Faculty Bibliography

The incidence of thyroid cancer in Graves'Disease (GD) patients is estimated to be low. However, it is unclear what impact the recent rise in the incidence of thyroid cancers has had in this population. Furthermore, it is not clear if these cancers behave more aggressively than cancers in the general population. We investigated the incidence of malignancy and its features in a contemporary cohort of GD patients treated by surgery. All patients who underwent thyroidectomy for GD in our center were reviewed from 2013-2018. Demographics, clinicopathologic features, rate of incidental cancer and outcomes were reviewed. We identified 130 patients with GD who underwent thyroidectomy. Median age was 40.5 (16-80). Majority were female (112, 86%). All but five (4%) were radioactive iodine naive. Thirtyfour (26%) were found to harbor malignancy. While the majority (18, 53%) were papillary microcarcinoma; 12 (34%) had multifocal disease; 10 (29%) had tall cell features, 3 (9%) had positive lymph nodes, and 2 (6%) had extrathyroidal extension. One patient (3%) was diagnosed with follicular carcinoma. No permanent hyperparathyroidism or recurrent laryngeal nerve injury was encountered. With a median follow up of 23 months no recurrences were identified. The risk of incidental malignancy in GD patients was high in our cohort. While the majority were low risk microcarcinomas, a number of patients harbored higher risk tall cell features. Our data suggest that for GD patients who are medically managed, careful surveillance and biopsy of suspicious nodules might be warranted. The outcome of surgical treatment was excellent for controlling both hyperthyroidism and cancer

Objectives: With the removal of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) from the follicular variant of papillary thyroid carcinoma (FVPTC) categorization, the question arises as to how the molecular profile of invasive encapsulated FVPTC (IEFVPTC) compares with NIFTP. Our study aimed to examine the molecular alterations associated with NIFTP, IEFVPTC, and infiltrative FVPTC (iFVPTC) to determine whether these entities are actually distinct at the molecular level.
Method(s): Forty-five NIFTP cases, 12 IEFVPTC cases, and 8 iFVPTC cases from 1/2013 to 8/2016 were assessed for presurgical fine-needle aspiration ThyroSeq V2 nextgeneration sequencing results.
Result(s): The NIFTP cases displayed alterations in BRAF K601E/EIF1AX, BRAF T599-R603, NRAS x15 (two with additional PTEN and one with P53), KRAS x3, HRAS x11 (one with an additional TERT/ EIF1AX), PAX8-PPARgamma x5, PTEN, THADA x3, MET x2, copy number alteration, EF1AX, and DICER1. The IEFVPTC displayed alterations in RAS x5 (1 NRAS/TERT, 2 HRAS, 2 NRAS), BRAF-K601E x2, and BRAF-pG469A with gene expression profile; PAX8-PPARgamma x2; THADA-IGF2BP3; and ETV6/ NTRK3. The iFVPTC cases displayed alterations in RAS x2 (NRAS and HRAS), TERT x2, BRAF-V600E mutation, ALK, MET, and NTRK3.
Conclusion(s): NIFTP and IEFVPTC cases most commonly displayed RAS mutations (64.4% and 41.7%, respectively) and lacked aggressive BRAF-V600E mutations, whereas iFVPTC harbored aggressive mutations such as BRAF-V600E and TERT more commonly, with fewer RAS mutations. The possibility of NIFTP and IEFVPTC being on a premalignant to malignant continuum must be raised and these entities may be more similar to each other than to other entities such as iFVPTC

