Thousands of induced germline mutations affecting immune cells identified by automated meiotic mapping coupled with machine learning.

Forward genetic studies use meiotic mapping to adduce evidence that a particular mutation, normally induced by a germline mutagen, is causative of a particular phenotype. Particularly in small pedigrees, cosegregation of multiple mutations, occasional unawareness of mutations, and paucity of homozygotes may lead to erroneous declarations of cause and effect. We sought to improve the identification of mutations causing immune phenotypes in mice by creating Candidate Explorer (CE), a machine-learning software program that integrates 67 features of genetic mapping data into a single numeric score, mathematically convertible to the probability of verification of any putative mutation-phenotype association. At this time, CE has evaluated putative mutation-phenotype associations arising from screening damaging mutations in ∼55% of mouse genes for effects on flow cytometry measurements of immune cells in the blood. CE has therefore identified more than half of genes within which mutations can be causative of flow cytometric phenovariation in Mus musculus The majority of these genes were not previously known to support immune function or homeostasis. Mouse geneticists will find CE data informative in identifying causative mutations within quantitative trait loci, while clinical geneticists may use CE to help connect causative variants with rare heritable diseases of immunity, even in the absence of linkage information. CE displays integrated mutation, phenotype, and linkage data, and is freely available for query online.

Renal Medullary Carcinoma: A Surveillance, Epidemiology, and End Results (SEER) Analysis.

INTRODUCTION: Renal medullary carcinoma (RMC) is an aggressive and rare renal malignancy that predominantly affects Black patients but is also found in individuals of other ethnicities. To date, only a few hundred cases have been reported in the urologic literature. Due to this extreme rarity, the exact pathophysiology and optimal treatment have yet to be well described. This study aims to determine the predictors of mortality and overall survival outcomes in patients with RMC. METHODS: We utilized the Surveillance, Epidemiology, and End Results Program (SEER) database 18 registries to retrieve demographic and clinical information on patients with RMC between 1996 and 2018. A multivariate analysis was performed to determine predictors of mortality in the study population. Kaplan-Meier survival curves were then created to display the differences in overall survival of Black versus non-Black patients diagnosed with renal medullary carcinoma during the study period. RESULTS: We identified 100 patients diagnosed with renal medullary carcinoma using the SEER Database in the study period. The mean age was 28.0 ± 12.0 (95% confidence interval [CI] 25.7-30.4). Among the patients, 76% were male and 24% were female. Most RMC patients were Black (83%) with only 17% identifying as White. The mean survival in months was 13.8 ± 3.0 (95% CI 7.9-19.7). The majority (70%) of patients in this study presented with distant, metastatic disease at the time of diagnosis. Black patients with RMC were less likely to receive surgery and five times more likely to die in comparison to their White counterparts OR = 5.4 (95% CI 1.09-26.9, P = 0.04). Not only did Black patients have a lower survival rate at 12 mo compared to White patients, but they also continued to experience a sharp decline in survival to 10.2% at 24 mo (P < 0.05) and 7.6% at 48 mo (P < 0.05) following diagnosis of renal medullary carcinoma. CONCLUSIONS: These data confirm that RMC is a rare disease that disproportionately affects Black patients. The prognosis appears to be substantially worse for Black subjects diagnosed with this cancer than non-Black patients. The worse outcomes seen in Black subjects are of an unclear etiology and are yet to be investigated.

Associations Between Race and Survival Outcomes Among Veterans With Head and Neck Cancer in a Racially Diverse Setting.

