesting that neutralizing immune response is not a barrier to efficacy.This first-in-human clinical trial found that localized generation of fluoroadenine within tumor tissues using E. coli PNP and fludarabine is safe and effective. The pronounced effect on tumor volume after a single treatment cycle suggests that phase II studies are warranted.NCT01310179.

    View details for DOI 10.1093/annonc/mdv196

    View details for Web of Science ID 000358170400033

    View details for PubMedID 25899782

    View details for PubMedCentralID PMC4560028

  • Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence. Cancer research Gao, R. W., Teraphongphom, N. T., van den Berg, N. S., Martin, B. A., Oberhelman, N. J., Divi, V., Kaplan, M. J., Hong, S. S., Lu, G., Ertsey, R., Tummers, W. S., Gomez, A. J., Holsinger, F. C., Kong, C. S., Colevas, A. D., Warram, J. M., Rosenthal, E. L. 2018


    For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for in situ imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor-mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. 21 adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 (n=3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A (n=5) received 0.5mg/kg, cohort 2B (n=7) received 1mg/kg, and cohort 3 (n=6) received 50 mg. Patients were followed 30 days post-infusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. In situ imaging demonstrated tumor-to-background ratio (TBR) of 2-3, compared to ex vivo specimen imaging TBR of 5-6. We obtained clear differentiation between tumor and normal tissue, with a three-fold signal difference between positive and negative specimens (p<0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy which are otherwise less amenable to image guidance.

    View details for DOI 10.1158/0008-5472.CAN-18-0878

    View details for PubMedID 29967260

  • Evaluation of fluorescence-guided surgery agents in a murine model of soft tissue fibrosarcoma JOURNAL OF SURGICAL ONCOLOGY Prince, A. C., McGee, A. S., Siegel, H., Rosenthal, E. L., Behnke, N. K., Warram, J. M. 2018; 117 (6): 1179–87


    Soft tissue sarcomas (STS) are mesenchymal malignancies. Treatment mainstay is surgical resection with negative margins ± adjuvant treatment. Fluorescence-guided surgical (FGS) resection can delineate intraoperative margins; FGS has improved oncologic outcomes in other malignancies. This novel strategy may minimize resection-associated morbidity while improving local tumor control.We evaluate the tumor-targeting specificity and utility of fluorescence-imaging agents to provide disease-specific contrast. Mice with HT1080 fibrosarcoma tumors received one of five probes: cetuximab-IRDye800CW (anti-EGFR), DC101-IRDye800CW (anti-VEGFR-2), IgG-IRDye800CW, the cathepsin-activated probe Prosense750EX, or the small molecule probe IntegriSense750. Tumors were imaged daily using open- and closed-field fluorescence imaging systems. Tumor-to-background ratios (TBR) were evaluated. On peak TBR days, probe sensitivity was evaluated. Tumors were stained and imaged microscopically.At peak, closed-field imaging TBR of cetuximab-IRDye800CW (16.8) was significantly greater (P < 0.0001) than Integrisense750 (7.0), Prosense750EX (5.8), and DC101-IRDye800CW (3.7). All agents successfully localized as little as 1.0 mg of tumor tissue in the post-resection bed; cetuximab-IRDye800CW generated the greatest contrast (2.5). Cetuximab-IRDye800CW revealed strong tumor affinity microscopically; tumor fluorescence intensity was significantly greater (P < 0.0004) than 0.2 mm away from tumor border.This study demonstrates cetuximab-IRDye800CW superiority. FGS has the potential to improve post-resection morbidity and mortality by improving disease detection.

    View details for DOI 10.1002/jso.24950

    View details for Web of Science ID 000439810400010

    View details for PubMedID 29284070

  • Panitumumab-IRDye800 as an Optical Agent for Image-Guided Surgery in Patients With Squamous Cell Carcinoma Gao, R. W., Teraphongphom, N., van den Berg, N. S., Hong, S., Martin, B. A., Divi, V., Kaplan, M. J., Ertsey, R., Oberhelman, N. J., Lu, G., Kong, C. S., Colevas, A. D., Rosenthal, E. L. ELSEVIER SCIENCE INC. 2018: 1312–13
  • Reducing the Time from Surgery to Adjuvant Radiation Therapy: An Institutional Quality Improvement Project. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Divi, V., Chen, M. M., Hara, W., Shah, D., Narvasa, K., Segura Smith, A., Kelley, J., Rosenthal, E. L., Porter, J. 2018: 194599818768254


    Objective The National Comprehensive Cancer Network guidelines recommend an interval between surgery and adjuvant radiation therapy of less than 6 weeks, but only 44% of patients meet this metric nationally. We sought to identify key components of an improvement process focused on starting adjuvant radiation therapy within 6 weeks of surgery. Methods This project used an A3 model to improve a defined process measure. We studied a consecutive sample of 56 patients with oral cavity carcinoma who were treated at our institution with upfront surgical resection followed by adjuvant radiation therapy. Twelve proposed interventions tested during the study period focused on 3 key drivers of delays: delayed dental evaluation and teeth extraction, delayed radiation oncology consults, and inadequate patient engagement. The primary outcome measure was the number of days from surgery to the start of radiation therapy. Results Prior to the intervention, 62% of patients received adjuvant radiation within 6 weeks of surgery. Following the intervention, 73% of patients achieved this metric. The percentage of patients with avoidable delays decreased from 24% to 9%. The percentage of patients with unavoidable delays was relatively constant before and after the intervention (15% and 18%, respectively). Discussion Defining disease-specific metrics is critical to improving care in our head and neck cancer patient population. We demonstrate several key components to develop and improve self-defined metrics. Implications for Practice As we transition to a system of value-based care, structured quality improvement projects can have a measurable impact on cancer patient process measures.

    View details for DOI 10.1177/0194599818768254

    View details for PubMedID 29631478

  • Regulatory Aspects of Optical Methods and Exogenous Targets for Cancer Detection (vol 77, pg 2197, 2017) CANCER RESEARCH Tummers, W. S., Warram, J. M., Tipirneni, K. E., Fengler, J., Jacobs, P., Shankar, L., Henderson, L., Ballard, B., Pfefer, T., Pogue, B. W., Weichert, J. P., Bouvet, M., Sorger, J., Contag, C. H., Frangioni, J. V., Tweedle, M. F., Basilion, J. P., Gambhir, S. S., Rosenthal, E. L. 2018; 78 (4): 1123
  • New Blood Test SEEKs To Detect and Localize Cancer before It's Too Late. Biochemistry Bogyo, M., Yim, J. J., Rosenthal, E. L. 2018; 57 (10): 1561–62

    View details for DOI 10.1021/acs.biochem.8b00179

    View details for PubMedID 29489339

  • Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers THERANOSTICS Gao, R. W., Teraphongphom, N., de Boer, E., van den Berg, N. S., Divi, V., Kaplan, M. J., Oberhelman, N. J., Hong, S. S., Capes, E., Colevas, A., Warram, J. M., Rosenthal, E. L. 2018; 8 (9): 2488–95


    Purpose: To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. Procedures: We conducted two phase I trials for anti-epidermal growth factor receptor antibodies cetuximab-IRDye800CW (n=12) and panitumumab-IRDye800CW (n=15). Adults with biopsy-confirmed head and neck squamous cell carcinoma scheduled for standard-of-care surgery were eligible. For cetuximab-IRDye800CW, cohort 1 was intravenously infused with 2.5 mg/m2, cohort 2 received 25 mg/m2, and cohort 3 received 62.5 mg/m2. For panitumumab-IRDye800CW, cohorts received 0.06 mg/kg, 0.5 mg/kg, and 1 mg/kg, respectively. Electrocardiograms and blood samples were obtained, and patients were followed for 30 days post-study drug infusion. Results: Both fluorescently labeled antibodies had similar pharmacodynamic properties and minimal toxicities. Two infusion reactions occurred with cetuximab and none with panitumumab. There were no grade 2 or higher toxicities attributable to cetuximab-IRDye800CW or panitumumab-IRDye800CW; fifteen grade 1 adverse events occurred with cetuximab-IRDye800CW, and one grade 1 occurred with panitumumab-IRDye800CW. There were no significant differences in QTc prolongation between the two trials (p=0.8). Conclusions: Panitumumab-IRDye800CW and cetuximab-IRDye800CW have toxicity and pharmacodynamic profiles that match the parent compound, suggesting that other therapeutic antibodies may be repurposed as imaging agents with limited preclinical toxicology data.

    View details for DOI 10.7150/thno.24487

    View details for Web of Science ID 000429880400005

    View details for PubMedID 29721094

    View details for PubMedCentralID PMC5928904

  • Specimen Mapping in Head and Neck Cancer Using Fluorescence Imaging LARYNGOSCOPE INVESTIGATIVE OTOLARYNGOLOGY Teraphongphom, N., Kong, C. S., Warram, J. M., Rosenthal, E. L. 2017; 2 (6): 447–52


    Although the agreed-upon standard is circumferential pathology analysis of the interface between the resected specimen and the patient, there is currently no consensus on the optimal methodology to achieve this in head and neck cancer specimens. This is most commonly conducted by either sampling the wound bed after resection or obtaining samples from the specimen. Regardless of the technique, only a fraction of the area of interest can be sampled due to the labor-intensive nature of frozen sections.This review will cover and define the possible role for optical mapping of the surgical specimen using fluorescence imaging in head and neck cancer.NA.

    View details for DOI 10.1002/lio2.84

    View details for Web of Science ID 000418761500018

    View details for PubMedID 29299522

    View details for PubMedCentralID PMC5743163

  • Characterizing the detection threshold for optical imaging in surgical oncology JOURNAL OF SURGICAL ONCOLOGY Prince, A. C., Jani, A., Korb, M., Tipirneni, K. E., Kasten, B. B., Rosenthal, E. L., Warram, J. M. 2017; 116 (7): 898–906

    View details for DOI 10.1002/jso.24733

    View details for Web of Science ID 000416926600015

  • Measuring Institutional Quality in Head and Neck Surgery Using Hospital-Level Data Negative Margin Rates and Neck Dissection Yield Schoppy, D., Rhoads, K. F., Ma, Y., Chen, M. M., Nussenbaum, B., Orosco, R. K., Rosenthal, E. L., Divi, V. AMER MEDICAL ASSOC. 2017: 1111–16


    Negative margins and lymph node yields (LNY) of 18 or more from neck dissections in patients with head and neck squamous cell carcinomas (HNSCC) have been associated with improved patient survival. It is unclear whether these metrics can be used to identify hospitals with improved outcomes.To determine whether 2 patient-level metrics would predict outcomes at the hospital level.A retrospective review of records from the National Cancer Database (NCDB) was used to identify patients who underwent primary surgery and concurrent neck dissection for HNSCC between 2004 and 2013. The percentage of patients at each hospital with negative margins on primary resection and an LNY 18 or more from a neck dissection was quantified. Cox proportional hazard models were used to define the association between hospital performance on these metrics and overall survival.Margin status and lymph node yield at hospital level. Overall survival (OS).We identified 1008 hospitals in the NCDB where 64 738 patients met inclusion criteria. Of the 64 738 participants, 45 170 (69.8%) were men and 19 568 (30.2%) were women. The mean SD age of included patients was 60.5 (12.0) years. Patients treated at hospitals attaining the combined metric of a 90% or higher negative margin rate and 80% or more of cases with LNYs of 18 or more experienced a significant reduction in mortality (hazard ratio [HR] 0.93; 95% CI, 0.89-0.98). This benefit in survival was independent of the patient-level improvement associated with negative margins (HR, 0.73; 95% CI, 0.71-0.76) and LNY of 18 or more (HR, 0.85; 95% CI, 0.83-0.88). Including these metrics in the model neutralized the association of traditional measures of hospital quality (volume and teaching status).Treatment at hospitals that attain a high rate of negative margins and LNY of 18 or more is associated with improved survival in patients undergoing surgery for HNSCC. These surgical outcome measures predicted outcomes independent of traditional, but generally nonmodifiable characteristics. Tracking of these metrics may help identify high-quality centers and provide guidance for institution-level quality improvement.

    View details for DOI 10.1001/jamaoto.2017.1694

    View details for Web of Science ID 000415373800010

    View details for PubMedID 28983555

    View details for PubMedCentralID PMC5710350

  • Laser-Assisted Indocyanine Green Dye Angiography for Postoperative Fistulas After Salvage Laryngectomy. JAMA otolaryngology-- head & neck surgery Partington, E. J., Moore, L. S., Kahmke, R., Warram, J. M., Carroll, W., Rosenthal, E. L., Greene, B. J. 2017


    Pharyngocutaneous fistula formation is an unfortunate complication after salvage laryngectomy for head and neck cancer that is difficult to anticipate and related to a variety of factors, including the viability of native pharyngeal mucosa.To examine whether noninvasive angiography with indocyanine green (ICG) dye can be used to evaluate native pharyngeal vascularity to anticipate pharyngocutaneous fistula development.This cohort study included 37 patients enrolled from June 1, 2013, to June 1, 2016, and follow-up was for at least 1 month postoperatively. The study was performed at the University of Alabama at Birmingham, a tertiary care center. Included patients were those undergoing salvage total laryngectomy who were previously treated with chemoradiotherapy or radiotherapy alone.The ICG dye was injected intraoperatively, and laser-assisted vascular imaging was used to evaluate the native pharyngeal mucosa after the ablative procedure. The center of the native pharyngeal mucosa was used as the reference to compare with the peripheral mucosa, and the lowest mean ICG dye percentage of mucosal perfusion was recorded for each patient.The primary outcome was the formation of a postoperative fistula, which was assessed by clinical and radiographic assessment to test the hypothesis formulated before data collection.A total of 37 patients were included (mean [SD] age, 62.3 [8.5] years; 32 [87%] male and 5 [14%] female); 20 had a history of chemoradiotherapy, and 17 had history of radiotherapy alone. Thirty-four patients (92%) had free flap reconstruction, and 3 had primary closure (8%). Ten patients (27%) developed a postoperative fistula. No significant difference was found in fistula rate between patients who underwent neck dissection and those who did not and patients previously treated with chemoradiotherapy and those treated with radiotherapy alone. A receiver operator characteristic curve was generated to determine the diagnostic performance of the lowest mean ICG dye percentage of mucosal perfusion determined by fluorescence imaging, which was found to be a threshold value of 26%. The area under the curve was 0.85 (95% CI, 0.73-0.97), which was significantly greater than the chance diagonal. The overall mean lowest ICG dye percentage of mucosal perfusion was 31.3%. The mean lowest ICG dye percentage of mucosal perfusion was 22.0% in the fistula group vs 34.9% in the nonfistula group (absolute difference, 12.9%; 95% CI, 5.1%-21.7%).Patients who developed postoperative fistulas had lower mucosal perfusion as detected by ICG dye angiography when compared with patients who did not develop fistulas.

    View details for DOI 10.1001/jamaoto.2017.0187

    View details for PubMedID 28520896

  • Effect of Overlapping Operations on Outcomes in Microvascular Reconstructions of the Head and Neck OTOLARYNGOLOGY-HEAD AND NECK SURGERY Sweeny, L., Rosenthal, E. L., Light, T., Grayson, J., Petrisor, D., Troob, S. H., Greene, B. J., Carroll, W. R., Wax, M. K. 2017; 156 (4): 627-635


    Objective To compare outcomes after microvascular reconstructions of head and neck defects between overlapping and nonoverlapping operations. Study Design Retrospective cohort study. Setting Tertiary care center. Subjects and Methods Patients undergoing microvascular free tissue transfer operations between January 2010 and February 2015 at 2 tertiary care institutions were included (n = 1315). Patients were divided into 2 cohorts by whether the senior authors performed a single or consecutive microvascular reconstruction (nonoverlapping; n = 773, 59%) vs performing overlapping microvascular reconstructions (overlapping; n = 542, 41%). Variables reviewed were as follows: defect location, indication, T classification, surgical details, duration of the operation and hospitalization, and complications (major, minor, medical). Results Microvascular free tissue transfers performed included radial forearm (49%, n = 639), osteocutaneous radial forearm (14%, n = 182), anterior lateral thigh (12%, n = 153), fibula (10%, n = 135), rectus abdominis (7%, n = 92), latissimus dorsi (6%, n = 78), and scapula (<1%, n = 4). The mean duration of the overlapping operations was 21 minutes longer than nonoverlapping operations ( P = .003). Mean duration of hospitalization was similar for nonoverlapping (9.5 days) and overlapping (9.1 days) cohorts ( P = .39). There was no difference in complication rates when stratified by overlapping (45%, n = 241) and nonoverlapping (45%, n = 344) ( P = .99). Subset analysis yielded similar results when minor, major, and medical complications between groups were assessed. The overall survival rate of free tissue transfers was 96%, and this was same for overlapping (96%) and nonoverlapping (96%) operations ( P = .71). Conclusions Patients had similar complication rates and durations of hospitalization for overlapping and nonoverlapping operations.

    View details for DOI 10.1177/0194599817691746

    View details for Web of Science ID 000400241900008

    View details for PubMedID 28322117

  • Worst Pattern Of Invasion and occult cervical metastases for oral squamous carcinoma. Head & neck Velosa, C., Shi, Q., Stevens, T. M., Chiosea, S. I., Purgina, B., Carroll, W., Rosenthal, E., Morlandt, A., Loree, T., Brandwein-Weber, M. S. 2017


    The Risk Model is a validated prognostic schema for patients with oral cavity squamous carcinoma. Here, we examine the relationship between Worst Pattern of Invasion-type 5 (WPOI-5) and occult cervical metastases, and also present an interim observational analysis of the impact of adjuvant radiotherapy on patients with low-stage oral cancer classified as either high risk or WPOI-5 alone.There were 323 patients with T1 T2 cNo oral cavity squamous carcinoma treated by primary resection, 152 of whom also underwent elective neck dissection (END). The resection specimens were examined for worst pattern of invasion, perineural invasion, and lymphocytic host responses, and classified as low risk, intermediate risk, or high risk. Fisher's 2-tailed exact test and Kaplan-Meier outcome analyses were performed.High-risk classification is significantly associated with decreased time to local recurrence (p = .0128; hazard ratio [HR], 2.82; 95% confidence interval [CI], 1.22-6.5) and regional metastasis (p = .052; HR, 3.27; 95% CI, 1.42-7.5). For patients undergoing END, 31 (20%) had occult-positive lymph nodes. WPOI-5 is significantly predictive of occult cervical metastases (p < .0001). We examined the impact of adjuvant radiotherapy on the WPOI-5 subgroup (n = 55). Despite being underpowered, Kaplan-Meier curves demonstrate good separation between patients with low-stage WPOI-5 who received postoperative adjuvant radiotherapy versus those treated by surgery alone, with respect to disease-specific mortality and disease-free survival.WPOI-5 is significantly predictive of occult metastatic disease in cervical lymph nodes. Interim analysis of patients with low-stage WPOI-5 for the impact of adjuvant radiotherapy justifies continuing patient accrual in an observational setting. These data can ultimately support a clinical trial for more aggressive treatment in this niche group. © 2017 Wiley Periodicals, Inc. Head Neck, 2017.

    View details for DOI 10.1002/hed.24754

    View details for PubMedID 28370646

  • Optical Surgical Navigation for Precision in Tumor Resections. Molecular imaging and biology Harmsen, S., Teraphongphom, N., Tweedle, M. F., Basilion, J. P., Rosenthal, E. L. 2017


    Optical imaging methods have significant potential as effective intraoperative tools to visualize tissues, cells, and biochemical events aimed at objective assessment of the tumor margin and guiding the surgeon to adequately resect the tumor while sparing critical tissues. The wide variety of approaches to guide resection, the range of parameters that they detect, and the interdisciplinary nature involving biology, chemistry, engineering, and medicine suggested that there was a need for an organization that could review, discuss, refine, and help prioritize methods to optimize patient care and pharmaceutical and instrument development. To address these issues, the World Molecular Imaging Society created the Optical Surgical Navigation (OSN) interest group to bring together scientists, engineers, and surgeons to develop the field to benefit patients. Here, we provide an overview of approaches currently under clinical investigation for optical surgical navigation and offer our perspective on upcoming strategies.

    View details for DOI 10.1007/s11307-017-1054-1

    View details for PubMedID 28271367

  • Fluorescence Imaging for Cancer Screening and Surveillance. Molecular imaging and biology Tipirneni, K. E., Rosenthal, E. L., Moore, L. S., Haskins, A. D., Udayakumar, N., Jani, A. H., Carroll, W. R., Morlandt, A. B., Bogyo, M., Rao, J., Warram, J. M. 2017


    The advent of fluorescence imaging (FI) for cancer cell detection in the field of oncology is promising for both cancer screening and surgical resection. Particularly, FI in cancer screening and surveillance is actively being evaluated in many new clinical trials with over 30 listed on Clinical . While surgical resection forms the foundation of many oncologic treatments, early detection is the cornerstone for improving outcomes and reducing cancer-related morbidity and mortality. The applications of FI are twofold as it can be applied to high-risk patients in addition to those undergoing active surveillance. This technology has the promise of highlighting lesions not readily detected by conventional imaging or physical examination, allowing disease detection at an earlier stage of development. Additionally, there is a persistent need for innovative, cost-effective imaging modalities to ameliorate healthcare disparities and the global burden of cancer worldwide. In this review, we outline the current utility of FI for screening and detection in a range of cancer types.

    View details for DOI 10.1007/s11307-017-1050-5

    View details for PubMedID 28155079

  • expression in oropharyngeal squamous cell carcinoma: Correlations with human papillomavirus status and recurrence after transoral robotic surgery. Head & neck Weaver, A. N., Cooper, T. S., Wei, S., Carroll, W. R., Rosenthal, E. L., Yang, E. S. 2017; 39 (2): 206-214


    Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has improved clinical outcomes compared to HPV-negative disease. However, the biology underlying differences in prognosis remains unclear.We characterized the expression of DNA-protein kinase catalytic subunit (DNA-PkCS ), a key DNA repair protein also associated with tumor progression, in 29 cases of oropharyngeal SCCs and correlated our findings with HPV status and disease recurrence. In addition, we assessed therapeutic response, migration, and invasion in head and neck cancer cell lines upon DNA-PkCS knockdown.DNA-PkCS expression was significantly decreased in HPV-positive compared to HPV-negative oropharyngeal SCC samples. Within the HPV-positive subgroup, DNA-PkCS expression was inversely related to HPV E6 and E7 expression and trended toward significance as a predictor of recurrence. DNA-PkCS knockdown in cell lines resulted in increased sensitivity to cisplatin and radiotherapy and reduced cell migration and invasion.These results suggest DNA-PkCS should be further studied as a potential marker of tumor progression in HPV-positive oropharyngeal SCCs. © 2016 Wiley Periodicals, Inc. Head Neck 39: 206-214, 2017.

    View details for DOI 10.1002/hed.24562

    View details for PubMedID 27507640

  • Transistor-like pH nanoprobes NATURE BIOMEDICAL ENGINEERING van den Berg, N. S., Rosenthal, E. L. 2017; 1 (1)
  • Oncologic Procedures Amenable to Fluorescence-guided Surgery. Annals of surgery Tipirneni, K. E., Warram, J. M., Moore, L. S., Prince, A. C., de Boer, E., Jani, A. H., Wapnir, I. L., Liao, J. C., Bouvet, M., Behnke, N. K., Hawn, M. T., Poultsides, G. A., Vahrmeijer, A. L., Carroll, W. R., Zinn, K. R., Rosenthal, E. 2016


    Although fluorescence imaging is being applied to a wide range of cancers, it remains unclear which disease populations will benefit greatest. Therefore, we review the potential of this technology to improve outcomes in surgical oncology with attention to the various surgical procedures while exploring trial endpoints that may be optimal for each tumor type.For many tumors, primary treatment is surgical resection with negative margins, which corresponds to improved survival and a reduction in subsequent adjuvant therapies. Despite unfavorable effect on patient outcomes, margin positivity rate has not changed significantly over the years. Thus, patients often experience high rates of re-excision, radical resections, and overtreatment. However, fluorescence-guided surgery (FGS) has brought forth new light by allowing detection of subclinical disease not readily visible with the naked eye.We performed a systematic review of using search terms "fluorescence," "image-guided surgery," and "near-infrared imaging" to identify trials utilizing FGS for those received on or before May 2016.fluorescence surgery for tumor debulking, wide local excision, whole-organ resection, and peritoneal metastases.fluorescence in situ hybridization, fluorescence imaging for lymph node mapping, nonmalignant lesions, nonsurgical purposes, or image guidance without fluorescence.Initial search produced 844 entries, which was narrowed down to 68 trials. Review of literature and clinical trials identified 3 primary resection methods for utilizing FGS: (1) debulking, (2) wide local excision, and (3) whole organ excision.The use of FGS as a surgical guide enhancement has the potential to improve survival and quality of life outcomes for patients. And, as the number of clinical trials rise each year, it is apparent that FGS has great potential for a broad range of clinical applications.

    View details for DOI 10.1097/SLA.0000000000002127

    View details for PubMedID 28045715

  • Lower facial reanimation techniques following cancer resection and free flap reconstruction. Laryngoscope Kejner, A. E., Rosenthal, E. L. 2016; 126 (9): 1990-1994


    Evaluate outcomes of the standard static sling and orthodromic temporalis tendon transfer reanimation for facial nerve paralysis.Retrospective case series at a tertiary care hospital of head and neck cancer patients with facial nerve palsy secondary to malignancy or resection.From 2004 to 2014, patients undergoing resection of malignancy that involved facial nerve palsy requiring facial reanimation were identified. All procedures were performed by the senior author (e.l.r.). Demographics, methods, revision rates, combination with other procedures, and complications were evaluated.A total of 77 patients underwent 92 procedures, with two patients requiring more than one revision, for a total of 20 revisions. Average time to revision was 9 months. Age, sex, race, side of repair, paralysis prior to procedure, sling type or method, timing of procedure, and radiation therapy were not significantly different between those requiring revision and those who did not. There was no difference in complications between patients who received radiation and those who did not (P = .5), nor between static versus orthodromic temporalis muscle transfer (P = .5). Complication rate was low at 5.4%.Sling procedures can be successfully performed in patients with facial nerve palsy secondary to cancer resection with radiation therapy, with a low revision rate and few complications.4 Laryngoscope, 2015.

    View details for DOI 10.1002/lary.25852

    View details for PubMedID 26808491

  • Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity. Molecular cancer research Weaver, A. N., Burch, M. B., Cooper, T. S., Della Manna, D. L., Wei, S., Ojesina, A. I., Rosenthal, E. L., Yang, E. S. 2016; 14 (9): 883-891


    Oral squamous cell carcinoma (OSCC) is a cancer subtype that lacks validated prognostic and therapeutic biomarkers, and human papillomavirus status has not proven beneficial in predicting patient outcomes. A gene expression pathway analysis was conducted using OSCC patient specimens to identify molecular targets that may improve management of this disease. RNA was isolated from 19 OSCCs treated surgically at the University of Alabama at Birmingham (UAB; Birmingham, AL) and evaluated using the NanoString nCounter system. Results were confirmed using the oral cavity subdivision of the Head and Neck Squamous Cell Carcinoma Cancer (HNSCC) study generated by The Cancer Genome Atlas (TCGA) Research Network. Further characterization of the in vitro phenotype produced by Notch pathway activation in HNSCC cell lines included gene expression, proliferation, cell cycle, migration, invasion, and radiosensitivity. In both UAB and TCGA samples, Notch pathway upregulation was significantly correlated with patient mortality status and with expression of the proinvasive gene FGF1 In vitro Notch activation in HNSCC cells increased transcription of FGF1 and induced a marked increase in cell migration and invasion, which was fully abrogated by FGF1 knockdown. These results reveal that increased Notch pathway signaling plays a role in cancer progression and patient outcomes in OSCC. Accordingly, the Notch-FGF interaction should be further studied as a prognostic biomarker and potential therapeutic target for OSCC.Patients with squamous cell carcinoma of the oral cavity who succumb to their disease are more likely to have upregulated Notch signaling, which may mediate a more invasive phenotype through increased FGF1 transcription. Mol Cancer Res; 14(9); 883-91. ©2016 AACR.

    View details for DOI 10.1158/1541-7786.MCR-16-0114

    View details for PubMedID 27353029

  • Outcomes after surgical salvage for recurrent oropharyngeal squamous cell carcinoma. Oral oncology Sweeny, L., Rosenthal, E. L., Clemons, L., Stevens, T. M., Cook McIntosh, E. R., Carroll, W. R. 2016; 60: 118-124


    Compare human papillomavirus (HPV) status and outcomes in patients undergoing salvage surgical resection for a recurrent oropharyngeal squamous cell carcinoma (OPSCC).Case series with chart review (2005-2013).Sixty-nine patients were identified who underwent salvage surgical resection for a recurrent OPSCC after primary radiation therapy. There was no difference in the incidence of HPV negative (52%; n=36) and HPV positive (48%; n=33) tumors. The mean time from completion of radiation therapy to salvage surgery was 2.4years. At the time of salvage operation, there was no correlation with HPV status, as assessed by p16 immunohistochemistry, and lymph node metastases (p=0.21), T classification (p=0.22), tracheostomy dependence (p=0.59), gastrostomy tube dependence (p=0.82), or duration from radiation therapy (p=0.63). The majority of patients were either current or former tobacco users (75%) and of the HPV positive patients, 66% were tobacco users. Development of a new recurrence after salvage surgical resection occurred in 33% of patients (n=26), with a higher incidence in patients with HPV negative disease (52%, n=17/33; p=0.05). The overall 2- and 5-year survival rates were 0.47 and 0.23. There was no difference in overall survival rates when stratified by HPV status or tobacco use. Decreased overall 5-year survival rates did correlate with cervical lymph node metastases (p=0.01), advanced tumor stage (p=0.04) and dependence on gastrostomy tube postoperatively (p=0.04).This study found cervical lymph node metastases, clinical stage, and dependence on gastrostomy tube for nutrition to have the greatest impact on overall survival for patients with recurrent OPSCC.

    View details for DOI 10.1016/j.oraloncology.2016.07.006

    View details for PubMedID 27531882

  • Parotid gland metastasis in Merkel cell carcinoma of the head and neck: A series of 14 cases. Ear, nose, & throat journal Day, K. E., Carroll, W. R., Rosenthal, E. L. 2016; 95 (9): 398-404


    Merkel cell carcinoma (MCC) is a rare cutaneous cancer of neuroendocrine cell origin that occurs frequently on the head and neck. With a high incidence of local recurrence and regional and distant metastasis, it carries a poor prognosis. We performed a retrospective study to determine the prognostic implications of parotid gland metastasis in MCC of the head and neck. Our study population was made up of 14 patients-13 men and 1 woman, aged 62 to 87 years (mean: 75.9)-who underwent a parotidectomy for the diagnosis of MCC over a period of 10 years and 9 months. Ten patients had a primary skin lesion of the head and neck and 4 presented with a parotid mass and an unknown primary. In all, 13 of the 14 patients were found to have parotid involvement-either a direct extension of MCC into the gland or a positive intraparotid lymph node; some patients had both. All patients underwent tumor excision, and 10 underwent neck dissection. Eleven patients received adjuvant radiotherapy; none received adjuvant chemotherapy. Of the 10 patients who underwent a neck dissection, 6 were found to have a cervical lymph node metastasis on pathologic examination. Follow-up ranged from 1.3 to 39.2 months (mean: 12.4). Three patients were lost to follow-up shortly after surgery, although some information was available on 2 of them. At the final follow-up, mortality data were available on 12 patients; of these, 11 had died. The lone survivor was the patient without a parotid metastasis. Among those known to have died, survival ranged from 1.6 to 49.2 months (mean: 16.0). We conclude that parotid metastasis in patients with MCC of the head and neck is associated with a dismal survival rate that is even worse than the poor survival associated with cervical node involvement.

    View details for PubMedID 27657318

  • Antiangiogenic antibody improves melanoma detection by fluorescently labeled therapeutic antibodies. Laryngoscope Sweeny, L., Prince, A., Patel, N., Moore, L. S., Rosenthal, E. L., Hughley, B. B., Warram, J. M. 2016


    Evaluate if vascular normalization with an antiangiogenic monoclonal antibody improves detection of melanoma using fluorescently labeled antibody-based imaging.Preclinical.Panitumumab and control IgG were covalently linked to a near-infrared fluorescent probe (IRDye800CW). Immunodeficient mice with ear xenografts of melanoma cell lines (A375 and SKMEL5) were systemically injected (200 μg, tail vein) with either IgG-IRDye800CW, panitumumab-IRDye800CW, or a combination (bevacizumab [5mg/kg], administered 72 hours prepanitumumab-IRDye800CW) (n = 5). Primary tumors were imaged with open-field (LUNA, Novadaq, Toronto, Ontario, Canada) and closed-field (Pearl, LI-COR Biosciences, Lincoln, NB) imaging devices. Postresection, the concentration of labeled antibody within the tumor (μg/g) was calculated using normalized standards.The mean fluorescence within the melanoma tumors was greater for the combination group compared to panitumumab alone for both cell lines (P < 0.001). The tumor-to-background ratio (TBR) for the A375 tumors was greater for the combination (3.4-7.1) compared to the panitumumab alone (3.2-5.0) (P = 0.04). The TBR for SKMEL5 tumors was greater for the combination (2.4-6.0) compared to the panitumumab alone (2.2-3.9) (P = 0.02). Within A375 tumors, the concentration was lower for panitumumab (0.51 μg/g) compared to combination group (0.68 μg/g) (P = 0.036). Within SKMEL5 tumors, the concentration was lower for panitumumab (0.0.17 μg/g) compared to combination group (0.35 μg/g) (P = 0.048). Residual tumor (1.0-0.2 mg) could be differentiated from background in both panitumumab and combination groups. For both cell lines, panitumumab and combination groups had greater mean fluorescence of the tumor compared to control IgG.The addition of antiangiogenic therapy improves uptake of fluorescently labeled monoclonal antibodies within melanoma tumors. Clinical translation could improve detection of melanoma intraoperatively, reducing positive margins and sparing normal tissue.NA Laryngoscope, 126:E387-E395, 2016.

    View details for DOI 10.1002/lary.26215

    View details for PubMedID 27576611

    View details for PubMedCentralID PMC5121084

  • Photoimmunotherapy of residual disease after incomplete surgical resection in head and neck cancer models CANCER MEDICINE Moore, L. S., de Boer, E., Warram, J. M., Tucker, M. D., Carroll, W. R., Korb, M. L., Brandwein-Gensler, M. S., van Dam, G. M., Rosenthal, E. L. 2016; 5 (7): 1526-1534


    Antibody-based photodynamic therapy, or photoimmunotherapy (PIT), is a novel, targeted cancer therapy, which can serve as both a diagnostic and a therapeutic agent. The primary objective of this study was to evaluate the capacity of panitumumab-IRDye700DX (Pan-IR700) to eliminate microscopic tumor remnants in the postsurgical setting, which was accomplished using novel in vitro and in vivo models of residual disease after incomplete resection. Additionally, PIT was evaluated in fresh human-derived cancer tissue. To determine a threshold for cellular regrowth after PIT, an in vitro assay was performed using a range of cells representing microscopic disease quantities. Long-term growth inhibition was induced after treatment of 5 × 10(3) and 1 × 10(4) cells at 6 J. A novel in vivo mouse model of subtotal tumor resection was used to assess the effectiveness of Pan-IR700 mediated PIT to eliminate residual disease and inhibit recurrence in the post-surgical wound bed. Mice receiving surgical treatment plus adjuvant PIT showed a threefold and fourfold reduction in tumor regrowth at 30 days post PIT in the 50% and 90% subtotal resection groups, respectively (as measured by bioluminescence imaging), demonstrating a significant (P < 0.001) reduction in tumor regrowth. To determine the translatability of epidermal growth factor receptor (EGFR)-targeted PIT, SCCHN human tissues (n = 12) were treated with Pan-IR700. A significant reduction (P < 0.001) in ATP levels was observed after treatment with Pan-IR700 and 100 J cm(-2) (48% ± 5%) and 150 J cm(-2) (49% ± 7%) when compared to baseline. Targeting EGFR with Pan-IR700 has robust potential to provide a tumor-specific mechanism for eliminating residual disease in the surgical setting, thereby increasing therapeutic efficacy, prolonging progression-free survival, and decreasing morbidity.

    View details for DOI 10.1002/cam4.752

    View details for Web of Science ID 000380048900019

    View details for PubMedID 27167827

    View details for PubMedCentralID PMC4867660

  • Biodistribution Study of Intravenously Injected Cetuximab-IRDye700DX in Cynomolgus Macaques MOLECULAR IMAGING AND BIOLOGY De Boer, E., Samuel, S., French, D. N., WARRAM, J. M., Schoeb, T. R., Rosenthal, E. L., Zinn, K. R. 2016; 18 (2): 232-242


    The use of receptor-targeted antibodies conjugated to photosensitizers is actively being explored to enhance treatment efficacy. To facilitate clinical testing, we evaluated cetuximab conjugated to IRDye700DX (IR700) in cynomolgus macaques.Total IR700 and intact cetuximab-IR700 were measured in 51 tissues at 2 and 14 days after intravenous injection of 40 and 80 mg/kg cetuximab-IR700, respectively, and compared with an unlabeled cetuximab-dosed control group (two each per sex per time point per group).The IR700 retrieved from all tissues at 2 and 14 days after dosing was estimated at 34.9 ± 1.8 and 2.53 ± 0.67 % of the total dose, respectively. The tissues with the highest levels of intact cetuximab-IR700 at 2 days after dosing were the blood, lung, and skin. Formalin-fixed paraffin-embedded tissue sections at 2 days after dosing showed the highest IR700 signals in the axillary lymph node, mammary gland, and gall bladder.Both IR700 and intact cetuximab-IR700 biodistributions were consistent with known epidermal growth factor receptor (EGFR) expression, and changes between 2 and 14 days were consistent with rapid metabolism and excretion of the cetuximab-IR700.

    View details for DOI 10.1007/s11307-015-0892-y

    View details for Web of Science ID 000372260900009

    View details for PubMedID 26335283

  • Fluorescence imaging to localize head and neck squamous cell carcinoma for enhanced pathological assessment. The journal of pathology. Clinical research Warram, J. M., de Boer, E., van Dam, G. M., Moore, L. S., Bevans, S. L., Walsh, E. M., Young, E. S., Carroll, W. R., Stevens, T. M., Rosenthal, E. L. 2016; 2 (2): 104-112


    Accurately identifying close or positive margins in real-time permits re-excision during surgical procedures. Intraoperative assessment of margins via gross examination and frozen section is a widely used tool to assist the surgeon in achieving complete resection. While this methodology permits diagnosis of freshly resected tissue, the process is fraught with misinterpretation and sampling errors. During fluorescence-guided surgery, an exogenous fluorescent agent specific for the target disease is imaged in order to navigate the surgical excision. As this technique quickly advances into the clinic, we hypothesize that the disease-specific fluorescence inherently contained within the resected tissues can be used to guide histopathological assessment. To evaluate the feasibility of fluorescence-guided pathology, we evaluated head and neck squamous cell carcinoma tumour specimens and margins resected from animals and patients after systemic injection of cetuximab-IRDye800CW. In a preclinical model of luciferase-positive tumour resection using bioluminescence as the gold standard, fluorescence assessment determined by closed-field fluorescence imaging of fresh resected margins accurately predicted the presence of disease in 33/39 positive margins yielding an overall sensitivity of 85%, specificity of 95%, positive predictive value (PPV) of 94%, and a negative predictive value (NPV) of 87%, which was superior to both surgical assessment (54%, 61%, 57%, and 58%) and pathological assessment (49%, 95%, 91%, and 66%), respectively. When the power of the technique was evaluated using human-derived tumour tissues, as little as 0.5mg (1mm(3)) of tumour tissue was identified (tumour-to-background-ratio:5.2). When the sensitivity/specificity of fluorescence-guided pathology was determined using traditional histological assessment as the gold standard in human tissues obtained during fluorescence-guided surgery, the technique was highly accurate with a sensitivity of 91%, specificity of 85%, PPV of 81%, and NPV of 93% for 90 human-derived samples. This approach can be used as a companion to the pathologist, eliminating confounding factors while impacting surgical intervention and patient management.

