Steven J. Wang

Role of Hyaluronan-Mediated CD44 Signaling in Head and Neck Squamous Cell Carcinoma Progression and Chemoresistance

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that may involve the oral cavity, pharynx, larynx, and paranasal sinuses. The mechanisms of tumor progression underlying the clinical behavior of HNSCC remain unclear. CD44 comprises a family of transmembrane receptors that can give rise to multiple CD44 variant isoforms. Hyaluronan (HA), a major extracellular matrix component is the primary ligand for CD44 receptors. HA and CD44 signaling play an important role in HNSCC progression. Several CD44 variant isoforms (including v3-, v6-, and v10-containing isoforms) are associated with advanced disease, possibly through unique growth factor interactions with binding domains in the inserted variant regions of the cytoplasmic domain of CD44. In HNSCC, HA mediates the formation of a complex including CD44 and the epidermal growth factor receptor (EGFR) which is overexpressed in a large proportion of HNSCCs. Downstream effectors under EGFR regulation are activated, promoting promote cell growth and tumor survival. The leukemia-associated Rho-guanine nucleotide exchange factor (LARG) also associates with CD44 and EGFR to promote several Ras and RhoA pathway effectors, leading to cell migration, growth, and tumor survival. The secretion of matrix metalloproteinases, necessary for tumor cell invasion, is also regulated by these HA/CD44-mediated pathways. Finally, EGFR-mediated pathways play major roles in the HA/CD44 promotion of chemoresistance in HNSCC. Understanding HA/CD44-mediated signaling pathways may lead to improved treatment of HNSCC.

Oncologic Outcomes After Transoral Robotic Surgery : A Multi-institutional Study

IMPORTANCE Large patient cohorts are necessary to validate the efficacy of transoral robotic surgery (TORS) in the management of head and neck cancer. OBJECTIVES To review oncologic outcomes of TORS from a large multi-institutional collaboration and to identify predictors of disease recurrence and disease-specific mortality. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of records from 410 patients undergoing TORS for laryngeal and pharyngeal cancers from January 1, 2007, through December 31, 2012, was performed. Pertinent data were obtained from 11 participating medical institutions. INTERVENTIONS Select patients received radiation therapy and/or chemotherapy before or after TORS. MAIN OUTCOMES AND MEASURES Locoregional control, disease-specific survival, and overall survival were calculated. We used Kaplan-Meier survival analysis with log-rank testing to evaluate individual variable association with these outcomes, followed by multivariate analysis with Cox proportional hazards regression modeling to identify independent predictors. RESULTS Of the 410 patients treated with TORS in this study, 364 (88.8%) had oropharyngeal cancer. Of these 364 patients, information about post-operative adjuvant therapy was known about 338: 106 (31.3) received radiation therapy alone, and 72 (21.3%) received radiation therapy with concurrent chemotherapy. Neck dissection was performed in 323 patients (78.8%). Mean follow-up time was 20 months. Local, regional, and distant recurrence occurred in 18 (4.4%), 15 (3.7%), and 10 (2.4%) of 410 patients, respectively. Seventeen (4.1%) died of disease, and 13 (3.2%) died of other causes. The 2-year locoregional control rate was 91.8% (95% CI, 87.6%-94.7%), disease-specific survival 94.5% (95% CI, 90.6%-96.8%), and overall survival 91% (95% CI, 86.5%-94.0%). Multivariate analysis identified improved survival among women (P = .05) and for patients with tumors arising in tonsil (P = .01). Smoking was associated with worse overall all-cause mortality (P = .01). Although advanced age and tobacco use were associated with locoregional recurrence and disease-specific survival, they, as well as tumor stage and other adverse histopathologic features, did not remain significant on multivariate analysis. CONCLUSIONS AND RELEVANCE This large, multi-institutional study supports the role of TORS within the multidisciplinary treatment paradigm for the treatment of head and neck cancer, especially for patients with oropharyngeal cancer. Favorable oncologic outcomes have been found across institutions. Ongoing comparative clinical trials funded by the National Cancer Institute will further evaluate the role of robotic surgery for patients with head and neck cancers.

Association of CD44 V3-containing isoforms with tumor cell growth, migration, matrix metalloproteinase expression, and lymph node metastasis in head and neck cancer

The CD44 family of receptors includes multiple variant isoforms, some of which have been linked to tumor progression. The objective of this study was to investigate whether CD44 v3‐containing isoforms are involved in head and neck squamous cell carcinoma (HNSCC) tumor progression.

Downregulation of Fanconi Anemia Genes in Sporadic Head and Neck Squamous Cell Carcinoma

Background/Aims: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. Methods: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. Results: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. Conclusion: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study.

Electrophysiologic facial nerve monitoring during parotidectomy.

Facial nerve monitoring is an adjunctive method available to a surgeon during parotid surgery to assist with the functional preservation of the facial nerve. This review describes the goals, applications, technique, and benefits of electrophysiologic facial nerve monitoring during parotid surgery. A review and analysis of the relevant medical literature related to electrophysiologic facial nerve monitoring during parotid surgery are included.

