Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis.

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.

High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11-encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10-3 ), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS-independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD-ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

Cholesteatoma in the pediatric aerodigestive population.

OBJECTIVES: To report the prevalence of cholesteatoma and related comorbidities in pediatric aerodigestive patients requiring tracheostomy or airway reconstruction procedures. To use study findings to inform clinical management of these complex patients. METHODS: A repository of clinical data drawn from our institution's electronic medical records was queried to identify airway reconstruction (airway) and complex hospital control (control) patient cohorts. Retrospective chart review was then performed to investigate the occurrence of cholesteatoma and related pathologies in these patients, as well as clinical management. RESULTS: The prevalence of cholesteatoma in airway and control patients was 6/374 (1.60 %) and 35/30,565 (0.11 %), respectively. The relative risk of cholesteatoma diagnosis in airway patients was 14.01 (95 % CI 6.06-32.14). Airway patients were more likely than control patients to have pressure equalization tube history (relative risk 3.25, 95 % CI 2.73-3.82). Age at cholesteatoma diagnosis and first surgical intervention was younger in airway compared to control patients (5.43 vs. 8.33, p = 0.0182, and 6.07 vs. 8.82, p = 0.0236). However, time from diagnosis to intervention and extent of surgery were similar between the groups. CONCLUSION: This is the first study to investigate the prevalence of cholesteatoma in the pediatric aerodigestive population. The relative risk of cholesteatoma diagnosis was found to be 14 times higher in patients with tracheostomy or airway reconstruction history. Underlying eustachian tube and palatal dysfunction are likely contributing factors to the elevated risk. Additionally, cholesteatoma in this population was diagnosed and required surgical intervention at a younger age, which may suggest a more aggressive disease course. Providers should maintain a high degree of suspicion for cholesteatoma in this complex population.

Otolaryngology Training in Uganda: The Mbarara University of Science and Technology Experience.

Sub-Saharan Africa has a high otolaryngologic disease burden exacerbated by an inadequate number of otolaryngologists. The Otolaryngology department at Mbarara University of Science & Technology in Uganda is addressing this problem by having created Uganda's second national residency training program in 2010. We chronicled an early period in the program's development by reporting surgical case quantity and complexity, as defined by "key indicator procedure" classification per the United States Accreditation Council for Graduate Medical Education, and interpreting it with respect to a timeline of significant events. Procedure complexity, but not total number per year, increased over the study period-KIPs increased from 3% in 2012 (6 of 175 total procedures) to 29% in 2016 (35 of 135 total procedures). During this period of complexity increase, operating room capacity expanded, faculty received advanced training and increased in number, and operative equipment improved.

A Large Thyroid Goiter in a Newborn With Congenital Hypothyroidism: Timeline for Decrease in Size of Thyroid.

Congenital hypothyroidism rarely causes a clinically significant neck mass in newborns. We present the case of a newborn with congenital hypothyroidism and significantly enlarged goiter and discuss imaging considerations and medical and surgical management. This infant was prenatally discovered to have a midline neck mass on 28 week ultrasound measuring 6.0 cm × 3.4 cm × 5.8 cm. Diagnostic cordocentesis demonstrated elevated thyroid-stimulating hormone (TSH, 361 µIU/mL). Maternal evaluation for thyroid disease and antithyroid antibodies was negative. A Cesarean section at 38 weeks gestation was recommended due to hyperextension of the fetal neck. The infant was intubated for respiratory distress. Postnatal magnetic resonance imaging revealed a 5.5 cm × 4.4 cm × 7.6 cm goiter and laboratory studies confirmed the diagnosis of primary hypothyroidism (TSH 16.7 µIU/mL). Treatment was initiated with intravenous levothyroxine and transitioned to oral supplementation. Serial ultrasounds showed decreased goiter volume over several weeks, with recent volume per lobe being 22% and 44% of original volume. This case demonstrates the importance of prompt diagnosis and initiation of thyroid hormone replacement, allowing for significant goiter regression without surgical intervention and ensuring normal growth and neurodevelopmental outcome. Surgical management should be considered for those with persistent compressive symptoms despite optimal medical management.

