Faculty Bibliography

Interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNα is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFNα and others do not. Here, we identify and characterize a pathway involving PKCδ-dependent phosphorylation of ULK1 on serine residues 341 and 495, required for subsequent activation of p38 MAPK. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from MPN patients, and that increased levels of ULK1 and p38 MAPK correlate with clinical response to IFNα therapy in these patients. We also demonstrate that IFNα treatment induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vitro and in vivo, triggering a negative feedback loop that suppresses IFN responses. Overexpression of ROCK1/2 is seen in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid precursors from MPN patients. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs.

PURPOSE:Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4-positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti-CTLA-4 mAb, to cetuximab-radiotherapy. PATIENTS AND METHODS:A (3 + 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus-negative (HPV-)] or intermediate-risk HPV-positive (HPV+)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. RESULTS:From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N  =  12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57-92] and 72% (90% CI, 56-92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83-37.8; P = 0.08). CONCLUSIONS:The RP2D for ipilimumab plus standard cetuximab-radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.

Pediatric voice disorders are increasing being noted as a barrier to success in school and socialization. Significant advances over the past decade in evaluation, diagnosis, and management of pediatric voice disorders have improved both short-term and long-term outcomes. Practitioners should have a thorough understanding of anatomy and physiology, accurately work up a pediatric voice disorder, and efficiently treat voice disorders. Comprehensive voice evaluation in children is essential to properly assessing pediatric dysphonia. Diagnosis and treatment are best managed by a multidisciplinary team. Accurate diagnosis allows for effective treatment, which includes voice therapy, medical therapy, and surgical intervention as needed.

OBJECTIVE:The objective of this disease state clinical review is to provide clinicians with a summary of the nonsurgical, minimally invasive approaches to managing thyroid nodules/malignancy, including their indications, efficacy, side effects, and outcomes. METHODS:A literature search was conducted using PubMed and appropriate key words. Relevant publications on minimally invasive thyroid techniques were used to create this clinical review. RESULTS:Minimally invasive thyroid techniques are effective and safe when performed by experienced centers. To date, percutaneous ethanol injection therapy is recommended for recurrent benign thyroid cysts. Both ultrasound-guided laser and radiofrequency ablation can be safely used for symptomatic solid nodules, both toxic and nontoxic. Microwave ablation and high-intensity focused ultrasound are newer approaches that need further clinical evaluation. Despite limited data, encouraging results suggest that minimally invasive techniques can also be used in small-size primary and locally recurrent thyroid cancer. CONCLUSION/CONCLUSIONS:Surgery and radioiodine treatment remain the conventional and established treatments for nodular goiters. However, the new image-guided minimally invasive approaches appear safe and effective alternatives when used appropriately and by trained professionals to treat symptomatic or enlarging thyroid masses.

OBJECTIVE:The effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues. DESIGN/METHODS:Antinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells. RESULTS:NFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit β-arrestins and evoke MOPr endocytosis. CONCLUSION/CONCLUSIONS:In a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.

Introduction: The inner lining of the upper airway includes ciliated epithelium and lamina propria essential for barrier function. This layer is disrupted upon injury and results in inflammation and fibrotic scarring[1]. We developed a model to study the impact of basement architectural cues on the epithelial-fibroblast interaction at air-liquid interface by using randomly-oriented and aligned polycaprolactone (PCL) fibers.
Material(s) and Method(s): Plasma treated randomly oriented and aligned PCL electrospun fibers were placed in transwell chambers and were seeded with human tracheal fibroblasts (HTFs) for 7 days and then human bronchial epithelial cells (HBEs) were introduced above the HTF layer. An air-liquid interface was established on day 14 to promote HBE differentiation. Permeability, cell proliferation, and expression of fibroblast (fibronectin and S100A4) and epithelial (MUC5A) markers were evaluated using ELISA and immunofluorescence (IHC) imaging (n = 6). Quantitative data were compared using one-way Analysis of Variance (ANOVA) followed by Tukey's test for post hoc determination of significant differences at p < 0.05.Results and Discussion: Fiber alignment resulted in higher expression of fibroblast markers during the first 7 days while randomly oriented fibers generally caused higher (27%) cell proliferation over time. In addition, IHC images revealed homogenous HBE growth above the HTFs layer with significant laminin- rich matrix deposited at the interface and dispersed spheroidal epithelial clusters observed in both groups. Larger epithelial spheres were observed in coculture on randomly oriented fibers with rudimentary ciliated structures.
Conclusion(s): A successful epithelial-fibroblast coculture system with pro-fibrotic behavior was achieved by controlling architectural cues introduced during initial fibroblastepithelial interactions