Objective: There is limited data on the impact of clinical-demographic factors on survival outcomes among veterans with head and neck squamous cell carcinoma (HNSCC). This study was undertaken to evaluate the impact of race and other factors on overall survival (OS) in a population of veterans with HNSCC treated with curative intent. Methods: Demographic and clinical data were collected on veterans with HNSCC treated with curative intent at our institution between 1999 and 2021. The primary outcome was 3-year OS. Secondary outcomes included treatment delay intervals, including time to treatment initiation (TTI), total package time, and duration of chemoradiation (DCRT). Results: Of 260 veterans with HNSCC, black veterans had significantly lower 3-year OS (49.4%) compared to white veterans (65%, P = .019). Black veterans were also more likely to experience delays in treatment initiation (median TTI 46 vs 41 days; P = .047). Black patients were more likely to receive radiation alone (25.8% [black] vs 8.4% [white]; P < .001) and less likely to receive adjuvant therapy if treated surgically (11.1% [black] vs 22.4% [white]; P = .004), despite any statistically significant difference in stage of their tumor at presentation (Stage I: 21.2% [black] vs 19.6% [white]; P = .372); (Stage IV: 44.4% [black] vs 48.6% [white]; P = .487). Other factors associated with worse 3-year OS included older age (P = .023), lower body mass index (P = .026), neurocognitive disorder/dementia (P = .037), mental health disorders (P = .020), hypopharyngeal primary (P = .001), higher stage disease (P = .002), treatment type (P = .001), need for prophylactic gastrostomy tube (P = .048) or tracheotomy (P = .005), recurrent disease (P = .036), persistent disease (P < .001), distant metastases (P = .002), longer TTI (P = .0362), and longer DCRT (P = .004). Discussion: Black race appears to be an independent predictor of 3-year OS in veterans with HNSCC. Further studies are warranted to determine the factors responsible for disparities in survival. Implications for Practice: This study evaluated the ways in which race affects survival for US veterans with head and neck cancer. The authors found that black veterans had an increased risk of death compared to white patients, and also experienced delays when receiving treatment. Level of Evidence: Level IV.

Quantitative Ergonomic Comparison of Traditional Versus Endoscopic-Assisted Tonsillectomies: A Prospective Case-Control Study.

Objective: Quantitatively compare the ergonomics of traditional tonsillectomy versus an endoscopic-assisted tonsillectomy. Methods: The physical positioning of the senior author was studied during a simulation of two different operative approaches to tonsillectomy: one using an endoscope and one using direct visualization without the aid of an endoscope. Whole-body postural data was collected and analyzed using the validated Rapid Upper Limb Assessments (RULA) tool to calculate the risk of musculoskeletal injuries. Results: Severe neck and trunk flexion are high-risk postures unique to the traditional approach. The RULA score for the traditional, non-endoscopic approach was 5, with a Neck, Trunk, and Leg Score of 6 and a Wrist/Arm score of 1. The RULA score for the endoscopic-assisted approach was 3, with a Neck, Trunk, and Leg score of 4 and a Wrist/Arm score of 1. The difference between the two approaches narrowed down to the effect on neck positioning (angle decreased from > 20 degrees with traditional to nearly 0 degrees with endoscopic) and trunk positioning (angle decreased from 20 to 60 degrees with traditional to 0 degrees with endoscopic). Conclusion: An endoscopic-assisted approach to tonsillectomy allowed for a lower RULA score compared to the traditional tonsillectomy. This study suggests that an endoscopic approach may decrease the potential for musculoskeletal strain and reduce occupational-related pain and injury seen in practicing otolaryngologists.

Emerging concepts in sinonasal tumor research.

PURPOSE OF REVIEW: Sinonasal malignancies are rare and understudied, often diagnosed at late stages, and may behave aggressively. This review explores investigative diagnostic, therapeutic, and scientific advances specific to sinonasal undifferentiated carcinoma (SNUC), intestinal-type adenocarcinoma (ITAC), and olfactory neuroblastoma (ONB). RECENT FINDINGS: A number of studies have recently contributed more robust knowledge of the genetic and molecular landscapes of SNUC, ITAC, and ONB. These analyses have identified SMARCB1 and IDH2 mutations in SNUC, potentially allowing for the tumor's subdivision. Recent studies have also defined a role for induction chemotherapy in SNUC. Somatic mutations for ITAC have been identified and may be potentially targetable with FDA approved therapies. Studies defining the tumor microenvironment for ITAC and ONB have introduced the possibility of immune checkpoint inhibition for these tumor types. SUMMARY: Studies reviewed here detail promising results of the most current and novel characterization of SNUC, ITAC, and ONB genetic and molecular landscapes, which have informed ongoing therapeutic discovery. With continued multi-institutional efforts, the field of sinonasal tumor research will achieve higher disease control and improved treatment outcomes for patients afflicted with these rare cancers.