Trends in Positive Surgical Margins in cT3-T4 Oral Cavity Squamous Cell Carcinoma.

OBJECTIVE: Positive surgical margins in oral cavity squamous cell carcinoma are associated with cost escalation, treatment intensification, and greater risk of recurrence and mortality. The positive margin rate has been decreasing for cT1-T2 oral cavity cancer over the past 2 decades. We aim to evaluate positive margin rates in cT3-T4 oral cavity cancer over time, and determine factors associated with positive margins. STUDY DESIGN: Retrospective analysis of a national database. SETTING: National Cancer Database 2004 to 2018. METHODS: All adult patients diagnosed between 2004 and 2018 who underwent primary curative intent surgery for previously untreated cT3-T4 oral cavity cancer with known margin status were included. Logistic univariable and multivariable regression analyses were performed to identify factors associated with positive margins. RESULTS: Among 16,326 patients with cT3 or cT4 oral cavity cancer, positive margins were documented in 2932 patients (18.1%). Later year of treatment was not significantly associated with positive margins (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.96-1.00). The proportion of patients treated at academic centers increased over time (OR 1.02, 95% CI 1.01-1.03). On multivariable analysis, positive margins were significantly associated with hard palate primary, cT4 tumors, advancing N stage, lymphovascular invasion, poorly differentiated histology, and treatment at nonacademic or low-volume centers. CONCLUSION: Despite increased treatment at academic centers for locally advanced oral cavity cancer, there has been no significant decrease in positive margin rates which remains high at 18.1%. Novel techniques for margin planning and assessment may be required to decrease positive margin rates in locally advanced oral cavity cancer.

Quality of life after segmental mandibulectomy and free flap for mandibular osteonecrosis: Systematic review.

OBJECTIVE: Review QOL outcomes among patients undergoing segmental mandibulectomy and bony free flap reconstruction for ONJ. DATA SOURCES: PubMed was searched for MeSH terms "Quality of life," "Osteonecrosis," "Osteoradionecrosis," "Bisphosphonate-associated osteonecrosis of the jaw," "Free tissue flaps," and "Mandibular reconstruction." REVIEW METHODS: English language studies with QOL outcomes data for patients undergoing free flap reconstruction for advanced ONJ were included. 197 records were initially screened; 18 full texts assessed; 10 full texts included. PRISMA guidelines were followed. RESULTS: Ten studies were included in this systematic review: six retrospective, three retrospective with comparison groups, and one prospective. In studies with comparison groups, ONJ patients have worse self-reported QOL than the general population as well as head and neck cancer patients without ONJ. Nearly all patients with QOL measurements (220/235 patients) had ONJ from prior radiation. Segmental mandibulectomy and bony free flap improved overall QOL in over half of patients, as well as pain associated with ONJ in 70-75 % of patients. Surgery did not improve long-term effects of radiation such as chewing, swallowing, and salivary production. Donor site morbidity rarely affects QOL. CONCLUSIONS: Osteonecrosis of the jaw (ONJ) worsens quality-of-life, and advanced disease often requires segmental mandibulectomy and bony free flap reconstruction. Patients and surgeons may expect improvement in some, but not all, domains of patient-reported QOL by the use of segmental mandibulectomy and reconstruction for advanced ONJ.

Beta 3 Adrenergic Receptor Activation Rescues Metabolic Dysfunction in Female Estrogen Receptor Alpha-Null Mice.

Metabolic disease risk escalates following menopause. The mechanism is not fully known, but likely involves reduced signaling through estrogen receptor alpha (ERα), which is highly expressed in brown and white adipose tissue (BAT and WAT). Objective: Test the hypothesis that uncoupling protein (UCP1) activation mitigates metabolic dysfunction caused by loss of signaling through ERα. Methods: At 8 weeks of age, female ERα knock out (KO) and wild-type mice were housed at 28°C and fed a Western-style high-fat, high sucrose diet (HFD) or a normal low-fat chow diet (NC) for 10 weeks. During the final 2 weeks, they received daily injections of CL 316,256 (CL), a selective ß3 adrenergic agonist, or vehicle control (CTRL), creating eight groups: WT-CTRL, WT-CL, KO-CTRL, and KO-CL on HFD or NC; n = 4-10/group. Results: ERαKO demonstrated exacerbated HFD-induced adiposity gain (P < 0.001) and insulin resistance (P = 0.006). CL treatment improved insulin sensitivity (P < 0.05) and normalized ERαKO-induced adiposity increase (P < 0.05). In both genotypes, CL increased resting energy expenditure (P < 0.05) and induced WAT beiging indicated by increased UCP1 protein in both perigonadal (PGAT) and subcutaneous (SQAT) depots. These effects were attenuated under HFD conditions (P < 0.05). In KO, CL reduced HFD energy consumption compared to CTRL (P < 0.05). Remarkably, CL increased WAT ERß protein levels of both WT and KO (P < 0.001), revealing CL-mediated changes in estrogen signaling may have protective metabolic effects. Conclusion: CL completely restored metabolic dysfunction in ERαKO mice. Thus, UCP1 may be a therapeutic target for treating metabolic dysfunction following loss of estrogen receptor signaling.

Increased susceptibility to OVX-associated metabolic dysfunction in UCP1-null mice.

Premenopausal females are protected against adipose tissue inflammation and insulin resistance, until loss of ovarian hormone production (e.g., menopause). There is some evidence that females have greater brown adipose tissue (BAT) thermogenic capacity. Because BAT mass correlates inversely with insulin resistance, we hypothesized that increased uncoupling protein 1 (UCP1) expression contributes to the superior metabolic health of females. Given that UCP1 transiently increases in BAT following ovariectomy (OVX), we hypothesized that UCP1 may 'buffer' OVX-mediated metabolic dysfunction. Accordingly, female UCP1 knock-out (KO) and wild-type (Digby, et al.) mice received OVX or sham (SHM) surgeries at 12 weeks of age creating four groups (n=10/group), which were followed for 14 weeks and compared for: body weight and adiposity, food intake, energy expenditure and spontaneous physical activity (metabolic chambers), insulin resistance (HOMA-IR, ADIPO-IR, and glucose tolerance testing), and adipose tissue phenotype (histology, gene, and protein expression). Two-way ANOVA was used to assess main effects of genotype (G), OVX treatment (O), and genotype by treatment (GxO) interactions, which were considered significant when P<0.05. UCP1KO mice experienced a more adverse metabolic response to OVX than WT. Whereas OVX-induced weight gain was not synergistically greater for KO compared to WT (GxO, NS), OVX-induced insulin resistance was significantly exacerbated in KO compared to WT (GxO for HOMA-IR, P<0.05). These results suggest UCP1 is protective against metabolic dysfunction associated with loss of ovarian hormones and support the need for more research into therapeutics to selectively target UCP1 for prevention and treatment of metabolic dysfunction following ovarian hormone loss.

Deletion of UCP1 enhances ex vivo aortic vasomotor function in female but not male mice despite similar susceptibility to metabolic dysfunction.

Females are typically more insulin sensitive than males, which may be partly attributed to greater brown adipose tissue (BAT) activity and uncoupling protein 1 (UCP1) content. Accordingly, we tested the hypothesis that UCP1 deletion would abolish sex differences in insulin sensitivity and that whitening of thoracic periaortic BAT caused by UCP1 loss would be accompanied with impaired thoracic aortic function. Furthermore, because UCP1 exerts antioxidant effects, we examined whether UCP1 deficiency-induced metabolic dysfunction was mediated by oxidative stress. Compared with males, female mice had lower HOMA- and AT-insulin resistance (IR) despite no significant differences in BAT UCP1 content. UCP1 ablation increased HOMA-IR, AT-IR, and whitening of BAT in both sexes. Expression of UCP1 in thoracic aorta was greater in wild-type females compared with males. Importantly, deletion of UCP1 enhanced aortic vasomotor function in females only. UCP1 ablation did not promote oxidative stress in interscapular BAT. Furthermore, daily administration of the free radical scavenger tempol for 8 wk did not abrogate UCP1 deficiency-induced increases in adiposity, hyperinsulinemia, or liver steatosis. Collectively, we report that 1) in normal chow-fed mice housed at 25°C, aortic UCP1 content was greater in females than males and its deletion improved ex vivo aortic vasomotor function in females only; 2) constitutive UCP1 content in BAT was similar between females and males and loss of UCP1 did not abolish sex differences in insulin sensitivity; and 3) the metabolic disruptions caused by UCP1 ablation did not appear to be contingent upon increased oxidative stress in mice under normal dietary conditions.