Faculty Bibliography

BACKGROUND:A major concern of patients who have stereotactic radiosurgery is the long-term risk of having a secondary intracranial malignancy or, in the case of patients with benign tumours treated with the technique, the risk of malignant transformation. The incidence of stereotactic radiosurgery-associated intracranial malignancy remains unknown; therefore, our aim was to estimate it in a population-based study to assess the long-term safety of this technique. METHODS:We did a population-based, multicentre, cohort study at five international radiosurgery centres (Na Homolce Hospital, Prague, Czech Republic [n=2655 patients]; Ruber International Hospital, Madrid, Spain [n=1080], University of Pittsburgh Medical Center, Pittsburgh, PA, USA [n=1027]; University of Virginia, Charlottesville, VA, USA [n=80]; and NYU Langone Health System, New York, NY, USA [n=63]). Eligible patients were of any age, and had Gamma Knife radiosurgery for arteriovenous malformation, trigeminal neuralgia, or benign intracranial tumours, which included vestibular or other benign schwannomas, WHO grade 1 meningiomas, pituitary adenomas, and haemangioblastoma. Patients were excluded if they had previously had radiotherapy or did not have a minimum follow-up time of 5 years. The primary objective of the study was to estimate the incidence of stereotactic radiosurgery-associated intracranial malignancy, including malignant transformation of a benign lesion or development of radiation-associated secondary intracranial cancer, defined as within the 2 Gy isodose line. Estimates of age-adjusted incidence of primary CNS malignancies in the USA and European countries were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS) and the International Agency for Research on Cancer (IARC) Global Cancer statistics. FINDINGS/RESULTS:Of 14 168 patients who had Gamma Knife stereotactic radiosurgery between Aug 14, 1987, and Dec 31, 2011, in the five contributing centres, 4905 patients were eligible for the analysis (had a minimum follow-up of 5 years and no history of previous radiation therapy). Diagnostic entities included vestibular schwannomas (1011 [20·6%] of 4905 patients), meningiomas (1490 [30·4%]), arteriovenous malformations (1089 [22·2%]), trigeminal neuralgia (565 [11·5%]), pituitary adenomas (641 [13·1%]), haemangioblastoma (29 [0·6%]), and other schwannomas (80 [1·6%]). With a median follow-up of 8·1 years (IQR 6·0-10·6), two (0·0006%) of 3251 patients with benign tumours were diagnosed with suspected malignant transformation and one (0·0002%) of 4905 patients was considered a case of radiosurgery-associated intracranial malignancy, resulting in an incidence of 6·87 per 100 000 patient-years (95% CI 1·15-22·71) for malignant transformation and 2·26 per 100 000 patient-years (0·11-11·17) for radiosurgery-associated intracranial malignancy. Two (0·0004%) of 4905 patients developed intracranial malignancies, which were judged unrelated to the radiation field. Overall incidence of radiosurgery-associated malignancy was 6·80 per 100 000 patients-years (95% CI 1·73-18·50), or a cumulative incidence of 0·00045% over 10 years (95% CI 0·00-0·0034). The overall incidence of 6·8 per 100 000, which includes institutions from Europe and the USA, after stereotactic radiosurgery was found to be similar to the risk of developing a malignant CNS tumour in the general population of the USA and some European countries as estimated by the CBTRUS and IARC data, respectively. INTERPRETATION/CONCLUSIONS:These data show that the estimated risk of an intracranial secondary malignancy or malignant transformation of a benign tumour in patients treated with stereotactic radiosurgery remains low at long-term follow-up, and is similar to the risk of the general population to have a primary CNS tumour. Although prospective cohort studies with longer follow-up are warranted to support the results of this study, the available evidence suggests the long-term safety of stereotactic radiosurgery and could support physicians counselling patients on Gamma Knife stereotactic radiosurgery. FUNDING/BACKGROUND:None.

