Decline in circulating viral and human tumor markers after resection of head and neck carcinoma.

BACKGROUND: DNA sequencing panels can simultaneously quantify human and viral tumor markers in blood. We explored changes in levels of plasma tumor markers following surgical resection of head and neck carcinoma. METHODS: In preresection and postresection plasmas, targeted DNA sequencing quantified variants in 28 human cancer genes and levels of oncogenic pathogens (human papillomavirus [HPV], Epstein-Barr virus [EBV], Helicobacter pylori) from 21 patients with head and neck squamous cell carcinoma. RESULTS: Preresection, 11 of 21 patients (52%) had detectable tumor markers in plasma, most commonly TP53 mutation or HPV genome. Several days postresection, levels fell to undetectable in 8 of 10 evaluable patients, while two high-stage patients retained circulating tumor markers. CONCLUSIONS: Modern sequencing technology can simultaneously quantify human gene variants and oncogenic viral genomes in plasma. Falling levels of cancer-specific markers upon resection can help identify viral and human markers to track at subsequent timepoints as a means to evaluate efficacy of interventions.

Robot-assisted epiglottopexy as a method for managing adult obstructive sleep apnea.

INTRODUCTION: Patients who do not tolerate continuous positive airway pressure (CPAP) for treatment of obstructive sleep apnea (OSA) often seek surgical management. A variety of procedures exist to address the nasal passages, oropharynx, hypopharynx, and larynx. Diagnostic studies including drug-induced sleep endoscopy (DISE) are helpful in identifying areas of obstruction. One potential site of obstruction is at the level of the epiglottis. We describe the use of robotic technology to assist with epiglottopexy to manage epiglottic retroflexion as a cause of two patients' OSA. This is the first reported robot-assisted epiglottopexy in the adult otolaryngology literature. METHODS: This is a case series of two patients with OSA who demonstrated epiglottis collapse into the airway during DISE. They were evaluated by polysomnographic testing (PSG), Epworth Sleepiness Scale (ESS), and physical exam. Given their epiglottic collapse seen on DISE, they underwent robot-assisted epiglottopexy. RESULTS: Both patients had moderate to severe OSA preoperatively. They successfully underwent robot-assisted epiglottopexy as a surgical intervention. They tolerated the procedure, and there have been no complications. Each reported improved symptoms, with patient one showing a decrease in total AHI and a substantial decrease in oxygen desaturations at night. The second patient reported a significant decrease in AHI and ESS. CONCLUSION: There are many options for surgical intervention in patients with OSA. Epiglottopexy is one method for addressing collapse of the epiglottis and can be achieved successfully through robot-assisted epiglottopexy in adult patients with OSA. LEVEL OF EVIDENCE: IV.

Postoperative Analgesic Requirement and Pain Perceptions after Nonaerodigestive Head and Neck Surgery.

OBJECTIVES: Little data exist on associations between patient factors and postoperative analgesic requirement after head and neck (H&N) surgeries. Such information is important for optimizing postoperative care considering concerns regarding opioid misuse. We analyzed factors associated with narcotic use and pain perception following H&N surgery sparing the upper aerodigestive tract. STUDY DESIGN: Prospective cohort. SETTING: Tertiary referral center. SUBJECTS AND METHODS: From May to October 2017, data were collected for patients undergoing nonaerodigestive H&N procedures requiring hospitalization. Patients completed a preoperative survey querying chronic pain history, narcotic usage, and postoperative pain expectation. Demographics, surgical data, postoperative narcotic use defined by morphine milligram equivalents (MME), pain scores, and Overall Benefit of Analgesia Score (OBAS) were analyzed. RESULTS: Seventy-six patients, 44 (57.9%) females and 32 (42.1%) males with a mean age of 54.0 years, met inclusion criteria. The most common procedures were parotidectomy (27.6%) and total thyroidectomy (19.7%). Average cumulative 24-hour postoperative MME and calculated MME per hospital day (MME/HD, cumulative MME for hospitalization divided by length of stay) were 40.5 ± 30.6 and 60.8 ± 60.1, respectively. Average pain score throughout the initial 24 hours after surgery was 3.7/10 ± 2.0. Female sex and prior chronic pain diagnosis were associated with higher OBAS after multivariate linear adjustments. CONCLUSION: Postoperative narcotic requirement in nonaerodigestive H&N surgery is overall low. Female sex and prior chronic pain diagnosis may be associated with higher postoperative OBAS, a validated assessment of pain and opioid-related side effects. This study may serve as a comparison for future studies evaluating narcotic-sparing analgesia and pain perception in nonaerodigestive H&N surgery.

