The Prognostic Implications of Neutrophil-to-Lymphocyte Ratio in Olfactory Neuroblastoma.

OBJECTIVE: Olfactory neuroblastoma is a rare sinonasal malignancy with comparatively positive prognosis and survival, but with a range of biological behaviors that can be difficult to prognosticate with current means of risk stratification. Neutrophil-to-lymphocyte ratio (NLR) has been found across a diverse range of malignancies to be associated with poorer outcomes. This paper aims to elucidate the relationship of NLR with olfactory neuroblastoma to assess its prognostic value in this setting. STUDY DESIGN: Retrospective chart review. SETTING: A single tertiary care academic hospital. METHODS: The study cohort included all patients treated for initial presentation of olfactory neuroblastoma from 2004 to 2020. NLR was calculated from preoperative labs, and each patient was evaluated for Kadish staging, Hyams grade, intraoperative positive margin, use of adjuvant therapy, posttreatment recurrence, and death. All statistical analysis was conducted using R and relationship between NLR and variables was assessed via binomial logistic regression. RESULTS: Forty-four patients were included, 24 were male. Average age 52.8, average length of follow-up was 9.6 years. Patients were grouped by low (Kadish A/B) and advanced (Kadish C/D) stage, n = 23 and n = 21, respectively, and low (Hyams I/II) and high (Hyams III/IV) risk, n = 15 and n = 11, respectively. Advanced Kadish stage was associated with elevated NLR, odds ratio 5.69 [2.30, 20.7], P = .001. No other variables were associated with elevated NLR including Hyams grade, margin status, recurrence, and mortality. CONCLUSION: Higher Kadish grade is associated with elevated NLR which may provide novel prognostic value to current risk-stratifying systems.

An Inherent Difference between Serine and Threonine Phosphorylation: Phosphothreonine Strongly Prefers a Highly Ordered, Compact, Cyclic Conformation.

Phosphorylation and dephosphorylation of proteins by kinases and phosphatases are central to cellular responses and function. The structural effects of serine and threonine phosphorylation were examined in peptides and in proteins, by circular dichroism, NMR spectroscopy, bioinformatics analysis of the PDB, small-molecule X-ray crystallography, and computational investigations. Phosphorylation of both serine and threonine residues induces substantial conformational restriction in their physiologically more important dianionic forms. Threonine exhibits a particularly strong disorder-to-order transition upon phosphorylation, with dianionic phosphothreonine preferentially adopting a cyclic conformation with restricted ϕ (ϕ ∼ -60°) stabilized by three noncovalent interactions: a strong intraresidue phosphate-amide hydrogen bond, an n → π* interaction between consecutive carbonyls, and an n → σ* interaction between the phosphate Oγ lone pair and the antibonding orbital of C-Hß that restricts the χ2 side-chain conformation. Proline is unique among the canonical amino acids for its covalent cyclization on the backbone. Phosphothreonine can mimic proline's backbone cyclization via noncovalent interactions. The preferred torsions of dianionic phosphothreonine are ϕ,ψ = polyproline II helix > α-helix (ϕ ∼ -60°); χ1 = g-; χ2 ∼ +115° (eclipsed C-H/O-P bonds). This structural signature is observed in diverse proteins, including in the activation loops of protein kinases and in protein-protein interactions. In total, these results suggest a structural basis for the differential use and evolution of threonine versus serine phosphorylation sites in proteins, with serine phosphorylation typically inducing smaller, rheostat-like changes, versus threonine phosphorylation promoting larger, step function-like switches, in proteins.

Validity of the American College of Radiology Thyroid Imaging Reporting and Data System in Children.

OBJECTIVE: To assess the validity of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) for evaluating thyroid nodules in children. METHODS: Patients aged <19 years with thyroid nodule(s) evaluated by ultrasound (US) from 2007-2018 at a tertiary children's hospital were included. Two radiologists scored de-identified thyroid US images using ACR TI-RADS (from 1, "benign" to 5, "highly suspicious"). The radiologists recorded size and rated vascularity for each nodule. Ultrasound findings were compared to pathology results (operative cases, n = 91) and clinical follow-up without disease progression (non-operative cases, n = 15). RESULTS: Thyroid images from 115 patients were reviewed. Nine patients were excluded due to the absence of an evaluable nodule. Forty-seven benign and 59 malignant nodules were included. Median age at ultrasound was 15 years (range 0.9-18 years). Twenty (18.9%) patients were male. There was moderate agreement between TI-RADS levels assigned by the two raters (kappa = 0.57, p < 0.001). When the raters' levels were averaged, >3 as the threshold for malignancy correctly categorized the greatest percentage of nodules (68.9%). Eleven (18.6%) malignant nodules received a TI-RADS level of 2 (n = 3) or 3 (n = 8). Sensitivity, specificity, and positive and negative predictive values were 81.4%, 53.2%, 68.6%, and 69.4%, respectively. Although not part of TI-RADS, vascularity was similar between benign and malignant nodules (p = 0.56). CONCLUSION: In a pediatric population, TI-RADS can help distinguish between benign and malignant nodules with comparable sensitivity and specificity to adults. However, the positive and negative predictive values suggest TI-RADS alone cannot eliminate the need for FNA. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2394-2401, 2023.