OBJECTIVE:Clear cell carcinoma (CCC) is a rare salivary gland malignancy, believed to be generally low grade. We investigated CCC epidemiology and clinical behavior, using the National Cancer Database (NCDB). STUDY DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:NCDB. SUBJECTS AND METHODS/METHODS:All CCCs of the salivary glands were selected between 2004 and 2015. Patient demographics, tumor characteristics, treatments, and survival were analyzed. Cox regression analyses were performed in treated patients. RESULTS:We identified 268 patients with CCC. Median age was 61 (21-90) years. Most were female (145, 54%). The most common site was oral cavity (119, 44%), followed by major salivary glands (68, 25%) and oropharynx (41, 15%). Most tumors were low grade (81, 68%) and stages I to II (117, 60.6%). Nodal (36, 17.5%) and distant metastases (6, 2.4%) were rare. Most were treated by surgery alone (134, 50.0%), followed by surgery and radiotherapy (69, 25.7%). Five-year overall survival (OS) was 77.6% (95% CI, 71.4%-84.2%). In univariate analysis, older age, major salivary gland and sinonasal site, stages III to IV, high grade, and positive margins were associated with worse OS. In multivariate analysis, only high tumor grade (hazard ratio [HR], 5.76; 95% CI, 1.39-23.85; P = .02), positive margins (HR, 4.01; 95% CI, 1.20-13.43; P = .02), and age ≥60 years (HR, 3.45; 95% CI, 1.39-8.55; P = .01) were significantly associated with OS. CONCLUSION/CONCLUSIONS:We report the largest series of clear cell carcinomas of the head and neck. Outcomes are generally favorable following surgical-based treatments. In this series, pathologic tumor grade is associated with worse survival. Routine evaluation and reporting of tumor grade might better guide physicians in recommending appropriate treatments in this rare malignancy.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:To determine if a long segment of trachea can be transplanted as a vascularized organ and to determine if a tracheal transplant is a potential surgical option for a long-segment circumferential tracheal defect. STUDY DESIGN/METHODS:Animal model. METHODS:Four (two donors and two recipients) adult domestic Yorkshire swine were used. Two sets of transplants were performed from a donor to recipient pig. The transplant was placed heterotopically (not in continuity with the airway), and the recipient animals were monitored for 14 days to ensure the transplants were well vascularized. Immunosuppressive therapies included methylprednisolone, cyclosporine, and azathioprine. Gross as well as histological examination of multiple tissues types including mucosa, cartilage, muscle, and blood vessels were performed postsacrifice on day 14. RESULTS:Recipient animal weights ranged from 40 to 42 kilograms. Both recipient pigs survived the full 14 days of study and exhibited normal activity and appetite. Ischemia time of transplanted grafts ranged from 63 to 72 minutes. Transplanted tracheas included a minimum of 15 cartilaginous rings and measured greater than 10 cm in length. Both grafts maintained a robust blood supply throughout the duration of study. CONCLUSIONS:The entire visceral compartment can be reliably transplanted, either as a single component (trachea) or as a chimeric flap with multiple components (trachea, esophagus, larynx, and pharynx). Further studies in the swine model should be considered to study the effects of transplanting the trachea orthotopically into the native airway. Further studies are needed into the reliability of this technique of transplantation in humans. LEVEL OF EVIDENCE/METHODS:NA Laryngoscope, 128:S1-S9, 2018.

Objectives/UNASSIGNED:Recognizing preoperative characteristics of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is important for clinical management. Therefore, we assessed presurgical NIFTP molecular profiles using fine-needle aspiration (FNA) material. Methods/UNASSIGNED:Presurgical FNA reports of 39 surgically confirmed NIFTP cases from January 2013 through May 2017 were assessed for Afirma and ThyroSeq results. Results/UNASSIGNED:Twenty-one of 39 NIFTP nodules were preoperatively tested with Afirma with two benign and 19 suspicious results. Twenty-seven of 39 nodules were tested with ThyroSeq (nine of 39 had both Afirma and Thyroseq): 18 (67%) had RAS mutations (13 NRAS, four HRAS, one KRAS), and three of 18 had multiple alterations (NRAS + TP53, n = 1; NRAS + PTEN, n = 2). BRAF T599_R603 + EIF1AX mutation (n = 1), PTEN mutation (n = 1), MET overexpression (n = 1), PAX8/PPARG fusion (n = 3), and THADA/IGF2BP3 fusion (n = 3) comprised the remainder. Conclusions/UNASSIGNED:NIFTP cases most commonly displayed suspicious Afirma results and RAS mutations on ThyroSeq, lacking aggressive/BRAF-V600E-like mutations. While NIFTP remains a surgical entity, the lack of aggressive/BRAF-V600E-like mutations can aid in determining the extent of surgery.

Oral cancer is often painful and lethal. Oral cancer progression and pain may result from shared pathways that involve unresolved inflammation and elevated levels of pro-inflammatory cytokines. Resolvin D-series (RvDs) are endogenous lipid mediators derived from omega-3 fatty acids that exhibit pro-resolution and anti-inflammatory actions. These mediators have recently emerged as a novel class of therapeutics for diseases that involve inflammation; the specific roles of RvDs in oral cancer and associated pain are not defined. The present study investigated the potential of RvDs (RvD1 and RvD2) to treat oral cancer and alleviate oral cancer pain. We found down-regulated mRNA levels of GPR18 and GPR32 (which code for receptors RvD1 and RvD2) in oral cancer cells. Both RvD1 and RvD2 inhibited oral cancer proliferation in vitro. Using two validated mouse oral squamous cell carcinoma xenograft models, we found that RvD2, the more potent anti-inflammatory lipid mediator, significantly reduced tumor size. The mechanism of this action might involve suppression of IL-6, C-X-C motif chemokine 10 (CXCL10), and reduction of tumor necrosis. RvD2 generated short-lasting analgesia in xenograft cancer models, which coincided with decreased neutrophil infiltration and myeloperoxidase activity. Using a cancer supernatant model, we demonstrated that RvD2 reduced cancer-derived cytokines/chemokines (TNF-α, IL-6, CXCL10, and MCP-1), cancer mediator-induced CD11b⁺Ly6G^- myeloid cells, and nociception. We infer from our results that manipulation of the endogenous pro-resolution pathway might provide a novel approach to improve oral cancer and cancer pain treatment.