    View details for DOI 10.1002/cjp2.40

    View details for PubMedID 27499920

  • On the horizon: Optical imaging for cutaneous squamous cell carcinoma HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK de Boer, E., Moore, L. S., Warram, J. M., Huang, C. C., Brandwein-Gensler, M. S., van Dam, G. M., Rosenthal, E. L., Schmalbach, C. E. 2016; 38: E2204-E2213


    Surgical resection with negative margins remains the standard of care for high-risk cutaneous squamous cell carcinoma (SCC). However, surgical management is often limited by poor intraoperative tumor visualization and inability to detect occult nodal metastasis. The inability to intraoperatively detect microscopic disease can lead to additional surgery, tumor recurrence, and decreased survival.A comprehensive literature review was conducted to identify studies incorporating optical imaging technology in the management of cutaneous SCC (January 1, 2000-December 1, 2014).Several innovative optical imaging techniques, Raman spectroscopy, confocal microscopy, and fluorescence imaging, have been developed for intraoperative surgical guidance. Fifty-seven studies review the ability of these techniques to improve cutaneous SCC localization at the gross and microscopic level.Significant advances have been achieved with real-time optical imaging strategies for intraoperative cutaneous SCC margin assessment and tumor detection. Optical imaging holds promise in improving the percentage of negative surgical margins and in the early detection of micrometastatic disease. © 2015 Wiley Periodicals, Inc. Head Neck, 2015.

    View details for DOI 10.1002/hed.24079

    View details for Web of Science ID 000375116400288

    View details for PubMedID 25899874

  • Grant-Writing Pearls and Pitfalls: Maximizing Funding Opportunities. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Liu, J. C., Pynnonen, M. A., St John, M., Rosenthal, E. L., Couch, M. E., Schmalbach, C. E. 2016; 154 (2): 226-232


    This invited article reviews the grant process to include the following objectives: (1) to provide an understanding of otolaryngology funding mechanisms in the context of career progression; (2) to outline key components of a well-written grant; (3) to highlight vital members of a successful research team, with emphasis on the mentor-mentee relationship; and (4) to clarify grant scoring with emphasis on common pitfalls to avoid. Current otolaryngology funding mechanisms and up-to-date resources are provided. The review is aimed to assist otolaryngology residents, faculty new to the grant process, as well as experienced researchers striving to improve their grant review scores.

    View details for DOI 10.1177/0194599815620174

    View details for PubMedID 26626133

  • Epidermal growth factor receptor inhibition by anti-CD147 therapy in cutaneous squamous cell carcinoma HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Frederick, J. W., Sweeny, L., Hartman, Y., Zhou, T., Rosenthal, E. L. 2016; 38 (2): 247-252


    Advanced cutaneous squamous cell carcinoma (SCC) is an uncommon and aggressive malignancy. As a result, there is limited understanding of its biology and pathogenesis. CD147 and epidermal growth factor receptor (EGFR) have been identified as oncologically important targets, but their relationship remains undefined in cutaneous SCC.Multiple cutaneous SCC cell lines (Colo-16, SRB-1, and SRB-12), were treated in vitro with a range of chimeric anti-CD147 monoclonal antibody (mAb) (0, 50, 100, and 200 µg/mL) or transfected with a small interfering RNA against CD147 (SiCD147). Cell proliferation, migration (scratch wound healing assay), and protein expression was then assessed. In vivo, Colo-16 flank xenografts were treated anti-CD147 mAb (150 µg i.p. triweekly).After treatment with anti-CD147 (200 µg/mL), there was a significant decrease in proliferation for all cell lines relative to controls (p < .005). In addition, treatment with anti-CD147 (200 µg/mL) resulted in decreased cell migration for all cell lines, with an average of 43% reduction in closure compared to controls (p < .001). Colo-16 SiCD147 expression demonstrated similar reduction in proliferation and wound closure. Anti-CD147 antibody therapy and siRNA mediated reduction in CD147 expression were both found to decrease protein expression of EGFR, which correlated with a reduction in downstream total and phosphorylated protein kinase B (pAKT). Tumor growth in vivo was reduced for both the anti-CD147 treatment group and the SiCD147 group relative to controls.Inhibition and downregulation of CD147 in cutaneous SCC resulted in suppression of the malignant phenotype in vitro and in vivo, which may be mediated in part by an alteration in EGFR expression. As a result, CD147 may serve as a potential therapeutic target for advanced cutaneous SCC. © 2014 Wiley Periodicals, Inc. Head Neck 38: 247-252, 2016.

    View details for DOI 10.1002/hed.23885

    View details for Web of Science ID 000368735100021

    View details for PubMedID 25270595

  • Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Rosenthal, E. L., Warram, J. M., de Boer, E., Basilion, J. P., Biel, M. A., Bogyo, M., Bouvet, M., Brigman, B. E., Colson, Y. L., DeMeester, S. R., Gurtner, G. C., Ishizawa, T., Jacobs, P. M., Keereweer, S., Liao, J. C., Nguyen, Q. T., Olson, J. M., Paulsen, K. D., Rieves, D., Sumer, B. D., Tweedle, M. F., Vahrmeijer, A. L., Weichert, J. P., Wilson, B. C., Zenn, M. R., Zinn, K. R., van Dam, G. M. 2016; 57 (1): 144-150


    Navigation with fluorescence guidance has emerged in the last decade as a promising strategy to improve the efficacy of oncologic surgery. To achieve routine clinical use, the onus is on the surgical community to objectively assess the value of this technique. This assessment may facilitate both the Food and Drug Administration (FDA) approval of new optical imaging agents and reimbursement for the imaging procedures. It is critical to characterize fluorescence-guided procedural benefits over existing practices and to elucidate both the costs and safety risks. This report is the result of a meeting of the International Society of Image Guided Surgery (ISIGS, on February 6th, 2015 in Miami, Florida and reflects a consensus of the participants' opinions. Our objective is to critically evaluate the imaging platform technology and optical imaging agents, and to make recommendations for successful clinical trial development of this highly promising approach in oncologic surgery.

    View details for DOI 10.2967/jnumed.115.158915

    View details for PubMedID 26449839

  • Smoking Cessation and Electronic Cigarette Use among Head and Neck Cancer Patients OTOLARYNGOLOGY-HEAD AND NECK SURGERY McQueen, N., Partington, E. J., Harrington, K. F., Rosenthal, E. L., Carroll, W. R., Schmalbach, C. E. 2016; 154 (1): 73-79
  • Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report JOURNAL OF NUCLEAR MEDICINE Rosenthal, E. L., Warram, J. M., de Boer, E., Basilion, J. P., Biel, M. A., Bogyo, M., Bouvet, M., Brigman, B. E., Colson, Y. L., DeMeester, S. R., Gurtner, G. C., Ishizawa, T., Jacobs, P. M., Keereweer, S., Liao, J. C., Nguyen, Q. T., Olson, J. M., Paulsen, K. D., Rieves, D., Sumer, B. D., Tweedle, M. F., Vahrmeijer, A. L., Weichert, J. P., Wilson, B. C., Zenn, M. R., Zinn, K. R., van Dam, G. M. 2016; 57 (1): 144-150
  • Fluorescence-guided resection of experimental malignant glioma using cetuximab-IRDye 800CW BRITISH JOURNAL OF NEUROSURGERY Warram, J. M., de Boer, E., Korb, M., Hartman, Y., Kovar, J., Markert, J. M., Gillespie, G. Y., Rosenthal, E. L. 2015; 29 (6): 850-858


    The standard treatment for glioblastoma multiforme (GBM) remains maximal safe surgical resection. Here, we evaluated the ability of a systemically administered antibody-dye probe conjugate (cetuximab-IRDye 800CW) to provide sufficient fluorescent contrast for surgical resection of disease in both subcutaneous and orthotopic animal models of GBM. Multiple luciferase-positive GBM cell lines (D-54MG, U-87MG, and U-251MG; n = 5) were implanted in mouse flank and tumors were fluorescently imaged daily using a closed-field near-infrared (NIR) system after cetuximab-IRDye 800CW systemic administration. Orthotopic models were also generated (n = 5), and tumor resection was performed under white light and fluorescence guidance using an FDA-approved wide-field NIR imaging system. Residual tumor was monitored using luciferase imaging. Immunohistochemistry was performed to characterize tumor fluorescence, epidermal growth factor receptor (EGFR) expression, and vessel density. Daily imaging of tumors revealed an average tumor-to-background (TBR) of 4.5 for U-87MG, 4.1 for D-54MG, and 3.7 for U-251MG. Fluorescence intensity within the tumors peaked on day-1 after cetuximab-IRDye 800CW administration, however the TBR increased over time in two of the three cell lines. For the orthotopic model, TBR on surgery day ranged from 19 to 23 during wide-field, intraoperative imaging. Surgical resection under white light on day 3 after cetuximab-IRDye 800CW resulted in an average 41% reduction in luciferase signal while fluorescence-guided resection using wide-field NIR imaging resulted in a significantly (P = 0.001) greater reduction in luciferase signal (87%). Reduction of luciferase signal was found to correlate (R (2) = 0.99) with reduction in fluorescence intensity. Fluorescence intensity was found to correlate (P < 0.05) with EGFR expression in D-54MG and U-251MG tumor types but not U-87MG. However, tumor fluorescence was found to correlate with vessel density for the U-87MG tumors. Here we show systemic administration of cetuximab-IRDye 800CW in combination with wide-field NIR imaging provided robust and specific fluorescence contrast for successful localization of disease in subcutaneous and orthotopic animal models of GBM.

    View details for DOI 10.3109/02688697.2015.1056090

    View details for Web of Science ID 000370647000019

    View details for PubMedID 26073144

  • Dynamic contrast-enhanced MRI evaluates the early response of human head and neck tumor xenografts following anti-EMMPRIN therapy with cisplatin or irradiation. Journal of magnetic resonance imaging Kim, H., Hartman, Y. E., Zhai, G., Chung, T. K., Korb, M. L., Beasley, T. M., Zhou, T., Rosenthal, E. L. 2015; 42 (4): 936-945


    To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X-ray radiation in head and neck cancer mouse models using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Mice bearing SCC1 (or OSC19) tumor xenografts were treated with anti-EMMPRIN antibody, radiation, cisplatin, or anti-EMMPRIN antibody plus cisplatin (or radiation) for a week (n = 4-5 per group). DCE-MRI was carried out on a 9.4T small animal MR scanner on days 0, 3, and 7, and K(trans) values were averaged in a 0.5-mm-thick peripheral tumor region. Ki67 and CD31 staining were implemented for all tumors after imaging.The K(trans) changes of SCC1 and OSC19 tumors treated with anti-EMMPRIN antibody for 3 days were -18 ± 8% and 4 ± 7%, respectively, which were significantly lower than those of control groups (39 ± 5% and 45 ± 7%; P = 0.0025 and 0.0220, respectively). When cisplatin was added, those were -42 ± 9% and -44 ± 9%, respectively, and with radiation, -45 ± 9% and -27 ± 10%, respectively, which were also significantly lower than those of control groups (P < 0.0001 for all four comparisons). In the eight groups untreated (served as control) or treated with anti-EMMPRIN antibody with/without cisplatin or radiation, the mean K(trans) change for 3 days was significantly correlated with the mean tumor volume change for 7 days (r = 0.74, P = 0.0346), Ki67-expressing cell density (r = 0.96, P = 0.0001), and CD31 density (r = 0.84, P = 0.0084).DCE-MRI might be utilized to assess the early therapeutic effects of anti-EMMPRIN antibody with/without chemotherapy or radiotherapy in head and neck cancer. J. Magn. Reson. Imaging 2015;42:936-945.

    View details for DOI 10.1002/jmri.24871

    View details for PubMedID 25704985

  • DNA double strand break repair defect and sensitivity to poly ADP-ribose polymerase (PARP) inhibition in human papillomavirus 16-positive head and neck squamous cell carcinoma ONCOTARGET Weaver, A. N., Cooper, T. S., Rodriguez, M., Trummell, H. Q., Bonner, J. A., Rosenthal, E. L., Yang, E. S. 2015; 6 (29): 26995-27007


    Patients with human papillomavirus-positive (HPV+) head and neck squamous cell carcinomas (HNSCCs) have increased response to radio- and chemotherapy and improved overall survival, possibly due to an impaired DNA damage response. Here, we investigated the correlation between HPV status and repair of DNA damage in HNSCC cell lines. We also assessed in vitro and in vivo sensitivity to the PARP inhibitor veliparib (ABT-888) in HNSCC cell lines and an HPV+ patient xenograft. Repair of DNA double strand breaks (DSBs) was significantly delayed in HPV+ compared to HPV- HNSCCs, resulting in persistence of γH2AX foci. Although DNA repair activators 53BP1 and BRCA1 were functional in all HNSCCs, HPV+ cells showed downstream defects in both non-homologous end joining and homologous recombination repair. Specifically, HPV+ cells were deficient in protein recruitment and protein expression of DNA-Pk and BRCA2, key factors for non-homologous end joining and homologous recombination respectively. Importantly, the apparent DNA repair defect in HPV+ HNSCCs was associated with increased sensitivity to the PARP inhibitor veliparib, resulting in decreased cell survival in vitro and a 10-14 day tumor growth delay in vivo. These results support the testing of PARP inhibition in combination with DNA damaging agents as a novel therapeutic strategy for HPV+ HNSCC.

    View details for DOI 10.18632/oncotarget.4863

    View details for Web of Science ID 000363161300044

    View details for PubMedID 26336991

  • Accidental dropping or misplacement of free flaps LARYNGOSCOPE Wax, M. K., Futran, N. D., Rosenthal, E. L., Blackwell, K. E., Cannady, S. 2015; 125 (8): 1807-1810


    Standard operating procedures have been developed in many surgical practices to ensure quality of care as it relates to specimens removed from the body. Most of these specimens are sent to pathology. Some, such as calvarial bone harvested during craniotomy are replaced in the body. Free tissue transfer involves harvesting tissue from one body site, storage for a variable period of time outside of the body, and then insertion in another location. As with any system there is ample opportunity for accidental "misplacement." We undertook a multi-institutional study to examine the incidence, etiology, and opportunity for process improvement.Retrospective review.A retrospective review was performed at five institutions (8,382 free flaps).Thirteen (0.15%) flaps were dropped or wrapped in a towel/sponge and placed in a waste bucket. Eight radial forearm, three fibula, one latissimus dorsi, and one anterolateral thigh flap were misplaced. All flaps were retrieved, washed in saline/betadine, and implanted into the patient. All flaps survived; no altered outcomes were encountered. The etiology of the misplacement of the free tissue from the sterile field included miscommunication among nursing staff (seven), miscommunication among medical staff (two), and dropping the flap (four). As a result of these events, changes in the handling procedures were instituted including standard labeling methodologies and communication strategies.Inadvertent misplacement of free tissue from the sterile field does occur in a sporadic fashion. Process improvement evaluation at all institutions led to improved strategies for prevention. No long-lasting altered outcomes were encountered.4

    View details for DOI 10.1002/lary.25282

    View details for Web of Science ID 000358379700018

    View details for PubMedID 25877212

  • A ratiometric threshold for determining presence of cancer during fluorescence-guided surgery JOURNAL OF SURGICAL ONCOLOGY Warram, J. M., de Boer, E., Moore, L. S., Schmalbach, C. E., Withrow, K. P., Carroll, W. R., Richman, J. S., Morlandt, A. B., Brandwein-Gensler, M., Rosenthal, E. L. 2015; 112 (1): 2-8


    Fluorescence-guided imaging to assist in identification of malignant margins has the potential to dramatically improve oncologic surgery. However, a standardized method for quantitative assessment of disease-specific fluorescence has not been investigated. Introduced here is a ratiometric threshold derived from mean fluorescent tissue intensity that can be used to semi-quantitatively delineate tumor from normal tissue.Open-field and a closed-field imaging devices were used to quantify fluorescence in punch biopsy tissues sampled from primary tumors collected during a phase 1 trial evaluating the safety of cetuximab-IRDye800 in patients (n = 11) undergoing surgical intervention for head and neck cancer. Fluorescence ratios were calculated using mean fluorescence intensity (MFI) from punch biopsy normalized by MFI of patient-matched tissues. Ratios were compared to pathological assessment and a ratiometric threshold was established to predict presence of cancer.During open-field imaging using an intraoperative device, the threshold for muscle normalized tumor fluorescence was found to be 2.7, which produced a sensitivity of 90.5% and specificity of 78.6% for delineating disease tissue. The skin-normalized threshold generated greater sensitivity (92.9%) and specificity (81.0%).Successful implementation of a semi-quantitative threshold can provide a scientific methodology for delineating disease from normal tissue during fluorescence-guided resection of cancer.

    View details for DOI 10.1002/jso.23946

    View details for Web of Science ID 000358296100002

    View details for PubMedID 26074273

  • Laparoscopic Fluorescent Visualization of the Ureter With Intravenous IRDye800CW JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY Korb, M. L., Huh, W. K., Boone, J. D., Warram, J. M., Chung, T. K., de Boer, E., Bland, K. I., Rosenthal, E. L. 2015; 22 (5): 799-806


    Ureter injury is a serious complication of laparoscopic surgery. Current strategies to identify the ureters, such as placement of a ureteral stent, carry additional risks for patients. We hypothesize that the systemically injected near-infrared (NIR) dye IRDye800CW-CA can be used to visualize ureters intraoperatively.Adult female mixed-breed pigs weighing 24 to 41 kg (n = 2 per dose) were given a 30, 60, or 120 μg/kg systemic injection of IRDye800CW-CA. Using the Food and Drug Administration-cleared Pinpoint laparoscopic NIR system, images of the ureter and bladder were captured every 10 minutes for 60 minutes after injection. To determine the biodistribution of the dye, tissues were collected for ex vivo analysis with the Pearl Impulse system. ImageJ software was used to quantify fluorescence signal and signal-to-background ratio (SBR) for the intraoperative images.The ureter was identified in all pigs at each dose, with peak intensity reached by 30 minutes and remaining elevated throughout the duration of imaging (60 minutes). The 60 μg/kg dose was determined to be optimal for differentiating ureters according to absolute fluorescence (>60 counts/pixel) and SBR (3.1). Urine fluorescence was inversely related to plasma fluorescence (R(2) = -0.82). Ex vivo imaging of kidney, ureter, bladder, and abdominal wall tissues revealed low fluorescence.Systemic administration of IRDye800CW-CA shows promise in providing ureteral identification with high specificity during laparoscopic surgery. The low dose required, rapid time to visualization, and absence of invasive ureteral instrumentation inherent to this technique may reduce complications related to pelvic surgery.

    View details for DOI 10.1016/j.jmig.2015.03.008

    View details for Web of Science ID 000368758500014

    View details for PubMedID 25796218

  • In Vivo Fluorescence Immunohistochemistry: Localization of Fluorescently Labeled Cetuximab in Squamous Cell Carcinomas SCIENTIFIC REPORTS de Boer, E., Warram, J. M., Tucker, M. D., Hartman, Y. E., Moore, L. S., de Jong, J. S., Chung, T. K., Korb, M. L., Zinn, K. R., van Dam, G. M., Rosenthal, E. L., Brandwein-Gensler, M. S. 2015; 5


    Anti-EGFR (epidermal growth factor receptor) antibody based treatment strategies have been successfully implemented in head and neck squamous cell carcinoma (HNSCC). Unfortunately, predicting an accurate and reliable therapeutic response remains a challenge on a per-patient basis. Although significant efforts have been invested in understanding EGFR-mediated changes in cell signaling related to treatment efficacy, the delivery and histological localization in (peri-)tumoral compartments of antibody-based therapeutics in human tumors is poorly understood nor ever made visible. In this first in-human study of a systemically administered near-infrared (NIR) fluorescently labeled therapeutic antibody, cetuximab-IRDye800CW (2.5 mg/m(2), 25 mg/m(2), and 62.5 mg/m(2)), we show that by optical molecular imaging (i.e. denominated as In vivo Fluorescence Immunohistochemistry) we were able to evaluate localization of fluorescently labeled cetuximab. Clearly, optical molecular imaging with fluorescently labeled antibodies correlating morphological (peri-)tumoral characteristics to levels of antibody delivery, may improve treatment paradigms based on understanding true tumoral antibody delivery.

    View details for DOI 10.1038/srep10169

    View details for Web of Science ID 000357041200001

    View details for PubMedID 26120042

  • Intraoperative Nerve Monitoring and Vocal Cord Paralysis: Controlling Bias In reply to Nguyen and Wang JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Chung, T. K., Rosenthal, E. L., Porterfield, J. R., Carroll, W. R., Richman, J., Hawn, M. T. 2015; 220 (5): 973-974

    View details for Web of Science ID 000353342200036

    View details for PubMedID 25907881

  • The protective effect of p16(INK4a) in oral cavity carcinomas: p16(Ink4A) dampens tumor invasion-integrated analysis of expression and kinomics pathways MODERN PATHOLOGY Isayeva, T., Xu, J., Ragin, C., Dai, Q., Cooper, T., Carroll, W., Dayan, D., Vered, M., Wenig, B., Rosenthal, E., Grizzle, W., Anderson, J., Willey, C. D., Yang, E. S., Brandwein-Gensler, M. 2015; 28 (5): 631-653


    A large body of evidence shows that p16(INK4a) overexpression predicts improved survival and increased radiosensitivity in HPV-mediated oropharyngeal squamous cell carcinomas.(OPSCC). Here we demonstrate that the presence of transcriptionally active HPV16 in oral cavity squamous cell carcinomas does not correlate with p16(INK4a) overexpression, enhanced local tumor immunity, or improved outcome. It is interesting that HPV-mediated oropharyngeal squamous cell carcinomas can be categorized as having a 'nonaggressive' invasion phenotype, whereas aggressive invasion phenotypes are more common in HPV-negative squamous cell carcinomas. We have developed primary cancer cell lines from resections with known pattern of invasion as determined by our validated risk model. Given that cell lines derived from HPV-mediated oropharyngeal squamous cell carcinomas are less invasive than their HPV-negative counterparts, we tested the hypothesis that viral oncoproteins E6, E7, and p16(INK4a) can affect tumor invasion. Here we demonstrate that p16(INK4a) overexpression in two cancer cell lines (UAB-3 and UAB-4), derived from oral cavity squamous cell carcinomas with the most aggressive invasive phenotype (worst pattern of invasion type 5 (WPOI-5)), dramatically decreases tumor invasiveness by altering expression of extracellular matrix remodeling genes. Pathway analysis integrating changes in RNA expression and kinase activities reveals different potential p16(INK4a)-sensitive pathways. Overexpressing p16(INK4a) in UAB-3 increases EGFR activity and increases MMP1 and MMP3 expression, possibly through STAT3 activation. Overexpressing p16(INK4a) in UAB-4 decreases PDGFR gene expression and reduces MMP1 and MMP3, possibly through STAT3 inactivation. Alternatively, ZAP70/Syk might increase MUC1 phosphorylation, leading to the observed decreased MMP1 expression.

    View details for DOI 10.1038/modpathol.2014.149

    View details for Web of Science ID 000353774200003

    View details for PubMedID 25523612

  • Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies CANCER BIOLOGY & THERAPY Chung, T. K., Warram, J., Day, K. E., Hartman, Y., Rosenthal, E. L. 2015; 16 (5): 790-798


    Inadequate delivery of therapeutics into tumors has been suggested as a reason for poor response. We hypothesize that bevacizumab, an antibody to vascular endothelial growth factor (VEGF), can improve cetuximab uptake in squamous cell carcinoma tumors. Athymic nude mice were implanted with OSC19 and SCC1 human cancer lines in a subcutaneous flank model. Mice were imaged daily for 14 days after intravenous tail vein injections of the following groups: IgG-IRDye800 (Control), cetuximab-IRDye800 (CTX800 Only), bevacizumab-IRDye800 (BVZ800 Only), cetuximab-IRDye800 + bevacuzimuab-IRDye800 (Simultaneous), and unlabeled bevacizumab followed by cetuximab-IRDye800 3 days later (Neoadjuvant). Within single-agent groups, the CTX800 Only tumor-specific uptake (TSU) was significantly higher than BVZ800 Only at Day 13 (TSU 8.6 vs 2.8, P < 0.001). The Simultaneous treatment with BVZ800 and CTX800 demonstrated no increase in antibody delivery. However, administration of unlabeled bevacizumab 3 days prior to CTX800 (Neoadjuvant group) resulted in significantly higher tumor specific delivery than administration of both antibodies at the same time (11.8 vs Simultaneous 5.0, P < 0.001). This difference can be attributed to a slower decline in tumor fluorescence intensity (-6.8% vs. Simultaneous -11.5% per day, respectively). Structural changes in pericyte coverage and functional vessel changes demonstrating decreased proliferation and tumor growth corroborate these fluorescence results. Although simultaneous administration of bevacizumab with cetuximab failed to increase antibody delivery to the tumor, pretreatment with bevacizumab improved TSU reflecting an increase in tumor-specific uptake of cetuximab as a result of vessel normalization.

    View details for DOI 10.1080/15384047.2015.1016664

    View details for Web of Science ID 000354981300020

    View details for PubMedID 25719497

  • Multimodality Management of High-Risk Head and Neck Basal Cell Carcinoma Requiring Free-Flap Reconstruction OTOLARYNGOLOGY-HEAD AND NECK SURGERY Burch, M. B., Chung, T. K., Rosenthal, E. L., Schmalbach, C. E. 2015; 152 (5): 868-873


    (1) Investigate overall survival (OS) and disease-free survival (DFS) for high-risk head and neck basal cell carcinoma (HNBCC) requiring large extirpation with free-flap reconstruction. (2) Determine impact of prognostic features-tumor size, subsite, number of high-risk features, perineural invasion, and bony invasion-on high-risk HNBCC survival. (3) Determine survival benefit of adjuvant radiation for high-risk HNBCC.Case series with chart review (2002-2013).Academic tertiary care center.Consecutive head and neck patients (N = 431) required free-flap reconstruction following tumor extirpation, 38 for aggressive HNBCC. All cases were high risk. DFS and OS were examined using Kaplan-Meier analysis. Prognostic variables and adjuvant radiation were analyzed utilizing Student's t test for continuous variables and Fisher's exact testing for categorical dependent variables. Complications were reported.Mean tumor diameter was 5.17 cm (range, 1.2-15.0 cm). Mean follow-up was 19.9 months. Overall 2-year survival was 80%, falling to 66% at 5 years. Two-year disease-free survival was 72%. Six patients recurred (n = 5 local, 1 distant). Adjuvant radiotherapy improved DFS (P < .01) but not OS (P = .66). Tumors >2.5 cm did not affect OS (P = .61), regardless of subsite. Bone involvement (44.7% cases) did not affect DFS (P = .39) or OS (P = .18).Larger HNBCC warranting free tissue transfer do not confer worse outcomes, independent of subsite. Adjuvant radiotherapy does not improve OS but significantly affected DFS, allowing for 13.7 additional months of DFS. Bone involvement does not influence DFS or OS and should not preclude surgery, even in advanced cases requiring free-flap reconstruction.

    View details for DOI 10.1177/0194599815575720

    View details for Web of Science ID 000354261400018

    View details for PubMedID 25805638

  • Breast Cancer Imaging Using the Near-Infrared Fluorescent Agent, CLR1502 MOLECULAR IMAGING Korb, M. L., Warram, J. M., Grudzinski, J., Weichert, J., Jeffery, J., Rosenthal, E. L. 2015; 14
  • IND-Directed Safety and Biodistribution Study of Intravenously Injected Cetuximab-IRDye800 in Cynomolgus Macaques MOLECULAR IMAGING AND BIOLOGY Zinn, K. R., Korb, M., Samuel, S., Warram, J. M., Dion, D., Killingsworth, C., Fan, J., Schoeb, T., Strong, T. V., Rosenthal, E. L. 2015; 17 (1): 49-57


    The use of receptor-targeted antibodies conjugated to fluorophores is actively being explored for real-time imaging of disease states; however, the toxicity of the bioconjugate has not been assessed in non-human primates.To this end, the in vivo toxicity and pharmacokinetics of IRDye800 conjugated to cetuximab (cetuximab-IRDye800; 21 mg/kg; equivalent to 250 mg/m(2) human dose) were assessed in male cynomolgus monkeys over 15 days following intravenous injection and compared with an unlabeled cetuximab-dosed control group.Cetuximab-IRDye800 was well tolerated. There were no infusion reactions, adverse clinical signs, mortality, weight loss, or clinical histopathology findings. The plasma half-life for the cetuximab-IRDye800 and cetuximab groups was equivalent (2.5 days). The total recovered cetuximab-IRDye800 in all tissues at study termination was estimated to be 12 % of the total dose. Both cetuximab-IRDye800 and cetuximab groups showed increased QTc after dosing. The QTc for the cetuximab-dosed group returned to baseline by day 15, while the QTc of the cetuximab-IRDye800 remained elevated compared to baseline.IRDye800 in low molar ratios does not significantly impact cetuximab half-life or result in organ toxicity. These studies support careful cardiac monitoring (ECG) for human studies using fluorescent dyes.

    View details for DOI 10.1007/s11307-014-0773-9

    View details for Web of Science ID 000351093700006

    View details for PubMedID 25080323

  • Transoral Robotic Surgery for Oropharyngeal and Tongue Cancer in the United States LARYNGOSCOPE Chung, T. K., Rosenthal, E. L., Magnuson, J. S., Carroll, W. R. 2015; 125 (1): 140-145


    To compare the clinical and cost outcomes of transoral robotic surgery (TORS) versus open procedures following the U.S. Food and Drug Administration approval in December 2009.Retrospective analysis of the Nationwide Inpatient Sample from 2008 to 2011.Elective partial pharyngectomies and partial glossectomies for neoplasm were identified by International Classification of Diseases, 9th Revision, Clinical Modification code.TORS represented 2.1% in 2010 and 2.2% in 2011 of all transoral ablative procedures. Patients undergoing open partial pharyngectomy for oropharyngeal neoplasms (n = 1426) had more severe illness compared to TORS (n = 641). However, after controlling for minor-to-moderate severity of illness, open partial pharyngectomy was associated with longer hospital stay (5.2 vs. 3.7 days, P < 0.001), higher charge ($98,228 vs. $67,317, P < 0.001), higher cost ($29,365 vs. $20,706, P < 0.001), higher rates of tracheostomy and gastrostomy tube placement, and more wound and bleeding complications. TORS was associated with a higher rate of dysphagia (19.5% vs. 8.0%, P < 0.001). The lower cost of TORS remained significant in the major-to-extreme severity of illness group but was associated with higher complication rates when compared to open cases of the same severity of illness. A similar analysis of TORS partial glossectomy for base of tongue tumors had similar cost and length of stay benefits, whereas TORS partial glossectomy for anterior tongue tumors revealed longer hospital stays and no benefit in charge or cost compared to open.Early data demonstrate a clinical and cost benefit in TORS partial pharyngectomy and partial glossectomy for the base of tongue but no benefit in partial glossectomy of the anterior tongue. It is likely that anatomic accessibility and extent of surgery factor into the effectiveness of TORS.

    View details for DOI 10.1002/lary.24870

    View details for Web of Science ID 000346909700032

    View details for PubMedID 25093603

  • Association between human papilloma virus/Epstein-Barr virus coinfection and oral carcinogenesis JOURNAL OF ORAL PATHOLOGY & MEDICINE Jiang, R., Ekshyyan, O., Moore-Medlin, T., Rong, X., Nathan, S., Gu, X., Abreo, F., Rosenthal, E. L., Shi, M., Guidry, J. T., Scott, R. S., Hutt-Fletcher, L. M., Nathan, C. O. 2015; 44 (1): 28-36


    The recent epidemic of head and neck squamous cell carcinomas associated with human papilloma virus (HPV) has not addressed its association with lymphoid tissue in the oropharynx or the potential role of Epstein-Barr virus (EBV)/HPV coinfection.The prevalence of HPV and EBV infection/coinfection and CD21 mRNA expression were determined in normal and cancerous tissues from the oropharynx using in situ hybridization (ISH), p16, and quantitative reverse transcriptase PCR (qRT-PCR). The effects of coinfection on tumorigenicity were evaluated using proliferation and invasion assays.Normal oropharynx, tonsil, non-cancer base of tongue (BOT), and BOT from sleep apnea patients demonstrated EBV positivity ranging from 7% to 36% depending on the site and methods of detection used (qRT-PCR or ISH). Among non-malignant BOT samples, HPV positivity was noted only in 20%. The percent of tonsil and BOT cancers positive for HPV (up to 63% and 80%, respectively) or coinfected with HPV/EBV (up to 25% and 70%, respectively) were both significantly associated with cancer status. Notably, HPV/EBV coinfection was observed only in malignant tissue originating in lymphoid-rich oropharynx sites (tonsil, BOT). CD21 mRNA (the major EBV attachment receptor) was detected in tonsil and BOT epithelium, but not in soft-palate epithelium. Coinfected cell lines showed a significant increase in invasiveness (P < 0.01).There is a high prevalence of HPV/EBV infection and coinfection in BOT and tonsil cancers, possibly reflecting their origins in lymphoid-rich tissue. In vitro, cells modeling coinfection have an increased invasive potential.

    View details for DOI 10.1111/jop.12221

    View details for Web of Science ID 000347346700003

    View details for PubMedID 25040496

  • The Status of Contemporary Image-Guided Modalities in Oncologic Surgery ANNALS OF SURGERY Rosenthal, E. L., Warram, J. M., Bland, K. I., Zinn, K. R. 2015; 261 (1): 46-55


    To review the current trends in optical imaging to guide oncologic surgery.Surgical resection remains the cornerstone of therapy for patients with early stage solid malignancies and more than half of all patients with cancer undergo surgery each year. The technical ability of the surgeon to obtain clear surgical margins at the initial resection remains crucial to improve overall survival and long-term morbidity. Current resection techniques are largely based on subjective and subtle changes associated with tissue distortion by invasive cancer. As a result, positive surgical margins occur in a significant portion of tumor resections, which is directly correlated with a poor outcome.A comprehensive review of studies evaluating optical imaging techniques is performed.A variety of cancer imaging techniques have been adapted or developed for intraoperative surgical guidance that have been shown to improve functional and oncologic outcomes in randomized clinical trials. There are also a large number of novel, cancer-specific contrast agents that are in early stage clinical trials and preclinical development that demonstrate significant promise to improve real-time detection of subclinical cancer in the operative setting.There has been an explosion of intraoperative imaging techniques that will become more widespread in the next decade.

    View details for DOI 10.1097/SLA.0000000000000622

    View details for Web of Science ID 000346409600041

    View details for PubMedID 25599326

  • Optical innovations in surgery BRITISH JOURNAL OF SURGERY De Boer, E., Harlaar, N. J., Taruttis, A., Nagengast, W. B., Rosenthal, E. L., Ntziachristos, V., van Dam, G. M. 2015; 102 (2): E56-E72


    In the past decade, there has been a major drive towards clinical translation of optical and, in particular, fluorescence imaging in surgery. In surgical oncology, radical surgery is characterized by the absence of positive resection margins, a critical factor in improving prognosis. Fluorescence imaging provides the surgeon with reliable and real-time intraoperative feedback to identify surgical targets, including positive tumour margins. It also may enable decisions on the possibility of intraoperative adjuvant treatment, such as brachytherapy, chemotherapy or emerging targeted photodynamic therapy (photoimmunotherapy).This article reviews the use of optical imaging for intraoperative guidance and decision-making.Image-guided cancer surgery has the potential to be a powerful tool in guiding future surgical care. Photoimmunotherapy is a theranostic concept (simultaneous diagnosis and treatment) on the verge of clinical translation, and is highlighted as an effective combination of image-guided surgery and intraoperative treatment of residual disease. Multispectral optoacoustic tomography, a technique complementary to optical image-guided surgery, is currently being tested in humans and is anticipated to have great potential for perioperative and postoperative application in surgery.Significant advances have been achieved in real-time optical imaging strategies for intraoperative tumour detection and margin assessment. Optical imaging holds promise in achieving the highest percentage of negative surgical margins and in early detection of micrometastastic disease over the next decade.

    View details for DOI 10.1002/bjs.9713

    View details for Web of Science ID 000348912800007

    View details for PubMedID 25627136

  • Assessment of Erlotinib as Adjuvant Chemoprevention in High-Risk Head and Neck Cancer Patients ANNALS OF SURGICAL ONCOLOGY Rosenthal, E. L., Chung, T. K., Carroll, W. R., Clemons, L., Desmond, R., Nabell, L. 2014; 21 (13): 4263-4269


    To determine the tolerability and efficacy of long-term treatment with erlotinib for head and neck squamous cell carcinoma after salvage surgery.An open-label study was conducted of 150 mg of daily erlotinib for 12 months in patients who completed definitive surgical therapy for recurrent head and neck squamous cell carcinoma. The primary outcome measures were tolerability of prolonged erlotinib therapy and disease-free survival and overall survival at 1 and 2 years.Thirty-one patients were enrolled onto this study. Mean duration of erlotinib therapy was 5 months (range 2-374 days), with 8 patients completing the full 12-month course of erlotinib. Of the remaining patients, 8 discontinued therapy as a result of recurrence, 10 for medical or surgical complications deemed unrelated to the study medication, and 3 for drug-related toxicities. There were 25 grade 3 adverse events; 4 were classified as possibly related to study medication. The most common adverse events included acneiform rash (n = 26 patients), fatigue (n = 22), and diarrhea (n = 22). Overall survival was 61 % at 1 year and 56 % at 2 years. Disease-free survival was 54 % at 1 year and 45 % at 2 years. Mean time to recurrence (n = 16) was 8.7 months.Long-term erlotinib is safe and demonstrates some potential survival benefit compared to historical controls. However, despite the absence of grade 3/4 adverse events attributable to the drug, tolerance of long-term erlotinib was a significant barrier to completion of a 12-month course of therapy.

    View details for DOI 10.1245/s10434-014-3878-0

    View details for Web of Science ID 000344626400032

    View details for PubMedID 25001094

  • A Standardized Light-Emitting Diode Device for Photoimmunotherapy JOURNAL OF NUCLEAR MEDICINE de Boer, E., Warram, J. M., Hartmans, E., Bremer, P. J., Bijl, B., Crane, L. M., Nagengast, W. B., Rosenthal, E. L., van Dam, G. M. 2014; 55 (11): 1893-1898


    Antibody-based photodynamic therapy-photoimmunotherapy (PIT)-is an ideal modality to improve cancer treatment because of its selective and tumor-specific mode of therapy. Because the use of PIT for cancer treatment is continuing to be described, there is great need to characterize a standardized light source for PIT application. In this work, we designed and manufactured a light-emitting diode (LED)/PIT device and validated the technical feasibility, applicability, safety, and consistency of the system for cancer treatment.To outline the characteristics and photobiologic safety of the LED device, multiple optical measurements were performed in accordance with a photobiologic safety standard. A luciferase-transfected breast cancer cell line (2LMP-Luc) in combination with panitumumab-IRDye 700DX (pan-IR700) was used to validate the in vitro and in vivo performance of our LED device.Testing revealed the light source to be safe, easy to use, and independent of illumination and power output (mW cm(-2)) variations over time. For in vitro studies, an LED dose (2, 4, 6 J cm(-2))-dependent cytotoxicity was observed using propidium iodide exclusion and annexin V staining. Dose-dependent blebbing was also observed during microscopic analysis. Bioluminescence signals of tumors treated with 0.3 mg of pan-IR700 and 50 J cm(-2) decreased significantly (>80%) compared with signals of contralateral nontreated sites at 4 h and at 1 d after PIT.To our knowledge, a normalized and standardized LED device has not been explicitly described or developed. In this article, we introduce a standardized light source and validate its usability for PIT applications.

