20 pack-year smoking history as strongest smoking metric predictive of HPV-positive oropharyngeal cancer outcomes.

OBJECTIVES: While smoking is associated with worse outcomes in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), the magnitude of this association is unclear given the heterogenous smoking definitions and outcomes. Our objective was to investigate the association between smoking, survival, and recurrence in HPV-related OPSCC using multiple smoking metrics reported in the literature. MATERIALS AND METHODS: This was a retrospective cohort study of 375 adults with p16+ OPSCC undergoing surgical resection (n = 272) or definitive chemoradiation (n = 103) at a tertiary academic institution from 2006 to 2017. The primary outcome was overall survival (OS). Secondary outcomes included disease-free survival (DFS), disease-specific survival (DSS), and recurrence. We used multiple smoking metrics commonly cited in previous studies, including ever versus never smokers, current versus former/never smokers, ≤10 versus >10 pack-year, ≤20 versus >20 pack-year, and continuous pack-year. RESULTS: There were 375 patients, median age 58 years, with 326 (87%) males, and median follow-up of 52 months. Of all smoking metrics, >20 pack-year history was the strongest predictor of both OS (HR 2.24, 95% CI: 1.19-4.20) and DFS (HR 1.67, 95% CI: 1.04-2.66) on univariable and multivariable analysis after adjusting for age, overall stage, and comorbidities. Patients with >20 pack-year smoking history were also more likely to have recurrence (HR 1.59, 95% CI: 0.95-2.67) after adjusting for overall stage. CONCLUSION: Heavier smoking >20 pack-years was the strongest smoking metric associated with 2-times worse survival and recurrence. Our findings suggest that >20 pack-year smoking history may be a more useful cutoff for risk stratification models but requires further validation.

Fluorescence-based alternative splicing reporters for the study of epithelial plasticity in vivo.

Alternative splicing generates a vast diversity of protein isoforms from a limited number of protein-coding genes, with many of the isoforms possessing unique, and even contrasting, functions. Fluorescence-based splicing reporters have the potential to facilitate studies of alternative splicing at the single-cell level and can provide valuable information on phenotypic transitions in almost real time. Fibroblast growth factor receptor 2 (FGFR2) pre-mRNA is alternatively spliced to form the epithelial-specific and mesenchymal-specific IIIb and IIIc isoforms, respectively, which are useful markers of epithelial-mesenchymal transitions (EMT). We have used our knowledge of FGFR2 splicing regulation to develop a fluorescence-based reporter system to visualize exon IIIc regulation in vitro and in vivo. Here we show the application of this reporter system to the study of EMT in vitro in cell culture and in vivo in transgenic mice harboring these splicing constructs. In explant studies, the reporters revealed that FGFR2 isoform switching is not required for keratinocyte migration during cutaneous wound closure. Our results demonstrate the value of the splicing reporters as tools to study phenotypic transitions and cell fates at single cell resolution. Moreover, our data suggest that keratinocytes migrate efficiently in the absence of a complete EMT.

Cost-Effectiveness of Diffusion Weighted MRI Versus Planned Second-Look Surgery for Cholesteatoma.

OBJECTIVE: To compare the cost-effectiveness of serial non-echo planar diffusion weighted MRI (non-EP DW MRI) versus planned second look surgery following initial canal wall up tympanomastoidectomy for the treatment of cholesteatoma. METHODS: A decision-analytic model was developed. Model inputs including residual cholesteatoma rates, rates of non-EP DW MRI positivity after surgery, and health utility scores were abstracted from published literature. Cost data were derived from the 2022 Centers for Medicare and Medicaid Services fee rates. Efficacy was defined as increase in quality-adjusted life year (QALY). One- and 2-way sensitivity analyses were performed on variables of interest to probe the model. Total time horizon was 50 years with a willingness to pay (WTP) threshold set at $50 000/QALY. RESULTS: Base case analysis revealed that planned second-look surgery ($11 537, 17.30 QALY) and imaging surveillance with non-EP DWMRI ($10 439, 17.26 QALY) were both cost effective options. Incremental cost effectiveness ratio was $27 298/QALY, which is below the WTP threhshold. One-way sensitivity analyses showed that non-EP DW MRI was more cost effective than planned second-look surgery if the rate of residual disease after surgery increased to 48.3% or if the rate of positive MRI was below 45.9%. A probabilistic sensitivity analysis at WTP of $50 000/QALY found that second-look surgery was more cost-effective in 56.7% of iterations. CONCLUSION: Non-EP DW MRI surveillance is a cost-effect alternative to planned second-look surgery following primary canal wall up tympanomastoidectomy for cholesteatoma. Cholesteatoma surveillance decisions after initial canal wall up tympanomastoidectomy should be individualized. LEVEL OF EVIDENCE: V.

