Search

ImportanceDespite growing scientific knowledge and research, it is still unknown if office flexible laryngoscopy (FL) is aerosol generating and thereby potentially increases the risk of SARS-CoV-2 transmission. The limited literature that exists is conflicting, precluding formal conclusions.ObjectiveTo determine whether FL is aerosol generating.Design, Setting, and ParticipantsThis prospective cohort study included 134 patients seen in the otolaryngology clinic at a single tertiary care academic institution between February and May 2021. Two optical particle sizer instruments were used, quantifying particles ranging from 0.02 μm to 5 μm. Measurements were taken every 30 seconds, with sample periods of 15 seconds throughout the patient encounter. Instruments were located 12 inches from the patient’s nares. Timing of events was recorded, including the start and end of physical examination, topical spray administration, start and end of laryngoscopy, and other potential aerosol-generating events (eg, coughing, sneezing). Data analysis was performed from February to May 2021.ExposuresOffice examination and office FL.Main Outcomes and MeasuresBayesian online change point detection (OCPD) algorithm was used to detect significant change points (CPs) in this time-series data. The primary outcome was significant CP after FL compared with baseline physiologic variations, such as breathing and phonation.ResultsData were collected from 134 patients between February and May 2021. Ninety-one encounters involved FL. Of this group, 51 patients (56%) wore no mask over their mouth during FL. There was no statistically significant CP in either visits involving FL or visits where FL was not performed. Use of nasal spray did not result in CP in aerosol levels. Overall, neither the number of people present in the examination room, masks over patients’ mouth, the duration of the visit, nor the duration of FL were associated with mean aerosol counts, regardless of the exposure. For larger aerosol sizes (≥1 μm), however, rooms with higher air exchange rates had significantly higher reductions in mean aerosol counts for visits involving FL.Conclusions and RelevanceThe findings of this cohort study support that FL, including topical spray administration, is not a significant aerosol-generating procedure. The Bayesian OCPD model has a promising application for future aerosol studies in otolaryngology.

Radiofrequency ablation (RFA) for thyroid nodules confers tangible advantages over surgery, which include promising outcomes in the context of a minimally invasive procedure and the functional benefits of organ preservation. However, the ubiquity of benign nodules worldwide may spur the risk of misuse in cases where there is negligible gain over conventional surveillance. This review summarizes new developments in RFA and examines its judicious utilization in benign nodules.RFA appears to be safe and effective for addressing compressive or cosmetic issues caused by benign functional and nonfunctional thyroid nodules. Volume regression occurs over 12 months, with some cases requiring multiple staged RFA procedures to achieve adequate shrinkage or to address regrowth. Complication rates including recurrent laryngeal nerve injury are reportedly low and are mitigated by strategic technical maneuvers, training, and experience. Consensus guidelines across international societies have emerged to better define appropriate patient candidates. Although association of overuse in analogous disciplines has been well established, no evidence of misuse in thyroid RFA has been described thus far.Compelling multi-institutional data support RFA as first-line treatment for select benign thyroid nodules. Defining the nuances of patient selection and long-term surveillance are necessary to substantiate current observed results. Given the high incidence of thyroid nodules worldwide, it is important to emphasize that the majority of benign nodules will not require any intervention. Thorough consideration and careful implementation of recommended guidelines will hopefully lead to measurable benefit and avoid financial misuse.

