Stage Migration and Survival Trends in Laryngeal Cancer.

BACKGROUND: During the last two decades, significant advancements in the treatment of laryngeal cancer have occurred. Although survival of head and neck cancer patients has improved over time, the temporal trend of laryngeal cancer survival is an area of controversy. METHODS: From 2004 to 2016, 77,527 patients who had laryngeal cancer treated with curative intent in the United States were identified in the National Cancer Database. Relative and observed survival rates were assessed for temporal trends. Multinomial logistic regression investigated the relationship between American Joint Committee on Cancer (AJCC) stage and increasing calendar year. RESULTS: No significant improvement in 2- or 5-year observed survival (OS) or relative survival (RS) was observed. The 5-year RS ranged from 61.72 to 63.97%, and the 5-year OS ranged from 54.26 to 56.52%. With each increasing year, the proportion of stage 4 disease increased, with risk for stage 4 disease at the time of diagnosis increasing 2.2% annually (adjusted odds ratio [aOR], 1.022; 95% confidence interval [CI], 1.017-1.028; p < 0.001). This increase was driven by a 4.7% yearly increase in N2 disease (aOR, 1.047; 95% CI, 1.041-1.053; p < 0.001), with an annual 1.2% increase in T3 disease (aOR, 1.012; 95% CI, 1.007-1.018; p < 0.001) and a 1.2% increase in T4 disease (aOR, 1.012; 95% CI, 1.005-1.018; p < 0.001). CONCLUSION: Despite advances in the field, laryngeal cancer survival in the United States is not improving over time. This may be due to an increase in the proportion of stage 4 disease, driven primarily by increasing nodal disease. To achieve survival improvement commensurate with scientific and technologic advances, efforts should be made to diagnose and treat laryngeal cancer at earlier stages to prevent further stage migration.

National treatment trends in human papillomavirus-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC) is associated with dramatically improved survival in comparison with HPV-negative OPC and can be successfully treated with surgical and nonsurgical approaches. National treatment trends for OPC were investigated with the National Cancer Data Base (NCDB). METHODS: The NCDB was reviewed for primary HPV-mediated OPC in 2010-2014. Multivariable regression was used to identify predictors of both nonsurgical therapy and receipt of adjuvant chemoradiation (CRT). RESULTS: There were 13,363 patients identified with a median age at diagnosis of 58 years. The incidence of triple-modality treatment (surgery with adjuvant chemotherapy) decreased from 23.7% in 2010 to 16.9% in 2014 (R2  = 0.96), whereas the incidence of nonsurgical treatment increased from 63.9% to 68.7% (R2  = 0.89). Hospitals in the top treatment volume quartile (quartile 1 [Q1]; n = 29) had a lower rate of positive margins (16.3%) than bottom-quartile centers (n = 741; rate of positive margins, 36.4%; P < .001); Q1 hospitals used surgical therapy significantly more. Independent predictors of nonsurgical therapy included older age, advanced disease, lower hospital volume, and living closer to the hospital or outside the Pacific United States. In surgically treated patients, younger age, lower hospital volume, nodal disease, positive surgical margins, and extranodal extension (ENE) also predicted more adjuvant CRT use. CONCLUSIONS: The use of upfront surgical treatment decreased from 2010 to 2014. Hospital volume shows a strong, inverse correlation with the rate of positive surgical margins. The upfront treatment strategy is predicted not only by staging but also by patient-, geographic-, and hospital-specific factors. Lower hospital volume remains independently associated with increased triple-modality therapy after adjustments for positive margins, ENE, and pathologic staging.

Margin Analysis in Head and Neck Cancer: State of the Art and Future Directions.

BACKGROUND: The status of surgical margins is the most important prognosticator for patients undergoing surgical resection of head and neck squamous cell carcinoma (HNSCC). Despite this, analysis of surgical margins is fraught with inconsistencies, including the ways in which margins are sampled and interpreted. Fundamentally, even the definition what constitutes a "clear" (or negative) margin may vary between institutions, surgeons, and pathologists. METHODS: The PubMed database was queried for articles relevant to the topic, and experts in the field were consulted regarding key articles for inclusion. Abstracts were reviewed and the full text was accessed for articles of particular interest. RESULTS: Data regarding various approaches to traditional margin analysis have been published without consensus. Several next-generation technologies have emerged in recent years that hold promise. CONCLUSION: An overview and appraisal of traditional margin analysis techniques are provided. Additionally, we explore novel technologies that may assist in more accurate margin assessment, guide the extent of surgical resections intraoperatively, and inform decisions regarding adjuvant treatment postoperatively.

