Terance T. Tsue

Risk factors for pulmonary complications in the postoperative head and neck surgery patient

Pulmonary complications are a primary source of increased cost and morbidity in surgically treated head and neck cancer patients. This study investigates potential risk factors related to postoperative pulmonary complications (pneumonia, adult respiratory distress syndrome (ARDS), and prolonged mechanical ventilation) in head and neck cancer patients.

Radiation-Induced Malignancy of the Head and Neck:

OBJECTIVE: Our goal was to evaluate our experience with radiation-induced malignancy (RIM), compare that experience to the literature, and review treatment modalities. STUDY DESIGN AND SETTING: The setting is the University of Kansas Medical Center. A retrospective review was performed to identify patients with RIM. Patients were included if they met the criteria for RIM as delineated in the literature. RESULTS: Thirteen patients met the criteria for RIM. The mean latency period was 22 years. Sarcomas were the most common type of RIM and the paranasal sinuses were the most common location. Surgical resection was our treatment of choice. CONCLUSIONS: Our patient series differs from previous reports in that sarcomas were the predominating RIM and the paranasal sinuses were the most common location. We noted a shorter latency period than has been previously published. Surgical excision is the treatment of choice. EBM rating: C.

The role of the osteocutaneous radial forearm free flap in the treatment of mandibular osteoradionecrosis.

OBJECTIVE: To evaluate the role of the osteocutaneous radial forearm free flap (OCRFFF) in the treatment of mandibular osteoradionecrosis (ORN). STUDY DESIGN AND SETTING: Retrospective case review of patients who underwent OCRFFF oromandibular reconstruction after resection of nonviable tissue at an academic tertiary care center because of ORN. Patients with reconstructions other than OCRFFF were excluded from this study. RESULTS: Nine patients underwent a composite oromandibular resection for ORN with a reconstruction using an OCRFFF between April 1998 and February 2003. All patients had failed previous less aggressive surgical and medical management of the ORN. Mean follow-up was 36 months (range, 14-67 months). There were no flap failures or significant immediate postoperative or long-term complications observed. All patients had successful restoration of mandibular integrity and continuity, with 100% success rate of stabilization of ORN. All patients were able to tolerate PO diet, with only one third having to supplement their diet with gastrostomy feedings, compared with 89% gastrostomy dependence preoperatively. CONCLUSIONS: Primary or adjuvant radiotherapy for head and neck malignancies can result in ORN of the mandible. This difficult problem often requires surgical intervention. In our experience, the OCRFFF can be successfully used for oromandibular reconstruction, even in the setting of the heavily radiated tissue with excellent postoperative outcomes. SIGNIFICANCE: This is the first study that demonstrates the efficacy of the OCRFFF as a treatment of mandibular ORN.

Acellular dermis compared to skin grafts in oral cavity reconstruction

To compare the efficacy of acellular dermal matrix (ADM) and split thickness skin grafts (STSG) in oral cavity reconstruction.

Use of the 2.0-mm Locking Reconstruction Plate in Primary Oromandibular Reconstruction after Composite Resection

OBJECTIVE: To review our experience with 2.0-mm locking reconstruction plate (LRP) system for patients requiring oromandibular reconstruction. STUDY DESIGN: Retrospective case review of 43 consecutive patients who underwent mandibular composite resection with immediate reconstruction. SETTING: Tertiary care center. RESULTS: Forty-three patients underwent oromandibular reconstruction with the 2.0-mm mandibular LRP system and free flaps containing vascularized bone. Mean follow-up was 11 months. There were no intraoperative difficulties utilizing this system. Two (5%) patients had partial fasciocutaneous flap loss resulting in plate exposure. There were no instances of plate fracture or complications requiring plate removal to date. CONCLUSION: 2.0-mm LRP mandibular system is reliable even in the setting of previous or adjuvant radiation therapy. Its technical ease of application, contouring malleability, and very low profile have proven to be advantageous in oromandibular reconstruction. SIGNIFICANCE: No previous descriptions of use of the 2.0-mm LRP in combination with osteocutaneous free flaps for mandibular reconstruction are found in the literature. EBM rating: C.

Outcomes of the Osteocutaneous Radial Forearm Free Flap for Mandibular Reconstruction

IMPORTANCE Limited donor and recipient site complications support the osteocutaneous radial forearm free flap (OCRFFF) for mandibular reconstruction as a useful option for single-stage mandibular reconstruction. OBJECTIVE To examine and report long-term outcomes and complications at the donor and recipient sites for patients undergoing the OCRFFF for mandibular reconstruction. DESIGN Retrospective review. SETTING Academic, tertiary care medical center. PATIENTS The study population comprised 167 consecutive patients who underwent single-staged mandibular reconstruction with an OCRFFF. MEAN OUTCOME MEASURES Rates of complications at the donor and recipient sites. RESULTS The mean patient age was 61 years (range, 20-93 years). Men compromised 68% of the population. Follow-up interval ranged from 2 to 99 months (mean, 25.9 months). The median length of bone harvested was 7 cm (range, 2.5-12.0 cm). Prophylactic plating was completed for each of the radii at the time of harvest. Donor site complications included radial fracture (1 patient [0.5%]), tendon exposure (47 patients [28%]), and donor hand weakness or numbness (13 patients [9%]). Recipient site complications included mandible hardware exposure (29 patients [17%]), mandible nonunion or malunion (4 patients [2%]), and mandible bone or hardware fracture (4 patients [2%]). Using regression analysis, we found that patients were 1.3 times more likely to have plate exposure for every increase of 1 cm of bone harvest length; this was statistically significant (P = .04). CONCLUSIONS AND RELEVANCE This is the largest single study reporting outcomes and complications for patients undergoing OCRFFF for mandibular reconstruction. Prophylactic plating of the donor radius has nearly eliminated the risk of pathologic radial bone fractures. Limited long-term donor and recipient site complications support the use of this flap for single-stage mandibular reconstruction.