BACKGROUND:We ascertain the role of a low cervical paraspinal skeletal muscle index (CPSMI) as a biomarker for poor treatment tolerance in patients with operable mucosal head and neck squamous cell carcinoma (HNSCC). METHODS:A prospective cohort of patients with operable HNSCC requiring microvascular reconstruction was evaluated. Low CPSMI was calculated using preoperative CT neck imaging. Poor treatment tolerance, a composite measure of incomplete therapy or severe morbidity/mortality during treatment, was the primary outcome. RESULTS:One hundred and twenty-seven patients underwent extirpative surgery with a mean age was 60.5. Poor treatment tolerance occurred in 71 (56%) patients with 21 not completing recommended adjuvant therapy and 66 having severe treatment-related morbidity. A low CPSMI was independently associated with poor treatment tolerance (OR 2.49, 95%CI 1.10-5.93) and delay to adjuvant therapy (OR 4.48, 95%CI 1.07-27.6) after adjusting for multiple confounders. CONCLUSION:Low CPSMI was independently associated with poor treatment tolerance in patients with operable HNSCC.

OBJECTIVES:Increasing use of transoral robotic surgery (TORS) is likely to impact outcomes for HPV+ oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to describe oncologic outcomes for a large HPV+ OPSCC cohort after TORS and develop a risk prediction model for recurrence under this treatment paradigm. MATERIALS AND METHODS:634 HPV+ OPSCC patients receiving TORS-based therapy at a single institution were reviewed retrospectively to describe survival across the entire cohort and for patients suffering recurrence. Risks for distant metastatic recurrence (DMR) and locoregional recurrence (LRR) were modeled using multivariate logistic regression analyses of case-control sub-cohorts. RESULTS:5-year overall and recurrence-free survival were 91.2% and 86.1%, respectively. 5-year overall survival was 52.5% following DMR and 83.3% after isolated LRR (P = .01). In case-control analyses, positive surgical margins were associated with DMR (adjusted OR 5.8, CI 2.1-16.0, P = .001), but not isolated LRR, and increased DMR risk 4.2 fold in patients with early clinical stage disease. By contrast, LRR was associated with not receiving recommended adjuvant therapy (OR 13.4, CI 6.3-28.5, P < .001). CONCLUSIONS:This study sets a benchmark for oncologic outcomes from HPV+ OPSCC after TORS-based therapy. Under this treatment paradigm, margins are relevant for assessing lethal recurrence risk during clinical trial design and post-treatment surveillance.

Thyroidectomy remains the gold standard treatment for benign, symptomatic, or enlarging thyroid nodules, malignant nodules, and metastatic lymph node disease. However, in the past 2 decades, image-guided interventional techniques have emerged as promising alternative treatments for these conditions. Percutaneous ethanol ablation is now an accepted first-line treatment for recurring cystic thyroid nodules. Thermal ablation techniques such as high-intensity focused ultrasound, laser ablation, radiofrequency ablation, and microwave ablation have shown efficacy in producing a nodular volume reduction of greater than 50% that is maintained for several years with resolution of local compressive symptoms. There is also increasing evidence that these techniques can effectively treat papillary thyroid microcarcinomas and recurrent metastatic lymph node disease. Because these interventional ablation techniques are performed safely in an outpatient setting, are well tolerated, and the risk for needing thyroid hormone supplementation is negligible, they are becoming a popular alternative treatment to surgical resection. In this comprehensive review, we discuss each of these percutaneous interventions: the devices and techniques, the advantages and disadvantages of each energy, and summarize the outcomes published in the literature.