Multimodal Analgesia Protocol after Head and Neck Surgery: Effect on Opioid Use and Pain Control.

OBJECTIVE: To assess the effect that implementation of a multimodal analgesic plan has on opioid requirements and pain control in head and neck (H&N) surgery patients. STUDY DESIGN: Prospective cohort. SETTING: Tertiary academic hospital. SUBJECTS AND METHODS: An institutional review board (IRB)-approved quality improvement initiative was undertaken to implement a multimodal analgesic protocol for all admitted H&N surgery patients starting November 2017. Postprotocol data from January to May 2018 were compared to preprotocol data from May to October 2017. Data were obtained from the electronic health records as well as through preoperative and postoperative surveys. Average pain scores and opioid use in morphine milligram equivalents (MMEs) before and after protocol implementation were compared. RESULTS: In total, 139 postprotocol patients were compared to 89 preprotocol patients. The adjusted MMEs in the first 24 hours after surgery decreased significantly from 93.7 mg to 58.6 mg (P = .026) with protocol implementation. When averaged over the length of stay (MME/hospital day), the change was no longer statistically significant (57.9 vs 46.8 mg, P = .211). The average pain score immediately after surgery and on day of discharge did not change with protocol implementation. CONCLUSION: Implementation of a multimodal analgesia plan reduced opioid use immediately after surgery but not over the course of hospitalization without any change in reported pain scores. This study shows that multimodal opioid-sparing analgesia after H&N surgery is feasible. Future studies are needed further refine the optimal analgesic strategy for H&N patients and assess the long-term efficacy, safety, and cost of such regimens.

Dual-phase CT angiography for presurgical planning in patients with vessel-depleted neck.

BACKGROUND: Microvascular reconstruction in vessel-depleted necks is challenging due to limited availability of recipient vessels. We examine the utility of dual-phase CT angiography (CTA), which delineates both arteries and veins, for preoperative planning in such difficult cases. METHODS: Retrospective chart review of a single surgeon from July 2013 to July 2017 in a tertiary referral center was performed. Patient characteristics, operative details, and surgical outcomes were examined. RESULTS: Thirteen patients met inclusion criteria. The operative plan was changed to a local flap for one patient as a result of imaging; free tissue transfer was performed for the remaining cases with 100% flap survival rate. Average operative time and ischemia time were 524 ± 110 minutes and 153 ± 47 minutes, respectively. CONCLUSIONS: Dual-phase CTA can evaluate potential venous and arterial recipient vessel and guide surgical explorations. As such, it may aid in presurgical planning for microvascular free tissue transfer in vessel-depleted necks.

Long-term Survival in Head and Neck Cancer: Impact of Site, Stage, Smoking, and Human Papillomavirus Status.

OBJECTIVES/HYPOTHESIS: Literature examining long-term survival in head and neck squamous cell carcinoma (HNSCC) with human papillomavirus (HPV) status is lacking. We compare 10-year overall survival (OS) rates for cases to population-based controls. STUDY DESIGN: Prospective cohort study. METHODS: Cases surviving 5 years postdiagnosis were identified from the Carolina Head and Neck Cancer Study. We examined 10-year survival by site, stage, p16, and treatment using Kaplan-Meier and Cox proportional hazard models. Cases were compared to age-matched, noncancer controls with stratification by p16 and smoking status. RESULTS: Ten-year OS for HNSCC is less than controls. In 581 cases, OS differed between sites with p16+ oropharynx having the most favorable prognosis (87%), followed by oral cavity (69%), larynx (67%), p16- oropharynx (56%), and hypopharynx (51%). Initial stage, but not treatment, also impacted OS. When compared to controls matched on smoking status, the hazard ratio (HR) for death in p16+ oropharynx cases was 1.5 (95% confidence interval [CI]: 0.7-3.1) for smokers and 2.4 (95% CI: 0.7-8.8) for nonsmokers. Similarly, HR for death in non-HPV-associated HNSCC was 2.2 (95% CI: 1.7-3.0) for smokers and 2.4 (95% CI: 1.4-4.9) for nonsmokers. CONCLUSIONS: OS for HNSCC cases continues to decrease 5 years posttreatment, even after stratification by p16 and smoking status. Site, stage, smoking, and p16 status are significant factors. These data provide important prognostic information for HNSCC. LEVEL OF EVIDENCE: 2 Laryngoscope, 129:2506-2513, 2019.

Radiographic muscle invasion not a recurrence predictor in HPV-associated oropharyngeal squamous cell carcinoma.