Free Flap Reconstruction of the Anterior Skull Base: A Systematic Review.

Objectives Given the limitations in the available literature, the precise indications, techniques, and outcomes of anterior skull base free flap reconstruction remain uncertain. The objective of this study was to perform a systematic review of published literature and evaluate indications, methods, and complications for anterior skull base free flap reconstruction. Methods A systematic review of the literature was performed using a set of search criteria to identify patients who underwent free flap reconstruction of the anterior skull base. Articles were reviewed for inclusion based on relevance, with the primary outcome being surgical complications. Results After a comprehensive search, 406 articles were obtained and 16 articles were ultimately found to be relevant to this review-79 patients undergoing free flap reconstruction were identified. Overall complication rates were 17.7% (95% confidence interval [CI]: 16.6-33.1%) for major complications and 19.0% (95% CI: 17.8-35.5%) for minor complications. Conclusion Microvascular reconstruction of the anterior skull base is feasible with high reliability reported in the literature.

Early Hearing Preservation Outcomes Following Cochlear Implantation With New Slim Lateral Wall Electrode Using Electrocochleography.

OBJECTIVE: Describe early hearing preservation (HP) cochlear implantation (CI) outcomes using a new slim lateral wall electrode (SLWE). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENTS: Adult CI candidates with preoperative low-frequency pure-tone average (LFPTA; 125, 250, 500 Hz) ≤60 dB HL. INTERVENTION: CI with and without intracochlear real-time electrocochleography (RT-ECochG). MAIN OUTCOME MEASURE: HP (LFPTA ≤80 dB HL), LFPTA shift, speech-perception performance measures, postoperative CT reconstruction. RESULTS: Forty-two subjects were implanted with the SLWE. Thirty patients underwent full insertion without RT-ECochG feedback, and HP was maintained at 3-months postactivation for 7 (23.3%) patients with mean LFPTA shift of 57.5 ±â€Š25.6 dB HL. RT-ECochG feedback was utilized on 12 patients, of whom 6 patients had full insertions and 6 patients had anywhere from 1 to 3 electrodes left outside of the cochlea based on RT-ECochG feedback. At 3 months postoperatively, HP was achieved on 10 (83.3%) patients and mean LFPTA shift was 18.9 c 11.7 dB HL. Mean difference between LFPTA threshold shift at 3-months postactivation with and without RT-ECochG was 38.6 dB HL (95% CI, 25.6-51.67). There was an improvement in delta CNC from preoperative to 3-months postactivation when using RT-ECochG, with mean difference 20.7% (95% CI, 3.3-38.1). CONCLUSIONS: Use of RT-ECochG monitoring during SLWE placement results in fewer full electrode insertions and significantly better HP rates and speech-perception outcomes when compared with unmonitored insertions. Further investigation is needed to evaluate long-term audiologic outcomes to better understand the relationships among ECochG, cochlear trauma, functional outcomes, and HP.

Prevalence, Surgical Management, and Audiologic Impact of Sigmoid Sinus Dehiscence Causing Pulsatile Tinnitus.

