Search

Background: Neck dissections (ND) are a routine procedure in head and neck oncology. Given the post-operative functional impact that some patients experience, it is imperative to identify and track quality of life (QoL) symptomatology in order to tailor each patient’s therapeutic needs. To date, there is no validated francophone questionnaire for this patient-population. We therefore sought to translate and validate the Neck Dissection Impairment Index (NDII) in French. Methods: A three-phased approach was used. Phase 1: The NDII was translated from English to French using a “forward and backward” translational technique following international guidelines. Phase 2: A cognitive debriefing session was held with ten French-speaking otolaryngology patients to evaluate understandability and acceptability. Phase 3: The final version was administered prospectively to 30 patients with prior history of ND and 30 control patients. These patients were asked to complete the questionnaire 2 weeks after their first response. Test-retest reliability was calculated with Spearman’s correlation. Internal consistency was elicited using Cronbach’s alpha. Results: NDII was successfully translated and validated to French. Cronbach’s alpha revealed high internal consistency (0.92, lower 95% CL 0.89). The correlation for test-retest validity were strong or very-strong (0.61-0.91). Conclusion: NDII is an internationally recognized QoL tool for the identification of ND-related impairments. This validated French version will allow clinicians to adequately assess the surgery-related QoL effect of neck surgery in the French-speaking population, while allowing French institutions to conduct and/or participate in multi-site clinical trials requiring the NDII as an outcome measure.

BackgroundDespite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development.Material and MethodsTwelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents.ResultsSeventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53.ConclusionsHTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.

Introduction Anaplastic thyroid cancer (ATC) is rare with a poor prognosis. There are no approved treatments for non-BRAF-mutated ATCs, leading to an unmet need. Phase II studies of single-agent lenvatinib or immunotherapy showed minimal benefit (lenvatinib: overall response rate (ORR) 2.9%, progression free survival (PFS) 2.6 months, overall survival (OS) 3.2 months; spartalizumab: ORR 19%, PFS 1.7 months, OS 5.9 months). Synergism between lenvatinib and pembrolizumab (L/P) has been reported. We sought to assess the efficacy and safety of L/P in ATC. Methods Thisis a retrospective, single-center study of ATC patients treated with L/P, between 1/2015-10/2021. L/P had to be started before first restaging. Those with pembrolizumab added at the time of progression on lenvatinib alone were excluded. The endpoints were ORR and PFS (primary) and OS and safety (secondary). Response evaluation was assessed by a single radiologist using RECIST v1.1. Treatment start date was the date of either lenvatinib or pembrolizumab initiation. Results 18 patients were included: 61% men; median age 64; initial stage: IVA (17%), IVB (11%), IVC (72%); common distant metastases: lung (83%), mediastinum (39%), bone (22%). Previous therapies: surgery (78%), chemoradiation (39%), cytotoxic chemotherapy (11%), palliative neck radiation (17%), BRAF-targeted therapy (6%), and immunotherapy (6%). All patients had mutation testing, and the common included TP53 (67%), PTEN (50%), TERTp (39%), NF1 (28%), RAS (22%), PIK3CA (17%), BRAF-V600E (6%). 11/12 tested tumors had a PDL-1 score >1%. Lenvatinib was started at 14-24 mg daily. With respect to lenvatinib, pembrolizumab was started from -14 to +49 days (median +6 days) at a fixed dose of 200 mg every 3 weeks. ORR was evaluable in 12 patients (outside hospital restaging scans unavailable in 6 patients): 1/12 (8%) confirmed complete response, 7/12 (58%) partial response (3 confirmed), 2/12 (17%) stable disease, and 2/12 (17%) progressive disease. The median PFS was 4.1 months (95% CI, 2.2 to NA), with treatment durations ranging from 0.5-33.5 months. The median OS of the 18 patients was 6.2 months (95% CI, 4.6 to NA). Respective 12-month PFS and OS rates were 25% and 22%. Grade III/IV toxicities were fatigue (22%); anorexia, weakness, arthralgia, dry mouth, pneumonitis (6%, each). AEs leading to death were pulmonary hemorrhage (17%), gastrointestinal bleed, pulmonary embolism (6%, each). Lenvatinib dose reduction, interruption, and discontinuation rates were 28%, 6%, and 28%, respectively. Pembrolizumab dose interruption and discontinuation rates were 6% and 11%, respectively. Conclusions The combination L/P had an ORR of 66%. Although most responses were short-lived, a quarter of patients benefited for more than 1 year. The ORR, PFS, and OS were better than lenvatinib alone. The toxicity profile was as expected. Our results represent the largest single-institution experience thus far with L/P in ATC and warrant further investigation (NCT04171622). Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

