DNA polymerase θ promotes CAG•CTG repeat expansions in Huntington's disease via insertion sequences of its catalytic domain.

Huntington's disease (HD), a neurodegenerative disease characterized by progressive dementia, psychiatric problems, and chorea, is known to be caused by CAG repeat expansions in the HD gene HTT. However, the mechanism of this pathology is not fully understood. The translesion DNA polymerase θ (Polθ) carries a large insertion sequence in its catalytic domain, which has been shown to allow DNA loop-outs in the primer strand. As a result of high levels of oxidative DNA damage in neural cells and Polθ's subsequent involvement in base excision repair of oxidative DNA damage, we hypothesized that Polθ contributes to CAG repeat expansion while repairing oxidative damage within HTT. Here, we performed Polθ-catalyzed in vitro DNA synthesis using various CAG•CTG repeat DNA substrates that are similar to base excision repair intermediates. We show that Polθ efficiently extends (CAG)n•(CTG)n hairpin primers, resulting in hairpin retention and repeat expansion. Polθ also triggers repeat expansions to pass the threshold for HD when the DNA template contains 35 repeats upward. Strikingly, Polθ depleted of the catalytic insertion fails to induce repeat expansions regardless of primers and templates used, indicating that the insertion sequence is responsible for Polθ's error-causing activity. In addition, the level of chromatin-bound Polθ in HD cells is significantly higher than in non-HD cells and exactly correlates with the degree of CAG repeat expansion, implying Polθ's involvement in triplet repeat instability. Therefore, we have identified Polθ as a potent factor that promotes CAG•CTG repeat expansions in HD and other neurodegenerative disorders.

MutSß abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions.

CTG•CAG repeat expansions cause at least twelve inherited neurological diseases. Expansions require the presence, not the absence, of the mismatch repair protein MutSß (Msh2-Msh3 heterodimer). To evaluate properties of MutSß that drive expansions, previous studies have tested under-expression, ATPase function or polymorphic variants of Msh2 and Msh3, but in disparate experimental systems. Additionally, some variants destabilize MutSß, potentially masking the effects of biochemical alterations of the variations. Here, human Msh3 was mutated to selectively inactivate MutSß. Msh3-/- cells are severely defective for CTG•CAG repeat expansions but show full activity on contractions. Msh3-/- cells provide a single, isogenic system to add back Msh3 and test key biochemical features of MutSß on expansions. Msh3 overexpression led to high expansion activity and elevated levels of MutSß complex, indicating that MutSß abundance drives expansions. An ATPase-defective Msh3 expressed at normal levels was as defective in expansions as Msh3-/- cells, indicating that Msh3 ATPase function is critical for expansions. Expression of two Msh3 polymorphic variants at normal levels showed no detectable change in expansions, suggesting these polymorphisms primarily affect Msh3 protein stability, not activity. In summary, CTG•CAG expansions are limited by the abundance of MutSß and rely heavily on Msh3 ATPase function.

Rate of dupilumab use and symptom severity of patients with chronic rhinosinusitis with nasal polyposis after Draf 3 frontal sinusotomy.

