Subcategorization of Perineural Invasion Stratifies Oral Cavity Squamous Cell Carcinoma Prognosis.

OBJECTIVE: To evaluate whether subcategorization of perineural invasion (PNI) improves the prognostic resolution of the American Joint Committee on Cancer, Eighth Edition (AJCC8) staging system in oral cavity squamous cell carcinoma (OCSCC). METHODS: OCSCC tumor specimens from patients seen at a tertiary care institution who underwent primary surgical resection between January 2019 and June 2021 were sorted into four PNI categories: negative, intratumoral, peripheral, and extratumoral. The prognostic effect of these PNI categories were assessed through Kaplan-Meier, Cox regression, and log-rank testing using recurrence-free survival (RFS) and overall survival (OS) as primary and secondary outcomes respectively. RESULTS: A total of 158 patients were examined. The median follow-up time was 21 months. PNI subcategorization further stratified RFS (p = 0.007) and OS (p = 0.002). Extratumoral PNI was associated with a 4.5-fold increase in recurrence risk (adjusted hazards ratio [aHR]: 4.53; 95% confidence interval [CI]: 1.1-18.66) and worse OS when compared with PNI negative disease (aHR: 5.71; 95% CI: 1.0-32.67). Peripheral PNI was associated with worse OS (aHR: 5.7; 95% CI: 1.35-24.08) but not worse RFS (p = 0.18) when compared with PNI negative disease. Interestingly, intratumoral PNI was not associated with significant differences in RFS (p = 0.087) or OS (p = 0.22) when compared with PNI negative disease. CONCLUSIONS: Subcategorization of OCSCC tumors into extratumoral, peripheral, and intratumoral PNI stratifies RFS and OS when compared with patients with PNI negative disease in an incremental fashion. This pilot study suggests that there may be added benefit in subcategorization of PNI in the prognostic evaluation of OCSCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1656-1662, 2024.

Co-surgery in head and neck microvascular reconstruction.

PURPOSE: Co-surgery with two attending reconstructive surgeons is becoming increasingly common in breast microvascular reconstruction due to case complexity and the potential for improved outcomes and operative efficiency. The impact of co-surgery on outcomes in head and neck microvascular reconstruction has not been studied. METHODS: Our multidisciplinary head and neck reconstruction team (Otolaryngology, Plastic Surgery) at the University of Pittsburgh transitioned to a practice of co-surgery on head and neck free flaps. In this study, we compare outcomes of two surgeon head and neck reconstruction to single surgeon reconstruction in a prospectively maintained database. RESULTS: 384 patients met our inclusion criteria from 2020 to 2022. Cases were performed by a single surgeon in 77.8 % of cases (299/384) and two surgeons in 22.1 % (85/384). The mean age was 62.5 years. There was no difference between the single surgeon cohort and the co-surgery cohort in terms of flap survival, procedure time, ischemia time, hospital length of stay, recipient site complications, or rates of return to the operating room. Donor site complications were less common in the co-surgery cohort (0 % vs 4.7 %, p = 0.021). For our reconstructive team, the transition to co-surgery has increased total surgeon fee collection per free flap by 28 % and increased surgeon flap related RVU production by 35 %. CONCLUSION: Co-surgery is feasible and safe in head and neck microvascular reconstruction. Benefits may include reduced complications, increased reimbursement, and improved interdisciplinary collaboration.

Prognosis.

Prognosis is defined as the likely outcome or course of a disease and is the result of a complex interplay between patient and tumor factors. Unfortunately, the prognosis of patients with laryngeal cancer has not changed significantly over the past several decades. However, as our understanding of these patient and tumor factors becomes more nuanced and the resulting treatment options become more precise, there is the potential to improve the prognosis for these patients.

Venous Thromboembolism Rates After Free Flap Reconstruction of the Head and Neck Region.