Early geriatric consultation increases adherence to TQIP Geriatric Trauma Management Guidelines.

BACKGROUND: The American College of Surgeons' Trauma Quality Improvement Program (TQIP) Geriatric Trauma Management Guidelines recommend geriatric consultation for injured older adults. However it is not known how or whether geriatric consultation improves compliance to these quality measures. METHODS: This study is a retrospective chart review of our institutional trauma databank. Adherence to quality measures was compared before and after implementation of specific triggers for geriatric consultation. Secondary analyses evaluated adherence by service: trauma service (Trauma) or a trauma service with early geriatric consultation (GeriTrauma). RESULTS: The average age of the 245 patients was 76.7 years, 47% were women, and mean Injury Severity Score was 9.5 (SD ±8.1). Implementation of the GeriTrauma collaborative increased geriatric consultation rates from 2% to 48% but had minimal effect on overall adherence to TQIP quality measures. A secondary analysis comparing those in the post implementation group who received geriatric consultation (n = 94) to those who did not (n = 103) demonstrated higher rates of delirium diagnosis (36.2% vs 14.6%, P < 0.01) and better documentation of initial living situation, code status, and medication list in the GeriTrauma group. Physical therapy was consulted more frequently for GeriTrauma patients (95.7% vs 68.0%, P < 0.01) Documented goals of care discussions were rare and difficult to abstract. A subgroup analysis of only patients with fall-related injuries demonstrated similar outcomes. CONCLUSIONS: Early geriatric consultation increases adherence to TQIP guidelines. Further research into the long term significance and validity of these geriatric trauma quality indicators is needed.

Blood RNA profiling in a large cohort of multiple sclerosis patients and healthy controls.

Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS). It is characterized by the infiltration of autoreactive immune cells into the CNS, which target the myelin sheath, leading to the loss of neuronal function. Although it is accepted that MS is a multifactorial disorder with both genetic and environmental factors influencing its development and course, the molecular pathogenesis of MS has not yet been fully elucidated. Here, we studied the longitudinal gene expression profiles of whole-blood RNA from a cohort of 195 MS patients and 66 healthy controls. We analyzed these transcriptomes at both the individual transcript and the biological pathway level. We found 62 transcripts to be significantly up-regulated in MS patients; the expression of 11 of these genes was counter-regulated by interferon treatment, suggesting partial restoration of a 'healthy' gene expression profile. Global pathway analyses linked the proteasome and Wnt signaling to MS disease processes. Since genotypes from a subset of individuals were available, we were able to identify expression quantitative trait loci (eQTL), a number of which involved two genes of the MS gene signature. However, all these eQTL were also present in healthy controls. This study highlights the challenge posed by analyzing transcripts from whole blood and how these can be mitigated by using large, well-characterized cohorts of patients with longitudinal follow-up and multi-modality measurements.

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes.

Previously, we demonstrated concordance in differentially expressed genes in sarcoidosis blood and lung, implicating shared dysfunction of specific immune pathways. In the present study, we hypothesised that expression levels of candidate genes in sarcoidosis blood could predict and track with disease outcomes longitudinally. We applied Ingenuity Pathway Analysis to a cross-sectional derivation microarray dataset (n=38) to identify canonical pathways and candidate genes associated with sarcoidosis. In a separate longitudinal sarcoidosis cohort (n=103), we serially measured 48 candidate gene transcripts, and assessed their relation to disease chronicity and severity. In the cross-sectional derivation study, pathway analysis showed upregulation of genes related to interferon signalling and the role of pattern recognition receptors, and downregulation of T-cell receptor (TCR) signalling pathways in sarcoidosis. In the longitudinal cohort, factor analysis confirmed coregulation of genes marking these pathways and identified CXCL9 as an additional candidate pathway. CXCL9 and TCR factors discriminated between chronic versus nonprogressive disease, and CXCL9 predicted disease outcomes longitudinally. Interferon factor was similarly increased in both disease phenotypes. Factors associated with lung function decline included decreased TCR factor and increased CXCL9. These findings demonstrate blood transcriptomic signatures reflecting TCR signalling and CXCL9 predict sarcoidosis chronicity and correlate with disease severity longitudinally.

State of Head and Neck Microvascular Reconstruction: Current and Future Directions.

Since its inception, microvascular free tissue transfer has broadened possibilities for oncologic ablation and restoration of form and function. Developments throughout recent decades have resulted in increasing flap success rates and complexity. Advances in technology and knowledge gained from past experiences will continue to improve surgical efficiency, flap success rates, and ultimately, patient outcomes.

