Facial Plastic and Reconstructive Surgery During the COVID-19 Pandemic: Implications in Craniomaxillofacial Trauma and Head and Neck Reconstruction.

BACKGROUND: The global COVID-19 pandemic has had a profound impact on facial plastic and reconstructive surgery. Our review serves as a safety resource based on the current literature and is aimed at providing best-practice recommendations. Specifically, this article is focused on considerations in the management of craniomaxillofacial trauma as well as reconstructive procedures after head and neck oncologic resection. METHODS: Relevant clinical data were obtained from peer-reviewed journal articles, task force recommendations, and published guidelines from multiple medical organizations utilizing data sources including PubMed, Google Scholar, MEDLINE, and Google search queries. Relevant publications were utilized to develop practice guidelines and recommendations. CONCLUSIONS: The global COVID-19 pandemic has placed a significant strain on health care resources with resultant impacts on patient care. Surgeons operating in the head and neck are particularly at risk of occupational COVID-19 exposure during diagnostic and therapeutic procedures and must therefore be cognizant of protocols in place to mitigate exposure risk and optimize patient care.

Satellite and In-Transit Metastatic Disease in Melanoma Skin Cancer: A Retrospective Review of Disease Presentation, Treatment, and Outcomes.

BACKGROUND: Satellitosis and in-transit metastases (SITM) are uncommon in cutaneous melanoma and are associated with poor prognosis. However, the disease- and treatment-specific variables that predict outcomes among patients with SITM are poorly defined. OBJECTIVE: To identify factors that predict prognosis among patients with SITM. MATERIALS AND METHODS: Retrospective chart review of patients treated for melanoma at a large academic medical center in central Pennsylvania between 2000 and 2012. Patients with pathology reports containing "satellite lesions" or "in-transit metastases" were selected for analysis. Data were collected regarding tumor stage, the timing of SITM discovery, treatment, recurrence-free survival after SITM discovery, and overall survival (OS). RESULTS: We identified SITM in 32 (1.9%) of 1,650 patients with pathology-diagnosed melanoma over the study period. Reduced recurrence-free survival after SITM discovery was associated with higher pathologic stage, metastatic disease, lymph node dissection, and use of adjuvant chemotherapy. Reduced OS was associated with higher T, N, M, and overall prognostic stage; positive surgical margins; disease recurrence; and SITM on initial presentation. CONCLUSION: Our data support previous findings that higher stage disease confers a worse prognosis among patients with SITM. Patients with SITM on initial presentation had worse outcomes, suggesting SITM is indicative of more aggressive disease.

The effect of aging on the anatomic position of the thyroid gland.

Thyroid disease is common among elderly patients, frequently necessitating thyroid gland examination, imaging, and surgery. However, no prior studies have determined the effect of age on the anatomic position of the thyroid gland in the anterior neck. We hypothesized that the thyroid gland resides at a more caudal position in the neck in elderly patients as compared to younger patients. Head and neck CT scans were collected from 122 atraumatic patients without thyroid disease aged 18-39 years, 40-59 years, 60-79 years, and 80+ years. Measurements of thyroid gland position and other aspects of head and neck anatomy were conducted in the mid-sagittal plane. The distance between the thyroid gland and the sternal notch decreased from 45 ± 10.4 mm in the 18-39 age group to 30.8 ± 9 mm in the 80+ age group (P < 0.001). The position of the gland did not change significantly relative to anatomic landmarks in the head or neck, although the trachea was angled more closely to the horizontal plane in elderly patients (P < 0.001). Cervical spine height was also lower among patients ≥60 years of age compared to those <60 years of age (P < 0.001). Multivariate linear modeling suggested that thyroid gland position was dependent on changes in cervical spine height, hyoid bone to hard palate distance, and tracheal angle (P = 1.7 × 10-11 ; r2 = 0.37). Clinicians should be aware of the more caudad positioning of the gland when planning surgery or screening for thyroid disease in the elderly. Clin. Anat. 30:205-212, 2017. © 2016 Wiley Periodicals, Inc.

A murine retrovirus co-Opts YB-1, a translational regulator and stress granule-associated protein, to facilitate virus assembly.

