Comprehensive functional evaluation of head and neck squamous cell carcinoma with BH3-profiling demonstrates apoptotic competency and therapeutic efficacy of BH3-mimetics.

Evasion of apoptosis promotes tumor survival and contributes to resistance to cancer therapeutics in head and neck squamous cell carcinoma (HNSCC). Our recent work has demonstrated that HNSCC's highly express pro-survival anti-apoptotic proteins Bcl-xL and Mcl-1. Nevertheless, the mechanism of HNSCC to evade apoptosis is still not well understood. We used BH3 profiling, a functional assay which measures mitochondrial depolarization in response to the introduction of BH3 peptides, to evaluate apoptosis competency and dependency upon BCL-2 family anti-apoptotic proteins in a panel of immortalized and patient-derived HNSCC lines. We assessed response to BH3 mimetics including ABT-263 (navitoclax), an inhibitor of Bcl-2/Bcl-xL/Bcl-w, and S63845, an inhibitor of Mcl-1, both as single agents and in combination. We demonstrate that apoptosis signaling appears to be intact in the majority of HNSCC cells, and they are co-dependent upon Bcl-xL and Mcl-1 for survival. We found the combination to be highly synergistic in 2D culture and in 3D organoid models of HHNSCC. Given our findings that co-dependency on Bcl-xL and Mcl-1 is common, and co-inhibition of these molecules is synergistic for growth suppression in HNSCC cells, these results elucidate the therapeutic potential of BCL-xL and MCL-1 inhibition in HNSCC.

Association of tumor growth rate with overall survival and recurrence among patients with laryngeal squamous cell carcinoma.

BACKGROUND: Delay in time to treatment initiation (TTI) is associated with worsened survival outcomes in laryngeal squamous cell carcinoma (LSCC). It is unclear whether this is due to tumor growth or an increased risk of metastatic disease. METHODS: This retrospective cohort study at one academic center included patients with LSCC who underwent radiotherapy/chemoradiotherapy between 2005 and 2017. We examined the association between tumor growth rate (TGR) and survival outcomes. RESULTS: Among 105 patients (mean age, 63.8 ± 11.1 years; 72% male), the threshold between "slow-growing" and "fast-growing" tumors was >0.036 mL/day (survival) and >0.082 mL/day (recurrence). Faster growth was associated with worse overall survival (OS) (hazard ratio, 1.97; 95% confidence interval [CI], 0.94-4.13) and increased recurrence (odds ratio, 9.10; 95% CI, 2.40-34.4). CONCLUSIONS: TGR >0.036 mL/day during TTI was associated with decreased OS, and >0.082 mL/day was associated with increased recurrence. Tumor measurement in patients experiencing delay may identify those who could benefit from escalated therapy.

Early, precise, and safe clinical evaluation of the pharmacodynamic effects of novel agents in the intact human tumor microenvironment.

Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.

Characterization of a Diverse Set of Conditionally Reprogrammed Head and Neck Cancer Cell Cultures.

OBJECTIVE: To establish and characterize a diverse library of head and neck squamous cell cancer (HNSCC) cultures using conditional reprogramming (CR). METHODS: Patients enrolled on an IRB-approved protocol to generate tumor cell cultures using CR methods. Tumor and blood samples were collected and clinical information was recorded. Successful CR cultures were validated against banked reference tumors with short tandem repeat genotyping. Cell morphology was archived with photodocumentation. Clinical and demographic factors were evaluated for associations with successful establishment of CR culture. Human papilloma virus (HPV) genotyping, clonogenic survival, MTT assays, spheroid growth, and whole exome sequencing were carried out in selected cultures. RESULTS: Forty four patients were enrolled, with 31 (70%) successful CR cultures, 32% derived from patients who identified as Black and 61% as Hispanic. All major head and neck disease sites were represented, including 15 (48%) oral cavity and 8 (26%) p16-positive oropharynx cancers. Hispanic ethnicity and first primary tumors (vs. second primary or recurrent tumors) were significantly associated with successful CR culture. HPV expression was conserved in CR cultures, including CR-024, which carried a novel HPV-69 serotype. CR cultures were used to test cisplatin responses using MTT assays. Previous work has also demonstrated these models can be used to assess response to radiation and can be engrafted in mouse models. Whole exome sequencing demonstrated that CR cultures preserved tumor mutation burden and driver mutations. CONCLUSION: CR culture is highly successful in propagating HNSCC cells. This study included a high proportion of patients from underrepresented minority groups. LEVEL OF EVIDENCE: Not Applicable Laryngoscope, 134:2748-2756, 2024.