    View details for DOI 10.2967/jnumed.114.142299

    View details for Web of Science ID 000344209200022

    View details for PubMedID 25315245

  • Examining National Outcomes after Thyroidectomy with Nerve Monitoring JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Chung, T. K., Rosenthal, E. L., Porterfield, J. R., Carroll, W. R., Richman, J., Hawn, M. T. 2014; 219 (4): 765-770


    Previous intraoperative nerve monitoring (IONM) studies have demonstrated modest-to-no benefit and did not include a nationwide sample of hospitals representative of broad thyroidectomy practices. This national study was designed to compare vocal cord paralysis (VCP) rates between thyroidectomy with IONM and without monitoring (conventional).We performed a retrospective analysis of 243,527 thyroidectomies during 2008 to 2011 using the Nationwide Inpatient Sample.Use of IONM increased yearly throughout the study period (2.6% [2008], 5.6% [2009], 6.1% [2010], 6.9% [2011]) and during this time, VCP rates in the IONM group initially increased year-over-year (0.9% [2008], 2.4% [2009], 2.5% [2010], 1.4% [2011]). In unadjusted analyses, IONM was associated with significantly higher VCP rates (conventional 1.4% vs IONM 1.9%, p < 0.001). After propensity score matching, IONM remained associated with higher VCP rates in partial thyroidectomy and lower VCP rates for total thyroidectomy with neck dissection. Hospital-level analysis revealed that VCP rates were not explained by differential laryngoscopy rates, decreasing the likelihood of ascertainment bias. Additionally, for hospitals in which IONM was applied to more than 50% of thyroidectomies, lower VCP rates were observed (1.1%) compared with hospitals that applied IONM to less than 50% (1.6%, p = 0.016). Higher hospital volume correlated with lower VCP rates in both groups (<75, 75 to 299, >300 thyroidectomies/year: IONM, 2.1%, 1.7%, 1.7%; conventional, 1.5%, 1.3%, 1.0%, respectively).According to this study, IONM has not been broadly adopted into practice. Overall, IONM was associated with a higher rate of VCP even after correction for numerous confounders. In particular, low institutional use of IONM and use in partial thyroidectomies are associated with higher rates of VCP. Further studies are warranted to support the broader application of IONM in patients where benefit can be reliably achieved.

    View details for DOI 10.1016/j.jamcollsurg.2014.04.013

    View details for Web of Science ID 000342422500022

    View details for PubMedID 25158909

  • Transoral Robotic versus Open Surgical Approaches to Oropharyngeal Squamous Cell Carcinoma by Human Papillomavirus Status OTOLARYNGOLOGY-HEAD AND NECK SURGERY Ford, S. E., Brandwein-Gensler, M., Carroll, W. R., Rosenthal, E. L., Magnuson, J. S. 2014; 151 (4): 606-611


    (1) Investigate oncologic survival outcomes and (2) analyze the impact of human papillomavirus status on prognosis in patients with oropharyngeal squamous cell carcinoma treated with transoral robotic versus open surgery.Retrospective cohort study.Tertiary care referral center, University of Alabama at Birmingham Hospital.One hundred thirty total (65 per treatment arm) with primary oropharyngeal squamous cell carcinoma (OPSCC).Patients treated for primary oropharyngeal squamous cell carcinoma with either transoral robotic (TORS) or open surgery plus standard of care adjuvant therapy between October 2004 and March 2012 were matched based on TNM staging before a retrospective chart review was performed. Carcinoma tissue was stained both prospectively and retrospectively with CINtec p16-INK4a kits for surrogate human papillomavirus typing. Recurrence-free survival was used to evaluate the impact of human papillomavirus tumor status and method of surgical intervention on prognosis.As a whole, patients treated with transoral robotic surgery survived more frequently (94%, 91%, 89% at 1, 2, 3 years, respectively) than those treated with open surgery (85%, 75%, 73% at 1, 2, 3 years, correspondingly) (P = .035). The subgroup of patients with human papillomavirus-negative malignancies treated with open surgery survived without recurrence less frequently at 1, 2, and 3 year rates of 58%, 25%, 25%, respectively (P < .01).These retrospective data suggest that oncologic outcomes are not being sacrificed when patients with OPSCC are treated with TORS instead of open surgery regardless of tumor human papillomavirus immunohistochemical staining.

    View details for DOI 10.1177/0194599814542939

    View details for Web of Science ID 000342982900013

    View details for PubMedID 25049265

  • Free Tissue Transfer for Head and Neck Reconstruction A Contemporary Review JAMA FACIAL PLASTIC SURGERY Cannady, S. B., Rosenthal, E. L., Knott, P. D., Fritz, M., Wax, M. K. 2014; 16 (5): 367-373


    Microvascular free tissue transfer is used for complex composite tissue defects in previously treated fields, in particular after treatment of malignant disease. The increasing incidence of skin cancer in the general population has increased the number of patients with massive tumors that require the expertise of the free flap reconstructive surgeon. We herein examine a number of the recent advances in the field that use free tissue transfer for orbitomaxillary and scalp reconstruction, including maxillary reconstruction, virtual surgical planning in head and neck reconstruction, and scalp reconstruction. Advanced computer algorithms allow planning of these procedures at a savings of time and cost. Free tissue transfer is a reconstructive modality that is often at the top of the reconstructive ladder and, in some instances, is the reconstructive method of choice. The ability to harvest composite tissue that matches the tissue defect in composition, surface area, and volume makes free tissue transfer a versatile modality.

    View details for DOI 10.1001/jamafacial.2014.323

    View details for Web of Science ID 000342357500011

    View details for PubMedID 24994489

  • Synthesis and biological evaluation of panitumumab-IRDye800 conjugate as a fluorescence imaging probe for EGFR-expressing cancers MEDCHEMCOMM Bhattacharyya, S., Patel, N. L., Wei, L., Riffle, L. A., Kalen, J. D., Hill, G. C., Jacobs, P. M., Zinn, K. R., Rosenthal, E. 2014; 5 (9): 1337-1346

    View details for DOI 10.1039/c4md00116h

    View details for Web of Science ID 000341017700009

  • Antibody-based imaging strategies for cancer CANCER AND METASTASIS REVIEWS Warram, J. M., de Boer, E., Sorace, A. G., Chung, T. K., Kim, H., Pleijhuis, R. G., van Dam, G. M., Rosenthal, E. L. 2014; 33 (2-3): 809-822


    Although mainly developed for preclinical research and therapeutic use, antibodies have high antigen specificity, which can be used as a courier to selectively deliver a diagnostic probe or therapeutic agent to cancer. It is generally accepted that the optimal antigen for imaging will depend on both the expression in the tumor relative to normal tissue and the homogeneity of expression throughout the tumor mass and between patients. For the purpose of diagnostic imaging, novel antibodies can be developed to target antigens for disease detection, or current FDA-approved antibodies can be repurposed with the covalent addition of an imaging probe. Reuse of therapeutic antibodies for diagnostic purposes reduces translational costs since the safety profile of the antibody is well defined and the agent is already available under conditions suitable for human use. In this review, we will explore a wide range of antibodies and imaging modalities that are being translated to the clinic for cancer identification and surgical treatment.

    View details for DOI 10.1007/s10555-014-9505-5

    View details for Web of Science ID 000339879100030

    View details for PubMedID 24913898

  • Harmonic Scalpel versus electrocautery and surgical clips in head and neck free-flap harvesting. Ear, nose, & throat journal Dean, N. R., Rosenthal, E. L., Morgan, B. A., Magnuson, J. S., Carroll, W. R. 2014; 93 (6): E36-9


    We sought to determine the safety and utility of Harmonic Scalpel-assisted free-flap harvesting as an alternative to a combined electrocautery and surgical clip technique. The medical records of 103 patients undergoing radial forearm free-flap reconstruction (105 free flaps) for head and neck surgical defects between 2006 and 2008 were reviewed. The use of bipolar electrocautery and surgical clips for division of small perforating vessels (n = 53) was compared to ultrasonic energy (Harmonic Scalpel; Ethicon Endo-Surgery, Inc., Cincinnati, Ohio) (n = 52) free-tissue harvesting techniques. Flap-harvesting time was reduced with the use of the Harmonic Scalpel when compared with electrocautery and surgical clip harvest (31.4 vs. 36.9 minutes, respectively; p = 0.06). Two patients who underwent flap harvest with electrocautery and surgical clips developed postoperative donor site hematomas, whereas no donor site complications were noted in the Harmonic Scalpel group. Recipient site complication rates for infection, fistula, and hematoma were similar for both harvesting techniques (p = 0.77). Two flap failures occurred in the clip-assisted radial forearm free-flap harvest group, and none in the Harmonic Scalpel group. Median length of hospitalization was significantly reduced for patients who underwent free-flap harvest with the Harmonic Scalpel when compared with the other technique (7 vs. 8 days; p = 0.01). The Harmonic Scalpel is safe, and its use is feasible for radial forearm free-flap harvest.

    View details for PubMedID 24932828

  • Use of monoclonal antibody-IRDye800CW bioconjugates in the resection of breast cancer JOURNAL OF SURGICAL RESEARCH Korb, M. L., Hartman, Y. E., Kovar, J., Zinn, K. R., Bland, K. I., Rosenthal, E. L. 2014; 188 (1): 119-128


    Complete surgical resection of breast cancer is a powerful determinant of patient outcome, and failure to achieve negative margins results in reoperation in between 30% and 60% of patients. We hypothesize that repurposing Food and Drug Administration-approved antibodies as tumor-targeting diagnostic molecules can function as optical contrast agents to identify the boundaries of malignant tissue intraoperatively.The monoclonal antibodies bevacizumab, cetuximab, panitumumab, trastuzumab, and tocilizumab were covalently linked to a near-infrared fluorescence probe (IRDye800CW) and in vitro binding assays were performed to confirm ligand-specific binding. Nude mice bearing human breast cancer flank tumors were intravenously injected with the antibody-IRDye800 bioconjugates and imaged over time. Tumor resections were performed using the SPY and Pearl Impulse systems, and the presence or absence of tumor was confirmed by conventional and fluorescence histology.Tumor was distinguishable from normal tissue using both SPY and Pearl systems, with both platforms being able to detect tumor as small as 0.5 mg. Serial surgical resections demonstrated that real-time fluorescence can differentiate subclinical segments of disease. Pathologic examination of samples by conventional and optical histology using the Odyssey scanner confirmed that the bioconjugates were specific for tumor cells and allowed accurate differentiation of malignant areas from normal tissue.Human breast cancer tumors can be imaged in vivo with multiple optical imaging platforms using near-infrared fluorescently labeled antibodies. These data support additional preclinical investigations for improving the surgical resection of malignancies with the goal of eventual clinical translation.

    View details for DOI 10.1016/j.jss.2013.11.1089

    View details for Web of Science ID 000333971300016

    View details for PubMedID 24360117

  • Head and Neck Cutaneous Squamous Cell Carcinoma Requiring Parotidectomy Prognostic Indicators and Treatment Selection OTOLARYNGOLOGY-HEAD AND NECK SURGERY Sweeny, L., Zimmerman, T., Carroll, W. R., Schmalbach, C. E., Day, K. E., Rosenthal, E. L. 2014; 150 (4): 610-617


    Evaluate characteristics and risk factors for patients with advanced cutaneous squamous cell carcinoma (cSCC).Retrospective case series.Tertiary care center.Chart review of patients with cSCC undergoing a parotidectomy (2003-2012).Of 218 patients identified, 49% presented with a new primary lesion (n = 107) and 51% with a recurrence (n = 111). Parotid lymph nodes were positive in 52% of patients; 81% had a concurrent neck dissection, and 28% had cervical lymph node metastases. In 18% of patients, both parotid and cervical nodes were positive, while 44% were both parotid and cervical node negative; 33% had positive parotid and negative cervical nodes, and only 5% had negative parotid and positive cervical nodes. The overall 2- and 5-year survival rates were 0.71 and 0.58. Overall 5-year survival was lower for patients presenting with recurrent (0.49) versus new primary disease (0.69; P = .04). In addition, decreased overall 5-year survival rates were associated with cervical lymph node involvement (0.47 vs. 0.62; P = .01). There was no difference in overall survival when stratified by parotid lymph node involvement (P = .85), margin status (P = .67), perineural invasion (P = .42), facial nerve sacrifice (P = .92), or type of parotid operation performed (P = .51).In this study, cervical, but not parotid, lymph node involvement was associated with poor outcomes in patients with advanced cSCC requiring a parotidectomy. In patients without evidence of cervical or parotid lymph node involvement, a neck dissection may be spared, given there is a 5% chance of occult disease.

    View details for DOI 10.1177/0194599814520686

    View details for Web of Science ID 000333682700017

    View details for PubMedID 24474713



    Microbubbles triggered with localized ultrasound (US) can improve tumor drug delivery and retention. Termed US-stimulated drug delivery, this strategy was applied to head and neck cancer (HNC) in a post-surgical tumor resection model. Luciferase-positive HNC squamous cell carcinoma (SCC) was implanted in the flanks of nude athymic mice (N = 24) that underwent various degrees of surgical tumor resection (0%, 50% or 100%). After surgery, animals received adjuvant therapy with cetuximab-IRDye alone, or cetuximab-IRDye in combination with US-stimulated drug delivery or saline injections (control) on days 4, 7 and 10. Tumor drug delivery was assessed on days 0, 4, 7, 10, 14 and 17 with an in vivo fluorescence imaging system, and tumor viability was evaluated at the same times with in vivo bioluminescence imaging. Tumor caliper measurements occurred two times per week for 24 d. Optical imaging revealed that in the 50% tumor resection group, US-stimulated drug delivery resulted in a significant increase in cetuximab delivery compared with administration of drug alone on day 10 (day of peak fluorescence) (p = 0.03). Tumor viability decreased in all groups that received cetuximab-IRDye in combination with US-stimulated drug delivery, compared with the group that received only the drug. After various degrees of surgical resection, this novel study reports positive improvements in drug uptake in the residual cancer cells when drug delivery is stimulated with US.

    View details for DOI 10.1016/j.ultrasmedbio.2013.11.002

    View details for Web of Science ID 000332027300011

    View details for PubMedID 24412168

  • Negative Pressure Wound Therapy in Head and Neck Surgery JAMA FACIAL PLASTIC SURGERY Asher, S. A., White, H. N., Golden, J. B., Magnuson, J. S., Carroll, W. R., Rosenthal, E. L. 2014; 16 (2): 120-126


    IMPORTANCE Negative pressure wound therapy has been shown to accelerate healing. There is a paucity of literature reporting its use as a tool to promote wound healing in head and neck reconstruction. OBJECTIVE To review 1 institution's experience with negative pressure dressings to further describe the indications, safety, and efficacy of this technique in the head and neck. DESIGN, SETTING, AND PARTICIPANTS Retrospective case series at a tertiary care academic hospital. One hundred fifteen patients had negative pressure dressings applied between April 2005 and December 2011. Data were gathered, including indications, details of negative pressure dressing use, adverse events, wound healing results, potential risk factors for compromised wound healing (defined as previous radiation therapy, hypothyroidism, or diabetes mellitus), and wound characteristics (complex wounds included those with salivary contamination, bone exposure, great vessel exposure, in the field of previous microvascular free tissue transfer, or in the case of peristomal application in laryngectomy). EXPOSURE Negative pressure wound therapy utilized after head and neck reconstruction. MAIN OUTCOMES AND MEASURES Indications for therapy, length and number of dressing applications, identification of wound healing risk factors, classification of wound complexity, wound healing results, and adverse events related to the use of the device. RESULTS Negative pressure wound therapy was used primarily for wounds of the neck (94 of 115 patients [81.7%]) in addition to other head and neck locations (14 of 115 patients [12.2%]), and free tissue transfer donor sites (7 of 115 patients [6.1%]). The mean (SD) wound size was 5.6 (5.0) cm. The mean number of negative pressure dressing applications was 1.7 (1.2), with an application length of 3.7 (1.4) days. Potential risk factors for compromised wound healing were present in 82 of 115 patients (71.3%). Ninety-one of 115 patients (79.1%) had complex wounds. Negative pressure dressings were used in wounds with salivary contamination (n = 64), bone exposure (n = 40), great vessel exposure (n = 25), previous free tissue transfer (n = 55), and peristomal application after laryngectomy (n = 32). Adverse events occurred in 4 of 115 patients (3.5%). CONCLUSIONS AND RELEVANCE Negative pressure wound therapy in head and neck surgery is safe and has potential to be a useful tool for complex wounds in patients with a compromised ability to heal. LEVEL OF EVIDENCE 4.

    View details for DOI 10.1001/jamafacial.2013.2163

    View details for Web of Science ID 000335961900008

    View details for PubMedID 24357046

  • Intraluminal Negative Pressure Wound Therapy for Optimizing Pharyngeal Reconstruction JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Asher, S. A., White, H. N., Illing, E. A., Carroll, W. R., Magnuson, J. S., Rosenthal, E. L. 2014; 140 (2): 143-149


    Pharyngocutaneous fistula formation after pharyngeal reconstruction is one of the most common and challenging problems to manage. Despite many advances in management, the published success rates indicate a role for any adjuvant therapy that could potentially decrease this complication.To describe the use of intraluminal negative pressure dressings (NPDs) in pharyngeal reconstruction.Retrospective case series at a tertiary care academic hospital. Twelve laryngectomy patients underwent pharyngeal reconstruction augmented by placement of an intrapharyngeal NPD in combination with the introduction of vascularized tissue from August 2011 to May 2012. All patients had potential risk factors for compromised wound healing defined as previous radiation therapy, hypothyroidism, diabetes mellitus, compromised nutrition, or established pharyngocutaneous fistula.An NPD was placed in an intraluminal position spanning the length of the pharyngeal defect as part of the reconstructive procedure. The negative pressure sponge was attached to a standard nasogastric tube to which negative pressure was applied. External closure of the pharynx was then achieved with regional or free tissue transfer.Pharyngeal closure rates, timing until return to oral diet, identification of wound healing risk factors, and adverse events related to use of the device.Eleven of 12 patients (92%) achieved pharyngeal closure with reconstruction using negative pressure wound therapy. All patients had at least 1 potential risk factor for compromised wound healing, with 11 of 12 (92%) having 2 or more. Seven patients had an established pharyngocutaneous fistula, and 5 patients underwent primary reconstruction after laryngopharyngectomy. In 6 of these 7 patients undergoing fistula repair, pharyngeal closure was achieved, and they resumed an oral diet at 1 week postoperatively. The other had successful leak repair initially, but 1 week later developed a separate area of wound breakdown and a second fistula. All 5 patients in whom an intraluminal NPD was placed at the time of initial vacularized tissue reconstruction were able to resume an oral diet by 3 weeks postoperatively, with 3 of them eating by mouth at 1 week postoperatively. No serious adverse events could be attributed to the use of intraluminal NPDs.Intraluminal negative pressure wound therapy is feasible and safe. Future research should be conducted to determine its potential in optimizing pharyngeal reconstruction in high-risk patients.

    View details for DOI 10.1001/jamaoto.2013.6143

    View details for Web of Science ID 000332767800010

    View details for PubMedID 24370595

  • Optical Imaging of Head and Neck Cancer Opportunities and Challenges JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Rosenthal, E. L. 2014; 140 (2): 93-94

    View details for DOI 10.1001/jamaoto.2013.6166

    View details for Web of Science ID 000332767800001

    View details for PubMedID 24370727

  • A comparative study of affibody, panitumumab, and EGF for near-infrared fluorescence imaging of EGFR- and EGFRvIII-expressing tumors CANCER BIOLOGY & THERAPY Gong, H., Kovar, J. L., Cheung, L., Rosenthal, E. L., Olive, D. M. 2014; 15 (2): 185-193


    Aberrant overexpression and/or activation of epidermal growth factor receptor (EGFR) is associated with many types of cancers. EGFR variant III (EGFRvIII) is a common in-frame deletion mutant, which lacks a large part of the extracellular portion (exons 2-7), including components of the ligand-binding domain. Although EGFR has been extensively studied as a molecular imaging target, information about EGFRvIII-targeted molecular imaging is lacking. In this study, the EGFR-specific affibody, therapeutic antibody panitumumab, and ligand EGF were labeled with IRDye 800CW (Ex/Em: 774/789 nm), yielding Aff800, Pan800, and EGF800, respectively. The binding affinities of the labeled agents were compared in cell-based assays using a rat glioma cell line F98 parental (F98-p) lacking EGFR expression, and 2 F98-derived transgenic cell lines expressing EGFR or EGFRvIII (designated as F98-EGFR and F98-vIII, respectively). Results showed that all agents could bind to F98-EGFR, with Pan800 having the highest binding affinity, followed by Aff800 and EGF800. Pan800 and Aff800, but not EGF800, also bound to F98-vIII. In vivo animal imaging demonstrated that compared with F98-p tumors, F98-EGFR tumors generated higher signals with all three agents. However, in the case of F98-vIII, only Pan800 and Aff800 signals were higher. Analysis of tissue lysates showed that a large portion of Pan800 was degraded into small fragments in F98-EGFR and F98-vIII tumors, possibly due to proteolytic digestion after its specific binding and internalization. In conclusion, Pan800 and Aff800 could be used as imaging agents for both wild-type EGFR and EGFRvIII, whereas EGF800 only targets wild-type EGFR.

    View details for DOI 10.4161/cbt.26719

    View details for Web of Science ID 000331333200006

    View details for PubMedID 24100437

  • Nasal Myiasis in Hinduism and Contemporary Otorhinolaryngology. Journal of religion & health Bosmia, A. N., Zimmermann, T. M., Griessenauer, C. J., Shane Tubbs, R., Rosenthal, E. L. 2014: -?


    Various case reports on nasal myiasis written during the 1990s and 2000s state that nasal myiasis, which is known as peenash among South Asian natives, is a form of divine punishment in Hindu mythology, but do not provide citations from Hindu scriptures that would suggest this interpretation. This paper aims to discuss the phenomenon of peenash in a historical context by examining medical literature written during the nineteenth and early twentieth centuries, to identify Hindu texts contributing to the belief of some Hindus that nasal myiasis is a form of divine punishment, and to provide an overview of contemporary treatment for and management of nasal myiasis.

    View details for PubMedID 24385004

  • Breast cancer imaging using the near-infrared fluorescent agent, CLR1502. Molecular imaging Korb, M. L., Warram, J. M., Grudzinski, J., Weichert, J., Jeffery, J., Rosenthal, E. L. 2014; 13


    Positive margins after breast conservation surgery represent a significant problem in the treatment of breast cancer. The near-infrared fluorescence agent CLR1502 (Cellectar Biosciences, Madison, WI) was studied in a preclinical breast cancer model to determine imaging properties and ability to detect small islands of malignancy. Nude mice bearing human breast cancer flank xenografts were given a systemic injection of CLR1502, and imaging was performed using LUNA (Novadaq Technologies Inc., Richmond, BC) and Pearl Impulse (LI-COR Biosciences, Lincoln, NE) devices. Normal tissues were examined for fluorescence signal, and conventional and fluorescence histology was performed using the Odyssey scanner. Peak tumor to background ratio occurred 2 days after injection with CLR1502. The smallest amount of tumor that was imaged and detected using these devices was 1.9 mg, equivalent to 1.9 × 10⁶ cells. The highest fluorescence signal was seen in tumor and normal lymph node tissue, and the lowest fluorescence signal was seen in muscle and plasma. Human breast cancer tumors can be imaged in vivo with multiple optical imaging platforms using CLR1502. This pilot study supports further investigations of this fluorescent agent for improving surgical resection of malignancies, with the goal of eventual clinical translation.

    View details for DOI 10.2310/7290.2014.00040

    View details for PubMedID 25743270

  • Characterizing fluorescent imaging properties of antibodies conjugated to IRDye800CW for use in imaging of head and neck cancer PHOTONIC THERAPEUTICS AND DIAGNOSTICS X Foster, R. C., Krell, A. M., Chung, T. K., Warram, J. M., Zinn, K. R., Rosenthal, E. L. 2014; 8926

    View details for DOI 10.1117/12.2044435

    View details for Web of Science ID 000337574500038

  • A histological evaluation and in vivo assessment of intratumoral near infrared photothermal nanotherapy-induced tumor regression INTERNATIONAL JOURNAL OF NANOMEDICINE Green, H. N., Crockett, S. D., Martyshkin, D. V., Singh, K. P., Grizzle, W. E., Rosenthal, E. L., Mirov, S. B. 2014; 9: 5093-5102


    Nanoparticle (NP)-enabled near infrared (NIR) photothermal therapy has realized limited success in in vivo studies as a potential localized cancer therapy. This is primarily due to a lack of successful methods that can prevent NP uptake by the reticuloendothelial system, especially the liver and kidney, and deliver sufficient quantities of intravenously injected NPs to the tumor site. Histological evaluation of photothermal therapy-induced tumor regression is also neglected in the current literature. This report demonstrates and histologically evaluates the in vivo potential of NIR photothermal therapy by circumventing the challenges of intravenous NP delivery and tumor targeting found in other photothermal therapy studies.Subcutaneous Cal 27 squamous cell carcinoma xenografts received photothermal nanotherapy treatments, radial injections of polyethylene glycol (PEG)-ylated gold nanorods and one NIR 785 nm laser irradiation for 10 minutes at 9.5 W/cm(2). Tumor response was measured for 10-15 days, gross changes in tumor size were evaluated, and the remaining tumors or scar tissues were excised and histologically analyzed.The single treatment of intratumoral nanorod injections followed by a 10 minute NIR laser treatment also known as photothermal nanotherapy, resulted in ~100% tumor regression in ~90% of treated tumors, which was statistically significant in a comparison to the average of all three control groups over time (P<0.01).Photothermal nanotherapy, or intratumoral nanorod injections followed by NIR laser irradiation of tumors and tumor margins, demonstrate the potential of NIR photothermal therapy as a viable localized treatment approach for primary and early stage tumors, and prevents NP uptake by the reticuloendothelial system.

    View details for DOI 10.2147/IJN.S60648

    View details for Web of Science ID 000344173300001

    View details for PubMedID 25395847

  • Hardware Removal after Osseous Free Flap Reconstruction OTOLARYNGOLOGY-HEAD AND NECK SURGERY Day, K. E., Desmond, R., Magnuson, J. S., Carroll, W. R., Rosenthal, E. L. 2014; 150 (1): 40-46


    Identifying risk factors for hardware removal in patients undergoing mandibular reconstruction with vascularized osseous free flaps remains a challenge. The purpose of this study is to identify potential risk factors, including osteocutaneous radial forearm versus fibular flap, for need for removal and to describe the fate of implanted hardware.Case series with chart review Setting Academic tertiary care medical center.Two hundred thirteen patients undergoing 227 vascularized osseous mandibular reconstructions between the years 2004 and 2012. Data were compiled through a manual chart review, and patients incurring hardware removals were identified.Thirty-four of 213 evaluable vascularized osseous free flaps (16%) underwent surgical removal of hardware. The average length of time to removal was 16.2 months (median 10 months), with the majority of removals occurring within the first year. Osteocutaneous radial forearm free flaps (OCRFFF) incurred a slightly higher percentage of hardware removals (9.9%) compared to fibula flaps (6.1%). Partial removal was performed in 8 of 34 cases, and approximately 38% of these required additional surgery for removal.Hardware removal was associated with continued tobacco use after mandibular reconstruction (P = .03). Removal of the supporting hardware most commonly occurs from infection or exposure in the first year. In the majority of cases the bone is well healed and the problem resolves with removal.

    View details for DOI 10.1177/0194599813512103

    View details for Web of Science ID 000328690800007

    View details for PubMedID 24201061

  • Putting Numbers to Fluorescent Guided Surgery MOLECULAR IMAGING AND BIOLOGY Rosenthal, E. L., Zinn, K. R. 2013; 15 (6): 647-648


    Development of fluorescence standards may help improve the comparison between near-infrared fluorescence imaging devices, especially if they become commercially available. As translation of optical imaging for oncologic resections puts these techniques into the hands of more surgeons and operating personnel, improving the ability to compare results between devices and the simplicity of the device will be critical to improve adoption of this technology.

    View details for DOI 10.1007/s11307-013-0662-7

    View details for Web of Science ID 000327216300001

    View details for PubMedID 23836503

  • Preclinical Comparison of Near-Infrared-Labeled Cetuximab and Panitumumab for Optical Imaging of Head and Neck Squamous Cell Carcinoma MOLECULAR IMAGING AND BIOLOGY Day, K. E., Sweeny, L., Kulbersh, B., Zinn, K. R., Rosenthal, E. L. 2013; 15 (6): 722-729


    Though various targets have been proposed and evaluated, no agent has yet been investigated in a clinical setting for head and neck cancer. The present study aimed to compare two fluorescently labeled anti-epidermal growth factor receptor (EGFR) antibodies for detection of head and neck squamous cell carcinoma (HNSCC).Antigen specificities and in vitro imaging of the fluorescently labeled anti-EGFR antibodies were performed. Next, immunodeficient mice (n = 22) bearing HNSCC (OSC-19 and SCC-1) tongue tumors received systemic injections of cetuximab-IRDye800CW, panitumumab-IRDye800CW, or IgG-IRDye800CW (a nonspecific control). Tumors were imaged and resected using two near-infrared imaging systems, SPY and Pearl. Fluorescent lymph nodes were also identified, and all resected tissues were sent for pathology.Panitumumab-IRDye800CW and cetuximab-IRDye800CW had specific and high affinity binding for EGFR (K D = 0.12 and 0.31 nM, respectively). Panitumumab-IRDye800CW demonstrated a 2-fold increase in fluorescence intensity compared to cetuximab-IRDye800CW in vitro. In vivo, both fluorescently labeled antibodies produced higher tumor-to-background ratios compared to IgG-IRDye800CW. However, there was no significant difference between the two in either cell line or imaging modality (OSC-19: p = 0.08 SPY, p = 0.48 Pearl; SCC-1: p = 0.77 SPY, p = 0.59 Pearl; paired t tests).There was no significant difference between the two fluorescently labeled anti-EGFR monoclonal antibodies in murine models of HNSCC. Both cetuximab and panitumumab can be considered suitable targeting agents for fluorescent intraoperative detection of HNSCC.

    View details for DOI 10.1007/s11307-013-0652-9

    View details for Web of Science ID 000327216300010

    View details for PubMedID 23715932

  • Bone Morphogenetic Protein 6 Expression in Oral Cavity Squamous Cell Cancer is Associated With Bone Invasion LARYNGOSCOPE Kejner, A. E., Burch, M. B., Sweeny, L., Rosenthal, E. L. 2013; 123 (12): 3061-3065


    To evaluate bone invasion, survival, and expression of bone morphogenetic protein-6 (BMP-6) in oral cavity cancer in the context of known biomarkers indicative of poor prognosis.Molecular expression study combined with retrospective chart review of corresponding patients at a tertiary care center.Between 2000 and 2009, a total of 197 patients underwent resection for oral cavity squamous cell carcinoma. Of these, 30 pathologic specimens were chosen for further molecular analysis. These 30 patients were separated into three groups (10 per group) based on American Joint Committee on Cancer (AJCC) staging and staging based on size alone (TAJCC /SIZE ). The first group consisted of tumors staged as T2 /2 based on size less than 4 cm and that had no evidence of bone invasion. The T2 /4 group consisted of tumors that were upstaged from T2 based on bone invasion. The T4 /4 group consisted of tumors that were large with and without bone invasion. The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), BMP-6, and epidermal growth factor receptor (EGFR) was examined using immunohistochemistry techniques. Patient demographics, tumor characteristics, survival, and recurrence were compared.Average follow-up was 21 months. Expression of BMP-6 was significantly higher in the T2 /4 cohort (tumor less than 4 cm with bony invasion) than the larger tumors without bone invasion (T4 /4 cohort, P = .05). In addition, increased BMP-6 expression correlated with aggressive behavior in the smaller tumors. Furthermore, increased EGFR expression positively correlated with increased levels of BMP-6.Increased expression of BMP-6 in oral cavity cancer may affect bone invasion.

    View details for DOI 10.1002/lary.24267

    View details for Web of Science ID 000327310500047

    View details for PubMedID 23775772

  • Fluorescently Labeled Therapeutic Antibodies for Detection of Microscopic Melanoma LARYNGOSCOPE Day, K. E., Beck, L. N., Deep, N. L., Kovar, J., Zinn, K. R., Rosenthal, E. L. 2013; 123 (11): 2681-2689


    Detection of microscopic disease during surgical resection of melanoma remains a significant challenge. To assess real-time optical imaging for visualization of microscopic cancer, we evaluated three US Food and Drug Administration (FDA)-approved therapeutic monoclonal antibodies.Prospective, basic science.Melanoma cell lines (A375 and SKMEL5) were xenografted into the ears of immunodeficient mice. Bevacizumab, panitumumab, tocilizumab, or a nonspecific immunoglobin G (IgG) were covalently linked to a near-infrared (NIR) fluorescent probe (IRDye800CW) and systemically injected. Primary tumors were imaged and then resected under fluorescent guidance using the SPY (Novadaq, Toronto, Ontario, Canada), an NIR imaging system used in plastic and reconstructive surgeries to evaluate perfusion. Mice were also imaged with the Pearl Impulse small animal imager (LI-COR Biosciences, Lincoln, NE), an NIR imaging system designed for use with IRDye800CW. Postresection, small tissue fragments were fluorescently imaged and the presence of tumor subsequently confirmed by correlation with histology.All fluorescently labeled therapeutic monoclonal antibodies could adequately delineate tumor from normal tissue based on tumor-to-background ratios (TBR) compared to IgG-IRDye800CW. On serial imaging, panitumumab achieved the highest TBRs with both SPY and Pearl (3.8 and 6.6, respectively). When used to guide resections, the antibody-dye conjugates generated TBRs in the range of 1.3 to 2.2 (average, 1.6) using the SPY and 1.9 to 6.3 (average, 2.7) using the Pearl. There was no significant difference among the antibodies with either imaging modality or cell line (one-way analysis of variance).Our data suggest that FDA-approved antibodies may be suitable targeting agents for the intraoperative fluorescent detection of melanoma.

    View details for DOI 10.1002/lary.24102

    View details for Web of Science ID 000326231200030

    View details for PubMedID 23616260

  • Impact of Pharyngeal Closure Technique on Fistula After Salvage Laryngectomy JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Patel, U. A., Moore, B. A., Wax, M., Rosenthal, E., Sweeny, L., Militsakh, O. N., Califano, J. A., Lin, A. C., Hasney, C. P., Butcher, R. B., Flohr, J., Arnaoutakis, D., Huddle, M., Richmon, J. D. 2013; 139 (11): 1156-1162


    No consensus exists as to the best technique, or techniques, to optimize wound healing, decrease pharyngocutaneous fistula formation, and shorten both hospital length of stay and time to initiation of oral intake after salvage laryngectomy. We sought to combine the recent experience of multiple high-volume institutions, with different reconstructive preferences, in the management of pharyngeal closure technique for post-radiation therapy salvage total laryngectomy in an effort to bring clarity to this clinical challenge.To determine if the use of vascularized flaps in either an onlay or interposed fashion reduces the incidence or duration of pharyngocutaneous fistula after salvage laryngectomy compared with simple primary closure of the pharynx.Multi-institutional retrospective review of all patients undergoing total laryngectomy after having received definitive radiation therapy with or without chemotherapy between January 2005 and January 2012, conducted at 7 academic medical centers.Academic, tertiary referral centers.The study population comprised 359 patients from 8 institutions. All patients had a history of laryngeal irradiation and underwent laryngectomy between 2005 and 2012. They were grouped as primary closure, pectoralis myofascial onlay flap, or interposed free tissue. All patients had a minimum of 4 months follow-up.Fistula incidence, severity, and predictors of fistula.Of the 359 patients, fistula occurred in 94 (27%). For patients with fistula, hospital stay increased from 8.9 to 12.1 days (P < .001) and oral diet initiation was delayed from 10.5 days to 29.9 days (P < .001). Patients were grouped according to closure technique: primary closure (n = 99), pectoralis onlay flap (n = 40), and interposed free tissue (n = 220). Incidence of fistula with primary closure was 34%. For the interposed free flap group, the fistula rate was lower at 25% (P = .07). Incidence of fistula was the lowest for the pectoralis onlay group at 15% (P = .02). Multivariate analysis confirmed a significantly lower fistula rate with either flap technique. For patients who developed fistula, mean duration of fistula was significantly prolonged with primary closure (14.0 weeks) compared with pectoralis flap (9.0 weeks) and free flap (6.5 weeks).Pharyngocutaneous fistula remains a significant problem following salvage laryngectomy. Use of nonirradiated, vascularized flaps reduced the incidence and duration of fistula and should be considered during salvage laryngectomy.

    View details for DOI 10.1001/jamaoto.2013.2761

    View details for Web of Science ID 000328944900010

    View details for PubMedID 23576219

  • Mandibulectomy and Free Flap Reconstruction for Bisphosphonate-Related Osteonecrosis of the Jaws JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Hanasono, M. M., Militsakh, O. N., Richmon, J. D., Rosenthal, E. L., Wax, M. K. 2013; 139 (11): 1135-1142


    Bisphosphonate-related osteonecrosis of the jaws is an increasingly recognized complication of intravenous and oral bisphosphonate therapy. Our experience suggests that mandibulectomy and free flap reconstruction is an effective treatment for patients with stage 3 and recalcitrant stage 2 disease.To analyze indications for segmental mandibulectomy and microvascular free flap reconstruction for bisphosphonate-related osteonecrosis of the jaws and surgical outcomes following this procedure.In a multi-institutional case series study conducted in academic tertiary care centers, 13 patients underwent segmental mandibulectomy and microvascular free flap reconstruction, including 8 patients with stage 3 disease and 5 patients with recalcitrant stage 2 disease. All patients had persistent or progressive disease despite conservative oral care and antibiotic treatment.Segmental mandibulectomy and microvascular free flap reconstruction.Treatment efficacy and postoperative complications. RESULTS There was 1 total flap loss due to infection. The patient with a flap loss ultimately underwent a successful fibula osteocutaneous free flap reconstruction after serial irrigation and debridement. The overall complication rate was 46% (n = 6). All complications occurred in patients with stage 3 disease. Ultimately, all patients achieved a successful reconstruction, with no recurrences. All patients tolerated a soft or regular diet postoperatively.Bisphosphonate-related osteonecrosis of the jaws is an increasingly recognized complication of intravenous and oral bisphosphonate therapy that can occasionally progress to involve full-thickness mandibular destruction, pathologic fracture, and fistulization, as well as chronic pain and infection. Mandibulectomy and free flap reconstruction is an effective treatment for patients with stage 3 and recalcitrant stage 2 bisphosphonate-related osteonecrosis of the jaws. High rates of chronic infection and underlying medical comorbidities may predispose to a substantial perioperative complication rate.

    View details for DOI 10.1001/jamaoto.2013.4474

    View details for Web of Science ID 000328944900007

    View details for PubMedID 24051498

  • A novel extracellular drug conjugate significantly inhibits head and neck squamous cell carcinoma ORAL ONCOLOGY Sweeny, L., Hartman, Y. E., Zinn, K. R., Prudent, J. R., Marshall, D. J., Shekhani, M. S., Rosenthal, E. L. 2013; 49 (10): 991-997


    Despite advances in treatment modalities, head and neck squamous cell carcinoma (HNSCC) remains a challenge to treat with poor survival and high morbidity, necessitating a therapy with greater efficacy. EDC22 is an extracellular drug conjugate of the monoclonal antibody targeting CD147 (glycoprotein highly expressed on HNSCC cells) linked with a small drug molecule inhibitor of Na, K-ATPase. In this study, EDC22's potential as a treatment modality for HNSCC was performed.HNSCC cell lines (FADU, OSC-19, Cal27, SCC-1) were cultured in vitro and proliferation and cell viability were assessed following treatment with a range of concentrations of EDC22 (0.25-5.00μg/mL). Mice bearing HNSCC xenografts (OSC-19, SCC-1) were treated with either EDC22 (3-10mg/kg), anti-CD147 monoclonal antibody, cisplatin (1mg/kg) or radiation therapy (2Gy/week) monotherapy or in combination.In vitro, treatment with minimal concentration of EDC22 (0.25μg/mL) significantly decreased cellular proliferation and cell viability (p<0.0001). In vivo, systemic treatment with EDC22 significantly decreased primary tumor growth rate in both an orthotopic mouse model (OSC-19) and a flank tumor mouse model (SCC-1) (p<0.05). In addition, EDC22 therapy resulted in a greater reduction in tumor growth in vivo compared to radiation monotherapy (p<0.05) and a similar reduction in tumor growth compared to cisplatin monotherapy. Combination therapy provided no significant further reduction in tumor growth relative to EDC22 monotherapy.EDC22 is a potent inhibitor of HNSCC cell proliferation in vitro and in vivo, warranting further investigations of its clinical potential in the treatment of HNSCC.