UNLABELLED: The Gag protein of the murine retrovirus mouse mammary tumor virus (MMTV) orchestrates the assembly of immature virus particles in the cytoplasm which are subsequently transported to the plasma membrane for release from the cell. The morphogenetic pathway of MMTV assembly is similar to that of Saccharomyces cerevisiae retrotransposons Ty1 and Ty3, which assemble virus-like particles (VLPs) in intracytoplasmic ribonucleoprotein (RNP) complexes. Assembly of Ty1 and Ty3 VLPs depends upon cellular mRNA processing factors, prompting us to examine whether MMTV utilizes a similar set of host proteins to facilitate viral capsid assembly. Our data revealed that MMTV Gag colocalized with YB-1, a translational regulator found in stress granules and P bodies, in intracytoplasmic foci. The association of MMTV Gag and YB-1 in cytoplasmic granules was not disrupted by cycloheximide treatment, suggesting that these sites were not typical stress granules. However, the association of MMTV Gag and YB-1 was RNA dependent, and an MMTV RNA reporter construct colocalized with Gag and YB-1 in cytoplasmic RNP complexes. Knockdown of YB-1 resulted in a significant decrease in MMTV particle production, indicating that YB-1 plays a role in MMTV capsid formation. Analysis by live-cell imaging with fluorescence recovery after photobleaching (FRAP) revealed that the population of Gag proteins localized within YB-1 complexes was relatively immobile, suggesting that Gag forms stable complexes in association with YB-1. Together, our data imply that the formation of intracytoplasmic Gag-RNA complexes is facilitated by YB-1, which promotes MMTV virus assembly. IMPORTANCE: Cellular mRNA processing factors regulate the posttranscriptional fates of mRNAs, affecting localization and utilization of mRNAs under normal conditions and in response to stress. RNA viruses such as retroviruses interact with cellular mRNA processing factors that accumulate in ribonucleoprotein complexes known as P bodies and stress granules. This report shows for the first time that mouse mammary tumor virus (MMTV), a mammalian retrovirus that assembles intracytoplasmic virus particles, commandeers the cellular factor YB-1, a key regulator of translation involved in the cellular stress response. YB-1 is essential for the efficient production of MMTV particles, a process directed by the viral Gag protein. We found that Gag and YB-1 localize together in cytoplasmic granules. Functional studies of Gag/YB-1 granules suggest that they may be sites where virus particles assemble. These studies provide significant insights into the interplay between mRNA processing factors and retroviruses.

Alterations in the MA and NC domains modulate phosphoinositide-dependent plasma membrane localization of the Rous sarcoma virus Gag protein.

Retroviral Gag proteins direct virus particle assembly from the plasma membrane (PM). Phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P(2)] plays a role in PM targeting of several retroviral Gag proteins. Here we report that depletion of intracellular PI(4,5)P(2) and phosphatidylinositol-(3,4,5)-triphosphate [PI(3,4,5)P(3)] levels impaired Rous sarcoma virus (RSV) Gag PM localization. Gag mutants deficient in nuclear trafficking were less sensitive to reduction of intracellular PI(4,5)P(2) and PI(3,4,5)P(3), suggesting a possible connection between Gag nuclear trafficking and phosphoinositide-dependent PM targeting.

Nucleolar trafficking of the mouse mammary tumor virus gag protein induced by interaction with ribosomal protein L9.

The mouse mammary tumor virus (MMTV) Gag protein directs the assembly in the cytoplasm of immature viral capsids, which subsequently bud from the plasma membranes of infected cells. MMTV Gag localizes to discrete cytoplasmic foci in mouse mammary epithelial cells, consistent with the formation of cytosolic capsids. Unexpectedly, we also observed an accumulation of Gag in the nucleoli of infected cells derived from mammary gland tumors. To detect Gag-interacting proteins that might influence its subcellular localization, a yeast two-hybrid screen was performed. Ribosomal protein L9 (RPL9 or L9), an essential component of the large ribosomal subunit and a putative tumor suppressor, was identified as a Gag binding partner. Overexpression of L9 in cells expressing the MMTV(C3H) provirus resulted in specific, robust accumulation of Gag in nucleoli. Förster resonance energy transfer (FRET) and coimmunoprecipitation analyses demonstrated that Gag and L9 interact within the nucleolus, and the CA domain was the major site of interaction. In addition, the isolated NC domain of Gag localized to the nucleolus, suggesting that it contains a nucleolar localization signal (NoLS). To determine whether L9 plays a role in virus assembly, small interfering RNA (siRNA)-mediated knockdown was performed. Although Gag expression was not reduced with L9 knockdown, virus production was significantly impaired. Thus, our data support the hypothesis that efficient MMTV particle assembly is dependent upon the interaction of Gag and L9 in the nucleoli of infected cells.

Incidental Papillary Thyroid Cancer Identified During Parathyroidectomy.

