Immunoregulatory Potential of Exosomes Derived from Cancer Stem Cells.

Head and neck squamous cell carcinomas (HNSCCs) are malignancies that originate in the mucosal lining of the upper aerodigestive tract. Despite advances in therapeutic interventions, survival rates among HNSCC patients have remained static for years. Cancer stem cells (CSCs) are tumor-initiating cells that are highly resistant to treatment, and are hypothesized to contribute to a significant fraction of tumor recurrences. Consequently, further investigations of how CSCs mediate recurrence may provide insights into novel druggable targets. A key element of recurrence involves the tumor's ability to evade immunosurveillance. Recent published reports suggest that CSCs possess immunosuppressive properties, however, the underlying mechanism have yet to be fully elucidated. To date, most groups have focused on the role of CSC-derived secretory proteins, such as cytokines and growth factors. Here, we review the established immunoregulatory role of exosomes derived from mixed tumor cell populations, and propose further study of CSC-derived exosomes may be warranted. Such studies may yield novel insights into new druggable targets, or lay the foundation for future exosome-based diagnostics

The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial

Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies. We have previously shown that Tadalafil lowers MDSCs and regulatory T cells (Treg) in the blood and in the tumor, primes a tumor specific immune response, and increases the number of activated intratumoral CD8+T cells in patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC). However, despite these important immune modulatory actions, to date no clinically significant effects have been reported following PDE5 inhibition. Here we report for the first time interim results of our ongoing phase I clinical trial (NCT02544880) in patients with recurrent HNSCC to evaluate the safety of and immunological effects of combining Tadalafil with the antitumor vaccine composed of Mucin1 (MUC1) and polyICLC. The combined treatment of Tadalafil and MUC1/polyICLC vaccine was well-tolerated with no serious adverse events or treatment limiting toxicities. Immunologically, this trial also confirms the positive immunomodulation of Tadalafil in patients with recurrent HNSCC and suggests an adjuvant effect of the anti-tumor vaccine MUC1/polyICLC. Additionally, image cytometry analysis of scanned tumors indicates that the PDE5 inhibitor Tadalafil in conjunction with the MUC1/polyICLC vaccine effectively reduces the number of PDL1+macrophages present at the tumor edge, and increases the number of activated tumor infiltrating T cells, suggesting reversion of immune exclusion. However, this analysis shows also that CD163 negative cells within the tumor upregulate PDL1 after treatment, suggesting the instauration of additional mechanisms of immune evasion. In summary, our data confirm the safety and immunologic potential of PDE5 inhibition in HNSCC but also point to PDL1 as additional mechanism of tumor evasion. This supports the rationale for combining checkpoint and PDE5 inhibitors for the treatment of human malignancies

Otolith Dysfunction Is Prevalent in Refractory Benign Paroxysmal Positional Vertigo

Objectives: Determine the prevalence of otolith dysfunction in patients who have failed treatment for benign paroxysmal positional vertigo (BPPV). Methods: Case-control study of patients with BPPV who failed standard treatment and subsequently underwent vestibular testing and supervised vestibular rehabilitation. Interventions included videonystagmography, rotary chair, subjective visual vertical test (SVV), and cervical vestibular evoked myogenic potentials (VEMP). We compared the prevalence of abnormalities in tests of otolith dysfunction (SVV and VEMP) in patients who responded or failed vestibular rehabilitation. Results: In 2012, 46 of 251 patients with BPPV failed initial treatment with canalith repositioning maneuvers performed in the office; of these 46 patients, 28 patients had posterior semicircular canal BPPV and 18 cases had atypical presentations (multicanal BPPV, anterior canal BPPV, or signs of uncompensated unilateral peripheral vestibulopathy). Vestibular testing followed by customized vestibular rehabilitation was completed in 40 patients: 21 patients had resolution of their positional vertigo and nystagmus, and 19 patients did not respond to therapy. Abnormal otolith tests (SVV and/or VEMP) were more common in patients who failed therapy (Pearson Chi square, P = 0.002). Conversely, abnormalities of caloric testing did not predict response to therapy. Conclusions: Abnormalities of utricle and saccular function are prevalent in patients with refractory BPPV. This fact is important to take into account when designing rehabilitation strategies for BPPV patients who fail canalith repositioning maneuvers

