ABSTRACT
BACKGROUND: Leiomyosarcoma is a rare neoplasm of the head and neck. The purpose of this study was to present our single-institution case series of head and neck leiomyosarcoma and a review of cases in the National Cancer Data Base (NCDB). METHODS: Patients with head and neck leiomyosarcoma at the University of Pennsylvania and in the NCDB were identified. Demographic characteristics, tumor factors, treatment paradigms, and outcomes were evaluated for prognostic significance. RESULTS: Nine patients with head and neck leiomyosarcoma from the institution were identified; a majority had high-grade disease and cutaneous leiomyosarcoma, with a 5-year survival rate of 50%. Two hundred fifty-nine patients with leiomyosarcoma were found in the NCDB; macroscopic positive margins and high-grade disease were associated with poor prognosis (P < .01), and positive surgical margins were related to adjuvant radiation (P < .001). CONCLUSION: Head and neck leiomyosarcoma presents at a high grade and is preferentially treated with surgery. Several demographic and tumor-specific factors are associated with outcomes and prognosis.
Subject(s)
Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/therapy , Leiomyosarcoma/pathology , Leiomyosarcoma/therapy , Neoplasm Recurrence, Local/pathology , Adult , Aged , Aged, 80 and over , Cohort Studies , Databases, Factual , Disease-Free Survival , Female , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/mortality , Hospitals, University , Humans , Kaplan-Meier Estimate , Leiomyosarcoma/diagnostic imaging , Leiomyosarcoma/mortality , Male , Middle Aged , Neck Dissection/methods , Neoplasm Invasiveness/pathology , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Pennsylvania , Prognosis , Proportional Hazards Models , Radiotherapy, Adjuvant , Retrospective Studies , Risk Assessment , Survival AnalysisABSTRACT
HYPOTHESIS: A chitosan-hydrogel-based nanoparticle (nanohydrogel) delivery system can be used to deliver therapeutic biomaterials across the round window membrane (RWM) into the inner ear in a mouse model. BACKGROUND: Delivering therapies to the inner ear has always been a challenge for the otolaryngologist. Advances in biomedical nanotechnology, increased understanding of the RWM diffusion properties, and discovery of novel therapeutic targets and agents, have all sparked interest in the controlled local delivery of drugs and biomaterials to the inner ear using nanoparticles (NPs). METHODS: Fluorescently-labeled liposomal NPs were constructed and loaded into a chitosan-based hydrogel to form a nanohydrogel, and in vitro studies were performed to evaluate its properties and release kinetics. Furthermore, the nanohydrogel was applied to the RWM of mice, and perilymph and morphologic analysis were performed to assess the NP delivery and distribution within the inner ear. RESULTS: NPs with an average diameter of 160 nm were obtained. In vitro experiments showed that liposomal NPs can persist under physiologic conditions for at least two weeks without significant degradation and that the nanohydrogel can carry and release these NPs in a controlled and sustained manner. In vivo findings demonstrated that the nanohydrogel can deliver intact nanoparticles into the perilymphatic system and reach cellular structures in the scala media of the inner ear of our mouse model. CONCLUSION: Our study suggests that the nanohydrogel system has great potential to deliver therapeutics in a controlled and sustained manner from the middle ear to the inner ear without altering inner ear structures.
Subject(s)
Chitosan/administration & dosage , Drug Delivery Systems , Ear, Inner/drug effects , Hydrogel, Polyethylene Glycol Dimethacrylate/administration & dosage , Nanoparticles/administration & dosage , Perilymph/drug effects , Animals , Biocompatible Materials , Ear, Inner/metabolism , Female , Male , Mice , Perilymph/metabolismABSTRACT
PURPOSE: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi). EXPERIMENTAL DESIGN: Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively. RESULTS: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo. CONCLUSION: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers.
Subject(s)
DNA Repair , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/metabolism , Telomere/genetics , Telomere/metabolism , Acid Anhydride Hydrolases , Animals , BRCA1 Protein/genetics , Carcinoma, Squamous Cell/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Breaks, Single-Stranded/drug effects , DNA Repair Enzymes/metabolism , DNA-Binding Proteins/metabolism , Disease Models, Animal , Female , Genomic Instability , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/therapy , Humans , MRE11 Homologue Protein , Mice , Models, Biological , Multiprotein Complexes/metabolism , Nuclear Proteins/metabolism , Organic Chemicals/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases/metabolism , Squamous Cell Carcinoma of Head and Neck , Telomere Shortening , Tumor Burden/drug effects , Tumor Burden/genetics , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: We have recently developed a novel inner ear drug delivery system using chitosan glycerophosphate (CGP) hydrogel loaded with drugs commonly used for treatment of inner ear diseases, significantly improving the drugs' sustained delivery. The goal of this study is to evaluate the effectiveness of chitosanase as a "switch off" mechanism for this drug delivery system when side effects and potential ototoxicities appear during treatment. To evaluate this effect, we tested gentamicin (GENT) in the inner ear following CGP delivery with/without regulation. METHODS: Purified chitosanase was obtained and used for regulating the CGP delivery system. In vitro studies were performed to evaluate the effect of the interaction between chitosanase and CGP-hydrogel loaded with GENT or Texas Red-labeled GENT (GTTR). In vivo studies were performed using our mouse model to investigate the regulatory effect of chitosanase application on the delivery of GENT to the inner ear. To assess the potential drug rerouting regulatory effect of chitosanase the GTTR fluorescence intensity was evaluated at the round window niche (RWN) and the Eustachian tube (ET). To further characterize this regulatory effect, GENT concentration in the perilymph of the inner ear was analyzed by chromatographic tandem mass spectrometry (LC-MS/MS), and the uptake in the inner ear cells was measured using fluorescence microscopy following CGP delivery with/without chitosanase application. RESULTS: The chitosanase effectively digested the CGP-hydrogel, quickly releasing GENT and GTTR from the system in vitro. When reacted with GENT alone chitosanase did not produce any reducing sugars and did not affect GENT's antimicrobial activity. In vivo GTTR was effectively rerouted from the RWN to the ET, limiting its uptake in inner ear hair cells. Concurrent with these findings, GENT concentration in the inner ear perilymph was significantly decreased after chitosanase application. CONCLUSION: Our study findings suggest that, for the first time, sustained and controlled inner ear drug delivery can be successfully regulated enhancing its translation potential for clinical application. The use of chitosanase to digest the CGP-hydrogel results in the rerouting of the loaded drug away from the RWN, effectively downregulating its delivery to the inner ear. This important modification to our drug delivery system has the ability to deliver therapy to the inner ear until desired effect is achieved and to stop this process when side effects or treatment-related ototoxicities start to occur, providing a novel and salient approach for safe and effective delivery to the inner ear.
