Single Nucleotide Polymorphisms in Coronary Microvascular Dysfunction.

Coronary microvascular dysfunction is an underdiagnosed pathologic process that is associated with adverse clinical outcomes. There are data to suggest that coronary microvascular dysfunction, in some cases, may be genetically determined. We present an updated review of single nucleotide polymorphisms in coronary microvascular dysfunction.

The impact of digital inequities on laryngeal cancer disparities in the US.

OBJECTIVES: To develop and implement a novel, comprehensive tool, the Digital Inequity Index (DII), that quantifiably measures modern-technology access in the US to assess the impact of digital inequity on laryngeal cancer (LC) care nationwide. METHODS: DII was calculated based on 17 census-tract level variables derived from the American Community Survey and Federal Communications Commission. Variables were categorized as infrastructure-access (i.e., electronic device ownership, type of broadband, internet provider availability, income-broadband subscription ratio) or sociodemographic (i.e., education, income, disability status), ranked and then averaged into a composite score. 22,850 patients from 2008 to 2017 in SEER were assessed for regression trends in long-term follow-up, survival, prognosis, and treatment across increasing overall digital inequity, as measured by the DII. This methodology allows for us to assess the independent contribution of digital inequity adjusted for socioeconomic confounders. RESULTS: With increasing overall digital inequity, length of long-term follow-up (p < 0.001) and survival (p = 0.025) decreased. Compared to LC patients with low DII, high DII was associated with increased odds of advanced preliminary staging (OR 1.06; 95 % CI 1.03-1.08), treatment with chemotherapy (OR 1.06; 95 % CI 1.04-1.08), and radiation therapy (OR 1.02; 95 % CI 1.00-1.04), as well as decreased odds of surgical resection (OR 0.96; 95 % CI 0.94-97). CONCLUSIONS: Digital inequities are associated with detrimental trends in LC patient outcomes in the US, allowing discourse for targeted means of alleviating disparities while contextualizing national sociodemographic trends of the impact of online access on informed care.

Transthyretin Cardiac Amyloidosis Disguised as Light Chain Amyloidosis or Multiple Myeloma?

We describe 2 challenging cases of cardiac transthyretin amyloidosis initially treated as cardiac amyloidosis light chain in the setting of active myeloma. Endomyocardial biopsy with mass spectrometry was essential to confirm the appropriate diagnosis to direct the treatment.

Recurrent Cardiac Sarcoidosis and Giant Cell Myocarditis After Heart Transplant: A Case Report and Systematic Literature Review.

Recurrence of cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) after heart transplant is rare, with rates of 5% in CS and 8% in GCM. We aim to identify all reported cases of recurrence in the literature and to assess clinical course, treatments, and outcomes to improve understanding of the conditions. A systematic review, utilizing Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, was conducted by searching MEDLINE/PubMed and Embase of all available literature describing post-transplant recurrent granulomatous myocarditis, CS, or GCM. Data on demographics, transplant, recurrence, management, and outcomes data were collected from each publication. Comparison between the 2 groups were made using standard statistical approaches. Post-transplant GM recurrence was identified in 39 patients in 33 total publications. Reported cases included 24 GCM, 12 CS, and 3 suspected cases. Case reports were the most frequent form of publication. Mean age of patients experiencing recurrence was 42 years for GCM and 48 years for CS and favored males (62%). Time to recurrence ranged from 2 weeks to 9 years post-transplant, occurring earlier in GCM (mean 1.8 vs 3.0 years). Endomyocardial biopsies (89%) were the most utilized diagnostic method over cardiac magnetic resonance and positron emission tomography. Recurrence treatment regimens involved only steroids in 40% of CS, whereas other immunomodulatory regimens were utilized in 70% of GCM. In conclusion, GCM and CS recurrence after cardiac transplantation holds associated risks including concurrent acute cellular rejection, a higher therapeutic demand for GCM recurrence compared with CS, and mortality. New noninvasive screening techniques may help modify post-transplant monitoring regimens to increase both early detection and treatment of recurrence.

Assessment of Cardiovascular Risk for Noncardiac and Nonsurgical Activities.

Cardiovascular risk stratification is a frequent evaluation performed by health professionals. Not uncommonly, requests for risk stratification involve activities or procedures that fall outside of the scope of current evidence-based guidelines. Estimating risk and providing guidance for these requests can be challenging due to limited available evidence. This review focuses on some of these unique requests, each of which are real examples encountered in our practice. We offer guidance by synthesizing the available medical literature and formulating recommendations on topics such as the initiation of testosterone and erectile dysfunction therapy, SCUBA and skydiving, polygraphy, and electroconvulsive therapy.