Response to induction chemotherapy in sinonasal malignancies: A single-institutional experience.

BACKGROUND: Sinonasal malignancy (SNM) is a heterogeneous group of diseases for which induction chemotherapy (IC) may reduce tumor burden. The purpose of this study was to characterize the response to IC in SNM as a prognostic factor through its effect on survival. METHODS: Retrospective cohort of patients undergoing IC for SNM between 2010 and 2019 at our quaternary referral center. RESULTS: Forty-two patients with advanced SNM were included in the analysis. Patients with a favorable response to IC had higher survival rates than those who had an unfavorable response (5-year OS: 66.8% vs. 9.7%; p < 0.001; PFS: 56.8% vs. 0%; p < 0.001). CONCLUSIONS: Response to IC in our patient cohort was a prognostic indicator of overall response to treatment. Further elucidation of predictors of response is needed for appropriate patient selection.

Factors affecting talker discrimination ability in adult cochlear implant users.

INTRODUCTION: Real-world speech communication involves interacting with many talkers with diverse voices and accents. Many adults with cochlear implants (CIs) demonstrate poor talker discrimination, which may contribute to real-world communication difficulties. However, the factors contributing to talker discrimination ability, and how discrimination ability relates to speech recognition outcomes in adult CI users are still unknown. The current study investigated talker discrimination ability in adult CI users, and the contributions of age, auditory sensitivity, and neurocognitive skills. In addition, the relation between talker discrimination ability and multiple-talker sentence recognition was explored. METHODS: Fourteen post-lingually deaf adult CI users (3 female, 11 male) with ≥1 year of CI use completed a talker discrimination task. Participants listened to two monosyllabic English words, produced by the same talker or by two different talkers, and indicated if the words were produced by the same or different talkers. Nine female and nine male native English talkers were paired, resulting in same- and different-talker pairs as well as same-gender and mixed-gender pairs. Participants also completed measures of spectro-temporal processing, neurocognitive skills, and multiple-talker sentence recognition. RESULTS: CI users showed poor same-gender talker discrimination, but relatively good mixed-gender talker discrimination. Older age and weaker neurocognitive skills, in particular inhibitory control, were associated with less accurate mixed-gender talker discrimination. Same-gender discrimination was significantly related to multiple-talker sentence recognition accuracy. CONCLUSION: Adult CI users demonstrate overall poor talker discrimination ability. Individual differences in mixed-gender discrimination ability were related to age and neurocognitive skills, suggesting that these factors contribute to the ability to make use of available, degraded talker characteristics. Same-gender talker discrimination was associated with multiple-talker sentence recognition, suggesting that access to subtle talker-specific cues may be important for speech recognition in challenging listening conditions.

Outcomes with culture-directed antibiotics following microvascular free tissue reconstruction for osteonecrosis of the jaw.

OBJECTIVES: Radiation (ORNJ) and bisphosphonate-related (BRONJ) osteonecrosis of the jaw represent challenging entities to treat, with many patients requiring segmental resection and reconstruction with microvascular free tissue transfer (MFTT) in the setting of failed conservative therapy. Microvascular reconstruction is associated with higher post-operative complication rates when performed for advanced osteonecrosis versus oncologic defects. We hypothesize that basing antibiotic therapy on cultures obtained from the healthy bone marrow following resection during MFTT for ORNJ or BRONJ reduces rates of post-operative wound and surgical complications. MATERIALS AND METHODS: In a retrospective cohort study spanning January 2016 to October 2018, 44 patients undergoing MFTT for ORNJ or BRONJ were identified. Patients were categorized into two cohorts: residual healthy marrow culture (n = 11; RHM), treated with antibiotics guided by cultures from healthy appearing mandible, and all others (n = 33; AO), treated with antibiotics guided by cultures from resected necrotic bone or purulent drainage. Patient, reconstruction, and outcome variables were compared via appropriate statistical tools. RESULTS: 81.8% of the RHM cohort versus 24.2% of the AO cohort received long-term IV antibiotics. Rates of post-operative wound complications, including those necessitating operative management, were significantly lower in the RHM cohort. Rates of flap failure were similar across both groups. CONCLUSION: Administration of long-term IV antibiotics directed by native mandible cultures may decrease complication rates following MFTT for ORNJ or BRONJ by treating residual, smoldering infection. Concurrently, transplantation of well-vascularized free tissue likely improves antibiotic delivery. Findings are crucial for the development of a standardized treatment algorithm following microvascular reconstruction for advanced osteonecrosis.

