Faculty Bibliography

PURPOSE/OBJECTIVE:Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the maximum tolerated dose (MTD)/Recommended phase 2 Dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection. EXPERIMENTAL DESIGN/METHODS:) for 7-10 days pre-operatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts. RESULTS:for 21 and 28 days, respectively. Steady state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations and CSF samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range: 2.22- 53.4). CONCLUSIONS:Ribociclib and everolimus were well tolerated and demonstrated similar pharmacokinetic properties as in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.

Although malpositioning of the cochlear implant (CI) electrode array is rare in patients with normal anatomy, when occurring it may result in reduced hearing outcome. In addition to intraoperative electrophysiologic tests, imaging is an important modality to assess correct electrode array placement. The purpose of this report was to assess the incidence and describe cases in which intraoperative plain radiographs detected a malpositioned array. Intraoperative anti-Stenver"™s view plain X-rays are conducted routinely in all CI surgeries in our tertiary center before awakening the patient and breaking the sterile field. Data of patients undergoing 399 CI surgeries were retrospectively analyzed. A total of 355 had normal inner ear and temporal bone anatomy. Patients with intra or extracochlear malpositioned electrode arrays demonstrated in the intraoperative X-ray were described. There were four cases of electrode array malposition out of 355 implantations with normal anatomy (1.1%): two tip fold-overs, one extracochlear placement and one partial insertion. All electrodes were reinserted immediately; repeated radiographs were normal and the patients achieved good hearing function. Intraoperative plain anti-Stenver"™s view X-rays are valuable to confirm electrode array location, allowing correction before the conclusion of surgery. These radiographs are cheaper, faster, and emit much less radiation than other imaging options, making them a viable cost-effective tool in patients with normal anatomy.

Purpose: This research aimed to perform an overview on adjuvant vaginal brachytherapy (VBT) in stage I to II endometrial carcinoma (EC) according to ESMO-ESGO-ESTRO risk group consensus in China from multi-institutional analysis.Materials and Methods: We retrospectively analyze patients with stage I to II EC at 13 institutions in China treated between 2003 and 2015. All patients underwent adjuvant radiotherapy and were divided into low-risk (LR), intermediate-risk (IR), high-intermediate risk (HIR) and high-risk (HR) groups according to ESMO-ESGO-ESTRO risk group consensus. XXResult(s): A total of 1048 cases were included. Stage I disease accounted for 85.9% of the cohort. Proportion of HR disease was 27.6%, HIR 17.7%, IR 27.7% and LR 27.1%. Patients received adjuvant VBT alone (n = 474), pelvic external beam radiotherapy (EBRT) alone (n = 116) or combined EBRT with VBT (n = 458). An increasing trend was found toward referrals for VBT alone. Historical data demonstrate that the clinical practice of adjuvant VBT alone increased significantly in the LR to HIR groups over the past 13 years. However, in the HR group, the proportion of VBT alone or as a boost after EBRT stayed stable in the corresponding period.All institutions commonly use High-dose-rate VBT prescribed to 0.5-cm depth from the vaginal surface with 14 and 17 different dose-fractionation schedules for VBT alone and VBT boost, respectively. The most common fractionation for VBT alone is 5 Gy in six fraction (407/474) and the most common fractionation for VBT as a boost after EBRT is 5 Gy in two fractions (178/458). Proximal 2-3 cm vagina was the most often irradiated vaginal target (61.3%). The most commonly used applicators were the multichannel vaginal cylinder (79.6%). The median follow-up time was 56 months. For LR to HIR patients, VBT alone achieved comparable survival to EBRT. Compared to EBRT, patients receiving VBT had significantly decreased incidence of grade 1-2 early and late gastrointestinal and urinary reactions, and the rate of grade 3-4 acute hematological toxicity. XXConclusion(s): There is remarkable heterogeneity among VBT dose-fractionation schedules. An increasing trend was found toward referrals for VBT alone. The clinical practice of adjuvant VBT alone increased significantly in LR to HIR groups over the past 13 years. In LR to HIR group, VBT alone achieved comparable survival to EBRT.XXCopyright

Background/UNASSIGNED:One frequent consequence of radiation therapy (RT) for head and neck cancer (HNC) is weight loss (WL). HNC patients reportedly lose about 9% of their weight during treatment, regardless of pre-treatment WL and nutritional support. We investigated whether high WL during RT has an association with overall (OS) and cancer-specific survival (CSS). Methods/UNASSIGNED:We retrospectively reviewed weight during RT in HNC patients treated at Roswell Park Comprehensive Cancer Center between 2003 and 2017. High WL was defined as greater than or equal to the median WL. Logistic regression analysis was performed to identify predictors for WL during RT. Multivariate Cox regression and Kaplan-Meier analyses were used to estimate survival outcomes. Propensity score matching was performed to obtain balanced matched-pairs and compare survival outcomes. Results/UNASSIGNED:A total of 843 patients received either definitive (71%) or post-operative (29%) RT. Median follow-up was 53.6 months [interquartile range (IQR) 35.7-88.9]. Median WL was 5.8% (IQR 0.24-10.6) from baseline weight. Patients with high WL had better OS [hazard ratio (HR) 0.75, 95% confidence interval (CI), 0.61-0.93, P=0.01] and CSS (HR 0.71, 95% CI, 0.55-0.93, P=0.01). 258 matched-pairs were analyzed. Median follow-up was 54.8 months (IQR 35.8-90.4). Median OS was 39.2 months (IQR 21.4-75.7) for high WL versus 36.7 months (IQR 14.6-61.7) for low WL cohorts (P=0.047). Conclusions/UNASSIGNED:Different from previous reports, this study shows that patients with less WL have worse OS. WL during RT may not be a reliable marker for worse prognosis. A better way to evaluate malnutrition in patients undergoing RT is warranted.

