Estimation of the hyperelastic parameters of fresh human oropharyngeal soft tissues using indentation testing.

Patient-specific finite element (FE) modeling of the upper airway is an effective tool for accurate assessment of obstructive sleep apnea (OSA) syndrome. It is also useful for planning minimally invasive surgical procedures under severe OSA conditions. A major requirement of FE modeling is having reliable data characterizing the biomechanical properties of the upper airway tissues, particularly oropharyngeal soft tissue. While some data characterizing this tissue's linear elastic regime is available, reliable data characterizing its hyperelasticity is scarce. The aim of the current study is to estimate the hyperelastic mechanical properties of the oropharyngeal soft tissues, including the palatine tonsil, soft palate, uvula, and tongue base. Fresh tissue specimens of human oropharyngeal tissue were acquired from 13 OSA patients who underwent standard surgical procedures. Indentation testing was performed on the specimens to obtain their force-displacement data. To determine the specimens' hyperelastic parameters using these data, an inverse FE framework was utilized. In this work, the hyperelastic parameters corresponding to the commonly used Yeoh and 2nd order Ogden models were obtained. Both models captured the experimental force-displacement data of the tissue specimens reasonably accurately with mean errors of 11.65% or smaller. This study has provided estimates of the hyperelastic parameters of all upper airway soft tissues using fresh human tissue specimens for the first time.

Role of voice rest following laser resection of vocal fold lesions: A randomized controlled trial.

OBJECTIVES/HYPOTHESIS: Voice rest is often prescribed following phonosurgery by most surgeons despite limited empiric evidence to support its practice. This study assessed the effect of postphonosurgery voice rest on vocal outcomes. STUDY DESIGN: Prospective, randomized controlled trial. METHODS: Patients with unilateral vocal fold lesions undergoing CO2 laser excision were recruited in a prospective manner and randomized into one of two groups: 1) an experimental arm consisting of 7 days of absolute voice rest, or 2) a control arm consisting of no voice rest. The primary outcome measure was the Voice Handicap Index-10 (VHI-10) questionnaire. Secondary outcomes included aerodynamic measurements (maximum phonation time), acoustic measures (fundamental frequency, jitter, shimmer, and harmonic-to-noise ratio), and auditory-perceptual measures. Primary and secondary outcomes were assessed preoperatively and reassessed postoperatively at the 1- and 3-month follow-up. Patient compliance to voice rest instructions were controlled for using subjective and objective parameters. RESULTS: Thirty patients were enrolled with 15 randomized to each arm of the study. Statistical analysis for the entire cohort showed a significant improvement in the mean preoperative VHI-10 compared to postoperative assessments at 1-month (19.0 vs. 7.3, P < .05) and 3-month (19.0 vs. 6.2, P < .05) follow-up. However, between-group comparisons showed no significant difference in postoperative VHI-10 at either time point. Similarly, secondary outcome measures yielded no significant difference in between-group comparisons. CONCLUSIONS: Our study shows no significant benefit to voice rest on postoperative voice outcomes as determined by patient self-perception, acoustic variables, and auditory-perceptual analysis. LEVEL OF EVIDENCE: 1b CLINICAL TRIAL NUMBER: NCT02788435 (clinicaltrials.gov) Laryngoscope, 130:1750-1755, 2020.

Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition.

Phosphoinositide 3-kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K-PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K-activated Akt signaling is well established in HNSCC, the significance of mTORC2-driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2-specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy.

Therapeutic trials of biologics in primary biliary cholangitis: An open label study of abatacept and review of the literature.

Primary biliary cholangitis (PBC) is a classic autoimmune disease in which humoral, cytotoxic, and innate immune responses have been implicated with the specific targeting of a mitochondrial antigen. The mainstay of treatment remains the bile acid ursodeoxycholic acid (UDCA). Corticosteroids may have some benefits, but to date, clinical trials of biologics targeting B cells and IL-12/23 have not shown any efficacy. Because activated T cells target the intrahepatic bile ducts in PBC and pre-clinical models suggested that blocking CD80/CD86 with CTLA-4 Ig might have therapeutic benefit in PBC, we performed an open-label trial to determine if CTLA-4 Ig (abatacept) is safe and potentially efficacious in PBC patients with an incomplete response to UDCA. PBC patients with an alkaline phosphatase (ALP) > 1.67 × the upper limit of normal after 6 months on UDCA treatment or who were intolerant of UDCA received abatacept 125 mg s.q. weekly for 24 weeks. The co-primary endpoint was ALP normalization or a >40% reduction from baseline. Among 16 subjects enrolled and who received at least 1 dose of abatacept, 1 (6.3%) met the co-primary endpoint. Absolute and percent changes in ALP [median (95% CI)] were +2.8 U/L (-90.9-96.6) and -0.28% (-21.1-15.5), respectively. No significant changes were observed in ALP, ALT, total bilirubin, albumin, immunoglobulins, or liver stiffness. Abatacept treatment decreased several non-terminally differentiated CD4+ but not CD8+ T cell populations, including decreases in CD4+ CCR5+ (p = 0.02) and CD4+ PD1+ (p = 0.03) lymphocytes. In contrast there were increases in CD4+ CCR7+ lymphocytes (p = 0.034). Treatment emergent adverse events occurred in 4 subjects. Abatacept was well tolerated in this population of PBC patients but like other biologics in PBC was ineffective in achieving biochemical responses associated with improved clinical outcomes.

Estimation of the Young's moduli of fresh human oropharyngeal soft tissues using indentation testing.

