Oral leiomyosarcoma presenting as a recurrent hard palate mass: a case report

Objective: Leiomyosarcoma (LMS), a sarcoma with smooth muscle differentiation rarely affects the oral cavity due to the paucity of smooth muscle tissues in the region. Because of the intricacy of the anatomy of the oral cavity, tumors affecting this region usually require complex surgeries. We are thus presenting this case, due to the rarity of the disease and its successful treatment by a multidisciplinary team. Case Presentation: A 30-year-old female who was previously diagnosed with a benign smooth muscle neoplasm, had a partial maxillectomy in another institution, came to us for tumor recurrence with a histopathologic report of a smooth muscle tumor of uncertain malignant potential (SmTUMP). Facial and neck CT scan, as well as facial MRI revealed a resectable disease with unremarkable metastatic workup. Results: The clinical aggressiveness of the disease prompted the multidisciplinary team to proceed with infrastructure maxillectomy with the defect covered by a surgical obturator. Final histopathologic report revealed that the tumor is LMS with good margins. Thereafter, the patient underwent adjuvant radiation therapy. At 1-year post-surgery, the patient had minimal speech deficit with good deglutition function and no recurrence. Conclusions: LMS is exceedingly rare in the head and neck region. It is also difficult to diagnose. However, it should be considered a differential diagnosis when dealing with smooth muscle tumors. Successful treatment of this disease entails high index of suspicion and involvement of a multidisciplinary team

RVX-208, an Inducer of ApoA-I in Humans, Is a BET Bromodomain Antagonist

<div><p>Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes <i>in vitro</i>, and <i>in vivo</i> in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.</p></div

Selective release of BET proteins from chromatin in Huh7 cells by RVX-208.

<p>Salt extraction of chromatin releases BET proteins into the soluble (S) fraction in RVX-208 stimulated cells, whereas another dual bromodomain protein PHIP stays in the insoluble (pellet, P) fraction. The solubility of other transcription factors (HNF4a, NR2F2) is unaltered.</p

X-ray crystal structure of RVX-208 bound to BRD4[BD1].

<p>A. Surface rendering model showing disposition of RVX-208 in hydrophobic pocket. B. A closer view of the BRD4[BD1] ligand binding site. The electron density (sigmaA-weighted, 1σ contour level, 1.24 Å resolution) corresponding to the compound is shown in blue. For clarity, only interacting residues and some water molecules are shown with a ribbon diagram of the protein main chain course.</p

Binding of RVX-208 to individual bromodomains.

<p>Binding of RVX-208 to individual bromodomains.</p

Schematic of domain structure of the human BET proteins.

<p>Bromdomains are designated by BD1 and BD2 and the Extraterminal domains by ET.</p

Stimulation of ApoA-I and inhibition of IL-6 production by RVX-208 and JQ-1.

<p>A. Dose dependent induction of ApoA-I in Huh7 cells by RVX-208 and JQ-1 at 48 h, B. Selective dose dependent inhibition of IL-6 but not TNFα mRNA in U937 cells stimulated with LPS for 4 h.</p

X-ray crystal structure of RVX-208 bound to BRD2[BD2].

<p>A. Surface rendering model showing disposition of RVX-208 in hydrophobic pocket. B. A closer view of the BRD2[BD2] ligand binding site. The electron density (sigmaA-weighted, 1σ contour level, 1.08 Å resolution) corresponding to the compound is shown in blue. For clarity, only interacting residues and some water molecules are shown with a ribbon diagram of the protein main chain course. The waters were removed for clarity.</p

X-ray data reduction statistics and crystal parameters.

<p>^a Numbers in the parentheses are for the highest resolution shell of 1.28-1.24 Å for BRD4[BD1]/RVX-208) and 1.12-1.08 Å for BRD2[BD2]/RVX-208.</p

Selective binding of RVX-208 to bromodomains of the BET family.

<p>A. Competition of RVX-208 for binding to BRD4 bromodomains 1 and 2 individually or in tandem as measured in a competition FRET assay with acetylated histone 4 peptide. B. Same as A except for JQ-1. C. TR-FRET IC₅₀ for binding of 23 RVX-208 analogues to Brd4 [BD1BD2] is plotted against EC170 for induction of ApoA-I mRNA in Huh7 cells.</p