The Difference in Clinical Behavior of Gene Fusions Involving RET/PTC Fusions and THADA/IGF2BP3 Fusions in Thyroid Nodules.

BACKGROUND: Molecular testing has been used as an adjunct to morphological evaluation in the workup of thyroid nodules. This study investigated the impact of two gene fusions, RET/PTC and THADA/IGF2BP3, that have been described as oncogenic events in thyroid neoplasms. METHODS: We performed a retrospective, single-centered study at a McGill University teaching hospital in Montreal, Canada, from January 2016 to August 2021. We included patients who underwent surgery for thyroid nodules that pre-operatively underwent molecular testing showing either RET/PTC or THADA/IGF2BP3 gene fusion. RESULTS: This study included 697 consecutive operated thyroid nodules assessed using molecular testing, of which five had the RET/PTC fusion and seven had the THADA/IGF2BP3 fusion. Of the five nodules in the RET/PTC group, 100% were malignant and presented as Bethesda V/VI. Eighty percent (4/5) were found to have lymph node metastasis. Twenty percent (1/5) had extrathyroidal extensions. Sixty percent (3/5) were a diffuse sclerosing variant of papillary thyroid carcinoma, and the rest were the classical variant. Of the seven THADA/IGF2BP3 nodules, all presented as Bethesda III/IV and 71.4% (5/7) were malignant based on the final pathology analysis, and 28.6% (2/7) were NIFTP. All the THADA/IGF2BP3 fusion malignancies were a follicular variant of papillary thyroid carcinoma. None had lymph node metastasis or displayed extrathyroidal extensions. CONCLUSIONS: RET/PTC nodules presented as Bethesda V/VI and potentially had more aggressive features, whereas THADA/IGF2BP3 nodules presented as Bethesda III/IV and had more indolent behavior. This understanding may allow clinicians to develop more targeted treatment plans, such as the extent of surgery and adjuvant radioactive iodine treatment.

Levels of Evidence in Rhinology and Skull Base Surgery Research.

OBJECTIVE: The purpose of this study was to evaluate the quality of evidence of rhinology and rhinologic skull base surgery (RSBS) research and its evolution over the past decade. STUDY DESIGN: Review article. SETTING: We reviewed articles from 2007 to 2019 in 4 leading peer-reviewed otolaryngology journals and 3 rhinology-specific journals. METHODS: The articles were reviewed and levels of evidence were assigned using the Oxford Centre for Evidence-Based Medicine 2011 guidelines. High quality was defined as level of evidence 1 or 2. RESULTS: In total, 1835 articles were reviewed in this study spanning a 13-year period. Overall, the absolute number of RSBS publications increased significantly 22.6% per year, from 108 articles in 2007 to 481 in 2019 (P < .001; 95% CI, 7.9-37.2). In 2007, only 13 articles, or 15%, were high quality, and this grew to 146 articles, or 39%, in 2019. A 14.0% per year exponential increase in the number of high-quality publications was found to be statistically significant (P < .001; 95% CI, 7.2, 20.7). Overall, high-quality publications represented just 25.8% of RSBS articles overall. There was no significant difference in quality between rhinology-specific journals and general otolaryngology journals (χ2 = 3.1, P = .077). CONCLUSION: The number of overall publications and of high-quality RSBS publications has significantly increased over the past decade. However, the proportion of high-quality studies continues to represent a minority of total RSBS research.

The SHCA adapter protein cooperates with lipoma-preferred partner in the regulation of adhesion dynamics and invadopodia formation.

SHC adaptor protein (SHCA) and lipoma-preferred partner (LPP) mediate transforming growth factor ß (TGFß)-induced breast cancer cell migration and invasion. Reduced expression of either protein diminishes breast cancer lung metastasis, but the reason for this effect is unclear. Here, using total internal reflection fluorescence (TIRF) microscopy, we found that TGFß enhanced the assembly and disassembly rates of paxillin-containing adhesions in an SHCA-dependent manner through the phosphorylation of the specific SHCA tyrosine residues Tyr-239, Tyr-240, and Tyr-313. Using a BioID proximity labeling approach, we show that SHCA exists in a complex with a variety of actin cytoskeletal proteins, including paxillin and LPP. Consistent with a functional interaction between SHCA and LPP, TGFß-induced LPP localization to cellular adhesions depended on SHCA. Once localized to the adhesions, LPP was required for TGFß-induced increases in cell migration and adhesion dynamics. Mutations that impaired LPP localization to adhesions (mLIM1) or impeded interactions with the actin cytoskeleton via α-actinin (ΔABD) abrogated migratory responses to TGFß. Live-cell TIRF microscopy revealed that SHCA clustering at the cell membrane preceded LPP recruitment. We therefore hypothesize that, in the presence of TGFß, SHCA promotes the formation of small, dynamic adhesions by acting as a nucleator of focal complex formation. Finally, we defined a previously unknown function for SHCA in the formation of invadopodia, a process that also required LPP. Our results reveal that SHCA controls the formation and function of adhesions and invadopodia, two key cellular structures required for breast cancer metastasis.