A 43-Year-Old Woman With Pleuritic Chest Pain, Shortness of Breath, and Weakness of All Extremities.

CASE PRESENTATION: A 43-year-old woman with a medical history of hypothyroidism, psoriasis, and tobacco abuse (30-pack year history) who had quit smoking several months prior to presentation presented with pleuritic chest pain. She also noted a 2-year history of progressive numbness and weakness in her bilateral upper and lower extremities that now prevented her from completing her activities of daily living. She had worsening exertional dyspnea and a subjective 50-lb weight loss over the past year.

Postacute COVID-19 Laryngeal Injury and Dysfunction.

OBJECTIVE: Patients with COVID-19 are at risk for laryngeal injury and dysfunction secondary to respiratory failure, prolonged intubation, and other unique facets of this illness. Our goal is to report clinical features and treatment for patients presenting with voice, airway, and/or swallowing concerns postacute COVID-19. STUDY DESIGN: Case series. SETTING: Academic tertiary care center. METHODS: Patients presenting with laryngeal issues following recovery from COVID-19 were included after evaluation by our laryngology team. Data were collected via retrospective chart review from March 1, 2020, to April 1, 2021. This included details of the patient's COVID-19 course, initial presentation to laryngology, and subsequent treatment. RESULTS: Twenty-four patients met inclusion criteria. Twenty (83%) patients were hospitalized, and 18 required endotracheal intubation for a median (range) duration of 14 days (6-31). Ten patients underwent tracheostomy. Patients were evaluated at a median 107 days (32-215) after their positive SARS-CoV-2 test result. The most common presenting concerns were dysphonia (n = 19, 79%), dyspnea (n = 17, 71%), and dysphagia (n = 6, 25%). Vocal fold motion impairment (50%), early glottic injury (39%), subglottic/tracheal stenosis (22%), and posterior glottic stenosis (17%) were identified in patients who required endotracheal intubation. Patients who did not need intubation were most frequently treated for muscle tension dysphonia (67%). CONCLUSION: Patients may develop significant voice, airway, and/or swallowing issues postacute COVID-19. These complications are not limited to patients requiring intubation or tracheostomy. Multidisciplinary laryngology clinics will continue to play an integral role in diagnosing and treating patients with COVID-19-related laryngeal sequelae.

Discordant SARS-CoV-2 Detection in the Nasopharynx Versus Trachea for Patients With Tracheostomies.

OBJECTIVES/HYPOTHESIS: Patients with tracheostomies have an anatomically altered connection between their upper and lower airways that could impact SARS-CoV-2 testing. Our goal was to evaluate for discordance in SARS-CoV-2 detection in hospitalized patients with COVID-19 and tracheostomies based on the site analyzed. STUDY DESIGN: Retrospective chart review. METHODS: This single-institution study evaluated hospitalized patients with COVID-19 who had tracheostomies placed during their treatment. We analyzed SARS-CoV-2 RNA nucleic acid amplification test (NAAT) results after tracheostomy. All included patients had nasopharyngeal (NP) and tracheal (TR) samples taken within a 48-hour period, allowing us to characterize rate of test concordance. RESULTS: Forty-five patients met our inclusion criteria. Thirty-two (71.1%) patients had entirely concordant results after tracheostomy. However, 13 (28.9%) patients had at least one set of discordant results, the majority of which were NP negative and TR positive. There were no statistically significant differences in demographic or clinical variables, including time to tracheostomy and time to testing, among patients with concordant versus discordant SARS-CoV-2 results. CONCLUSION: This represents the first study to examine SARS-CoV-2 RNA NAAT concordance between NP and TR sites in hospitalized patients with COVID-19 and tracheostomies. One-third of patients demonstrated discordant testing when NP and TR specimens were collected within a 48-hour time period. Thus, patients with tracheostomies may have a higher false-negative rate if only one site is assessed for SARS-CoV-2. We recommend analyzing samples from both the nasopharynx and trachea for these patients until more prospective data exist. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2634-E2638, 2021.

Heparin-mediated antibiotic delivery from an electrochemically-aligned collagen sheet.