OBJECTIVE:To assess the impact of implementing a dedicated Patient Safety and Quality Improvement (PSQI) curriculum for otolaryngology residents. METHODS:Residents in two otolaryngology residency programs were recruited to participate in the study. Residents at institution A (intervention group) participated in a formal, newly developed, year-long PSQI curriculum. Residents at institution B (control group) participated in traditional, morbidity, and mortality conference-based PSQI education, with no formal curriculum in place. Curriculum participants completed anonymous surveys to assess learner satisfaction. Validated instruments were administered to assess for changes in resident confidence in the ability to develop PSQI projects, their attitudes toward patient safety, and PSQI-related knowledge. The number and quality of PSQI-related resident projects were also assessed. RESULTS:Survey responses demonstrated excellent learner satisfaction with the curriculum. Based on validated instrument-based responses, both programs demonstrated similar confidence scores (P = 0.05), safety attitudes (P = 0.82), and PSQI knowledge (P = 0.29) at the beginning of the year. The residents of institution A demonstrated significant improvement in confidence (P = 0.00009) and knowledge (P = 0.0006) after completing the curriculum, with no improvement noted for residents at institution B in either confidence (P = 0.06) or knowledge (P = 0.79). Neither program demonstrated improvement in attitudes toward patient safety at the end of the year-long curriculum. CONCLUSION/CONCLUSIONS:Implementing a formal curriculum dedicated to PSQI led to an improvement in PSQI-related project development confidence and PSQI knowledge. Attitudes toward safety did not improve over the course of a year. Longer-term studies involving multiple institutions and other interventions are needed to evaluate the impact and duration of changes that occur. LEVEL OF EVIDENCE/METHODS:1b. Laryngoscope, 2018.

Introduction/UNASSIGNED:Inhalation injury is an independent risk factor in burn mortality, imparting a 20% increased risk of death. Yet there is little information on the natural history, functional outcome, or pathophysiology of thermal injury to the laryngotracheal complex, limiting treatment progress. Methods/UNASSIGNED:Case series (n=3) of significant thermal airway injury. Results/UNASSIGNED:In all cases, the initial injury was far exceeded by the subsequent immune response and aggressive fibro-inflammatory healing. Serial examination demonstrated progressive epithelial injury, mucosal inflammation, airway remodeling, and luminal compromise. Histologic findings in the first case demonstrate an early IL-17A response in the human airway following thermal injury. This is the first report implicating IL-17A in the airway mucosal immune response to thermal injury. Our 2nd and 3rd patients received Azithromycin targeting IL-17A and showed clinical responses. The third patient also presented with exposed tracheal cartilage and underwent mucosal reconstitution via split-thickness skin graft over an endoluminal stent in conjunction with tracheostomy. This was associated with rapid abatement of mucosal inflammation, resolution of granulation tissue and return of laryngeal function. Conclusion/UNASSIGNED:Patients who present with thermal inhalation injury should receive a thorough multidisciplinary airway evaluation, including early otolaryngologic evaluation. New early endoscopic approaches (scar lysis, and mucosal reconstitution with autologous grafting over an endoluminal stent), when combined with targeted medical therapy aimed at components of mucosal airway inflammation (local corticosteroids and systemic Azithromycin targeting IL-17A) may have potential to limit chronic cicatricial complications.

BACKGROUND:Awareness of disease status has been identified as a factor in the treatment decision-making process. Women with recurrent ovarian cancer are facing the challenge of making treatment decisions throughout the disease trajectory. It is not understood how women with ovarian cancer perceive their disease and subsequently make treatment decisions. PURPOSE/OBJECTIVE:The purpose of this phenomenological study was to understand the lived experience of women with recurrent ovarian cancer, how they understood their disease and made their treatment decisions. METHODS:A qualitative design with a descriptive phenomenological method was used to conduct 2 in-depth interviews with 12 women (n = 24 interviews). Each interview was ∼60 minutes and was digitally recorded and professionally transcribed. Data collection focused on patients' understanding of their disease and how patients participated in treatment decisions. A modified version of Colaizzi's method of phenomenological reduction guided data analysis. RESULTS:Three themes emerged to describe the phenomenon of being aware of disease status: (1) perceiving recurrent ovarian cancer as a chronic illness, (2) perceived inability to make treatment decisions, and (3) enduring emotional distress. CONCLUSIONS AND IMPLICATIONS/CONCLUSIONS:This study revealed how 12 women conceptualized recurrent ovarian cancer as a chronic disease and their perceived inability to make treatment decisions because of lack of information and professional qualifications, resulting in enduring emotional distress. Future research should replicate the study to confirm the persistence of the themes for racially, ethnically, and religiously diverse patient samples and to improve understanding of awareness of disease status and decision-making processes of patients.