Reduction of Hyaluronan-CD44-Mediated Growth, Migration, and Cisplatin Resistance in Head and Neck Cancer Due to Inhibition of Rho Kinase and PI-3 Kinase Signaling

OBJECTIVES To investigate whether hyaluronan (HA), a ligand for the transmembrane receptor CD44, and CD44, which acts through multiple signaling pathways to influence cellular behavior, promote Rho kinase- and phosphatidylinositol 3 (PI-3) kinase-mediated oncogenic signaling to alter cisplatin sensitivity and stimulate tumor cell proliferation, migration, and matrix metalloproteinase secretion in head and neck squamous cell carcinoma (HNSCC). DESIGN Laboratory investigation using the HNSCC cell line HSC-3. SETTING University laboratory. MAIN OUTCOME MEASURES Rho kinase and PI-3 kinase activity, myosin phosphatase and AKT phosphorylation, tumor cell growth, migration, and matrix metalloproteinase secretion were measured in the presence or absence of HA, cisplatin, and inhibitors of Rho kinase and PI-3 kinase. RESULTS The addition of HA, but not HA plus anti-CD44 antibody, resulted in increased Rho kinase and PI-3 kinase activity. Results of immunoblotting studies demonstrated that HA promotes Rho kinase-mediated myosin phosphatase phosphorylation and PI-3 kinase-mediated AKT phosphorylation. Hyaluronan was shown to promote migration and increased matrix metalloproteinase secretion through Rho kinase-mediated signaling. Hyaluronan treatment promoted increased tumor proliferation and resulted in a 12-fold reduced ability of cisplatin to cause HNSCC cell death. On the other hand, the presence of Y-27632, a Rho kinase inhibitor, and LY-294002, a PI-3 kinase inhibitor, blocked HA-mediated cisplatin resistance by HNSCC. CONCLUSIONS Our results suggest that HA and CD44 promote Rho kinase- and PI-3 kinase-mediated oncogenic signaling and cisplatin resistance. Perturbation of HA-CD44-mediated Rho kinase and PI-3 kinase signaling pathways may be a novel strategy to treat HNSCC.

The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer

Human papillomavirus (HPV) is a well‐established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non‐OP) head and neck squamous cell cancers (HNSCCs).

Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia–ischemia in mice with neuronal Fyn overexpression

The Src family kinases (SFKs) Src and Fyn are implicated in hypoxic-ischemic (HI) injury in the developing brain. However, it is unclear how these particular SFKs contribute to brain injury. Using neuron-specific Fyn overexpressing (OE) mice, we investigated the role of neuronal Fyn in neonatal brain HI. Wild type (WT) and Fyn OE mice were subjected to HI using the Vannucci model at postnatal day 7. Brains were scored five days later for evaluation of damage using cresyl violet and iron staining. Western blotting with postsynaptic density (PSD)-associated synaptic membrane proteins and co-immunoprecipitation with cortical lysates were performed at various time points after HI to determine NMDA receptor tyrosine phosphorylation and Fyn kinase activity. Fyn OE mice had significantly higher mortality and brain injury compared to their WT littermates. Neuronal Fyn overexpression led to sustained NR2A and NR2B tyrosine phosphorylation and enhanced NR2B phosphorylation at tyrosine (Y) 1472 and Y1252 in synaptic membranes. These early changes correlated with higher calpain activity 24h after HI in Fyn OE mice relative to WT animals. Our findings suggest a role for Fyn kinase in neuronal death after neonatal HI, possibly via up-regulation of NMDA receptor tyrosine phosphorylation.

Predictors of quality of life after treatment for oral cavity and oropharyngeal carcinoma

BACKGROUND: Treatment for head and neck cancer, including surgery, radiation, and chemotherapy, can impact quality of life. DESIGN: Patients seen at an academic institution and treated for oral cavity and oropharyngeal carcinoma were asked to participate. The standardized University of Michigan Head and Neck Specific Quality of Life questionnaire was distributed. RESULTS: Eighty-seven patients completed the questionnaire. The majority had squamous cell carcinoma (94%), stage III or IV disease (53%), and a history of tobacco or alcohol dependence (59%), and were male (62%). Eighteen percent had free-tissue transfer (fibula free flap in 8% and radial forearm free flap in 10%). Predictors of worse quality of life included advanced stage, gastrostomy-tube dependence, complication, or recurrence. CONCLUSION: Stage, gastrostomy-tube dependence, complication, recurrence, and treatment modality influence quality of life. A better understanding of the impact of oral cavity and oropharyngeal cancer treatment on quality of life will enable us to better advise our patients.

Quality-of-life impact of participation in a head and neck cancer support group

Objective To assess if participation by patients in a head and neck cancer support group improves perceived quality of life (QOL). Study Design and Setting Subjects for this study included 47 patients at a tertiary Veterans Affairs Medical Center who were previously treated for head and neck cancer. This was a quasi-experimental, post-test study comparing the QOL of 24 patients who participated in a head and neck cancer support group with 23 patients who did not participate. The validated University of Michigan Head and Neck Quality of Life (HNQOL) instrument was used to evaluate head and neck cancer-related QOL. Results Patients who participated in the head and neck cancer support group exhibited significantly better scores in the domains of eating, emotion, and pain as well as in the global bother and response to treatment questions of the HNQOL instrument compared with those patients who did not participate. Additional subgroup analysis comparing age, type of treatment, and length of time since cancer diagnosis suggests that these variables were less important predictors of QOL than was support group participation. Conclusions Our findings suggest that patient participation in a head and neck cancer support group is associated with improved QOL. Significance Support groups may be beneficial in improving QOL after head and neck cancer treatment.