Current treatment guidelines recommend surgical excision of papillary thyroid carcinoma. However, the precise surgical treatment, including thyroid lobectomy, total thyroidectomy, and the need for neck dissection, is dictated by disease extent and tumor cytology. Incidental papillary thyroid carcinoma discovered during another surgery therefore presents a surgical conundrum due to lack of information. Surgeons must consider short- and long-term surgical morbidities, as well as individual patient factors, when deciding how to treat an unexpected thyroid carcinoma.

In-depth analysis of thyroid cancer mortality.

BACKGROUND: There are reports of an increasing thyroid cancer mortality rate. This study aimed to analyze the latest trends in this rate over time and compare findings from different cancer registries. METHODS: Thyroid cancer incidence-based mortality (IBM) rates were obtained from the Surveillance, Epidemiology, and End Results (SEER) program, including SEER-9, SEER-13, and SEER-18. The National Center for Health Statistics (NCHS) thyroid cancer mortality rate was acquired for comparison. Statistical analysis was performed using the JoinPoint software. RESULTS: NCHS data revealed an overall annual percent change (APC) over 1987 to 2017 of 0.61 (P < .01), and the value was nearly four times greater for males compared to females. The overall IBM APC values for SEER-9, SEER-13, and SEER-18 were also positive and statistically significant (P < .01). CONCLUSIONS: The increased thyroid cancer mortality rate observed in previous studies continues to be statistically significant based on updated NCHS and SEER IBM data.

Pediatric Thyroid Cancer: To Whom Do You Send the Referral?

Pediatric thyroid cancer is rare, but increasing in annual incidence. Differentiated thyroid cancer in pediatric patients is treated surgically. Pediatric thyroidectomies are performed by general surgeons, otolaryngologists, general pediatric surgeons, and pediatric otolaryngologists. In a comprehensive literature review, we discuss the evidence supporting the importance of surgeon subspecialty and surgeon volume on outcomes for pediatric thyroid cancer patients. Pediatric general surgeons and pediatric otolaryngologists perform most pediatric thyroidectomies. Certain subpopulations specifically benefit from a combined approach of a pediatric surgeon and a high-volume thyroid surgeon. The correlation between high-volume surgeons and lower complication rates in adult thyroid surgery applies to the pediatric population; however, the definition of high-volume for pediatric thyroidectomies requires further investigation. The development of dedicated pediatric thyroid malignancy centers and multidisciplinary or dual-surgeon approaches are advantageous.

A Commentary on Safety Precautions for Otologic Surgery during the COVID-19 Pandemic.

There are insufficient data regarding the safety of otologic procedures in the setting of the coronavirus disease 2019 (COVID-19) pandemic. Given the proclivity for respiratory pathogens to involve the middle ear and the significant aerosolization associated with many otologic procedures, safety precautions should follow current recommendations for procedures involving the upper airway. Until preoperative diagnostic testing becomes standardized and readily available, elective cases should be deferred and emergent/urgent cases should be treated as high risk for COVID-19 exposure. Necessary otologic procedures on positive, suspected, or unknown COVID-19 status patients should be performed using enhanced personal protective equipment, including an N95 respirator and eye protection or powered air-purifying respirator (PAPR, preferred), disposable cap, disposable gown, and gloves. Powered instrumentation should be avoided unless absolutely necessary, and if performed, PAPR or sealed eye protection is recommended.

Commentary on the management of total laryngectomy patients during the COVID-19 pandemic.

The coronavirus disease-2019 (COVID-19) pandemic has rapidly spread across the world, placing unprecedented strain on the health care system. Health care resources including hospital beds, ICUs, as well as personal protective equipment are becoming increasingly rationed and scare commodities. In this environment, the laryngectomee (patient having previously undergone a total laryngectomy) continues to represent a unique patient with unique needs. Given their surgically altered airway, they pose a challenge to manage for the otolaryngologist within the current COVID-19 pandemic. In this brief report, we present special considerations and best practice recommendations in the management of total laryngectomy patients. We also discuss recommendations for laryngectomy patients and minimizing community exposures.

Impact of coronavirus (COVID-19) on otolaryngologic surgery: Brief commentary.

BACKGROUND: The Coronavirus disease-2019 (COVID-19) pandemic is a global health crisis and otolaryngologists are at increased occupational risk of contracting COVID-19. There are currently no uniform best-practice recommendations for otolaryngologic surgery in the setting of COVID-19. METHODS: We reviewed relevant publications and position statements regarding the management of otolaryngology patients in the setting of COVID-19. Recommendations regarding clinical practice during the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) outbreaks were also reviewed. RESULTS: Enhanced personal protective equipment (N95 respirator and face shield or powered air-purifying respirator, disposable cap and gown, gloves) is required for any otolaryngology patient with unknown, suspected, or positive COVID-19 status. Elective procedures should be postponed indefinitely, and clinical practice should be limited to patients with urgent or emergent needs. CONCLUSION: We summarize current best-practice recommendations for otolaryngologists to ensure safety for themselves, their clinical staff, and their patients.

