Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

An adolescent case of sellar osteochondromyxoma in the setting of spondyloepiphyseal dysplasia.

PURPOSE: Osteochondromyxomas (OMX) are rare congenital bone tumors that have only been described in the context of Carney complex syndrome (CNC). Data on OMX as a separate entity and in association with other disorders remain limited, making both diagnosis and treatment difficult. METHODS: A case report of a 17-year-old female diagnosed with sellar OMX is presented in the setting of spondyloepiphyseal dysplasia (SED). We discuss the radiographic and histopathological interpretations in addition to reviewing the current literature on OMX. RESULTS: A successful gross total resection of the tumor was achieved via an endonasal endoscopic transsphenoidal approach. A diagnosis was established radiographically and pathologically. CONCLUSION: The diagnosis and treatment of OMX are best achieved via tissue biopsy. Following confirmed osteochondromyxoma cases long term for recurrence and outcomes will be essential in understanding its natural tumor history and in establishing standard treatments.

Pediatric benign triton tumor of trigeminal nerve: a case report and literature review.

PURPOSE: Benign triton tumors (BTTs) in the pediatric population are extremely rare occurrences. Paucity of data on BTTs poses both diagnostic and therapeutic challenges, particularly when found intracranially. METHODS: A case report of a 10-year-old male diagnosed with incidental maxillary trigeminal (V2) BTT is presented. We discuss radiographic and histopathological interpretations. Furthermore, we provide a brief review of current literature and historical background on pediatric trigeminal BTT diagnosis, histopathology, and management. RESULTS: Successful gross total resection of the tumor was achieved via Dolenc approach to the cavernous sinus. Management options with consideration of outcomes from the few prior cases reported in the literature are presented. CONCLUSION: Treatment of trigeminal nerve tumors requires a broad differential diagnosis and understanding rare tumors is essential in the diagnosis and treatment algorithm.

Infantile Fibrosarcoma With NTRK3-ETV6 Fusion Successfully Treated With the Tropomyosin-Related Kinase Inhibitor LOXO-101.

Infantile fibrosarcoma (IFS) is a rare pediatric cancer typically presenting in the first 2 years of life. Surgical resection is usually curative and chemotherapy is active against gross residual disease. However, when recurrences occur, therapeutic options are limited. We report a case of refractory IFS with constitutive activation of the tropomyosin-related kinase (TRK) signaling pathway from an ETS variant gene 6-neurotrophin 3 receptor gene (ETV6-NTRK3) gene fusion. The patient enrolled in a pediatric Phase 1 trial of LOXO-101, an experimental, highly selective inhibitor of TRK. The patient experienced a rapid, radiographic response, demonstrating the potential for LOXO-101 to provide benefit for IFS harboring NTRK gene fusions.

Social Vulnerability Association with Thyroid Cancer Disparities in the United States.

Background: As thyroid cancer incidence rises, it is increasingly valuable to recognize disparities in treatment and diagnosis. Prior investigations into social determinants of health (SDoH) are limited to pediatric populations or studies looking at single factors such as race or environmental influences. Utilizing the CDC-social vulnerability index and SEER-patient database to assess the amalgamated, real-world influence of varied SDoH and their quantifiable impact on thyroid cancer disparities across the United States. Methods: In a retrospective cohort study, 199,340 adult thyroid cancer patients from 1975 to 2017 were assessed for significant regression trends in months of follow-up/surveillance, survival, late staging, and treatment receipt across thyroid cancer-subtypes with increasing overall social vulnerability, as well as in 15 SDoH variables regarding socioeconomic status, minority-language status, household composition, and housing-transportation across all the U.S. counties while accounting for sociodemographic regional differences. Results: With increasing overall social vulnerability, decreases in months of follow-up were observed with patients with papillary, follicular, medullary, oncocytic, and anaplastic thyroid cancer (p = 0.001). Comparing lowest with highest vulnerability cohorts, relative decreases in months of surveillance ranged from 55.6% (14.5-6.5 months) with anaplastic to 17% (108.6-90.2) with oncocytic. Socioeconomic status vulnerabilities, followed by vulnerabilities in household composition and housing-transportation type, contributed to these overall trends. Similar survival decreases occurred across all thyroid cancer patients, ranging from 55.9% (9.6-4.2) with anaplastic to 28.3% (97-69.5) with oncocytic. Minority-language status vulnerabilities and housing-transportation types largely contributed to these trends. Increasing overall vulnerability was associated with increased odds of advanced staging for papillary (odds ratio [OR] = 1.07 [confidence interval, CI 1.03-1.12]) and decreased odds of indicated treatment via surgery (lowest, medullary: 0.91 [CI 0.84-0.99]), radiation therapy (lowest, anaplastic: 0.88 [CI 0.82-0.93]), and chemotherapy (lowest, oncocytic: 0.81 [CI 0.67-0.98]) were observed. Vulnerabilities in minority-language status and housing-transportation, followed by socioeconomic status vulnerabilities, were differential contributors to these overall vulnerability trends. Conclusions: Our results show significant detriments in thyroid cancer care and prognosis in the United States with increasing overall social vulnerability while identifying which SDoH quantifiably contribute more to disparities in inter-relational, real-world-like contexts.