OBJECTIVE: To determine whether muscle invasion evident on pretreatment imaging in p16 + oropharyngeal squamous cell carcinoma (OPSCC) correlates with recurrence. STUDY DESIGN: Retrospective review. METHODS: Two-hundred and seventy-six patients with p16 + OPSCC treated at a tertiary referral center from 2003 to 2015 were analyzed. All scans were reviewed by a dedicated neuroradiologist with subspecialty expertise in head and neck imaging. Radiographic evidence of muscle invasion to the genioglossus, hyoglossus, medial pterygoid, and prevertebral muscles was analyzed. Local and regional recurrence rates were compared between the muscle invasion and no muscle invasion groups. RESULTS: One hundred and ninety patients met inclusion criteria with adequate follow-up data and pretreatment imaging. Patients were predominantly male (87.5% male) and smokers (65.6% smokers) with a mean age of 56.7 (standard deviation: 9.0 years). Most commonly invaded muscles in the muscle invasion group were hyoglossus (57.8%) and genioglossus (56.3%). There was no statistically significant difference in primary site or nodal recurrence between the combined group, including definite or possible muscle invasion and the group without muscle invasion (P = 0.205 and P = 0.569, respectively). Additionally, no statistically significant difference was present in recurrence-free and disease-specific survival between the two groups at 3- and 5-year follow-up (P > 0.05). CONCLUSION: Radiographic evidence of muscle invasion does not appear to be a predictor of human papilloma virus (+) OPSCC recurrence. Additional studies are needed to validate our findings. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:871-876, 2019.

Tumor Debulking in the Management of Laryngeal Cancer Airway Obstruction.

Patients presenting with advanced aerodigestive malignancy and respiratory compromise often undergo tracheotomy as initial airway management. Tumor debulking is a potential alternative. We present a case series with chart review to communicate our institutional experience with this technique. T3/4 glottic and supraglottic cancers treated between 2004 and 2014 underwent review, and 14 patients were identified for this study. Of these, 5 (35.7%) required subsequent tracheotomy, and 9 (64.3%) did not. Patients requiring subsequent tracheotomy had a delay in initiating definitive treatment when compared with those who did not (83.3 vs 31.3 days, P = .0025). No patient required a tracheotomy after initiation of definitive treatment. Our experience suggests that tumor debulking may be a viable option in select patients but that a delay in initiating treatment is associated with patients requiring tracheotomy subsequent to debulking. Further research is needed to better delineate patient scenarios in which tumor debulking alone is sufficient.

Refining the utility and role of Frozen section in head and neck squamous cell carcinoma resection.

OBJECTIVES/HYPOTHESIS: Previous studies report high-accuracy rates for intraoperative frozen sections, but reliability of frozen sections in predicting the ultimate final margin status is unknown. We compared frozen and permanent reads to identify risk factors for overall discrepancies between intraoperative and final margin status. STUDY DESIGN: Retrospective chart review. METHODS: Pathology reports of 437 surgical resections between 2010 and 2013 were retrospectively reviewed. A total of 253 cases, generating 1,109 individual specimens, met inclusion criteria. Patient demographics, treatment, recurrence, and survival, as well as pathology data pertaining to the specimen, were recorded. RESULTS: Frozen read accuracy was 96.7% (83.1% sensitivity, 97.9% specificity) relative to permanent evaluation. However, 4.3% of cases had a final positive margin not detected by frozen section; 17.8% had a close margin not detected by frozen section. In eight of 11 cases with missed positive margins, the involved margin was never sampled intraoperatively. Cases where intraoperative margins were only taken from surrounding tissue had a higher risk of missing a close or positive final margin when compared to cases where some or all margins were taken from the specimen (odds ratio = 5.05, 95% confidence interval [2.31, 11.07], P <0.0001). Disease subsite, risk score, prior radiation, staging, and p16 expression were not significantly associated with the likelihood of missing a close or positive final margin. CONCLUSION: Individual frozen section reads are highly accurate. However, negative intraoperative margins do not guarantee margin-negative resections. The process of selecting representative margins for intraoperative analysis, specifically the practice of sampling the resection bed, should be refined. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1768-1775, 2016.

Inter-Observer Variation in the Pathologic Identification of Extranodal Extension in Nodal Metastasis from Papillary Thyroid Carcinoma.