OBJECTIVES/OBJECTIVE:Adequate treatment of laryngopharyngeal malignancy often incorporates radiation therapy. Structures surrounding laryngopharynx exposed to traditional radiation doses are susceptible to posttreatment toxicity. Among poorly understood sequelae is the rare manifestation of sternoclavicular joint (SCJ) osteoradionecrosis (ORN). METHODS:Three institutional encounters prompted a comprehensive literature search, generating three published case reports. Systematic extraction and analysis (n = 6) of demographics, cancer history, comorbidities, ORN presentation, imaging, and management established the largest series to investigate this pathology. RESULTS:Patients were males (6), 54 to 70 years old, smokers (4), with Hypertension/dyslipidemia, myocardial infarction/coronary artery disease, second primary (2), diabetes mellitus (1), and myelofibrosis(1). Four underwent total laryngectomy, one primary, three as salvage. Five patients had concurrent chemoradiation (≥70 Gy). All patients presented with swollen, tender neck wounds concerning for persistent/recurrent malignancy. Computed tomography (CT) demonstrated bone erosion (5 of 5) and increased bone scan uptake (2 of 2). All responded to surgical exploration with drainage alone (1), sequestrectomy (2), or bone resection with synovectomy (3). Complete healing took 2 months to 3 years. One unrelated patient death occurred before control of ORN was achieved. DISCUSSION/CONCLUSIONS:Given varied patient characteristics, synergistic risk factors exist that alter bone radiation threshold, resulting in irreversible ischemic damage and osteoradionecrosis. Vascular susceptibility and inability to repair may regulate that threshold. Understanding this relationship will facilitate early detection and intervention. CONCLUSION/CONCLUSIONS:Integrating cases of sternoclavicular joint ORN promotes awareness of atypical laryngopharyngeal radiation complications, elucidates contributing factors, educates physicians on presentation and management, and provides a platform for prospective investigation. LEVEL OF EVIDENCE/METHODS:4. Laryngoscope, 2018.

Tissue inelasticity and the hair-bearing nature of the scalp and forehead pose unique challenges during reconstruction. A thorough understanding of the surgical anatomy of the scalp and forehead is paramount for optimal reconstructive outcomes. Primary wound closure is usually preferred over secondary intention healing and skin grafting. Use of dermal alternatives and tissue expansion are adjunctive therapies to facilitate scalp wound closure. Local skin and soft tissue flaps are commonly used for most small to medium defects; however, microsurgical free tissue transfer can be considered for large full-thickness skin defects of the forehead and scalp.

OBJECTIVES/OBJECTIVE:In-office or operative injection laryngoplasty requires needle stability for accurate material placement. To date, no reports compare injection forces based on needle gauge, bends, length, or material type or temperature. We hypothesize these factors alter injection forces and could impact clinical use. METHODS:Swine larynges were placed in a compression testing machine. Syringes were affixed to a stabilizing crossbeam. Straight needles (25G 1.5-inch; 27G 1.25-inch; or 9.8-inch malleable shaft 16G per oral with 24G tapered needle tip) were inserted into the swine vocal folds to simulate realistic tissue resistance pressure. Compressive loading was conducted at 40 mm/minute until steady-state force was achieved. Tests were completed with calcium hydroxylapatite (CaHa), carboxymethylcellulose, and hyaluronic acid at various temperatures and CaHa with various bends in the needles (n = 3 per group, comparisons performed by two-way analysis of variance (ANOVA), Tukey's post-hoc). RESULTS:Needle size, shape, and temperature altered injection force. Steady-state force was highest with the per-oral needle at a mean of 44.55N compared to 26.44N and 29.77N in the 25G and 27G percutaneous needles, respectively (P < 0.001). Stiffness rate (initial increasing force vs. distance to initiate injection) ranged from 19.75N/mm (per oral) to 22.06N/mm (25G) to 24.56N/mm (27G), (P = 0.875). Adding multiple bends to the per-oral needle increased stiffness rate to 24.99N/mm (P = 0.035), whereas the 25G needle stiffness rate remained unchanged (P = 0.941), with the stiffness rate decreasing in the 27G needle with increasing bends (P = 0.033). Increased temperature decreased injection forces across all materials. CONCLUSION/CONCLUSIONS:Needle caliber, length, and bends impact steady-state forces and stiffness rates during vocal fold injection. LEVEL OF EVIDENCE/METHODS:NA. Laryngoscope, 2018.

