Faculty Bibliography

This article discusses complications that may occur after procedures on the lips, specifically focusing on injectable fillers. Evidence-based guidelines and suggested methods to manage these complications are presented in a systematic format.

We introduce a real-time capable algorithm which estimates the long-term signal to noise ratio (SNR) of the speech in multi-talker babble noise. In real-time applications, long-term SNR is calculated over a sufficiently long moving frame of the noisy speech ending at the current time. The algorithm performs the real-time long-term SNR estimation by averaging "speech-likeness" values of multiple consecutive short-frames of the noisy speech which collectively form a long-frame with an adaptive length. The algorithm is calibrated to be insensitive to short-term fluctuations and transient changes in speech or noise level. However, it quickly responds to non-transient changes in long-term SNR by adjusting the duration of the long-frame on which the long-term SNR is measured. This ability is obtained by employing an event detector and adaptive frame duration. The event detector identifies non-transient changes of the long-term SNR and optimizes the duration of the long-frame accordingly. The algorithm was trained and tested for randomly generated speech samples corrupted with multi-talker babble. In addition to its ability to provide an adaptive long-term SNR estimation in a dynamic noisy situation, the evaluation results show that the algorithm outperforms the existing overall SNR estimation methods in multi-talker babble over a wide range of number of talkers and SNRs. The relatively low computational cost and the ability to update the estimated long-term SNR several times per second make this algorithm capable of operating in real-time speech processing applications.

BACKGROUND: There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a ?hypermutator phenotype?. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily trans- formed IDH-mutant GBMs. Safety-lead-in results will be presented.
METHOD(S): This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE.
RESULT(S): Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5-54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade >= 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade <= 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4-5.7). Median OS was 10.1 (range 6.8-21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual.
CONCLUSION(S): Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen

BACKGROUND: While most hemangioblastomas (~70%) are sporadic and occur predominantly in the cerebellum, they may present as well as familial form associated with von Hippel-Lindau (VHL) syndrome, an autosomal dominant disorder caused by germline mutations of the VHL gene that trigger nuclear translocation of hypoxia-inducible factor (HIF)- 1alpha and angiogenesis. Although inactivation of VHL, a tumor suppressor gene, has been observed in hemangioblastomas, the underlying pathogenic mechanisms responsible for familial and sporadic hemangioblastomas remain incompletely understood.
METHOD(S): Whole exome sequencing of cerebellar hemangioblastoma tumors and matched blood leukocytes from 24 patients, age 24-63, was performed. After preparation and amplification of barcoded libraries, exomes were captured using Kapa Biosystems methodology and paired-end sequenced on Illumina HiSeq 2500 to an average 100-fold coverage. Following read alignment to hg19 genome, tumor and germline (leukocyte) sequences were compared, and pathogenic single nucleotide variants (SNVs) identified and validated by re-sequencing followed by pathway analysis. Additionally, tumor RNA isolated using Maxwell Promega was sequenced on Illumina instrument and the expression counts determined and normalized.
RESULT(S): We found 314 pathogenic and/or highly deleterious mutations (both germline and somatic) with a median of 13 mutations per patient. Five patients had VHL syndrome (germline VHL mutation) and 4 carried somatic VHL mutations. Among the VHL tumors, 82 mutations were identified, including HNF1B, NOTCH1 and TCF7L1, suggesting a potential contribution of altered RNA metabolism based upon pathway analysis. Among all hemangioblastomas, germline growth factor receptor variants (FGFR4 p.G388R (14/23 (61%) patients), IGF1R, PDGFRA and TYK2) known to activate STAT3 signaling and induce HIF-1alpha and angiogenesis, were identified. Non-hierarchical clustering of RNA sequencing data revealed two transcriptionally-distinct subtypes of hemangioblastomas.
CONCLUSION(S): Our findings indicate that hemangioblastomas can also occur by germline mutations known to activate STAT3 signaling, which may have significant implication in genetic testing and counseling of patients with hemangioblastomas

OBJECTIVES/OBJECTIVE:The application of laser (light amplification by stimulated emission of radiation) energy in the larynx relies on thermal injury. The impact of this injury on adjacent tissue can be undesirable. Attempts have been made to limit the extent and range of injury to adjacent tissue. The O-Pel Surgical System (Precise Light Surgical, Inc., Campbell, CA), a new technology, utilizes kinetic energy through Pressure Induced Tissue Resection (PITR) (Precise Light Surgical, Inc.) to cut tissue, theoretically eliminating injury to adjacent tissue. The purpose of this study was to evaluate the PSL in canine vocal folds. METHODS:Four dogs underwent PITR incisions (4 mJ pulses at 200 Hz) on their vocal folds, through mucosa into the muscle. The animals were sacrificed at days 0, 3, 7, and 21 days postsurgery. The larynges were harvested and histology was performed with hematoxylin and eosin, Masson trichrome, and Verhoeff-van Gieson. RESULTS:At day 0, focal denudation of the epithelium and coagulation necrosis in the lamina propria and adjacent connective tissue are noted. On days 3 and 7, an inflammatory infiltrate of neutrophils is seen within the lamina propria and surrounding connective tissue with minimal edema and early deposition of collagen. At day 21, the mucosa is completely regenerated with the area of previous PITR into the muscle replaced with thick bundles of collagen. CONCLUSION/CONCLUSIONS:The unique PITR characteristics offer a potentially unique cutting technology for laryngeal microsurgery. The current canine study suggests appropriate and rapid healing. With refinements of the tip size of the probe and adjustment of energy, PITR will likely be an appropriate alternate to traditional lasers in laryngeal surgery. LEVEL OF EVIDENCE/METHODS:NA. Laryngoscope, 2019.