Harnessing In Situ Simulation to Identify Human Errors and Latent Safety Threats in Adult Tracheostomy Care.

BACKGROUND: Tracheostomies are associated with high rates of complications and preventable harm. Safe tracheostomy management requires highly functioning teams and systems, but health care providers are poorly equipped with tracheostomy knowledge and resources. In situ simulation has been used as a quality improvement tool to audit multidisciplinary team emergency response in the actual clinical environment where care is delivered but has been underexplored for tracheostomy care. METHODS: From July 2021 to May 2022, the study team conducted in situ simulations of a tracheostomy emergency scenario at Montefiore Medical Center to identify human errors and latent safety threats (LSTs). Simulations included structured debriefs as well as audiovisual recording that allowed for blind rating of these human errors and LSTs. Provider knowledge deficits were further characterized using pre-simulation quizzes. RESULTS: Twelve human errors and 15 LSTs were identified over 20 simulations with 88 participants overall. LSTs were divided into the following categories: communication, equipment, and infection control. Only 50.0% of teams successfully replaced the tracheostomy tube within the scenario's five-minute time limit. In addition, knowledge gaps were highly prevalent, with a median pre-simulation quiz score of 46% (interquartile range 36-64) among participants. CONCLUSION: An in situ simulation-based quality improvement approach shed light on human errors and LSTs associated with tracheostomy care across multiple settings in one health system. This method of engaging frontline health care provider key stakeholders will inform the development, adaptation, and implementation of interventions.

Complications related to thyroidectomy among patients with hyperthyroidism: Exploring the potential for ambulatory surgery.

BACKGROUND: Total thyroidectomy for hyperthyroidism is typically followed by overnight admission to monitor for complications including thyrotoxicosis. Outpatient thyroid surgery is increasingly common, but its safety in patients with hyperthyroidism has not been well studied. METHODS: This retrospective study reviewed 183 patients with hyperthyroidism who underwent total thyroidectomy from 2015 to 2022 at one urban, academic center. The main outcomes were rates of thyroid storm, surgical complications, and 30-day ED visits and readmissions. RESULTS: Among 183 patients with hyperthyroidism (mean age, 45 ± 14.5 years; 82.5% female), there were no cases of thyroid storm and complications included recurrent laryngeal nerve (RLN) palsy (7.0%), symptomatic hypocalcemia (4.4%), and hematoma (1.6%). ED visits were present in 1.1% and no patients were readmitted. CONCLUSION: Total thyroidectomy was not associated with thyroid storm and <6% of patients required inpatient management. Ambulatory total thyroidectomy for hyperthyroidism warrants further consideration through identification of predictive factors for postoperative complications.

Value of Adherence to Posttreatment Follow-Up Guidelines for Head and Neck Squamous Cell Carcinoma.

OBJECTIVES: The utility of intensive posttreatment surveillance of head and neck squamous cell carcinoma (HNSCC) has been debated. The objective is to investigate adherence to the National Comprehensive Cancer Network (NCCN) posttreatment follow-up guidelines and assess the association with recurrence and survival. METHODS: A total of 452 patients diagnosed with HNSCC at an academic medical center in a socioeconomically disadvantaged, urban setting were categorized by adherence to NCCN follow-up guidelines. Survival analyses were conducted to study the association between adherence and the 5-year overall survival and disease-specific survival in the entire cohort and subset of patients with documented recurrence. RESULTS: We found that 23.5% of patients were adherent to NCCN follow-up guidelines in the first year after treatment, and 15.9% were adherent over 5 years. Adherence in the first year was significantly associated with 5-year overall survival (HR 0.634; 95% CI 0.443-0.906; p = 0.0124) and disease-specific survival (HR 0.556; 95% CI 0.312-0.992; p = 0.0470), but consistent adherence over 5 years did not show a significant association. Among the 21.7% of the cohort with recurrence, adherence was not associated with early-stage recurrence (AJCC stage I/II). In this subset, first year adherence was associated with improved disease-specific but not overall survival, and adherence over 5 years was not associated with survival. CONCLUSION: Adherence to NCCN follow-up guidelines in the first year after treatment was associated with a better chance of 5-year overall and disease-specific survival, but this significant association was not observed among those who demonstrated consistent adherence over 5 years. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:708-716, 2024.

Establishment of a diverse head and neck squamous cancer cell bank using conditional reprogramming culture methods.

