A novel pipeline for prioritizing cancer type-specific therapeutic vulnerabilities using DepMap identifies PAK2 as a target in head and neck squamous cell carcinomas.

There is limited guidance on exploiting the genome-wide loss-of-function CRISPR screens in cancer Dependency Map (DepMap) to identify new targets for individual cancer types. This study integrated multiple tools to filter these data in order to seek new therapeutic targets specific to head and neck squamous cell carcinoma (HNSCC). The resulting pipeline prioritized 143 targetable dependencies that represented both well-studied targets and emerging target classes like mitochondrial carriers and RNA-binding proteins. In total, 14 targets had clinical inhibitors used for other cancers or nonmalignant diseases that hold near-term potential to repurpose for HNSCC therapy. Comparing inhibitor response data that were publicly available for 13 prioritized targets between the cell lines with high vs. low dependency on each target uncovered novel therapeutic potential for the PAK2 serine/threonine kinase. PAK2 gene dependency was found to be associated with wild-type p53, low PAK2 mRNA, and diploid status of the 3q amplicon containing PAK2. These findings establish a generalizable pipeline to prioritize clinically relevant targets for individual cancer types using DepMap. Its application to HNSCC highlights novel relevance for PAK2 inhibition and identifies biomarkers of PAK2 inhibitor response.

Functional Outcomes in Patients with Human Papillomavirus-Associated Oropharyngeal Squamous Cell Cancer Treated with Trimodality Therapy.

OBJECTIVES: To describe swallowing and feeding-tube outcomes in patients with high-risk oropharyngeal cancer treated with trimodality therapy (TMT), including transoral robotic surgery (TORS) and adjuvant chemoradiotherapy. METHODS: A chart review was conducted on patients with HPV+ OPSCC receiving TMT with TORS at an academic medical center from March 2010 to March 2021. Data collected included demographics, treatment, feeding tube placement, functional oral intake scale (FOIS) scores, and swallowing-language pathology (SLP) evaluations. RESULTS: A total of 255 patients met selection criteria (mean age 61 years, 88% male). Following intraoperative nasogastric tube (NG) placement, 31% remained NG tube dependent after 3 weeks. A gastrostomy tube was placed in 19% of patients, and at 1 year after end-of-treatment (EOT), 3.5% overall remained tube-dependent. Mean FOIS scores were 6.9 (SD = 0.3) at pre-operative visit, 2.6 (1.8) at first post-operative visit, and 5.5 (1.5) after EOT. In the subset of patients with follow-up longer than 2 years (n = 118), the mean FOIS was 6.1 (SD = 1.3) at most recent visit. Clinical signs of aspiration/penetration were suspected on SLP evaluation in 18% of patients. These patients were subsequently evaluated with fiberoptic endoscopic evaluation of swallowing (FEES) and/or barium swallow study, which confirmed signs of aspiration in 2.7% of patients overall. Delayed NG tube removal after 3 weeks was predictive of (1) gastrostomy tube requirement and (2) clinical signs of aspiration on an SLP visit after EOT. CONCLUSIONS: Favorable functional and feeding-tube outcomes are demonstrated in patients with HPV-associated OPSCC undergoing TMT. In this single-institution study, we found low rates of long-term feeding tube dependence and high median FOIS following treatment. Review of routine SLP visits provides a detailed and easily accessible means for assessing swallowing function in this cohort. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:3013-3020, 2023.

Diagnostic Yield and Utility of Radiographic Imaging in the Evaluation of Pulsatile Tinnitus: A Systematic Review.