BACKGROUND: Venous thromboembolism (VTE) is a major concern for the postoperative hospitalized patient, especially after long and complex procedures. Cancer itself also contributes to the hypercoagulable state, further complicating the management of patients. Despite prophylaxis, breakthrough events can occur. We aimed to assess our institutional VTE and bleeding rates after free flap reconstruction of the head and neck (H&N) region and the factors associated with VTE events. METHODS: A retrospective review of the patients who underwent H&N free flap reconstruction at an academic center from 2012 to 2021 was performed from a prospectively maintained database. Data regarding patient demographics, medical history, surgical details, and overall outcomes were collected. Outcomes studied included postoperative 30-day VTE rates and major bleeding events. Patients who had a VTE event were compared with the rest of the cohort to identify factors associated with VTE. RESULTS: Free flap reconstruction of the H&N region was performed in 949 patients. Reconstruction after cancer extirpation for squamous cell carcinoma was the most common etiology (79%). The most common flap was thigh based (50%), followed by the fibula (29%). The most common postoperative VTE chemoprophylaxis regimen was enoxaparin 30 mg twice daily (83%). The VTE and bleeding rates over the 10-year period were 4.6% (n = 44) and 8.7% (n = 83), respectively. Body mass index (28.7 ± 5.8 vs 26.2 ± 6.6, P = 0.013) and pulmonary comorbidities were found to be significantly higher in patients who had a VTE event (43% vs 27%, P = 0.017). Patients with a VTE event had a prolonged hospital stay of 8 more days (19.2 ± 17.4 vs 11 ± 7, P = 0.003) and a higher incidence of bleeding events (27% vs 8%, P < 0.001). CONCLUSIONS: Postoperative VTE is a significant complication associated with increased length of hospitalization in patients undergoing free flap reconstruction of the H&N region. Institutional measures should be implemented on an individualized basis based on patient comorbidities to improve the postoperative VTE rates, while balancing the bleeding events.

Assessment of BMI and Venous Thromboembolism Rates in Patients on Standard Chemoprophylaxis Regimens After Undergoing Free Tissue Transfer to the Head and Neck.

Importance: Venous thromboembolism (VTE) is a severe complication after free tissue transfer to the head and neck (H&N). Enoxaparin 30 mg twice daily (BID) is a common regimen for chemoprophylaxis. However, differences in enoxaparin metabolism based on body weight may influence its efficacy and safety profile. Objective: To assess the association between BMI and postoperative VTE and hematoma rates in patients treated with prophylactic enoxaparin 30 mg BID. Design, Setting, and Participants: This was a retrospective review of a prospectively collected cohort from 2012 to 2022. Postoperative VTE, hematoma, and free flap pedicle thrombosis were recorded within 30 days of index surgery. The setting was a tertiary academic referral center. Participants included patients undergoing H&N reconstruction with free flaps that received fixed-dose subcutaneous enoxaparin 30 mg BID postoperatively. Statistical analysis was conducted from April to May 2022. Main Outcomes and Measures: Outcomes include incidence of VTE, hematoma, and flap pedicle thrombosis events within 30 days of the surgery. Univariate and multivariable regression models were used to evaluate associations between BMI and other patient factors with these outcomes. Results: Among the 765 patients included, 262 (34.24%) were female; mean (SD) age was 60.85 (12.64) years; and mean (SD) BMI was 26.36 (6.29). The rates of VTE and hematoma in the cohort were 3.92% (30 patients) and 5.09% (39 patients), respectively. After adjusting for patient factors, BMI was the only factor associated with VTE (OR, 1.07; 95% CI, 1.015-1.129). Obesity (BMI >30) was associated with increased odds of VTE (OR, 2.782; 95% CI, 1.197-6.564). Hematoma was not associated with BMI (OR, 0.988; 95% CI, 0.937-1.041). Caprini score of at least 9 was not associated with VTE (OR, 1.259; 95% CI, 0.428-3.701). Conclusions and Relevance: This cohort study found that obesity was associated with an increased risk of VTE in patients after microvascular H&N reconstruction and while on standard postoperative chemoprophylaxis regimens. This association may suggest insufficient VTE prophylaxis in this group and a potential indication for weight-based dosing.