Most laboratory models of head and neck squamous cell cancer (HNSCC) rely on established immortalized cell lines, which carry inherent bias due to selection and clonality. We established a robust panel of HNSCC tumor cultures using a "conditional reprogramming" (CR) method, which utilizes a rho kinase inhibitor (Y-27632) and co-culture with irradiated fibroblast (J2 strain) feeder cells to support indefinite tumor cell survival. Sixteen CR cultures were successfully generated from 19 consecutively enrolled ethnically and racially diverse patients with HNSCC at a tertiary care center in the Bronx, NY. Of the 16 CR cultures, 9/16 were derived from the oral cavity, 4/16 were derived from the oropharynx, and 3/16 were from laryngeal carcinomas. Short tandem repeat (STR) profiling was used to validate culture against patient tumor tissue DNA. All CR cultures expressed ΔNp63 and cytokeratin 5/6, which are markers of squamous identity. Human papillomavirus (HPV) testing was assessed utilizing clinical p16 staining on primary tumors, reverse transcription polymerase chain reaction (RT-PCR) of HPV16/18-specific viral oncogenes E6 and E7 in RNA extracted from tumor samples, and HPV DNA sequencing. Three of four oropharyngeal tumors were p16 and HPV-positive and maintained HPV in culture. CR cultures were able to establish three-dimensional spheroid and murine flank and orthotopic tongue models. CR methods can be readily applied to all HNSCC tumors regardless of patient characteristics, disease site, and molecular background, providing a translational research model that properly includes patient and tumor diversity.

Biphenotypic Sinonasal Sarcoma: A Case Report and Review of Literature.

OBJECTIVES: Biphenotypic sinonasal sarcoma (BSNS), previously low-grade sinonasal sarcoma with neural and myogenic features, is a rare tumor of the sinonasal tract first described in 2012. Due to its rarity, limited literature is available in providing clinicians with a standardized treatment regimen, particularly in cases of positive surgical margins. This article aims to provide a clinical review of the currently available reported cases of BSNS, as well as presenting clinical, radiologic, and pathologic details of 2 novel cases. METHODS: Online electronic databases include PubMed and Embase where queried for reports of biphenotypic sinonasal sarcoma or low-grade sinonasal sarcoma with neural and myogenic features. Two previously unpublished cases were included in the results. Data including clinical presentation, epidemiologic data, radiologic evaluation, intraoperative details, histopathology, treatment modality, and postoperative follow-up information were included. RESULTS: A total of 100 previously published cases were identified in 12 prior articles. Mean age at presentation was 52.9 years. Extrasinonasal extension was observed in 27.4% of cases with most common site of extension being cribriform plate. Forty-seven cases included treatment details with surgical excision being the most common modality. Recurrence rates were identical for both surgical excision alone and surgical excision with adjuvant radiotherapy (33.3%). CONCLUSIONS: Biphenotypic sinonasal sarcoma is a slow-growing tumor that is amenable to surgical resection. Recurrence rates are similar between surgical excision and surgical excision with adjuvant radiation therapy, but limited data in reported cases preclude a determination of treatment superiority.

The surgical airway in the COVID-19 era.

The aim is to summarize the guidelines for tracheostomy management during the COVID-19 pandemic. This is a comparative study analysis and literature review using articles found in the PubMed/MEDLINE database. Here we summarize published work on tracheostomy timing, technique, outcomes, mortality, and decannulation rates during the COVID-19 pandemic, with a focus on expertise from our own institution. Among 12 studies, 2,692 tracheostomies were performed at an average of 17.5 days from intubation. 66.4% were performed open, and 33.6% percutaneously. A total of 85.6% were performed bedside, and 14.4% in the operating room. 19.5% experienced all-cause mortality, and 43.4% were decannulated. In these studies, only 1 proceduralist became infected with COVID-19. Early COVID-19 recommendations advocated for tracheostomy a minimum of 14 days from intubation. Currently, tracheostomy is performed more closely to prepandemic criteria. Bedside tracheostomy comprised most procedures during the pandemic. Tracheostomy in COVID-19 patients, when performed with techniques to minimize aerosolization, is safe and poses minimal risk of infection to providers performing the procedure.

Left-sided facial mass in an adult female.

A left maxillary sinus soft tissue mass was discovered on computed tomography in a 70-year-old woman who had been experiencing blood-tinged mucus for 2 years. The lesion demonstrated mild enhancement, and bony destruction. Magnetic resonance imaging displayed a cerebriform appearance of the mass, which mimicked the appearance of inverted papilloma. However, histology and staining identified the lesion as ameloblastoma. Resection of the tumor was successful with no recurrence 1 month later on follow-up computed tomography. This case represents an unusual imaging presentation of ameloblastoma, and an opportunity to avoid the misdiagnosis of inverted papilloma in similar future cases.

Impact of Nonadherence to NCCN Adjuvant Radiotherapy Initiation Guidelines in Head and Neck Squamous Cell Carcinoma in an Underserved Urban Population.