BACKGROUND: The indications for endoscopic modified Lothrop procedure (Draf 3) in patients with refractory chronic rhinosinusitis with nasal polyposis (CRSwNP) remain unclear. This study evaluates the effectiveness of Draf 3 for refractory CRSwNP focusing on improvements in disease severity and need for subsequent dupilumab rescue therapy. METHODS: Retrospective review of patients with CRSwNP undergoing Draf 3 surgery at a tertiary center between 2012 and 2022. Clinicodemographic variables were compared across those who did versus did not require rescue with postoperative dupilumab. Time to postoperative dupilumab rescue was analyzed and longitudinal disease-specific outcomes were measured using the sinonasal outcomes test (SNOT-22). RESULTS: Within 87 patients with CRSwNP, 24.1% had aspirin-exacerbated respiratory disease (AERD). Significant improvement in SNOT-22 score was found in CRSwNP with AERD (p < 0.001) and without AERD (p = 0.01) up to 24 months postoperative. 14.9% eventually required rescue with a dupilumab. More specifically, of 21 patients with AERD, 24.1% eventually required rescue with dupilumab. Dupilumab rescue was associated with a greater number of prior sinus surgeries (p = 0.02), prior aspirin desensitization (p = 0.02), and worse preoperative Lund-MacKay scores (p < 0.001). No association between biologic rescue and frontal recess antero-posterior diameter was found (p = 0.20). CONCLUSIONS: Draf 3 surgery in CRSwNP was associated with significant improvement in SNOT-22 score at 24 months. Furthermore, only 14.9% of patients required dupilumab rescue. Patients with AERD were more likely to require rescue with dupilumab even though 75.1% avoided treatment with the biologic over the study period.

Discovery of a potent, selective, and tumor-suppressing antibody antagonist of adenosine A2A receptor.

New immune checkpoints are emerging in a bid to improve response rates to immunotherapeutic drugs. The adenosine A2A receptor (A2AR) has been proposed as a target for immunotherapeutic development due to its participation in immunosuppression of the tumor microenvironment. Blockade of A2AR could restore tumor immunity and, consequently, improve patient outcomes. Here, we describe the discovery of a potent, selective, and tumor-suppressing antibody antagonist of human A2AR (hA2AR) by phage display. We constructed and screened four single-chain variable fragment (scFv) libraries-two synthetic and two immunized-against hA2AR and antagonist-stabilized hA2AR. After biopanning and ELISA screening, scFv hits were reformatted to human IgG and triaged in a series of cellular binding and functional assays to identify a lead candidate. Lead candidate TB206-001 displayed nanomolar binding of hA2AR-overexpressing HEK293 cells; cross-reactivity with mouse and cynomolgus A2AR but not human A1, A2B, or A3 receptors; functional antagonism of hA2AR in hA2AR-overexpressing HEK293 cells and peripheral blood mononuclear cells (PBMCs); and tumor-suppressing activity in colon tumor-bearing HuCD34-NCG mice. Given its therapeutic properties, TB206-001 is a good candidate for incorporation into next-generation bispecific immunotherapeutics.

A VHH single-domain platform enabling discovery and development of monospecific antibodies and modular neutralizing bispecifics against SARS-CoV-2 variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, escape coronavirus disease 2019 therapeutics and vaccines, and jeopardize public health. To combat SARS-CoV-2 antigenic escape, we developed a rapid, high-throughput pipeline to discover monospecific VHH antibodies and iteratively develop VHH-Fc-VHH bispecifics capable of neutralizing emerging SARS-CoV-2 variants. By panning VHH single-domain phage libraries against ancestral or beta spike proteins, we discovered high-affinity VHH antibodies with unique target epitopes. Combining two VHHs into a tetravalent bispecific construct conferred broad neutralization activity against multiple variants and was more resistant to antigenic escape than the monospecific antibody alone. Following the rise of the Omicron variant, a VHH in the original bispecific construct was replaced with another VHH discovered against the Omicron BA.1 receptor binding domain; the resulting bispecific exhibited neutralization against both BA.1 and BA.5 sublineage variants. A heavy chain-only tetravalent VHH-Fc-VHH bispecific platform derived from humanized synthetic libraries held a myriad of unique advantages: (i) synthetic preconstructed libraries minimized risk of liabilities and maximized discovery speed, (ii) VHH scaffolds allowed for a modular "plug-and-play" format that could be rapidly iterated upon as variants of concern arose, (iii) natural dimerization of single VHH-Fc-VHH polypeptides allowed for straightforward bispecific production and purification methods, and (iv) multivalent approaches enhanced avidity boosting effects and neutralization potency, and conferred more robust resistance to antigenic escape than monovalent approaches against specific variants. This iterative platform of rapid VHH discovery combined with modular bispecific design holds promise for long-term viral control efforts.