Large-data contextualizations of social determinant associations in pediatric head and neck cancers.

PURPOSE OF REVIEW: Prior investigations in social determinants of health (SDoH) and their impact on pediatric head and neck cancers are limited by the narrow scope of cancer types and SDoH being studied while lacking inquiry on the interrelational contribution of varied SDoH in real-world contexts. The purpose of this review is to discuss the current research tackling these shortcomings of SDoH-based studies in head and neck cancer and to discuss means of applying these findings in prospective initiatives and implementations. RECENT FINDINGS: Through leveraging contemporary, large-data analyses measuring diverse social vulnerabilities, several studies have identified comprehensive delineations of which social disparities contribute the largest quantifiable impact on the care of head and neck cancer patients. Progressing from prior SDoH-based research of the decade, these studies contextualize the effect of social vulnerabilities and have laid the foundations to begin addressing these issues in the complex, modern-day environment of interrelatedsocial factors. SUMMARY: Social determinants of health markedly affect pediatric head and neck cancer care and prognosis in complex and surprising ways. Modern-day tools and analyses derived from large-data techniques have unveiled the quantifiable underpinnings of how SDoH impact these pathologies.

Assessment of Social Vulnerability in Pediatric Head and Neck Cancer Care and Prognosis in the United States.

Importance: Prior investigations in social determinants of health (SDoH) in pediatric head and neck cancer (HNC) have only considered a narrow scope of HNCs, SDoH, and geography while lacking inquiry into the interrelational association of SDoH with disparities in clinical pediatric HNC. Objectives: To evaluate the association of SDoH with disparities in HNC among children and adolescents and to assess which specific aspects of SDoH are most associated with disparities in dynamic and regional sociodemographic contexts. Design, Setting, and Participants: This retrospective cohort study included data about patients (aged ≤19 years) with pediatric HNC who were diagnosed from 1975 to 2017 from the Surveillance, Epidemiology, and End Results Program (SEER) database. Data were analyzed from October 2021 to October 2022. Exposures: Overall social vulnerability and its subcomponent contributions from 15 SDoH variables, grouped into socioeconomic status (SES; poverty, unemployment, income level, and high school diploma status), minority and language status (ML; minoritized racial and ethnic group and proficiency with English), household composition (HH; household members aged ≥65 and ≤17 years, disability status, single-parent status), and housing and transportation (HT; multiunit structure, mobile homes, crowding, no vehicle, group quarters). These were ranked and scored across all US counties. Main Outcomes and Measures: Regression trends were performed in continuous measures of surveillance and survival period and in discrete measures of advanced staging and surgery receipt. Results: A total of 37 043 patients (20 729 [55.9%] aged 10-19 years; 18 603 [50.2%] male patients; 22 430 [60.6%] White patients) with 30 different HNCs in SEER had significant relative decreases in the surveillance period, ranging from 23.9% for malignant melanomas (mean [SD] duration, lowest vs highest vulnerability: 170 [128] months to 129 [88] months) to 41.9% for non-Hodgkin lymphomas (mean [SD] duration, lowest vs highest vulnerability: 216 [142] months vs 127 [94] months). SES followed by ML and HT vulnerabilities were associated with these overall trends per relative-difference magnitudes (eg, SES for ependymomas and choroid plexus tumors: mean [SD] duration, lowest vs highest vulnerability: 114 [113] months vs 86 [84] months; P < .001). Differences in mean survival time were observed with increasing social vulnerability, ranging from 11.3% for ependymomas and choroid plexus tumors (mean [SD] survival, lowest vs highest vulnerability: 46 [46] months to 41 [48] months; P = .43) to 61.4% for gliomas not otherwise specified (NOS) (mean [SD] survival, lowest vs highest vulnerability: 44 [84] months to 17 [28] months; P < .001), with ML vulnerability followed by SES, HH, and HT being significantly associated with decreased survival (eg, ML for gliomas NOS: mean [SD] survival, lowest vs highest vulnerability: 42 [84] months vs 19 [35] months; P < .001). Increased odds of advanced staging with non-Hodgkin lymphoma (OR, 1.21; 95% CI, 1.02-1.45) and retinoblastomas (OR, 1.31; 95% CI, 1.14-1.50) and decreased odds of surgery receipt for melanomas (OR, 0.79; 95% CI, 0.69-0.91) and rhabdomyosarcomas (OR, 0.90; 95% CI, 0.83-0.98) were associated with increasing overall social vulnerability. Conclusions and Relevance: In this cohort study of patients with pediatric HNC, significant decreases in receipt of care and survival time were observed with increasing SDoH vulnerability.