Evolving Criteria for Adult and Pediatric Cochlear Implantation.

The indications for cochlear implantation have gradually expanded as advancements in technology have evolved, resulting in improved audiologic outcomes for both adult and children. There remains a significant underutilization of cochlear implant technology in the United States, and recognition of the potential benefits of cochlear implantation for non-traditional indications is critical for encouraging the evolution of candidacy criteria. Adult cochlear implantation candidacy has progressed from patients with bilateral profound sensorineural hearing loss (SNHL) to include patients with greater degrees of residual hearing, single-sided deafness and asymmetric hearing, and atypical etiologies of hearing loss (eg, vestibular schwannoma, Ménière's disease, and otosclerosis). Indications for pediatric cochlear implantation have similarly evolved from children with bilateral severe to profound SNHL to implanting children at a younger age, including those with residual hearing, asymmetric hearing loss, inner ear malformations, as well as cochlear nerve deficiency. In this editorial, the literature investigating cochlear implantation for nontraditional indications is reviewed with an aim to use the best available evidence to encourage the evolution of candidacy criteria.

Modulation of Synthetic Tracheal Grafts with Extracellular Matrix Coatings.

Synthetic scaffolds for the repair of long-segment tracheal defects are hindered by insufficient biocompatibility and poor graft epithelialization. In this study, we determined if extracellular matrix (ECM) coatings improved the biocompatibility and epithelialization of synthetic tracheal grafts (syn-TG). Porcine and human ECM substrates (pECM and hECM) were created through the decellularization and lyophilization of lung tissue. Four concentrations of pECM and hECM coatings on syn-TG were characterized for their effects on scaffold morphologies and on in vitro cell viability and growth. Uncoated and ECM-coated syn-TG were subsequently evaluated in vivo through the orthotopic implantation of segmental grafts or patches. These studies demonstrated that ECM coatings were not cytotoxic and, enhanced the in vitro cell viability and growth on syn-TG in a dose-dependent manner. Mass spectrometry demonstrated that fibrillin, collagen, laminin, and nephronectin were the predominant ECM components transferred onto scaffolds. The in vivo results exhibited similar robust epithelialization of uncoated and coated syn-TG patches; however, the epithelialization remained poor with either uncoated or coated scaffolds in the segmental replacement models. Overall, these findings demonstrated that ECM coatings improve the seeded cell biocompatibility of synthetic scaffolds in vitro; however, they do not improve graft epithelialization in vivo.

Tissue engineering applications in otolaryngology-The state of translation.

While tissue engineering holds significant potential to address current limitations in reconstructive surgery of the head and neck, few constructs have made their way into routine clinical use. In this review, we aim to appraise the state of head and neck tissue engineering over the past five years, with a specific focus on otologic, nasal, craniofacial bone, and laryngotracheal applications. A comprehensive scoping search of the PubMed database was performed and over 2000 article hits were returned with 290 articles included in the final review. These publications have addressed the hallmark characteristics of tissue engineering (cellular source, scaffold, and growth signaling) for head and neck anatomical sites. While there have been promising reports of effective tissue engineered interventions in small groups of human patients, the majority of research remains constrained to in vitro and in vivo studies aimed at furthering the understanding of the biological processes involved in tissue engineering. Further, differences in functional and cosmetic properties of the ear, nose, airway, and craniofacial bone affect the emphasis of investigation at each site. While otolaryngologists currently play a role in tissue engineering translational research, continued multidisciplinary efforts will likely be required to push the state of translation towards tissue-engineered constructs available for routine clinical use. LEVEL OF EVIDENCE: NA.

Molecular margins in head and neck cancer: Current techniques and future directions.

Complete tumor extirpation with clear surgical margins remains a central tenet of oncologic head and neck surgery. Rates of locoregional recurrence and survival are both significantly worse when clear margins are unable to be obtained. Current clinical practice relies on the use of frozen sections intra-operatively, followed by traditional histopathologic analysis post-operatively to assess the surgical margin. However, with improved understanding of tumor biology and advances in technology, new techniques have emerged to analyze margins at a molecular level. Such molecular margin analysis interrogates tissue for genetic, epigenetic, or proteomic changes that may belie tumor presence or aggressive features not captured by standard histopathologic techniques. Intra-operatively, this information may be used to guide resection, while post-operatively, it may help to stratify patients for adjuvant treatment. In this review, we summarize the current state of molecular margin analysis and describe directions for future research.