An alternative way for the evaluation of zinc status in the elderly; nail zinc levels and relationship with Alzheimer's disease.

BACKGROUND: Zinc is one of the most important elements for human body. Zinc deficiency can occur in any age, if it is seen in elderly its clinical results can be more harmful due to already diminished functions. Some studies showed zinc deficiency has an important role in the pathogenesis of Alzheimer disease. In this study we measured the nail zinc levels and aimed to show its clinical implications in geriatric patients, especially Alzheimer disease. PATIENTS AND METHODS: 43 patients with Alzheimer disease and 89 patients with normal cognitive function were evaluated. The diagnosis of Alzheimer disease was made according to DSM-IV and NINCDS-ADRDA criteria after cognitive assessment and neuroimaging performed using magnetic resonance. Hand fingernail samples are obtained from the patients. RESULTS: Mean zinc level from fingernail samples was 117.99 ± 73.44 ppm in Alzheimer Disease patients, 123.86 ± 77.98 ppm in control group (p: 0.680). CONCLUSIONS: This is the first study measuring nail zinc levels in elderly patients with and without Alzheimer disease. Our data reveal no significant difference in nail zinc levels between two groups. However, fingernail zinc may be a useful biomarker in elderly population.  

Work productivity and activity impairment in patients with chronic rhinosinusitis undergoing endoscopic sinus surgery-A prospective, multi-institutional study.

BACKGROUND: Productivity loss and activity limitations due to chronic rhinosinusitis (CRS) are known to contribute to the significant economic and personal burden of disease. The purpose of this study was to assess productivity and activity impairment before and after endoscopic sinus surgery (ESS) for medically refractory CRS. METHODS: This investigation was a prospective, multi-institutional, observational cohort study. Patients diagnosed with medically refractory CRS completed the Work Productivity and Activity Impairment-Specific Health Problem (WPAI-SHP) questionnaire before surgery and approximately 6 months after the procedure. Factors associated with minimal clinical important differences (MCIDs) for productivity and activity impairment were identified. RESULTS: A total of 279 study participants were screened for inclusion, of whom 176 (63.1%) with postoperative follow-up were included in the final cohort. Preoperative productivity and activity impairment were observed in 63.2% and 69.8% of the patients, respectively. Among these patients, postoperative improvement equaling at least 1 MCID was reported in both productivity (76.1%) and activity (76.4%) impairments. Multivariate regression identified sphenoidotomy (odds ratio [OR], 4.18; 95% confidence interval [CI], 1.03-17.02) as the only factor associated with increased likelihood of productivity improvement, whereas septoplasty during ESS (OR, 8.45; 95% CI, 2.33-30.68) and migraine (OR, 0.35; 95% CI, 0.12-0.96) were associated with differential odds of activity improvement. CONCLUSION: CRS is associated with a substantial burden on productivity and activity that significantly improves after treatment with ESS. These data may facilitate improved patient counseling and shared decision-making regarding surgical management for CRS.

Management paradigms for chronic rhinosinusitis in individuals with asthma: An evidence-based review with recommendations.

BACKGROUND: Despite the significant morbidity associated with chronic rhinosinusitis (CRS) in individuals with asthma (CRSwA), there is a paucity of codified, evidence-based management strategies for CRS in this population. METHODS: Using PubMed, Embase, and Cochrane Review Databases, a systematic review was performed covering management strategies for CRSwA. A total of 5903 articles were screened, and 70 were included for full-text analysis. After application of exclusion criteria, 53 articles comprised the qualitative synthesis. The level of evidence was graded and benefit-harm assessments, as well as value judgment and recommendations, were provided RESULTS: Strong evidence confirms the benefit of oral and topical medications on sinonasal-specific outcomes in individuals with CRSwA; there is low-grade evidence demonstrating that these agents improve lung function and/or asthma control. Moderate to strong evidence suggests that endoscopic sinus surgery (ESS) improves both sinonasal- and asthma-specific quality of life. Although there is insufficient to low evidence to indicate that ESS improves pulmonary function in this population, data indicate a positive impact of this intervention on asthma control. Biologic medications strongly improve both subjective and objective sinonasal- and asthma-specific outcomes. CONCLUSION: Evidence supports managing CRS in individuals with CRSwA in a stepwise fashion, starting with traditional nonbiologic oral and topical medication, and escalating to second-line treatments, such as ESS and biologics. Optimal treatment of individuals who have CRSwA often requires concurrent, directed management of asthma, as not all CRS interventions impact asthma status.

Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism.

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic ß-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the ß-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. ARTICLE HIGHLIGHTS: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.

Financial Hardship Impacts Depression and Anxiety Among U.S. Patients with Sinusitis.

BACKGROUND: Mental health conditions are common in the United States, and recent efforts have examined the development of mental health conditions among patients with sinusitis. OBJECTIVES: The purpose of this study was to investigate the association between depression, anxiety, and financial hardship among patients with sinusitis. METHODS: Cross-sectional study using the 2018 National Health Interview Survey (NHIS). Data regarding demographics, perceived financial hardship, self-reported depression and anxiety, mental healthcare utilization, and treatment compliance were obtained. RESULTS: Among patients with sinusitis (N = 28 million adults), 9% reported depression and 24% reported anxiety. Sinusitis patients with depression and anxiety reported an increased severity of financial insecurity (p < 0.001). On multivariable logistic regression, worsening financial insecurity increased the odds of depression and anxiety. Patients reporting the highest financial insecurity severity had the highest odds of depression (OR = 3.88, 95% CI = 3.84-3.93, p < 0.001) and anxiety (OR = 2.09, 95% CI = 2.08-2.10, p < 0.001) among measures of financial stress. Specific financial stressors were independently associated with patient-reported depression and anxiety. Sinusitis patients with increased financial insecurity were more likely to require mental health services and treatment (p < 0.001), but were also more likely to report cost-related treatment noncompliance (p < 0.001) and reduced access to mental healthcare due to costs (p < 0.001). CONCLUSION: Perceived financial hardship is associated with self-reported depression and anxiety among patients with sinusitis. Sinusitis patients with financial hardship also face challenges in accessing and maintaining mental health services and treatment due to costs. Understanding the burden of financial insecurity on mental health and access to treatment may improve quality of care through the development of screening tools and individualized treatment strategies.

Pain and Opioid Consumption Following Endoscopic Sinus Surgery: A Prospective Cohort Study.

OBJECTIVES/HYPOTHESIS: Surgeons have a critical role in the current opioid epidemic, and there is a need to prospectively understand patterns of pain and opioid use among patients undergoing endoscopic sinus surgery (ESS). STUDY DESIGN: Prospective observational cohort. METHODS: This was a prospective, observational cohort study that included patients undergoing ESS from November 2019 to March 2020. Demographic data were collected at baseline, as was respondent information regarding preoperative anxiety, pain, and postoperative pain expectations. Opioid use was converted to milligram morphine equivalents (MME). All patients received 10 tablets of 5 mg oxycodone (75 MME). Patients quantified postoperative pain and opioid consumption via telephone follow-up every 48 hours. The primary outcome was total MME utilized. RESULTS: There were 91 patients included in the final cohort. Mean opioid use was 35.2 ± 47.3 MME. There were 29 (32%) patients who did not use any opioids after surgery, and six (7%) patients who required opioid refills. Postoperative opioid use was associated with increased preoperative anxiety (r = 0.41, P < .001), preoperative pain (r = 0.28, P = .007), and expectations for postoperative pain (r = 0.36, P < .001). Increased postoperative pain was only associated with increased opioid use on postoperative days 0-2 (r = 0.33, P = .001) and 3-4 (r = 0.59, P < .001). On multivariate regression, former smoking (ß = 23.4 MME, SE = 10.1, 95% confidence interval [CI]: 3.3-43.5, P = .023) and anxiety (ß = 35.9, SE = 10.2, 95% CI: 15.6-56.3, P < .001) were associated with increased MME. CONCLUSIONS: The majority of patients have minimal opioid use after ESS, and pain appears to influence opioid use within the first 4 days after surgery. Additionally, patients with anxiety may benefit from alternative pain management strategies to mitigate opioid consumption. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:2096-2102, 2022.