OBJECTIVE: To evaluate the prevalence, surgical management, and audiologic impact of pulsatile tinnitus caused by sigmoid sinus dehiscence. STUDY DESIGN AND SETTING: Retrospective chart review at a tertiary care hospital. PATIENTS: Adults with unilateral pulsatile tinnitus attributable to sigmoid sinus dehiscence who underwent resurfacing between January 2010 and January 2020. INTERVENTIONS: Transmastoid sigmoid resurfacing. MAIN OUTCOME MEASURES: Resolution of pulsatile tinnitus; audiologic outcomes; complications; tinnitus etiologies. RESULTS: Nineteen patients (89.4% women) had surgery for suspected sigmoid sinus dehiscence. The mean dehiscence size was 6.1 mm (range, 1-10.7 mm). Eight patients had concurrent sigmoid sinus diverticulum and one patient also had jugular bulb dehiscence. Only two patients (10.5%) had the defect identified by radiology. Low-frequency pure-tone average, measured at frequencies of 250 and 500 Hz, showed a significant median improvement of 8.8 dB following resurfacing (18.8 dB versus 10.0 dB, p = 0.02). The majority of patients had complete resolution of pulsatile tinnitus (16/19, 84.2%). Of those without complete resolution, two patients had partial response and one patient had no improvement. There were no significant complications. Of 41 consecutively tracked patients with a pulsatile tinnitus chief complaint, sigmoid pathology represented 32% of cases. CONCLUSIONS: Sigmoid sinus dehiscence represents a common vascular cause of pulsatile tinnitus that, if properly assessed, may be amenable to surgical intervention. Sigmoid sinus resurfacing is safe, does not require decompression, and may improve low-frequency hearing. Radiographic findings of dehiscence are often overlooked without a high index of clinical suspicion. Its relationship with transverse sinus pathology and idiopathic intracranial hypertension remain unclear.

Outcomes of Patients With Single-Node Metastasis of Human Papillomavirus-Related Oropharyngeal Cancer Treated With Transoral Surgery.

Importance: Regional lymph node metastasis remains an important prognostic factor in patients with oropharyngeal squamous cell carcinoma (OPSCC). Although survival among patients with regional metastasis in human papillomavirus (HPV)-related OPSCC is more favorable compared with patients who are HPV negative, prognostic variables associated with failure in patients with single-node metastasis are not known. Objective: To evaluate recurrence and survival in patients with HPV-related OPSCC with single-lymph node metastasis treated with transoral surgery. Design, Setting, and Participants: A retrospective cohort study was conducted of 207 adults with newly diagnosed p16-positive OPSCC and pathology-confirmed single-node disease who underwent surgical resection with or without adjuvant therapy at 2 tertiary academic medical centers from January 1, 2007, to December 31, 2016. Statistical analysis was performed from September 1, 2018, to September 1, 2020. Interventions: Surgery alone (n = 59), surgery with adjuvant radiation (n = 75), or surgery with adjuvant chemoradiation (n = 73). Main Outcomes and Measures: The primary outcome was regional recurrence. Secondary outcomes included overall survival, any recurrence, and identification of factors associated with regional recurrence and overall survival. Results: Among 207 patients, 178 (86%) were men, with a median age of 57 years (range, 35-82 years) at the time of surgery. Median follow-up was 36.2 months (range, 7-127 months). Regional recurrence occurred in 11 patients (5%). Of these, 1 patient (9%) was lost to follow-up after diagnosis, 1 (9%) was treated with palliative chemotherapy, and 9 (82%) were treated with curative intent. Ultimately, 7 patients received successful salvage treatment, and 3 died with disease. Overall, there were 21 patients (10%) with any recurrence, with 4 patients (19%) experiencing local recurrence, 11 (52%) experiencing regional recurrence, and 6 (29%) experiencing distant metastasis. The 5-year overall survival was 95% (95% CI, 89%-98%) for all patients. Older age (odds ratio [OR], 1.2; 95% CI, 1.1-1.2), advanced T stage (OR, 3.5; 95% CI, 0.9-14.0), and positive margins (OR, 10.9; 95% CI, 1.8-67.5) were associated with increased regional recurrence. Extranodal extension (OR, 0.2; 95% CI, 0.04-0.8), lymph node size greater than 3 cm (OR, 0.2; 95% CI, 0.1-0.7), and adjuvant therapy (OR, 0.08; 95% CI, 0.02-0.4) were associated with decreased regional recurrence. Advanced comorbidities (hazard ratio, 6.20; 95% CI, 1.4-27.7), lymphovascular invasion (hazard ratio, 4.7; 95% CI, 1.0-21.2), and regional recurrence (hazard ratio, 16.0; 95% CI, 3.1-82.0) were associated with worse overall survival. Conclusions and Relevance: The findings of this cohort study suggest that patients with HPV-related OPSCC and single-node disease undergoing surgical resection with or without adjuvant treatment have excellent survival. Adjuvant therapy appears to improve regional control. Among patients with regional recurrence of OPSCC, there is a high rate of successful salvage treatment.