BACKGROUND: Lactate dehydrogenase (LDH) is a critical metabolic enzyme. LDH A (LDHA) overexpression is a hallmark of aggressive malignancies and has been linked to tumour initiation, reprogramming and progression in multiple tumour types. However, successful LDHA inhibition strategies have not materialised in the translational and clinical space. We sought to develop a rational strategy for LDHA suppression in the context of solid tumour treatment. METHODS: We utilised a doxycycline-inducible short hairpin RNA (shRNA) system to generate LDHA suppression. Lactate and LDH activity levels were measured biochemically and kinetically using hyperpolarised (13)C-pyruvate nuclear magnetic resonance spectroscopy. We evaluated effects of LDHA suppression on cellular proliferation and clonogenic survival, as well as on tumour growth, in orthotopic models of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), alone or in combination with radiation. RESULTS: shRNA suppression of LDHA generated a time-dependent decrease in LDH activity with transient shifts in intracellular lactate levels, a decrease in carbon flux from pyruvate into lactate and compensatory shifts in metabolic flux in glycolysis and the Krebs cycle. LDHA suppression decreased cellular proliferation and temporarily stunted tumour growth in ATC and HNSCC xenografts but did not by itself result in tumour cure, owing to the maintenance of residual viable cells. Only when chronic LDHA suppression was combined with radiation was a functional cure achieved. CONCLUSIONS: Successful targeting of LDHA requires exquisite dose and temporal control without significant concomitant off-target toxicity. Combinatorial strategies with conventional radiation are feasible as long as the suppression is targeted, prolonged and non-toxic.

Utilization of biologic skin substitutes for the management of soft tissue defects as an alternative to autologous skin grafts has expanded over the past 2 decades. The purpose of this case series study was to report our experience with Integra® bilayer wound matrix for reconstruction of intraoral oncologic defects. Case records of 6 patients with intraoral oncologic defects reconstructed with Integra® bilayer wound matrix were retrospectively reviewed. The surgical defect location, size, and time to removal of surgical splint varied. Clinically, normal oral epithelialization was noted for all patients. One patient demonstrated a small area of dehiscence and bone exposure after adjuvant radiation therapy which resolved with minimal intervention. Integra bilayer wound matrix is a viable and versatile option for reconstruction of intraoral oncologic surgical defects. Further exploration of wound healing with Integra® matrix, surgical techniques, and cost‐effectiveness is advocated., Integra® bilayer wound matrix is a viable and versatile option for reconstruction of small to large intraoral oncologic surgical defects on movable and nonmoveable mucosa.

Author(s): MD Anderson Head and Neck Surgery Treatment Guidelines Consortium; Consortium members; Maniakas, Anastasios; Jozaghi, Yelda; Zafereo, Mark E; Sturgis, Erich M; Su, Shirley Y; Gillenwater, Ann M; Gidley, Paul W; Lewis, Carol M; Diaz, Eduardo; Goepfert, Ryan P; Kupferman, Michael E; Gross, Neil D; Hessel, Amy C; Pytynia, Kristen B; Nader, Marc-Elie; Wang, Jennifer R; Lango, Miriam N; Kiong, Kimberley L; Guo, Theresa; Zhao, Xiao; Yao, Christopher MKL; Appelbaum, Eric; Alpard, Jennifer; Garcia, Jose A; Terry, Shawn; Flynn, Jill E; Bauer, Sarah; Fournier, Danielle; Burgess, Courtlyn G; Wideman, Cayla; Johnston, Matthew; You, Chenxi; De Luna, Rolando; Joseph, Liza; Diersing, Julia; Prescott, Kaitlin; Heiberger, Katherine; Mugartegui, Lilian; Rodriguez, Jessica; Zendehdel, Sara; Sellers, Justin; Friddell, Rebekah A; Thomas, Ajay; Khanjae, Sonam J; Schwarzlose, Katherine B; Chambers, Mark S; Hofstede, Theresa M; Cardoso, Richard C; Wesson, Ruth Aponte; Won, Alex; Otun, Adegbenga O; Gombos, Dan S; Al-Zubidi, Nagham; Hutcheson, Katherine A; Gunn, G Brandon; Rosenthal, David I; Gillison, Maura L; Ferrarotto, Renata; Weber, Randal S; Hanna, Ehab Y; Myers, Jeffrey N; Lai, Stephen Y | Abstract: BackgroundCOVID-19 pandemic has strained human and material resources around the world. Practices in surgical oncology had to change in response to these resource limitations, triaging based on acuity, expected oncologic outcomes, availability of supportive resources, and safety of health care personnel.MethodsThe MD Anderson Head and Neck Surgery Treatment Guidelines Consortium devised the following to provide guidance on triaging head and neck cancer (HNC) surgeries based on multidisciplinary consensus. HNC subsites considered included aerodigestive tract mucosa, sinonasal, salivary, endocrine, cutaneous, and ocular.RecommendationsEach subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred.ConclusionThese guidelines are intended to help clinicians caring for patients with HNC appropriately allocate resources during a health care crisis, such as the COVID-19 pandemic. We continue to advocate for individual consideration of cases in a multidisciplinary fashion based on individual patient circumstances and resource availability.