    View details for DOI 10.1016/j.oraloncology.2013.07.006

    View details for Web of Science ID 000324467800005

    View details for PubMedID 23920309

  • Validation of the risk model: high-risk classification and tumor pattern of invasion predict outcome for patients with low-stage oral cavity squamous cell carcinoma. Head and neck pathology Li, Y., Bai, S., Carroll, W., Dayan, D., Dort, J. C., Heller, K., Jour, G., Lau, H., Penner, C., Prystowsky, M., Rosenthal, E., Schlecht, N. F., Smith, R. V., Urken, M., Vered, M., Wang, B., Wenig, B., Negassa, A., Brandwein-Gensler, M. 2013; 7 (3): 211-223


    The risk model is a validated outcome predictor for patients with head and neck squamous cell carcinoma (Brandwein-Gensler et al. in Am j surg pathol 20:167-178, 2005; Am J Surg Pathol 34:676-688, 2010). This model may potentially shift treatment paradigms for patients with low-stage cancers, as current protocols dictate that they might receive only primary surgery. Here we test the hypothesis that the Risk Model has added prognostic value for low-stage oral cavity squamous cell carcinoma (OCSCC) patients. 299 patients with Stage I/II OCSCC were characterized according to the risk model (Brandwein-Gensler et al. in Am J Surg Pathol 20:167-178, 2005; Am J Surg Pathol 34:676-688, 2010). Cumulative incidence and competing risk analysis were performed for locoregional recurrence (LRR) and disease-specific survival (DSS). Receiver operating characteristic analyses were performed for worst pattern of invasion (WPOI) and the risk categories. 292 patients were analyzed; 30 T1N0 patients (17%) and 26 T2N0 patients (23%) developed LRR. Disease-specific mortality occurred in 9 T1N0 patients (6%) and 9 T2N0 patients (10%). On multivariable analysis, the risk model was significantly predictive of LRR (p = 0.0012, HR 2.41, 95% CI 1.42, 4.11) and DSS (p = 0.0005, HR 9.16, 95% CI 2.65, 31.66) adjusted for potential confounders. WPOI alone was also significantly predictive for LRR adjusted for potential confounders with a cut-point of either WPOI-4 (p = 0.0029, HR 3.63, 95% CI 1.56, 8.47) or WPOI-5 (p = 0.0008, HR 2.55, 95% CI 1.48, 4.41) and for DSS (cut point WPOI-5, p = 0.0001, HR 6.34, 95% CI 2.50, 16.09). Given a WPOI-5, the probability of developing locoregional recurrence is 42%. Given a high-risk classification for a combination of features other than WPOI-5, the probability of developing locoregional recurrence is 32%. The Risk Model is the first validated model that is significantly predictive for the important niche group of low-stage OCSCC patients.

    View details for DOI 10.1007/s12105-012-0412-1

    View details for PubMedID 23250819

  • Airway management after maxillectomy with free flap reconstruction HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Brickman, D. S., Reh, D. D., Schneider, D. S., Bush, B., Rosenthal, E. L., Wax, M. K. 2013; 35 (8): 1061-1065


    BACKGROUND: Maxillectomy defects require complex 3-dimensional reconstructions often best suited to microvascular free tissue transfer. Postoperative airway management during this procedure has little discussion in the literature and is often dictated by surgical dogma. The purpose of this article was to review our experience in order to evaluate the effect of airway management on perioperative outcomes in patients undergoing maxillectomy with free flap reconstruction. METHODS: A retrospective chart review was performed on patients receiving maxillectomy with microvascular reconstruction at 2 institutions between 1999 and 2011. Patient's airways were managed with or without elective tracheotomy at the surgical team's discretion and different perioperative outcomes were measured. The primary outcome was incidence of airway complication including pneumonia and need for further airway intervention. Secondary outcome was measured as factors leading to perioperative performance of the tracheotomy. RESULTS: Seventy-nine of 143 patients received elective tracheotomy perioperatively. The incidence of airway complication was equivalent between groups (10.1% vs 9.4%; p = .89). Patients with cardiopulmonary comorbidities were more likely to receive perioperative tracheotomy (74.1% vs 50.9%; p = .03) without a difference in airway complications. Other patient cofactors did not have an impact on perioperative tracheotomy or airway complication rate. CONCLUSIONS: Elective tracheotomy may safely be avoided in a subset of patients undergoing maxillectomy with microvascular reconstruction. Elective tracheotomy should be considered in patients with cardiopulmonary risk factors. Head Neck, 2012.

    View details for DOI 10.1002/hed.23082

    View details for Web of Science ID 000329216700010

    View details for PubMedID 22907774

  • Salvage Surgery for Recurrent Cancers of the Oropharynx Comparing TORS With Standard Open Surgical Approaches JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY White, H., Ford, S., Bush, B., Holsinger, F. C., Moore, E., Ghanem, T., Carroll, W., Rosenthal, E., Magnuson, J. S. 2013; 139 (8): 773-778


    Surgical salvage may be the only viable treatment option for recurrent tumors of the oropharynx. To our knowledge, there have been no published reports directly comparing the oncologic and functional outcomes of patients with recurrent oropharyngeal squamous cell carcinoma (SCC) treated with transoral robotic-assisted surgery (TORS) with those treated with traditional open surgical approaches.To compare the oncologic and functional outcomes of patients with recurrent oropharyngeal SCC treated with TORS with those treated with traditional open surgical approaches.Retrospective multi-institutional case-control study; study dates, March 2003 through October 2011.Four tertiary care institutions (University of Alabama at Birmingham; M. D. Anderson Cancer Center, Houston, Texas; Mayo Clinic, Rochester, Minnesota; and Henry Ford Hospital, Detroit, Michigan). PARTICIPANTS Sixty-four patients who underwent salvage TORS for recurrent oropharyngeal SCC were matched by TNM stage to 64 patients who underwent open salvage resection. INTERVENTION OR EXPOSURE: Salvage TORS for recurrent SCC of the oropharynx.Patient demographics, operative data, functional, and oncologic outcomes were recorded and compared with a similarly TNM-matched patient group that underwent salvage surgical resection by traditional open surgical approaches. RESULTS Patients treated with TORS were found to have a significantly lower incidence of tracheostomy use (n = 14 vs n = 50; P < .001), feeding tube use (n = 23 vs n = 48; P < .001), shorter overall hospital stays (3.8 days vs 8.0 days; P < .001), decreased operative time (111 minutes vs 350 minutes; P < .001), less blood loss (49 mL vs 331 mL; P < .001), and significantly decreased incidence of positive margins (n = 6 vs n = 19; P = .007). The 2-year recurrence-free survival rate was significantly higher in the TORS group than in the open approach group (74% and 43%, respectively) (P = .01).This study demonstrates that TORS offers an alternative surgical approach to recurrent tumors of the oropharynx with acceptable oncologic outcomes and better functional outcomes than traditional open surgical approaches. This adds to the growing amount of clinical evidence to support the use of TORS in selected patients with recurrent oropharyngeal SCC as a feasible and oncologically sound method of treatment.

    View details for DOI 10.1001/jamaoto.2013.3866

    View details for Web of Science ID 000323545800003

    View details for PubMedID 23949352

  • Outcomes in head and neck reconstruction by surgical site and donor site LARYNGOSCOPE Frederick, J. W., Sweeny, L., Carroll, W. R., Peters, G. E., Rosenthal, E. L. 2013; 123 (7): 1612-1617


    Define surgical outcomes of specific donor sites for free tissue transfer in head and neck reconstruction.Retrospective cohort review at an academic tertiary care center.A review was made of free tissue transfer procedures performed at a university-based tertiary care facility from October 2004 to April 2011. A total of 1,051 patients underwent six types of free flaps: fasciocutaneous radial forearm (53%), osteocutaneous radial forearm (16%), rectus abdominis (11%), fibula (10%), anterior lateral thigh (7%), and latissimus dorsi (2%). Demographic data were collected, and outcomes measured were: length of hospital stay, flap viability, and major complications (infection, fistula, and hematoma).Of the 1,051 flaps performed, the most common operative site was oral cavity (40%, n = 414) followed by hypopharynx/larynx (22%, n = 234), cutaneous (20%, n = 206), oropharynx (9%, n = 98), midface (7%, n = 76), and skull base (2%, n = 23). The median hospital stay was 7.9 days (range, 1-76), and the overall failure rate was 2.8%. Cutaneous defects required the shortest length of hospitalization (5.8 days, P < .0001), a low free flap failure rate (1.5%, n = 3), and limited major complications (6%, n = 12). Conversely, oropharynx defects were associated with the longest hospitalization (8.9 days). Midface defects had a high incidence of complications (15%, n = 11, P = .10). Defects above the angle of the mandible had higher overall complications when compared to below. Similarly, reconstruction for primary or recurrent cancer had a total failure rate of 2.5%, whereas secondary reconstruction and radionecrosis had a failure rate of 4.0% (P = .29). Additionally, there was no statistical difference between outcomes based on donor site.This review demonstrates that certain subsets of patients are at higher risk for complications after free tissue transfer. Patients undergoing free flap reconstruction for cutaneous defects have substantially shorter hospital stays and are at lower risk of flap complications, whereas reconstruction for radionecrosis and secondary reconstruction tend to have higher overall flap failure rates.

    View details for DOI 10.1002/lary.23775

    View details for Web of Science ID 000320784300010

    View details for PubMedID 23686870

  • Microvascular Anastomotic Coupler Assessment in Head and Neck Reconstruction OTOLARYNGOLOGY-HEAD AND NECK SURGERY Frederick, J. W., Sweeny, L., Carroll, W. R., Rosenthal, E. L. 2013; 149 (1): 67-70


    To assess the advantages of using mechanical anastomotic systems in head and neck free tissue transfer.Case series with chart review.A university-based tertiary care center.A retrospective review of mechanical venous coupler devices in head and neck reconstruction performed between October 2004 and December 2006. A total of 261 venous anastomoses were performed in 234 consecutive patients. Five types of flaps were performed: radial forearm (66%), anterior lateral thigh (12%), fibula (9%), rectus abdominis (8%), and latissimus dorsi (2%). Demographic data were collected, and the outcomes measured were flap survival and microvascular complications.The size of the venous anastomosis ranged from 1.5 to 4.0 mm, with most being 3.0 mm (56%) followed by 3.5 mm (23%). The most common recipient vein used was a stump off the internal jugular vein (76%) followed by the external jugular vein (17%). Microvascular complications occurred in <5% (n = 11) of patients, with >50% of those being arterial insufficiency (n = 7). Total failures occurred in 3% (n = 7) of patients: 1.5% (n = 4) acute failures (<5 days) and 1.5% (n = 3) late failures. Of the acute failures, causes included venous congestion (n = 1) and arterial insufficiencies (n = 3). The venous coupler used in the failures was 3.0 mm in diameter. Free flap failures resulting from arterial insufficiency involved coupling to the external jugular vein, while the remaining free flap failures (n = 4) used the internal jugular vein.With an early venous failure rate of 0.38%, mechanical anastomosis is an adequate alternative to hand-sewn techniques.

    View details for DOI 10.1177/0194599813486875

    View details for Web of Science ID 000329427400009

    View details for PubMedID 23585150

  • Hemorrhage after Transoral Robotic-Assisted Surgery OTOLARYNGOLOGY-HEAD AND NECK SURGERY Asher, S. A., White, H. N., Kejner, A. E., Rosenthal, E. L., Carroll, W. R., Magnuson, J. S. 2013; 149 (1): 112-117


    An increasing number of head and neck surgeons have begun using transoral robotic-assisted surgery. Our objective was to examine the postoperative bleeding complications we have encountered to determine risk factors and to discuss the topic of hemorrhage control.Case series with chart review.Medical records were reviewed in 147 consecutive patients undergoing transoral robotic-assisted surgery for any indication at one tertiary academic medical center between March 2007 and September 2011.Eleven of 147 (7.5%) patients undergoing transoral robotic-assisted surgery experienced some degree of postoperative hemorrhage, with 9 patients requiring reoperation for examination and/or control of bleeding. Bleeding occurred at a mean of 11.1 ± 9.2 days after initial operation. Eight of 11 (72%) patients who bled were on antithrombotic medication (anticoagulants or antiplatelet agents) for other medical comorbidities. The postoperative hemorrhage rate in patients taking antithrombotic medication (8/48 patients = 17%) was significantly higher than in those not taking antithrombotics (3/99 patients = 3%), P = .0057. While the bleeding rate in salvage surgery (3/29 = 10.3%) was slightly higher than in primary surgery (8/118 = 6.8%), this difference did not reach statistical significance.Potential for postoperative bleeding in association with antithrombotic medications in patients undergoing transoral robotic-assisted surgery should be recognized. Various effective techniques for management of these patients without robotic assistance were demonstrated.

    View details for DOI 10.1177/0194599813486254

    View details for Web of Science ID 000329427400016

    View details for PubMedID 23585156

  • Use of Panitumumab-IRDye800 to Image Cutaneous Head and Neck Cancer in Mice OTOLARYNGOLOGY-HEAD AND NECK SURGERY Heath, C. H., Deep, N. L., Beck, L. N., Day, K. E., Sweeny, L., Zinn, K. R., Huang, C. C., Rosenthal, E. L. 2013; 148 (6): 982-990


    To assess the feasibility of panitumumab in real-time fluorescent imaging and histologic processing of cutaneous squamous cell carcinoma (cSCC) in mice.A near-infrared (NIR) fluorescent probe (IRDye800CW) was covalently linked to a monoclonal antibody-targeting epidermal growth factor receptor (panitumumab) or nonspecific IgG and injected into mice bearing flank xenografts from a cSCC cell line (SCC-13 or SRB-12; n = 7), human split-thickness skin grafts (STSGs; n = 3), or a human tumor explant (n = 1). The tumor and lymph nodes were imaged and dissected using fluorescence guidance with the SPY imaging system and verified with a charge-coupled NIR system. An NIR scanning device (Odyssey) was used to measure fluorescence intensity in histological sections.Immunodeficient mice.In vivo and in vitro imaging lab.Tumor tissue could be delineated from the human STSG with tumor-to-background ratios of 4.5 (Pearl) and 3.4 (SPY). Tumor detection was substantially improved with panitumumab-IRDye800 compared with IgG-IRDye800. Biopsies positive for fluorescence were assessed by histology and immunohistochemistry (n = 18/18) to confirm the presence of tumor, yielding a 100% sensitivity. Biopsies of nonfluorescent tissue negative for malignancy (n = 18/18) yielded a specificity of 100%. Furthermore, the SPY system was able to detect residual disease as small as 200 µm in diameter. In addition, the Odyssey confirmed fluorescence of microscopic disease (in tumor samples of frozen and paraffin-embedded histologic specimens) but not in adjacent noncancerous tissue.These data suggest panitumumab-IRDye800 may have clinical utility in detection and removal of subclinical cSCC using Food and Drug Administration-approved imaging hardware.

    View details for DOI 10.1177/0194599813482290

    View details for Web of Science ID 000329433000014

    View details for PubMedID 23525846

  • Static and Dynamic Repairs of Facial Nerve Injuries ORAL AND MAXILLOFACIAL SURGERY CLINICS OF NORTH AMERICA White, H., Rosenthal, E. 2013; 25 (2): 303-?


    The patient with facial paralysis presents a daunting challenge to the reconstructive surgeon. A thorough evaluation is key in directing the surgeon to the appropriate treatment methods. Aggressive and immediate exploration with primary repair of the facial nerve continues to be the standard of care for traumatic transection of the facial nerve. Secondary repair using dynamic techniques is preferred over static procedures, because the outcomes have proved to be superior. However, patients should be counseled that facial movement and symmetry are difficult to mimic and none of the procedures described is able to restore all of the complex vectors and overall balance of facial movement and expression.

    View details for DOI 10.1016/j.coms.2013.02.002

    View details for Web of Science ID 000319626900013

    View details for PubMedID 23642673

  • Phase 1 Study of Erlotinib Plus Radiation Therapy in Patients With Advanced Cutaneous Squamous Cell Carcinoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Heath, C. H., Deep, N. L., Nabell, L., Carroll, W. R., Desmond, R., Clemons, L., Spencer, S., Magnuson, J. S., Rosenthal, E. L. 2013; 85 (5): 1275-1281


    To assess the toxicity profile of erlotinib therapy combined with postoperative adjuvant radiation therapy in patients with advanced cutaneous squamous cell carcinoma.This was a single-arm, prospective, phase 1 open-label study of erlotinib with radiation therapy to treat 15 patients with advanced cutaneous head-and-neck squamous cell carcinoma. Toxicity data were summarized, and survival was analyzed with the Kaplan-Meier method.The majority of patients were male (87%) and presented with T4 disease (93%). The most common toxicity attributed to erlotinib was a grade 2-3 dermatologic reaction occurring in 100% of the patients, followed by mucositis (87%). Diarrhea occurred in 20% of the patients. The 2-year recurrence rate was 26.7%, and mean time to cancer recurrence was 10.5 months. Two-year overall survival was 65%, and disease-free survival was 60%.Erlotinib and radiation therapy had an acceptable toxicity profile in patients with advanced cutaneous squamous cell carcinoma. The disease-free survival in this cohort was comparable to that in historical controls.

    View details for DOI 10.1016/j.ijrobp.2012.09.030

    View details for Web of Science ID 000316790500034

    View details for PubMedID 23182701

  • Increased likelihood of long-term gastrostomy tube dependence in head and neck cancer survivors without partners HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Magnuson, J. S., Durst, J., Rosenthal, E. L., Carroll, W. R., Ritchie, C. S., Kilgore, M. L., Locher, J. L. 2013; 35 (3): 420-425


    We evaluated factors associated with long-term dependence on percutaneous endoscopic gastrostomy (PEG) tubes.One hundred fifty-four patients receiving treatment at the University of Alabama at Birmingham between 2002 and 2004 who underwent PEG tube placement were identified through retrospective review of medical records. Using binary logistic regression, we evaluated the association of various factors on long-term dependence on PEG tubes.A total of 25.3% of survivors remained PEG tube-dependent at 12 months. The odds of long-term PEG tube-dependence were greater for those who did not have partners compared with those who had partners (odds ratio [OR], 3.33; p = .004), for patients who received radiation therapy (OR, 6.21; p = .018), and for those who had a tracheotomy in place for longer than 30 days (OR, 4.328; p = .035).Data suggest that interventions targeted at reducing long-term dependence on PEG tubes take into account not only treatment-related factors, but also the important role that social support plays.

    View details for DOI 10.1002/hed.22996

    View details for Web of Science ID 000314997800024

    View details for PubMedID 22505332

  • Identification of the optimal therapeutic antibody for fluorescent imaging of cutaneous squamous cell carcinoma CANCER BIOLOGY & THERAPY Day, K. E., Beck, L. N., Heath, C. H., Huang, C. C., Zinn, K. R., Rosenthal, E. L. 2013; 14 (3): 271-277


    Intraoperative, real-time fluorescence imaging may significantly improve tumor visualization and resection and postoperatively, in pathological assessment. To this end, we sought to determine the optimal FDA approved therapeutic monoclonal antibody for optical imaging of human cutaneous squamous cell carcinoma (cSCC). A near-infrared (NIR) fluorescent probe (IRDye800) was covalently linked to bevacizumab, panitumumab or tocilizumab and injected systemically into immunodeficient mice bearing either cutaneous tumor cell lines (SCC13) or cutaneous human tumor explants. Tumors were then imaged and resected under fluorescent guidance with the SPY, an FDA-approved intraoperative imaging system, and the Pearl Impulse small animal imaging system. All fluorescently labeled antibodies delineated normal tissue from tumor in SCC13 xenografts based on tumor-to-background (TBR) ratios. The conjugated antibodies produced TBRs of 1.2-2 using SPY and 1.6-3.6 using Pearl; in comparison, isotype control antibody IgG-IRDye produced TBRs of 1.0 (SPY) and 0.98 (Pearl). Comparison between antibodies revealed them to be roughly equivalent for imaging purposes with both the SPY and Pearl (p = 0.89 SPY, p = 0.99 Pearl; one way ANOVA). Human tumor explants were also imaged and tumor detection was highest with panitumumab-IRDye800 when using the SPY (TBR 3.0) and Pearl (TBR 4.0). These data suggest that FDA approved antibodies may be clinically used for intraoperative detection of cSCC.

    View details for DOI 10.4161/cbt.23300

    View details for Web of Science ID 000315873600009

    View details for PubMedID 23298904

  • Optical Fluorescent Imaging to Monitor Temporal Effects of Microbubble-Mediated Ultrasound Therapy IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL Sorace, A. G., Saini, R., Rosenthal, E., Warram, J. M., Zinn, K. R., Hoyt, K. 2013; 60 (2): 281-289


    Microbubble-mediated ultrasound therapy can noninvasively enhance drug delivery to localized regions in the body. This technique can be beneficial in cancer therapy, but currently there are limitations to tracking the therapeutic effects. The purpose of this experiment was to investigate the potential of fluorescent imaging for monitoring the temporal effects of microbubble-mediated ultrasound therapy. Mice were implanted with 2LMP breast cancer cells. The animals underwent microbubble-mediated ultrasound therapy in the presence of Cy5.5 fluorescent-labeled IgG antibody (large molecule) or Cy5.5 dye (small molecule) and microbubble contrast agents. Control animals were administered fluorescent molecules only. Animals were transiently imaged in vivo at 1, 10, 30, and 60 min post therapy using a small animal optical imaging system. Tumors were excised and analyzed ex vivo. Tumors were homogenized and emulsion imaged for Cy5.5 fluorescence. Monitoring in vivo results showed significant influx of dye into the tumor (p < 0.05) using the small molecule, but not in the large molecule group (p > 0.05). However, after tumor emulsion, significantly higher dye concentration was detected in therapy group tumors for both small and large molecule groups in comparison to their control counterparts (p <0.01). This paper explores a noninvasive optical imaging method for monitoring the effects of microbubble-mediated ultrasound therapy in a cancer model. It provides temporal information following the process of increasing extravasation of molecules into target tumors.

    View details for DOI 10.1109/TUFFC.2013.2564

    View details for Web of Science ID 000314370100003

    View details for PubMedID 23357902

  • Evaluation of tyrosine receptor kinases in the interactions of head and neck squamous cell carcinoma cells and fibroblasts ORAL ONCOLOGY Sweeny, L., Zimmermann, T. M., Liu, Z., Rosenthal, E. L. 2012; 48 (12): 1242-1249


    Despite treatment advancements, disease-free survival of head and neck squamous cell carcinoma (HNSCC) has not significantly improved. This may be a result of tumor-fibroblasts interactions providing protective pathways for oncogenic cells to resist therapy. Further understanding of these relationships in HNSCC may improve effectiveness of targeted therapies. In this article, we investigated the role of several receptor tyrosine kinases (RTKs) in the interactions between HNSCC cells and supporting cells (fibroblasts).HNSCC cell lines and human tumor samples were evaluated for FGFR1/2/3, and PDGF-beta expression levels. Cell lines (FADU, SCC1, OSC19, Cal27, SCC22A) were treated with a range of physiological concentrations of dovitinib and assessed for proliferation, cytotoxicity, and apoptosis. Mice bearing HNSCC xenografts were treated with dovitinib (20 mg/kg).Evaluation of HNSCC tumor specimens, cell lines and fibroblasts found variable expression of multiple RTKs (fibroblasts growth factor receptor, platelet derived growth factor receptor and vascular endothelial growth factor receptor) and their ligands, supporting previous theories of paracrine and autocrine signaling within the microenvironment. In a dose-dependent fashion, RTK inhibition reduced proliferation of HNSCC cell lines and fibroblast in vitro. When HNSCC cells were cocultured with fibroblasts, RTK inhibition resulted in a smaller reduction in the proliferation relative to untreated conditions. In vivo, RTK inhibition resulted in significant tumor regression and growth inhibition (p<0.05) and reduced the incidence of regional lymph node metastasis.Effective treatment of HNSCC, therefore, may require inhibition of multiple RTKs in order to adequately inhibit the microenvironment's various signaling pathways.

    View details for DOI 10.1016/j.oraloncology.2012.06.011

    View details for Web of Science ID 000311151200008

    View details for PubMedID 22795534

  • Use of Panitumumab-IRDye800 to Image Microscopic Head and Neck Cancer in an Orthotopic Surgical Model ANNALS OF SURGICAL ONCOLOGY Heath, C. H., Deep, N. L., Sweeny, L., Zinn, K. R., Rosenthal, E. L. 2012; 19 (12): 3879-3887


    Fluorescence imaging hardware (SPY) has recently been developed for intraoperative assessment of blood flow via detection of probes emitting in the near-infrared (NIR) spectrum. This study sought to determine if this imaging system was capable of detecting micrometastatic head and neck squamous cell carcinoma (HNSCC) in preclinical models.A NIR fluorescent probe (IRDye800CW) was covalently linked to a monoclonal antibody targeting epidermal growth factor receptor (EGFR; panitumumab) or nonspecific IgG. HNSCC flank (SCC-1) and orthotopic (FADU and OSC19) xenografts were imaged 48-96 h after systemic injection of labeled panitumumab or IgG. The primary tumor and regional lymph nodes were dissected using fluorescence guidance with the SPY system and grossly assessed with a charge-coupled NIR system (Pearl). Histologic slides were also imaged with a NIR charged-coupled device (Odyssey) and fluorescence intensity was correlated with pathologic confirmation of disease.Orthotopic tongue tumors were clearly delineated from normal tissue with tumor-to-background ratios of 2.9 (Pearl) and 2.3 (SPY). Disease detection was significantly improved with panitumumab-IRDye compared to IgG-IRDye800 (P < 0.05). Tissue biopsy samples (average size 3.7 mm) positive for fluorescence were confirmed for pathologic disease by histology and immunohistochemistry (n = 25 of 25). Biopsy samples of nonfluorescent tissue were proven to be negative for malignancy (n = 28 of 28). The SPY was able to detect regional lymph node metastasis (<1.0 mm) and microscopic areas of disease. Standard histological assessment in both frozen and paraffin-embedded histologic specimens was augmented using the Odyssey.Panitumumab-IRDye800 may have clinical utility in detection and removal of microscopic HNSCC using existing intraoperative optical imaging hardware and may augment analysis of frozen and permanent pathology.

    View details for DOI 10.1245/s10434-012-2435-y

    View details for Web of Science ID 000310225700036

    View details for PubMedID 22669455

  • CD147 and AGR2 expression promote cellular proliferation and metastasis of head and neck squamous cell carcinoma EXPERIMENTAL CELL RESEARCH Sweeny, L., Liu, Z., Bush, B. D., Hartman, Y., Zhou, T., Rosenthal, E. L. 2012; 318 (14): 1788-1798


    The signaling pathways facilitating metastasis of head and neck squamous cell carcinoma (HNSCC) cells are not fully understood. CD147 is a transmembrane glycoprotein known to induce cell migration and invasion. AGR2 is a secreted peptide also known to promote cell metastasis. Here we describe their importance in the migration and invasion of HNSCC cells (FADU and OSC-19) in vitro and in vivo. In vitro, knockdown of CD147 or AGR2 decreased cellular proliferation, migration and invasion. In vivo, knockdown of CD147 or AGR2 expression decreased primary tumor growth as well as regional and distant metastasis.

    View details for DOI 10.1016/j.yexcr.2012.04.022

    View details for Web of Science ID 000310092500019

    View details for PubMedID 22659167

  • Assessment and incidence of salivary leak following laryngectomy LARYNGOSCOPE White, H. N., Golden, B., Sweeny, L., Carroll, W. R., Magnuson, J. S., Rosenthal, E. L. 2012; 122 (8): 1796-1799


    To determine the incidence and risk factors of pharyngocutaneous fistula formation in patients undergoing either primary or salvage laryngectomies and evaluate the role of barium esophagram in these patients.Retrospective cohort study.Medical records of 259 patients who underwent total laryngectomy between 2003 and 2009 at our institution were reviewed. Risk factors for fistula formation were analyzed, including primary treatment modality, comorbidities, and operative details, which included use of a free flap for closure, concurrent neck dissections, margin status, and preoperative tracheostomy. The length of time until leak, postoperative swallow study results, and fistula management strategies were also assessed.Fifty-five patients developed a pharyngocutaneous fistula (overall incidence, 21%) in a median time of 12 days (range, 4-105 days). Twenty of these patients underwent laryngectomy as their initial treatment modality, and 35 had failed previous radiotherapy. Fistula formation was significantly higher in salvage surgery patients (P = .03), particularly those with hypothyroidism (P < .0002). A barium swallow performed at approximately 1 week after laryngectomy demonstrated a sensitivity of 26% with a specificity of 94%. Sixty-two percent of the fistulas healed with conservative measures only.Our data confirmed that previous radiotherapy and hypothyroidism, particularly in salvage laryngectomy patients, are important significant predictors of postoperative pharyngocutaneous fistula. The use of a postoperative barium swallow in these patients may be useful but was not found to be highly sensitive in predicting who will develop a clinically evident leak and should be used with caution.

    View details for DOI 10.1002/lary.23443

    View details for Web of Science ID 000306894500026

    View details for PubMedID 22648757

  • Free tissue transfer for head and neck reconstruction in solid organ transplant patients HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Miller, M. W., Dean, N. R., Cannady, S. B., Rosenthal, E. L., Wax, M. K. 2012; 34 (8): 1143-1146


    Patients with head and neck malignancies who have had solid organ transplant and require free tissue transfer are a unique population. This study was performed to evaluate the effect of immunosuppression on the rate of perioperative complications and the success of free tissue transfer in the head and neck.Complications in solid organ transplant patients undergoing free tissue transfer for reconstruction of head and neck malignancies from 1998 to 2010 were evaluated.A total of 22 flaps in 17 patients were performed. Eight patients (11 of 22 flaps) had complications. The median hospital stay was 6 days (range, 4-26 days). The median length of follow-up was 13.5 months (range, 3.5-49.9 months).Solid organ transplant patients are at an increased risk of de novo malignancies due to chronic immunosuppression. This study demonstrates that free tissue transfer is a viable option in transplant patients with morbidity similar to nontransplant patients.

    View details for DOI 10.1002/hed.21893

    View details for Web of Science ID 000306560800014

    View details for PubMedID 22076843

  • Use of Recombinant Bone Morphogenetic Protein 2 in Free Flap Reconstruction for Osteonecrosis of the Mandible JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY Sweeny, L., Lancaster, W. P., Dean, N. R., Magnuson, J. S., Carroll, W. R., Louis, P. J., Rosenthal, E. L. 2012; 70 (8): 1991-1996


    Osteoradionecrosis of the mandible is a debilitating consequence of radiation therapy for head-and-neck malignancy. It can result in pain, bone exposure, fistula formation, and pathologic fracture. Recombinant human bone morphogenetic protein 2 (rhBMP-2) has shown promise in reconstruction of bone defects. The purpose of this study is to determine whether the addition of rhBMP-2 at the union of vascularized bone and native bone improves surgical outcomes in patients with osteonecrosis of the mandible.This study was a retrospective analysis of patients who were treated between 2006 and 2010 for osteonecrosis of the mandible. Patients requiring definitive reconstruction after failure of a course of conservative management were included. Patients were divided into 2 cohorts depending on whether rhBMP-2 was used during the reconstruction. The primary outcome measure was defined as stable mandibular union.Seventeen patients were included. The development of malunion was similar in both groups (13% for rhBMP-2 group vs 11% for non-rhBMP-2 group). Infectious complications were similar between the groups (25% in rhBMP-2 group vs 56% in non-rhBMP-2 group, P = .33). The rates of hardware removal were similar for the 2 groups (33% in non-rhBMP-2 group vs 25% in rhBMP-2 group, P = .10). No cancer recurrences were observed in patients receiving rhBMP-2.The use of rhBMP-2 is safe in free flap reconstruction of the mandible, but its ability to significantly improve patient outcomes, as measured by rates of malunion, reoperation, or infection, is still unknown.

    View details for DOI 10.1016/j.joms.2011.08.037

    View details for Web of Science ID 000306996100040

    View details for PubMedID 22177824

  • Molecular Targeting of Ultrasonographic Contrast Agent for Detection of Head and Neck Squamous Cell Carcinoma ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Knowles, J. A., Heath, C. H., Saini, R., Umphrey, H., Warram, J., Hoyt, K., Rosenthal, E. L. 2012; 138 (7): 662-668


    To investigate the feasibility of ultrasonographic (US) imaging of head and neck cancer with targeted contrast agents both in vitro and in vivo. We hypothesize that conjugation of microbubble contrast agent to tumor-specific antibodies may improve US detection of head and neck squamous cell carcinoma (HNSCC).Preclinical blinded assessment of anti-EGFR and anti-CD147 microbubble contrast agents for US imaging of HNSCC.Animal study.Immunodeficient mice.Injection of targeted microbubbles.Microbubble uptake in tumors as detected by US.In vitro assessment of anti-epidermal growth factor receptor (EGFR) and anti-CD147-targeted microbubbles in 6 head and neck cancer cell lines yielded a 6-fold improvement over normal dermal fibroblasts (P < .001). Binding of targeted agents had a positive correlation to both epidermal growth factor receptor (EGFR) (R(2) = 0.81) and CD147 (R(2) = 0.72) expression among all cell lines. In vivo imaging of flank tumors in nude mice (N = 8) yielded enhanced resolution of anti-EGFR-and anti-CD147-targeted microbubble agents over IgG control (P < .001), while dual-targeted contrast agents offered enhanced imaging over single-targeted contrast agents (P = .02 and P = .05, respectively). In a blinded in vivo assessment, targeted contrast agents increased intratumoral enhancement of flank tumors over controls. Targeted US contrast agents to both EGFR and CD147 were 100% sensitive and 87% specific in the detection of flank tumors.This preclinical study demonstrates feasibility of using molecular US to target HNSCC for contrast-enhanced imaging of HNSCC tumor in vivo.

    View details for Web of Science ID 000306418000011

    View details for PubMedID 22801891

  • Inhibition of fibroblasts reduced head and neck cancer growth by targeting fibroblast growth factor receptor LARYNGOSCOPE Sweeny, L., Liu, Z., Lancaster, W., Hart, J., Hartman, Y. E., Rosenthal, E. L. 2012; 122 (7): 1539-1544


    Head and neck squamous cell carcinoma (HNSCC) is a complex disease process involving interactions with carcinoma-associated fibroblasts and endothelial cells. We further investigated these relationships by suppressing stromal cell growth through the inhibition of fibroblast growth factor receptor (FGFR).Preclinical investigation.HNSCC cell lines (FADU, OSC19, Cal27, SCC1, SCC5, SCC22A), fibroblast (HS27), and endothelial cells (human umbilical vascular endothelial cell) were cultured individually or in coculture. Proliferation was assessed following treatment with a range of physiologic concentrations of FGFR inhibitor PD173074. Mice bearing established HNSCC xenografts were treated with PD173074 (12 mg/kg), and tumor histology was analyzed for stromal composition, proliferation (Ki67 staining), and apoptosis (TUNEL [terminal deoxynucleotidyl transferase dUTP nick end labeling] staining).In vitro, inhibition of FGFR with PD173074 dramatically reduced proliferation of fibroblasts and endothelial cells compared to untreated controls. However, HNSCC cell proliferation was not affected by inhibition of FGFR. When cocultured with fibroblasts, HNSCC cells proliferation increased by 15% to 80% (P < .01). Furthermore, this fibroblast-enhanced tumor cell growth was suppressed by FGFR inhibition. Additionally, treatment of mice bearing HNSCC xenografts with PD173074 resulted in significant growth inhibition (P < .001). Additionally, those tumors from mice treated with PD173074 had a smaller stromal component, decreased proliferation, and increased apoptosis.Targeting the FGFR pathway in head and neck cancer acts through the stromal components to decrease HNSCC growth in vivo and in vitro.

    View details for DOI 10.1002/lary.23266

    View details for Web of Science ID 000305577400020

    View details for PubMedID 22460537

  • CD147 expression in advanced cutaneous squamous cell carcinoma JOURNAL OF CUTANEOUS PATHOLOGY Sweeny, L., Dean, N. R., Frederick, J. W., Magnuson, J. S., Carroll, W. R., Desmond, R. A., Rosenthal, E. L. 2012; 39 (6): 603-609


    CD147 is upregulated in multiple cancer types, but its expression in advanced cutaneous squamous cell carcinoma (SCC) is unknown. Our purpose was to evaluate the expression patterns of CD147 and related monocarboxylate transporters (MCT1, MCT4) to determine their correlation with survival.This is a retrospective cohort study of patients with advanced stage cutaneous SCC of the head and neck who presented to a tertiary care center between 1998 and 2006 (n=50). CD147, MCT1 and MCT4 expression levels were assessed using immunofluorescence analysis of archived tumor samples and correlated with survival and clinicopathologic characteristics.The majority of patients (92%, n = 46) were diagnosed with stage III disease, with 46% (n = 23) having positive regional lymph node metastasis and 8% (n = 4) with distant metastasis. Primary malignancies had an overexpression of CD147 (78%; n = 35), MCT1 (23%; n = 10) and MCT4 (47%; n = 20). In addition, there was a significant relationship between the overexpression of CD147 and node positive disease (p = 0.048). Two- and five-year survival rates were 69 and 61%, respectively. There was a trend toward decreased survival in patients with overexpression of CD147 (p = 0.17), MCT1 (p = 0.11) and MCT4 (p = 0.15).CD147 may represent a biomarker or potential therapeutic target in advanced cutaneous SCC.

    View details for DOI 10.1111/j.1600-0560.2012.01912.x

    View details for Web of Science ID 000304343600007

    View details for PubMedID 22575025

  • Microbubble Therapy Enhances Anti-tumor Properties of Cisplatin and Cetuximab In Vitro and In Vivo OTOLARYNGOLOGY-HEAD AND NECK SURGERY Heath, C. H., Sorace, A., Knowles, J., Rosenthal, E., Hoyt, K. 2012; 146 (6): 938-945


    To determine if microbubble-mediated ultrasound therapy (MB-UST) can improve cisplatin or cetuximab cytotoxicity of head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo by increasing tumor-specific drug delivery by disruption of tumor cell membranes and enhancing vascular permeability.In vitro and in vivo study.University medical center.Immunodeficient mice (6 weeks old) and 4 HNSCC cell lines.Changes to cell permeability were assessed in vitro after MB-UST. Cellular apoptosis resulting from adjuvant MB-UST with subtherapeutic doses of cisplatin or cetuximab was assessed by cell survival assays in vitro. The in vivo effect of adjuvant MB-UST in flank tumors was assessed in vivo with histological analysis and diffusion-weighted magnetic resonance imaging (DW-MRI).In vitro results revealed that MB-UST can increase cell permeability and enhance drug uptake and apoptosis in 4 HNSCC cell lines. In vivo adjuvant MB-UST with cetuximab or cisplatin showed a statistically significant reduction in tumor size when compared with untreated controls. TUNEL analysis yielded a larger number of cells undergoing apoptosis in tumors treated with cetuximab and adjuvant MB-UST than did cetuximab alone but was not significantly greater in tumors treated with cisplatin and adjuvant MB-UST compared with cisplatin alone. DW-MRI analysis showed more free water, which corresponds to increased cell membrane disruption, in tumors treated with MB-UST.MB-UST promotes disruption of cell membranes in tumor cells in vitro, which may be leveraged to selectively improve the uptake of conventional and targeted therapeutics in vivo.

