Faculty Bibliography

Importance/UNASSIGNED:Data regarding outcomes after major head and neck ablation and reconstruction in the growing geriatric population (specifically ≥80 years of age) are limited. Such information would be extremely valuable in preoperative discussions with elderly patients about their surgical risks and expected functional outcomes. Objectives/UNASSIGNED:To identify patient and surgical factors associated with 30-day postoperative complications, 90-day mortality, and 90-day functional decline; to explore whether an association exists between the type of reconstructive procedure and outcome; and to create a preoperative risk stratification system for these outcomes. Design, Setting, and Participants/UNASSIGNED:This retrospective, multi-institutional cohort study included patients 80 years or older undergoing pedicle or free-flap reconstruction after an ablative head and neck surgery from January 1, 2015, to December 31, 2017, at 17 academic centers. Data were analyzed from February 1 through April 20, 2019. Main Outcomes and Measures/UNASSIGNED:Thirty-day serious complication rate, 90-day mortality, and 90-day decline in functional status. Preoperative comorbidity and frailty were assessed using the American Society of Anesthesiologists classification, Adult Comorbidity Evaluation-27 score, and Modified Frailty Index. Multivariable clustered logistic regressions were performed. Conjunctive consolidation was used to create a risk stratification system. Results/UNASSIGNED:Among 376 patients included in the analysis (253 [67.3%] men), 281 (74.7%) underwent free-flap reconstruction. The median age was 83 years (range, 80-98 years). A total of 193 patients (51.3%) had 30-day serious complications, 30 (8.0%) died within 90 days, and 36 of those not dependent at baseline declined to dependent status (11.0%). Type of flap (free vs pedicle, bone vs no bone) was not associated with these outcomes. Variables associated with worse outcomes were age of at least 85 years (odds ratio [OR] for 90-day mortality, 1.19 [95% CI 1.14-1.26]), moderate or severe comorbidities (OR for 30-day complications, 1.80 [95% CI, 1.34-2.41]; OR for 90-day mortality, 3.33 [95% CI, 1.29-8.60]), body mass index (BMI) of less than 25 (OR for 30-day complications, 0.95 [95% CI, 0.91-0.99]), high frailty (OR for 30-day complications, 1.72 [95% CI, 1.10-2.67]), duration of surgery (OR for 90-day functional decline, 2.94 [95% CI, 1.81-4.79]), flap failure (OR for 90-day mortality, 3.56 [95% CI, 1.47-8.62]), additional operations (OR for 30-day complications, 5.40 [95% CI, 3.09-9.43]; OR for 90-day functional decline, 2.94 [95% CI, 1.81-4.79]), and surgery of the maxilla, oral cavity, or oropharynx (OR for 90-day functional decline, 2.51 [95% CI, 1.30-4.85]). Age, BMI, comorbidity, and frailty were consolidated into a novel 3-tier risk classification system. Conclusions and Relevance/UNASSIGNED:Important demographic, clinical, and surgical characteristics were found to be associated with postoperative complications, mortality, and functional decline in patients 80 years or older undergoing major head and neck surgery. Free flap and bony reconstruction were not independently associated with worse outcomes. A novel risk stratification system is presented.

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis¹. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC^2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

Nanoparticle-mediated drug delivery is especially useful for targets within endosomes because of the endosomal transport mechanisms of many nanomedicines within cells. Here, we report the design of a pH-responsive, soft polymeric nanoparticle for the targeting of acidified endosomes to precisely inhibit endosomal signalling events leading to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK₁R) redistributes from the plasma membrane to acidified endosomes, where it signals to maintain pain. Therefore, the NK₁R in endosomes provides an important target for pain relief. The pH-responsive nanoparticles enter cells by clathrin- and dynamin-dependent endocytosis and accumulate in NK₁R-containing endosomes. Following intrathecal injection into rodents, the nanoparticles, containing the FDA-approved NK₁R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. Treatment with the nanoparticles leads to complete and persistent relief from nociceptive, inflammatory and neuropathic nociception and offers a much-needed non-opioid treatment option for chronic pain.

