Eben L. Rosenthal

Pretreatment, Preoperative Swallowing Exercises May Improve Dysphagia Quality of Life

Objectives: 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).

Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity.

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 μmol/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 ∼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. (Mol Cancer Res 2006;4(7):437–47)

MATRIX METALLOPROTEASES IN HEAD AND NECK CANCER

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.

Safety and Tumor-specificity of Cetuximab-IRDye800 for Surgical Navigation in Head and Neck Cancer

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 21(16); 3658–66. ©2015 AACR.

Robot-Assisted Surgery for Upper Aerodigestive Tract Neoplasms

OBJECTIVES 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. DESIGN Prospective nonrandomized clinical trial. SETTING Academic tertiary referral center. PATIENTS Thirty-six patients with oral cavity, oropharyngeal, hypopharyngeal, or laryngeal tumors. INTERVENTION Robot-assisted resection of indicated tumors. MAIN OUTCOME MEASURES 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. RESULTS 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). CONCLUSIONS 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.

Transoral Robotic-Assisted Surgery for Head and Neck Squamous Cell Carcinoma: One- and 2-Year Survival Analysis

OBJECTIVE to report 2-year survival outcomes for head and neck squamous cell carcinoma using transoral robotic-assisted resection. DESIGN prospective case study. SETTING two tertiary care centers. PATIENTS 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. MAIN OUTCOME MEASURES disease-free survival, cancer recurrence, and gastrostomy tube dependence RESULTS seventy-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. CONCLUSION 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.

Free tissue transfer to manage salvage laryngectomy defects after organ preservation failure

Objective: 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.

Influence of social support on health-related quality of life outcomes in head and neck cancer.

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.

Fibroblast-derived MT1-MMP promotes tumor progression in vitro and in vivo

BackgroundIdentification 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.MethodsThe 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.ResultsHere 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.ConclusionThese data suggest a role for fibroblast-derived MMP-2 and MT1-MMP in HNSCC tumor invasion in vitro and tumor growth in vivo.

Simplifying head and neck microvascular reconstruction

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.