p90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against cisplatin resistance. Our results strongly support the role of p90RSK in cisplatin resistance and identify the combination of p90RSK inhibitor, BI-D1870, with cisplatin as a novel therapeutic strategy to overcome cisplatin resistance. In addition, we have identified TMEM16A expression as a potential upstream regulator of p90RSK through the ERK pathway and a biomarker of response to p90RSK targeted therapy in the context of cisplatin resistance.

Polyamine transport inhibition and cisplatin synergistically enhance tumor control through oxidative stress in murine head and neck cancer models.

Background: Surgery and/or platinum-based chemoradiation remain standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While these therapies are effective in a subset of patients, a substantial proportion experience recurrence or treatment resistance. As cisplatin mediates cytotoxicity through oxidative stress while polyamines play a role in redox regulation, we posited that combining cisplatin with polyamine transport inhibitor, AMXT-1501, would increase oxidative stress and tumor cell death in HNSCC cells. Methods: Cell proliferation was measured in syngeneic mouse HNSCC cell lines treated with cisplatin ± AMXT-1501. Synergy was determined by administering cisplatin and AMXT-1501 at a ratio of 1:10 to cancer cells in vitro . Cancer cells were transferred onto mouse flanks to test the efficacy of treatments in vivo . Reactive oxygen species (ROS) were measured. Cellular apoptosis was measured with flow cytometry using Annexin V/PI staining. High-performance liquid chromatography (HPLC) was used to quantify polyamines in cell lines. Cell viability and ROS were measured in the presence of exogenous cationic amino acids. Results: The combination of cisplatin and AMXT-1501 synergize in vitro on HNSCC cell lines. In vivo combination treatment resulted in tumor growth inhibition greater than either treatment individually. The combination treatment increased ROS production and induced apoptotic cell death. HPLC revealed the synergistic mechanism was independent of intracellular polyamine levels. Supplementation of cationic amino acids partially rescued cancer cell viability and reduced ROS. Conclusion: AMXT-1501 enhances the cytotoxic effects of cisplatin in vitro and in vivo in aggressive HNSCC cell lines through a polyamine-independent mechanism.

Total times to treatment completion and clinical outcomes in odontogenic sinusitis.

BACKGROUND: Multidisciplinary collaboration is essential for effective odontogenic sinusitis (ODS) management. One point of debate has been the optimal timing of primary dental treatment and endoscopic sinus surgery (ESS), but differences in time to completion of these treatment pathways have not been studied. METHODS: A retrospective cohort study was conducted on ODS patients from 2015 to 2022. Demographic and clinical variables were recorded, and various durations of time were analyzed from rhinologic consultation through treatment completion. Resolution of sinusitis symptoms and purulence on endoscopy was also recorded. RESULTS: Eighty-nine ODS patients were analyzed (47.2 % male, median 59 years-old). Of the 89 ODS patients, 56 had treatable dental pathology, and 33 had no treatable dental pathology. Median time to treatment completion for all patients was 103 days. Of 56 ODS patients with treatable dental pathology, 33 had primary dental treatment, and 27 (81 %) required secondary ESS. In patients who underwent primary dental treatment followed by ESS, median time from initial evaluation to treatment completion was 236.0 days. If ESS was pursued primarily followed by dental treatment, median time from initial evaluation to treatment completion was 112.0 days, which was significantly shorter than if dental treatment was pursued primarily (p = 0.002). Overall symptomatic and endoscopic resolution was 97.8 %. CONCLUSIONS: After dental and sinus surgical treatment, ODS patients experienced 97.8 % resolution of symptoms and purulence on endoscopy. In patients with ODS due to treatable dental pathology, primary ESS followed by dental treatment resulted in a shorter overall treatment duration than primary dental treatment followed by ESS.

Sinonasal Packing is Not a Requisite for Successful Cerebrospinal Fluid Leak Repair.