Background TMPRSS2, ACE2 and TMPRSS11D are genes coding for proteins necessary for SARS-CoV-2 activation, infection and transmission. Once SARS-CoV-2 enters the host cell, it leads to an exaggerated inflammatory state of the lungs mediated by overexpressed TNF-, IL-6, and IL-1β. We assessed azithromycin's effect on the aforementioned genes and their associated pathways to evaluate its potential use as a possible treatment. Objective Confirm the role azithromycin may play in the regulation of pathways and genes involved in inflammation and SARS-CoV-2 activation and cell-to-cell transmission. Methods Primary airway nasal epithelial cells collected from nasal biopsies of three patients with chronic rhinosinusitis (CRS) were primary cultured and treated or not with 10µg of azithromycin. RNA was extracted from these samples and analyzed using a microarray chip. Differential gene expression profiles and gene set enrichment analysis (GSEA) were obtained between both groups. Results Cell cultures treated with 10µg of azithromycin significantly downregulated receptor-mediated endocytosis canonical pathways involving TMPRSS2 and TMPRSS11D genes. Downregulated inflammation-associated genes included IL-1β and NDST1. Interestingly, numerous genes in the cholesterol biosynthesis pathway were significantly upregulated as part of a potential process named drug-induced phospholipidosis (DLP). Conclusions This proof of concept demonstrates azithromycin downregulates pathways involving serine proteases TMPRSS2 and TMPRSS11D required for SARS-CoV-2 activation and its cell-to-cell transmission while downregulating pro-inflammatory cytokine IL-1β, NDST-1 and their associated pathways. This may help reduce the characteristic excessive respiratory epithelial inflammation, key feature of SARS-CoV-2 infection. Finally, azithromycin may also decrease available cholesterol in lipid rafts which may hinder SARS-CoV-2 infection.

IMPORTANCE: Anaplastic thyroid carcinoma (ATC) historically has a 4-month median overall survival (OS) from time of diagnosis, with disease-specific mortality approaching 100%. The association between recent major advancements in treatment and OS has yet to be evaluated. OBJECTIVE: To evaluate rates of OS in patients with ATC over the last 2 decades. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study in a single tertiary care institution. Patients with histopathological confirmation of ATC from January 2000 to October 2019 were included and divided into 3 groups according to date of presentation: 2000-2013, 2014-2016, and 2017-2019. MAIN OUTCOMES AND MEASURES: Overall survival compared among different treatment eras and differing therapies, including targeted therapy, immunotherapy, and surgery. RESULTS: Of 479 patients (246 men [51%]; median age, 65.0 [range, 21.1-92.6] years) with ATC evaluated, 52 (11%) were stage IVA, 172 (36%) stage IVB, and 255 (53%) stage IVC at presentation. The median OS of the entire cohort was 0.79 years (9.5 months), ranging from 0.01 to 16.63. The OS at 1 and 2 years was 35% (95% CI, 29%-42%) and 18% (95% CI, 13%-23%) in the 2000-2013 group (n = 227), 47% (95% CI, 36%-56%) and 25% (95% CI, 17%-34%) in the 2014-2016 group (n = 100), and 59% (95% CI, 49%-67%) and 42% (95% CI, 30%-53%) in the 2017-2019 group (n = 152), respectively (P

Objective Rhinoliquorrhea is defined as a cerebrospinal fluid leakage from the nose. Our objective in this study is to determine the reduction of rhinoliquorrhea rates by Eustachian tube (ET) obliteration in the context of a translabyrinthine approach performed following vestibular schwannoma (VS) excision. Materials and methods This is a prospective study achieved in a tertiary-care center where the chart review revealed 94 VS operated by the translabyrinthine approach between 2009 and 2015. There were 40 males and 54 females aged from 28-76 years. The only exclusion criterion was a previous history of cranial surgery. ET obliteration was systematically executed when the petrous apex pneumatization level was at least 2 of 4. Our main outcome measure was the development of rhinoliquorrhea. Results Eighty-eight patients underwent ET obliteration and were followed for an average of 2.6±1.2 years. Rhinoliquorrhea was reported in 1.14% of the patients having had an ET obliteration. When compared to our previous sample of patients operated with a translabyrinthine approach, it represents a reduction of 84%. Conclusion Obliteration of the ET is a fast and simple procedure that reduces the rate of rhinoliquorrhea. We therefore recommend its use, specifically in cases of petrous apex pneumatization levels 2-4.

