Nichole R. Dean

Anti-EMMPRIN Monoclonal Antibody as a Novel Agent for Therapy of Head and Neck Cancer

Purpose: 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. Experimental Design: 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. Results: 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 1β (IL-1β), IL-6, and IL-8 cytokine production, in vitro and in vivo. Conclusions: 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.

Robotic-Assisted Surgery for Primary or Recurrent Oropharyngeal Carcinoma

OBJECTIVE To determine the feasibility of robotic-assisted salvage surgery for oropharyngeal cancer. DESIGN Retrospective case-controlled study. SETTING Academic, tertiary referral center. PATIENTS 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). MAIN OUTCOME MEASURES 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. RESULTS 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. CONCLUSION When feasible, robotic-assisted surgery is an acceptable procedure for resection of both primary and recurrent oropharyngeal tumors. Trial Registration clinicaltrials.gov Identifier: NCT00473564.

Outcomes of static and dynamic facial nerve repair in head and neck cancer.

Determine outcomes associated with nerve grafting versus static repair following facial nerve resection.

Free flap reconstruction for osteoradionecrosis of the jaws—Outcomes and predictive factors for success

The purpose of this study was to determine factors to predict the success of free flap surgery in the treatment of osteoradionecrosis (ORN).

Free Flap Reconstruction of Lateral Mandibular Defects: Indications and Outcomes

Objective. To compare outcomes following osteocutaneous radial forearm and fibula free flap reconstruction of lateral mandibular defects. Study Design. Retrospective case-controlled study. Setting. Historical cohort study. Subjects and Methods. 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. Results. 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. Conclusion. The osteocutaneous radial forearm and fibula free flap provide equivalent wound healing and functional outcomes in patients undergoing lateral mandibular defect reconstruction.

Outcomes Following Temporal Bone Resection

To evaluate survival outcomes in patients undergoing temporal bone resection.

Optical imaging predicts tumor response to anti-EGFR therapy.

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.

Assessment of tissue autofluorescence and reflectance for oral cavity cancer screening.

Objective. 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. Study Design. Prospective, cross-sectional analysis. Setting. Tertiary care medical center. Subjects and Methods. 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. Results. 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. Conclusion. 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.

EGFR expression in advanced head and neck cutaneous squamous cell carcinoma

The significance of epidermal growth factor receptor (EGFR) expression in advanced cutaneous squamous cell carcinoma (SCC) of the head and neck remains poorly understood.

Anti-EMMPRIN antibody treatment of head and neck squamous cell carcinoma in an ex-vivo model

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.