Background Numerous methods have been described to repair nasal cerebrospinal fluid (CSF) leaks. Most studies have focused on optimizing CSF leak repair success, leading to closure rates of 90 to 95%. Objective This study aimed to determine if excellent reconstruction rates could be achieved without using sinonasal packing. Methods A prospective case series of 73 consecutive patients with various CSF leak etiologies and skull base defects was conducted to evaluate reconstruction success without sinonasal packing. The primary outcome measure was postoperative CSF leak. Secondary outcome measures were postoperative epistaxis requiring intervention in operating room or emergency department, infectious sinusitis, and 22-item sinonasal outcome test (SNOT-22) changes. Results Mean age was 54.5 years and 64% were female. Multilayered reconstructions were performed in 55.3% of cases, with collagen or bone epidural inlay grafts, and nasal mucosal grafts or nasoseptal flaps for onlay layers. Onlay-only reconstructions with mucosal grafts or nasoseptal flaps were performed in 44.7% of cases. Tissue sealants were used in all cases, and lumbar drains were used in 40.8% of cases. There were two initial failures (97.4% initial success), but both resolved with lumbar drains alone (no revision surgeries). There were no instances of postoperative epistaxis requiring intervention in the operating room or emergency department. Infectious sinusitis occurred in 2.7% of patients in the first 3 months postoperatively. SNOT-22 did not change significantly from preoperatively to first postoperative visits, then improved over time. Conclusion Nasal CSF leaks from various etiologies and defect sites were successfully repaired without using sinonasal packing, and patients experienced minimal sinonasal morbidity.

Atypical Presentation of Mammary Analogue Secretory Carcinoma of the Lip.

Mammary analogue secretory carcinoma (MASC) of the salivary gland is a rare tumor that was first described by Skalova et al in 2010, and since then, only a few hundred cases have been reported in the literature. Prior to Skalova's report, MASC was histologically misclassified as acinic cell carcinoma (ACC), pleomorphic adenoma, mucoepidermoid carcinoma, or adenocarcinoma, not otherwise specified. Mammary analogue secretory carcinoma has a low incidence rate overall, accounting for less than 0.3% of all salivary gland tumors. Histopathologic and cytogenic analysis of MASC is identical to secretory carcinoma of the breast, leading to the proposed name by Skalova. The purpose of this case presentation is to describe an atypical presentation of MASC, to compare this case with the classic description of MASC, and to contrast the various features of MASC to ACC in order to improve the accuracy of future diagnoses and help guide treatment.

Comparison of bacterial maxillary sinus cultures between odontogenic sinusitis and chronic rhinosinusitis.

BACKGROUND: Bacterial odontogenic sinusitis (ODS) is distinct from other forms of rhinosinusitis. Diagnosing ODS can be challenging because of nonspecific clinical presentations and underrepresentation in the literature. The purpose of this study was to compare maxillary sinus bacterial cultures between patients with ODS and chronic rhinosinusitis (CRS), to determine whether certain bacteria are associated with ODS. METHODS: This was a retrospective case-control study of 276 consecutive patients from August 2015 to August 2019 who underwent endoscopic sinus surgery (ESS) for bacterial ODS, CRS without nasal polyps (CRSsNP), or CRS with nasal polyps (CRSwNP). When present, pus was sterilely cultured from maxillary sinuses after maxillary antrostomy, and aerobic and anaerobic cultures were immediately sent for processing. Demographics and culture results were compared between ODS and CRS patients, and then separately between ODS and CRSsNP, and ODS and CRSwNP. ODS culture results were also compared between different dental pathologies (endodontic vs oroantral fistula). RESULTS: The following bacteria were significantly more likely in ODS compared to CRS: mixed anaerobes, Fusobacterium spp., Eikenella corrodens, Streptococcus intermedius, Streptococcus anginosus, and Streptococcus constellatus. Staphylococcus aureus and Pseudomonas aeruginosa were inversely related to ODS. There were no significant differences in cultures between the different dental pathologies. CONCLUSION: Certain bacteria were more likely to be associated with ODS compared to CRS when purulence was cultured from the maxillary sinus. Physicians should evaluate for an odontogenic source of sinusitis when these ODS-associated bacteria are identified in maxillary sinus cultures.