The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has significantly increased in recent decades due to human papillomavirus (HPV)‐mediated oncogenesis. Unfortunately, a growing number of HPV‐positive (+) OPSCC survivors are living with the irreversible side effects of treatment. The novel, well‐tolerated chemotherapeutics with improved side effect profiles are, therefore, in high demand. Metformin is one such drug, widely used as a first‐line oral agent in the treatment of type 2 diabetes mellitus. Curcumin is another well‐tolerated agent quickly gaining attention for its medicinal properties. Both metformin and curcumin have been shown to display anticancer properties. This study aimed to determine the antitumor effects of these agents, individually and combined, in HPV+​​​​ ​​​and HPV‐negative (−) head and neck squamous cell carcinoma (HNSCC) cell lines. This was achieved by assessing the efficacy of varying drug concentrations on the overall cell viability, proliferation, and expression of common HNSCC biomarkers. The results from protein and RNA expression data are highly variable, as expected, with multiple pathways being affected in cancer. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays and immunofluorescence microscopy suggest that both agents are capable of slowing proliferation and inducing apoptosis. We conclude that curcumin and metformin display effective antitumor effects in both HPV+ and HPV− HNSCC cell lines. The curcumin effects appear more pronounced in the HPV− cell lines. Metformin appears to be more effective at reducing the overall cell numbers in HPV+ cell lines. Metformin and curcumin combined did not appear to have synergistic effects on the proliferation or apoptosis of the treated cell lines.

Vasoactive intestinal peptide (VIP), a neuropeptide, controls multiple functions in exocrine tissues, including inflammation, and relaxation of airway and vascular smooth muscles, and regulates CFTR-dependent secretion, which contributes to mucus hydration and local innate defense of the lung. We had previously reported that VIP stimulates the VPAC1 receptor, PKCϵ signaling cascade, and increases CFTR stability and function at the apical membrane of airway epithelial cells by reducing its internalization rate. Moreover, prolonged VIP stimulation corrects the molecular defects associated with F508del, the most common CFTR mutation responsible for the genetic disease cystic fibrosis. In the present study, we have examined the impact of the absence of VIP on CFTR maturation, cellular localization, and function in vivo using VIP knockout mice. We have conducted pathological assessments and detected signs of lung and intestinal disease. Immunodetection methods have shown that the absence of VIP results in CFTR intracellular retention despite normal expression and maturation levels. A subsequent loss of CFTR-dependent chloride current was measured in functional assays with Ussing chamber analysis of the small intestine ex vivo, creating a cystic fibrosis-like condition. Interestingly, intraperitoneal administration of VIP corrected tissue abnormalities, close to the wild-type phenotype, as well as associated defects in the vital CFTR protein. The results show in vivo a primary role for VIP chronic exposure in CFTR membrane stability and function and confirm in vitro data.

The most common cystic fibrosis causing mutation F508del induces early degradation and reduced trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels to the apical membrane of epithelial cells. In the human nasal epithelial cells JME/CF15, we previously reported that vasoactive intestinal peptide (VIP) exposure corrects trafficking and membrane insertion of functional F508del-CFTR channels at 37°C. Correction of trafficking was PKA dependent, whereas enhanced membrane localization involved PKC. In the present study, we have identified PKCε as the isoform involved in VIP-dependent F508del-CFTR membrane insertion. Iodide effluxes were used to monitor the presence of VIP-rescued functional F508del-CFTR channels at the surface of JME/CF15 cells maintained at 37°C. Iodide efflux peaks measured in response to stimulation with forskolin were insensitive to PKC α, β, γ, δ, ζ inhibitors. In contrast, efflux peaks were completely inhibited by pretreatment with the PKCε inhibitor peptide EAVSLKPT with an IC(50) of 4.9 μM or by PKCε small interfering RNA (siRNA). Immunostaining and confocal microscopy confirmed that membrane localization of F508del-CFTR induced by VIP was abolished in the presence of EAVSLKPT but not with other isoform inhibitors. In recombinant baby hamster kidney cells, endogenously expressing PKCε but no VIP receptor, wild-type, and F508del-CFTR sensitivity to cpt-cAMP stimulation was increased by PMA treatment. Biotinylation assays and immunoblots confirmed that PMA (0.5-2 h) induced a greater than threefold increase in membrane CFTR, whereas forskolin had no effect. The PMA effect was abolished by specifically inhibiting PKCε (EAVSLKPT IC(50) = 5.7 μM) but not other PKC isoforms. Taken together, these results indicate that stimulating PKCε by VIP or PMA increases membrane insertion and activity of WT- and F508del-CFTR.

Background: The tongue is an essential organ for human interaction, communication and survival. To date, there is a paucity of objective functional, patient reported, or quality of life outcomes of patients undergoing a total glossectomy with preservation of the larynx (TGLP). Objective: To examine prospectively collected objective, self-reported functional and quality of life (QOL) data in patients undergoing TGLP and free flap reconstruction. Methods: Sixteen TGLP patients were identified in the prospective head and neck cancer and functional outcomes database between January of 2009 and December 2017. Data collection included patient age, sex, performance status, TNM staging, diagnosis and adjuvant treatment. Swallowing and speech functions were measured and prospectively recorded pre-and postoperatively. Patient reported outcomes were measured with the Speech Handicap Index (SHI) and the M.D. Anderson Dysphagia Inventory (MDADI). Results: All patients had a significant reduction in their objective swallowing (P = 0.035), sentence (P = 0.001) and word intelligibility (P < .001) scores. There was no significant reduction in SHI or total MDADI scores. All patients maintained their QOL in the post-treatment time frame. There was no relationship between free-flap type and outcome. Conclusion: Total glossectomy with laryngeal sparing and free flap reconstruction results in significant reduction in objective functional measurements, but patients report stable functional and quality of life outcomes after treatment.

ObjectiveUtilization of free tissue transfers in head and neck reconstruction has greatly increased due to their dependability and reliability. Anterolateral thigh (ALT) and rectus abdominus (RA) free flaps may provide too much soft tissue bulk, especially in patients with a large body habitus. A radial forearm free flap (RFFF) may be modified with a “beaver tail” (BT), which provides a flap whose bulk may be tailored to a defect. The purpose of this paper is to describe the technique, how it can be used for a variety of defects and the outcomes of these reconstructions.MethodsA retrospective review of prospectively collected data was performed at single tertiary care center between 2012 and 2022. BT‐RFFF was designed by leaving a fibroadipose tail vascularized to branches of the radial artery or separated from the vascular pedicle and left attached to the proximal portion of the skin paddle. Functional outcomes, tracheostomy dependence, and gastrostomy tube (G‐tube) dependence as well as complications were determined.ResultsFifty‐eight consecutive patients undergoing BTRFFF were included. Defects reconstructed included: oral tongue and/or floor of mouth 32 (55%), oropharynx 10 (17%), parotid 6 (10%), orbit 6 (10%), lateral temporal bone 3 (5%), and mentum 1 (2%). Indications for BTRFF were: need for bulk when the ALT and RA were too thick (53%) and need for a separate subcutaneous flap for contouring or deep defect lining (47%). Complications directly related to beavertail included a widened forearm scar (100%), wrist contracture (2%) partial flap loss (2%), and flap loss requiring a revision flap (3%). Ninety‐three percent of patients with oral/oropharyngeal defects and 12‐month follow‐up tolerated oral intake without aspiration and 76% were tube‐independent. Ninety‐three percent were tracheostomy‐free at last follow‐up.ConclusionThe BTRFF is a useful tool for reconstructing complex 3D defects requiring bulk where an ALT or rectus would otherwise provide too much bulk.