A Review of Otolaryngology Malpractice Cases with Associated Court Proceedings from 2010 to 2019.

OBJECTIVES/HYPOTHESIS: To report key characteristics of the landscape of malpractice litigation with associated court proceedings in otolaryngology over the previous decade. STUDY DESIGN: Retrospective database review. METHODS: The LexisNexis database was queried to identify otolaryngology-related malpractices cases that yielded court opinions, jury verdicts, and settlements from federal and state courts across the United States from 2010 to 2019. Cases settled outside of court were not identifiable. Provider subspecialty, procedures, error type, legal allegations, and case outcomes were recorded. Frequency of error type was compared between otolaryngology subspecialties using Fisher exact tests. RESULTS: Ninety-four medical malpractice cases related to otolaryngology with evidence of court proceedings were identified for the period between 2010 and 2019. An otolaryngologist was named as the sole defendant in 39 cases (41%). Rhinology was the most frequently implicated subspecialty (28% of all cases), followed by head and neck surgery (17%) and facial plastics (7%). Improper surgical performance was cited in nearly half of the identified cases (49%), followed by failure to diagnose/refer/treat (32%). Outcome and liability data were available for 56 cases (60%). Of these 56 cases, 50 (89%) were ruled in favor of the defendant otolaryngologist. Of the cases ruled in favor of the plaintiff, the average indemnity was $4.24 M (range, $150,000 M-$10.25 M). Fisher exact tests demonstrated statistically significant differences in consent issues (P = .040), failure to diagnose/refer/treat (P = .024), and improper surgical performance (P = .026) between subspecialties. CONCLUSIONS: In a limited, database-derived sample of medical malpractice cases involving otolaryngologists, trends in error type by subspecialty may warrant further investigation to identify specialty-wide and subspecialty-specific areas of practice improvement and education. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:E1081-E1085, 2021.

A Novel Cough Simulation Device for Education of Risk Mitigation Techniques During Aerosol-Generating Medical Procedures.

The COVID-19 pandemic has drawn attention to aerosol-generating medical procedures (AGMPs) in health care environments as a potential mode of transmission. Many organizations and institutions have published AGMP safety guidelines, and several mention the use of simulation in informing their recommendations; however, current methods used to simulate aerosol generation are heterogenous. Creation of a high-fidelity, easily producible aerosol-generating cough simulator would meet a high-priority educational need across all medical specialties. In this communication, we describe the design, construction, and user study of a novel cough simulator, which demonstrates the utility of simulation in raising AGMP safety awareness for providers of all roles, specialties, and training levels.

Impact of Lymph Node Yield on Survival in Surgically Treated Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES: (1) To estimate the association between neck dissection lymph node yield (LNY) and survival among patients with surgically treated human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). (2) To identify a clinically relevant quality metric for surgical treatment of HPV-related OPSCC. STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database. SUBJECTS AND METHODS: From the National Cancer Database, 4130 patients were identified with HPV-associated OPSCC treated with primary surgery from 2010 to 2016. Based on prior literature, an adequate neck dissection LNY was defined as ≥18 lymph nodes. To determine whether LNY is associated with survival, univariable and multivariable Cox proportional hazards regression was performed. Analysis was stratified by adjuvant therapy regimen. RESULTS: A total of 2113 patients (51.2%) underwent surgery with or without adjuvant radiation (S ± RT), and 2017 patients (48.8%) underwent surgery with adjuvant chemoradiation. LNY ≥18 was associated with a 5-year survival benefit of 7.15% (91.7% for LNY ≥18, 84.5% for LNY <18, P = .004) for the S ± RT cohort on unadjusted survival analysis. For the S ± RT group, LNY ≥18 was associated with decreased hazard of death (hazard ratio, 0.45; 95% CI, 0.29-0.70; P < .001) after adjustment for patient characteristics, TNM staging, surgical margins, extranodal extension, and treating facility characteristics. For surgery with adjuvant chemoradiation, the adjusted hazard ratio estimate for LNY ≥18 was 0.64 (95% CI, 0.41-1.00), but the result was not statistically significant (P = .052). CONCLUSION: An adequate LNY from a neck dissection may affect survival when HPV-related OPSCC is treated with up-front surgery.