Opioid use after endoscopic skull base surgery: A descriptive, prospective, longitudinal cohort study.

BACKGROUND: Opioid abuse is a public health crisis and the perioperative period can be a time of first opioid exposure. Little is known about postoperative pain management after endoscopic skull base surgery (ESBS). METHODS: This investigation was a single-institution, longitudinal, prospective cohort study of adult patients undergoing ESBS between November 2019 and March 2020. Participants completed preoperative questionnaires and were contacted every 48 hours postoperatively to quantify pain and opioid consumption. RESULTS: A total of 33 patients were enrolled and 28 of 33 patients (85%) underwent ESBS for sellar pathology. Mean total morphine milligram equivalents (MME) consumed was 381.9 ± 476.0. History of a headache disorder (p = 0.025) and previous opioid use within 60 days preoperatively (p < 0.001) were significantly associated with greater opioid use. Mean duration of opioid use was 6.7 ± 5.1 (range, 0-20) days. Headache disorder (p = 0.01), depression (p = 0.03), anxiety (p = 0.03), age ≤46 years (p = 0.029), and previous opioid use (p = 0.008) were all associated with longer mean opioid use. Patients with headache disorder also reported higher mean postoperative pain scores. Fewer than half of the participants required opioids by postoperative day 8. Prescription of nonsteroidal anti-inflammatory drugs at discharge was significantly associated with less outpatient opioid use (p = 0.032). At 2-month follow-up, 37% of patients reported keeping excess opioids. CONCLUSION: After ESBS, greater total opioid use was significantly associated with history of headaches and previous opioid use within 60 days. Overall, opioid use declined among all patients in the postoperative period, but several factors may contribute to longer duration of use.

Perceived Financial Insecurity Impacts Healthcare Decision-Making Among Patients With Sinusitis.

OBJECTIVES/HYPOTHESIS: The economic burden of sinusitis is significant, and socioeconomic factors can impact patient decision-making. The purpose of this study was to examine the impact of perceived financial insecurity on healthcare decision-making and treatment compliance among sinusitis patients. STUDY DESIGN: Cross-sectional study using the 2018 National Health Interview Survey. METHODS: Survey responses to nine questions regarding financial stressors and nine questions regarding cost-saving healthcare actions were recorded, which included seeking lower cost medication, medication noncompliance, and avoiding care visits due to costs. RESULTS: There was a total weighted sample size of 28.9 million patients who self-reported a diagnosis of sinusitis (12% of the U.S. population). Sinusitis patients who reported cost-saving actions had an increased severity of perceived financial insecurity than those without cost-saving actions (P < .001). Sinusitis patients with perceived financial insecurity had the highest odds of at least one cost-saving action (odds ratio [OR] = 5.94, 95% CI = 5.911-5.970, P < .001), followed by lack of health insurance (OR = 5.13, 95% CI = 5.107-5.159, P < .001), and poor self-reported health status (OR = 2.81, 95% CI = 2.792-2.822, P < .001). Increasing the number of financial stressors increased the odds of at least one cost-saving action (P < .001). Across all financial stressors, the most commonly performed cost-saving action was asking for lower cost medication. CONCLUSIONS: Perceived financial insecurity is associated with cost-saving healthcare actions among sinusitis patients, including treatment noncompliance. Interventions to assess financial insecurity among sinusitis patients may facilitate shared decision-making for optimal, individualized treatment plans that may lead to improved outcomes and quality of life. LEVEL OF EVIDENCE: NA Laryngoscope, 131:2403-2412, 2021.