Utilization of microvascular couplers in salvage arterial anastomosis in head and neck free flap surgery: Case series and literature review.

BACKGROUND: In microvascular reconstruction of ablative oncologic defects, coupler devices have traditionally been used for venous anastomosis, whereas the arterial anastomosis is hand-sewn. In the setting of repeated intraoperative arterial anastomotic thrombosis, a coupler device may be of use in reducing the risk of rethrombosis. METHODS: Two patients were seen with advanced stage head and neck cancer and underwent oncologic resection. During microvascular reconstruction, a clot at the arterial anastomosis was encountered in both cases. RESULTS: After starting therapeutic anticoagulation and attempting unsuccessful suture reanastomosis, coupler devices were used for arterial anastomosis, resulting in viable free-tissue transfer. CONCLUSIONS: Although traditionally used for venous anastomosis, coupler devices may serve a purpose in the salvage setting when facing repeated intraoperative arterial thrombosis.

The Use of Vasopressor Agents in Free Tissue Transfer for Head and Neck Reconstruction: Current Trends and Review of the Literature.

BACKGROUND/OBJECTIVES: Microvascular free tissue transfer has become essential to head and neck reconstruction and recent advancements in microvascular surgery have led to excellent surgical outcomes. However, there continues to be controversy and a stigma associated with the use of perioperative intravenous vasopressor agents among both surgeons and anesthesiologists. Due to concern for vasoconstriction of peripheral vasculature flowing to the denervated tissue flap, there remains concerns about potential thrombosis, decreased tissue perfusion and ultimately flap failure. This topic becomes even more important as vasopressors play an essential role in new Extended Recovery After Surgery (ERAS) protocols being put in place to optimize postoperative recovery for patients. The purpose of this study was to comprehensively review the role and safety as well as discuss current trends with intraoperative vasopressor agents in free tissue transfer for head and neck reconstruction. METHODS: A scoping literature review was conducted of all studies that examined the use of vasopressor agents during head and neck free flap tissue transfer. Primary and secondary outcomes included free flap survival, arterial thrombosis, venous congestion, need for revision surgery, and other postoperative complications. RESULTS: One prospective and nine retrospective studies were identified. Phenylephrine and ephedrine were the most common vasopressors reported; the rate of vasopressor use ranged from 53% to 85% and administration methods included both bolus and infusion. The included studies did not show any significant association between the use of vasopressors and free flap failure, pedicle thrombosis, or other flap complications. CONCLUSION: The administration of vasopressors during microvascular free tissue transfer for head and neck reconstruction does not seem to be associated with increased flap failure rates or other postoperative morbidities. Moreover, vasopressors may provide overall improved hemodynamic stability and help to limit overall fluid administration and subsequent postoperative complications. Additional prospective investigation is warranted to further elucidate and establish evidence-based recommendations regarding the type, timing, and dose of vasopressors to further enhance free flap survival and patient outcomes.

Alkaline phosphatase-positive colony formation is a sensitive, specific, and quantitative indicator of undifferentiated human embryonic stem cells.

Human embryonic stem cells (hESCs) can be maintained in vitro as immortal pluripotent cells but remain responsive to many differentiation-inducing signals. Investigation of the initial critical events involved in differentiation induction would be greatly facilitated if a specific, robust, and quantitative assay for pluripotent hESCs with self-renewal potential were available. Here we describe the results of a series of experiments to determine whether the formation of adherent alkaline phosphatase-positive (AP(+)) colonies under conditions optimized for propagating undifferentiated hESCs would meet this need. The findings can be summarized as follows. (a) Most colonies obtained under these conditions consist of >or=30 AP(+) cells that coexpress OCT4, NANOG, SSEA3, SSEA4, TRA-1-60, and TRA-1-81. (b) Most such colonies are derived from SSEA3(+) cells. (c) Primary colonies contain cells that produce secondary colonies of the same composition, including cells that initiate multilineage differentiation in embryoid bodies (EBs). (d) Colony formation is independent of plating density or the colony-forming cell (CFC) content of the test population over a wide range of cell concentrations. (e) CFC frequencies decrease when differentiation is induced by exposure either to retinoic acid or to conditions that stimulate EB formation. Interestingly, this loss of AP(+) clonogenic potential also occurs more rapidly than the loss of SSEA3 or OCT4 expression. The CFC assay thus provides a simple, reliable, broadly applicable, and highly specific functional assay for quantifying undifferentiated hESCs with self-renewal potential. Its use under standardized assay conditions should enhance future elucidation of the mechanisms that regulate hESC propagation and their early differentiation.