Faculty Bibliography

BACKGROUND:The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0). METHODS:A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed. RESULTS:There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC. CONCLUSIONS:AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion, status outperformed pT as a predictor of LR and LRR in patients with early OTSCC.

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors' platinum resistance identifies novel approach to treating these tumors.

PURPOSE:ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A "window-of-opportunity" study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC. PATIENTS AND METHODS:Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed. RESULTS:= 0.04; 95% confidence interval, 27.7%-84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment-related toxicity was grade 1-2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus-negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment. CONCLUSIONS:This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.

BACKGROUND:The anterior skull base (ASB) remains one of the greatest challenges for reconstructive surgeons. The current armamentarium includes endoscopic placement of free grafts, endonasal vascularized pedicled flaps, regional flaps, and microvascular free flaps. As the defect size increases, reconstruction complexity increases along with potential complications. Here, we report an endoscopic-assisted paramedian forehead flap, a novel adaptation of an age-old technique, for ASB reconstruction. CASE DESCRIPTION/METHODS:A 66-year-old male underwent a dual bifrontal and transnasal endoscopic approach for the resection of a T4N0M0 sinonasal squamous cell carcinoma. The resulting ASB defect was repaired using simultaneous pericranial and nasoseptal flaps. Adjuvant radiation therapy resulted in delayed radiation necrosis in the right frontal lobe 3 years later requiring debridement via a supraorbital approach. Recovery from this operation was complicated by an ASB defect and cerebrospinal fluid (CSF) leak. The defect remained despite multiple attempts at endoscopic repairs. Due to multiple medical comorbidities, the patient was not a candidate for microvascular reconstruction. Prior surgeries had disrupted the traditional regional flaps (i.e., pericranial, nasoseptal, and temporoparietal fascia flaps) bilaterally. Therefore the novel endoscopic-assisted paramedian forehead flap was used to successfully repair the ASB defect. Postoperatively, the patient has done well with no recurrences in the CSF leak. CONCLUSIONS:The endoscopic-assisted paramedian forehead flap is a robust regional flap whose advantages include the utilization of muscle, low donor morbidity, and endoscopic placement with avoidance of craniotomies. Therefore it should be considered an important option for ASB reconstruction of recalcitrant CSF leaks when all other options are unavailable.

BACKGROUND:No head to head comparison is available between surgical lip lifting and upper lip filler injections to decide which technique yields the best results in patients. Despite the growing popularity of upper lip augmentation, its effect on societal perceptions of attractiveness, successfulness and overall health in woman is unknown. METHODS:Blinded casual observers viewed three versions of independent images of 15 unique patient lower faces for a total of 45 images. Observers rated the attractiveness, perceived success, and perceived overall health for each patient image. Facial perception questions were answered on a visual analog scale from 0 to 100, where higher scores corresponded to more positive responses. RESULTS:Two hundred and seventeen random observers with an average age of 47 years (standard deviation, 15.9) rated the images. The majority of observers were females (n=183, 84%) of white race (n=174, 80%) and had at least some college education (n=202, 93%). The marginal mean score for perceived attractiveness from the natural condition was 1.5 points (95% confidence interval [CI], 0.9-2.18) higher than perceived attractiveness from the simulated upper lip filler injection condition, and 2.6 points higher (95% CI, 1.95-3.24) than the simulated upper lip lift condition. There was a moderate to strong correlation between the scores of the same observer. CONCLUSIONS:Simulated upper lip augmentation is amenable to social perception analysis. Scores of the same observer for attractiveness, successfulness, and overall health are strongly correlated. Overall, the natural condition had the highest scores in all categories, followed by simulated upper lip filler, and lastly simulated upper lip lift.

OBJECTIVE:To use mid-infrared (IR) spectroscopy to assess changes in the cartilaginous framework of human trachea during decellularization. STUDY DESIGN:Laboratory-based study. SETTING:Research laboratory. METHODS:Six cadaveric human tracheas were decellularized using a detergent enzymatic method (DEM). Tissue samples were obtained from each specimen after 0, 1, 10, and 25 DEM cycles for histologic and spectroscopic analysis. Decellularization was confirmed using hematoxylin and eosin (H&E) and 2-(4-amidinophenyl)-1H-indole-6-carboxamidine (DAPI) staining. Changes in cartilaginous framework were examined using Fourier transform infrared imaging spectroscopy (FT-IRIS) and an attenuated total reflectance (ATR) probe in the mid-IR frequencies. Results were statistically analyzed using 1-way analysis of variance (ANOVA) and principal component analysis (PCA). RESULTS:) showed a significant decrease after 1 DEM cycle ( P = .0007). Examination of the luminal surface of the trachea with an ATR probe showed raw mid-IR spectra consistent with cartilage. PCA showed significant separation of spectra corresponding to treatment cycle along the principal components 1 and 2. CONCLUSION:Mid-IR spectroscopy is a viable method of monitoring changes in extracellular matrix components during the decellularization of human trachea.