Mucosal Eosinophilia and Neutrophilia Are Not Associated With QOL or Olfactory Function in Chronic Rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is often differentiated by histopathologic phenotypes (eosinophilic versus neutrophilic), which may impact disease severity measures and outcomes. As such, it has been suggested that counts of cellular elements be included as part of a standard pathological report following endoscopic sinus surgery (ESS). OBJECTIVES: This cross-sectional study evaluated associations of mucosal eosinophilia and neutrophilia with measures of quality-of-life (QoL) and olfactory function. METHODS: Patients with medically refractory CRS completed the SNOT-22 survey and Brief Smell Identification Test (BSIT) at enrollment. In addition, baseline Lund-Mackay computed tomography (CT) and Lund-Kennedy endoscopy scores were collected. Ethmoid mucosa was biopsied during ESS and reviewed using microscopy to quantify densest infiltrate of eosinophils or neutrophils per high-powered-field (HPF). Eosinophilic CRS (eCRS) and neutrophilic CRS (nCRS), both with and without nasal polyposis (NP), were compared across SNOT-22 and BSIT scores. RESULTS: 77/168 patients demonstrated mucosal eosinophilia (eCRS) while a total of 42/168 patients demonstrated mucosal neutrophilia (nCRS). After adjusting for polyp status, 35/168 had eCRSsNP, 42/168 eCRSwNP, 75/168 non-eCRSsNP, 16/168 non-eCRSwNP. Additionally, 22/161 were noted to have nCRSsNP, 20/161 nCRSwNP, 84/161 non-nCRSwNP, and 35/161 non-nCRSsNP. A small subset of patients demonstrated both eosinophilia and neutrophilia: 14 CRSwNP and 7 CRSsNP. When evaluating average Lund-Mackay Scores (LMS), significant differences existed between non-eCRSsNP and eCRSsNP (p = 0.006). However, after controlling for nasal polyps, eosinophilia did not significantly associate with differences in the Lund-Kennedy Score. Neutrophilia did not significantly associate with any changes in LMS or LKS after controlling for NP. Eosinophilic and neutrophilic histopathologic subtypes did not significantly associate with differences in baseline SNOT-22 or BSIT measures after controlling for NP. CONCLUSION: Neither the presence of mucosal eosinophilia nor mucosal neutrophilia demonstrated significant associations with SNOT-22 quality-of-life or BSIT olfactory function scores when controlling for comorbid nasal polyposis.

Predictors of survival outcomes in sinonasal squamous cell carcinoma: an analysis of the National Cancer Database.

BACKGROUND: Sinonasal squamous cell carcinoma (SNSCC) is a rare malignancy that poses management challenges. Although surgery and chemoradiation therapy (CRT) remain therapeutic mainstays, induction chemotherapy (IC) has emerged as a useful adjunct with locally advanced disease. This study used the National Cancer Data Base (NCDB) to examine treatment outcomes for patients diagnosed with SNSCC. METHODS: The NCDB (2004-2015) was queried for cases with SNSCC. Multivariate hazard regression modeling was used to identify significant predictors of 24-month and 60-month overall survival (OS) including treatment modality. RESULTS: A total of 3516 patients with SNSCC met inclusion criteria, including 1750 patients (49.8%) treated with surgery ± adjuvant therapy, 1352 (38.5%) treated with definitive radiotherapy (RT) or CRT, 300 (8.5%) who underwent IC followed by definitive CRT, and 114 (3.2%) who received IC followed by surgery and adjuvant therapy. Hazard modeling for confirmed treatment modality significantly associated (p < 0.001) with OS after adjustment. Patients who received surgical intervention ± adjuvant therapy had lower 24-month and 60-month mortality risk compared to definitive RT or CRT (hazard ratio [HR] ≥ 1.97; p < 0.001) or IC followed by definitive CRT (HR ≥ 1.73; p < 0.001). Compared to primary surgery ± adjuvant therapy, patients undergoing IC then surgery had similar 24-month and 60-month OS (p ≥ 0.672) after adjustment. CONCLUSION: Multimodality therapy, including surgical intervention, associates with improved OS after multifactorial adjustments. IC followed by surgery associated with improved OS compared to IC, followed by CRT and CRT alone. Study results highlight the utility of surgery toward optimizing OS in patients with SNSCC and demonstrates the potential utility of IC when primary surgical management is not preferred.