Best Practice Recommendations for Pediatric Otolaryngology during the COVID-19 Pandemic.

OBJECTIVE: To review the impact of coronavirus disease 2019 (COVID-19) on pediatric otolaryngology and provide recommendations for the management of children during the COVID-19 pandemic. DATA SOURCES: Clinical data were derived from peer-reviewed primary literature and published guidelines from national or international medical organizations. Preprint manuscripts and popular media articles provided background information and illustrative examples. METHODS: Included manuscripts were identified via searches using PubMed, MEDLINE, and Google Scholar, while organizational guidelines and popular media articles were identified using Google search queries. Practice guidelines were developed via consensus among all authors based on peer-reviewed manuscripts and national or international health care association guidelines. Strict objective criteria for inclusion were not used due to the rapidly changing environment surrounding the COVID-19 pandemic and a paucity of rigorous empirical evidence. CONCLUSIONS: In the face of the COVID-19 pandemic, medical care must be judiciously allocated to treat the most severe conditions while minimizing the risk of long-term sequelae and ensuring patient, physician, and health care worker safety. IMPLICATIONS FOR PRACTICE: The COVID-19 pandemic will have a profound short- and long-term impact on health care worldwide. Although the full repercussions of this disease have yet to be realized, the outlined recommendations will guide otolaryngologists in the treatment of pediatric patients in the face of an unprecedented global health crisis.

Genetic Variants Implicate Dual Oxidase-2 in Familial and Sporadic Nonmedullary Thyroid Cancer.

Highly penetrant hereditary thyroid cancer manifests as familial nonmedullary thyroid cancer (FNMTC), whereas low-penetrance hereditary thyroid cancer manifests as sporadic disease and is associated with common polymorphisms, including rs965513[A]. Whole-exome sequencing of an FNMTC kindred identified a novel Y1203H germline dual oxidase-2 (DUOX2) mutation. DUOX2Y1203H is enzymatically active, with increased production of reactive oxygen species. Furthermore, patients with sporadic thyroid cancer homozygous for rs965513[A] demonstrated higher DUOX2 expression than heterozygous rs965513[A/G] or homozygous rs965513[A]-negative patients. These data suggest that dysregulated hydrogen peroxide metabolism is a common mechanism by which high- and low-penetrance genetic factors increase thyroid cancer risk. SIGNIFICANCE: This study provides novel insights into the genetic and molecular mechanisms underlying familial and sporadic thyroid cancers.

Evidence of a positive association between malpractice climate and thyroid cancer incidence in the United States.

The incidence of thyroid cancer has risen dramatically in the past few decades. The cause of this is unclear, but several lines of evidence indicate it is largely due to overdiagnosis, the diagnosis of tumors that would have never manifest clinically if untreated. Practices leading to overdiagnosis may relate to defensive medicine. In this study, we evaluated the association between malpractice climate and incidence of thyroid, breast, prostate, colon, and lung cancer in U.S. states from 1999-2012 using publicly available government data. State-level malpractice risk was quantified as malpractice payout rate, the number of malpractice payouts per 100,000 people per state per year. Associations between state-level cancer incidence, malpractice payout rate, and several cancer risk factors were evaluated. Risk factors included several social determinants of health, including factors predicting healthcare access. States with higher malpractice payout rate had higher thyroid cancer incidence, on both univariate analysis (r = 0.51, P = 0.009, Spearman) and multivariate analysis (P<0.001, multilevel model). In contrast, state-level malpractice payout rate was not associated with incidence of any other cancer type. Malpractice climate may be a social determinant for being diagnosed with thyroid cancer. This may be a product of greater defensive medicine in states with higher malpractice risk, which leads to increased diagnostic testing of patients with thyroid nodules and potential overdiagnosis. Alternatively, malpractice risk may be a proxy for another, unmeasured risk factor.

Integrative detection and analysis of structural variation in cancer genomes.

Structural variants (SVs) can contribute to oncogenesis through a variety of mechanisms. Despite their importance, the identification of SVs in cancer genomes remains challenging. Here, we present a framework that integrates optical mapping, high-throughput chromosome conformation capture (Hi-C), and whole-genome sequencing to systematically detect SVs in a variety of normal or cancer samples and cell lines. We identify the unique strengths of each method and demonstrate that only integrative approaches can comprehensively identify SVs in the genome. By combining Hi-C and optical mapping, we resolve complex SVs and phase multiple SV events to a single haplotype. Furthermore, we observe widespread structural variation events affecting the functions of noncoding sequences, including the deletion of distal regulatory sequences, alteration of DNA replication timing, and the creation of novel three-dimensional chromatin structural domains. Our results indicate that noncoding SVs may be underappreciated mutational drivers in cancer genomes.

