Brandel, Michael G.

Abstract Olfactory neuroblastoma (ONB) is a rare head and neck cancer arising from the upper nasal cavity, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to utilize a patient-level genomic repository to identify potential therapeutic targets and improve disease modeling in ONB. Retrospective genomic analysis. Data analysis was performed using the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database. Patients with confirmed ONB who have undergone targeted sequencing within GENIE. Data were analyzed for recurrent somatic mutations, along with their clinical and demographic correlations, with significance set at p < 0.05. A high prevalence of mutations in TP53 (tumor protein p53) and FRK (fibroblast growth factor receptor kinase) genes was identified. A moderate prevalence of mutations in NOTCH3 (notch receptor 3), SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4), RET (rearranged during transfection), and CTCF (CCCTC-binding factor) was also identified. The mutation patterns differed between pediatric and adult ONB cases. Specific mutations were enriched in metastatic tumors compared with primary tumors. This study provides a genomic profile for ONB, identifying key mutations and potential therapeutic targets. The identification of frequently mutated genes like TP53 and FRK suggests potential targets for novel therapies. The observation that certain genes are mutated in pediatric ONB but not adult ONB (and vice versa), and the presence of specific mutations in metastatic tumors that are absent in primary tumors, offers valuable insights for future precision medicine and the design of targeted therapeutic interventions for these distinct clinical presentations.

BACKGROUND AND IMPORTANCE: Juvenile nasopharyngeal angiofibroma (JNA) is a rare, locally aggressive vascular tumor that primarily affect adolescent males. This work illustrates a step-by-step surgical approach of an advanced-stage JNA resection in a prepubescent 5-year-old child, utilizing a hybrid endoscopic endonasal and transmaxillary approach that provides highly effective results without employing traditional open techniques. CLINICAL PRESENTATION: A previously healthy 5-year-old male presented with one-year history of nasal obstruction, mouth breathing, and recurrent otitis media. The patient was found to have a large, space-occupying hypervascular tumor obstructing the nasopharynx. Preoperative radiographic imaging revealed an extensive heterogeneous, avidly enhancing mass that occupied the nasopharynx, right pterygopalatine fossa, infratemporal fossa, masticator space, and middle cranial fossa. Following superselective endovascular embolization, a hybrid endoscopic endonasal approach was planned for JNA resection, incorporating an anterior maxillotomy to allow for direct access to lateral compartments not classically amenable to conventional transnasal corridors. CONCLUSION: This study demonstrates the technical feasibility of a combined endoscopic endonasal and transmaxillary approach for single-stage JNA resection with intracranial extension in pediatric patients. Key principles include tumor embolization, dynamic endoscopic visualization, avoidance of brain retraction, direct access to critical neurovascular structures, and minimizing craniofacial morbidity.

Background: Nasopharyngeal carcinoma (NPC) is a rare head and neck cancer arising from the mucosal lining of the nasopharynx, for which systemic therapeutic options remain scarce, reflecting the limited characterization of its genomic profile. This study utilized a large patient-level genomic repository to characterize genetic alterations, identify potential therapeutic targets, and improve disease modeling in NPC. Methods: A retrospective analysis of NPC samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were identified in KMT2D (20%), TP53 (16%), CYLD (9.6%), NFKBIA (6.4%), and PIK3CA (5.6%), implicating the p53, NF-κB, and PI3K pathways in NPC development. Notably, significantly distinct mutational profiles were observed based on both sex and race, with female patients exhibiting higher frequencies of PIK3C2G, ETV6, and CDKN1B mutations and non-Asian patients showing enrichment in KDM5A, CCND2, and TP53 mutations. Conclusions: This study presents a detailed genomic profile of NPC, identifying key mutations within established cancer-associated pathways. The identification of frequently mutated pathways (p53, NF-κB, and PI3K) suggests potential targets for novel therapies. Furthermore, distinct mutational landscapes in female and Asian NPC patients offer possibilities for precision therapeutic interventions.

Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling. Methods: A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations were also common among the TERT promoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified among PBRM1, BRCA2, and KMT2D mutations. CDKN2A/B deletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults. Conclusions: This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions.

It is well established that traumatic brain injury (TBI) is associated with the development of psychiatric disorders. However, the impact of psychiatric disorders on TBI outcome is less well understood. We examined the outcomes of patients who experienced a traumatic subdural hemorrhage and whether a comorbid psychiatric disorder was associated with a change in outcome. A retrospective observational study was performed in the California Office of Statewide Health Planning and Development (OSHPD) and the Nationwide Inpatient Sample (NIS). Patients hospitalized for acute subdural hemorrhage were identified using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. Patients with coexisting psychiatric diagnoses were identified. Outcomes studied included mortality and adverse discharge disposition. In OSPHD, diagnoses of depression (OR = 0.64, p < 0.001), bipolar disorder (OR = 0.45, p < 0.05), and anxiety (OR = 0.37, p < 0.001) were associated with reduced mortality during hospitalization for TBI, with a trend toward psychosis (OR = 0.56, p = 0.08). Schizophrenia had no effect. Diagnoses of psychosis (OR = 2.12, p < 0.001) and schizophrenia (OR = 2.60, p < 0.001) were associated with increased adverse discharge. Depression and bipolar disorder had no effect, and anxiety was associated with reduced adverse discharge (OR = 0.73, p = 0.01). Results were confirmed using the NIS. Analysis revealed novel associations between coexisting psychiatric diagnoses and TBI outcomes, with some subgroups having decreased mortality and increased adverse discharge. Potential mechanisms include pharmacological effects of frequently prescribed psychiatric medications, the pathophysiology of individual psychiatric disorders, or under-coding of psychiatric illness in the most severely injured patients. Because pharmacological mechanisms, if validated, might lead to improved outcome in TBI patients, further studies may provide significant public health benefit.