Faculty Bibliography

Background/UNASSIGNED:While effective for the repair of large skull base defects, the Hadad-Bassagasteguy nasoseptal flap increases operative time and can result in a several-week period of postoperative crusting during re-mucosalization of the denuded nasal septum. Endoscopic transsphenoidal surgery for pituitary adenoma resection is generally not associated with large dural defects and high-flow cerebrospinal fluid (CSF) leaks requiring extensive reconstruction. Here, we present the posterior nasoseptal flap as a novel technique for closure of skull defects following endoscopic resection of pituitary adenomas. This flap is raised in all surgeries during the transnasal exposure using septal mucoperiosteum that would otherwise be discarded during the posterior septectomy performed in binostril approaches. Methods/UNASSIGNED:We present a retrospective, consecutive case series of 43 patients undergoing endoscopic transsphenoidal resection of a pituitary adenoma followed by posterior nasoseptal flap placement and closure. Main outcome measures were extent of resection and postoperative CSF leak. Results/UNASSIGNED:The mean extent of resection was 97.16 ± 1.03%. Radiographic measurement showed flap length to be adequate. While a defect in the diaphragma sellae and CSF leak were identified in 21 patients during surgery, postoperative CSF leak occurred in only one patient. Conclusions/UNASSIGNED:The posterior nasoseptal flap provides adequate coverage of the surgical defect and is nearly always successful in preventing postoperative CSF leak following endoscopic transsphenoidal resection of pituitary adenomas. The flap is raised from mucoperiosteum lining the posterior nasal septum, which is otherwise resected during posterior septectomy. Because the anterior septal cartilage is not denuded, raising such flaps avoids the postoperative morbidity associated with the larger Hadad-Bassagasteguy nasoseptal flap.

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.

The auditory system can theoretically encode frequencies by either the rate or place of stimulation within the cochlea. Previous work with cochlear implants has demonstrated that both changes in timing and place can be described as pitch changes but are perceptually orthogonal. Using multidimensional scaling, the present experiment extends the previous findings that timing and place changes are perceptually orthogonal into the cochlear apex using long 31-mm electrode arrays. However, temporal cues seem to be more reliable across subjects at the apex while place cues seem to be more reliable at the middle of the cochlea.

Myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to evolve into accelerated and blast-phase disease (MPN-AP/BP), carrying a dismal prognosis. Conventional antileukemia therapy has limited efficacy in this setting. Thus, MPN-AP/BP is an urgent unmet clinical need. Modest responses to hypomethylating agents and single-agent ruxolitinib have been reported. More recently, combination of ruxolitinib and decitabine has demonstrated synergistic in vitro activity in human and murine systems. These observations led us to conduct a phase 1 study to explore the safety of combined decitabine and dose-escalated ruxolitinib in patients with MPN-AP/BP. A total of 21 patients were accrued to this multicenter study. Ruxolitinib was administered at doses of 10, 15, 25, or 50 mg twice daily in combination with decitabine (20 mg/m² per day for 5 days) in 28-day cycles. The maximum tolerated dose was not reached. The most common reasons for study discontinuation were toxicity/adverse events (37%) and disease progression (21%). Fourteen patients died during study treatment period or follow-up. The median overall survival for patients on study was 7.9 months (95% confidence interval, 4.1-not reached). Among evaluable patients, the overall response rate by protocol-defined criteria (complete remission with incomplete count recovery + partial remission) was 9/17 (53%) and by intention-to-treat analysis was 9/21 (42.9%). The combination of decitabine and ruxolitinib was generally well tolerated by patients with MPN-AP/BP and demonstrates potentially promising clinical activity. A phase 2 trial evaluating the efficacy of this combination regimen is ongoing within the Myeloproliferative Disorder Research Consortium.