Complications and Outcomes of Chimeric Free Flaps: A Systematic Review.

OBJECTIVE: Ablations of locally advanced or recurrent head and neck cancer commonly result in large composite orofacial defects. Chimeric flaps represent a unique surgical option for these defects, as they provide diverse tissue types from a single donor site. The purpose of the study was to consolidate the literature on chimeric flaps with regard to postoperative complication rates to help inform surgical decision making. DATA SOURCES: The librarian created search strategies with a combination of keywords and controlled vocabulary in Ovid Medline (1946), Embase (1947), Scopus (1823), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinicaltrails.gov (1997). REVIEW METHODS: Candidate articles were independently reviewed by 2 authors familiar with the subject material, and inclusion/exclusion criteria were uniformly applied for article selection. Articles were considered eligible if they included patients who received a single chimeric flap for reconstruction of head and neck defects and if they provided data on complication rates. RESULTS: A total of 521 chimeric flaps were included in the study. The major complication rate was 22.6%, while the minor complication rate was 14.0%. There were 7 flap deaths noted in the series. Median operative time and harvest time were 15.0 and 2.5 hours, respectively. CONCLUSION: Chimeric flaps represent a viable option for reconstruction of complex head and neck defects and have complication rates similar to those of double free flaps and single free flaps with locoregional flap while only modestly increasing total operative time.

Utility of the LACE Scoring System in Predicting Readmission Following Tracheotomy and Laryngectomy.

In the current value-based health-care environment, 30-day unplanned hospital readmissions have been identified as a quality measure and an opportunity to help reduce health-care costs. The LACE Index Scoring Tool for Risk Assessment of Death and Readmission utilizes length of stay, acuity of admission, comorbidities, and emergency department visits to stratify patients into high and low risk of readmission. A retrospective chart review of 161 patients who underwent a tracheotomy or laryngectomy for head and neck indications at a tertiary care academic center demonstrated that the readmitted patient cohort was not statistically or clinically different from the nonreadmitted cohort when comparing LACE scores ( P = .789), length of hospital stay ( P = .237), discharge disposition ( P = .569), or insurance status ( P = .85). Addressing the problem of unplanned 30-day readmissions will likely require enhanced patient education, improved coordination of care, and further research.

Association between Eosinophilic Esophagitis and Esophageal Food Impaction in the Pediatric Population.

Objectives (1) To describe the presentation, management, and outcomes associated with pediatric esophageal food impaction (EFI) at a single tertiary care institution. (2) To identify the key clinical features of pediatric EFI that are associated with a diagnosis of eosinophilic esophagitis (EoE). Study Design Case series with chart review. Setting Tertiary care children's hospital. Subjects and Methods Thirty-five children <18 years of age presenting with EFI between November 1, 2006, and October 31, 2013, were included. Presenting symptoms, medical history, biopsy results, endoscopic findings, and underlying etiology were examined. Fisher exact test, t tests, and logistic regression were used to compare between patients with and without EoE. Results Thirty-five patients had isolated EFI and were included in the study. EoE accounted for 74% (n = 26) of pediatric EFI, with the remaining cases being attributed to neurologic impairment (n = 5, 15%), prior surgeries (n = 1, 3%), reflux esophagitis (n = 1, 3%), or unknown etiologies (n = 2, 6%). EFI was the initial manifestation of EoE in 81% (n = 21) of patients. The most common presenting symptoms were dysphagia (n = 34), choking (n = 26), and vomiting (n = 23). Linear furrowing was the only endoscopic finding that was significantly associated with EoE ( P < .001). Conclusion Most esophageal food impactions in the pediatric population are associated with an underlying diagnosis of EoE and are often the initial manifestation of the disease. EoE must be considered in all pediatric patients with EFI; esophageal biopsies should be strongly considered in these patients at the time of endoscopic management of the EFI.

Cetuximab ameliorates suppressive phenotypes of myeloid antigen presenting cells in head and neck cancer patients.