PURPOSE/OBJECTIVE:Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct glioma molecular subtype for which no effective molecularly-directed therapy exists. Low-grade gliomas, which are 80-90% IDH mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by immunohistochemistry in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in IDH mutant glioma. EXPERIMENTAL DESIGN/METHODS:We evaluated DLL3 expression by RNA using TCGA data and by immunohistochemistry in a discovery set of 63 gliomas and 20 non-tumor brain tissues and a validation set of 62 known IDH wildtype and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous IDH mutant glioma tumorspheres was determined by cell viability assay. RESULTS:Compared to IDH wildtype glioblastoma, IDH mutant gliomas have significantly higher DLL3 RNA (P<1x10-15) and protein by immunohistochemistry (P=0.0014 and P<4.3x10-6 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner. CONCLUSIONS:DLL3 is selectively and homogeneously expressed in IDH mutant gliomas and can be targeted with Rova-T in patient-derived IDH mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.

Bone cancer metastasis is extremely painful and decreases the quality of life of the affected patients. Available pharmacological treatments are not able to sufficiently ameliorate the pain and as cancer patients are living longer new treatments for pain management are needed. Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferases inhibitor, has analgesic properties in pre-clinical models of post-surgical and soft tissue oral cancer pain by inducing an up-regulation of endogenous opioids. In this study, we report that daily treatment with decitabine (2µg/g, i.p.) attenuated nociceptive behavior in the 4T1-luc2 mouse model of bone cancer pain. We hypothesized that the analgesic mechanism of decitabine involved activation of the endogenous opioid system through demethylation and reexpression of the transcriptionally silenced endothelin B receptor gene, Ednrb. Indeed, Ednrb was hypermethylated and transcriptionally silenced in the mouse model of bone cancer pain. We demonstrated that expression of Ednrb in the cancer cells lead to release of β-endorphin in the cell supernatant which reduced the number of responsive DRG neurons in an opioid-dependent manner. Our study supports a role of demethylating drugs, such as decitabine, as unique pharmacological agents targeting the pain in the cancer microenvironment.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Various animal models have been employed to investigate vocal fold (VF) and phonatory function. However, biomechanical testing techniques to characterize vocal fold structural properties vary and have not compared critical properties across species. We adapted a nondestructive, automated indentation mapping technique to simultaneously quantify VF structural properties (VF cover layer and intact VF) in commonly used species based on the hypothesis that VF biomechanical properties are largely preserved across species. STUDY DESIGN/METHODS:Ex vivo animal model. METHODS:Canine, leporine, and swine larynges (n = 4 each) were sagittally bisected, measured, and subjected to normal indentation mapping (indentation at 0.3 mm; 1.2 mm/s) with a 2-mm spherical indenter to quantify normal force along the VF cover layer, structural stiffness, and displacement at 0.8 mN; two-dimensional maps of the free VF edge through the conus elasticus were created for these characterizations. RESULTS:Structural stiffness was 7.79 gf/mm (0.15-74.55) for leporine, 2.48 gf/mm (0.20-41.75) for canine, and 1.45 gf (0.56-4.56) for swine. For each species, the lowest values were along the free VF edge (mean ± standard deviation; leporine: 0.40 ± 0.21 gf/mm, canine: 1.14 ± 0.49 gf/mm, swine: 0.89 ± 0.28 gf/mm). Similar results were obtained for the cover layer normal force at 0.3 mm. On the free VF edge, mean (standard deviation) displacement at 0.08 gf was 0.14 mm (0.05) in leporine, 0.11 mm (0.03) in canine, and 0.10 mm (0.02) in swine. CONCLUSIONS:Automated indentation mapping yielded reproducible biomechanical property measurement of the VF cover and intact VF. Divergent VF structural properties across canine, swine, and leporine species were observed. LEVEL OF EVIDENCE/METHODS:NA. Laryngoscope, 2018.