    View details for DOI 10.1177/0194599812436648

    View details for Web of Science ID 000305522400011

    View details for PubMedID 22323435

  • All-Cause Mortality after Tracheostomy at a Tertiary Care Hospital over a 10-Month Period OTOLARYNGOLOGY-HEAD AND NECK SURGERY Kejner, A. E., Castellanos, P. F., Rosenthal, E. L., Hawn, M. T. 2012; 146 (6): 918-922


    To evaluate perioperative mortality after tracheostomy in intensive care unit (ICU) patients undergoing routine tracheostomy over a 10-month period.Case series with planned data collection.Tertiary care hospital.Mechanically ventilated patients.Prospective analysis of ICU patients undergoing tracheostomy placement over 10 months was performed. Variables evaluated were demographics, pretracheostomy length of stay, time on ventilator, time to death, preoperative comorbidities, and cause of death.There were 129 consultations resulting in 115 tracheostomies, of which 100 were included for study. The overall 30-day postoperative mortality rate was 25%, including palliative care deaths. Cause of death in all cases was due to a preexisting condition and not from tracheostomy. Patients who died within the 30-day postoperative period were found to have significant differences in age, pretracheostomy length of stay, location of tracheostomy, and preoperative comorbidity scores. No significant difference was found in time on ventilator, sex, or race/ethnicity. Mean time from consultation to tracheostomy was 2.5 days (range, 0-12 days).High rates of mortality after tracheostomy can possibly affect hospital quality ratings for surgical services. There were no deaths directly related to surgery. Despite this, the mortality rate in this population was quite high. This illustrates the significant disease burden in these patients and the need to stratify postoperative mortality as well as to consider comorbidity and age when evaluating patients for tracheostomy.

    View details for DOI 10.1177/0194599812437316

    View details for Web of Science ID 000305522400008

    View details for PubMedID 22344290

  • EGFR expression in advanced head and neck cutaneous squamous cell carcinoma HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Sweeny, L., Dean, N. R., Magnuson, J. S., Carroll, W. R., Helman, E. E., Hyde, S. O., Desmond, R. L., Rosenthal, E. L. 2012; 34 (5): 681-686


    The significance of epidermal growth factor receptor (EGFR) expression in advanced cutaneous squamous cell carcinoma (SCC) of the head and neck remains poorly understood.We performed a retrospective review of patients with advanced-stage (stage III or stage IV) cutaneous SCC of the head and neck (n = 56).The majority of patients (91%) had stage III disease, with 54% having regional metastasis and 9% with distant metastasis. Two-year survival was 64% and the 5-year survival was 56%. EGFR was found to be overexpressed in 56% of primary tumors and 58% of regional metastatic disease. Overall survival did not correlate with EGFR (p = .47) expression in primary lesions, nor was it associated with an increase in regional (p = .74) or distant metastasis (p = .56). Furthermore, there was no correlation between clinicopathologic characteristics and EGFR expressionThese data do not suggest upregulation of EGFR is associated with poor survival or aggressive disease.

    View details for DOI 10.1002/hed.21802

    View details for Web of Science ID 000302549100012

    View details for PubMedID 21739514

  • Assessment of donor site morbidity for free radial forearm osteocutaneous flaps MICROSURGERY Sinclair, C. F., Gleysteen, J. P., Zimmermann, T. M., Wax, M. K., Givi, B., Schneider, D., Rosenthal, E. L. 2012; 32 (4): 255-260


    Assessment of donor site morbidity and recipient site complications following free radial forearm osteocutaneous flap (FRFOCF) harvest and evaluation of patient perceived upper limb disability for free radial forearm osteocutaneous versus fasciocutaneous flaps (FRFF).First a case series was undertaken of 218 patients who underwent an FRFOCF at two tertiary referral centers between February 1998 and November 2010. Outcomes included forearm donor site morbidity and recipient site complications. Second, the disability of the arm, shoulder, and hand (DASH) questionnaire assessing patient perceived arm disability was administered by phone to 60 consecutive patients who underwent an FRFOCF or FRFF.Mean patient age was 63 years with male predominance (62.8%). Median bone length harvested was 8 cm (range, 3-12 cm) with prophylactic plating of the radius following harvest. Donor site morbidity included fracture (1 patient, 0.5%) and sensory neuropathy (5 patients, 2.3%). Mean DASH scores were comparative between groups and to established normative values. Mandibular malunion rate was 3.2% and hardware extrusion at the recipient site occurred in 15.6%.Reluctance to perform FRFOCF by surgeons usually centers on concerns regarding potential donor site morbidity and adequacy of available bone stock; however, we identified minimal objective or patient perceived donor site morbidity or recipient site complications following harvest of FRFOCFs. Mild wrist weakness and stiffness are common but do not impede ability to perform activities of daily living. Data from this and other reports suggest this flap is particularly useful for midfacial and short segment mandibular reconstruction.

    View details for DOI 10.1002/micr.21950

    View details for Web of Science ID 000303746900001

    View details for PubMedID 22473601

  • F-18-FDG PET/CT Imaging Detects Therapy Efficacy of Anti-EMMPRIN Antibody and Gemcitabine in Orthotopic Pancreatic Tumor Xenografts MOLECULAR IMAGING AND BIOLOGY Shah, N., Zhai, G., Knowles, J. A., Stockard, C. R., Grizzle, W. E., Fineberg, N., Zhou, T., Zinn, K. R., Rosenthal, E. L., Kim, H. 2012; 14 (2): 237-244


    The objective of this study is to evaluate the therapeutic response to a novel monoclonal antibody targeting human extracellular matrix metalloproteinase inducer (EMMPRIN) in combination with gemcitabine in a pancreatic-tumor xenograft murine model by sequential 2-deoxy-2-[18F]fluoro-D-glucose ((18)F-FDG) positron emission tomography/computed tomgraphy (PET/CT) imaging.Four groups of SCID mice bearing orthotopic pancreatic tumor xenografts were injected with phosphate-buffered saline, gemcitabine (120 mg/kg BW), anti-EMMPRIN antibody (0.2 mg), or combination, respectively, twice weekly for 2 weeks, while (18)F-FDG PET/CT imaging was performed weekly for 3 weeks. Changes in mean standardized uptake value (SUV(mean)) of (18)F-FDG and volume of tumors were determined.The tumor SUV(mean) change in the group receiving combination therapy was significantly lower than those of the other groups. Tumor-volume changes of groups treated with anti-EMMPRIN monotherapy or combined therapy were significantly lower than that of the control group.These data provide support for clinical studies of anti-EMMPRIN therapy with gemcitabine for pancreatic cancer treatment.

    View details for DOI 10.1007/s11307-011-0491-5

    View details for Web of Science ID 000301584100011

    View details for PubMedID 21494920

  • Free Flap Reconstruction of Lateral Mandibular Defects: Indications and Outcomes OTOLARYNGOLOGY-HEAD AND NECK SURGERY Dean, N. R., Wax, M. K., Virgin, F. W., Magnuson, J. S., Carroll, W. R., Rosenthal, E. L. 2012; 146 (4): 547-552


    To compare outcomes following osteocutaneous radial forearm and fibula free flap reconstruction of lateral mandibular defects.Retrospective case-controlled study.Historical cohort study.All patients who underwent free flap reconstruction of lateral mandibular defects from 1999 to 2010 were included in this study. Patients were classified into 2 groups based on type of reconstruction: (1) osteocutaneous radial forearm (n = 73) and (2) fibula free flap reconstruction (n = 51). Patient characteristics, length of hospital stay, recipient and donor site complications, and long-term outcomes including postoperative diet were evaluated.Most patients were male (68%) and presented with advanced T-stage (71%) squamous cell carcinoma (94%) involving the alveolus (21%), retromolar trigone (23%), or oral tongue (21%). Median length of hospital stay was 8 days (range, 4-22 days). The recipient site complication rate approached 27% and included infection (n = 11), mandibular malunion (n = 9), exposed bone or mandibular plates (n = 9), and flap failure (n = 5). Most patients demonstrated little to no trismus following reconstruction (94%) and were able to resume a regular or edentulous diet (73%). No difference in complication rates or postoperative outcomes was seen between osteocutaneous radial forearm and fibula free flap groups (P > .05). One patient underwent dental implantation following osteocutaneous radial forearm free flap reconstruction. No patients from the fibula free flap group underwent dental implantation.The osteocutaneous radial forearm and fibula free flap provide equivalent wound healing and functional outcomes in patients undergoing lateral mandibular defect reconstruction.

    View details for DOI 10.1177/0194599811430897

    View details for Web of Science ID 000303546600007

    View details for PubMedID 22166963

  • Closure of laryngectomy defects in the age of chemoradiation therapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Hanasono, M. M., Lin, D., Wax, M. K., Rosenthal, E. L. 2012; 34 (4): 580-588


    The use of chemoradiation therapy in laryngeal cancer has resulted in significant reconstructive challenges. Although reconstruction of salvage laryngectomy defects remains controversial, current literature supports aggressive management of these defects with vascularized tissue, even when there is sufficient pharyngeal tissue present for primary closure. Significant advancement in reconstructive techniques has permitted improved outcomes in patients with advanced disease who require total laryngopharyngectomy or total laryngoglossectomy. Use of enteric and fasciocutaneous flaps result in good patient outcomes. Finally, wound complication rates after salvage surgery approach 60% depending on comorbid conditions such as cardiac insufficiency, hypothyroidism, or extent of previous treatment. Neck dehiscence, great vessel exposure, fistula formation, or cervical skin necrosis results in complex wounds that can often be treated initially with negative pressure dressings followed by definitive reconstruction. The timing of repair and approach to the vessel-depleted neck also present challenges in this patient population. Currently, there is significant institutional bias in the management of the patient with postchemoradiation salvage laryngectomy. Future prospective multi-institutional studies are certainly needed to more clearly define optimal treatment of these difficult patients.

    View details for DOI 10.1002/hed.21712

    View details for Web of Science ID 000300980800018

    View details for PubMedID 21416549

  • Incidence and Outcomes of Stricture Formation Postlaryngectomy OTOLARYNGOLOGY-HEAD AND NECK SURGERY Sweeny, L., Golden, J. B., White, H. N., Magnuson, J. S., Carroll, W. R., Rosenthal, E. L. 2012; 146 (3): 395-402


    Postlaryngectomy stricture formation and dysphagia negatively affect quality of life and result in nutritional compromise. Understanding risk factors and successful treatment strategies may improve treatment outcomes.Historical cohort study.Tertiary care medical center.Patients at a tertiary care center who underwent a total laryngectomy between 2003 and 2009 (N = 263) were evaluated in a retrospective manner. Patient demographics, comorbidities, tobacco and alcohol usage, dietary outcomes, feeding tube dependence, and treatment modalities were assessed. Management strategies and outcomes were evaluated.Strictures developed in 19% (n = 49) of patients, and the majority (82%) occurred in the first year. Incidences of stricture formation were similar for primary (19%) and salvage laryngectomy (19%) patients. Patients undergoing salvage laryngectomy were 2 times more likely to be reconstructed with a free flap, whereas those undergoing a primary laryngectomy were 3 times more likely to be closed primarily. Tubed flap reconstruction significantly increased the incidence of stricture formation compared to primary closure (P = .02) in salvage laryngectomy cases. In primary laryngectomy patients, stricture formation did not correlate with flap reconstruction (P = .34) or adjuvant radiation therapy (P = .79). Patients who required a single dilation had better dietary outcomes compared to patients who required serial dilations (P = .14). There was no difference in overall disease-free survival in primary vs salvage laryngectomy patients (P = .95).Rates of stricture formation were the same in patients undergoing salvage compared to primary total laryngectomy.

    View details for DOI 10.1177/0194599811430911

    View details for Web of Science ID 000303545100011

    View details for PubMedID 22166968

  • Use of Internal Mammary Vessels in Head and Neck Microvascular Reconstruction ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Schneider, D. S., McClain, L., Robb, P. K., Rosenthal, E. L., Wax, M. K. 2012; 138 (2): 172-176


    To describe the use of the internal mammary vessels (IMVs) in microvascular head and neck reconstruction in a small case series with select donor sites.Retrospective medical record review study.Oregon Health and Science University and University of Alabama.Patients for whom IMVs were used for head and neck reconstruction from January 1, 1998, through December 31, 2010.Intraoperative or postoperative complications, flap survival, and morbidity due to the flap.Of 2721 free tissue transfers, 55 (2%) (in 48 patients) used IMVs. Use of IMVs was associated with ablative surgery with sternal resection (25 of 55 [45%]), a vessel depleted neck (23 of 55 [42%]), and fistula repair with gross contamination due to prior flap failure or chronic pharyngocutaneous fistula with vessel depleted neck (7 of 55 [13%]). Flaps included radial forearm (33 of 55 [60%]), jejunum (9 of 55 [16]), ulnar (5 of 55 [9%]), and other (8 of 55 [14%]). No vein grafts were used. Pneumothorax developed in 1 patient (2%). Postoperative fistulas were observed in 14 of 48 patients (29%); the fistulas healed conservatively in 7 patients (50%), rotation of flap tissue was required in 2 patients (14%), and the fistulas persisted in 5 patients (36%). The flap survival rate was 98%.Internal mammary vessels provide reliable recipient vessels for cervical and sternal microvascular reconstruction.

    View details for Web of Science ID 000300525900010

    View details for PubMedID 22351864

  • Reconstruction of scalp defects with the radial forearm free flap. Head & neck oncology Sweeny, L., Eby, B., Magnuson, J. S., Carroll, W. R., Rosenthal, E. L. 2012; 4: 21-?


    Advanced and recurrent cutaneous squamous cell carcinoma of the scalp and forehead require aggressive surgical excision often resulting in complex defects requiring reconstruction. This study evaluates various microvascular free flap reconstructions in this patient population, including the rarely utilized radial forearm free flap.A retrospective review of patients undergoing free flap surgeries (n = 47) of the scalp between 1997 and 2011 were included. Patients were divided primarily into two cohorts: a new primary lesion (n = 21) or recurrence (n = 26). Factors examined include patient demographics, indication for surgery, defect, type of flap used, complications (major and minor), and outcomes.The patients were primarily male (n = 34), with a mean age of 67 years (25-91). A total of 58 microvascular free flap reconstructions were performed (radial forearm free flap: n = 28, latissimus dorsi: n = 20, rectus abdominis: n = 9, scapula: n = 1). Following reconstruction with a radial forearm free flap, duration of hospitalization was shorter (P = 0.04) and complications rates were similar (P = 0.46). Donor site selection correlated with defect area (P < 0.001), but not with the extent of skull defect (P = 0.70). Larger defect areas correlated with higher complications rates (P = 0.03) and longer hospitalization (P = 0.003). Patients were more likely to require multiple reconstructions if referred for a recurrent lesions (P = 0.01) or received prior radiation therapy (P = 0.02).Advanced and recurrent malignancies of the scalp are aggressive and challenging to treat. The radial forearm free flap is an underutilized free flap in the reconstruction of complex scalp defects.

    View details for DOI 10.1186/1758-3284-4-21

    View details for PubMedID 22583845

  • Assessment of Tissue Autofluorescence and Reflectance for Oral Cavity Cancer Screening OTOLARYNGOLOGY-HEAD AND NECK SURGERY Sweeny, L., Dean, N. R., Magnuson, J. S., Carroll, W. R., Clemons, L., Rosenthal, E. L. 2011; 145 (6): 956-960
  • Assessment of tissue autofluorescence and reflectance for oral cavity cancer screening. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Sweeny, L., Dean, N. R., Magnuson, J. S., Carroll, W. R., Clemons, L., Rosenthal, E. L. 2011; 145 (6): 956-960


    Although approved by the US Food and Drug Administration for clinical use, the utility of handheld tissue reflectance and autofluorescence devices for screening head and neck cancer patients is poorly defined. There is limited published evidence regarding the efficacy of these devices. The authors investigated the sensitivity and specificity of these modalities compared with standard examination.Prospective, cross-sectional analysis.Tertiary care medical center.Patients who were treated previously for head and neck cancer (n = 88) between 2009 and 2010 were included. Patients were screened using white light visualization (standard of care) and compared with tissue reflectance and autofluorescence visualization. Screening results were compared with biopsy or long-term follow-up.Autofluorescence visualization had a specificity of 81% and a sensitivity of 50% for detecting oral cavity cancer, whereas white light visualization had a specificity of 98% and a sensitivity of 50%. Tissue reflectance visualization had low sensitivity (0%) and good specificity (86%). The power of this study was insufficient to compare the positive and negative predictive values of standard white light examination (50% and 98%, respectively) to tissue autofluorescence (11% and 97%) or reflectance (0% and 95%). In addition, stratification by previous radiation therapy found no statistically significant difference in screening results.Standard clinical lighting has a higher specificity than tissue reflectance and autofluorescence visualization for detection of disease in patients with a history of head and neck cancer. This study does not support the added costs associated with these devices.

    View details for DOI 10.1177/0194599811416773

    View details for PubMedID 21804026

  • Dynasplint for the management of trismus after treatment of upper aerodigestive tract cancer: A retrospective study ENT-EAR NOSE & THROAT JOURNAL Baranano, C. F., Rosenthal, E. L., Morgan, B. A., McColloch, N. L., Magnuson, J. S. 2011; 90 (12): 584-?


    In order to evaluate the Dynasplint Trismus System (DTS) for the relief of trismus secondary to the treatment of head and neck cancer, we conducted a retrospective chart review of patients who had undergone DTS therapy during a 1-year period. Our inclusion criteria were cancer of the upper aerodigestive tract; treatment with radiation, chemotherapy, and/or surgery; and a maximal incisal opening (MIO) of less than 30 mm. MIO and the rate of improvement of trismus ("gain") were measured at selected intervals. Twenty-six patients met our study criteria; their pretherapy mean MIO was 19.3 mm. At the time of their most recent measurement, the mean MIO had increased to 25.5 mm-a measured gain of 32%. Although the initial rate of gain was 0.36 mm/day during the first 6 weeks, improvement leveled off over time, and the overall rate of gain was 0.16 mm/day. We conclude that the DTS is effective in increasing the mandibular range of motion at a rate of change that is maximized during initial treatment.

    View details for Web of Science ID 000305721900009

    View details for PubMedID 22180114



    The literature directly comparing the utility of clinical examination (CE) to that of CT in detecting recurrence of squamous cell carcinoma (SCC) for primary site recurrences is lacking.Patients who received both CT scans and CEs after primary treatment for SCC of the upper aerodigestive tract (oropharynx, hypopharynx, and larynx) were identified. Individual CT scans and CEs were evaluated for their ability to detect recurrence status.One hundred thirty-one patients underwent a total of 886 CEs and 346 CT scans during the follow-up period. The sensitivity for CE and CT was 84.0% and 66.7%, respectively; for specificity, 98.7% and 90.7%, respectively; for positive predictive value, 65.6% and 31.8%, respectively; and for negative predictive value the values were 99.5% and 97.7%, respectively.Due to the low sensitivity and positive predictive value of CT scans compared to physical examination in evaluating primary site tumor recurrences, the utility of CT for surveillance may be limited.

    View details for DOI 10.1002/hed.21636

    View details for Web of Science ID 000296426700001

    View details for PubMedID 21990217

  • Functional and Survival Outcomes in Patients Undergoing Total Glossectomy Compared with Total Laryngoglossectomy OTOLARYNGOLOGY-HEAD AND NECK SURGERY Sinclair, C. F., Carroll, W. R., Desmond, R. A., Rosenthal, E. L. 2011; 145 (5): 755-758


    To compare functional and survival outcomes for patients undergoing total glossectomy (TG) or total glossectomy plus laryngectomy (TGL) for advanced squamous cell carcinoma (SCC) of the tongue.Case series with chart review.Academic tertiary referral center.There were 30 included patients (20 TG, 10 TGL). Outcomes included tumor recurrence, disease-free survival, and functional data (swallowing, gastrostomy tube dependence, speech, airway).Mean patient age was 56 years with a male predominance (90%). Compared with TG, TGL was more commonly performed for recurrent tumors (90% vs 55%, P = .06). Perineural invasion and extracapsular extension occurred more commonly in the TGL group (80% vs 50%, P = .12). At 12 months postoperatively, 61% of TG patients had disease recurrence compared with 40% of TGL patients (P = .43), and 12-month disease-free survival was 40% (TG) and 50% (TGL). Functionally, more TG patients were totally gastrostomy tube dependent (70% vs 30%, P = .04), and 50% of TG patients were also tracheostomy dependent. Intelligible speech was achieved by 30% of TG and 10% of TGL patients (P = .68).Patients undergoing TGL had similar functional and survival outcomes to patients undergoing TG alone despite the presence of more locally advanced disease with greater adverse pathological features. Following TG alone, positive or close margins occurred most commonly at the inferior margin of resection (hyoid/valleculae), which could explain why TGL in patients with advanced tongue SCC may improve local disease control.

    View details for DOI 10.1177/0194599811412724

    View details for Web of Science ID 000296461700011

    View details for PubMedID 21670476

  • UTILITY OF CT SURVEILLANCE FOR PRIMARY SITE RECURRENCE OF SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK HEPATOLOGY Sullivan, B. P., Parks, K. A., Dean, N. R., Rosenthal, E. L., Carroll, W. R., Magnuson, J. S. 2011; 54 (5): 1547-1550

    View details for DOI 10.1002/hed.21636

    View details for Web of Science ID 000296443100009

  • Patient-Perceived and Objective Functional Outcomes Following Transoral Robotic Surgery for Early Oropharyngeal Carcinoma ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Sinclair, C. F., McColloch, N. L., Carroll, W. R., Rosenthal, E. L., Desmond, R. A., Magnuson, J. S. 2011; 137 (11): 1112-1116


    To evaluate changes in patient-perceived swallowing function over time following transoral robotic surgery (TORS) for primary T1 and T2 oropharyngeal squamous cell carcinomas.Prospective case series.Academic tertiary referral center.Forty-two patients with T1 or T2 oropharyngeal squamous cell carcinomas.TORS-assisted resection of indicated tumors.Changes in patient-perceived swallowing function over time (using the M. D. Anderson Dysphagia Inventory) and gastrostomy tube dependence.Between March 19, 2007, and April 21, 2010, forty-two patients with primary T1 or T2 oropharyngeal squamous cell carcinomas underwent TORS-assisted resection. Most (76% [32 of 42]) patients had stage III disease; 93% (39 of 42) of patients underwent staged neck dissection. The median postoperative follow-up time was 17 months (range, 4-40 months). There were no complications or tumor recurrences. Postoperative chemotherapy use predicted gastrostomy tube retention for longer than 3 months (P = .01). Immediate mean postoperative M. D. Anderson Dysphagia Inventory scores in each assessed domain (global, emotional, physical, and functional) decreased compared with preoperative baseline scores; however, ongoing improvement in all domains was observed over time. Nodal status (P = .049), follow-up time of less than 12 months (P = .03), and preoperative physical scores of less than 100 (P = .01) predicted poorer physical M. D. Anderson Dysphagia Inventory outcomes. Positive pathological margins predicted poorer functional scores (P = .03).After TORS-assisted resection of T1 and T2 oropharyngeal squamous cell carcinomas, approximately one-third of patients will experience a sustained decrease in perceived swallowing function. However, ongoing improvement of swallowing function over time is likely even after 12 months. Patients receiving adjuvant chemotherapy after TORS should be counseled about the possibility of prolonged gastrostomy tube dependence.

    View details for Web of Science ID 000297228100007

    View details for PubMedID 22106235

  • Disruption of the AKT Pathway Inhibits Metastasis in an Orthotopic Model of Head and Neck Squamous Cell Carcinoma LARYNGOSCOPE Knowles, J. A., Golden, B., Yan, L., Carroll, W. R., Helman, E. E., Rosenthal, E. L. 2011; 121 (11): 2359-2365


    MK-2206 is an orally active, allosteric inhibitor of AKT, a component of the phosphatidylinositol-3 kinase (PI3K) pathway. The PI3K-AKT pathway is a downstream signaling pathway that has recently been found to play an important role in head and neck squamous cell carcinoma (HNSCC). The objective of this study is to examine the role AKT inhibition may play in treatment of HNSCC.In vivo and in vitro study.Cell migration after 24-hour treatment with subtherapeutic doses of MK-2206 was assessed using an enzyme-linked immunosorbent assay in four HNSCC cell lines: CAL27, FaDu, SCC-1, and SCC-5. In vitro effect of MK-2206 on cell migration was assessed by making linear scratches in culture plates after cell lines were grown to confluency. Images were taken at 8, 16, and 24 hours. In vivo analysis was performed on nude mice with human SCC1-orthotopic tongue tumors. After tumors were allowed to grow for 7 days, mice were treated with oral dosing of 120 mg/kg of MK-2206 every other day for 2 weeks. Tumor size was assessed after each treatment using a pair of digital calipers. At the end of the treatment period, mice were sacrificed and cervical lymph nodes were assessed for metastasis using fluorescent imaging of tumor cell markers.Subtherapeutic doses of MK-2206 were sufficient to significantly reduce cell migration in FaDu, SCC-1, and SCC-5 cell lines (P < .001) but not in Cal27 (P = .09). In vitro scratch test results in SCC-1 cells yielded significant reduction in cell movement at 8, 16, and 14 hours (P < .001). In vivo orthotopic model yielded significant reduction in primary tumor size (P = .04) and reduction in positive cervical lymph nodes (P = .01) between treatment and control mice. In addition we found 100% survival of MK-2206 treated mice after 2 weeks of treatment compared with 70% survival in our control group (P = .03).Treatment with MK-2206 is sufficient to inhibit HNSCC chemotaxis and migration in vitro. In an orthotopic model, treatment with MK-2206 reduces primary tumor size and cervical metastasis while improving survival. MK-2206 currently is being used in phase II clinical trials for combination treatment of metastatic solid tumors and may be useful for treating HNSCC as well.

    View details for DOI 10.1002/lary.22180

    View details for Web of Science ID 000296714800015

    View details for PubMedID 22020886

  • Extracelluar matrix metalloproteinase as a novel target for pancreatic cancer therapy ANTI-CANCER DRUGS Kim, H., Zhai, G., Liu, Z., Samuel, S., Shah, N., Helman, E. E., Knowles, J. A., Stockard, C. R., Fineberg, N. S., Grizzle, W. E., Zhou, T., Zinn, K. R., Rosenthal, E. L. 2011; 22 (9): 864-874


    The objective of this study was to evaluate extracellular matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3-7, whereas MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1-3 (residual tumor model) and at 21 days after cell implantation for groups 4-7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2-1.0 mg) twice weekly for 2-3 weeks, whereas the other groups served as the control. In the residual tumor model, tumor growth of anti-EMMPRIN-treated group was successfully arrested for 21 days (15 ± 4 mm(3)), which was significantly lower than that of the EMMPRIN knockdown group (80 ± 15 mm(3); P=0.001) or the control group (240 ± 41 mm(3); P<0.001). In the established tumor model, anti-EMMPRIN therapy lowered tumor volume increase by approximately 40% compared with the control, regardless of the dose amount. Ki67-expressed cell density of group 5 was 939 ± 150 mm(-2), which was significantly lower than that of group 4 (1709 ± 145 mm(-2); P=0.006). Microvessel density of group 5 (30 ± 6 mm(-2)) was also significantly lower than that of group 4 (53 ± 5 mm(-2); P=0.014), whereas the microvessel size of group 5 (191 ± 22 μm(2)) was significantly larger than that of group 4 (113 ± 26 μm(2); P=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer and support its clinical translation.

    View details for DOI 10.1097/CAD.0b013e328349311e

    View details for Web of Science ID 000294416900004

    View details for PubMedID 21730821

  • Current Strategies in Reconstruction of Maxillectomy Defects ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Andrades, P., Militsakh, O., Hanasono, M. M., Rieger, J., Rosenthal, E. L. 2011; 137 (8): 806-812


    To outline a contemporary review of defect classification and reconstructive options.Review article.Tertiary care referral centers.Although prosthetic rehabilitation remains the standard of care in many institutions, the discomfort of wearing, removing, and cleaning a prosthesis; the inability to retain a prosthesis in large defects; and the frequent need for readjustments often limit the value of this cost-effective and successful method of restoring speech and mastication. However, flap reconstruction offers an option for many, although there is no agreement as to which techniques should be used for optimal reconstruction. Flap reconstruction also involves a longer recovery time with increased risk of surgical complications, has higher costs associated with the procedure, and requires access to a highly experienced surgeon.The surgeon and reconstructive team must make individualized decisions based on the extent of the maxillectomy defect (eg, the resection of the infraorbital rim, the extent of palate excision, skin compromise) and the need for radiation therapy.

    View details for Web of Science ID 000293857000011

    View details for PubMedID 21844415

  • Fibroblast Growth Factor Receptor Mediates Fibroblast-Dependent Growth in EMMPRIN-Depleted Head and Neck Cancer Tumor Cells MOLECULAR CANCER RESEARCH Liu, Z., Hartman, Y. E., Warram, J. M., Knowles, J. A., Sweeny, L., Zhou, T., Rosenthal, E. L. 2011; 9 (8): 1008-1017


    Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma-mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer, there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here, we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were cocultured with fibroblasts or inoculated with fibroblasts into severe combined immunodeficient mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Coculture experiments showed fibroblast-dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN-silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN-silenced cells compared with control vector-transfected cells, whereas inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast coculture, suggesting the importance of FGFR2 signaling in fibroblast-mediated tumor growth. Analysis of xenografted tumors revealed that EMMPRIN-silenced tumors had a larger stromal compartment compared with control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast-independent tumor growth.

    View details for DOI 10.1158/1541-7786.MCR-11-0043

    View details for Web of Science ID 000293885600004

    View details for PubMedID 21665938

  • Method for Removing Hypopharyngeal Salivary Bypass Tubes LARYNGOSCOPE Kejner, A. E., Rosenthal, E. L. 2011; 121 (7): 1478-1479


    To describe a novel method for the removal of the salivary bypass tube (SBT) that precludes the need for extraction under general anesthesia.Retrospective case series.Patients who had undergone laryngectomy/laryngopharyngectomy with subsequent development of pharyngocutaneous fistula and intraoperative placement of a salivary bypass tube were included in this series. The tubes were removed at the bedside or in clinic utilizing a Fogarty-type method over a Foley catheter.Three patients underwent removal of hypopharyngeal salivary bypass tubes 1 to 2 weeks after placement. Inflation of the Foley catheter within the lumen of the salivary bypass tube facilitated successful removal without the need for additional procedures. All three patients required only topical anesthetic and tolerated the procedure with minimal discomfort.Compared to current methods, this technique is cost-effective and time-efficient while not compromising patient safety or comfort.

    View details for DOI 10.1002/lary.21833

    View details for Web of Science ID 000292425300023

    View details for PubMedID 21541946

  • Primary versus Delayed Tracheoesophageal Puncture for Laryngopharyngectomy with Free Flap Reconstruction LARYNGOSCOPE Sinclair, C. F., Rosenthal, E. L., McColloch, N. L., Magnuson, J. S., Desmond, R. A., Peters, G. E., Carroll, W. R. 2011; 121 (7): 1436-1440


    To determine whether postoperative complication rates and speech outcomes differ between patients undergoing primary versus secondary tracheoesophageal puncture following total laryngectomy with free flap reconstruction.Retrospective clinical study in a tertiary academic center.Between November 2004 and June 2010, 137 patients underwent total laryngectomy or laryngopharyngectomy with pharyngeal free flap reconstruction for malignant disease. Data was collected on patient and operative demographics, early postoperative complications, speech outcomes, and predictive factors for tracheoesophageal puncture failure.Thirty patients (22%) had a primary tracheoesophageal puncture performed at the time of laryngectomy, 27 patients (20%) received secondary punctures (>3 months postlaryngectomy), and 80 patients (58%) never received a puncture. Patient and operative demographics were similar between groups (P < .05), apart from proportionately more hypopharyngeal tumors in the "no puncture" group (P < .002). Similar numbers of patients in primary and secondary puncture groups achieved intelligible speech (67% vs. 71%, P = .82) and both groups reported good patient-perceived voice-related quality of life. Salvage surgery and nonpatch radial forearm free flap reconstruction both trended toward increased early postoperative complication rates (P = .09).There is no difference in the early postoperative complication rate for primary versus secondary tracheoesophageal puncture following total laryngectomy with concurrent free flap reconstruction. Radial forearm patch free flap reconstruction achieves good speech outcomes.

    View details for DOI 10.1002/lary.21836

    View details for Web of Science ID 000292425300015

    View details for PubMedID 21541947

  • Closure of post-laryngectomy pharyngocutaneous fistulae HEAD & NECK ONCOLOGY Bohannon, I. A., Carroll, W. R., Magnuson, J. S., Rosenthal, E. L. 2011; 3


    Closure of salvage laryngectomy defects with vascularized tissue remains controversial.We evaluate outcomes in patients who required repair of a fistula after attempted primary closure of salvage laryngectomy defect and assess risk factors for persistent fistula. Between 2001 and 2010, 20 patients were treated for pharyngocutaneous fistulae after primary closure of a salvage laryngectomy. All patients required free flap repair for definitive fistula management.Patients presented with fistulae from one to 18 months in duration; median time to closure was seven days. Radial forearm free flap was used in 86% of patients. With free flap alone 50% of patients achieved fistula closure. Additional procedures improved closure rate to 85%. Recipient vessels were used in the neck in 54.5%, compared to internal mammary vessels in 45.5%. Hypothyroidism was identified as a risk factor for persistent fistula (p = 0.01). Chronic steroid use (p = 0.08) did not reach significance as a risk factor for fistula closure. Gastroesophageal reflux disease was newly diagnosed or noted as a comorbidity in 14 patients (70%) in this study. It did not reach statistical significance as a risk factor in refistulization (p = 0.12). Complications included leak, carotid blowout, infection, free flap loss, and late refistulization. Overall flap failure in this study was 4.5%.Delayed secondary repair of pharygocutaneous fistulas after salvage laryngectomy is associated with a higher complication rate and poor success rates compared to use of vascularized tissue at the time of salvage laryngectomy. Prolonged wound healing in these patients is associated with hypothyroidism.

    View details for DOI 10.1186/1758-3284-3-29

    View details for Web of Science ID 000296448300001

    View details for PubMedID 21615952

  • Ethnic Pride and Cardiovascular Health Among Mexican American Adults Along the US-Mexico Border HISPANIC JOURNAL OF BEHAVIORAL SCIENCES de Heer, H. D., Balcazar, H. G., Rosenthal, E. L., Cardenas, V. M., Schulz, L. O. 2011; 33 (2): 204-220
  • Wound healing following combined radiation and cetuximab therapy in head and neck cancer patients JOURNAL OF WOUND CARE Dean, N. R., SWEENY, L., Harari, P. M., Bonner, J. A., Jones, V., Clemons, L., Geye, H., Rosenthal, E. L. 2011; 20 (4): 166-170


    This study set out to determine if cetuximab treatment increases the risk of wound healing complications when combined with radiation therapy.We performed a retrospective chart review of head and neck cancer patients who received salvage neck dissections between 1999 and 2007, at two academic tertiary care centres. Complications from wound healing were compared between radiation and combined therapy groups.A total of 35 patients received radiation (n=20) or combined radiation and cetuximab therapy (n=15) prior to neck dissection. The treatment groups were similar in regard to demographic and primary tumour-related characteristics. The time between treatment and salvage neck dissection did not differ between the radiation (3.9 months) and combination treatment (3.0 months) groups (p=0.15). Wound healing complications occurred in 13% (2/15) of the patients treated with radiation and cetuximab and there were no complications in patients who received radiation alone (p=0.20).Cetuximab did not significantly increase the risk of post-surgical wound complications, although a higher absolute number of wound complications was observed in the group treated with cetuximab and radiation therapy, compared with the group treated with radiation alone.This work was supported by a grant from the National Institute of Health (2T32 CA091078-06). One of the authors, JAB, is an occasional consultant and honoraria for ImClone and Bristol-Meyers Squibb.

    View details for Web of Science ID 000303102900004

    View details for PubMedID 21537303



    The purpose of this study was to determine factors to predict the success of free flap surgery in the treatment of osteoradionecrosis (ORN).Univariate analysis of overall and flap complications was performed. The effect of time to ORN, and the time interval between ORN to reconstruction was evaluated.Fifty-five flaps on 53 patients for ORN were done with a 90% resolution rate. Univariate parameter analysis was significant for infield mandibulotomy. An increased time interval from radiation therapy (XRT) to ORN development significantly predicted for flap-specific complications and flap loss (p < .05). Increased time from ORN diagnosis to flap surgery resulted in greater length of bone involvement (p = .01). Anastomotic complications occurred in 13 cases resulting in 7 complete flap losses.An increased risk of complication was encountered with greater time from XRT to ORN. Thus, in patients developing ORN long after treatment, surgery should be accordingly more aggressive.

    View details for DOI 10.1002/hed.21463

    View details for Web of Science ID 000287372900020

    View details for PubMedID 20645290

  • Free flap reconstruction of self-inflicted submental gunshot wounds. Craniomaxillofacial trauma & reconstruction Dean, N. R., McKinney, S. M., Wax, M. K., Louis, P. J., Rosenthal, E. L. 2011; 4 (1): 25-34


    In this study, we review outcomes for 15 patients with self-inflicted submental gunshot wounds requiring free flap reconstruction. Patients presented to two tertiary care centers over a 7-year period. Mean age was 46 years (range, 16 to 76 years), 67% (n = 10) had a psychiatric history, and four were known to abuse illicit substances. Patients with oromandibular involvement required on average a total of 2.8 procedures, and those with midface (3.7) or combined defects (6) required more total procedures (p = 0.21). Donor sites included osteocutaneous radial forearm (n = 8), fibula (n = 4), fasciocutaneous radial forearm (n = 5), and anterior lateral thigh (n = 1). Median length of hospitalization was 8 days. Overall complication rate was 33% (n = 5), and included hematoma (n = 1), fistula (n = 1), and mandibular malunion (n = 2). Most patients were able to tolerate a regular or soft diet (92%), maintain oral competency (58%), and demonstrate intelligible speech (92%) at a median time to follow-up of 12 months. Despite the devastating nature of this injury, free flap reconstruction of self-inflicted submental gunshot wounds results in acceptable functional results for the majority of patients.

    View details for DOI 10.1055/s-0031-1272899

    View details for PubMedID 22379504

  • A Minimally Invasive Multifunctional Nanoscale System for Selective Targeting, Imaging, and NIR Photothermal Therapy of Malignant Tumors Conference on Reporters, Markers, Dyes, Nanoparticles, and Molecular Probes for Biomedical Applications III Green, H. N., Martyshkin, D. V., Rosenthal, E. L., Mirov, S. B. SPIE-INT SOC OPTICAL ENGINEERING. 2011

    View details for DOI 10.1117/12.875792

    View details for Web of Science ID 000297729300006

  • Outcomes of recurrent head and neck cutaneous squamous cell carcinoma. Journal of skin cancer Dean, N. R., Sweeny, L., Magnuson, J. S., Carroll, W. R., Robinson, D., Desmond, R. A., Rosenthal, E. L. 2011; 2011: 972497-?


    Recurrent, advanced stage cutaneous squamous cell carcinoma (cSCC) is uncommon with limited publications on patient outcomes. A retrospective study including patients who underwent surgical resection for recurrent, advanced stage cSCC of the head and neck was performed (n = 72). Data regarding tumor site, stage, treatment, parotid involvement, perineural invasion, positive margins, metastasis, and disease-free survival was analyzed. The majority of patients were male (85%) and presented with recurrent stage III (89%) cSCC. Two-year disease-free survival was 62% and decreased to 47% at 5 years. Parotid involvement, positive margins, nodal metastasis, or the presence of perineural invasion did not correlate with decreased survival (P > .05). Distant metastasis was a strong indicator of poor overall survival (P < .001). Adjuvant postoperative radiotherapy did not improve overall survival (P = .42). Overall survival was poor for patients with advanced recurrent cSCC despite the combined treatment with surgery and radiotherapy.