OBJECTIVE:To examine the relationships among self-assessment of knowledge in otology via an individualized learning plan (ILP), otology milestone achievement rate, and otolaryngology training exam (OTE) otology scores. STUDY DESIGN/METHODS:Prospective study. SETTING/METHODS:One otolaryngology residency covering a tertiary care facility, trauma and hospital center, outpatient ambulatory surgery center, and outpatient clinics. PARTICIPANTS/METHODS:Twenty otolaryngology residents, four from each class. METHODS:Residents identified four milestones from otology-related sub-competencies to achieve in a 3-month rotation via an ILP. During the same rotation, the residents sat for the OTE, and their overall and otology scores were analyzed. MAIN OUTCOME MEASURES/METHODS:Completion of an ILP before and at the end of the rotation, self-reported achievement of otology milestones, and OTE score components including total percent correct, scaled score, group stanine, national stanine, and residency group weighted scores. RESULTS:Group stanine OTE otology scores were higher for those residents who completed pre- and post-rotation ILPs compared with those who did not, 4.0 (±0.348) versus 2.75 (±0.453), respectively (p = 0.04). Residents who self-reported achieving all four otology milestones had significantly higher otology group stanine scores than the residents who achieved less, 4.1 (±0.348) versus 2.9 ± 0.433, respectively (p = 0.045). Residents who performed well in their PGY program cohort on the otology OTE 1 year were less inclined to complete an ILP for otology in the subsequent year (Pearson correlation -0.528, p = 0.035). CONCLUSION/CONCLUSIONS:In the otology subspecialty, residents who completed ILPs scored better on OTE examinations independent of resident class. Consequently, programs may find ILPs useful in other otolaryngology subspecialties and across residencies.

OBJECTIVE:Currently no established criteria exist to guide use of ex utero intrapartum treatment (EXIT) for fetal neck mass management. This study aims to correlate prenatal radiographic findings with incidence of ex utero intrapartum treatment and necessity of airway intervention at delivery. METHODS:We reviewed our EXIT experience between 2012 and 17. Furthermore, we performed a literature review of articles reporting incidences of fetal neck masses considered for EXIT. Articles that were included (1) discussed prenatal radiographic findings such as size, features, and evidence of compression and (2) reported extractable data on delivery outcomes and airway status. RESULTS:Ten cases at our institution were reviewed. Another 137 cases across 81 studies met inclusion criteria. These studies showed aerodigestive tract compression to be significantly associated with neck masses undergoing EXIT. Additionally, there was significantly higher incidence of airway intervention in cases where polyhydramnios, anatomic compression, and solid masses were seen on prenatal diagnostic imaging, while mass location and size did not correlate with airway intervention. CONCLUSION/CONCLUSIONS:With this data, we propose that any neck mass with anatomic compression on fetal imaging in the 3rd trimester should be considered for EXIT. When radiographic findings do not show compression but do display polyhydramnios or a solid neck mass (regardless of polyhydramnios), an airway surgeon should be available for perinatal airway assistance.

We describe the use of minimally invasive trigeminal ablation, an endoscopic ablative technique to treat trigeminal neuralgia in patients who are traditionally poor surgical candidates. We present 4 patients who presented with refractory unilateral trigeminal neuralgia. Three of the patients had previously failed stereotactic radiosurgery and three of them have multiple sclerosis. Due either to lack of neurovascular compression, minimally invasive trigeminal ablation was offered. Intraoperatively, an incision is made along the buccal mucosa or mid-brow and the tissue is endoscopically dissected in a plane towards the symptomatic nerve. Once isolated, the epineurium is partially ablated with thermocautery and the tissue surrounding the nerve is decompressed. All patients reported resolution of their pain post-operatively and were pain free at last follow up. Two patients had mild hypesthesia over the ablated nerve territory. Minimally invasive trigeminal ablation is a safe and effective technique for symptomatic control of trigeminal neuralgia. The efficacy, low risk, and relative ease of the procedure makes it ideal for use in patients who are refractory to medical management and have no neurovascular compression, are unable to tolerate traditional surgery or have failed other therapies.

Objective/UNASSIGNED:were assayed to optimize siRNA-mediated alteration of gene expression. Methods/UNASSIGNED:-siRNA complex. Results/UNASSIGNED:-complexed Smad3 siRNA at 1 day postinjection. Qualitative suppression of Smad3 expression persisted to 3 days following injury, but did not achieve statistical significance. Conclusions/UNASSIGNED:yielded effective, yet temporally limited knockdown of Smad3 in vivo. Peptoids may provide a versatile platform for the discovery of siRNA delivery vehicles optimized for clinical application. Level of Evidence/UNASSIGNED:NA.

IDH1/2 mutations are early drivers present in diverse human cancer types arising in various tissue sites. IDH1/2 mutation is known to induce a global hypermethylator phenotype. However, the effects on DNA methylation across IDH mutant cancers and functionally different genome regions, remain unknown. We analyzed DNA methylation data from IDH1/2 mutant acute myeloid leukemia, oligodendroglioma, astrocytoma, solid papillary breast carcinoma with reverse polarity, sinonasal undifferentiated carcinoma and cholangiocarcinoma, which clustered by their embryonal origin. Hypermethylated common probes affect predominantly gene bodies while promoters in IDH1/2 mutant cancers remain unmethylated. Enhancers showed global hypermethylation, however commonly hypomethylated enhancers were associated with tissue differentiation and cell fate determination. We demonstrate that some chromosomes, chromosomal arms and chromosomal regions are more affected by IDH1/2 mutations while others remain resistant to IDH1/2 mutation induced methylation changes. Therefore IDH1/2 mutations have different methylation effect on different parts of the genome, which may be regulated by different mechanisms.