Faculty Bibliography

OBJECTIVE/UNASSIGNED:This study aimed to compare the historical incidence rate of severe oral mucositis (OM) in head and neck cancer patients undergoing definitive concurrent chemoradiation therapy (CRT) versus a prospective cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with prophylactic photobiomodulation therapy (PBMT). METHODS/UNASSIGNED:This US-based, institutional, single-arm, phase Ⅱ prospective clinical trial was initiated in 50 patients (age ≥ 18 years, Karnofsky Performance Scale Index > 60, with locally advanced HNSCC (excluding oral cavity) receiving definitive or adjuvant radiation therapy (RT) with concurrent platinum-based chemotherapy (CT). PBMT was delivered three times per week throughout RT utilizing both an intraoral as well extraoral delivery system. Primary outcome measure was incidence of severe OM utilizing both the National Cancer Institute Common Toxicity Criteria, version 4.0 (NCI-CTCAE) Grade ≥3 and the World Health Organization Mucositis Grading Scale (WHO) Grade ≥3 versus historical controls; secondary outcome measures included time to onset of severe OM following therapy initiation. RESULTS/UNASSIGNED:, respectively. Severe OM was observed in 11 of 47 patients (23%, confidence interval: 12, 38). OM toxicity grade trended upward during treatment, reaching a maximum at 7 weeks (WHO: 1.8 vs. NCI-CTCAE: 1.7). Subsequently, OM grade returned to baseline 3 months following completion of RT. The mean time to onset of severe OM was (35 ± 12) days. The mean time to resolution of severe OM was (37 ± 37) days. CONCLUSIONS/UNASSIGNED:Compared to historical outcomes, PBMT aides in decreasing severe OM in patients with locally advanced HNSCC. PBMT represents a minimally invasive, prophylactic intervention to decrease OM as a major treatment-related side effect.

Most pediatric central nervous system (CNS) tumors are located in eloquent anatomic areas, making surgical resection and, in some cases, even biopsy risky or impossible. This diagnostic predicament coupled with the move toward molecular classification for diagnosis has exposed an urgent need to develop a minimally invasive means to obtain diagnostic information. In non-CNS solid tumors, the detection of circulating tumor DNA (ctDNA) in plasma and other bodily fluids has been incorporated into routine practice and clinical trial design for selection of molecular targeted therapy and longitudinal monitoring. For primary CNS tumors, however, detection of ctDNA in plasma has been challenging. This is likely related at least in part to anatomic factors such as the blood-brain barrier. Due to the proximity of primary CNS tumors to the cerebrospinal fluid (CSF) space, our group and others have turned to CSF as a rich alternative source of ctDNA. Although multiple studies at this time have demonstrated the feasibility of CSF ctDNA detection across multiple types of pediatric CNS tumors, the optimal role and utility of CSF ctDNA in the clinical setting has not been established. This review discusses the work-to-date on CSF ctDNA liquid biopsy in pediatric CNS tumors and the associated technical challenges, and reviews the promising opportunities that lie ahead for integration of CSF ctDNA liquid biopsy into clinical care and clinical trial design.

Introduction: Thyroid fine-needle aspiration (FNA) cytology combined with molecular testing guides individualized patient management by providing information regarding tumor biology and the risk of recurrence associated with specific mutations in the indeterminate groups (Bethesda group III-V). Thyroid adenomaassociated (THADA)-IGF2BP3 fusions have been identified as an oncogenic event in thyroid neoplasms, but the clinical-pathologic features and subsequent management are not well-established. Here we report the findings associated with thyroid nodules with THADA-IGFBP3 fusions in our institution.
Material(s) and Method(s): FNA cytology samples of thyroid nodules during 01/2015-12/2016 with the diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS; Bethesda III), follicular neoplasm/ suspicious for follicular neoplasm (FN/SFN; Bethesda IV) and suspicious for malignancy (Bethesda V) with corresponding ThyroSeqV2 data were assessed. Molecular test results yielding a THADA gene fusion were identified. In addition, follow-up surgical pathology and available radiology results were reviewed.
Result(s): 186 out of 558 (33.3%) thyroid nodules displayed molecular alterations; 7 out of 186 (3.8%) Bethesda category III-V nodules with ThyroSeq molecular alterations displayed isolated THADA-IGFBP2 fusions (Table 1). The median age was 45 years. The female to male ratio was 5:2. The nodule sizes ranged from 1.8 to 5.0 cm. Four (57%) patients had surgery; three cases displayed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on histology; one case was a follicular adenoma. No patients had recurrence or metastasis on follow-up.
Conclusion(s): Our pilot study shows that thyroid nodules with THADA-IGF2BP3 fusions display low-risk/indolent features. These findings may aid in clinical management decisions in patients presenting with thyroid nodules with isolated THADAIGF2BP3 fusions on molecular testing

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To create a model of the anatomic distribution, recurrence, and growth patterns of recurrent respiratory papillomatosis (RRP). STUDY DESIGN/METHODS:Prospective, multi-institutional cohort study. METHODS:Adult patients with a diagnosis of RRP evaluated between August 1, 2018 and February 1, 2021 at six participating centers were invited to enroll. At each office or operating room encounter, laryngologists recorded the location and size of RRP lesions using a 22-region schematic. A generalized linear mixed effects model was used to compare region variations in lesion prevalence and recurrence. RESULTS:The cohort comprised 121 patients: 74% were male, 81% had been diagnosed with adult-onset RRP, and a plurality (34%) had undergone 0 to 3 RRP interventions prior to enrollment. Across the study period, the odds of a lesion occurring in the glottis was significantly higher (odds ratio [OR]: 26.51; 95% confidence interval [CI]: 11.76-59.75, P < .001) compared with all other areas of the larynx and trachea. Within the true vocal folds, the membranous vocal folds had significantly higher odds (OR: 6.16; 95% CI: 2.66-14.30, P < .001) of lesion occurrence compared to the cartilaginous vocal folds. Despite these strong trends in lesion distribution, there were no differences in the odds of lesion recurrence, growth, or in the time to recurrence, between anatomic subsites. CONCLUSIONS:RRP lesions are most likely to occur in the glottis, particularly the membranous vocal folds, compared with other regions of the larynx or trachea. However, all lesions demonstrate similar behavior with respect to recurrence, growth, and time to recurrence regardless of anatomic location. LEVEL OF EVIDENCE/METHODS:3 Laryngoscope, 2022.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage^1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes^4-7. 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.

OBJECTIVE/UNASSIGNED:Evaluate rates of Advanced Bionics Ultra 3D/Ultra cochlear implant failure in the setting of a worldwide device recall and report surgical and auditory outcomes after revision. METHODS/UNASSIGNED:Retrospective chart review was performed for adult and pediatric patients implanted with at risk devices at our center from 2016 to 2020. Device failure rates, surgical, and auditory outcomes were recorded and analyzed. RESULTS/UNASSIGNED: = 0.95). DISCUSSION/UNASSIGNED:Patients with device failure due to this field action performed well after revision implantation. Patients with bilateral at-risk devices but evidence of unilateral failure may elect to undergo simultaneous empiric revision of the contralateral device. Three patients who elected to change device manufacturers on revision have variable results that require further investigation. CONCLUSIONS/UNASSIGNED:Patients requiring revision for a device field action overall perform well. At-risk devices continue to require monitoring as a growing number are likely to fail over time.