    View details for DOI 10.1155/2011/972497

    View details for PubMedID 21773040

  • Transoral Robotic-Assisted Surgery for Head and Neck Squamous Cell Carcinoma One- and 2-Year Survival Analysis ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY White, H. N., Moore, E. J., Rosenthal, E. L., Carroll, W. R., Olsen, K. D., Desmond, R. A., Magnuson, J. S. 2010; 136 (12): 1248-1252


    to report 2-year survival outcomes for head and neck squamous cell carcinoma using transoral robotic-assisted resection.prospective case study.two tertiary care centers.eighty-nine patients from 2 tertiary care centers (University of Alabama at Birmingham and the Mayo Clinic in Rochester, Minnesota) with head and neck squamous cell carcinoma of all stages and subsites, who underwent transoral robotic-assisted resection between March 2007 and December 2008, with a median follow-up time of 26 months.disease-free survival, cancer recurrence, and gastrostomy tube dependenceseventy-one patients had T1 (n = 29) or T2 (n = 42) tumors while 18 patients had T3 (n = 8) or T4 (n = 10) tumors. There were 24 patients with overall stage I or II disease and 65 with stage III or IV disease. At the time of the last follow-up visit (median, 26 months), there had been a total of 11 patients with recurrent cancer: 3 with local; 7, regional (2 of whom also had distant metastases); and 1, distant. Seven patients were treated for recurrent disease. Eighty-two patients had no evidence of disease, 1 patient died of the disease, 2 died of other disease, and 4 were alive with disease at the last follow-up visit. Results of Kaplan-Meier survival analysis showed that the 2-year recurrence-free survival rate for the cohort was 86.5%. None of the patients were gastrostomy tube dependent at the last follow-up visit.the 2-year functional and oncologic results justify the continued treatment of select patients with head and neck squamous cell carcinoma with robotic-assisted surgical resection.

    View details for Web of Science ID 000285323000012

    View details for PubMedID 21173375

  • Anti-EMMPRIN antibody treatment of head and neck squamous cell carcinoma in an ex-vivo model ANTI-CANCER DRUGS Dean, N. R., Knowles, J. A., Helman, E. E., Aldridge, J. C., Carroll, W. R., Magnuson, J. S., Clemons, L., Ziober, B., Rosenthal, E. L. 2010; 21 (9): 861-867


    Targeting the molecular pathways associated with carcinogenesis remains the greatest opportunity to reduce treatment-related morbidity and mortality. Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a cell surface molecule known to promote tumor growth and angiogenesis in preclinical studies of head and neck carcinoma making it an excellent therapeutic target. To evaluate the feasibility of anti-EMMPRIN therapy, an ex-vivo human head and neck cancer model was established using specimens obtained at the time of surgery (n=22). Tumor slices were exposed to varying concentrations of anti-EMMPRIN monoclonal antibody and cetuximab for comparison purposes. Cetuximab is the only monoclonal antibody currently approved for the treatment of head and neck carcinoma. After treatment, tumor slices were assessed by immunohistochemistry and western blot analysis for apoptosis (TUNEL) and EMMPRIN expression. Of the tumor specimens 33% showed a significant reduction in mean ATP levels after treatment with cetuximab compared with untreated controls, whereas 58% of the patients responded to anti-EMMPRIN therapy (P<0.05). Samples, which showed reactivity to anti-EMMPRIN, also had greater EMMPRIN expression based on immunohistochemistry staining (49%) when compared with nonresponders (25%, P=0.06). In addition, TUNEL analysis showed a larger number of cells undergoing apoptosis in antibody-treated tumor slices (77%) compared with controls (30%, P<0.001) with activation of apoptotic proteins, caspase 3 and caspase 8. This study shows the potential of anti-EMMPRIN to inhibit proliferation and promote apoptosis and suggests its future role in the targeted treatment of head and neck carcinoma.

    View details for DOI 10.1097/CAD.0b013e32833d1a11

    View details for Web of Science ID 000281621200008

    View details for PubMedID 20700044

  • Outcomes Following Temporal Bone Resection LARYNGOSCOPE Dean, N. R., White, H. N., Carter, D. S., Desmond, R. A., Carroll, W. R., McGrew, B. M., Rosenthal, E. L. 2010; 120 (8): 1516-1522


    To evaluate survival outcomes in patients undergoing temporal bone resection.Retrospective review.From 2002 to 2009 a total of 65 patients underwent temporal bone resection for epithelial (n = 47) and salivary (n = 18) skull base malignancies. Tumor characteristics, defect reconstruction, and postoperative course were assessed. Outcomes measured included disease-free survival and cancer recurrence.The majority of patients presented with recurrent (65%), advanced stage (94%), cutaneous (72%), and squamous cell carcinoma (57%). Thirty-nine patients had perineural invasion (60%) and required facial nerve resection; 16 (25%) had intracranial extension. Local (n = 6), regional (n = 2), or free flap (n = 46) reconstruction was required in 80% of patients. Free flap donor sites included the anterolateral thigh (31%), radial forearm free flap (19%), rectus (35%), and latissimus (4%). The average hospital stay was 4.9 days (range, 1-28 days). The overall complication rate was 15% and included stroke (n = 4), cerebrospinal fluid leak (n = 2), hematoma formation (n = 1), infection (n = 1), flap loss (n = 1), and postoperative myocardial infarction (n = 1). A total of 22 patients (34%) developed cancer recurrence during the follow-up period (median, 10 months), 17 (77%) of whom presented with recurrent disease at the time of temporal bone resection. Two-year disease-free survival was 68%, and 5-year disease-free survival was 50%.Aggressive surgical resection and reconstruction is recommended for primary and recurrent skull base malignancies with acceptable morbidity and improved disease-free survival.

    View details for DOI 10.1002/lary.20999

    View details for Web of Science ID 000280695000005

    View details for PubMedID 20641083

  • Optical imaging predicts tumor response to anti-EGFR therapy CANCER BIOLOGY & THERAPY Helman, E. E., Newman, J. R., Dean, N. R., Zhang, W., Zinn, K. R., Rosenthal, E. L. 2010; 10 (2): 166-171


    To evaluate cetuximab treatment in head and neck squamous cell carcinoma xenografts and cell lines, we investigated a preclinical model of head and neck squamous cell carcinoma. Head and neck squamous cell carcinoma cell lines SCC-1, FaDu, CAL27, UM-SCC-5 and UM-SCC-22A were used to generate subcutaneous flank xenografts in SCID mice. Mice were divided into control and cetuximab treatment groups, mice in the latter group received 250 μg cetuximab once weekly for four weeks. After completion of therapy, SCC-1 (p < 0.001), UM-SCC-5 (p < 0.001), UM-SCC-22A (p = 0.016) and FaDu (p = 0.007) tumors were significantly smaller than control, while CAL27 tumors were not different from controls (p = 0.90). Mice were systemically injected with 50 μg of the Cy5.5-cetuximab bioconjugate and imaged by stereomicroscopy to determine if tumor fluorescence predicted tumor response. Intact tumor fluorescence did not predict response. Tissue was harvested from untreated xenografts to evaluate ex vivo imaging. Cell lines were then evaluated in vitro for fluorescence imaging after Cy5.5-cetuximab bioconjugate labeling. The location of fluorescence observed in labeled cells was significantly different for cell lines that responded to treatment, relative to unresponsive cells. Tumors from cell lines that showed low internalized signal in vitro responded best to treatment with cetuximab. This preclinical model may aid in determining which cancer patients are best suited for cetuximab therapy.

    View details for Web of Science ID 000280154100007

    View details for PubMedID 20505368

  • Functional Outcomes of Fibula and Osteocutaneous Forearm Free Flap Reconstruction for Segmental Mandibular Defects LARYNGOSCOPE Virgin, F. W., Iseli, T. A., Iseli, C. E., Sunde, J., Carroll, W. R., Magnuson, J. S., Rosenthal, E. L. 2010; 120 (4): 663-667


    To demonstrate that the osteocutaneous radial forearm free flap provides equivalent functional outcomes and improved morbidity compared to the fibular free flap in mandibular reconstruction.Retrospective review.There were 168 patients requiring free flap reconstruction of segmental mandibular defects between January 2001 and December 2008. Mean follow-up was 31 months for fibula free flap (FFF) (n = 117) and 20 months for osteocutaneous radial forearm free flaps (OCRFFF) (n = 51), reflecting an increasing use of forearms.OCRFFF were more commonly used in older patients (mean 63.7 years vs. 59 years, P = .03). The majority (96.2%) of reconstruction was for malignant pathology. Flap failure was 3.4% for the fibula group and 3.9% in the forearm group. Malunion was infrequent (2.0% OCRFFF, 6.0% FFF, P = .26). Donor site complications were higher in the FFF group (4.3%) versus none in the OCRFF group (P = .13). Despite a high rate of long-term survival in this patient population (75% at 5 years for carcinoma), dental implants were rarely placed (2.3% of patients) and were more common in forearm than fibula free flaps. Functional outcomes demonstrated no significant difference between groups with respect to oral diet (FFF 72.6% vs. OCRFFF 79.1%, P = .49) or retained enterogastric feeding tube (20.9% OCRFFF vs. 27.4% FFF, P = .49).Osteocutaneous radial forearm flaps provide comparable functional outcomes with less morbidity compared to fibula free flaps for selected segmental mandibulectomy defects. The overall dental implantation rate was low and more commonly performed in osteocutaneous radial forearm flaps compared to fibula flaps.

    View details for DOI 10.1002/lary.20791

    View details for Web of Science ID 000276335100003

    View details for PubMedID 20213660

  • Robotic-Assisted Surgery for Primary or Recurrent Oropharyngeal Carcinoma ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Dean, N. R., Rosenthal, E. L., Carroll, W. R., Kostrzewa, J. P., Jones, V. L., Desmon, R. A., Clemons, L., Magnuson, J. S. 2010; 136 (4): 380-384


    To determine the feasibility of robotic-assisted salvage surgery for oropharyngeal cancer.Retrospective case-controlled study.Academic, tertiary referral center.Patients who underwent surgical resection for T1 and T2 oropharyngeal cancer between 2001 and 2008 were classified into the following 3 groups based on type of resection: (1) robotic-assisted surgery for primary neoplasms (robotic primary) (n = 15), (2) robotic-assisted salvage surgery for recurrent disease (robotic salvage) (n = 7), and (3) open salvage resection for recurrent disease (n = 14).Data regarding tumor subsite, stage, and prior treatment were evaluated as well as margin status, nodal disease, length of hospital stay, diet, and tracheotomy tube dependence.The median length of stay in the open salvage group was longer (8.2 days) than robotic salvage (5.0 days) (P = .14) and robotic primary (1.5 days) resection groups (P < .001). There was no difference in postoperative diet between robotic primary and robotic salvage surgery groups. However, a greater proportion of patients who underwent open salvage procedures were gastrostomy tube dependent 6 months following treatment (43%) compared with robotic salvage resection (0%) (P = .06). A greater proportion of patients who underwent open salvage procedures also remained tracheotomy tube dependent after 6 months (7%) compared with robotic salvage or robotic primary patients (0%) (P = .48). No complications were reported in the robotic salvage group. Two patients who underwent open salvage resection developed postoperative hematomas and 2 developed wound infections.When feasible, robotic-assisted surgery is an acceptable procedure for resection of both primary and recurrent oropharyngeal tumors. Trial Registration Identifier: NCT00473564.

    View details for Web of Science ID 000276687600010

    View details for PubMedID 20403855

  • Outcomes of Static and Dynamic Facial Nerve Repair in Head and Neck Cancer LARYNGOSCOPE Iseli, T. A., Harris, G., Dean, N. R., Iseli, C. E., Rosenthal, E. L. 2010; 120 (3): 478-483


    Determine outcomes associated with nerve grafting versus static repair following facial nerve resection.Retrospective chart review.Charts from 105 patients who underwent facial nerve reconstruction between January 1999 and January 2009 were reviewed. The majority had parotid malignancy (78.1%), most commonly squamous cell carcinoma (50.5%). Patients underwent static (n = 72) or dynamic (n = 33) reconstruction with nerve grafting. Facial nerve function was measured using the House-Brackmann (H-B) scale.Patients receiving static reconstruction were on average 10.3 years older (P = .002). Mean overall survival for tumor cases was 61.9 months; parotid squamous cell carcinoma was associated with worse prognosis (P = .10). Median follow-up was 16.1 months (range, 4-96.1 months). Most (97%) patients receiving a nerve graft had some return of function at a median of 6.2 months postoperatively (range, 4-9 months) and the majority (63.6%) had good function (H-B score 6 cm), and prolonged preoperative dysfunction.

    View details for DOI 10.1002/lary.20789

    View details for Web of Science ID 000275224200008

    View details for PubMedID 20131366

  • Outcomes of Salvage Surgery With Free Flap Reconstruction for Recurrent Oral and Oropharyngeal Cancer LARYNGOSCOPE Kostrzewa, J. P., Lancaster, W. P., Iseli, T. A., Desmond, R. A., Carroll, W. R., Rosenthal, E. L. 2010; 120 (2): 267-272


    To evaluate outcomes of salvage surgery with free flap reconstruction for recurrent squamous cell carcinoma of the oropharynx and oral cavity with increased use of chemoradiotherapy.Retrospective patient review.All patients undergoing salvage surgery with free flap reconstruction for oropharynx (n = 36) and oral cavity (n = 36) squamous cell carcinomas between January 2001 and January 2008 were obtained. Mean follow-up was 14 months. Previous chemoradiotherapy was used in 40% and radiotherapy alone in 60%.Complications were more frequent in oropharynx than oral cavity tumors (36% and 14%, respectively; P = .05) requiring more secondary procedures (15 for oropharynx vs. six for oral cavity). Few patients returned to a normal diet (8%), and a majority retained an enterogastric feeding tube (56%). Median survival overall following salvage surgery was 44.8 months for oral cavity and 53.8 months for oropharynx head and neck squamous cell carcinoma. Overall estimated 1-, 2-, and 5-year observed survivals were 98%, 77.2%, and 43.7%, respectively. Twelve patients had a disease-free interval of <6 months, 92% of whom died of disease. Of 17 patients with disease at the primary site and involved regional lymph nodes, 94% died of disease.Salvage surgery with free flap reconstruction for recurrent oral and oropharyngeal tumors after chemoradiotherapy has acceptable morbidity and similar cure rates as salvage following radiotherapy without chemotherapy. Concurrent nodal recurrence and short disease-free interval are associated with reduced cure rates. A significant proportion will require enterogastric feeding and few will tolerate a normal diet.

    View details for DOI 10.1002/lary.20743

    View details for Web of Science ID 000274605000010

    View details for PubMedID 20013840

  • Management of the N0 Neck in Recurrent Laryngeal Squamous Cell Carcinoma LARYNGOSCOPE Bohannon, I. A., Desmond, R. A., Clemons, L., Magnuson, J. S., Carroll, W. R., Rosenthal, E. L. 2010; 120 (1): 58-61


    To evaluate the utility of neck dissections in patients undergoing salvage laryngectomy with a clinically negative neck.Retrospective cohort study.This retrospective review identified 71 patients with N0 necks who underwent salvage laryngectomy from 2001 to 2007. The standard practice of surgeons within our institution was different, thus neck dissections were performed on approximately one half of the patients, creating two groups for comparison. The number of neck dissections with positive metastasis were examined. Postoperative complications, overall survival, and site of recurrence were compared between patients with neck dissection and no neck dissection.Thirty-eight patients underwent 71 neck dissections concurrently with salvage laryngectomy. A total of 33 patients had salvage laryngectomy without neck dissection. Only three of 71 neck dissections (4%) had positive nodal metastasis. The rate of fistula, wound infection, hematoma/bleeding, chyle leak, wound dehiscence, and flap failure did not reveal any statistical differences. However, the overall complication rate in neck dissections patients was higher (42.2 %) than no neck dissections (21.3%; P = .04). Neck dissection patients had a higher proportion of fistulas (32%) than no dissections (18%; P = .2). Regional failure occurred in 7.9% of the patients with neck dissections and 15% of patients without neck dissection (P = .5). There was no survival advantage for patients who underwent neck dissection compared to no neck dissection (P = .47).There was no survival advantage gained by performing neck dissection in the clinically negative neck. However, a trend toward reduced regional failure with neck dissection must be balanced by the increased potential for complications and fistulae.

    View details for DOI 10.1002/lary.20675

    View details for Web of Science ID 000273245900011

    View details for PubMedID 19877259



    African Amercians afflicted with head and neck squamous cell carcinoma (HNSCC) have a strikingly worse survival than do whites. One apparent cause is an advanced stage of presentation in African Americans. This study was designed to identify barriers to early treatment among African American men.Twenty-four African American male HNSCC survivors completed structured interviews. Interviewers elicited the participants' experiences from symptom recognition to receiving definitive care.Most participants were seen with advanced-stage HNSCC. Overall, 10% experienced barriers to obtaining early medical care, though 30% were hesitant to seek care due to perceived barriers. Definitive treatment began for 81% within 3 months of initial care seeking.Once participants sought care, most of them received definitive treatment within a reasonable time frame. To explain the advanced stage at presentation, either tumor growth rate was extremely rapid or participants sought care when the tumor was quite advanced. The themes suggested by this elicitation study require further validation.

    View details for DOI 10.1002/hed.21125

    View details for Web of Science ID 000272340100006

    View details for PubMedID 19431197

  • Postoperative Reirradiation for Mucosal Head and Neck Squamous Cell Carcinomas ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Iseli, T. A., Iseli, C. E., Rosenthal, E. L., Caudell, J. J., Spencer, S. A., Magnuson, J. S., Smith, A. N., Carroll, W. R. 2009; 135 (11): 1158-1164


    To compare toxic effects and functional outcomes of reirradiation with and without salvage surgery for nonnasopharyngeal mucosal head and neck squamous cell carcinoma.Retrospective review.Academic tertiary referral hospital.Between December 1992 and March 2007, a total of 87 patients underwent reirradiation (64 for cure and 23 for palliation).Patients underwent reirradiation with (n = 38) or without salvage surgery (n = 49). After January 2000 there was increased use of concurrent platinum-based chemotherapy (80% vs 5%) and intensity-modulated radiation therapy (82% vs 0%).Early and late toxic effects of treatment by Radiation Therapy Oncology Group criteria, tracheostomy retention, gastrostomy tube dependence, and survival.The median follow-up among patients alive at last contact was 5.0 years. Compared with reirradiation without surgery, postoperative reirradiation was associated with increased early grade 3 to grade 5 toxic effects (50% [19 of 38] vs 29% [14 of 49], P = .04) and with longer median survival (17.3 vs 8.9 months, P < .001). Free-flap reconstruction decreased early toxic effects in the surgical cohort by 16% (from 60% [9 of 15] to 43% [10 of 23], P = .32). Gastrostomy tube dependence (P = .05) and tracheostomy retention (P = .04) have increased since 2000. The median survival for curative patients was 12.5 months. The estimated 2-year survival was 25%, and the estimated 5-year survival was 8%.Reirradiation represents the only chance for cure in patients with unresectable disease. After surgery, reirradiation is performed in patients at high risk of locoregional recurrence and may increase acute toxic effects. However, free-flap reconstruction may reduce toxic effects. Functional outcomes have declined since 2000 likely because of the addition of concurrent platinum-based chemotherapy. Future research may define the subpopulation of postoperative patients for whom survival benefits most outweigh reirradiation toxic effects.

    View details for Web of Science ID 000271860900018

    View details for PubMedID 19917931

  • Functional outcomes after transoral robotic surgery for head and neck cancer OTOLARYNGOLOGY-HEAD AND NECK SURGERY Iseli, T. A., Kulbersh, B. D., Iseli, C. E., Carroll, W. R., Rosenthal, E. L., Magnuson, J. S. 2009; 141 (2): 166-171


    To evaluate functional outcomes following transoral robotic surgery for head and neck cancer.Case series with planned data collection.Academic hospital.Between March 2007 and December 2008, 54 of 62 candidate patients underwent transoral robotic tumor resection. Outcomes include airway management, swallowing (MD Anderson Dysphagia Inventory), and enterogastric feeding.Tumors were most commonly oropharynx (61%) or larynx (22%) and T1 (35%) or T2 (44%). Many received radiotherapy (22% preoperatively, 41% postoperatively) and chemotherapy (31%). Endotracheal intubation was retained (22%) for up to 48 hours, tracheostomy less frequently (9%), and all were decannulated by 14 days. Most commenced oral intake prior to discharge (69%) or within two weeks (83%). A worse postoperative Dysphagia Inventory score was associated with retained feeding tube (P=0.020), age>60 (P=0.017), higher T stage (P=0.009), laryngeal site (P=0.017), and complications (P=0.035). At a mean 12 months' follow-up, 17 percent retained a feeding tube (9.5% among primary cases). Retained feeding tube was associated with preoperative tube requirement (P=0.017), higher T stage (P=0.043), oropharyngeal/laryngeal site (P=0.034), and recurrent/second primary tumor (P=0.008). Complications including airway edema (9%), aspiration (6%), bleeding (6%), and salivary fistula (2%) were managed without major sequelae.Transoral robotic surgery provides an emerging alternative for selected primary and salvage head and neck tumors with low morbidity and acceptable functional outcomes. Patients with advanced T stage, laryngeal or oropharyngeal site, and preoperative enterogastric feeding may be at increased risk of enterogastric feeding and poor swallowing outcomes.

    View details for DOI 10.1016/j.otohns.2009.05.014

    View details for Web of Science ID 000268558400002

    View details for PubMedID 19643246

  • Anti-EMMPRIN Monoclonal Antibody as a Novel Agent for Therapy of Head and Neck Cancer CLINICAL CANCER RESEARCH Dean, N. R., Newman, J. R., Helman, E. E., Zhang, W., Safavy, S., Weeks, D. M., Cunningham, M., Snyder, L. A., Tang, Y., Yan, L., McNally, L. R., Buchsbaum, D. J., Rosenthal, E. L. 2009; 15 (12): 4058-4065


    Extracellular matrix metalloprotease inducer (EMMPRIN) is a tumor surface protein that promotes growth and is overexpressed in head and neck cancer. These features make it a potential therapeutic target for monoclonal antibody (mAb)-based therapy. Because molecular therapy is considered more effective when delivered with conventional cytotoxic agents, anti-EMMPRIN therapy was assessed alone and in combination with external beam radiation.Using a murine flank model, loss of EMMPRIN function was achieved by transfection with a small interfering RNA against EMMPRIN or treatment with a chimeric anti-EMMPRIN blocking mAb. Cytokine expression was assessed for xenografts, tumor cells, fibroblasts, and endothelial cells.Animals treated with anti-EMMPRIN mAb had delayed tumor growth compared with untreated controls, whereas treatment with combination radiation and anti-EMMPRIN mAb showed the greatest reduction in tumor growth (P = 0.001). Radiation-treated EMMPRIN knockdown xenografts showed a reduction in tumor growth compared with untreated knockdown controls (P = 0.01), whereas radiation-treated EMMPRIN-expressing xenografts did not show a delay in tumor growth. Immunohistochemical evaluation for Ki67 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) resulted in a reduction in proliferation (P = 0.007) and increased apoptosis in anti-EMMPRIN mAb-treated xenografts compared with untreated controls (P = 0.087). In addition, we provide evidence that EMMPRIN suppression results in decreased interleukin 1beta (IL-1beta), IL-6, and IL-8 cytokine production, in vitro and in vivo.These data suggest that anti-EMMPRIN antibody inhibits tumor cell proliferation in vivo and may represent a novel targeted treatment option in head and neck squamous cell carcinoma.

    View details for DOI 10.1158/1078-0432.CCR-09-0212

    View details for Web of Science ID 000267080800020

    View details for PubMedID 19509148

  • Functional Outcomes Following Secondary Free Flap Reconstruction of the Head and Neck LARYNGOSCOPE Iseli, T. A., Yelverton, J. C., Iseli, C. E., Carroll, W. R., Magnuson, J. S., Rosenthal, E. L. 2009; 119 (5): 856-860


    To evaluate head and neck patients undergoing secondary (delayed) free flap reconstructions.Retrospective chart review.Of the 523 free flaps between October 2004 and May 2008, 70 patients underwent 71 secondary free flaps. Outcomes include: hospital stay, complications, flap operative time, enterogastric tube, and tracheostomy requirement. Variables assessed include donor site, indication, prior radiation, and extra-cervical vascular anastomosis.Radial forearm (40.8%) and fibula free flaps (29.6%) were most commonly used. Mean hospital stay was 7.9 days, follow-up 23.5 months, and operative time 323 minutes. Complications occurred in 39.4% in hospital (early) and 31.4% after discharge (late). Many required further surgery (33.8%), tracheostomy at discharge (26.8%), and prolonged enterogastric tube feeding (31%). In-hospital mortality was 1.4%, total flap failure 1.4%, and partial failure 5.6%. The radial forearm required the least operative time (P = .002), and had least tracheostomies at discharge (P = .040). Osteocutaneous fibula took longest (P = .0001), and had the highest tracheostomy rate (P = .047). Early complications were highest with anterolateral thigh flaps (P = .001). Osteoradionecrosis resulted in higher tracheostomy rates at discharge (P = .0001). Osteocutaneous flaps took 111 minutes longer (P = .001), and required more tracheostomies on discharge (P = .031), but with lower fistula rates (P = .046). Previous irradiation and extra-cervical vessels did not significantly impact outcomes.Secondary free flaps are technically feasible for head and neck reconstruction with low mortality and flap failure rates. The extra-cervical and external carotid vessels were equally effective. Patients considering semi-elective free flap reconstruction for osteoradionecrosis should be cautioned about complication rates and tracheostomy retention.

    View details for DOI 10.1002/lary.20200

    View details for Web of Science ID 000265866000004

    View details for PubMedID 19358194

  • Reconstruction of periauricular and temporal bone defects. Facial plastic surgery clinics of North America Iseli, T. A., Rosenthal, E. L. 2009; 17 (2): 253-262


    Large periauricular and temporal bone defects most commonly follow resection of advanced nonmelanoma skin cancers. Reconstruction aims to cover the cutaneous defect and adjacent vital structures with the ability to heal in an irradiated field and withstand further treatment. Preferred reconstructions are class I, cervicofacial rotation or radial forearm free flap; class II, anterolateral thigh; and class II, rectus abominis free flap. Ancillary procedures, especially for associated facial paralysis, often are required. Although free flap reconstruction provides rapid wound healing, local and regional flaps are alternatives for patients unable to tolerate prolonged anesthesia and for use after recurrence or complications.

    View details for DOI 10.1016/j.fsc.2009.01.005

    View details for PubMedID 19393947

  • Robot-Assisted Surgery for Upper Aerodigestive Tract Neoplasms ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Boudreaux, B. A., Rosenthal, E. L., Magnuson, J. S., Newman, J. R., Desmond, R. A., Clemons, L., Carroll, W. R. 2009; 135 (4): 397-401


    To assess the feasibility and safety of performing robot-assisted resections of head and neck tumors, and to predict which variables lead to successful robot-assisted resection and better functional outcome.Prospective nonrandomized clinical trial.Academic tertiary referral center.Thirty-six patients with oral cavity, oropharyngeal, hypopharyngeal, or laryngeal tumors.Robot-assisted resection of indicated tumors.Ability to perform robot-assisted resection, final pathologic margin status, ability to extubate postoperatively, need for tracheotomy tube, and need for gastrostomy tube. Any clinically significant complications were recorded.Thirty-six patients participated in the study. Eight patients had previously been treated for head and neck cancer. Twenty-nine patients (81%) underwent successful robotic resection. Negative margins were obtained in all 29 patients. Twenty-one of 29 patients were safely extubated prior to leaving the operating room. One patient required short-term tracheotomy tube placement. A total of 9 patients were gastrostomy tube dependent (2 preoperatively, 7 postoperatively). Factors associated with successful robotic resection were lower T classification (P = .01) and edentulism (P = .07). Factors associated with gastrostomy tube dependence were advanced age (P = .02), tumor location in the larynx (P < .001), higher T classification (P = .02), and lower preoperative M. D. Anderson Dysphagia Inventory score (P = .04).Robot-assisted surgery is feasible and safe for the resection of select head and neck tumors. This clinical series demonstrates that robotic surgery can be utilized successfully in patients with T1 to T4 lesions located in the oral cavity, oropharynx, hypopharynx, and larynx with good preservation of swallow function.

    View details for Web of Science ID 000265381100013

    View details for PubMedID 19380364

  • Therapy of head and neck squamous cell carcinoma with replicative adenovirus expressing tissue inhibitor of metalloproteinase-2 and chemoradiation CANCER GENE THERAPY McNally, L. R., Rosenthal, E. L., Zhang, W., Buchsbaum, D. J. 2009; 16 (3): 246-255


    Recent studies have demonstrated the efficacy of targeted therapy combined with radiotherapy in head and neck squamous cell carcinoma (HNSCC). We hypothesized that a combination treatment including a replicating adenovirus armed with tissue inhibitor of metalloproteinase-2 (TIMP-2), radiation and Cisplatin will augment treatment response and reduce tumor growth in vivo of HNSCC xenografts. Both single-agent (TIMP-2 virus, radiation and Cisplatin) and the combination therapies were evaluated in vitro and in vivo. The efficacy of both single-agent and combination therapies in vivo was determined by monitoring tumor growth and immunohistochemistry. Treatment with replicative Ad-TIMP-2 virus and radiation decreased cell viability in vitro and resulted in an additional antiangiogenic response in vivo. Tumor response rates to treatment with replicative Ad-TIMP-2, radiation, Cisplatin or combination therapies ranged from limited inhibition of tumor growth of the single-agent therapy to a statistically significant additive antitumor response with the combination therapies. Replicative Ad-TIMP-2+radiation+Cisplatin in the SCC1 nude mice demonstrated the greatest response rates in tumor growth and angiogenesis. Combination of Ad-TIMP-2 gene therapy with radiation and the triple treatment group resulted in an augmented therapeutic response. This is the first report of the potential benefits of combining radiation and MMP inhibitor treatment.

    View details for DOI 10.1038/cgt.2008.76

    View details for Web of Science ID 000263320300006

    View details for PubMedID 18846112

  • EMMPRIN expression is required for response to bevacizumab therapy in HNSCC xenografts CANCER LETTERS Newman, J. R., Helman, E. E., Safavy, S., Zhang, W., Rosenthal, E. L. 2009; 274 (2): 313-318


    The HNSCC cell line, FaDu was stably transfected with control vector (FaDu) or with plasmid expressing small interfering RNA against EMMPRIN (FaDu/siE). Tumor cells were treated with bevacizumab (0, 25, 50, and 75 ng/ml) in vitro, and then cell counts were performed at 72 h. For in vivo analysis, tumor cells were xenografted onto the flank of SCID mice, and were treated with 100 microg bevacizumab twice weekly for three weeks. Xenograft samples from the control and treatment groups were analyzed for microvessel density. Escalating doses of bevacizumab had no effect on the growth of tumor cells in vitro (P.or=0.086). However, tumor xenografts expressing EMMPRIN responded to bevacizumab treatment (P=0.0013), whereas the EMMPRIN knockdown cell line did not (P=0.7942). Immunohistochemical analysis demonstrated that microvascular density was reduced in the treated FaDu tumors (P=0.005), but not in the FaDu/siE tumors (P=0.48). Currently there is limited information on biomarkers to predict response to bevacizumab. By demonstrating effectiveness of bevacizumab therapy in tumors that express EMMPRIN, but not in tumors with silenced EMMPRIN expression, this study suggests that EMMPRIN may serve as a biomarker for response to bevacizumab treatment.

    View details for DOI 10.1016/j.canlet.2008.09.033

    View details for Web of Science ID 000263206100019

    View details for PubMedID 18990485

  • In vivo Efficacy of Marimastat and Chemoradiation in Head and Neck Cancer Xenografts ORL-JOURNAL FOR OTO-RHINO-LARYNGOLOGY AND ITS RELATED SPECIALTIES Skipper, J. B., McNally, L. R., Rosenthal, E. L., Wang, W., Buchsbaum, D. J. 2009; 71 (1): 1-5


    To assess the effect of combining a synthetic matrix metalloprotease inhibitor and chemoradiation therapy on tumor growth in a murine model of head and neck squamous-cell carcinoma (SCC).Athymic, nude mice bearing SCC-1 xenografts were used to comprise 4 treatment groups: (1) control receiving vehicle alone, (2) marimastat alone, (3) cisplatin + radiation in combination and (4) marimastat + cisplatin + radiation in combination. The marimastat was administered at a dose of 8.7 mg/kg/day over a 14-day period via a subcutaneous osmotic pump. The control group received vehicle only via a subcutaneous osmotic pump. Radiotherapy was given in 4 fractions of 8 Gy divided over days 8, 12, 16 and 20 with 4 intraperitoneal doses of cisplatin (3 mg/kg) 1 h before each fraction of radiation.Animals receiving triple treatment had delayed growth, measured as lengthened tumor doubling time, compared to the cisplatin + radiation combination (p = 0.03). Also, compared to control, the triple-treatment group (p = 0.005) had delayed growth in terms of doubling time. Factor VIII immunohistochemistry to assess microvessel density did not demonstrate a reduction in neovascularization between the triple-treatment and cisplatin + radiation combination groups. Statistical analysis failed to demonstrate any significant difference among groups.Chemoradiation + marimastat therapy had delayed tumor growth, compared to the chemoradiation alone. Based on these results, marimastat may work in combination with chemotherapy and radiation to inhibit tumor growth.

    View details for DOI 10.1159/000163217

    View details for Web of Science ID 000261521900001

    View details for PubMedID 18931526

  • INDICATIONS AND OUTCOMES OF DOUBLE FREE FLAPS IN HEAD AND NECK RECONSTRUCTION MICROSURGERY Andrades, P., Bohannon, I. A., Baranano, C. F., Wax, M. K., Rosenthal, E. 2009; 29 (3): 171-177


    This study describes the clinical setting and operative outcomes for simultaneous double free flap treatment of extensive composite head and neck cancers.A retrospective review at two tertiary referral centers was performed. Patient demographics, cancer characteristics, reconstruction methods, and postoperative course were recorded. All patients were assessed for diet, speech, esthetics, socialization, and satisfaction using specific evaluation scales.A total of 30 patients underwent double free flap reconstruction between 2001 and 2007. There were 19 men and 11 women, mean age of 62 years (range, 42-79). Comorbidities were present in 67% of the cases and 70% smoked. Most frequently the cancer was a squamous cell carcinoma (90%), in advanced stage (87%), and recurrent (67%), affecting the oral cavity (43%), larynx (23%) or pharynx (20%). The fibula osteoseptocutaneous/radial forearm fasciocutaneous flap combination was most commonly used (n = 13), followed by the jejunum-radial forearm flap (n = 10). Three flaps required early anastomosis revision and only two partial flap losses were observed. In 11 cases, there was a severe recipient site complication: wound dehiscence (n = 3), oral incompetence (n = 4), fistula (n = 2), and stenosis (n = 2). Two patients died in the postoperative period due to medical problems (7%). The mean follow up was 15.3 months. Patient satisfaction was poor to moderate and the overall functional evaluation score was low.Double free flaps for one-stage reconstruction of extensive head and neck defects should be used in selected cases. Although a reliable procedure, immediate postoperative morbidity and mortality is high, and the long-term functional and esthetic results are modest. Realistic outcomes should be discussed with patients during planning and consent.

    View details for DOI 10.1002/micr.20588

    View details for Web of Science ID 000264417700001

    View details for PubMedID 18946887

  • Indications and Outcomes of Double Free Flaps in Head and Neck Reconstruction LARYNGOSCOPE Andrades, P., Bohannon, I. A., Baranano, C. F., Wax, M. K., Rosenthal, E. L. 2009; 119: S58-S58

    View details for DOI 10.1002/lary.20329

    View details for Web of Science ID 000207862500058

  • Use of Optical Imaging to Predict Tumor Response to anti-EGFR Therapy LARYNGOSCOPE Dean, N. R., Newman, J. R., Helman, E. E., Zhang, W., Rosenthal, E. L. 2009; 119: S63-S63

    View details for DOI 10.1002/lary.20334

    View details for Web of Science ID 000207862500063

  • Modulation of Tumor Cell Growth In Vivo by Extracellular Matrix Metalloprotease Inducer ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Newman, J. R., Bohannon, I. A., Zhang, W., Skipper, J. B., Grizzle, W. E., Rosenthal, E. L. 2008; 134 (11): 1218-1224


    To investigate if loss of extracellular matrix metalloprotease inducer (EMMPRIN) will inhibit the growth of head and neck squamous cell carcinoma (HNSCC) tumor cell lines in vivo. Tumor cell-derived EMMPRIN is highly overexpressed in HNSCC and is thought to be induced by surrounding fibroblasts to stimulate matrix metalloproteases, which modulate tumor cell invasion, growth, and angiogenesis.In vivo study using FaDu tumor xenografts.Academic research facility.Severe combined immunodeficiency (SCID) mice.The HNSCC cell line FaDu was transfected with EMMPRIN (FaDu/E), control vector (FaDu), or plasmid-expressing small-interfering RNA against EMMPRIN (FaDu/siE). Tumor cells combined with fibroblast cells were xenografted onto the flank of SCID mice. Tumors were measured biweekly over 4 weeks, at which time the mice were killed, and tumor samples were analyzed for proliferation (Ki-67 immunohistochemical analysis), vascularization (factor VIII staining), and apoptosis (TUNEL [terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling] assay).Growth of head and neck cancer cell lines genetically engineered to express variable levels of EMMPRIN.Tumor growth positively correlated and animal survival negatively correlated with increasing EMMPRIN expression. FaDu/E tumor growth was significantly larger at 4 weeks compared with FaDu tumors (P = .006). Similarly, the control vector-transfected FaDu tumors were significantly larger than FaDu/siE (P < .001). Immunohistochemical analysis demonstrated increased Ki-67 in EMMPRIN-transfected cells, without a significant change in the rate of apoptosis between groups. Vascular density and tumor formation rate also increased significantly with EMMPRIN expression.This study suggests that anti-EMMPRIN-targeted therapy may prove to be a novel treatment option in HNSCC.

    View details for Web of Science ID 000261739700016

    View details for PubMedID 19015455

  • Zygomaticomaxillary buttress reconstruction of midface defects with the osteocutaneous radial forearm free flap HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Andrades, P., Rosenthal, E. L., Carroll, W. R., Baranano, C. F., Peters, G. E. 2008; 30 (10): 1295-1302


    The purpose of this study was to evaluate morbidity, functional, and aesthetic outcomes in midface zygomatic-maxillary buttress reconstruction using the osteocutaneous radial forearm free flap (OCRFFF).A retrospective review of 24 consecutive patients that underwent midface reconstruction using the OCRFFF was performed. All patients had variable extension of maxillectomy defects that requires restoration of the zygomatic-maxillary buttress. After harvest, the OCRFFF was fixed transversely with miniplates connecting the remaining zygoma to the anterior maxilla. The orbital support was given by titanium mesh when needed that was fixed to the radial forearm bone anteriorly and placed on the remaining orbital floor posteriorly. The skin paddle was used for intraoral lining, external skin coverage, or both. The main outcome measures were flap success, donor-site morbidity, orbital, and oral complications. Facial contour, speech understandability, swallowing, oronasal separation, and socialization were also analyzed.There were 6 women and 18 men, with an average age of 66 years old (range, 34-87). The resulting defects after maxillectomy were (according to the Cordeiro classification; Disa et al, Ann Plast Surg 2001;47:612-619; Santamaria and Cordeiro, J Surg Oncol 2006;94:522-531): type I (8.3%), type II (33.3%), type III (45.8%), and type IV (12.5%). There were no flap losses. Donor-site complications included partial loss of the split thickness skin graft (25%) and 1 radial bone fracture. The most significant recipient-site complications were severe ectropion (24%), dystopia (8%), and oronasal fistula (12%). All the complications occurred in patients with defects that required orbital floor reconstruction and/or cheek skin coverage. The average follow-up was 11.5 months, and over 80% of the patients had adequate swallowing, speech, and reincorporation to normal daily activities.The OCRFFF is an excellent alternative for midface reconstruction of the zygomatic-maxillary buttress. Complications were more common in patients who underwent resection of the orbital rim and floor (type III and IV defects) or external cheek skin.