OBJECTIVES/HYPOTHESIS:Thyroid cancer with distant metastasis (TCDM) at diagnosis has significantly worse survival rates when compared to localized/regional thyroid cancer. This study sought to report on the characteristics of patients presenting with TCDM and the potential survival advantage of surgical resection. STUDY DESIGN:Data were acquired from the Surveillance, Epidemiology, and End Results (SEER) database with cases from 2004 to 2015. METHODS:TCDM cases (n = 2,558) were identified from the SEER database. The Bonferroni correction was applied for multivariate analysis. Kaplan-Meier analysis was utilized to obtain disease-specific survival (DSS) rates. Cox regression analysis was utilized to identify independent factors significantly associated with survival. RESULTS:The average age of diagnosis of TCDM was 62.0 (±17.5) years. Patients were predominantly white (74.6%), female (54.6%), in a relationship (56.0%), and between ages 36 and 80 years (76.4%). Cases consisted of papillary (57.2%), follicular (16.0%), medullary (8.9%), anaplastic (17.9%) TCDM histological variants. Overall 1-, 5-, and 10-year DSS rates were 72.0%, 56.8%, and 43.8%, respectively. Anaplastic and medullary variants had the worst 10-year DSS (0% and 25.5%, respectively). Patients who underwent surgical resection only and surgical resection with radiation were 49% and 59% less likely to die, respectively. Treatment, age, histology, T staging, relationship status, and metastasis site were determined to be significant predictors of survival. CONCLUSIONS:Surgical resection with radiation was found to be a significant predictor of survival after applying the Bonferroni correction for all thyroid cancer variants except medullary. To increase survival, surgical intervention should be recommended in patients who are deemed to be medically tolerant of surgery. LEVEL OF EVIDENCE:4 Laryngoscope, 131:1026-1034, 2021.

Introduction.In vitro experimentation is intentionally contrived to isolate specific phenomena in the context of profound biological complexity. Mycoplasmas in the upper airway likely contribute to this complexity and play a largely unknown role in both health and disease. Similarly, the presence and role of mycoplasma in in vitro investigation are largely unknown.Hypothesis. We hypothesize mycoplasma in human vocal fold fibroblasts (VFF) will affect both basal gene-expression patterns as well as the cell response to exogenous stimuli.Aim. We sought to determine mycoplasma presence across vocal fold fibroblast cultures, basal transcriptional changes as a function of mycoplasma, and responsiveness to exogenous glucocorticoids in mycoplasma-positive and -negative VFF.Methodology. PCR-based mycoplasma detection was performed in an immortalized human VFF line as well as rat and rabbit primary VFF cultures and extracted rat laryngeal tissue. RNA sequencing was performed in mycoplasma-positive and -negative human cells at baseline and in response to dexamethasone.Results. Mycoplasma was identified in the human cell line as well as primary culture from rabbits. Mycoplasma was not detected in tissue or primary culture from rat vocal folds. Basal mRNA expression in human VFF differed significantly following mycoplasma treatment. In addition, differential responses to dexamethasone were observed across multiple pathways as a function of mycoplasma presence in these cells. Pathways including apoptosis, DNA damage repair, and G1 to S cell cycle signalling were significantly enriched in mycoplasma-positive cells.Conclusion. Variability of mycoplasma presence across culture conditions and differential responses to exogenous stimuli as a function of mycoplasma presence are potentially problematic for the translation of in vitro experimentation in the upper aerodigestive tract. It remains unclear if these findings represent contamination or the baseline state of this specialized tissue.

Background/UNASSIGNED:To compare head and neck cancer (HNC) patients treated with three-weekly versus weekly cisplatin-based or other chemotherapy-based concurrent chemoradiation (CRT) and CRT with versus without induction chemotherapy (ICT) to investigate differences in overall survival (OS) and cancer-specific survival (CSS). Methods/UNASSIGNED:HNC patients treated with definitive or adjuvant CRT at Roswell Park Comprehensive Cancer Center between 2003 and 2017 were retrospectively reviewed. Propensity score matching was performed to obtain three sets of balanced matched pairs: three-weekly and weekly cisplatin CRT, three weekly and non-cisplatin CRT, CRT with and without ICT. Multivariate Cox regression and Kaplan-Meier analyses were used to estimate and compare survival outcomes. Results/UNASSIGNED:64.7%, P=0.45). Conclusions/UNASSIGNED:No significant difference in OS and CSS was observed in any of the three pairs of CRT regimens. ICT prior to CRT did not improve survival of CRT alone. Non-cisplatin and weekly cisplatin regimens did not prove to be inferior to the standard three-weekly cisplatin.

The application of exercise science training knowledge has been of growing interest to voice professionals. This tutorial, derived from the authors' invited presentations from the "Exercise and the Voice" Special Session at the 2018 Voice Foundation Symposium, proposes a foundational theoretical structure based in exercise science, clarifies the wide range of variables that may influence voice training, and summarizes our present understanding of voice physiology from the perspective of muscle training. The body of literature on voice exercise was then analyzed from the perspective of this framework, identifying what we currently know and what we still have yet to learn.

Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.