Utricular Dysfunction in Refractory Benign Paroxysmal Positional Vertigo

To determine the prevalence of otolith dysfunction in patients with refractory benign paroxysmal positional vertigo (BPPV). Unmatched case control. Tertiary care institution. Patients included were diagnosed with BPPV, failed initial in-office canalith repositioning maneuvers (CRMs), and completed vestibular testing and vestibular rehabilitation (n = 40). Refractory BPPV (n = 19) was defined in patients whose symptoms did not resolve despite vestibular rehabilitation. These patients were compared with a control group of those with nonrefractory BPPV (n = 21) for results of a caloric test, cervical vestibular evoked myogenic potential (cVEMP), and subjective visual vertical (SVV). Forty-six of 251 patients failed initial treatment with in-office CRM. Forty patients met inclusion criteria. There was no significant difference between the cases (refractory BPPV) (n = 19) and controls (nonrefractory BPPV) (n = 21) in terms of age, duration of symptoms, laterality of BPPV, and BPPV symptoms. There was no difference in the prevalence of caloric weakness and cVEMP abnormalities (P > .05), with odds ratios (ORs [95% confidence interval (CI)]) of having abnormal results among cases vs controls of 1.1818 (0.3329-4.1954) and 4.3846 (0.7627-25.2048), for caloric and cVEMP, respectively. Abnormal eccentric SVV was more prevalent in refractory BPPV cases (58%) than in controls (14%) (P < .0072). The OR (95% CI) of having abnormal SVV was 8.25 (1.7967-37.8822) higher among patients with refractory BPPV than those with nonrefractory BPPV. Patients with refractory BPPV are more likely to have abnormal eccentric SVV and thus underlying utricular dysfunction. This finding is important to take into account when designing rehabilitation strategies for patients with BPPV who fail CRM

Transoral laser microsurgery in previously irradiated patients with laryngeal cancer

Early laryngeal cancer is successfully managed with transoral laser microsurgery. Previously radiated patients may experience more post-operative complications. We investigate disease-free survival and secondarily prolonged pain and chondronecrosis. Retrospective review of 52 patients undergoing transoral laser microsurgery after previous radiation. Mean disease-free survival was 36.7 months. Overall disease-free survival was 57.6% at 3-year and 48.4% at 5-year follow-up, with no significant difference between surgery within as opposed to after 60 months of radiation or within as opposed to after 12 months of radiation. Thirteen patients, all with surgery within 60 months of radiation, experienced prolonged pain. Twelve experienced chondronecrosis, all within 12 months of surgery. Transoral laser microsurgery for early laryngeal cancer is an adequate therapeutic option in patients with history of radiation with comparable disease-free survival to other reports. Patients undergoing transoral laser microsurgery within 60 months of radiation treatment are more likely to experience prolonged pain

The effect of n‐acetyl‐cysteine on recovery of the facial nerve after crush injury