    View details for DOI 10.1002/hed.20874

    View details for Web of Science ID 000259855100003

    View details for PubMedID 18642322

  • Immediate nasal valve reconstruction after facial nerve resection ARCHIVES OF FACIAL PLASTIC SURGERY Soler, Z. M., Rosenthal, E., Wax, M. K. 2008; 10 (5): 312-315


    To highlight the problem of valve collapse after facial paralysis and review the efficacy of performing immediate reconstruction at the time of initial oncologic resection, using a suture technique of suspending the soft tissue of the nasal valve to the inferior orbital rim.A review of all patients undergoing immediate nasal valve reconstruction was undertaken. There was a total of 18 patients, 15 men and 3 women, with a median age of 64 years. All patients had undergone facial nerve resection as part of their initial ablative procedure with immediate reconstruction of the nasal valve. A suture technique was used that secured the nasal valve area to the inferior orbital rim periosteum. These patients were compared with a cohort of 10 patients who underwent similar oncologic and reconstructive procedures but had no nasal valve reconstruction.Patients were evaluated with the Nasal Obstruction Septoplasty Evaluation tool. In patients who underwent reconstruction, there was no evidence of valve collapse on clinical examination. Patients who did not undergo reconstruction demonstrated significantly more symptoms of (1) congestion or stuffiness (1.8 vs 0.4; P< .05), (2) nasal blockage or congestion (2.6 vs 0.3; P< .05), (3) trouble breathing through the nose (2.7 vs 0.3; P< .05); (4) trouble sleeping (2.7 vs 0.3; P< .05); and (5) inability to get enough air during exertion (1.2 vs 0.1; P< .05). Follow-up extended to a median of 2 years. In the reconstructed group, cosmesis was acceptable and there were no instances of suture breakage or granuloma.We propose that the nasal valve should be addressed at the time of initial facial nerve resection if immediate reconstruction is planned. A suture suspension technique is easily used at the time of primary resection and reconstruction.

    View details for Web of Science ID 000259228200003

    View details for PubMedID 18794408

  • Fistula Analysis After Radial Forearm Free Flap Reconstruction of Hypopharyngeal Defects LARYNGOSCOPE Andrades, P., Pehler, S. F., Baranano, C. F., Magnuson, J. S., Carroll, W. R., Rosenthal, E. L. 2008; 118 (7): 1157-1163


    To evaluate risk factors and management options for fistula formation after hypopharyngeal reconstruction using the radial forearm free flap reconstruction.Retrospective cohort study.Patients undergoing radial forearm free flap for hypopharyngeal reconstruction were retrospectively reviewed. A total of 104 patients underwent this procedure between 2001 and 2007. Fistulas were classified as mild or severe depending on the response to conservative management. Demographics, operative details, pathology, and postoperative course were recorded as the prognostic variables. Univariate analysis and a logistic regression model were used to identify associated factors.Pharyngocutaneous fistula developed in 30 (28.8%) patients. Recurrence, cancer stage, cancer location, type of ablative surgery, and the addition of other oncologic procedures were identified as significant predictors of fistula formation. Fistula significantly increases hospital stay and recipient site complications such as flap survival, infection, and bleeding. Functional results such as diet, deformity, and socialization were also negatively affected by fistula development. One third of the cases responded to conservative management, and 20 cases required a surgical procedure to definitively close the fistulous track.Fistula formation remains a significant cause of morbidity associated with hypopharyngeal-reconstruction. Postoperative course and successful preventive strategies are discussed.

    View details for DOI 10.1097/MLG.0b013e31816f695a

    View details for Web of Science ID 000260662400005

    View details for PubMedID 18438265

  • Stereomicroscopic fluorescence imaging of head and neck cancer xenografts targeting CD147 CANCER BIOLOGY & THERAPY Newman, J. R., Gleysteen, J. P., Baranano, C. F., Bremser, J. R., Zhang, W., Zinn, K. R., Rosenthal, E. L. 2008; 7 (7): 1063-1070


    To demonstrate that systemically administered fluorescently labeled anti-CD147 antibody can detect head and neck squamous cell carcinoma xenografts in vivo.In vivo immunodeficient murine model.Peak tumor fluorescence was visualized by near infrared stereomicroscopy in SCC-1 tumors at 24 hours after systemic injection of anti-CD147:Cy5.5 bioconjugate. SCC-1 xenografts demonstrated significantly higher fluorescent intensity after administration of CD147:Cy5.5 (48 au, p < 0.0001) compared to IgG1k:Cy5.5 isotype control antibody (9 au). FaDu tumors overexpressing CD147 (FaDu/E) demonstrated higher fluorescence (53 au) compared to control vector transfected cells (FaDu, 33 au, p < 0.0001) which was higher than CD147 knockdown cells (FaDu/siE, 5 au, p < 0.0001).To determine if fluorescently labeled anti-CD147 antibody was specific for tumors in vivo, anti-CD147 and non-specific IgG1k antibody were labeled with a near infrared fluorophore (Cy5.5) and administered systemically to immunodeficient mice bearing SCC-1 xenografts. Imaging was performed over a 72 hour period using brightfield and fluorescent (685-735 nm) stereomicroscopy. To determine if fluorescence varied with receptor expression, SCID mice were xenografted with cell lines expressing variable amounts of CD147: FaDu (control vector transfected), FaDu/siE (siRNA CD147 knockdown) or FaDu/E (CD147 overexpressing) cells.This data suggests fluorescently labeled anti-CD147 may have clinical utility in detection of HNSCC.

    View details for Web of Science ID 000258524300015

    View details for PubMedID 18431087

  • Fluorescent labeled anti-EGFR antibody for identification of regional and distant metastasis in a preclinical xenograft model HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Gleysteen, J. P., Newman, J. R., Chhieng, D., Frost, A., Zinn, K. R., Rosenthal, E. L. 2008; 30 (6): 782-789


    Detection of regional and distant metastatic disease has significant implications for patient management. Fluorescent imaging may be a useful technique for metastasis detection and removal.Anti-epidermal growth factor receptor antibody (cetuximab) and isotype-matched control antibody (immunoglobulin G [IgG]) were labeled with a near-infrared fluorophore (Cy5.5), then systemically administered to mice with tumors resulting from either intraoral or intravenous injections of head and neck squamous cell carcinoma. Mice were sacrificed before undergoing fluorescent stereomicroscopy to assess pulmonary or cervical lymph node metastasis. Fluorescent areas were serially excised until wound bed demonstrated negative fluorescence.Mice bearing pulmonary metastases displayed diffuse background after IgG-Cy5.5 injection, but demonstrated a speckled fluorescent pattern across lung surface following cetuximab-Cy5.5 injection. Mice bearing cervical metastases demonstrated clear fluorescence of primary tongue tumor and bilateral cervical nodes. Fluorescence correlated with histopathology.These data suggest that cetuximab-Cy5.5 may have clinical utility in the detection and guided the removal of regional and distant micrometastasis.

    View details for DOI 10.1002/hed.20782

    View details for Web of Science ID 000256537900014

    View details for PubMedID 18228526

  • Fluorescent Detection of Rat Parathyroid Glands via 5-Aminolevulinic Acid LARYNGOSCOPE Asher, S. A., Peters, G. E., Pehler, S. F., Zinn, K., Newman, J. R., Rosenthal, E. L. 2008; 118 (6): 1014-1018


    Anatomic identification of parathyroid glands during surgery is challenging and time consuming. We sought to determine whether 5-aminolevulinic acid (5-ALA) could produce parathyroid gland fluorescence to improve their detection in a preclinical model.Thirty-two rats were administered 0 to 700 mg/kg of 5-ALA by intraperitoneal injection prior to neck exploration under the illumination of a blue light (380-440 nm). Tissue fluorescence was assessed at 1, 2, or 4 hours postinjection and then removed for histologic confirmation of parathyroid tissue.Rat parathyroid glands could not be visualized under ambient light. At dosages of 300 mg/kg or greater, bilateral parathyroid glands were visualized in 18 of 19 rats using blue light illumination. At dosages less than 300 mg/kg, parathyroid gland fluorescence was detected in only 1 of 13 rats. At 2 hours after 5-ALA administration, the net mean intensity of parathyroid gland fluorescence was optimal with a dose of 500 mg/kg. At both 1 and 4 hours after 5-ALA injection, the net mean intensity of parathyroid gland fluorescence was optimal at the highest dose (700 mg/kg) and positively correlated with dosage increases.5-ALA can be used to selectively detect parathyroid tissue from surrounding tissue in a preclinical model. Our data support the use of this technique in the clinical setting.

    View details for DOI 10.1097/MLG.0b013e3181671b61

    View details for Web of Science ID 000260662200011

    View details for PubMedID 18520821

  • Evolution of a paradigm for free tissue transfer reconstruction of lateral temporal bone defects HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Rosenthal, E. L., King, T., McGrew, B. M., Carroll, W., Magnuson, J. S., Wax, M. K. 2008; 30 (5): 589-594


    Tumors of the lateral skull base are best treated with surgery plus or minus radiation therapy. Surgical ablation may involve cutaneous structures, the auricle, the parotid, and the lateral temporal bone. These composite soft tissue defects are best reconstructed with composite tissue. Multiple pedicled flaps have been used to reconstruct these defects. Free flaps have been shown to provide the best tissue for these reconstructions. We review our experience and present an algorithm for their reconstruction.A case series of consecutive patients treated between 1999 and 2006 at 2 tertiary care institutions, Oregon Health and Science University and University of Alabama at Birmingham were reviewed. There were 73 patients who had periauricular defects requiring 74 free tissue transfers in this retrospective chart review. All defects had extensive cutaneous loss and underwent some form of parotidectomy. There were 57 lateral temporal bone defects and 16 periauricular defects where the external auditory canal was preserved. The majority of patients had nonmelanoma skin malignancies (65%). Eighty percent of patients had undergone previous treatment (radiation therapy, surgery, or a combination therof).Early on, reconstruction was performed using a radial forearm (RFFF, n=29), evolving to lateral arm (n=6), rectus (n=11), and finally an anterolateral thigh (ALT, n=28) free flap. The average hospital stay was 6 days, and the overall complication rate was 22%. The rectus flap needed debulking in 34% of patients, and the anterolateral thigh in 9%. Periauricular defects were classified based on preservation of the external auditory canal (class I), lateral temporal bone resection with preservation of the auricle (class II), or lateral temporal bone with total auriculectomy (class III).Class I defects were best managed by RFFF reconstruction, class II defects were managed well with the ALT flap, and class III defects required the ALT or rectus flap.

    View details for DOI 10.1002/hed.20744

    View details for Web of Science ID 000255578300004

    View details for PubMedID 18213723

  • Assessment of bevacizumab conjugated to Cy5.5 for detection of head and neck cancer xenografts TECHNOLOGY IN CANCER RESEARCH & TREATMENT Withrow, K. P., Newman, J. R., Skipper, J. B., Gleysteen, J. P., Magnuson, J. S., Zinn, K., Rosenthal, E. L. 2008; 7 (1): 61-66


    Optical fluorescent technology has the potential to deliver real time imaging of cancer into the operating room and the clinic. To determine the efficacy of fluorescently labeled anti-vascular endothelial growth factor (VEGF) antibody to be used as a cancer specific optical contrast agent to guide surgical resections, we evaluated the sensitivity and specificity of this agent to detect microscopic residual disease in a preclinical model of head and neck squamous cell carcinoma (HNSCC). Using a flank murine model, mice were xenografted with SCC-1 tumor cells and injected with anti-VEGF antibody (bevacizumab) conjugated to an optically active fluorophore (Cy5.5). Tumors underwent sub-total resections and were assessed for the presence of residual disease by fluorescent stereomicroscopy. Expected positive and negative biopsies were taken according to the presence or absence of fluorescence, respectively. Histology was used to confirm the presence or absence of disease. Biopsies taken from areas of fluorescence within the wound bed (n=18) were found to be histologically malignant in all but one biopsy. Samples taken from a non-fluorescing tumor bed (n=15) were found to be histologically benign in 11 of 15. These findings correlated with a sensitivity and specificity of 80.9% and 91.7%, respectively. This data supports previous data presented by this group and supports further investigation of fluorescently labeled anti-tumor antibodies to detect disease in the surgical setting.

    View details for Web of Science ID 000253006300008

    View details for PubMedID 18198926

  • Role of microvascular density in nonlocalizing parathyroid Sestamibi scans LARYNGOSCOPE Peters, G., Kulbersh, B., Mantle, B., Bell, W., Grizzle, W., Rosenthal, E. 2007; 117 (12): 2163-2168


    Sestamibi scans for localization of abnormal parathyroid glands in patients with hyperparathyroidism are widely used at many institutions. Minimally invasive parathyroid surgery demands accurate preoperative localization imaging; however, nonlocalizing sestamibi scans occur in 15% of patients with primary hyperparathyroidism. It remains unknown why some sestamibi scans fail to localize. We hypothesize that an increase in microvascular density (MVD) within an adenoma will result in rapid tracer washout and a subsequent nonlocalizing scan. This study investigates the role of MVD in sestamibi localization.Retrospective chart review with immunohistochemical staining and data analysis.Medical records of 83 patients who had a sestamibi scan for evaluation of primary hyperparathyroidism and underwent initial parathyroidectomy from 2000 to 2002 were retrospectively reviewed. Patients' age, sex, preoperative imaging results, operative procedure, gland weight, and histologic findings were collected. Immunohistochemistry was performed to assess MVD.Of the 75 preoperative sestamibi scans used, 51 patients had a localizing scan, and 24 were nonlocalizing. Localizing sestamibi scans for primary hyperparathyroidism demonstrated a sensitivity of 94% and specificity of 85%. By identifying multiglandular hyperplasia, nonlocalizing sestamibi scans produced a sensitivity of 83%. The localizing group had a greater percentage of solitary adenomas (94%) compared with the nonlocalizing group (15.6%) (P < .001). The mean gland weight for the nonlocalizing group was less than 398 g compared with the localizing groupweight of 1,113 g (P < .001). The mean MVD for localizing scan group was 229 vessels per high-power field,and the mean for the nonlocalizing scans was 213 vessels per high-power field (P = .2).MVD does not predict whether sestamibi scans are localizing or nonlocalizing.

    View details for DOI 10.1097/MLG.0b013e318149241f

    View details for Web of Science ID 000251397200014

    View details for PubMedID 17921899

  • Assessment of indocyanine green-labeled cetuximab to detect xenografted head and neck cancer cell lines OTOLARYNGOLOGY-HEAD AND NECK SURGERY Withrow, K. P., Gleysteen, J. P., Safavy, A., Skipper, J., Desmond, R. A., Zinn, K., Rosenthal, E. L. 2007; 137 (5): 729-734


    The aim of this study is to determine the efficacy of indocyanine green (ICG) conjugated to antiepidermal growth factor receptor antibody (cetuximab) to image head and neck cancer.Mice (n = 3) were injected with unconjugated ICG and imaged at 100-second intervals for a total of 1000 seconds to assess imaging characteristics. Mice (n = 10) xenografted with SCC-1 cells were then systemically injected with cetuximab conjugated to indocyanine green and imaged over a 72-hour period. To assess the sensitivity and specificity, xenografted tumors underwent subtotal resections and then were assessed for residual disease by fluorescence stereomicroscopy and confirmed by histology.Tumors demonstrated excellent fluorescence 24 hours after injection of cetuximab-ICG. There was a direct relationship between fluorescence and the given dose of cetuximab-ICG. Following subtotal resection, we found fluorescence correlated with a sensitivity of 78.4% and specificity of 96%.This study provides evidence that supports further preclinical investigation of cetuximab in the evaluation of surgical margins, but linkage to ICG lacks the sensitivity for use in a clinical setting.

    View details for DOI 10.1016/j.otohns.2007.06.736

    View details for Web of Science ID 000250821700007

    View details for PubMedID 17967636

  • Etiology of late free flap failures occurring after hospital discharge LARYNGOSCOPE Wax, M. K., Rosenthal, E. 2007; 117 (11): 1961-1963


    Vascular compromise of free flaps most commonly occurs in the immediate postoperative period in association with failure of the microvascular anastomosis. Rarely do flaps fail in the late postoperative period. It is not well understood why free flaps can fail after 7 postoperative days. We undertook a case review series to assess possible causes of late free flap failure.Retrospective review at two tertiary referral centers: Oregon Health Sciences University and University of Alabama at Birmingham.A review of 1,530 flaps performed in 1,592 patients between 1998 and 2006 were evaluated to identify late flap failure. Late flap failure was defined as failure occurring after postoperative day 7 or on follow-up visits after hospital discharge. A prospective database with the following variables was examined: age, medical comorbidities, postreconstructive complications (fistula or infection), hematoma, seroma, previous surgery, radiation therapy, intraoperative findings at the time of debridement, nutrition, and, possibly, etiologies.A total of 13 patients with late graft failure were identified in this study population of 1,530 (less than 1%) flaps; 6 radial forearm fasciocutaneous flaps, 2 rectus abdominis myocutaneous flaps, 4 fibular flaps, and 1 latissimus dorsi myocutaneous flap underwent late failure. The time to necrosis was a median of 21 (range, 7-90) days. Etiology was believed to possibly be pressure on the pedicle in the postoperative period in four patients (no sign of local wound issues at the pedicle), infection (abscess formation) in three patients, and regrowth of residual tumor in six patients. Loss occurring within 1 month was more common in radial forearm flaps and was presented in the context of a normal appearing wound at the anastomotic site, as opposed to loss occurring after 1 month, which happened more commonly in fibula flaps secondary to recurrence.Although late free flap failure is rare, local factors such as infection and possibly pressure on the pedicle can be contributing factors. Patients presenting with late flap failure should be evaluated for residual tumor growth.

    View details for DOI 10.1097/MLG.0b013e31812e017a

    View details for Web of Science ID 000250663000013

    View details for PubMedID 17828052

  • Targeting of a conditionally replicative adenovirus agent to human squamous cell carcinomas of the head and neck INTERNATIONAL JOURNAL OF ONCOLOGY Zhu, Z. B., Mathis, J. M., Makhija, S. K., Lu, B., Wang, M., Ji, S., Rivera, A. A., Rosenthal, E. L., Siegal, G. P., Curiel, D. T. 2007; 31 (5): 1213-1222


    Conventional cancer treatments are not adequate for the majority of most patients stricken with squamous cell carcinomas of the head and neck (SCCHN). Conditionally replicating adenoviruses (CRAds) represent a promising new modality for treating of neoplastic diseases, including SCCHN. Specifically, CRAd agents infect tumor cells and selectively replicate within them, thus causing their death while sparing surrounding normal cells in the host. Oncolysis results from the replicative life cycle of the virus, which lyses infected tumor cells and releases viral progeny for propagation of infection and resultant lysis of neighboring cancer cells, sparing normal host cells. However, to date there have been two main limitations to successful clinical application of these CRAd agents: poor infectivity and poor tumor specificity. Here we report the construction of a CRAd agent, CRAd-CXCR4.F5/3, in which the adenovirus E1 gene is driven by a tumor-specific CXCR4 promoter, and the viral infectivity is enhanced by a fiber modification, F5/3, containing an Ad3 knob chimeric fiber protein. As expected, this agent improved both of the viral infectivity and tumor specificity as evaluated in established SCCHN tumor cell lines and in primary tumor tissues from multiple patients. As an added benefit, the activity of the CXCR4 promoter was low in human liver as described previously. Based on these data, the CRAd-CXCR4.F5/3 is a promising novel CRAd agent for SCCHN targeting with low host toxicity.

    View details for Web of Science ID 000250526100026

    View details for PubMedID 17912450

  • Fluorescently labeled cetuximab to evaluate head and neck cancer response to treatment CANCER BIOLOGY & THERAPY Gleysteen, J. P., Duncan, R. D., Magnuson, J. S., Skipper, J. B., Zinn, K., Rosenthal, E. L. 2007; 6 (8): 1181-1185


    Combining the therapeutic and diagnostic properties of targeted antibodies may improve clinical assessment of disease with limited added toxicity during treatment.Mice (n = 10) were xenografted with SCC-1 tumor cells and then treated with radiation, cisplatin and cetuximab. Brightfield and fluorescent imaging was performed after systemically injecting fluorescently labeled cetuximab prior to treatment and at six or ten weeks after initiation of treatment. The relative fluorescence intensity was determined for each image.The tumor luminosity measured before (week 0), during (week 6) and after treatment (week 10) did not significantly change. Actual tumor measurement corresponded to fluorescent measurements of tumors both before treatment and after treatment. Complete response to therapy occurred in one animal, where resolution of the tumor correlated with loss of fluorescent activity.This preclinical data suggests combining the diagnostic and therapeutic properties of cetuximab may be clinically useful.

    View details for Web of Science ID 000252666800018

    View details for PubMedID 17637562

  • Sensitivity and specificity of fluorescent immunoguided neoplasm detection in head and neck cancer xenografts ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Kulbersh, B. D., Duncan, R. D., Magnuson, J. S., Skipper, J. B., Zinn, K., Rosenthal, E. L. 2007; 133 (5): 511-515


    To determine whether fluorescently labeled anti-epidermal growth factor (EGFR) antibody could be used to detect residual disease and to guide surgical resections by comparing the sensitivity and specificity of optical fluorescence imaging with the sensitivity and specificity of histopathologic evaluation.A preclinical model of head and neck squamous cell carcinoma.Mice xenografted with SCC-1 tumor cells.The mice underwent systemic injection with anti-EGFR antibody (cetuximab) conjugated to an optically active fluorophore (Cy5.5). Both a subcutaneous flank model (n = 18) and an orthotopic murine model (n = 15) were used to assess for the presence of residual disease by fluorescent stereomicroscopy after subtotal resections of tumors. Histologic analysis was performed to confirm the presence or absence of disease.In the subcutaneous flank model, a diagnostic dose (50 microg) and therapeutic dose (250 microg) of fluorescent-labeled anti-EGFR were administered. When a diagnostic dose was given, the sensitivity was 86%, which was less than the 91% sensitivity when the higher dose was given. Tumor biopsy specimens in which disease was detected by histologic analysis but not by fluorescence (false-negative result) averaged 166 cells (range, 50-350 cells). The specificity of optical fluorescence to predict the presence of tumor in both groups was 100%. In the floor of the mouth model, we demonstrated a sensitivity of 81% and a specificity of 100%. False-negative results were obtained in a tumor fragment measuring less than 0.5 mm in diameter.These data support further investigation of fluorescently labeled anti-EGFR antibody to detect disease in the surgical setting.

    View details for Web of Science ID 000246522500013

    View details for PubMedID 17520766

  • Free tissue transfer to manage salvage laryngectomy defects after organ. preservation failure LARYNGOSCOPE Withrow, K. P., Rosenthal, E. L., Gourin, C. G., Peters, G. E., Magnuson, J. S., Terris, D. J., Carroll, W. W. 2007; 117 (5): 781-784


    Salvage laryngectomy to treat organ preservation failures results in significantly higher local wound complications. Even in the absence of extralaryngeal disease, primary closure of laryngeal defects can result in protracted wound care problems. We hypothesize that even when sufficient mucosa is present to close the defect primarily, introduction of vascularized tissue to close the defect may improve outcomes.Retrospective case-control study.Two academic tertiary care centers.Patients undergoing salvage surgery for laryngeal squamous cell carcinoma between 2000 to 2006 were considered for this study. Patients requiring total laryngopharyngectomy or partial pharyngectomy were excluded. There were 37 patients who met study criteria: 17 patients underwent free flap reconstruction (16 radial forearm flaps and 1 rectus flap), and 20 patients underwent primary closure. The median follow-up was 12 (range, 4-60) months. Previous treatment consisted of chemoradiation for 41% of the reconstruction group and 35% of the primary closure group; the remainder were treated with primary radiation alone.Pharyngocutaneous fistula, stricture, length of hospitalization, feeding tube dependence.The free flap reconstruction group had a lower rate of fistula (18%) compared with the primary closure group (50%). A lower rate of stricture formation (18% vs. 25%) and feeding tube dependence (23% vs. 45%) was observed in the free flap reconstruction group compared with the primary closure group. The development of a fistula in either group resulted in a prolonged hospital stay (mean, 19 vs. 7 days) and additional procedures.Planned reconstruction of salvage laryngectomy defects with vascularized tissue is associated with a lower fistula rate and may improve outcomes.

    View details for DOI 10.1097/MLG.0b013e3180332e39

    View details for Web of Science ID 000246141900004

    View details for PubMedID 17473668

  • Use of fluorescent labeled anti-epidermal growth factor receptor antibody to image head and neck squamous cell carcinoma xenografts MOLECULAR CANCER THERAPEUTICS Rosenthal, E. L., Kulbersh, B. D., King, T., Chaudhuri, T. R., Zinn, K. R. 2007; 6 (4): 1230-1238


    Physicians and surgeons rely on subtle tissue changes to detect the extent of tumors and the presence of residual disease in the clinical setting. The development of a cancer-specific fluorescent contrast agent has the potential to provide real-time tumor imaging in the clinic or operating room. Because epidermal growth factor receptor (EGFR) is highly overexpressed on the surface of head and neck squamous cell carcinoma (HNSCC), we sought to determine if fluorescently labeled anti-EGFR antibody could be used to image HNSCC xenografts in vivo. Cetuximab or control isotype-matched IgG1 was conjugated with the Cy5.5 fluorochrome and systemically injected into mice bearing human split thickness skin grafts, tumor cell line xenografts, transplanted human tumor xenografts, or mouse mesothelioma tumors. Xenografts were imaged by time-domain fluorescence imaging or fluorescence stereomicroscopy. Both imaging modalities detected specific uptake of cetuximab-Cy5.5 in HNSCC xenografts with significantly higher fluorescence levels relative to control IgG1-Cy5.5. Tumor xenograft fluorescence was higher compared with background (before injection), human split thickness skin grafts, or mouse mesothelioma tumors at 24, 48, and 72 h. Fluorescence was detected in multiple HNSCC tumor cell lines with variable EGFR expression levels. Mock resections of flank tumors using fluorescence stereomicroscopy showed that small (2 mm) specimens could be detected in the surgical wound bed. These results show the feasibility of using fluorescently labeled anti-EGFR antibody to detect human tumors in the surgical setting.

    View details for DOI 10.1158/1535-7160.MCT-06-0741

    View details for Web of Science ID 000245939000007

    View details for PubMedID 17431103

  • Current concepts in microvascular reconstruction OTOLARYNGOLOGY-HEAD AND NECK SURGERY Rosenthal, E., Couch, M., Farwell, D. G., Wax, M. K. 2007; 136 (4): 519-524

    View details for DOI 10.1016/j.otohns.2006.12.005

    View details for Web of Science ID 000245518600003

    View details for PubMedID 17418245

  • Influence of social support on health-related quality of life outcomes in head and neck cancer HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Karnell, L. H., Christensen, A. J., Rosenthal, E. L., Magnuson, J. S., Funk, G. F. 2007; 29 (2): 143-146


    Evidence that social support influences health-related quality of life (HRQOL) in oncologic patients could be particularly important for head and neck cancer because this disease can affect speech, eating, and facial aesthetics.Multiple regression analyses were used in this prospective, observational study to determine the association between 394 patients' ratings of perceived post-treatment social support and HRQOL outcomes while controlling for possible confounding variables.Higher social support scores were significantly associated with higher scores in speech (p = .007), aesthetics (p = .015), social disruption (p = .045), and general mental health (p = .016) and with fewer depressive symptoms (p = .023) but not with general physical health (p = .191) or eating (p = .114). The magnitude of differences in the HRQOL outcomes for patients whose social support scores fell in the lowest and highest quartiles were clinically meaningful.Given the association between social support and HRQOL outcomes in this patient population, modification of perceived social support through clinical interventions could improve the survivorship of these patients.

    View details for DOI 10.1002/hed.20501

    View details for Web of Science ID 000243697000008

    View details for PubMedID 17111431

  • In vivo detection of head and neck cancer orthotopic xenografts by immunofluorescence LARYNGOSCOPE Rosenthal, E. L., Kulbersh, B. D., Duncan, R. D., Zhang, W., Magnuson, J. S., Carroll, W. R., Zinn, K. 2006; 116 (9): 1636-1641


    To determine whether Cy5.5-labeled antiepidermal growth factor (EGFR) antibody could be used to detect head and neck squamous cell carcinoma (HNSCC) xenografts in vivo.AntiEGFR antibody (cetuximab) was labeled with Cy5.5, a fluorophore with emission in the near infrared range. The cetuximab-Cy5.5 conjugate was systemically administered in subtherapeutic doses (50 microg) to mice bearing orthotopically xenografted HNSCC cell lines (SCC1, CAL27, and FaDu). As a control, isotype-matched human immunoglobulin (Ig)G1k antibody labeled with Cy5.5 was systemically injected in parallel experiments. All tumor regions (n = 6) were imaged by fluorescent stereomicroscopy at 0, 6, 24, 48, or 72 hours. Tumor size was measured by high-frequency ultrasonography at 72 hours. Transcervical partial and near-total resections were then performed with stereomicroscopic imaging after each resection. The mandible and associated structures were then resected, paraffin embedded, and then serial sectioned for analysis.Tumors could be clearly visualized by near infrared fluorescent stereomicroscopy at 48 and 72 hours after systemic administration of cetuximab-Cy5.5 but not after administration with the labeled isotype control antibody, IgG1k-Cy5.5. Ultrasound measurement of tumors (n = 5) correlated with fluorescent measurements of tumor (Spearman's coefficient, 0.92, P

    View details for DOI 10.1097/01.mlg.0000232513.19873.da

    View details for Web of Science ID 000240326000022

    View details for PubMedID 16954995

  • Extracellular matrix metalloprotease inducer stimulates fibroblast-mediated tumor growth in vivo LARYNGOSCOPE Rosenthal, E. L., Vidrine, D. M., Zhang, W. 2006; 116 (7): 1086-1092


    Extracellular matrix metalloprotease inducer (EMMPRIN) is a molecule expressed on the cell surface of tumor cells that has been shown to induce both tumor cells and fibroblasts to express matrix metalloproteases in vitro. We hypothesize that fibroblasts are stimulated by EMMPRIN to create a microenvironment favorable to tumor growth.Case series review of laryngeal cancer and assessment of tumor cell lines in vivo.EMMPRIN immunoreactivity in 33 pathologic specimens from patients with supraglottic laryngeal cancer was correlated with clinicopathologic features and survival. The CAL 27 cell line was transfected with EMMPRIN (CAL 27E) or a control vector (CAL 27). Cells were xenografted into the flank of severe combined immunodeficient (SCID) mice with or without a co-injection of normal dermal fibroblasts (NDFs).Immunohistochemical detection of EMMPRIN in laryngeal cancer specimens demonstrated expression in all the tumors but not in adjacent, histologically normal mucosa. EMMPRIN membrane immunoreactivity (transmembrane EMMPRIN score) was associated with nodal positivity (P=.07), and it was associated with poorer survival (hazard ratio=2.4, 95% confidence interval 0.88, 6.55). As a categoric variable, higher EMMPRIN expression positively correlates with higher mortality. To determine whether EMMPRIN mediates tumor growth in vivo through fibroblast stimulation, EMMPRIN-expressing CAL 27 (CAL 27E) xenografted (n=20) onto the flank of SCID mice developed larger tumors than CAL 27 control vector transfected cells alone (n=20), but they were not significantly larger (P=.17). However, when CAL 27E cells were co-injected with NDFs, there was a statistically significant increase in tumor growth compared with the CAL 27 cells co-injected with NDFs (n=10, P=.0038).As a cell surface expressed protein that promotes tumor growth and high expression in head and neck squamous cell carcinoma but not in normal tissue, EMMPRIN may be a good target for directed molecular therapy.

    View details for DOI 10.1097/01.mlg.0000224368.58870.3c

    View details for Web of Science ID 000238873800004

    View details for PubMedID 16826041

  • Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity MOLECULAR CANCER RESEARCH Merrell, M. A., Ilvesaro, J. M., Lehtonen, N., Sorsa, T., Gehrs, B., Rosenthal, E., Chen, D., Shackley, B., Harris, K. W., Selander, K. S. 2006; 4 (7): 437-447


    Toll-like receptor 9 (TLR9) recognizes microbial DNA. We show here that TLR9 protein is expressed in human breast cancer cells and clinical breast cancer samples. Stimulation of TLR9-expressing breast cancer cells with the TLR9 agonistic CpG oligonucleotides (1-10 mumol/L) dramatically increased their in vitro invasion in both Matrigel assays and three-dimensional collagen cultures. Similar effects on invasion were seen in TLR9-expressing astrocytoma and glioblastoma cells and in the immortalized human breast epithelial cell line MCF-10A. This effect was not, however, dependent on the CpG content of the TLR9 ligands because the non-CpG oligonucleotides induced invasion of TLR9-expressing cells. CpG or non-CpG oligonucleotide-induced invasion in MDA-MB-231 cells was blunted by chloroquine and they did not induce invasion of TLR9(-) breast cancer cells. Treatment of MDA-MB-231 cells with CpG or non-CpG oligonucleotides induced the formation of approximately 50-kDa gelatinolytic band in zymograms. This band and the increased invasion were abolished by a matrix metalloproteinase (MMP) inhibitor GM6001 but not by a serine proteinase inhibitor aprotinin. Furthermore, CpG oligonucleotide treatment decreased tissue inhibitor of metalloproteinase-3 expression and increased levels of active MMP-13 in TLR9-expressing but not TLR9(-) breast cancer cells without affecting MMP-8. Neutralizing anti-MMP-13 antibodies inhibited the CpG oligonucleotide-induced invasion. These findings suggest that infections may promote cancer progression through a novel TLR9-mediated mechanism. They also propose a new molecular target for cancer therapy, because TLR9 has not been associated with cancer invasiveness previously.

    View details for DOI 10.1158/1541-7786.MCR-06-0007

    View details for Web of Science ID 000239215300002

    View details for PubMedID 16849519

  • Matrix metalloproteases in head and neck cancer HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Rosenthal, E. L., Matrisian, L. M. 2006; 28 (7): 639-648


    Matrix metalloproteases (MMPs) are a collection of enzymes capable of cleaving extracellular matrix components, growth factors, and cell-surface receptors. MMPs modulate most aspects of tumorigenesis and are highly expressed in cancer compared with normal tissues. Preclinical studies have demonstrated that head and neck squamous cell carcinomas (HNSCCs) express high levels of MMPs in vivo and that inhibition of these enzymes in vitro and in mouse models decreases invasion and metastasis. However, the clinical trials for MMP inhibitors have failed to demonstrate a significant survival advantage in most cancers. The disparity between preclinical and clinical studies has led to the reevaluation of how MMP functions in cancer and the design of clinical trials for molecularly targeted agents. Mouse model data and analysis of HNSCC tumor specimens suggests that membrane type-1 MMP (MT1-MMP) may be a critical enzyme in tumor cell invasion and survival in vivo. This accumulated data provide evidence for development of selective MT1-MMP inhibitors as therapy in HNSCC.

    View details for DOI 10.1002/hed.20365

    View details for Web of Science ID 000238690100011

    View details for PubMedID 16470875

  • Pretreatment, preoperative swallowing exercises may improve dysphagia quality of life LARYNGOSCOPE Kulbersh, B. D., Rosenthal, E. L., McGrew, B. M., Duncan, R. D., McColloch, N. L., Carroll, W. R., Magnuson, J. S. 2006; 116 (6): 883-886


    Dysphagia is commonly associated with head and neck cancer treatment. Traditional dysphagia management strategies focus on post-treatment therapy. This study evaluated the utility of pretreatment swallowing exercises in improving post-treatment swallowing quality of life (QOL).Prospective cohort study and cross-sectional QOL analysis.This study includes 37 patients who underwent primary radiation or combined chemoradiation treatment for newly diagnosed hypopharyngeal, laryngeal, or oropharyngeal primary tumors at the University of Alabama at Birmingham. Of the 37, 25 patients underwent swallowing exercises beginning 2 weeks prior to the start of radiation. The M.D. Anderson Dysphagia Inventory (MDADI) was administered an average of 14 months after treatment to assess the success of the protocol. Analysis of QOL scores related to gender, primary site, stage, and race were obtained.Patients who performed pretreatment swallowing exercises (n = 25) showed improvement in the overall MDADI score (P = .0002) compared to the control population (n = 12) who underwent post-treatment therapy. Furthermore, a separate analysis of individual domains of the MDADI (global, emotional, functional, and physical) demonstrated improved quality of life.Implementation of pretreatment swallowing education and exercise may improve dysphagia-specific QOL in head and neck cancer patients undergoing radiation and/or chemoradiation therapy.

    View details for DOI 10.1097/01.mlg.0000217278.96901.fc

    View details for Web of Science ID 000238031200007

    View details for PubMedID 16735913

  • Use of negative-pressure dressings to manage a difficult surgical neck wound. Ear, nose, & throat journal Shreenivas, S., Magnuson, J. S., Rosenthal, E. L. 2006; 85 (6): 390-391


    We used negative-pressure dressings to treat a poorly healing cervical rotation flap following radical neck dissection in an elderly man. The wound had failed to heal properly after 2 weeks of conservative management. Following application of the negative-pressure dressings, the wound granulated quickly and healed well by secondary intention.

    View details for PubMedID 16866117

  • Promotion of acellular dermal matrix resolution in vitro by matrix metalloproteinase-2 ARCHIVES OF FACIAL PLASTIC SURGERY Lindman, J. P., Talbert, M., Zhang, W., Powell, B., Accortt, N. A., Rosenthal, E. L. 2006; 8 (3): 208-212


    To determine whether acellular human dermis is degraded by matrix metalloproteinases (MMPs), a large class of matrix-degrading enzymes.The degradation of acellular human dermis specimens was evaluated in vitro. Wild-type murine fibroblasts with a broad-spectrum MMP inhibitor, GM6001, and MMP-2-deficient fibroblasts were placed on the basement membrane and dermal surfaces of acellular human dermis. Matrix degradation and fibroblast infiltration into the matrix were assessed after a 20-day incubation period.The basement membrane thickness of the specimens cultured with wild-type fibroblasts was significantly less than that of specimens cultured with GM6001 (P<.001), and the infiltration of fibroblasts into the dermal surface was limited by the addition of GM6001 (P=.002). To determine whether MMP-2 was involved in this in vitro phenotype, MMP-2-deficient fibroblasts were assessed in comparison with wild-type fibroblasts. Wild-type fibroblasts degraded the basement membrane surface (P<.001) and infiltrated the dermal surface (P = .003) more efficiently than did MMP-2-deficient fibroblasts.The results from our in vitro experiments suggest that MMPs and specifically MMP-2 may play an important role in the resorption of acellular human dermis. Addition of MMP inhibitors to implanted dermal matrices may slow fibroblast infiltration and improve their longevity in vivo.

    View details for Web of Science ID 000237543300008

    View details for PubMedID 16702534

  • Persistent posttreatment depressive symptoms in patients with head and neck cancer. Head & neck Karnell, L. H., Funk, G. F., Christensen, A. J., Rosenthal, E. L., Magnuson, J. S. 2006; 28 (5): 453-461


    This study examined the prevalence and risk factors of persistent (versus short-term) depressive symptoms in patients with head and neck cancer.Patients with 10+ and 18+ posttreatment Beck Depression Inventory scores for 6 or more months during their first year were identified. Regression analyses determined risk factors associated with persistently high scores.Of the 148 patients, 25.0% and 7.4% were persistently above the 10+ and 18+ cutoff scores, respectively (compared with 33.6% to 44.2% and 9.2% to 18.6% when measured at single points across this time period.) The strongest predictor of persistent posttreatment depressive symptoms was pretreatment depressive symptoms.The percentage of patients with persistently high levels of depressive symptoms, although considerable, is substantially lower when patients with transient mood disorders are omitted. A screening tool that determines high levels of pretreatment depressive symptoms could identify patients at high risk of experiencing posttreatment depression who would be good candidates for clinical intervention.

    View details for PubMedID 16320360

  • Expandable tracheal stenting for Benign disease: Worth the complications? ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY Eller, R. L., Livingston, W. J., Morgan, C. E., Peters, G. E., Sillers, M. J., Magnuson, J. S., Rosenthal, E. L. 2006; 115 (4): 247-252


    To characterize the limitations of self-expandable stents in the management of benign tracheal stenosis, we performed a retrospective review at a tertiary care medical center.Patients who underwent tracheal stenting were assessed for the cause and severity of tracheal stenosis, comorbidities, stent-related complications, and follow-up airway procedures.Sixteen adults (12 women, 4 men; mean age, 47 years) had a total of 26 stents placed for benign disease. Intubation-related stenoses were most frequent (81%). The average follow-up time was 20 months (range, 1 to 40 months). Each stent remained functional for an average of 12.4 months. In the study group, 87% had a complication that required surgical intervention to maintain a patent airway. The most common problem was granulation tissue formation at the ends of the stent causing airway restenosis (81%), and 5 patients (31%) required tracheotomy as a result of restenosis around the stent. Fourteen of the stents (56%) were removed or expelled from the patients.The implantation of self-expandable stents is a minimally invasive method of managing benign tracheal stenosis. Although a small subset of patients may benefit from placement, the majority of patients have complications that require intervention to maintain a patent airway. Thoughtful discretion is critical in selecting patients for this intervention.