Afirma GSC utilizes RNA sequencing and machine-learning algorithms to classify cytologically indeterminate thyroid nodules into benign (B) and suspicious (S) categories. Detection of genomic variants and fusions was recently expanded beyond BRAF V600E and RET/PTC1&3 by the Xpression Atlas (XA), which identifies 761 nucleotide variants and 130 fusion gene pairs in 511 genes. Here we used XA to analyze the mutational spectrum of 190 Bethesda III/IV nodules with gold standard histologic diagnoses.190 nodules previously collected in a prospective multicenter blinded trial design were analyzed with the XA.Among the 145 histologically benign nodules, 35 (24%) contained a variant or fusion (XA+). In the 99 benign nodules with GSC-B results there were 15 (15%) with XA variants and none with a fusion. These variants were 7 TSHR, 3 SPOP, 2 EIF1AX, 1 PTEN, 1 TSHR + EZH1, and 1 GNAS. In the 46 benign nodules with GSC-S results, 18 (39%) harbored a variant and 2 (4%) a fusion. There were 9 NRAS, 6 HRAS, 2 TSHR, and 1 SPOP. Two had a PAX8/PPRARG fusion. Among the 45 histologically malignant nodules (41 GSC-S; 91% sensitivity), 22 were XA+ (49% sensitivity). In the 41 malignant nodules with GSC-S results, there were 19 variants (46%) and 2 fusions (5%). The variants were 9 NRAS, 3 HRAS, 3 BRAF V600E, 1 SPOP, 1 KRAS + EIF1AX, 1 EIF1AX, and 1 BRAF K601E. Fusions were BRAF/MKRN1 and 1 ETV6/NTRK3. In the 4 GSC-B false negative nodules (2 PTC, 1 fvPTC, 1HCC), only theHCCcontained a variant (TSHR). In 190 thyroid nodules with definitive histology, malignant nodules were twice as likely to be XA+ than benign nodules (49% vs 24%, p = 0.003 [v2]). Although GSC-S nodules were nearly 3 times more likely than GSC-B nodules to be XA+ (47% vs 16%, p < 0.0001), the PPV for malignancy did not differ among all GSC-S, GSC-S XA+, and GSC-S XA-nodules (47%, 51%, and 43%, respectively; p = 0.77). When XA+, GSC S nodules expressed mainly RAS variants, and GSC B nodules predominantly TSHR variants. Conversely, the NPV for XA was 83%. These findings support GSC as better than XA to rule-out cancer while the addition of XA to GSC-S nodules may provide additional insights into pathway activation and potential cancer treatment targets

Measuring how the brain encodes and processes an animal's own motion presents major technical challenges. New approaches demonstrate the viability and merit of measuring vestibular responses throughout the entire brain.

DICER1 encodes an endoribonuclease involved in microRNA maturation and therefore has an important role in gene transcript regulation. Germline mutations scattered along DICER1 are associated with DICER1 syndrome which prominently features thyroid nodules. The tumors typically carry a second, somatic mutation in the RNase IIIb catalytic domain, referred to as "hotspot." These hotspot mutations occur in*1-2% of thyroid papillary carcinomas (PTC). The incidence of the hotspot mutations in thyroid nodules in adults, their association with malignancy and with other, germline DICER1 mutations remain largely unknown. We analyzed 6,734 consecutive clinical FNA samples from typically indeterminate cytology thyroid nodules for hotspot DICER1mutations using ThyroSeq v3 targeted next generation sequencing (NGS) assay from 11/2017-05/2018. Available follow-up was collected. A subgroup of cases underwent full DICER1 coding region and exon-intron boundaries analysis using a custom Fluidigm Access Array followed by NGS on Illumina MiSeq. Somatic DICER1 hotspot mutations were identified in 135 (2.0%) of nodules, with D1810H/V/Y and D1709G/E/N being most common. Median patient age was 37 years (range 19-79 y), 93% were females. Follow-up was available for 27 patients: 15 underwent surgery with benign diagnoses in 9 cases, NIFTP in 5 and follicular variant PTC in 1. Twelve patients were managed non-surgically, including one with a stable nodule harboring DICER1mutation at an allele frequency unchanged over 10 years between FNAs. A subset of 11 positive cases was tested for alteration in the entire DICER1 gene, which confirmed the hotspot mutations in 10 and detected additional alterations in 9 (90%), including non-hotspot mutations in 8 and LOH in 1 case. We report for the first time that likely somatic hotspot DICER1 mutations are relatively common and found in*2% of thyroid nodules in adults, who are typically mid-age women. At surgery, most of these nodules are benign, with*33% risk of NIFTP and*7% risk of follicular variant PTC. Our analysis also shows that somatic hotspot mutations are usually accompanied by a second, loss of function DICER1 mutation, which may in some cases be germline in nature

Evidence-based reviews of drugs causing medication-induced salivary gland dysfunction, such as xerostomia (sensation of oral dryness) and subjective sialorrhea are lacking. To compile a list of medicaments that influence salivary gland function, electronic databases were searched for relevant articles published up to June 2013. A total of 269 papers out of 3,867 records located satisfied the inclusion criteria (relevance, quality of methodology, strength of evidence). A total of 56 active substances with a higher level of evidence and 50 active substances with a moderate level of evidence of causing salivary gland dysfunction are described in this article. While xerostomia was a commonly reported outcome, the objective effect on salivary secretion was rarely measured. Xerostomia was, moreover, mostly reported as a negative side effect instead of the intended effect of that drug. A comprehensive list of medications having documented effects on salivary gland function or symptoms was compiled, which may assist practitioners in assessing patients who complain of dry mouth while taking medications