BACKGROUND: Implantable medical devices and hardware are prolific in medicine, but hardware associated infections remain a major issue. OBJECTIVE: To develop and evaluate a novel, biologic antimicrobial coating for medical implants. METHODS: Electrochemically compacted collagen sheets with and without crosslinked heparin were synthesized per a protocol developed by our group. Sheets were incubated in antibiotic solution (gentamicin or moxifloxacin) overnight, and in vitro activity was assessed with five-day diffusion assays against Pseudomonas aeruginosa. Antibiotic release over time from gentamicin-infused sheets was determined using in vitro elution and high performance liquid chromatography (HPLC). RESULTS: Collagen-heparin-antibiotic sheets demonstrated larger growth inhibition zones against P. aeruginosa compared to collagen-antibiotic alone sheets. This activity persisted for five days and was not impacted by rinsing sheets prior to evaluation. Rinsed collagen-antibiotic sheets did not produce any inhibition zones. Elution of gentamicin from collagen-heparin-gentamicin sheets was gradual and remained above the minimal inhibitory concentration for gentamicin-sensitive organisms for 29 days. Conversely, collagen-gentamicin sheets eluted their antibiotic load within 24 hours. Overall, heparin-associated sheets demonstrated larger inhibition zones against P. aeruginosa and prolonged elution profile via HPLC. CONCLUSION: We developed a novel, local antibiotic delivery system that could be used to coat medical implants/hardware in the future and reduce post-operative infections.

Anti-Trop2 blockade enhances the therapeutic efficacy of ErbB3 inhibition in head and neck squamous cell carcinoma.

ErbB3 has been widely implicated in treatment resistance, but its role as a primary treatment target is less clear. Canonically ErbB3 requires EGFR or ErbB2 for activation, whereas these two established treatment targets are thought to signal independently of ErbB3. In this study, we show that ErbB3 is essential for tumor growth of treatment-naive HNSCC patient-derived xenografts. This ErbB3 dependency occurs via ErbB3-mediated control of EGFR activation and HIF1α stabilization, which require ErbB3 and its ligand neuregulin-1. Here, we show that ErbB3 antibody treatment selects for a population of ErbB3-persister cells that express high levels of the transmembrane protein Trop2 that we previously identified as an inhibitor of ErbB3. Co-treatment with anti-ErbB3 and anti-Trop2 antibodies is synergistic and produces a greater anti-tumor response than either antibody alone. Collectively, these data both compel a revision of ErbB-family signaling and delineate a strategy for its effective inhibition in HNSCC.

RETRACTED: The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor.

The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process.

Defining the boundaries and expanding the utility of head and neck cancer patient derived xenografts.

BACKGROUND: Patient derived xenografts (PDXs) represent an essential tool in oncologic research, and we sought to further expand our repertoire of head and neck squamous cell carcinoma (HNSCC) while determining potential boundaries for this system. METHODS: We consented new patients for PDX development and determined if a 24-h time delay from tumor excision to xenograft implantation affected PDX establishment. We developed a tissue microarray (TMA) from formalin fixed, paraffin embedded PDXs and their subsequent passages and carried out quantitative immunohistochemistry for EGFR, pEGFR, pAkt, pERK and ERCC1. First and last passaged PDXs were compared via a paired t-test to examine for the stability of protein expression across passages. We performed a similar comparison of the mutational profile of the patient tumor and resulting xenografts using a targeted sequencing approach. RESULTS: No patient/tumor characteristics influenced PDX take rate and the 24-h time delay from tumor excision to xenograft implantation did not affect PDX establishment, growth or histology. There was no significant difference in biomarker expression between the first and last passaged PDXs for EGFR, pEGFR, pAkt, and ERCC1. For pERK there was a significant difference (p=0.002), but further analysis demonstrated this only arose in three of 15 PDXs. Targeted sequencing revealed striking stability of passenger and likely driver mutations from patient to xenograft. CONCLUSIONS: The stability of protein expression across PDX passages will hopefully allow greater investigation of predictive biomarkers in order to identify ones for further pre-clinical and clinical investigation.

Factors influencing sialocele or salivary fistula formation postparotidectomy.

BACKGROUND: Does the extent of parotidectomy or other patient or tumor characteristics influence the rate of sialocele/salivary fistula formation? METHODS: All patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013 were considered. Patients who developed a sialocele/salivary fistula were identified. Extent of dissection, age, sex, body mass index (BMI), volume of specimen, and rate of malignancy were examined. RESULTS: Seventy of 771 patients (9.1%) developed a sialocele/salivary fistula. Sixty-seven fistulae (96%) developed within 1 month and all resolved by 6 months. Age, sex, pathology, and BMI were not increased in the sialocele group. Inferior and middle superficial parotidectomy had a significantly higher rate of sialocele than other extents of dissection. Volume of tissue removed was not significantly different between dissection groups. CONCLUSION: Sialocele/salivary fistula is common postparotidectomy and is more likely with inferior and middle superficial parotidectomy. © 2016 Wiley Periodicals, Inc. Head Neck 39: 387-391, 2017.