    View details for Web of Science ID 000236820900001

    View details for PubMedID 16676820

  • Fibroblast-derived MT1-MMP promotes tumor progression in vitro and in vivo BMC CANCER Zhang, W. Y., Matrisian, L. M., Holmbeck, K., Vick, C. C., Rosenthal, E. L. 2006; 6


    Identification of fibroblast derived factors in tumor progression has the potential to provide novel molecular targets for modulating tumor cell growth and metastasis. Multiple matrix metalloproteases (MMPs) are expressed by both mesenchymal and epithelial cells within head and neck squamous cell carcinomas (HNSCCs), but the relative importance of these enzymes and the cell source is the subject of controversy.The invasive potential of HNSCC tumor cells were assessed in vitro atop type I collagen gels in coculture with wild-type (WT), MMP-2 null, MMP-9 null or MT1-MMP null fibroblasts. A floor of mouth mouse model of HNSCC was used to assess in vivo growth after co-injection of FaDu tumor cells with MMP null fibroblasts.Here we report changes in tumor phenotype when FaDu HNSCCs cells are cocultured with WT, MMP-2 null, MMP-9 null or MT1-MMP null fibroblasts in vitro and in vivo. WT, MMP-2 null and MMP-9 null fibroblasts, but not MT1-MMP null fibroblasts, spontaneously invaded into type I collagen gels. WT fibroblasts stimulated FaDu tumor cell invasion in coculture. This invasive phenotype was unaffected by combination with MMP-9 null fibroblasts, reduced with MMP-2 null fibroblasts (50%) and abrogated in MT1-MMP null fibroblasts. Co-injection of FaDu tumor cells with fibroblasts in an orthotopic oral cavity SCID mouse model demonstrated a reduction of tumor volume using MMP-9 and MMP-2 null fibroblasts (48% and 49%, respectively) compared to WT fibroblasts. Consistent with in vitro studies, MT1-MMP null fibroblasts when co-injected with FaDu cells resulted in a 90% reduction in tumor volume compared to FaDu cells injected with WT fibroblasts.These data suggest a role for fibroblast-derived MMP-2 and MT1-MMP in HNSCC tumor invasion in vitro and tumor growth in vivo.

    View details for DOI 10.1186/1471-2407-6-52

    View details for Web of Science ID 000237140600001

    View details for PubMedID 16515711

  • Validation of ultrasonography to evaluate murine orthotopic oral cavity tumors ORL-JOURNAL FOR OTO-RHINO-LARYNGOLOGY AND ITS RELATED SPECIALTIES Pezold, J. C., Zinn, K., Talbert, M. A., Desmond, R., Rosenthal, E. L. 2006; 68 (3): 159-163


    The murine orthotopic oral cavity tumor model allows evaluation of tumor growth and invasion. Currently, serial measurements of tissue growth are difficult to obtain since invasive procedures or animal sacrifice is necessary to evaluate tumor size. High-resolution ultrasound was evaluated as a noninvasive method to monitor tumor size in vivo.Sixteen immunodeficient mice, age 9 weeks, were injected transcervically with a human squamous cell carcinoma cell line into the tongue, and tumor volume was assessed by high-frequency ultrasound at 11 days. The animals were subsequently sacrificed and the tumors processed for histology. Tumor size was then calculated by caliper measurement in two dimensions.Tumor dimensions obtained using ultrasound were found to significantly correlate with the histologic measurements (Spearman coefficient 0.90, p < 0.0001). Tumor dimensions were on average larger using ultrasound versus histologic measurements, although this was not significantly different than zero (95% confidence interval -13.96 to 62.37 mm2).High-resolution ultrasound accurately measures tumor volume in the murine orthotopic oral cavity tumor model without sacrifice.

    View details for DOI 10.1159/000091324

    View details for Web of Science ID 000235580500008

    View details for PubMedID 16465070

  • Resynchronization therapy in pediatric and congenital heart disease patients - An international multicenter study JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Dubin, A. M., Janousek, J., Rhee, E., Strieper, M. J., Cecchin, F., Law, I. H., Shannon, K. M., Temple, J., Rosenthal, E., Zimmerman, F. J., Davis, A., Karpawich, P. P., Al Ahmad, A., Vetter, V. L., Kertesz, N. J., Shah, M., Snyder, C., Stephenson, E., Emmel, M., Sanatani, S., Kanter, R., Batra, A., Collins, K. K. 2005; 46 (12): 2277-2283


    Our objective was to evaluate the short-term safety and efficacy of cardiac resynchronization therapy (CRT) in children.Cardiac resynchronization therapy has been beneficial for adult patients with poor left ventricular function and intraventricular conduction delay. The efficacy of this therapy in the young and in those with congenital heart disease (CHD) has not yet been established.This is a multi-center, retrospective evaluation of CRT in 103 patients from 22 institutions.Median age at time of implantation was 12.8 years (3 months to 55.4 years). Median duration of follow-up was four months (22 days to 1 year). The diagnosis was CHD in 73 patients (71%), cardiomyopathy in 16 (16%), and congenital complete atrioventricular block in 14 (13%). The QRS duration before pacing was 166.1 +/- 33.3 ms, which decreased after CRT by 37.7 +/- 30.7 ms (p < 0.01). Pre-CRT systemic ventricular ejection fraction (EF) was 26.2 +/- 11.6%. The EF increased by 12.8 +/- 12.7 EF units with a mean EF after CRT of 39.9 +/- 14.8% (p < 0.05). Of 18 patients who underwent CRT while listed for heart transplantation, 3 improved sufficiently to allow removal from the transplant waiting list, 5 underwent transplant, 2 died, and 8 others are currently awaiting transplant.Cardiac resynchronization therapy appears to offer benefit in pediatric and CHD patients who differ substantially from the adult populations in whom this therapy has been most thoroughly evaluated to date. Further studies looking at the long-term benefit of this therapy in this population are needed.

    View details for DOI 10.1016/j.jacc.2005.05.096

    View details for Web of Science ID 000234090600017

    View details for PubMedID 16360058

  • Use of negative pressure dressings in head and neck reconstruction HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Rosenthal, E. L., Blackwell, K. E., McGrew, B., Carroll, W. R., Peters, G. E. 2005; 27 (11): 970-975


    Head and neck microvascular surgery commonly requires management of complex wounds of the upper aerodigestive tract and donor sites. Negative pressure dressings have been reported to promote healing in compromised wounds.Between February 2001 and June 2004, data were collected in a retrospective manner on 23 patients who underwent treatment with negative pressure dressings at two tertiary care institutions.Twenty-three patients underwent negative pressure wound treatment for donor site complications (n = 9) or head and neck wounds (n = 14) with a minimum of 5 months follow-up. Average duration of treatment was 6.5 days. Indications for use in wound complications included wound breakdown (n = 3), fistula with carotid exposure (n = 4), tendon exposure of donor site (n = 6), and others (n = 3). On average, granulation tissue was promoted in across 93% of the wound bed over the course of treatment. Two patients with anterior mandibular hardware exposure were managed successfully with negative pressure dressings. Large split-thickness skin grafts (average size, 135 cm2) at mobile sites were bolstered with negative pressure dressings in seven patients with an overall take rate of 74%.Although of limited use as a bolster for split-thickness skin grafts, negative pressure dressings are safe and effective in the management of complex head and neck wounds and in the treatment of donor site complications.

    View details for DOI 10.1002/hed.20265

    View details for Web of Science ID 000232826000007

    View details for PubMedID 16127668

  • Radial forearm osteocutaneous free flap in maxillofacial and oromandibular reconstructions LARYNGOSCOPE Kim, J. H., Rosenthal, E. L., Ellis, T., Wax, M. K. 2005; 115 (9): 1697-1701


    The radial forearm osteocutaneous free flap is an excellent reconstructive modality for oromandibular and maxillofacial reconstruction in certain well-defined circumstances. The initial concern over donor site morbidity and the ability of the bone to reconstruct mandibular defects have led to only a few published series.Retrospective study of the experience of two tertiary medical centers with radial forearm osteocutaneous free flap.Retrospectively, 52 patients were studied who underwent radial forearm osteocutaneous free flap reconstruction for cancer (49 cases) and trauma (3 cases). Bone length and skin paddle harvested, general morbidity (hematoma, wound infection, and dehiscence), recipient site morbidity (nonunion of neomandible, flap failure, and bone or plate exposure), and donor site morbidity (radius bone fracture, plate exposure, and skin graft failure) were reviewed.The average skin paddle size was 55.1 cm (range, 15-112 cm). The average radius bone harvest length was 6.3 cm (range, 2.5-11 cm). Donor site complications included tendon exposure (3 cases), radius bone fracture (1 case), and exposure of the plate (0). Recipient site complications included nonunion of the mandible (4), exposed mandible (1), exposed mandibular plates (2), exposed maxillary plates or bone (0), venous compromise (1), and flap failure (1). Two patients had perioperative deaths.Radial forearm osteocutaneous free flap is a valuable and viable option for oromandibular and maxillofacial reconstruction.

    View details for DOI 10.1097/01.mlg.0000174952.98927.9f

    View details for Web of Science ID 000232047100032

    View details for PubMedID 16148720

  • A comparison of negative-pressure dressings versus bolster and splinting of the radial forearm donor site OTOLARYNGOLOGY-HEAD AND NECK SURGERY Vidrine, D. M., Kaler, S., Rosenthal, E. L. 2005; 133 (3): 403-406


    Negative-pressure dressings (NPDs) have been reported to improve split-thickness skin graft survival in some settings; we assessed whether NPDs could improve skin graft results in radial forearm donor sites.Between October 2003 and November 2004, 45 radial forearm donor sites underwent split-thickness skin graft immobilization either with conventional bolster dressing and splint or with an NPD. Split-thickness skin graft take was recorded at 1 and 4 weeks postoperatively.Overall split-thickness skin graft healing was improved in the NPD group (92%) compared with the case of conventional splinting (81%) at 4 weeks (P = .10). The rate of major graft loss was less in NPDs (10%) compared with the case of conventional management (28%) after 4 weeks (P = .06).Split-thickness skin graft survival was significantly improved by the use of NPDs. Because the use of NPDs is expensive, we consider their use only in patients with potential wound-healing problems, when there is a need to monitor the hand, or when immediate postoperative hand immobilization might impede the patient's recovery.

    View details for DOI 10.1016/j.otohns.2005.04.028

    View details for Web of Science ID 000231748100019

    View details for PubMedID 16143190

  • Extracellular matrix metalloprotease inducer-expressing head and neck squamous cell carcinoma cells promote fibroblast-mediated type I collagen degradation In vitro MOLECULAR CANCER RESEARCH Rosenthal, E. L., Zhang, W. Y., Talbert, M., Raisch, K. P., Peters, G. E. 2005; 3 (4): 195-202


    Until recently, tumor progression has been considered a multistep process defined by tumor cell mutations and the importance of the surrounding stroma poorly understood. It is now recognized that matrix-degrading enzymes that promote tumor cell invasion are elaborated by both tumor cells and fibroblasts in vivo. To determine the relative role of tumor cell-derived proteases compared with fibroblast-derived proteases, coculture experiments were done with each cell type using an in vitro model of type I collagen degradation. Head and neck squamous cell carcinoma cells in coculture with normal dermal fibroblasts showed matrix degradation, but neither cell type alone produced this effect. Manipulating the in vitro coculture environment showed that collagenolysis in this model was a result of fibroblast-derived matrix metalloproteases (MMP). To explore the possible role of extracellular matrix metalloprotease inducer (EMMPRIN) in this interaction, transfection of EMMPRIN into a cell line with low endogenous EMMPRIN expression was done and showed a significant increase in collagenolysis. Inhibition of collagenolysis with a tissue inhibitor of metalloprotease-2 (TIMP-2) and a synthetic furin inhibitor was observed but not with TIMP-1, which suggested a possible role for membrane type-1 MMP. These results suggest that fibroblast-derived MMPs but not those from tumor cells are important for in vitro collagenolysis and that this process is promoted by tumor cell-expressed EMMPRIN.

    View details for Web of Science ID 000228439400002

    View details for PubMedID 15831673

  • Simplifying head and neck microvascular reconstruction HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Rosenthal, E., Carroll, W., Dobbs, M., Magnuson, J. S., Wax, M., Peters, G. 2004; 26 (11): 930-936


    Free-tissue transfer has become the preferred method of head and neck reconstruction but is a technique that is considered to use excessive hospital resources.This study is a retrospective review of 125 consecutive free flaps in 117 patients over a 16-month period at a tertiary care university hospital.Defects of the oral cavity/oropharynx (60%), midface (9%), hypopharynx (15%), or cervical and facial skin (16%) were reconstructed from three donor sites: forearm (70%), rectus (11%), and fibula (19%). Microvascular anastomoses were performed with a continuous suture technique or an anastomotic coupling device for end-to-end venous anastomoses. A single vein was anastomosed in 97% of tissue transfers. There were five flaps (4%) requiring exploration for vascular compromise, and the overall success rate was 97.6%. The major complication rate was 13%. Mean hospital stay was 7 days for all patients and 5 days for those with cutaneous defects. Combined ablative and reconstructive operative times were 6 hours 42 minutes, 7 hours 40 minutes, and 8 hours 32 minutes for forearm, rectus, and fibular free grafts, respectively. A subset of this patient series with oral cavity and oropharynx defects (76 patients; 58%) available for follow-up (74 patients) was assessed for deglutition. Forty-three patients (58%) had a regular diet, 22 patients (30%) had a limited diet or required supplemental tube feedings, and nine patients (12%) were dependent on tube feedings with a severely limited diet.This series suggests that most head and neck defects can be reconstructed by use of a simplified microvascular technique and a limited number of donor sites. Analysis of operative times and length of stay suggest improved efficiency with this approach to microvascular reconstruction. Complications and functional results are comparable to previously published results.

    View details for DOI 10.1002/hed.20076

    View details for Web of Science ID 000224792600002

    View details for PubMedID 15508120

  • Expression of proteolytic enzymes in head and neck cancer - Associated fibroblasts ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Rosenthal, E. L., McCrory, A., Talbert, M., Carroll, W., Magnuson, J. S., Peters, G. E. 2004; 130 (8): 943-947


    To elucidate tumor-stromal interactions during tumor invasion by assessing the expression of proteolytic enzymes by carcinoma-associated fibroblasts (CAFs) in vivo using complementary DNA (cDNA) array analysis.Tumor-associated stroma was isolated from tumor and adjacent mucosal specimens of the same patient by laser capture microdissection, and the messenger RNA (mRNA) was assessed by cDNA microarray specific for proteolytic enzymes and their inhibitors. Protein overexpression was then analyzed by immunoblotting of primary fibroblast isolates derived from skin, mucosa, and tumor specimens.Array analysis of 4 tumor and 4 adjacent mucosal samples demonstrated significant (2.6-fold) overexpression of membrane type 1 matrix metalloproteinase (MT1-MMP) but not of serine proteases or other matrix metalloproteinases. Analysis of normal dermal fibroblasts, normal mucosal fibroblasts, and CAFs similarly demonstrated up-regulation of MT1-MMP.These results suggest that MT1-MMP mRNA is specifically up-regulated in CAFs in vivo whereas MT1-MMP protein is specifically up-regulated in CAFs in vitro. Known to induce tumor cell invasion when expressed in tumor cells, CAF expression of MT1-MMP may be important in the stromal response to tumor cells that characterizes the desmoplastic reaction.

    View details for Web of Science ID 000223138800006

    View details for PubMedID 15313864

  • Elevated expression of TGF-beta 1 in head and neck cancer - Associated fibroblasts MOLECULAR CARCINOGENESIS Rosenthal, E., McCrory, A., Talbert, M., Young, G., Murphy-Ullrich, J., Gladson, C. 2004; 40 (2): 116-121


    Head and neck cancers are characterized by a vigorous desmoplastic response, but the contribution of stromal-derived growth factors to the tumor microenvironment is poorly understood. We evaluated the expression of stromal growth factor expression in head and neck squamous cell carcinoma (HNSCC) in normal and tumor-associated stromal cells. Stromal tissue was isolated from epithelial cells with laser capture microdissection (LCMD) and analyzed by cDNA array for the expression of TGFalpha, TGF-beta1, HGF, PDGF-alpha, IGFII, bFGF, aFGF, VEGFC, and VEGF. Primary fibroblasts were isolated in vitro from HNSCC tumors, adjacent histologically normal mucosa, and skin in vitro. Fibroblast populations were assessed for TGF-beta1 expression by ELISA and luciferase reporter assay to assess protein expression. We identified TGF-beta1 and IGFII overexpression in normal and tumor-associated stromal cells; however, only TGF-beta1 was significantly overexpressed (3.4-fold) in tumor-associated stroma. Assessment of carcinoma-associated fibroblasts (CAFs), normal dermal fibroblasts (NDFs), and normal mucosal fibroblasts (NMFs) in propagated fibroblasts demonstrated persistently elevated levels of TGF-beta1 in CAFs compared to NMF and NDF populations. Elevated levels of TGF-beta1 were identified in the stromal compartment of HNSCC tumors compared to normal mucosa by immunohistochemical analysis. These results suggest that TGF-beta1 mRNA and protein is specifically upregulated in CAFs in vitro and in vivo.

    View details for DOI 10.1002/mc.20024

    View details for Web of Science ID 000221811700005

    View details for PubMedID 15170816

  • Breast cancer cells with inhibition of p38 alpha have decreased MMP-9 activity and exhibit decreased bone metastasis in mice CLINICAL & EXPERIMENTAL METASTASIS Suarez-Cuervo, C., Merrell, M. A., Watson, L., Harris, K. W., Rosenthal, E. L., Vaananen, H. K., Selander, K. 2004; 21 (6): 525-533


    p38 belongs to a family of mitogen-activated protein kinases, which transfer extracellular signals into intracellular responses. p38 is also frequently detected in clinical breast cancer specimens, but its role as a prognostic factor is not known. Of the various p38 isoforms, p38alpha has been shown to mediate the in vitro invasiveness of breast cancer cells through up-regulation of urokinase plasminogen activator (uPA). We studied the role of p38alpha in breast cancer bone metastases, using dominant negative blockade approach. Human MDA-MB-231 breast cancer clones stably expressing dominant negative p38alpha (p38/AF) exhibited decreased basal MMP-9 activity. TGF-beta1-induced MMP-9 activity was also blunted in these clones, as compared with controls in which TGF-betal up-regulated MMP-9 activity. Consistent with these findings, SB202190, a specific p38 inhibitor, also inhibited TGF-beta1-induced MMP-9 activity in parental cells. The p38/AF clones exhibited also reduced uPA production after growth on vitronectin and decreased cell motility, as compared with controls. VEGF production levels in all the studied clones were similar. The p38/AF clone, which had similar in vitro growth rate as the control pcDNA3 clone, formed significantly less bone metastases in a mouse model, as compared with the control clone. In conclusion, inhibition of the p38alpha pathway results in decreased MMP-9 activity, impaired uPA expression and decreased motility, all of which may contribute to the decreased formation of bone metastasis.

    View details for Web of Science ID 000226108100006

    View details for PubMedID 15679050

  • The role of free tissue transfer in the reconstruction of massive neglected skin cancers of the head and neck. Archives of facial plastic surgery Wax, M. K., Burkey, B. B., Bascom, D., Rosenthal, E. L. 2003; 5 (6): 479-482


    Most skin cancers involving the head and neck region are easily managed with surgical resection and local flap rotation. Occasional patients present with massive neglected skin cancers or skin cancers that have recurred after multiple treatments. Management of these massive tumors may involve craniofacial resection, maxillectomy, or mandibulectomy to obtain clear margins. Reconstruction requires massive composite soft tissue replacement. We presented our experience with, to our knowledge, the largest series reported to date.A retrospective chart review of 43 patients with massive neglected skin cancer of the head and neck reconstructed by means of free tissue transfer from January 1, 1992, through October 1, 2001.Academic tertiary referral medical center.Seventeen patients with squamous cell carcinoma and 26 patients with basal cell carcinoma were treated. Primary sites included the cheek (n = 15), ear (n = 8), forehead (n = 5), neck (n = 4), scalp (n = 5), and nose (n = 6). Treatment involved a combination of orbital exenteration (n = 16), maxillectomy (n = 12), mandibulectomy (n = 6), auriculectomy (n = 5), craniofacial resection (n = 10), rhinectomy (n = 6), and lateral temporal bone excision (n = 5). Flaps used for reconstruction included the rectus abdominis (n = 22), latissimus dorsi (n = 11), radial forearm (n = 8), and lateral arm (n = 2). Radiotherapeutic exposure included pretreatment in 21 patients and posttreatment in 15. Twelve patients had undergone no previous surgeries; 15 patients, 1 to 5; and 16 patients, more than 5. Follow-up revealed evidence of local recurrence (n = 12), locoregional recurrence (n = 3), distant metastasis (n = 3), and no evidence of disease (n = 25).Massive skin cancers are generally associated with disfiguring, debilitating surgery and high mortality rates. We demonstrate that free tissue transfer yields acceptable survival with functional and cosmetic outcomes.

    View details for PubMedID 14623684

  • Expression of extracellular matrix metalloprotease inducer in laryngeal squamous cell carcinoma LARYNGOSCOPE Rosenthal, E. L., Shreenivas, S., Peters, G. E., Grizzle, W. E., Desmond, R., Gladson, C. L. 2003; 113 (8): 1406-1410


    Head and neck cancer tumor cell invasion is responsible for both local destruction and distant metastasis. Invasion is largely mediated by matrix metalloproteases that are thought to be induced by tumor cell derived extracellular matrix metalloprotease inducer (EMMPRIN) in surrounding fibroblasts. We hypothesize that EMMPRIN is overexpressed in laryngeal cancer.Retrospective analysis of patients with supraglottic laryngeal cancer.Total protein immunoblotting and immunohistochemical analysis of normal and malignant tissue were performed to determine EMMPRIN expression. EMMPRIN immunoreactivity in 33 patients was correlated with clinicopathological features and survival.Whole-tissue lysates of tumors (n = 8) and metastatic lymph nodes (n = 2), but not normal skin (n = 8) or mucosa (n = 6), expressed significant amounts of EMMPRIN by immunoblotting. EMMPRIN membrane immunoreactivity (transmembrane EMMPRIN score) was associated with nodal positivity (P =.07), and it was a borderline significant predictor of survival (Hazards Ratio = 2.4; 95% CI, 0.88-6.55). As a categorical variable, higher transmembrane EMMPRIN score was associated with higher mortality.The present study helps to establish EMMPRIN as a widely expressed protein in dysplastic mucosa and supraglottic laryngeal cancer, but not in normal epithelial counterparts.

    View details for Web of Science ID 000184790900023

    View details for PubMedID 12897567

  • Three-dose vs extended-course clindamycin prophylaxis for free-flap reconstruction of the head and neck ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Carroll, W. R., Rosenstiel, D., Fix, J. R., de la Torre, J., Solomon, J. S., Brodish, B., Rosenthal, E. L., Heinz, T., Niwas, S., Peters, G. E. 2003; 129 (7): 771-774


    Twenty-four hours of perioperative antibiotics provides effective prophylaxis for most head and neck cancer resections. Many reconstructive surgeons have been hesitant to apply this standard to free-flap reconstruction of the head and neck. This prospective clinical trial compared short-course and long-course clindamycin prophylaxis for wound infection in patients with head and neck cancer undergoing free-flap reconstruction.Seventy-four patients were randomized to receive short-course (3 doses) or long-course (15 doses) clindamycin perioperatively. Wound infections, fistulas, and other postoperative complications were documented by faculty surgeons who were blinded as to treatment group.The differences in wound infections and other complications were statistically insignificant. No other independent predictors of wound complications emerged in this series of patients.Short-course clindamycin is as effective as long-course clindamycin in preventing wound infections after free-flap surgery for head and neck ablative defects.

    View details for Web of Science ID 000184104400015

    View details for PubMedID 12874080

  • Duplicate publications in the otolaryngology literature LARYNGOSCOPE Rosenthal, E. L., Masdon, J. L., Buckman, C., Hawn, M. 2003; 113 (5): 772-774


    A duplicate publication duplicates other published work by the same author(s). The purpose of the study was to define the extent of this problem within the otolaryngology literature.Retrospective review of the literature.Original articles published in Archives of Otolaryngology-Head and Neck Surgery and Laryngoscope in 1999 were reviewed using the OVID search engine. Titles and abstracts from English articles written by the same first, second, or last author were analyzed, and suspected publications were evaluated. Duplicate publications were classified as dual (identical data set and conclusions) or suspected dual (nearly identical data set and conclusions) publications.Of the 492 articles evaluated, 40 index articles were identified. These led to a total of 42 (8.5%) duplicate articles of which 27 were classified as dual and 15 as suspected dual publications. Approximately half of the duplicate publications were published by authors in the United States (55%). Duplicate articles usually appeared within 12 months of the each other (74%) and failed to cross-reference the earlier publication (83%).Journal editors have become aware of an increase in the number of duplicate publications in the medical literature. The incidence of duplicate publications in the otolaryngology literature appears to be similar to that in other specialties.

    View details for Web of Science ID 000182729200002

    View details for PubMedID 12792309

  • The ulnar fasciocutaneous free flap in head and neck reconstruction LARYNGOSCOPE Wax, M. K., Rosenthal, E. L., Winslow, C. P., Bascom, D. A., Andersen, P. E. 2002; 112 (12): 2155-2160


    The radial forearm fasciocutaneous free flap has become the reconstructive tissue of choice for the majority of soft tissue defects in the head and neck. The forearm skin has many of the ideal soft tissue characteristics that optimize reconstruction and rehabilitation in these patients. The tissue is malleable, supple, and moldable in three dimensions; has a reliable pedicle; and can be harvested with a two-team approach. In some patients, the radial forearm cannot be used. An alternative is to use the adjacent tissue, which shares identical tissue characteristics. This tissue gets its vascular supply from the ulnar artery. The purpose of the report was to describe the authors' experience with the ulnar fasciocutaneous free flap in head and neck reconstruction.Prospective consecutive case series.Retrospective review of all patients undergoing ulnar fasciocutaneous free tissue transfer by a group of microvascular surgeons was performed. Thirty patients underwent free tissue transfer using the ulnar fasciocutaneous free flap. The male-to-female ratio was 3:1.Defects were located in the oral cavity (14), oropharynx (12), neck skin (1), and soft tissue of the lateral skull (3). The average size of the skin paddle that was transferred was 7 x 10 cm (range, 3 x 5 to 9 x 12 cm). The mean area of tissue that was transferred was 70 cm2 (range, 15-108 cm2). Vessel sizes were somewhat smaller than the comparable radial forearm. One patient had complete loss of the skin graft on the donor site. There were no median nerve or other wound-healing problems. Two flaps were lost in the postoperative period. Indications for use of the ulnar fasciocutaneous free flap were failed Allen's test (23), use of a less hairy part of the forearm (3), and surgical preference (4).The ulnar fasciocutaneous free flap has all of the tissue characteristics of the radial forearm flap. When a radial forearm flap cannot be used and forearm skin is desired, consideration of an ulnar fasciocutaneous free flap should be undertaken.

    View details for Web of Science ID 000179755900005

    View details for PubMedID 12461332

  • Surgical management of gastroesophageal reflux and outcome after laryngectomy in patients using tracheoesophageal speech AMERICAN JOURNAL OF SURGERY Jobe, B. A., Rosenthal, E., Wiesberg, T. T., Cohen, J. I., Domreis, J. S., Deveney, C. W., Sheppard, B. 2002; 183 (5): 539-543


    Gastroesophageal reflux disease (GERD) is common in patients with head and neck carcinoma. The impact of laparoscopic fundoplication on laryngectomy patients with tracheoesophageal prostheses for voice restoration is unknown.Nine laryngectomy patients who use tracheoesophageal speech underwent laparoscopic fundoplication for documented reflux. Preoperative and postoperative symptoms were recorded. Quality of speech was documented before and after fundoplication.Although 88% of patients had resolution of GERD symptoms, all developed bloating and hyperflatulence. There was no difference in quality of esophageal speech after laparoscopic fundoplication.Fundoplication in laryngectomy patients that use tracheoesophageal speech eliminates symptoms of gastroesophageal reflux and resolves regurgitation associated prosthesis erosion. Although nearly all patients are satisfied with outcome, there is a high incidence of postfundoplication bloating and hyperflatulence that may be life limiting. Poor quality tracheoesophageal speech should not be used as an indication for antireflux surgery.

    View details for Web of Science ID 000175894700010

    View details for PubMedID 12034388

  • Pulmonary atelectasis after reconstruction with a rectus abdominis free tissue transfer ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Wax, M. K., Rosenthal, E. L., Takaguchi, R., Cohen, J. I., Andersen, P. E., Futran, N. 2002; 128 (3): 249-252


    Atelectasis is one of the most common postoperative complications encountered in head and neck surgery. Risk factors include preexisting pulmonary disease, the procedure performed, and the length of anesthetic. Regional flaps used to reconstruct defects in the head and neck predispose to radiographic atelectasis. The rectus abdominis myocutaneous flap is usually transferred as a free tissue transfer. Harvesting the flap results in abdominal wall pain and postoperative splinting that may contribute to an increased development of atelectasis. To our knowledge, this issue has not been previously examined.Retrospective review.Fifty-three patients underwent rectus abdominis myocutaneous free flap reconstruction following major ablative procedures for head and neck cancer. The flap size ranged from 5 x 7 to 25 x 27 cm. Most flaps were 8 x 15 cm. The cutaneous area transferred ranged from 35 to 600 cm(2) (mean, 120 cm(2)). These patients were compared with a group of 53 patients who were matched for age, sex, length of the procedure, and stage of disease. Postoperative atelectasis was radiographically detected in 37 (70%) of the patients who underwent rectus abdominis myocutaneous free flap reconstruction vs 41 (77%) of the controls. Major atelectasis was not encountered in any patient in either group. Patients with a larger cutaneous paddle (>120 cm(2)) had a higher atelectasis score than patients with smaller cutaneous paddles (< or =120 cm(2)) (P =.02).The incidence of radiographic postoperative atelectasis in patients undergoing rectus abdominis myocutaneous free tissue transfer is high. The degree of atelectasis is small, and the clinical correlation and relevance are minimal.

    View details for Web of Science ID 000174388000007

    View details for PubMedID 11886338

  • Positron emission tomography in the evaluation of stage III and IV head and neck cancer HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Teknos, T. N., Rosenthal, E. L., Lee, D., Taylor, R., Marn, C. S. 2001; 23 (12): 1056-1060


    Detection of metastatic disease in head and neck cancer patients is critical to preoperative planning, because patients with distant metastasis will not benefit from surgical therapy. Conventional radiographic modalities, such as CT and MR, give excellent anatomic detail but poorly identify unenlarged lymph nodes harboring metastatic disease.A pilot study was conducted to evaluate the usefulness of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) detection of metastatic disease in patients with advanced-stage head and neck cancer.Total body FDG-PET imaging was performed in a prospective manner on 12 consecutive patients with a new diagnosis of stage III or IV mucosal squamous cell carcinoma of the head and neck. Chest CT was also performed on all 12 patients. Patients found to have metastatic disease on either CT or PET imaging underwent procedures to obtain histopathologic confirmation of disease.Three patients (25%) had FDG-PET scans demonstrating metastatic disease. Two of these patients had no evidence of disease on chest radiograph or chest CT but were noted to have positive FDG-PET imaging within the mediastinal lymphatics. Mediastinoscopy was performed confirming metastatic disease in these patients. The third patient had a peripheral lung lesion detected on chest radiograph, CT, and FDG-PET. This nodule was diagnosed by CT-guided biopsy as squamous cell carcinoma.FDG-PET scanning detected mediastinal disease in two patients (17%) with advanced-stage head and neck squamous cell carcinoma that was not identified with conventional imaging techniques. PET imaging seems to have significant potential in the detection of occult metastatic disease, particularly in the mediastinal lymphatics.

    View details for Web of Science ID 000172526900007

    View details for PubMedID 11774391

  • The mucosal invasion model - A novel in vitro model for evaluating the invasive behavior of mucocutaneous malignancies ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Rosenthal, E. L., Wax, M. K., Anderson, P., Kulecz-Martin, M. 2001; 127 (12): 1467-1470


    Prevention of regional and metastatic spread of cutaneous malignancies requires understanding the physiologic mechanism of tumor cell invasion. In vitro models are convenient for studying the in vitro invasive phenotype of normal cells, tumor cell lines, or genetically altered cells in a 3-dimensional matrix, but they should attempt to recapitulate the complex in vivo submucosal environment. A new acellular extracellular matrix, porcine submucosal matrix (PSM), is thought to accurately recapitulate the submucosal matrix. A novel in vitro model using PSM to assess mucocutaneous tumor cell invasion was studied.The morphologic characteristics, growth, and invasive behavior of human head and neck squamous cell carcinoma (UM-SCC-1, UM-SCC-5, UM-SCC-17B, and OSC-19) cell lines were assessed on the PSM gel and compared with commonly used in vitro invasion models (type I collagen and Matrigel matrices). The invasive phenotype of canine kidney cells was also assessed on each matrix, because this cell line is known to demonstrate a characteristic in vitro invasive phenotype.The PSM-supported head and neck squamous cell carcinoma tumor cell line growth and single cell invasion were seen under stimulated conditions, similar to type I collagen gels. The invasive phenotype of canine kidney cells behaved similarly on PSM and collagen. Matrigel did not support growth well, and invasion occurred only superficially in isolated areas.The PSM is a good in vitro model for assessment of pharmacologic and genetic manipulations of head and neck squamous cell carcinoma tumor cell lines and has several advantages over other commonly used matrices.

    View details for Web of Science ID 000172657600008

    View details for PubMedID 11735816

  • Emerging perceptions of facial plastic surgery among medical students OTOLARYNGOLOGY-HEAD AND NECK SURGERY Rosenthal, E., Clark, J. M., Wax, M. K., Cook, T. A. 2001; 125 (5): 478-482


    The purpose of this study was to examine the perceptions of medical students regarding facial aesthetic surgery and those specialists most likely to perform aesthetic or reconstructive facial surgery.A survey was designed based on a review of the literature to assess the desirable characteristics and the perceived role of the facial plastic and reconstructive surgeon (FPRS). The surveys were distributed to 2 populations: medical students from 4 medical schools and members of the general public.A total of 339 surveys were collected, 217 from medical students and 122 from the general public. Medical students and the public had similar responses. The results demonstrated that respondents preferred a male plastic surgeon from the ages of 41 to 50 years old and would look to their family doctor for a recommendation. Facial aesthetic and reconstructive surgery was considered the domain of maxillofacial and general plastic surgeons, not the FPRS.Integration of the FPRS into the medical school curriculum may help to improve the perceived role of the specialty within the medical community. It is important for the specialty to communicate to aspiring physicians the dedicated training of an otolaryngologist specializing in FPRS.

    View details for Web of Science ID 000172211300008

    View details for PubMedID 11700445

  • Role of membrane type 1-matrix metalloproteinase and gelatinase A in head and neck squamous cell carcinoma invasion in vitro OTOLARYNGOLOGY-HEAD AND NECK SURGERY Rosenthal, E. L., Hotary, K., Bradford, C., Weiss, S. J. 1999; 121 (4): 337-343


    The proteolytic activity of gelatinase A, a member of the matrix metalloproteinase (MMP) family, is considered to be a critical factor in tumor cell penetration of the extracellular matrix. To express catalytic activity, however, gelatinase A requires activation by another MMP, membrane type 1-matrix metalloproteinase (MT1-MMP). The head and neck squamous cell carcinoma cell line, UM-SCC-1, forms a quiescent monolayer atop collagen unless stimulated with epidermal growth factor (EGF; 3.5 nmol/L), which induces single cell invasion within 48 hours. To determine the role of the MT1-MMP/gelatinase A protease system in an in vitro stromal invasion model, expression vectors for MT1-MMP and gelatinase A were transfected into UM-SCC-1 (SCC-1/MT and SCC-1/gelA, respectively). SCC-1/MT tumor cells were found to invade in the absence of growth factor stimulation. Additionally, these cells displayed shorter onset to invasion and penetrated deeper into the collagen gel with EGF stimulation than did control vector transfectants. SCC-1/gelA cells similarly demonstrated invasion in the absence of EGF and a heightened invasive potential under EGF-stimulated conditions. These results suggest that the MT1-MMP/gelatinase A protease system participates in squamous cell carcinoma invasion of collagenous matrices.

    View details for Web of Science ID 000082961200001

    View details for PubMedID 10504584

  • Successful cochlear implantation in a patient with MELAS syndrome AMERICAN JOURNAL OF OTOLOGY Rosenthal, E. L., Kileny, P. R., Boerst, A., Telian, S. A. 1999; 20 (2): 187-190


    To describe methods of assessing cochlear implant candidacy in patients with potentially significant peripheral and central nervous system (CNS) degeneration.A patient with a degenerative CNS disease (MELAS syndrome) undergoing evaluation for cochlear implantation is described.This study took place at a tertiary care center.A patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) who had cortical blindness and profound sensorineural hearing loss was evaluated and rehabilitated with cochlear implantation.Pure-tone audiogram, behavioral responses to promontory stimulation electrical auditory brainstem response, and electrically evoked middle-latency responses (MLRs) were used to assess eighth nerve, auditory brainstem, and cortical auditory pathways. Cochlear implantation with Cochlear Corporation mini 22 implant was performed.Repeatable electrically evoked MLRs and behavioral responses to promontory stimulation documented the presence of auditory cortical responses. Successful implantation resulted in open set speech recognition and communication using the auditory/oral mode.This report describes successful implantation in a patient with MELAS syndrome and demonstrates the ability to preoperatively confirm the integrity of brainstem and cortical auditory pathways despite significant CNS degeneration.

    View details for Web of Science ID 000079245200010

    View details for PubMedID 10100521

  • Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor- and scatter factor-stimulated invasion of carcinoma cells CANCER RESEARCH Rosenthal, E. L., Johnson, T. M., Allen, E. D., Apel, I. J., Punturieri, A., Weiss, S. J. 1998; 58 (22): 5221-5230


    Normal as well as neoplastic cells traverse extracellular matrix barriers by mobilizing proteolytic enzymes in response to epidermal growth factor (EGF)-EGF receptor (EGFR) or hepatocyte growth factor/scatter factor (SF)-c-Met interactions. The plasminogen activator-plasminogen axis has been proposed to play a key role during cell invasion, but the normal development of plasminogen activator- as well as that of plasminogen-deficient mice supports the existence of alternate proteolytic systems that permit cells to traverse extracellular matrix barriers. To characterize the role that matrix-degrading proteinases play in EGF- or SF-stimulated invasion, a human squamous carcinoma cell line (UM-SCC-1) was triggered atop the matrices of type I collagen or human dermal explants in a three-dimensional culture system. During EGF- or SF-induced invasion, UM-SCC-1 cells expressed urokinase-type plasminogen activator (uPA) and uPA receptor as well as the matrix metalloproteinases (MMPs), membrane-type MMP-1, collagenase 1, stromelysin 1, and gelatinase B. Despite the presence of a positive correlation between uPA receptor-uPA expression and growth factor-stimulated invasion, UM-SCC-1 invasion was not affected by inhibitors directed against the plasminogen activator-plasminogen axis. In contrast, both recombinant and synthetic MMP inhibitors completely suppressed invasion by either EGF- or SF-stimulated cells without affecting either proteinase expression or cell motility across collagen-coated surfaces. These data demonstrate that MMPs, but not the plasminogen activator-plasmin system, can directly regulate the ability of either EGF- or SF-stimulated tumor cells to invade interstitial matrix barriers.

    View details for Web of Science ID 000077000400041

    View details for PubMedID 9823336