Does Subglottic Squamous Cell Carcinoma Warrant a Different Strategy Than Other Laryngeal Subsites?

OBJECTIVES/HYPOTHESIS: Subglottic squamous cell carcinoma (SSCC) is a rare cancer with limited evidence-based treatment guidelines. This study aimed to describe the treatment patterns for SSCC and to determine which treatments provide the best overall survival. STUDY DESIGN: Retrospective database review. METHODS: The National Cancer Database (NCDB) was queried for patients treated for SSCC from 2004 through 2014. Overall survival (OS) rates were determined by the Kaplan-Meier method. Clinicopathologic characteristics were assessed by univariable and multivariable Cox proportional hazards models, which corrected for age, sex, race, insurance status, income quartile, residence, Charlson-Deyo comorbidity score, facility type providing treatment, tumor grade, and clinical N and T category. RESULTS: In this cohort of 549 patients with SSCC, the 5-year OS was 48.2%. SSCC presented at an advanced stage (American Joint Committee on Cancer stage III or IV) in 60.1% of cases; 78.3% of cases had no nodal metastases. Among only stage IV cases, multivariable analysis showed that radiotherapy (RT) (hazard ratio [HR] = 5.944; 95% confidence interval [CI]: 2.76-12.8; P < .001) and chemoradiotherapy (CRT) (HR = 2.321; 95% CI: 1.36-3.97; P = .002) were both associated with decreased 5-year OS compared to a group consisting of all surgeries. When this analysis was repeated for only stage III cases, RT (HR = 1.134; 95% CI: 0.38-3.37; P = .821) and CRT (HR = 1.784; 95% CI: 0.78-4.08; P = .170) were equivalent to surgery. CONCLUSIONS: Using the NCDB to study the largest cohort of SSCC with known staging and treatment, primary surgery may provide a better 5-year OS in advanced-stage SSCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1117-E1124, 2021.

Safety of radiofrequency ablation for adenotonsillectomy after cochlear implantation.

OBJECTIVE: While a cadaveric animal study has suggested that radiofrequency ablation can be safely used in patients with cochlear implants, no in vivo studies have been published to confirm that radiofrequency ablation does not alter the integrity of the cochlear implant device. METHODS: Cochlear implant impedance and functional performance were studied through a prospective case series in five children with seven functioning multichannel implants before and after radiofrequency ablation adenotonsillectomy. RESULTS: There were 4 females and 1 male patient, aged 6-10 years (mean 8.5 ±â€¯1.95 years) with 7 functioning implants. Pre- and post-surgical impedance testing revealed all electrodes were within normal operating limits. There was no statistically significant difference between the mean pre and post-operative impedances in 5 of the 7 tested implants (P = 0.2-0.8). The other two implants showed statistically significant improvement in impedance values which were not clinically significant (P = 0.02 and P < 0.001). Speech perception was unchanged as was functional performance for all 7 tested implants. CONCLUSIONS: We found that radiofrequency ablation used in the oropharynx during adenotonsillectomy did not alter the integrity of the cochlear implant devices when assessed using electrode impedance testing, audiometry and speech perception evaluation. These results confirm those reported in previous in vitro studies and confirm the safety of radiofrequency ablation adenotonsillectomy for children who have undergone previous cochlear implant placement.

Complex interplay between the lipin 1 and the hepatocyte nuclear factor 4 α (HNF4α) pathways to regulate liver lipid metabolism.

Lipin 1 is a bifunctional protein that serves as a metabolic enzyme in the triglyceride synthesis pathway and regulates gene expression through direct protein-protein interactions with DNA-bound transcription factors in liver. Herein, we demonstrate that lipin 1 is a target gene of the hepatocyte nuclear factor 4α (HNF4α), which induces lipin 1 gene expression in cooperation with peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) through a nuclear receptor response element in the first intron of the lipin 1 gene. The results of a series of gain-of-function and loss-of-function studies demonstrate that lipin 1 coactivates HNF4α to activate the expression of a variety of genes encoding enzymes involved in fatty acid catabolism. In contrast, lipin 1 reduces the ability of HNF4α to induce the expression of genes encoding apoproteins A4 and C3. Although the ability of lipin to diminish HNF4α activity on these promoters required a direct physical interaction between the two proteins, lipin 1 did not occupy the promoters of the repressed genes and enhances the intrinsic activity of HNF4α in a promoter-independent context. Thus, the induction of lipin 1 by HNF4α may serve as a mechanism to affect promoter selection to direct HNF4α to promoters of genes encoding fatty acid oxidation enzymes.