BACKGROUND: Nonadherence to NCCN Guidelines during time from surgery to postoperative radiotherapy (S-PORT) can alter survival outcomes in head and neck squamous cell carcinomna (HNSCC). There is a need to validate this impact in an underserved urban population and to understand risk factors and reasons for delay. We sought to investigate the impact of delayed PORT with outcomes of overall survival (OS) in HNSCC, to analyze predictive factors of delayed PORT, and to identify reasons for delay. METHODS: We conducted a retrospective cohort study in an urban, community-based academic center. A total of 184 patients with primary HNSCC were identified through the Montefiore Medical Center cancer registry who had been treated between March 1, 2005, and March 8, 2017, and met the inclusion and exclusion criteria. The primary exposure was S-PORT. OS, recurrence, and risk factors and reasons for treatment delay were the main outcomes and measures. RESULTS: Among 184 patients with HNSCC treated with PORT, the median S-PORT was 48.5 days (interquartile range, 41-67 days). The S-PORT threshold that optimally differentiated worse OS outcomes was >50 days (46.7% of our cohort; n=86). Independent of other relevant factors, patients with HNSCC and S-PORT >50 days had worse OS (hazard ratio, 2.30; 95% CI, 1.34-3.95) and greater recurrence (odds ratio, 3.51; 95% CI, 1.31-9.39). Predictors of delayed S-PORT included being underweight or obese, prolonged postoperative length of stay, and age >70 years. The most frequent reasons for PORT delay were complications related to surgery (22.09%), unrelated medical comorbidities (18.60%), and nonadherence/missed appointments (6.98%). CONCLUSIONS: Delayed PORT beyond 50 days after surgery was associated with decreased OS and greater recurrence. Identification of predictive factors and reasons for treatment delay helps to target at-risk patients and facilitates interventions in underserved populations.

Use of Predictive Modeling to Tailor Molecular Testing Utilization for Thyroid Nodules.

OBJECTIVE: Various risk stratification systems for cytologically indeterminate thyroid nodules are available. However, malignancy risk assessment data, such as ultrasound features, are not always used when the decision is to order molecular testing or not. Our aim was to investigate the utility of molecular testing after incorporating an algorithm with ultrasound-based risk of malignancy (ROM) estimation. STUDY DESIGN: Diagnostic/prognostic study. SETTING: Single-institution urban tertiary care center. METHODS: We performed a single-institution retrospective chart review of all thyroid nodules that had undergone molecular testing. A web-based Malignancy Risk Estimation System for Thyroid Nodules was utilized with ultrasound findings to stratify malignancy risk according to the Korean Thyroid Imaging Reporting and Data System (TI-RADS), French TI-RADS, American Association of Clinical Endocrinology guideline, and American Thyroid Association guideline. A novel algorithm for utilizing molecular testing at our institution was developed with the Korean TI-RADS and with recommendations from the American Thyroid Association and National Comprehensive Cancer Network. RESULTS: The Korean TI-RADS performed best in our population (area under the curve = 0.83). A positive molecular test result had a positive association with a higher ROM according to all 4 models (P < .05). Use of our algorithm prior to molecular testing would have prevented 38% of benign/low-ROM negative nodules (n = 28) from being tested. CONCLUSION: In patients with indeterminate thyroid nodules, an algorithm built on pre- and posttest probability to guide molecular testing might reduce unnecessary testing of benign and low-risk nodules.

Tracheotomy Outcomes in 64 Ventilated COVID-19 Patients at a High-Volume Center in Bronx, NY.

OBJECTIVES/HYPOTHESIS: The COVID-19 pandemic has resulted in a dramatic increase in the number of patients requiring prolonged mechanical ventilation. Few studies have reported COVID-19 specific tracheotomy outcomes, and the optimal timing and patient selection criteria for tracheotomy remains undetermined. We delineate our outcomes for tracheotomies performed on COVID-19 patients during the peak of the pandemic at a major epicenter in the United States. METHODS: This is a retrospective observational cohort study. Mortality, ventilation liberation rate, complication rate, and decannulation rate were analyzed. RESULTS: Sixty-four patients with COVID-19 underwent tracheotomy between April 1, 2020 and May 19, 2020 at two tertiary care hospitals in Bronx, New York. The average duration of intubation prior to tracheotomy was 20 days ((interquartile range [IQR] 16.5-26.0). The mortality rate was 33% (n = 21), the ventilation liberation rate was 47% (n = 30), the decannulation rate was 28% (n = 18), and the complication rate was 19% (n = 12). Tracheotomies performed by Otolaryngology were associated with significantly improved survival (P < .05) with 60% of patients alive at the conclusion of the study compared to 9%, 12%, and 19% of patients undergoing tracheotomy performed by Critical Care, General Surgery, and Pulmonology, respectively. CONCLUSIONS: So far, this is the second largest study describing tracheotomy outcomes in COVID-19 patients in the United States. Our early outcomes demonstrate successful ventilation liberation and decannulation in COVID-19 patients. Further inquiry is necessary to determine the optimal timing and identification of patient risk factors predictive of improved survival in COVID-19 patients undergoing tracheotomy. LEVEL OF EVIDENCE: 4-retrospective cohort study Laryngoscope, 131:E1797-E1804, 2021.

Tracheotomy in a High-Volume Center During the COVID-19 Pandemic: Evaluating the Surgeon's Risk.

OBJECTIVE: Performing tracheotomy in patients with COVID-19 carries a risk of transmission to the surgical team due to potential viral particle aerosolization. Few studies have reported transmission rates to tracheotomy surgeons. We describe our safety practices and the transmission rate to our surgical team after performing tracheotomy on patients with COVID-19 during the peak of the pandemic at a US epicenter. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic hospital. METHODS: Tracheotomy procedures for patients with COVID-19 that were performed April 15 to May 28, 2020, were reviewed, with a focus on the surgical providers involved. Methods of provider protection were recorded. Provider health status was the main outcome measure. RESULTS: Thirty-six open tracheotomies were performed, amounting to 65 surgical provider exposures, and 30 (83.3%) procedures were performed at bedside. The mean time to tracheotomy from hospital admission for SARS-CoV-2 symptoms was 31 days, and the mean time to intubation was 24 days. Standard personal protective equipment, according to Centers for Disease Control and Prevention, was worn for each case. Powered air-purifying respirators were not used. None of the surgical providers involved in tracheotomy for patients with COVID-19 demonstrated positive antibody seroconversion or developed SARS-CoV-2-related symptoms to date. CONCLUSION: Tracheotomy for patients with COVID-19 can be done with minimal risk to the surgical providers when standard personal protective equipment is used (surgical gown, gloves, eye protection, hair cap, and N95 mask). Whether timing of tracheotomy following onset of symptoms affects the risk of transmission needs further study.

Global Tracheostomy Collaborative: data-driven improvements in patient safety through multidisciplinary teamwork, standardisation, education, and patient partnership.

There is growing recognition of the need for a coordinated, systematic approach to caring for patients with a tracheostomy. Tracheostomy-related adverse events remain a pervasive global problem, accounting for half of all airway-related deaths and hypoxic brain damage in critical care units. The Global Tracheostomy Collaborative (GTC) was formed in 2012 to improve patient safety and quality of care, emphasising knowledge, skills, teamwork, and patient-centred approaches. Inspired by quality improvement leads in Australia, the UK, and the USA, the GTC implements and disseminates best practices across hospitals and healthcare trusts. Its database collects patient-level information on quality, safety, and organisational efficiencies. The GTC provides an organising structure for quality improvement efforts, promoting safety of paediatric and adult patients. Successful implementation requires instituting key drivers for change that include effective training for health professionals; multidisciplinary team collaboration; engagement and involvement of patients, their families, and carers; and data collection that allows tracking of outcomes. We report the history of the collaborative, its database infrastructure and analytics, and patient outcomes from more than 6500 patients globally. We characterise this patient population for the first time at such scale, reporting predictors of adverse events, mortality, and length of stay indexed to patient characteristics, co-morbidities, risk factors, and context. In one example, the database allowed identification of a previously unrecognised association between bleeding and mortality, reflecting ability to uncover latent risks and promote safety. The GTC provides the foundation for future risk-adjusted benchmarking and a learning community that drives ongoing quality improvement efforts worldwide.

Tracheostomy during SARS-CoV-2 pandemic: Recommendations from the New York Head and Neck Society.

The rapid spread of SARS-CoV-2 in 2019 and 2020 has resulted in a worldwide pandemic characterized by severe pulmonary inflammation, effusions, and rapid respiratory compromise. The result of this pandemic is a large and increasing number of patients requiring endotracheal intubation and prolonged ventilator support. The rapid rise in endotracheal intubations coupled with prolonged ventilation requirements will certainly lead to an increase in tracheostomy procedures in the coming weeks and months. Performing tracheostomy in the setting of active SARS-CoV-2, when necessary, poses a unique situation, with unique risks and benefits for both the patient and the health care providers. The New York Head and Neck Society has collaborated on this document to provide guidance on the performance of tracheostomies during the SARS-CoV-2 pandemic.