Department of Otolaryngology, Head and Neck Surgery

Diabetic wounds have limited effective therapies to restore tissue repair and resolve excessive inflammation. This study aimed to identify mechanisms of diabetic wound healing defects and test a therapeutic intervention using diabetic mouse and pig models. Here, we show that Smad7 transgene expression in mouse epidermis promotes wound healing in diabetic mice. To restrict the therapeutic effects of Smad7 on wounds, we develop a Smad7-based biologic (Tat-PYC-Smad7) that penetrates cells of the wound. Topical Tat-PYC-Smad7 treatment to diabetic pig and mouse wounds accelerates healing. Tat-PYC-Smad7-treated wounds exhibit reduced TGFβ/NFκB signaling, faster re-epithelialization, and better extracellular matrix remodeling compared to vehicle controls. Tat-PYC-Smad7 also attenuates neutrophil extracellular trap (NET) formation, potentially acting through reductions in MPO enzymatic activity and MPO nuclear entry, consequently reducing chromatin decondensation and the release of NET components. Our study reveals that keratinocytes and neutrophils are the two major cell types targeted by Tat-PYC-Smad7 to promote diabetic wound healing, providing insight into mechanisms of diabetic wound healing defects targetable by Smad7-based therapy.

Canine oral squamous cell carcinoma (COSCC) is the second most common oral tumor in dogs and the most relevant for comparative human trials as a spontaneous large animal model of disease. Historical genomic work has focused primarily on bulk sequencing. The present study describes the complete transcriptomic landscape of COSCC with spatial distinction between the surface tumor, deep invasive tumor, peritumoral dysplastic epithelium, and tumor microenvironment compared to matched normal oral samples. Each region demonstrated distinct molecular signatures. Genes related to epithelial growth factor (EGFR) and epithelial-mesenchymal transformation (EMT) were upregulated in both peritumoral dysplasia and surface cancer. Additionally, the KRAS gene set, KRT17, and SSP1 were enriched in cancer. We identified five genes that represent dysplastic lesion with high potential for malignant transformation (FZD4, GAS1, HACD2, NOG, and SLC39A6). Also, three genes, SFRP4, FZD1, and IL34 represented a specific signature of the invasive portion of the COSCC that should be explored for prognostic value as a biomarker of malignancy. Lastly, we verified the immunomodulatory tumor microenvironment detecting an increase in macrophages and an abundance of IL-10 secretion. The other predominant leukocytes were T-cells, with CD4+ T-cells being the most prevalent. CD4+ T cells expressed transcripts for both stimulatory (Inducible T-cell Co-Stimulator (ICOS) and inhibitory molecules (CTLA4). The observed high CTLA4 suggests that this inhibitory signal may be preventing a robust antitumor immune response. Taken together, this study identified multiple targets to be explored for biomarkers of malignancy, prediction of tumor behavior, and potential targets for development of novel therapies.

Cancer is a daunting global health problem with a steadily rising incidence. Despite the wide arsenal of current anticancer therapies, challenges such as drug resistance, tumor heterogeneity, poor targeting, and severe side effects often lead to suboptimal efficacy and poor patient outcomes, highlighting the need for innovative therapies. Autophagy modulation has emerged as an attractive approach to complement existing therapies. The dual role of autophagy in cancer promotion and suppression has inspired the development of new drugs and therapeutic strategies focusing on both inhibition and induction. Despite the promising results of current autophagy modulators in preclinical studies, challenges such as the lack of selectivity and potency, toxicity, poor pharmacokinetics, and inadequate tumor targeting continue to limit their successful clinical translation. Many of these challenges could be overcome using nanomedicine. This review explores recent advancements in nanomedicine strategies for autophagy modulation. Successful combination strategies leveraging nanoparticles and autophagy modulators in synergy with chemotherapy, immunotherapy, phototherapy, gene therapy, and other modalities are presented. Additionally, nanomaterials with intrinsic autophagy-modulating capabilities, such as self-assembling autophagy inhibitors, are discussed. Finally, limitations of autophagy modulators currently in clinical trials are discussed, and future perspectives on designing nanomedicine for successful clinical implementation are explored.

Objective: The fibula free flap (FFF) remains the workhorse flap for head and neck defects necessitating osteocutaneous reconstruction. Although lower extremity angiography, ultrasound (US), and other vascular studies are routinely used for fibula assessment and patient selection, predictors of donor-site morbidity following harvest remain poorly understood. We sought to investigate the factors associated with FFF donor-site complications. Study Design: Retrospective analysis of patients at a tertiary care center. Setting: Tertiary care center. Methods: In total, 119 patients undergoing FFF reconstruction during the years 2012 to 2022 were included. Multivariable logistic regression was used to identify independent predictors of soft-tissue donor-site wound complications. Results: A total of 48 (40.3%) patients developed a donor-site wound complication with an average time to diagnosis of 24 days (±16) following surgery. In multivariable regression, history of alcohol use disorder (P = .0083) and method of donor-site closure (P = .0368) were independent predictors of donor-site wound complications. Split-thickness skin graft closure was associated with a 146% increased odds of wound complications (odds ratio [OR] = 2.46, 1.11-5.43, 95% confidence interval). Patient age, body mass index, Charlson comorbidity index, skin paddle size, and Doppler US characteristics were not predictive of postoperative donor-site morbidity. Conclusion: Predictors of FFF donor-site wound complications included history of alcohol abuse and method of donor-site closure. This study highlights unique lower extremity Doppler US findings in patients undergoing FFF reconstruction in addition to modifiable risk factors associated with fibula donor-site morbidity and soft-tissue complications. Our findings underscore the need to critically evaluate wound closure techniques in this population.