Lipin 2 is a liver-enriched phosphatidate phosphohydrolase enzyme that is dynamically regulated by fasting and obesity in mice.

Lipin 1 is a bifunctional intracellular protein that regulates fatty acid metabolism in the nucleus via interactions with DNA-bound transcription factors and at the endoplasmic reticulum as a phosphatidic acid phosphohydrolase enzyme (PAP-1) to catalyze the penultimate step in triglyceride synthesis. However, livers of 8-day-old mice lacking lipin 1 (fld mice) exhibited normal PAP-1 activity and a 20-fold increase in triglyceride levels. We sought to further analyze the hepatic lipid profile of these mice by electrospray ionization mass spectrometry. Surprisingly, hepatic content of phosphatidate, the substrate of PAP-1 enzymes, was markedly diminished in fld mice. Similarly, other phospholipids derived from phosphatidate, phosphatidylglycerol and cardiolipin, were also depleted. Another member of the lipin family (lipin 2) is enriched in liver, and hepatic lipin 2 protein content was markedly increased by lipin 1 deficiency, food deprivation, and obesity, often independent of changes in steady-state mRNA levels. Importantly, RNAi against lipin 2 markedly reduced PAP-1 activity in hepatocytes from both wild type and fld mice and suppressed triglyceride synthesis under conditions of high fatty acid availability. Collectively, these data suggest that lipin 2 plays an important role as a hepatic PAP-1 enzyme.

Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion.

OBJECTIVE: Lipin 1 controls fatty acid metabolism in the nucleus as a transcriptional regulator and in the cytosol as an enzyme catalyzing the penultimate step in phosphoglycerol triacylglyceride (TAG) synthesis. We sought to evaluate the effects of lipin 1 on hepatic TAG synthesis and secretion by gain-of-function and loss-of-function approaches. METHODS AND RESULTS: Rates of TAG synthesis were not impaired in hepatocytes isolated from adult lipin 1-deficient (fld) mice and were actually increased in 14-day-old fld mice. Additionally, compared to littermate controls, VLDL-TAG secretion rates were markedly increased in fld mice of both ages. Lipin 1 overexpression did not alter TAG synthesis rates but significantly suppressed VLDL-TAG secretion. The lipin 1-mediated suppression of VLDL-TAG secretion was linked to the peptide motif mediating its transcriptional-regulatory effects. However, the expression of candidate genes required for VLDL assembly and secretion was unaltered by lipin 1 activation or deficiency. Finally, the hepatic expression of lipin 1 was diminished in obese insulin-resistant mice, whereas adenoviral-mediated overexpression of lipin 1 in liver of these mice inhibits VLDL-TAG secretion and improves hepatic insulin signaling. CONCLUSIONS: Collectively, these studies reveal new and unexpected effects of lipin 1 on hepatic TAG metabolism and obesity-related hepatic insulin resistance.

OXPAT/PAT-1 is a PPAR-induced lipid droplet protein that promotes fatty acid utilization.

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as "OXPAT." Physiologic lipid loading of mouse liver by fasting enriches OXPAT in the lipid droplet tissue fraction. OXPAT resides on lipid droplets with the PAT protein adipophilin in primary cardiomyocytes. Ectopic expression of OXPAT promotes fatty acid-induced triacylglycerol accumulation, long-chain fatty acid oxidation, and mRNAs associated with oxidative metabolism. Consistent with these observations, OXPAT is induced in mouse adipose tissue, striated muscle, and liver by physiological (fasting), pathophysiological (insulin deficiency), pharmacological (peroxisome proliferator-activated receptor [PPAR] agonists), and genetic (muscle-specific PPARalpha overexpression) perturbations that increase fatty acid utilization. In humans with impaired glucose tolerance, PPARgamma agonist treatment induces adipose OXPAT mRNA. Further, adipose OXPAT mRNA negatively correlates with BMI in nondiabetic humans. Our collective data in cells, mice, and humans suggest that OXPAT is a marker for PPAR activation and fatty acid oxidation. OXPAT likely contributes to adaptive responses to the fatty acid burden that accompanies fasting, insulin deficiency, and overnutrition, responses that are defective in obesity and type 2 diabetes.

Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.

Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism.