Can Computed Tomography Findings Predict the Recurrence of Sinonasal Inverted Papilloma?

Objective: To evaluate the correlation between the ability to predict the attachment site of sinonasal inverted papilloma by computed tomography and the long-term surgical outcome. Study Design: Retrospective cohort study. Setting: Five tertiary medical centers. Methods: Study patients underwent attachment-oriented resection of inverted papilloma. The primary outcome was tumor recurrence. Results: Among 195 patients eligible for the study, focal hyperostosis was recognized on computed tomography in 65% (n = 127), in 71% of primary cases (n = 101), and in 50% of revision procedures (n = 26). There was a trend for a higher incidence of squamous cell carcinoma among the patients without detectable hyperostosis (P =.051). Location of hyperostosis coincided with the actual tumor attachment site in 114 patients (90%). Discordance between these parameters did not differ significantly (P =.463) between 11 primary and 2 revision cases. The overall rate of recurrence was 9.7% (n = 19), with a mean time to recurrence of 20 months (range, 7-96 months). The rate of recurrence did not correlate with any of the following: tumor stage, surgical approach, presence of squamous cell carcinoma, whether the surgery was primary or revision, and the presence or location of focal hyperostosis on computed tomography. Inverted papilloma recurred significantly more often (38.5%) when the intraoperative findings of the tumor attachment site did not match the location of hyperostosis observed on computed tomography (odds ratio, 6.5; 95% CI, 1.78-23.66). Conclusion: Detectability of focal hyperostosis on preoperative computed tomography does not affect the long-term outcome of inverted papilloma resection

Long-Term Weight-Loss in Gastric Bypass Patients Carrying Melanocortin 4 Receptor Variants

<div><p>Background</p><p>The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in <i>MC4R</i> are predominantly found in obese individuals. Though some rare variants in <i>MC4R</i> discovered in patients have defects in localization, ligand binding and signaling to cAMP, many have no recognized defects.</p><p>Subjects/Methods</p><p>In our cohort of 1433 obese subjects that underwent Roux-en-Y Gastric Bypass (RYGB) surgery, we found fifteen variants of <i>MC4R</i>. We matched rare variant carriers to patients with the <i>MC4R</i> reference alleles for gender, age, starting BMI and T2D to determine the variant effect on weight-loss post-RYGB. <i>In vitro</i>, we determined expression of mutant receptors by ELISA and western blot, and cAMP production by microscopy.</p><p>Results</p><p>While carrying a rare <i>MC4R</i> allele is associated with obesity, carriers of rare variants exhibited comparable weight-loss after RYGB to non-carriers. However, subjects carrying three of these variants, <i>V95I</i>, <i>I137T</i> or <i>L250Q</i>, lost less weight after surgery. <i>In vitro</i>, the R305Q mutation caused a defect in cell surface expression while only the I137T and C326R mutations showed impaired cAMP signaling. Despite these apparent differences, there was no correlation between <i>in vitro</i> signaling and pre- or post-surgery clinical phenotype.</p><p>Conclusions</p><p>These data suggest that subtle differences in receptor signaling conferred by rare <i>MC4R</i> variants combined with additional factors predispose carriers to obesity. In the absence of complete <i>MC4R</i> deficiency, these differences can be overcome by the powerful weight-reducing effects of bariatric surgery. In a complex disorder such as obesity, genetic variants that cause subtle defects that have cumulative effects can be overcome after appropriate clinical intervention.</p></div

BMIs of patients with rare variants only found in obese populations.

<p>The pre-surgery BMIs of patients with rare variants were matched with non-carrier patients of the same gender, T2D status, insulin medication status and similar age (within 5 years) (black symbols). The variant carrier's age, sex and T2D status is also listed (○). *The starting BMI range for the matched patient was extended to ±2.</p

cAMP Assay of MC4R mutants.

<p>cAMP production of MC4R mutants after stimulation with 10 nmol/L melanotan II (MTII) and then 100 µmol/L forskolin to activate maximum receptor-independent cAMP response. MTII stimulation was normalized to baseline cAMP production and plotted as a percentage of forskolin in the same cell. Mutants similar to wild-type (Black ○) are designated with the symbol (Gray ○). MC4R novel mutant G34A (Red ○) and those that have different statistically altered cAMP signaling (p<0.01 compared to wild-type by a one way ANOVA with Dunnet's post hoc test) (I137T (Green ○), D90N (Blue ○) and C326R (Purple ○)) are highlighted with different colored symbols. The D90N variant was not found in this cohort, but included as a control.</p

Expression of MC4R mutants.

<p>A) ELISA of HEK293 cells expressing wild-type MC4R or mutations. The cell surface expression was normalized to total expression for each mutant and then to wild-type receptor for that batch (* denotes p<0.05 compared to wild-type by a one way ANOVA with Dunnet's post-hoc test). □ MC4R mutant D90N was not found in our cohort. B) Cell surface localization of HEK-293 cells expressing mutant or wild-type (BBS-MC4R) constructs labeled with Bungarotoxin-Texas Red. C) Normalized GFP loading reveals no differences in HA-MC4R mutant lifespan. HA-MC4R expression was normalized to GFP expression and plotted as a percentage of wild-type for each blot (n≥3).</p

BMIs of patients with rare variants reported in both obese and lean populations.

<p>The pre-surgery BMIs of patients with rare variants were matched with non-carrier patients of the same gender, T2D status, insulin medication status and similar age (within 5 years) (black symbols). The variant carrier's age, sex and T2D status is also listed (○). *The starting BMI range for the matches was extended to ±2. **The starting BMI range for the matches was extended to ±3 or the age difference extended to ±8 years.</p