Objective: The objective of this study is to assess diagnostic yield of imaging modalities used to evaluate patients presenting with pulsatile tinnitus (PT). Databases Reviewed: PubMed, Embase, and Scopus were queried using the search terms "pulsatile tinnitus," "pulse-synchronous tinnitus," and "pulse synchronous tinnitus" with no date limitations. Methods: Studies that reported diagnostic imaging for patients presenting with PT were included. Data were reviewed for sample size, gender, age, imaging study, indications, and diagnoses. The primary outcome measure from aggregated data was the yield of positive diagnoses made with each imaging modality. The quality of evidence was assessed for risk of bias. Results: From an initial search of 1145 articles, 17 manuscripts met inclusion criteria, of which 12 studies evaluated individual imaging modalities. The number of unique patients included was 1232. The diagnostic yield varied between modalities: carotid ultrasound (21%, 95% confidence interval [CI]: 12%-35%), CT temporal bone (65%, CI: 20%-93%), computed tomographic angiography (86%, CI: 80%-90%), and MRI/magnetic resonance angiography (58%, CI: 43%-72%). Conclusion: Studies on the diagnostic approach to PT are limited by heterogeneity in both inclusion criteria and reporting standards. A wide range of imaging modalities are used in practice during the initial evaluation of PT, and the diagnostic yield for imaging can be improved by utilizing more specific clinical indications.

Use of the O-Z flap as an alternative to free tissue transfer for reconstruction of large scalp defects.

Objective: The reconstruction of large scalp defects poses both functional and cosmetic challenges. While free tissue transfer remains the standard for defects larger than 30 cm2, prolonged anesthesia and postoperative complications remain significant limitations. The purpose of this study is to evaluate the use of O-Z flaps for the reconstruction of large scalp defects and to describe the techniques employed. Methods: This is a retrospective analysis of ten patients who underwent reconstructive surgery using an O-Z flap approach for large scalp defects between July 2017 and June 2019. The parameters included in this study were patient demographics, tumor characteristics, and postoperative management, collected for at least a year after surgery. Results: In this cohort, the mean age was 76.1 years and 90% were male. All patients were treated for neoplastic skin lesions, with 70% located on the vertex and 30% located on the temporoparietal region. The mean size of defect was 52.0 cm2 (range: 38.6 to 63.8 cm2). The maximum hospital stay was two days, and no patients were readmitted within 30 days of surgery. There were no cases of wound infection or flap necrosis. All patients reported pain control with acetaminophen and ibuprofen. Four patients received adjuvant radiation, and there was no delay to receiving treatment following surgery. Conclusions: The O-Z flap is a reliable alternative for the reconstruction of non-irradiated scalp defects in the vertex and temporoparietal regions up to 63 cm2. This technique provides advantages for patients, including hairline preservation, shorter hospital stays, and decreased postoperative complications.

Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis.

Neural stem cells, the source of newborn neurons in the adult hippocampus, are intimately involved in learning and memory, mood, and stress response. Despite considerable progress in understanding the biology of neural stem cells and neurogenesis, regulating the neural stem cell population precisely has remained elusive because we have lacked the specific targets to stimulate their proliferation and neurogenesis. The orphan nuclear receptor TLX/NR2E1 governs neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is not well understood because its endogenous ligand is not known. Here, we identify oleic acid (18:1ω9 monounsaturated fatty acid) as such a ligand. We first show that oleic acid is critical for neural stem cell survival. Next, we demonstrate that it binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell-cycle and neurogenesis genes, which in turn increases neural stem cell mitotic activity and drives hippocampal neurogenesis in mice. Interestingly, oleic acid-activated TLX strongly up-regulates cell cycle genes while only modestly up-regulating neurogenic genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation and drive the progeny toward neuronal lineage. Oleic acid thus serves as a metabolic regulator of TLX activity that can be used to selectively target neural stem cells, paving the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.

Expression and Potential Prognostic Value of SOX9, MCL-1 and SPOCK1 in Gastric Adenocarcinoma.