Patient-reported sleep outcomes lack association with mucosal eosinophilia or neutrophilia in patients with chronic rhinosinusitis undergoing functional endoscopic sinus surgery.

BACKGROUND: Chronic rhinosinusitis (CRS) is associated with sleep dysfunction, but the underlying pathophysiology is poorly understood. The purpose of this study was to determine if mucosal eosinophilia or neutrophilia were associated with sleep dysfunction severity or altered the improvement in sleep dysfunction following functional endoscopic sinus surgery (FESS). METHODS: A total of 104 patients with medically refractory CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP), completed the Pittsburgh Sleep Quality Index (PSQI) before and after FESS. Anterior ethmoid mucosa was collected during FESS and densest infiltrates of eosinophilia and neutrophilia per high-power field (HPF) were determined by microscopy. Eosinophilic (>10 eosinophils/HPF) and neutrophilic (>4 neutrophils/HPF) CRS were then compared to preoperative and postoperative PSQI measures. RESULTS: Of 104 study participants, 88 (85%) reported preoperative PSQI scores consistent with "poor sleep," (PSQI total > 5). The cohort overall demonstrated significant improvement in poor sleep (65%; χ2 = 12.03; p < 0.001) 16.8 ± 5.0 months after FESS. Regardless of nasal polyposis, neither eosinophilic nor neutrophilic CRS was associated with differences in mean postoperative PSQI improvement. However, in patients with neutrophilic CRSsNP, there was a significant relationship between severity of neutrophilia and improvement in sleep latency (R = -0.798, p = 0.003) and sleep efficacy (R = -0.777, p = 0.005). CONCLUSION: Chronic inflammation has been hypothesized to play a pathophysiologic role in sleep dysfunction associated with CRS. This study suggests that in patients with medically refractory CRS, evidence of mucosal eosinophilia and neutrophilia lack strong associations with patient-reported sleep dysfunction or improvements in sleep quality after FESS, overall. However, neutrophilia may impact sleep latency and efficacy in patients with CRSsNP.

MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth.

How cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3' flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3' nuclease, excises flaps at the immediate 3' end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth.

Frontal sinus "mega-trephination" in a tertiary rhinology practice.

BACKGROUND: Frontal sinus trephination is traditionally performed through a small cutaneous incision and osteotomy, allowing irrigation of the frontal sinus. Utilizing the trephination osteotomy for endoscopic visualization and surgical manipulation requires a larger opening. This "mega-trephination" is thought to carry an increased risk of cosmetic deformity given the increased bony removal at the anterior table. The purpose of our study was to clarify the risks of frontal sinus mega-trephination and examine how this technique is incorporated into a modern, tertiary care rhinology practice. METHODS: Patients were identified through billing records and confirmed by retrospective chart review. All patients underwent frontal sinus mega-trephination, which is defined as an osteotomy large enough for insertion of a 4-mm endoscope and an operative instrument simultaneously. All patients had at least 2 years of follow-up. The primary outcome was complication rate, including cosmetic deformity. RESULTS: Sixty-four patients underwent frontal sinus mega-trephination from 2006 to 2016. The most common surgical indications were chronic sinusitis (34%), mucocele (19%), osteoma (17%), acute sinusitis (11%), and inverting papilloma (9%). Ten patients (16%) underwent mega-trephination alone, whereas the others had mega-trephination with endoscopic sinus surgery. Twenty-one patients (33%) had minor complications. The most common complications were self-limited paresthesia (11%), infection (8%), and epistaxis (3%). No patient complained of permanent cosmetic deformity or required revision surgery for cosmesis. CONCLUSION: Frontal sinus mega-trephination is a useful tool to augment the rhinologist's armamentarium in complex frontal sinus anatomy and pathology. This procedure is well tolerated, safe, and not associated with long-term cosmetic deformity.