Surgeon perceptions of volume threshold and essential practices for pediatric thyroidectomy✰.

INTRODUCTION: The topics of sub-specialization and regionalization of care have garnered increased attention among pediatric surgeons. Thyroid surgeries are one such sub-specialty and are commonly concentrated within practices. A national survey was conducted examining current surgeon practices and beliefs surrounding pediatric thyroid surgery. METHODS: Non-resident members of the American Pediatric Surgical Association (APSA) were surveyed in October 2020. Respondents were stratified based on self-reported thyroid surgical experience. Those who performed thyroid surgery were asked about surgical technique and operative practices; those who did not were asked about referral patterns. All respondents were asked about perceptions surrounding the volume-outcome relationship for pediatric thyroid surgery. RESULTS: Among 1015 APSA members, 405 (40%) responded, with 79% (317/400) practicing at academic hospitals, 58% (232/401) practicing in major metropolitan area, and 41% (161/392) with over 10 years of attending pediatric surgery experience. Most respondents (88%, n = 356) agreed that thyroid surgery volume affects outcome, though wide variation was reported in the annual case threshold for "high volume" surgery. Eighty-four respondents (21%) reported performing ≥ 1 pediatric thyroid surgery in the past year. Of these, 82% routinely use recurrent laryngeal nerve monitoring, 32% routinely send hemithyroidectomy patients home the same day, and there was little consensus surrounding postoperative hypocalcemia management. The majority of respondents endorse performing thyroid procedures with a colleague. CONCLUSIONS: Pediatric thyroid surgery appears to be performed by a subset of active pediatric surgeons, most of whom endorse the use of a dual operating team. More evidence is needed to build consensus around additional perioperative practices.

Pediatric intraoperative nerve monitoring during thyroid surgery: A review from the American Head and Neck Society Endocrine Surgery Section and the International Neural Monitoring Study Group.

Children are more likely to experience recurrent laryngeal nerve (RLN) injury during thyroid surgery. Intraoperative nerve monitoring (IONM) may assist in nerve identification and surgical decision making. A literature review of pediatric IONM was performed and used to inform a monitoring technique guide and expert opinion statements. Pediatric IONM is achieved using a variety of methods. When age-appropriate endotracheal tubes with integrated surface electrodes are not available, an alternative method should be used. Patient age and surgeon experience with laryngoscopy influence technique selection; four techniques are described in detail. Surgeons must be familiar with the nuances of monitoring technique and interpretation; opinion statements address optimizing this technology in children. Adult IONM guidelines may offer strategies for surgical decision making in children. In some cases, delay of second-sided surgery may reduce bilateral RLN injury risk.

Telemedicine During the COVID-19 Pandemic: A Pediatric Otolaryngology Perspective.

