Τρίτη 22 Φεβρουαρίου 2022

Selumetinib Plus Adjuvant Radioactive Iodine in Patients With High-Risk Differentiated Thyroid Cancer: A Phase III, Randomized, Placebo-Controlled Trial (ASTRA)

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J Clin Oncol. 2022 Feb 22:JCO2100714. doi: 10.1200/JCO.21.00714. Online ahead of print.

ABSTRACT

PURPOSE: Selumetinib can increase radioactive iodine (RAI) avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission (CR) rates in patients with differentiated thyroid cancer (DTC) at high risk of primary treatment failure versus RAI alone.

METHODS: ASTRA (NCT01843062) is an international, phase III, randomized, placebo-con trolled, double-blind trial. Patients with DTC at high risk of primary treatment failure (primary tumor > 4 cm; gross extrathyroidal extension outside the thyroid gland [T4 disease]; or N1a/N1b disease with ≥ 1 metastatic lymph node(s) ≥ 1 cm or ≥ 5 lymph nodes [any size]) were randomly assigned 2:1 to selumetinib 75 mg orally twice daily or placebo for approximately 5 weeks (no stratification). On treatment days 29-31, recombinant human thyroid-stimulating hormone (0.9 mg)-stimulated RAI (131I; 100 mCi/3.7 GBq) was administered, followed by 5 days of selumetinib/placebo. The primary end point (CR rate 18 months after RAI) was assessed in the intention-to-treat population.

RESULTS: Four hundred patients were enrolled (August 27, 2013-March 23, 2016) and 233 randomly assigned (selumetinib, n = 155 [67%]; placebo, n = 78 [33%]). No statistically significant difference in CR rate 18 months after RAI was observed (selumetinib n = 62 [40%]; placebo n = 30 [38%]; odds ratio 1.07 [95% CI, 0.61 to 1.87]; P = .8205). Treatment-related grade ≥ 3 adverse events were reported in 25/154 patients (16%) with selumetinib and none with placebo. The most common adverse event with selumetinib was dermatitis acneiform (n = 11 [7%]). No treatment-related deaths were reported.

CONCLUSION: Postoperative pathologic risk stratification identified patients with DTC at high risk of primary treatment failure, although the addition of selumetinib to adjuvant RAI failed to improve the CR rate for these patients. Future strategies should focus on tumor genotype-tailored drug selection and maintaining drug dosing to optimize RAI efficacy.

PMID:35192411 | DOI:10.1200/JCO.21.00714

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Cochlear Fluid Spaces and Structures of the Gerbil High-Frequency Region Measured Using Optical Coherence Tomography (OCT)

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Abstract

Since it has been difficult to directly observe the morphology of the living cochlea, our ability to infer the mechanical functioning of the living ear has been limited. Nearly all our knowledge about cochlear morphology comes from postmortem tissue that was fixed and processed using procedures that possibly distort the structures and fluid spaces of the organ of Corti. In this study, optical coherence tomography was employed to obtain volumetric images of the high-frequency hook region of the gerbil cochlea, as viewed through the round window, with far better resolution capability than had been possible before. The anatomical structures and fluid spaces of the organ of Corti were segmented and quantified in vivo and over a 90-min postmortem period. We find that the arcuate-zone and pectinate-zone widths change very little postmortem. The volume of the scala tympani between the round-window membrane and basilar membrane and the volume of the inner spiral sulcus d ecrease in the first 60-min postmortem. While textbook drawings of the mammalian organ of Corti and cortilymph prominently depict the tunnel of Corti, the outer tunnel is typically missing. This is likely because textbook drawings are typically made from images obtained by histological methods. Here, we show that the outer tunnel is nearly twice as big as the tunnel of Corti or the space of Nuel. This larger outer tunnel fluid space could have a substantial, little-appreciated effect on cochlear micromechanics. We speculate that the outer tunnel forms a resonant structure that may affect reticular-lamina motion.

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