BACKGROUND: Myeloid-derived suppressor cells (MDSC) and M2 monocytes/macrophages are two types of suppressive myeloid antigen presenting cells that have been shown to promote tumor progression and correlate with poor prognosis in cancer patients. Tumor antigen specific monoclonal antibodies (mAb) have emerged as important agents for cancer therapy. In addition to the direct inhibition of tumor growth, the Fc portions of the therapeutic mAbs, such as the IgG1 portion of the anti-epidermal growth factor receptor (EGFR) mAb cetuximab, might interact with the Fc-gamma receptors (FcγR) on myeloid cells and modulate their suppressive activity. METHODS: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) on the UPCI 08-013 NCT01218048 trial were treated with single-agent cetuximab before surgery. Blood were collected pre- and post-cetuximab treatment to analyze frequency of monocytic MDSC (CD11b(+)CD14(+)HLA-DR(lo/-)), granulocytic MDSC (LIN(-)CD11b(+)CD15(+)) and CD11b(+)CD14(+)HLA-DR(hi) monocytes by flow cytometry. Besides, CD11b(+)CD14(+)HLA-DR(hi) monocytes were sorted for qPCR analysis of IL-10 and IL-12B transcripts. MDSC were generated in vitro with or without coated hIgG1 and tested for suppressive activity in mixed leukocyte reaction (MLR). Naïve monocytes from HNSCC patients co-cultured with tumor cell lines in the presence of cetuximab or hIgG1 were analyzed for M1/2 surface markers and cytokines. RESULTS: We observed significantly increased monocytic MDSC in non-responders and decreased granulocytic MDSC in responders after cetuximab treatment. In addition, circulating CD11b(+)CD14(+)HLA-DR(hi) monocytes of cetuximab responders displayed attenuated M2 polarization, with decreased CD163(+) expression and IL-10 transcripts after cetuximab treatment. This beneficial effect appeared to be FcγR dependent, since CD16 ligation reproduced the reversal of suppressive activity of MDSC in vitro. CD14(+) naïve monocytes from the co-cultures of tumor cells, cetuximab and HNSCC patient PBMC or purified monocytes were skewed to an M1-like phenotype, with increased expression of HLA-DR, CD86 and production of IL-12 p70. Likewise, reduced M2 features (expression of CD163 and production of IL-10) were found after crosslinking CD16 on the surface of monocytes to cetuximab-coated tumor cells. CONCLUSION: Our studies demonstrate a novel function of cetuximab in ameliorating suppressive phenotypes of FcγR bearing myeloid cells in cancer patients, which is associated with better clinical outcome of cetuximab-treated patients. CLINICAL TRIAL REGISTRY: #NCT01218048. Registered 7 October 2010.

Button battery injuries in the pediatric aerodigestive tract.

Children with a button battery impaction present with nonspecific symptoms that may account for a delay in medical care. We conducted a retrospective study of the clinical presentation, management, and complications associated with button battery ingestion in the pediatric aerodigestive tract and to evaluate the associated long-term morbidity. We reviewed the medical records of 23 patients who were treated for button battery impaction at our tertiary care children's hospital from Jan. 1, 2000, through July 31, 2013. This population was made up of 14 boys and 9 girls, aged 7 days to 12 years (mean: 4 yr). Patients were divided into three groups based on the site of impaction; there were 9 impactions in the esophagus and 7 each in the nasal cavity and stomach. We compiled information on the type and size of each battery, the duration of the impaction, presenting symptoms, treatment, and outcomes. The mean duration of battery impaction was 40.6, 30.7, and 21.0 hours in the esophagus, nasal cavity, and stomach, respectively. We were able to identify the specific type of battery in 13 cases; 11 of these cases (85%) involved a 3-V 20-mm lithium ion battery, including all cases of esophageal impaction in which the type of battery was identified. The most common presenting signs and symptoms were vomiting (n = 7 [30%]), difficulty feeding (n = 5 [22%]), cough (n = 5), and bloody nasal discharge (n = 5); none of the presenting signs and symptoms predicted the severity of the injury or the outcome. The median length of hospital stay was far greater in the esophageal group (12 days) than in the nasal and stomach groups (1 day each; p = 0.006). Battery impaction in the esophagus for more than 15 hours was associated with a significantly longer postoperative hospital stay than impaction for less than 15 hours (p = 0.04). Esophageal complications included strictures (n = 5), perforation (n = 3), and tracheoesophageal fistula formation (n = 2). Clinicians should consider battery impaction in the upper aerodigestive tract as an emergency that can lead to significant long-term morbidity, and therefore immediate surgical intervention is required.