ObjectiveFacial nerve dysfunction can vary in severity and recovery is dependent on the character of the injury. N-acetyl-cysteine prevents oxidative stress and cellular damage, and its use in the setting of nerve dysfunction from crush injury has not yet been established. In this study, rats with facial nerve crush injury will be treated with n-acetyl-cysteine or control and functional recovery and electrophysiologic outcome will be compared.Study designProspective, randomized animal study.MethodsTwenty-four Wistar rats underwent unilateral facial nerve crush injury. Rats were implanted with a subcutaneous osmotic pump filled with saline (n = 12) or n-acetyl-cysteine 50 mg/kg/day (n = 12). Functional and electromyographic recovery was recorded at two and four weeks postoperatively.ResultsWhen compared to untreated rats, n-acetyl-cysteine treated rats had a greater electromyography amplitude recovery at 2 weeks with regard to eye blink (p=0.006) but not vibrissae function. At four weeks, the electromyography amplitude recovery of the vibrissae function was greater in n-acetyl-cysteine treated rats (P=0.001), but the amplitude recovery difference in eye blink was only marginally significant between groups (p=0.07). The functional score was higher in n-acetyl-cysteine-treated rats than in untreated rats at all of the time points.ConclusionThis study demonstrated that n-acetyl-cysteine facilitated facial nerve recovery with improved functional and electromyography outcomes in the setting of crush injury.Level of evidenceNA

Portrait of a Surgeon: Artificial Intelligence Reflections.

Text-to-image artificial intelligence (AI) programs are popular public-facing tools that generate novel images based on user prompts. Given that they are trained from Internet data, they may reflect societal biases, as has been shown for text-to-text large language model programs. We sought to investigate whether 3 common text-to-image AI systems recapitulated stereotypes held about surgeons and other health care professionals. All platforms queried were able to reproduce common aspects of the profession including attire, equipment, and background settings, but there were differences between programs most notably regarding visible race and gender diversity. Thus, historical stereotypes of surgeons may be reinforced by the publics use of text-to-image AI systems, particularly those without procedures to regulate generated output. As AI systems become more ubiquitous, understanding the implications of their use in health care and for health care-adjacent purposes is critical to advocate for and preserve the core values and goals of our profession

Open airway reconstruction in adults: Outcomes and prognostic factors

The purpose was to assess the success of open tracheal resection and re-anastomosis for non-malignant tracheal stenosis in adults. Successful operations were defined as T-tube or tracheostomy-free status by 6months post-operatively. Retrospective chart review was performed and data were recorded in a de-identified manner. The primary outcome was T-tube or tracheostomy-free status by 6months following tracheal resection. Clinical and demographic characteristics were evaluated as potential prognostic variables. Thirty-two patients met inclusion criteria, with a median age of 46. Seven patients underwent tracheal resection with primary closure, without stenting. Successful tracheal resection was defined as tracheostomy or T-tube free by 6months post-operation, and this was possible in 21 patients (66%). Eighty-two percent of patients with cricoid cartilage-sparing tracheal resection had a successful outcome, versus 30% of patients who underwent cricoid cartilage resection (HR 5.02, 95% CI 1.46-17.3; p=0.011). Patients with a history of tracheostomy-dependence were four times more likely to remain tube-dependent at 6months (HR 4.15, 95% CI 1.56-10.86; p=0.004). Tracheal stenosis remains a very difficult problem to treat. In our series, we confirm that patients with cricoid involvement or with a history of tracheostomy were more likely to be tube dependent at 6-months post-operation

Stratification of surgical margin distances by the millimeter on local recurrence in oral cavity cancer: A systematic review and meta-analysis.

There are limited data supporting the commonly suggested 5 mm margin cutoff as the optimum value in defining clear margins in oral cancer. A database search of Pubmed/Medline, Web of Science, and EBSCOhost was performed from inception to June 2022. A random-effects model was chosen for this meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed throughout this study. Seven studies met study criteria (2215 patients). The risk ratio was significantly higher for margins &lt;5 mm when compared to those ≥5 mm (2.09 (95%CI: 1.53-2.86, I2 &nbsp;= 0.47)). Subgroup analysis (I2 &nbsp;=&nbsp;0.15) of margin distances of 0.0-0.9, 1.0-1.9, 2.0-2.9, 3.0-3.9, and 4.0-4.9 mm calculated risk ratios for local recurrence of 2.96, 2.01, 2.17, 1.8, and 0.98, respectively. Margins between 4.0 and 4.9 mm had similar risk ratios for local recurrence compared to ≥5 mm, while margins &lt;4.0 were significantly higher