Gastric cancer is a common malignancy and remains one of the leading causes of cancer-related deaths, though its incidence is in decline in most developed countries. One of the major challenges of treating gastric cancer is tumor heterogeneity, which portends a high degree of prognostic variance and the necessity for different treatment modalities. Tumor heterogeneity is at least in part due to divergent differentiation of tumor cells to clones harboring different molecular alterations. Here we studied the expression of emerging prognostic markers SOX9, MCL-1, and SPOCK1 (Testican-1) in a cohort of gastric cancer by immunohistochemistry and investigated how individual biomarkers and their combinations predict disease prognosis. We found frequent expression of SPOCK1 (in both nuclei and cytoplasm), MCL-1 and SOX9 in gastric cancer. In univariate analysis, nuclear SPOCK1 expression and pathologic TNM stage were negative prognostic markers in this cohort. In multivariate analysis, SOX9 expression stood out as a predictor of poor prognosis. Further subgroup analysis suggested prognostic value of SOX9 expression in poorly differentiated gastric adenocarcinoma. MCL-1 showed no prognostic role in this cohort.

Objective screening for olfactory and gustatory dysfunction during the COVID-19 pandemic: a prospective study in healthcare workers using self-administered testing.

BACKGROUND: Smell and taste loss are highly prevalent symptoms in coronavirus disease 2019 (COVID-19), although few studies have employed objective measures to quantify these symptoms, especially dysgeusia. Reports of unrecognized anosmia in COVID-19 patients suggests that self-reported measures are insufficient for capturing patients with chemosensory dysfunction. OBJECTIVES: The purpose of this study was to quantify the impact of recent COVID-19 infection on chemosensory function and demonstrate the use of at-home objective smell and taste testing in an at-risk population of healthcare workers. METHODS: Two hundred and fifty healthcare workers were screened for possible loss of smell and taste using online surveys. Self-administered smell and taste tests were mailed to respondents meeting criteria for elevated risk of infection, and one-month follow-up surveys were completed. RESULTS: Among subjects with prior SARS-CoV-2 infection, 73% reported symptoms of olfactory and/or gustatory dysfunction. Self-reported smell and taste loss were both strong predictors of COVID-19 positivity. Subjects with evidence of recent SARS-CoV-2 infection (<45 days) had significantly lower olfactory scores but equivalent gustatory scores compared to other subjects. There was a time-dependent increase in smell scores but not in taste scores among subjects with prior infection and chemosensory symptoms. The overall infection rate was 4.4%, with 2.5% reported by PCR swab. CONCLUSION: Healthcare workers with recent SARS-CoV-2 infection had reduced olfaction and normal gustation on self-administered objective testing compared to those without infection. Rates of infection and chemosensory symptoms in our cohort of healthcare workers reflect those of the general public.

Current Practices in Endotracheal Tube Size Selection for Adults.

OBJECTIVES/HYPOTHESIS: Intubation with inappropriately sized endotracheal tubes (ETT) can cause long-term tracheal and laryngeal injuries often requiring surgical intervention. Although tracheal size has been demonstrated to vary based on height and sex, it is unclear whether these guidelines are regularly implemented in patients undergoing endotracheal intubation. The objective of this study is to determine the rate of appropriate ETT size selection in patients undergoing intubation and assess provider decision making in ETT size selection. STUDY DESIGN: Retrospective cohort study. METHODS: The study population was all patients who underwent endotracheal intubation over a two-week period at a tertiary academic medical center. Data were collected on patient age, gender, height, BMI, comorbidities, ETT size, duration of intubation, bronchoscopies, and type of practitioner who performed the intubation. A height-based nomogram for ETT size selection was used to determine the recommended ETT size for each patient. RESULTS: One hundred five patients met the inclusion criteria. 22% of patients were intubated with an inappropriately large tube, defined as 1.0 mm larger than the recommended size. Women were more likely to be intubated with an inappropriately large ETT (OR = 13.58, P = .001), as were patients with height less than 160 cm (OR = 141, P = .001). Other factors related to disease severity, anticipation for bronchoscopy, and BMI were not risk factors for the use of inappropriately large ETT. CONCLUSIONS: Although there is compelling evidence that height is a strong predictor of tracheal morphology and appropriate ETT size, height-based guidelines have yet to be universally adopted for ETT size selection. Laryngoscope, 131:1967-1971, 2021.