Sirtuin 2 (SIRT2) is a sirtuin family deacetylase, which maintains genome integrity and prevents tumorigenesis. Although Sirt2 deficiency in mice leads to tumorigenesis, the functional significance of somatic SIRT2 mutations in human tumors is unclear. Using structural insight combined with bioinformatics and functional analyses, we show that naturally occurring cancer-associated SIRT2 mutations at evolutionarily conserved sites disrupt its deacetylation of DNA-damage response proteins by impairing SIRT2 catalytic activity or protein levels but not its localization or binding with substrate. We observed that these SIRT2 mutant proteins fail to restore the replication stress sensitivity, impairment in recovery from replication stress, and impairment in ATR-interacting protein (ATRIP) focus accumulation of SIRT2 deficiency. Moreover, the SIRT2 mutant proteins failed to rescue the spontaneous induction of DNA damage and micronuclei of SIRT2 deficiency in cancer cells. Our findings support a model for SIRT2's tumor-suppressive function in which somatic mutations in SIRT2 contribute to genomic instability by impairing its deacetylase activity or diminishing its protein levels in the DNA-damage response. In conclusion, our work provides a mechanistic basis for understanding the biological and clinical significance of SIRT2 mutations in genome maintenance and tumor suppression.

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved carboxyl-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction but not dNTPase-inactive SAMHD1 fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity and prevents disease, including cancer.

Pro-angiogenic factors such as bFGF, VEGF, and PDGF play a significant role in the invasion, metastasis, and neovascularization of hepatocellular carcinoma (HCC) cells. The expression levels of VEGFR, FGFR, and PDGFR along with the expression of their respective ligands are elevated in HCC. Increased expression levels of bFGF, not acidic FGF, are observed in HCC patients showing capsular infiltration of tumorous cells. Overexpressed VEGF and VEGFR are correlated to progression, angiogenesis, metastasis, tumor recurrence, and poor prognosis in HCC patients. Overexpressed levels of PDGF are associated with an increase in the metastatic potential of HCC. In this chapter, I will discuss VEGF and PDGF roles in metastatic properties of HCC.

Many advances have been made in understanding the role of transcription factors in different types of cancer. With colorectal cancer being the third most commonly diagnosed cancer, studying critical transcription factors such as the lymphoid enhancer factor/T-cell factor (LEF/TCF) transcription factor family may assist in understanding its growth and progression but also serve as a therapeutic target in hopes for better patient outcomes. This chapter will discuss the pathway LEF/TCF transcription factors are known to be involved in, their regulation, and current studies that have investigated their role and function in colorectal cancer and normal cell maintenance.

Genetic markers for distant metastatic disease in patients with colorectal cancer (CRC) are not well defined. Identification of genetic alterations associated with metastatic CRC could help to guide systemic and local treatment strategies. We evaluated the association of tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) copy number variation (CNV) with distant metastatic disease in patients with CRC using The Cancer Genome Atlas (TCGA).Genetic sequencing data and clinical characteristics were obtained from TCGA for all available patients with CRC. There were 515 CRC patient samples with CNV and clinical outcome data, including a subset of 144 rectal adenocarcinoma patient samples. Using the TCGA CRC dataset, CNV of TNFRSF10C was evaluated for association with distant metastatic disease (M1 vs. M0). Multivariate logistic regression analysis with odds ratio (OR) using a 95% confidence interval (CI) was performed adjusting for age, T stage, N stage, adjuvant chemotherapy, gender, microsatellite instability (MSI), location, and surgical margin status.TNFRSF10C CNV in patients with CRC was associated with distant metastatic disease [OR 4.81 (95% CI, 2.13-10.85) P0.001] and positive lymph nodes [OR 18.83 (95% CI, 8.42-42.09)]; P0.001) but not MSI (OR P=0.799). On multivariate analysis, after adjusting for pathologic T stage, N stage, adjuvant chemotherapy, gender, and MSI, TNFRSF10C CNV remained significantly associated with distant metastatic disease (OR P=0.018). Subset analysis revealed that TNFRSF10C CNV was also significantly associated with distant metastatic disease in patients with rectal adenocarcinoma (OR P=0.016).TNFRSF10C CNV in patients with CRC is associated with distant metastatic disease. With further validation, such genetic profiles could be used clinically to support optimal systemic treatment strategies versus more aggressive local therapies in patients with CRC, including radiation therapy for rectal adenocarcinoma.