BACKGROUND: Extranodal extension (ENE) in lymph node metastases has been shown to worsen the prognosis of papillary thyroid cancer (PTC). Despite the clinical significance of ENE, there are no stringent criteria for its microscopic diagnosis, and its identification is subject to inter-observer variability. The objective of this study was to determine the level of agreement among expert pathologists in the identification of ENE in PTC cases. METHODS: Eleven expert pathologists from the United States, Italy, and Canada were asked to review 61 scanned slides of representative permanent sections of PTC specimens from Mount Sinai Beth Israel Medical Center in New York. Each slide was evaluated for the presence of ENE. The pathologists were also asked to report the criteria they use to identify ENE. RESULTS: The overall strength of agreement in identifying ENE was only fair (κ = 0.35), and the proportion of observed agreement was 0.68. The proportions of observed agreement for the identification of perinodal structures (fat, nerve, skeletal, and thick-walled vessel involvement) ranged from 0.61 to 0.997. CONCLUSIONS: Overall agreement for the identification of ENE is poor. The lack of agreement results from both variation in pathologists' identification of features and disagreement on the histologic criteria for ENE. This lack of concordance may help explain some of the discordant information regarding prognosis in clinical studies when this feature is identified.

Inter-Observer Variation in the Pathologic Identification of Minimal Extrathyroidal Extension in Papillary Thyroid Carcinoma.

BACKGROUND: Extrathyroidal extension (ETE) is a significant prognostic factor in papillary thyroid carcinoma (PTC). Minimal extrathyroidal extension (mETE) is characterized by involvement of the sternothyroid muscle or perithyroid soft tissue, and is generally identified by light microscope examination. Patients with mETE, identified pathologically, are automatically upstaged to pT3. However, the prognostic implications of mETE have been a source of controversy in the literature. Moreover, there is also controversy surrounding the identification of mETE on pathological specimens. The objective of this study was to determine the level of agreement among expert pathologists in the identification of mETE in PTC cases. METHODS: Eleven expert pathologists from the United States, Italy, and Canada were asked to perform a review of 69 scanned slides of representative permanent sections of PTC specimens. Each slide was evaluated for the presence of mETE. The pathologists were also asked to list the criteria they use to identify mETE. RESULTS: The overall strength of agreement for identifying mETE was slight (κ = 0.14). Inter-pathologist agreement was best for perithyroidal skeletal muscle involvement (κ = 0.46, moderate agreement) and worst for invasion around thick-walled vascular structures (κ = 0.02, slight agreement). In addition, there was disagreement over the constellation of histologic features that are diagnostic for mETE, which affected overall agreement for diagnosing mETE. CONCLUSIONS: Overall agreement for the identification of mETE is poor. Disagreement is a result of both variation in individual pathologists' interpretations of specimens and disagreement on the histologic criteria for mETE. Thus, the utility of mETE in staging and treatment of PTC is brought into question. The lack of concordance may explain the apparent lack of agreement regarding the prognostic significance of this pathologic feature.

Risk factors associated with severe and recurrent angioedema: an epidemic linked to ACE-inhibitors.

OBJECTIVES/HYPOTHESIS: To evaluate the etiology and risk factors for severe manifestation and recurrent episodes of angioedema; to evaluate efficacy of short-term and long-term management strategies for angioedema among a high-risk population. STUDY DESIGN: Institutional review board-approved retrospective review of a large, urban population. METHODS: Data from 875 adult patients treated from January 2008 to December 2013 with the diagnosis of angioedema were obtained using the Clinical Looking Glass utility and review of medical records. Demographic and clinicopathologic risk factors were recorded. The major outcomes evaluated were hospital admission, need for airway intervention, and recurrent episodes of angioedema following the first presentation. Initial treatment strategy and follow-up recommendations were also recorded. RESULTS: The most common cause of angioedema was angiotensin converting enzyme inhibitor (ACEi)-induced (496 [56.6%]). Significant risk factors for severe cases of angioedema included older age, Hispanic race, ACEi-induced angioedema type, American Society of Anesthesiologists class III or above, coexistent cardiopulmonary disease, and a positive smoking history. A total of 17.2% of patients experienced recurrent attacks of angioedema; of those patients, 25.9% were still taking an ACEi at subsequent presentation. Risk factors for recurrent episodes included older age, idiopathic angioedema type, and coexistent cardiopulmonary disease. Only 54.1% of patients who experienced ACEi-induced angioedema had electronic medical record documentation of these allergies. CONCLUSIONS: Knowledge of risk factors for severe and recurrent episodes of angioedema and improved education for both healthcare providers and patients, specifically related to ACEi use and allergy documentation, may significantly decrease the burden and morbidity of angioedema among high risk populations. LEVEL OF EVIDENCE: 2b.