Surgical factors associated with patient-reported quality of life outcomes after free flap reconstruction of the oral cavity.

OBJECTIVES: To determine which surgical factors are associated with quality-of-life (QOL) outcomes in oral cavity cancer survivors after free flap reconstruction of the oral cavity. PATIENTS AND METHODS: A cross-sectional study was conducted from a multidisciplinary head and neck cancer (HNC) survivorship clinic. Oral cavity cancer survivors with at least 6-months of postoperative follow-up from ablation and free flap reconstruction were included. Primary outcome measures were validated patient-reported outcome measures (PROMs) including the Eating Assessment Tool-10 (EAT-10) measure of swallowing-specific QOL, University of Washington Quality of Life (UW-QOL) physical and social-emotional subscale scores and feeding tube dependence. RESULTS: Extent of tongue resection was associated with EAT-10 and the UW-QOL Physical subscale scores. Patients with oral tongue defects reported worse scores than with composite defects in the EAT-10 and UW-QOL physical domain (p = 0.0004, 0.0025, respectively). This association no longer applies when controlling for differences in extent of tongue resection. Patients with anterior composite resections reported worse EAT-10 scores than lateral resections (p = 0.024). This association no longer applies when controlling for extent of tongue resection (p = 0.46). Gastric tube dependence demonstrates similar trends to PROMs. CONCLUSION: Extent of tongue resection was strongly associated with poor QOL outcomes after free tissue reconstruction of the oral cavity and mediates the associations between other defect characteristics and QOL. These findings demonstrate the need for emphasis on expected oral tongue defects when counseling patients and highlight the need to address QOL in a multidisciplinary fashion post-operatively.

Molecular Profile of Locally Aggressive Well Differentiated Thyroid Cancers.

Knowledge of the genetic landscape of aggressive well differentiated thyroid cancers (WDTC) is lacking. Retrospective review of institutional database was performed to identify locally-invasive thyroid carcinomas and a comparison cohort of low-risk WDTC. ThyroSeq v2 next-generation sequencing was performed on available tissue. Survival time was analyzed by Kaplan-Meier methods and compared between groups via the log-rank test. Time to recurrence, treating death as a competing risk, was analyzed by cumulative incidence and compared between groups. Of 80 T4 tumors, 29 (36%) were met inclusion criteria, of which, 25 had genetic and clinicopathologic data. Most (24/25, 96%) harbored at least one genetic alteration, most commonly BRAF V600E (19, 76%), followed by mutations in the promoter region of TERT (14, 56%). Co-occurrence of BRAF and TERT was identified in 12 (48%) and associated with significantly higher risk of recurrence (p < 0.05). Conversely, co-occurrence of BRAF and TERT was present in only 5 of 102 (5%) patients presenting with early-stage WDTC. Compared to early-stage WDTC, co-occurrence of BRAF and TERT mutations are common in locally advanced (T4) thyroid cancer and are associated with an increased risk of recurrence. This knowledge may help predict aggressive behavior pretreatment and inform perioperative decision-making.

HER3 targeting potentiates growth suppressive effects of the PI3K inhibitor BYL719 in pre-clinical models of head and neck squamous cell carcinoma.