The COVID-19 pandemic has created a situation unparalleled in our lifetime. As the medical community has attempted to navigate a sea of ever-changing information and policies, this uncertainty has instead bred creativity, community, and evolution. Necessity is the mother of invention, and one of the by-products of our rapidly changing environment is the increased reliance on telemedicine. Here, we discuss our experience with incorporating telemedicine into an urban academic pediatric otolaryngology practice, the challenges that we have encountered, and the principles unique to this population.

International neuromonitoring study group guidelines 2018: Part II: Optimal recurrent laryngeal nerve management for invasive thyroid cancer-incorporation of surgical, laryngeal, and neural electrophysiologic data.

The purpose of this publication was to inform surgeons as to the modern state-of-the-art evidence-based guidelines for management of the recurrent laryngeal nerve invaded by malignancy through blending the domains of 1) surgical intraoperative information, 2) preoperative glottic function, and 3) intraoperative real-time electrophysiologic information. These guidelines generated by the International Neural Monitoring Study Group (INMSG) are envisioned to assist the clinical decision-making process involved in recurrent laryngeal nerve management during thyroid surgery by incorporating the important information domains of not only gross surgical findings but also intraoperative recurrent laryngeal nerve functional status and preoperative laryngoscopy findings. These guidelines are presented mainly through algorithmic workflow diagrams for convenience and the ease of application. These guidelines are published in conjunction with the INMSG Guidelines Part I: Staging Bilateral Thyroid Surgery With Monitoring Loss of Signal. Level of Evidence: 5 Laryngoscope, 128:S18-S27, 2018.

Supraglottoplasty outcomes in relation to age and comorbid conditions.

OBJECTIVE: To determine if age and comorbid conditions effect outcomes in children undergoing supraglottoplasty for severe laryngomalacia. DESIGN: Retrospective study. SETTING: Urban tertiary-care children's hospital. PATIENTS: Children undergoing supraglottoplasty for severe laryngomalacia between February 2004 and July 2008. 56 patients were identified. OUTCOME MEASURES: Persistence of upper airway obstruction, revision surgery (supraglottoplasty), and additional surgery (tracheostomy). RESULTS: 33/56 (58.9%) patients had no comorbid conditions and 23/56 (41.1%) patients had comorbid conditions. In noncomorbid patients, 36.4% of those less than 2 months of age at the time of surgery required revision supraglottoplasty, compared to 5.3% of patients between 2 and 10 months (p<0.05). Compared to the 2-10-month age group, there was a significantly higher percentage of patients with comorbid conditions in the >10-month group (32.1% vs. 79%, p<0.01). Patients with comorbid conditions were diagnosed at a significantly later age than those without (6 mo vs. 2 mo, respectively), and had significantly higher rates of revision supraglottoplasty (47.8% vs. 18.2%) and tracheostomy (39.1% vs. 0.0%). 70% of children with neurological conditions required revision surgery, with 60% requiring tracheostomy. The revision surgery and tracheostomy rates were significantly higher compared to the noncomorbid group (p<0.01 and p<0.0001). Children with cardiac conditions had a higher rate of tracheostomy than noncomorbid children (30% vs. 0%, p<0.01). 16.7% of children with genetic conditions required supraglottoplasty, and none required tracheostomy. CONCLUSIONS: In noncomorbid patients, those undergoing supraglottoplasty less than 2 months of age had a significantly higher rate of revision supraglottoplasty. Patients with neurologic and cardiac comorbidities require tracheostomy at a significantly higher rate than noncomorbid patients.

Training otologic surgical skills through simulation-moving toward validation: a pilot study and lessons learned.

INTRODUCTION: Methods for surgical education and training have changed little over the years. Recent calls to improve surgical efficiency and safety impose additional pressures that have an impact on surgical education and training. USE OF SIMULATION: Integration of data from advanced imaging technologies and computer technologies are creating simulation environments of unprecedented realism. Surgical education and training are poised to exploit low-cost simulation technologies to mitigate these pressures that are having an adverse impact on curricula. To become effective, simulation needs to undergo rigorous validation studies. INTERVENTION: With funding from that National Institute on Deafness and Other Communicative Disorders, we have embarked on a research design project to develop, disseminate, and validate a surgical system for use in otologic resident training and assessment and present key steps from this process. DISCUSSION: We discuss limiting factors related to technology and conducting multi-institutional studies, along with current developments to integrate curricula, as well as training and assessment capabilities in surgical education using simulation.