Purification, quantification, and functional analysis of Complement Factor H.

Complement Factor H (FH) is an abundant, non-enzymic plasma/serum glycoprotein, which has a major role in regulating activation of the complement system. It can be purified from human plasma/serum by affinity chromatography, using a monoclonal anti-FH antibody as ligand. Other affinity chromatography ligands, including cardiolipin and trinitrophenyl-bovine serum albumin (TNP-BSA), can be used to purify human FH and also FH from a wide range of vertebrates, including mammals, birds, bony fish. Human FH protein concentration can be quantified by sandwich ELISA. The activity of FH is generally measured by assays which detect the cleavage, by complement factor I, of the complement protein C3b to form iC3b. Cleavage occurs only in the presence of a cofactor, and FH is one of a small number of cofactors for this reaction.

Mitogen-activated protein kinase phosphatase-1 (MKP-1) in retinal ischemic preconditioning.

We previously described the phenomenon of retinal ischemic pre-conditioning (IPC) and we have shown the role of various signaling proteins in the protective pathways, including the mitogen-activated protein kinase p38. In this study we examined the role in IPC of mitogen-activated protein kinase phosphatase-1 (MKP-1), which inactivates p38. Ischemia was produced by elevation of intraocular pressure above systolic arterial blood pressure in adult Wistar rats. Preconditioning was produced by transient retinal ischemia for 5 min, 24 h prior to ischemia. Small interfering RNA (siRNA) to MKP-1 or a control non-silencing siRNA, was injected into the vitreous 6 h prior to IPC. Recovery was assessed by electroretinography (ERG) and histology. The a-and b-waves, and oscillatory potentials (OPs), measured before and 1 week after ischemia, were then normalized relative to pre-ischemic baseline, and corrected for diurnal variation in the normal non-ischemic eye. The P2, or post-photoreceptor component of the ERG (which reflects function of the rod bipolar cells in the inner retina), was derived using the Hood-Birch model. MKP-1 was localized in specific retinal cells using immunohistochemistry; levels of mitogen-activated protein kinases were measured using Western blotting. Injection of siRNA to MKP-1 significantly attenuated the protective effect of IPC as reflected by decreased recovery of the electroretinogram a and b-waves and the P2 after ischemia. The injection of siRNA to MKP-1 reduced the number of cells in the retinal ganglion cell and outer nuclear layers after IPC and ischemia. Blockade of MKP-1 by siRNA also increased the activation of p38 at 24 h following IPC. MKP-1 siRNA did not alter the levels of phosphorylated jun N-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) after IPC. The results suggest the involvement of dual-specificity phosphatase MKP-1 in IPC and that MKP-1 is involved in IPC by regulating levels of activated MAPK p38.

Mitogen-activated protein kinase p38alpha and retinal ischemic preconditioning.

In previous studies, inhibition of mitogen-activated protein kinase (MAP) p38 significantly improved recovery and attenuated apoptosis after retinal ischemia in rats. Yet, ischemic preconditioning (IPC) attenuated the ischemia-induced increase in p38 expression. We hypothesized that p38 was required for induction of ischemic tolerance by IPC. We examined the mechanisms of involvement of p38 in IPC neuroprotection. IPC or ischemia was induced in rat retina in vivo. Recovery after ischemia performed 24h after IPC was assessed functionally (electroretinography) and histologically at 7d after ischemia in the presence or absence of inhibition of p38. We examined the role of p38alpha in the mimicking of IPC produced by opening mitochondrial KATP channels using diazoxide, or stimulation of p38 activation by anisomycin. The importance of adenosine receptors in p38 activation after IPC was assessed using specific blockers of adenosine A1 and A2a receptors. Interfering RNA (siRNA) or SB203580 was used to block p38alpha. Phosphorylated p38 levels were measured. Phosphorylated p38 protein increased with IPC. Interfering RNA (siRNA) to p38alpha prior to IPC, or inhibiting p38 activation with SB203580, with ischemia following 24h later, significantly attenuated the neuroprotective effect of IPC. Anisomycin administered to increase p38 mimicked IPC, an effect blocked by SB203580. IPC-mimicking with diazoxide, an opener of mitochondrial KATP channels, was diminished with p38alpha siRNA. Adenosine receptor blockade did not decrease the elevated levels of phosphorylated p38 after IPC. Specific inhibition of p38alpha suggests that this MAPK is involved in the protective effects of IPC, and that p38 is downstream of mitochondrial KATP channels, but not adenosine receptors, in this neuroprotection.