BYL719 is a PI3K inhibitor that has demonstrated efficacy in the treatment of head and neck squamous cell carcinoma. BYL719 exerts its therapeutic effect by suppressing AKT and other proliferative signaling mechanisms. Despite PI3K inhibition and AKT suppression, residual activity of protein S6, a core marker of proliferative activation, has been observed. HER3, either via dimerization or activation by its ligand neurgeulin (NRG), is known to activate PI3K. Thus, we hypothesized that co-targeting HER3 and PI3K would lead to greater suppression of the PI3K-AKT signaling pathway and greater tumor suppression than with BYL719 alone. We investigated biochemical expression and activation of the HER3-PI3K-AKT-S6 pathway in HNSCC cell lines and patient-derived xenografts (PDXs). Antitumor effects of HER3 and PI3K inhibitors alone and in combination were evaluated in cell culture and murine models. Treatment of HNSCC cell lines with BYL719 significantly reduced AKT activation and suppressed tumor growth. However, S6 was persistently activated despite suppression of AKT. Combination treatment with KTN3379, a monoclonal antibody targeted against HER3, and BYL719 led to enhanced suppression of in vitro and in vivo cancer growth and durable suppression of AKT and S6. Therefore, inhibition of HER3 with KTN3379 enhanced the effects of PI3K inhibition in pre-clinical HNSCC models. These data support co-targeting HER3 and PI3K for the treatment of HSNCC.

Rates of symptomatology are lower in recurrent sinonasal malignancy than in other recurrent cancers of the head and neck: a multi-institutional study.

BACKGROUND: Sinonasal malignancies are a rare subset of head and neck tumors, and surveillance strategies after definitive tumor treatment are often generalized from those for overall head and neck cancer outcomes data. However, recent literature suggests that the posttreatment period in sinonasal cancer is fundamentally different and a more tailored surveillance approach may be beneficial. Although rates of symptomatology are high in head and neck cancer recurrence and patient-driven follow-up is common, rates of symptomatology are unknown in sinonasal cancer specifically. METHODS: Patients with recurrence of sinonasal malignancy were identified at 3 academic rhinology and skull base surgery centers. Demographic, tumor, and treatment data were collected. Rates of symptomatology at presentation were tabulated and examined in the context of several other variables. RESULTS: Fifty-five patients had recurrence of sinonasal malignancy after definitive treatment. Fifty-one percent of patients had no suspicious symptoms at the time of tumor recurrence, with an average time to recurrence of 33 months. Male patients and patients with stage IVA or lower disease were significantly more likely to be asymptomatic at the time of recurrence (p < 0.05). CONCLUSION: Patients with sinonasal malignancy have a much lower rate of symptomatology during tumor recurrence than that observed in head and neck cancer overall. Furthermore, time to recurrence is substantially longer, as a majority of head and neck cancer recurrences occur in the first 12 months after treatment. These differences highlight the need for more tailored surveillance paradigms in asymptomatic patients with a history of a definitively treated sinonasal neoplasm.

TMEM16A/ANO1 suppression improves response to antibody-mediated targeted therapy of EGFR and HER2/ERBB2.

TMEM16A, a Ca2+ -activated Cl- channel, contributes to tumor growth in breast cancer and head and neck squamous cell carcinoma (HNSCC). Here, we investigated whether TMEM16A influences the response to EGFR/HER family-targeting biological therapies. Inhibition of TMEM16A Cl- channel activity in breast cancer cells with HER2 amplification induced a loss of viability. Cells resistant to trastuzumab, a monoclonal antibody targeting HER2, showed an increase in TMEM16A expression and heightened sensitivity to Cl- channel inhibition. Treatment of HNSCC cells with cetuximab, a monoclonal antibody targeting EGFR, and simultaneous TMEM16A suppression led to a pronounced loss of viability. Biochemical analyses of cells subjected to TMEM16A inhibitors or expressing chloride-deficient forms of TMEM16A provide further evidence that TMEM16A channel function may play a role in regulating EGFR/HER2 signaling. These data demonstrate that TMEM16A regulates EGFR and HER2 in growth and survival pathways. Furthermore, in the absence of TMEM16A cotargeting, tumor cells may acquire resistance to EGFR/HER inhibitors. Finally, targeting TMEM16A improves response to biological therapies targeting EGFR/HER family members.