Socioeconomic status impacts postoperative productivity loss and health utility changes in refractory chronic rhinosinusitis.

BACKGROUND: Social determinants of health can have a substantial impact on treatment outcomes. Prior study has shown that socioeconomic status influences the likelihood of improvement in quality-of-life (QOL) following endoscopic sinus surgery (ESS). However, the impact of socioeconomic factors on changes in productivity loss and health utility after ESS remains unknown. METHODS: Adult patients (≥18 years of age) with chronic rhinosinusitis (CRS) who underwent ESS were prospectively enrolled into a multi-institutional cohort study. Productivity losses were calculated using the human capital approach and monetized using U.S. government-estimated wage rates. Health utility values (HUVs) were derived from the Medical Outcomes Study Short-Form-12 survey using University of Sheffield algorithms. Independent socioeconomic factors of interest included: age, gender, ethnicity, insurance status, educational attainment, and household income categorized via the Thompson-Hickey model. RESULTS: A total of 229 patients met inclusion criteria, and 163 (71%) provided postoperative follow-up. All subjects reported significant, within-subject improvement in both mean monetized productivity loss (p < 0.001) and HUV postoperatively (p < 0.001). Using paired sample statistics, patients with lowest income (≤$25,000/year) and with Medicare insurance did not report significant improvement in productivity loss (p ≥ 0.112) or HUV (p ≥ 0.081), although sample size limitations may have contributed to this finding. Patients in higher income tiers ($25,001 to $100,000/year and $100,001+/year) and those with employer-provided/private health insurance reported significant postoperative improvements in productivity loss and HUV (all p ≤ 0.003). CONCLUSION: Socioeconomic factors, including income and insurance provision, may impact improvements in productivity loss and HUV following ESS. Further research to validate these findings, ascertain mechanisms behind these results, and improve these outcomes is warranted.

Long-term outcomes of endoscopic sinus surgery in the management of adult chronic rhinosinusitis.

BACKGROUND: There is a striking lack of long-term, prospective outcomes data for endoscopic sinus surgery (ESS) in chronic rhinosinusitis (CRS) using validated instruments. Our primary objective in this study was to report long-term outcomes (>10 years) after ESS for CRS obtained by prospective data collection. METHODS: An observational cohort (n = 59) of adult patients with CRS electing ESS was enrolled between 2004 and 2008. Long-term, disease-specific quality-of-life (QOL) outcomes, health utility values (HUV), revision surgery rate, development of asthma, and patient expectations/satisfaction with outcomes of ESS were examined using descriptive statistics and simple fixed-effects linear modeling. RESULTS: Fifty-nine adult patients were followed for 10.9 years (±13.8 months), on average. Mean QOL significantly improved between baseline and 6 months and remained durable to 10 years. HUV improved to normal. A 17% revision surgery rate within the 10-year follow-up period was observed with a 25% revision rate in CRS with polyposis. New-onset asthma after ESS occurred at a rate of 0.8%/year. Patient satisfaction with ESS outcomes was generally high. CONCLUSIONS: Ten-year prospective outcomes of ESS for CRS demonstrate that the initial clinically significant improvements in QOL seen 6 months postoperatively are durable over the long term. Over 75% of patients reported clinically significant long-term QOL and HUV improvement. HUV returned to normal. Revision surgery rate was 17% and worse postoperative endoscopy scores within 18 months of initial ESS were associated with higher likelihood of revision surgery. Most patients would pursue ESS again and recommend the procedure to other patients considering this treatment option.