BACKGROUND: Patient-reported outcome measures have been associated with survival in oncology patients. Altered intake and malnutrition are common symptoms for patients treated for head and neck cancer and esophageal cancer (HNC/EC). The purpose of this study was to examine the relationship between patient-reported satisfaction with medical care and nutrition status. METHODS: This prospective cohort study collected data from 11 international cancer care sites. RESULTS: One hundred and sixtythree adult patients (n = 115 HNC; n = 48 EC) completed a patient satisfaction questionnaire (the Canadian Health Care Evaluation Project Lite) and were included. HNC/EC patient global satisfaction with medical care was 88.3/100 ± 15.3 at baseline and remained high at 86.6/100 ± 16.8 by 6 months (100 max satisfaction score). Poor nutrition status, as defined by the Patient-Generated Subjective Global Assessment Short Form, was associated with lower patient satisfaction with overall medical care, relationship with doctors, illness management, communication, and decision-making 6 months into treatment (P < 0.01). There was no difference in global satisfaction between patients who did and did not report swallowing difficulty (P = 0.99) and patients with and without feeding tube placement (P = 0.36). Patients who were seen by a dietitian for at least one nutrition assessment had global satisfaction with care that was 16.7 percentage points higher than those with no nutrition assessment (89.3 ± 13.8 vs 72.6 ± 23.6; P = 0.005) CONCLUSION: In HNC/EC patient-centered oncology care, decreasing malnutrition risk and providing access to dietitian-led nutrition assessments should be prioritized and supported to improve patient satisfaction and standard of care. Feeding tube placement did not decrease patient satisfaction with medical care.

The repair of an infant with cleft lip includes treatment of the nasal deformity using surgical repositioning of the nasal cartilages. In some cases, the nose is molded before surgery, termed nasoalveolar molding, and in others, postoperatively with nostril stents for a variable amount of time. This best practice evaluation fails to make a definitive evidence-based conclusion, yet the benefits of stenting seem to outweigh the risks.

Recurrent respiratory papillomatosis (RRP) is a chronic airway disease caused by Human Papillomavirus (HPV). INO-3107, DNA immunotherapy designed to elicit T-cells against HPV-6 and HPV-11, was evaluated in a 52-week Phase 1/2 study for efficacy, safety, and immunogenicity (NCT04398433). Thirty-two eligible adults with HPV-6 and/or HPV-11 RRP, requiring ≥2 surgical interventions in the year preceding dosing were enrolled between October 2020 and November 2021 and administered 4 INO-3107 doses by intramuscular injection followed by electroporation. The primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included surgical intervention frequency and change in RRP Severity Score (modified) post-INO-3107 and assessment of immune responses. 81% (26/32) of patients experienced surgery reduction following INO-3107 compared with the year prior to treatment. Blood assessments revealed HPV-6 and HPV-11 antigen-specific T-cell induction. RNA sequencing identified an inflammatory response in papillomas, inclusive of cytolytic CD8 + T-cell signatures. T-cell receptor sequencing revealed emergent T-cell clones in blood and confirmed trafficking to papillomas. Treatment-related adverse events (AEs) were reported in 13/32 (41%) patients, all low-grade. INO-3107 provides clinical benefit to HPV-6 and/or HPV-11-associated RRP adults and is well-tolerated. Importantly, treatment-induced peripheral T-cell responses traffic to airway tissue and are associated with clinical response.

BACKGROUND: Oral potentially malignant disorders (OPMDs) occur in up to 4%-5% of the population, of which oral leukoplakia (OL) is the most common subtype. Predicting high-risk OL remains a challenge. Early diagnosis and effective treatment are thought to be of paramount importance to improve outcomes. METHODS: We searched PubMed and Clinicaltrials.gov data for updates in the clinical management of OL from 2015 to current. RESULTS: Recent publication of large cohorts of patients with OL aids in counseling patients regarding risk of malignant transformation. Management for OL includes surveillance, excision, and laser surgery, as well as local and systemic approaches to chemoprevention. Several new entities show promise regarding candidate biomarkers, chemoprevention agents, and diagnostic adjuncts, though all require further validation. CONCLUSION: This update serves to further inform clinical management of OL and provide impetus for future investigations. TRIAL REGISTRATION: NCT00099021, NCT00951379, NCT05727761, NCT05727761.