An Update on Nontumorous Disorders of the Salivary Glands and Their Management for Internists.

Salivary disease may present as pain or swelling in unilateral or bilateral salivary glands. Symptoms may be periprandial or recurrent and inflammatory. If a patient fails conservative treatment, they should be referred to an otolaryngologist. If there is no clear cause based on history and physical examination, sialendoscopy can be performed to directly visualize tissues, provide a diagnosis, drive treatment plans, and sometimes concurrently provide therapeutic intervention. Based on the pathology visualized on sialendoscopy, treatment options include endoscopic intervention, Botox, and gland-preserving surgical techniques, which promote healing of glandular tissue, ultimately preserving function.

Diagnostic Value of TI-RADS Classification System and Next Generation Genetic Sequencing in Indeterminate Thyroid Nodules.

RATIONALE AND OBJECTIVES: This study aims to evaluate the diagnostic accuracy, inter-reader, and intra-reader variability of the ACR Thyroid Imaging Reporting and Data System (TI-RADS) for risk-stratification of indeterminate thyroid nodules using next generation genetic sequencing and tissue histology as a reference standard. MATERIALS AND METHODS: Retrospective chart review was performed on all patients who underwent thyroid ultrasound for a nodule with subsequent fine-needle aspiration ± surgical resection from January 2017 to August 2018. Four radiologists with expertise in thyroid ultrasound assessed imaging twice, ≥1 month apart. Results of cytology and next generation genetic sequencing were used as a reference standard for high versus low risk of malignancy in each nodule. Inter-reader reliability between readers and intra-reader reliability between replicate self-reads for TI-RADS categorization were assessed. Univariate analysis, kappa statistics, and receiver operating characteristic curve were calculated. RESULTS: One hundred and thirty six nodules across 121 patients met inclusion criteria. 84.6% of patients were female and average age was 55.8 ± 14.1 years. One hundred and eighteen of 135 nodules (87%) had indeterminate cytology (Bethesda III or IV). One of 23 high-risk mutations was identified in 30.1% (42) of the nodules. Of the 52 patients who had surgery, 24 (47.1%) had confirmed malignant disease on surgical pathology. Inter-reader reliability between the four radiologists was marginal, κ = 0.293. Intra-reader reliability ranged from marginal to good, κ = 0.337 to κ = 0.560, respectively. The area under the receiver operating characteristic curve was 0.509, and no optimal TI-RADS Level for identifying high-risk nodules existed. CONCLUSION: The ACR TI-RADS classification system performs with low inter-reader and intra-reader reliability when assessing the genetic risk of nodules with indeterminate cytology.

Assessment of quality and consistency of monoclonal antibodies for CB1 and CB2 in head and neck squamous cell carcinoma.

BACKGROUND: Marijuana has numerous roles as an agonist in the endocannabinoid signaling system (ESS). This study evaluated monoclonal antibodies across experimental techniques to establish a framework for studying ESS receptors, CB1 and CB2. METHODS: Tissue from five patients with head and neck cancer were used to generate cell lines and formalin-fixed paraffin-embedded (FFPE) sections, which were analyzed by western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Subgroup analysis was performed on FFPE sections from 8 marijuana users and 10 controls by IHC. Results were compared across methods for consistency. RESULTS: In all patients, WB and IF were CB1 positive, whereas IHC was negative. Select samples were CB2 positive by WB, but failed IF and IHC applications. In subgroup analysis, 1 of 8 users and 3 of 10 nonusers were CB1 positive. CONCLUSIONS: Interpretation of CB1/CB2 antibody data should be performed cautiously and confirmation of findings across multiple experimental methods is recommended.

Therapeutic Cannabis and Endocannabinoid Signaling System Modulator Use in Otolaryngology Patients.

OBJECTIVES: 1) review benefits and risks of cannabis use, with emphasis on otolaryngic disease processes; 2) define and review the endocannabinoid signaling system (ESS); and 3) review state and federal regulations for the use and research of cannabis and ESS modulators. METHODS: This manuscript is a review of the current literature relevant to the stated objectives. RESULTS: Cannabis (marijuana) use is increasing. It is the most widely used illicit substance in the world. There is increasing interest in its therapeutic potential due to changing perceptions, new research, and legislation changes controlling its use. The legal classification of cannabis is complicated due to varied and conflicting state and federal laws. There are currently two synthetic cannabinoid drugs that are FDA approved. Current indications for use include chemotherapy-related nausea and vomiting, cachexia, and appetite loss. Research has demonstrated potential benefit for use in many other pathologies including pain, inflammatory states, and malignancy. Data exists demonstrating potential antineoplastic benefit in oral, thyroid, and skin cancers. CONCLUSIONS: ESS modulators may play both a causal and therapeutic role in several disorders seen in otolaryngology patients. The use of cannabis and cannabinoids is not without risk. There is a need for further research to better understand both the adverse and therapeutic effects of cannabis use. With increasing rates of consumption, elevated public awareness, and rapidly changing legislation, it is helpful for the otolaryngologist to be aware of both the adverse manifestations of use and the potential therapeutic benefits when talking with patients.