Pediatric Cystic Deep Neck Mass Presenting With Stridor and Dysphagia.

A 6-month-old girl presented to the emergency department for evaluation of fever and was noted to have mild inspiratory stridor, which began acutely at 4 months of age without any inciting illness or event. What is your diagnosis?

Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer.

Next-generation sequencing using exome capture is a common approach used for analysis of familial cancer syndromes. Despite the development of robust computational algorithms, the accrued experience of analyzing exome data sets and published guidelines, the analytical process remains an ad hoc series of important decisions and interpretations that require significant oversight. Processes and tools used for sequence data generation have matured and are standardized to a significant degree. For the remainder of the analytical pipeline, however, the results can be highly dependent on the choices made and careful review of results. We used primary exome sequence data, generously provided by the corresponding author, from a family with highly penetrant familial non-medullary thyroid cancer reported to be caused by HABP2 rs7080536 to review the importance of several key steps in the application of exome sequencing for discovery of new familial cancer genes. Differences in allele frequencies across populations, probabilities of familial segregation, functional impact predictions, corroborating biological support, and inconsistent replication studies can play major roles in influencing interpretation of results. In the case of HABP2 rs7080536 and familial non-medullary thyroid cancer, these factors led to the conclusion of an association that most data and our re-analysis fail to support, although larger studies from diverse populations will be needed to definitively determine its role.

Altered molecular profile in thyroid cancers from patients affected by the Three Mile Island nuclear accident.

OBJECTIVES/HYPOTHESIS: In 1979, Three Mile Island (TMI) nuclear power plant experienced a partial meltdown with release of radioactive material. The effects of the accident on thyroid cancer (TC) in the surrounding population remain unclear. Radiation-induced TCs have a lower incidence of single nucleotide oncogenic driver mutations and higher incidence of gene fusions. We used next generation sequencing (NGS) to identify molecular signatures of radiation-induced TC in a cohort of TC patients residing near TMI during the time of the accident. STUDY DESIGN: Case series. METHODS: We identified 44 patients who developed papillary thyroid carcinoma between 1974 and 2014. Patients who developed TC between 1984 and 1996 were at risk for radiation-induced TC, patients who developed TC before 1984 or after 1996 were the control group. We used targeted NGS of paired tumor and normal tissue from each patient to identify single nucleotide oncogenic driver mutations. Oncogenic gene fusions were identified using quantitative reverse transcription polymerase chain reaction. RESULTS: We identified 15 patients in the at-risk group and 29 patients in the control group. BRAFV600E mutations were identified in 53% patients in the at-risk group and 83% patients in the control group. The proportion of patients with BRAF mutations in the at-risk group was significantly lower than predicted by the The Cancer Genome Atlas cohort. Gene fusion or somatic copy number alteration drivers were identified in 33% tumors in the at-risk group and 14% of tumors in the control group. CONCLUSIONS: Findings were consistent with observations from other radiation-exposed populations. These data raise the possibility that radiation released from TMI may have altered the molecular profile of TC in the population surrounding TMI. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:S1-S9, 2017.

Novel Immunotherapeutic Approaches for Head and Neck Squamous Cell Carcinoma.

The immune system plays a key role in preventing tumor formation by recognizing and destroying malignant cells. For over a century, researchers have attempted to harness the immune response as a cancer treatment, although this approach has only recently achieved clinical success. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is associated with cigarette smoking, alcohol consumption, betel nut use, and human papillomavirus infection. Unfortunately, worldwide mortality from HNSCC remains high, partially due to limits on therapy secondary to the significant morbidity associated with current treatments. Therefore, immunotherapeutic approaches to HNSCC treatment are attractive for their potential to reduce morbidity while improving survival. However, the application of immunotherapies to this disease has been challenging because HNSCC is profoundly immunosuppressive, resulting in decreased absolute lymphocyte counts, impaired natural killer cell function, reduced antigen-presenting cell function, and a tumor-permissive cytokine profile. Despite these challenges, numerous clinical trials testing the safety and efficacy of immunotherapeutic approaches to HNSCC treatment are currently underway, many of which have produced promising results. This review will summarize immunotherapeutic approaches to HNSCC that are currently undergoing clinical trials.