Finite element (FE)-based biomechanical simulations of the upper airway are promising computational tools to study abnormal upper airway deformations under obstructive sleep apnea (OSA) conditions and to help guide minimally invasive surgical interventions in case of upper airway collapse. To this end, passive biomechanical properties of the upper airway tissues, especially oropharyngeal soft tissues, are indispensable. This research aimed at characterizing the linear elastic mechanical properties of the oropharyngeal soft tissues including palatine tonsil, soft palate, uvula, and tongue base. For this purpose, precise indentation experiments were conducted on freshly harvested human tissue samples accompanied by FE-based inversion schemes. To minimize the impact of the probable nonlinearities of the tested tissue samples, only the first quarter of the measured force-displacement data corresponding to the linear elastic regime was utilized in the FE-based inversion scheme to improve the accuracy of the tissue samples' Young's modulus calculations. Measured Young's moduli of the oropharyngeal soft tissues obtained in this study are presented. They include first estimates for palatine tonsil tissue samples while measured Young's moduli of other upper airway tissues were obtained for the first time using fresh human tissue samples.

Constructing a patient-specific computer model of the upper airway in sleep apnea patients.

OBJECTIVE: The use of computer simulation to develop a high-fidelity model has been proposed as a novel and cost-effective alternative to help guide therapeutic intervention in sleep apnea surgery. We describe a computer model based on patient-specific anatomy of obstructive sleep apnea (OSA) subjects wherein the percentage and sites of upper airway collapse are compared to findings on drug-induced sleep endoscopy (DISE). STUDY DESIGN: Basic science computer model generation. METHODS: Three-dimensional finite element techniques were undertaken for model development in a pilot study of four OSA patients. Magnetic resonance imaging was used to capture patient anatomy and software employed to outline critical anatomical structures. A finite-element mesh was applied to the volume enclosed by each structure. Linear and hyperelastic soft-tissue properties for various subsites (tonsils, uvula, soft palate, and tongue base) were derived using an inverse finite-element technique from surgical specimens. Each model underwent computer simulation to determine the degree of displacement on various structures within the upper airway, and these findings were compared to DISE exams performed on the four study patients. RESULTS: Computer simulation predictions for percentage of airway collapse and site of maximal collapse show agreement with observed results seen on endoscopic visualization. CONCLUSION: Modeling the upper airway in OSA patients is feasible and holds promise in aiding patient-specific surgical treatment. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:277-282, 2018.

Timing of endoscopic surgical decompression in traumatic optic neuropathy: a systematic review of the literature.

BACKGROUND: Traumatic optic neuropathy (TON) represents a rare but devastating complication of closed head injuries. No accepted guidelines are available for medical and surgical management algorithms. A systematic review of the literature was performed to determine the optimal timing and candidacy for endoscopic surgical intervention. METHODS: A systematic review of multiple databases was performed including Medline-Ovid, EMBASE, and PubMed. Data was extracted and patients stratified based on surgical delay from trauma (≤3 days, >3 days, ≤7 days, or >7 days) as well as preoperative and postoperative vision testing (no light perception [NLP]; light perception [LP]; hand motion [HM]; or finger counting [FC] or better). RESULTS: The literature review identified 24 studies meeting inclusion criteria. In the group of patients receiving surgery ≤3 days after the antecedent event, 57% (105/183) had visual improvement, whereas in the >7-days group 51% (145/283) of patients improved. In those with NLP preoperatively, 41% (172/411) saw improvement, whereas those with LP (89%), HM (93%), or FC (85%) fared better. CONCLUSION: The literature suggests that surgical intervention for TON is indicated despite delayed presentation, and is a better choice than no intervention at all. Patients with complete blindness on presentation (NLP) tend to have a poorer surgical outcome.

Does HPV type affect outcome in oropharyngeal cancer?

BACKGROUND: An epidemic of human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (OPSCC) has been reported worldwide largely due to oral infection with HPV type-16, which is responsible for approximately 90% of HPV-positive cases. The purpose of this study was to determine the rate of HPV-positive oropharyngeal cancer in Southwestern Ontario, Canada. METHODS: A retrospective search identified ninety-five patients diagnosed with OPSCC. Pre-treatment biopsy specimens were tested for p16 expression using immunohistochemistry and for HPV-16, HPV-18 and other high-risk subtypes, including 31,33,35,39,45,51,52,56,58,59,67,68, by real-time qPCR. RESULTS: Fifty-nine tumours (62%) were positive for p16 expression and fifty (53%) were positive for known high-risk HPV types. Of the latter, 45 tumors (90%) were identified as HPV-16 positive, and five tumors (10%) were positive for other high-risk HPV types (HPV-18 (2), HPV-67 (2), HPV-33 (1)). HPV status by qPCR and p16 expression were extremely tightly correlated (p < 0.001, Fishers exact test). Patients with HPV-positive tumors had improved 3-year overall (OS) and disease-free survival (DFS) compared to patients with HPV-negative tumors (90% vs 65%, p = 0.001; and 85% vs 49%, p = 0.005; respectively). HPV-16 related OPSCC presented with cervical metastases more frequently than other high-risk HPV types (p = 0.005) and poorer disease-free survival was observed, although this was not statistically significant. CONCLUSION: HPV-16 infection is responsible for a significant proportion of OPSCC in Southwestern Ontario. Other high-risk subtypes are responsible for a smaller subset of OPSCC that present less frequently with cervical metastases and may have a different prognosis.