Importance/UNASSIGNED:Surgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research. Objective/UNASSIGNED:To prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease. Design, Setting, and Participants/UNASSIGNED:In this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook. Main Outcomes and Measures/UNASSIGNED:The primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications. Results/UNASSIGNED:Of 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n = 603; 74.4%), ERMT (n = 121; 14.9%), and CTR (n = 86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score-matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk. Conclusions and Relevance/UNASSIGNED:In this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in patients with ET/PV previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC) 111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET/PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rate ORR (CR / PR) at 12 months was 69.2% (43.1% / 26.2%) in ET, and 60% (22%/38%) in PV patients. CR rates were higher in CALR mutated ET patients (56.5% vs. 28.0%, p= 0.01) as compared to subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction (VAF) was -6% (range -84%-47%) in patients achieving a CR versus +4% (range -18%-56%) in patients with PR/non-response (NR). Therapy was associated with a significant rate of adverse events (AE), most were manageable, and PEG discontinuation due to AEs occurred only in 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET/PV who were previously refractory and/or intolerant to HU. (ClinicalTrials.gov Identifier: NCT01259856).

Transient periods of childhood hearing loss can induce deficits in aural communication that persist long after auditory thresholds have returned to normal, reflecting long-lasting impairments to the auditory central nervous system. Here, we asked whether these behavioral deficits could be reversed by treating one of the central impairments: reduction of inhibitory strength. Male and female gerbils received bilateral earplugs to induce a mild, reversible hearing loss during the critical period of auditory cortex development. After earplug removal and the return of normal auditory thresholds, we trained and tested animals on an amplitude modulation detection task. Transient developmental hearing loss induced both learning and perceptual deficits, which were entirely corrected by treatment with a selective GABA reuptake inhibitor (SGRI). To explore the mechanistic basis for these behavioral findings, we recorded the amplitudes of GABA_A and GABA_B receptor-mediated inhibitory postsynaptic potentials (IPSPs) in auditory cortical and thalamic brain slices. In hearing loss-reared animals, cortical IPSP amplitudes were significantly reduced within a few days of hearing loss onset, and this reduction persisted into adulthood. SGRI treatment during the critical period prevented the hearing loss-induced reduction of IPSP amplitudes, but when administered after the critical period it only restored GABA_B receptor-mediated IPSP amplitudes. These effects were driven, in part, by the ability of SGRI to upregulate α1 subunit-dependent GABA_A responses. Similarly, SGRI prevented the hearing loss-induced reduction of GABA_A and GABA_B IPSPs in the ventral nucleus of the medial geniculate body. Thus, by maintaining, or subsequently rescuing, GABAergic transmission in the central auditory thalamocortical pathway, some perceptual and cognitive deficits induced by developmental hearing loss can be prevented.SIGNIFICANCE STATEMENTEven a temporary period of childhood hearing loss can induce communication deficits that persist long after auditory thresholds return to normal. These deficits may arise from long-lasting central impairments, including the loss of synaptic inhibition. Here, we asked whether hearing loss-induced behavioral deficits could be reversed by reinstating normal inhibitory strength. Gerbils reared with transient hearing loss displayed both learning and perceptual deficits. However, when animals were treated with a selective GABA reuptake inhibitor during or after hearing loss, behavioral deficits were entirely corrected. This behavioral recovery was correlated with the return of normal thalamic and cortical inhibitory function. Thus, some perceptual and cognitive deficits induced by developmental hearing loss were prevented with a treatment that rescues a central synaptic property.

Mature locomotion requires that animal nervous systems coordinate distinct groups of muscles. The pressures that guide the development of coordination are not well understood. To understand how and why coordination might emerge, we measured the kinematics of spontaneous vertical locomotion across early development in zebrafish (Danio rerio) . We found that zebrafish used their pectoral fins and bodies synergistically during upwards swims. As larvae developed, they changed the way they coordinated fin and body movements, allowing them to climb with increasingly stable postures. This fin-body synergy was absent in vestibular mutants, suggesting sensed imbalance promotes coordinated movements. Similarly, synergies were systematically altered following cerebellar lesions, identifying a neural substrate regulating fin-body coordination. Together these findings link the vestibular sense to the maturation of coordinated locomotion. Developing zebrafish improve postural stability by changing fin-body coordination. We therefore propose that the development of coordinated locomotion is regulated by vestibular sensation.