Immediate Gore-Tex sling suspension for management of facial paralysis in head and neck extirpative surgery.

OBJECTIVE: We sought to evaluate the functional and aesthetic outcomes of immediate facial reconstruction with a Gore-Tex (expanded polytetrofluoroethylene) sling in irradiated patients undergoing large head and neck tumor extirpation with facial nerve resection. STUDY DESIGN AND SETTING: We conducted a retrospective study of 17 patients at two academic institutions who underwent extirpative surgery with immediate Gore-Tex sling reconstruction and completed radiotherapy. Functional and aesthetic results were evaluated at three intervals. RESULTS: All patients had excellent immediate results and good or excellent intermediate-term results. At long-term follow-up, results were good to excellent in 47% and unacceptable in 35% of patients. CONCLUSION: In irradiated patients undergoing total parotidectomy with immediate facial reconstruction using Gore-Tex slings, early results are excellent, but there is a high incidence of major wound complications and unacceptable results in long-term follow-up. SIGNIFICANCE: There is a high rate of late complications associated with immediate facial reconstruction with Gore-Tex slings in irradiated patients.

Mitigation of Tumor-Associated Fibroblast-Facilitated Head and Neck Cancer Progression With Anti-Hepatocyte Growth Factor Antibody Ficlatuzumab.

IMPORTANCE Ficlatuzumab can be used to treat head and neck squamous cell carcinoma (HNSCC) by inhibiting c-Met receptor-mediated cell proliferation, migration, and invasion. OBJECTIVE To understand the effect of ficlatuzumab on HNSCC proliferation, migration, and invasion. DESIGN, SETTING, AND PARTICIPANTS The effects of ficlatuzumab on HNSCC proliferation, invasion, and migration were tested. Mitigation of c-Met and downstream signaling was assessed by immunoblotting. The tumor microenvironment has emerged as an important factor in HNSCC tumor progression. The most abundant stromal cells in HNSCC tumor microenvironment are tumor-associated fibroblasts (TAFs). We previously reported that TAFs facilitate HNSCC growth and metastasis. Furthermore, activation of the c-Met tyrosine kinase receptor by TAF-secreted hepatocyte growth factor (HGF) facilitates tumor invasion. Ficlatuzumab is a humanized monoclonal antibody that sequesters HGF, preventing it from binding to and activating c-Met. We hypothesized that targeting the c-Met pathway with ficlatuzumab will mitigate TAF-mediated HNSCC proliferation, migration, and invasion. Representative HNSCC cell lines HN5, UM-SCC-1, and OSC-19 were used in these studies. EXPOSURES FOR OBSERVATIONAL STUDIES The HNSCC cell lines were treated with ficlatuzumab, 0 to 100 µg/mL, for 24 to 72 hours. MAIN OUTCOMES AND MEASURES Ficlatuzumab inhibited HNSCC progression through c-Met and mitogen-activated protein kinase (MAPK) signaling pathway. RESULTS Ficlatuzumab significantly reduced TAF-facilitated HNSCC cell proliferation (HN5, P < .001; UM-SCC-1, P < .001), migration (HN5, P = .002; UM-SCC-1, P = .01; and OSC-19, P = .04), and invasion (HN5, P = .047; UM-SCC-1, P = .03; and OSC-19, P = .04) through a 3-dimensional peptide-based hydrogel (PGmatrix). In addition, ficlatuzumab also inhibited the phosphorylation of c-Met at Tyr1234/1235 and p44/42 MAPK in HNSCC cells exposed to recombinant HGF. CONCLUSIONS AND RELEVANCE We demonstrate that neutralizing TAF-derived HGF with ficlatuzumab effectively mitigates c-Met signaling and decreases HNSCC proliferation, migration, and invasion. Thus, ficlatuzumab effectively mitigates stromal influences on HNSCC progression.

The degree of intratumor mutational heterogeneity varies by primary tumor sub-site.

In an era where mutational profiles inform treatment options, it is critical to know the extent to which tumor biopsies represent the molecular profile of the primary and metastatic tumor. Head and neck squamous cell carcinoma (HNSCC) arise primarily in the mucosal lining of oral cavity and oropharynx. Despite aggressive therapy the 5-year survival rate is at 50%. The primary objective of this study is to characterize the degree of intratumor mutational heterogeneity in HNSCC. We used multi-region sequencing of paired primary and metastatic tumor DNA of 24 spatially distinct samples from seven patients with HNSCC of larynx, floor of the mouth (FOM) or oral tongue. Full length, in-depth sequencing of 202 genes implicated in cancer was carried out. Larynx and FOM tumors had more than 69.2% unique SNVs between the paired primary and metastatic lesions. In contrast, the oral tongue HNSCC had only 33.3% unique SNVs across multiple sites. In addition, HNSCC of the oral tongue had fewer mutations than larynx and FOM tumors. These findings were validated on the Affymetrix whole genome 6.0 array platform and were consistent with data from The Cancer Genome Atlas (TCGA). This is the first report demonstrating differences in mutational heterogeneity varying by subsite in HNSCC. The heterogeneity within laryngeal tumor specimens may lead to an underestimation of the genetic abnormalities within tumors and may foster resistance to standard treatment protocols. These findings are relevant to investigators and clinicians developing personalized cancer treatments based on identification of specific mutations in tumor biopsies.

Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target

Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679-91. ©2017 AACR.