Background: Well-differentiated thyroid cancer (DTC) presents at a more advanced stage in men than in women, and the mortality in men is higher than that in women. However, it is not clear whether ...

Background Anaplastic thyroid cancer (ATC) is a rare, aggressive, and deadly disease. Robust pre-clinical models are needed to adequately develop and study novel therapeutic agents. Patient-derived xenograft (PDX) models are thought to closely resemble patient tumors by preserving the tumor microenvironment, making them excellent pre-clinical models for drug response evaluation. We used two distinct ATC PDX models and evaluated drug response following a high-throughput screening (HTS). Methods A HTS, using NCI's Approved Oncology Set V (n=112) and a custom collection of agents (n=145), was conducted on patient-derived thyroid cancer cell lines. To identify the most effective drugs, we selected individual agents with maximal growth inhibition at each dose level relative to wells examined on the day of treatment (top 25th percentile) and subsequently used non-parametric statistics to compare effect size with other drugs and controls. This allowed us to identify classes of systemic agents which demonstrated preferential effectiveness against ATC cell lines and certain mutations. Following our prior successful work on orthotopic xenograft models, we used two established ATC PDX models, HOSC68 and HOSC199, harboring distinct genetic profiles and expanded each of them into 50 athymic mice. HOSC68 has a BRAFV600E and a TP53 mutation, while HOSC199 is wild-type for both genes, but has an HRAS mutation. Equal pieces of 4 × 4mm of tumor were transplanted subcutaneously at the level of the right flank. Following tumor growth, the mice were separated into four treatment arms. All mice received their treatment intraperitoneally following standard drug administration schedules. Tumor volume was measured on the first day of treatment and every two to three days thereafter until trial completion (14 days). Drug response was analyzed by evaluating percent tumor growth inhibition (TGI). Mouse weight was recorded over time to evaluate treatment toxicity. Following treatment completion, tumors were surgically retrieved and evaluated morphologically and histologically. Results Microtubule inhibitors, antimetabolites, and HDAC inhibitors were some of the most effective drug classes identified against ATC cell lines. Specifically, in this study, mice were treated with control (CTR), Docetaxel (DOC)-microtubule inhibitor, Pralatrexate (PRA)-antimetabolite, and LBH-589 (LBH)-HDAC inhibitor. Forty-four HOSC68 and 43 HOSC199 mice successfully grew tumor and were included in the trial. Compared to CTR, HOSC68 mice treated with DOC showed a 37% TGI (p=0.04), 88% with PRA (p&lt0.001), and 83% with LBH (p&lt0.001), while HOSC199 mice had a 2% TGI with DOC (p=0.56), 76% with PRA (p=0.005), and 83% with LBH (p=0.002). PRA and LBH were significantly more toxic than DOC and CTR (p&lt0.001) in HOSC68 mice, while all three drugs were significantly more toxic than CTR in the HOSC199 mice (p&lt0.001). Conclusion We report the first large-scale evaluation of drugs identified through a HTS analysis on ATC PDX models. This trial demonstrates the feasibility of using this platform for in vivo drug testing, while providing an avenue for future drug testing and resistance evaluation, as well as personalized therapeutics development. Citation Format: Anastasios Maniakas, Abdallah S. Mohamed, Ying C. Henderson, Hu Hei, Shaohua Peng, Diana Bell, Michelle D. Williams, Steve Scherer, David A. Wheeler, Gary L. Clayman, Mark Zafereo, Jennifer R. Wang, Maria E. Cabanillas, Clifford Stephan, Faye M. Johnson, Stephen Y. Lai. In vivo drug response evaluation in anaplastic thyroid cancer patient-derived tumor xenografts following high-throughput screening [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1662.

BACKGROUND: Symptoms of Eustachian tube (ET) dysfunction are seldom assessed in patients with chronic rhinosinusitis (CRS). The Sino-Nasal Outcome Test (SNOT-22) quality-of-life tool includes two questions that specifically screen for symptoms of ET dysfunction (Ear Fullness; Ear Pain). OBJECTIVE: The purpose of this study was to determine the extent to which these ET symptoms were present in patients with CRS, and whether these symptoms respond to endoscopic sinus surgery (ESS). METHODOLOGY: SNOT-22 data collected prospectively at time of recruitment into IRB-approved clinical trials or case-control studies in CRS was pooled to provide a cross section of the frequency and severity of ET dysfunction. When applicable to the trials, the SNOT-22 was repeated at least 3 months following ESS. RESULTS: Five trials rendering 131 patients were available for assessment. The control group comprised of 251 participants from two case-control studies. Ear Fullness of equal/greather than 1 was reported in 80/131 CRS patients compared to 45/251 control patients. Ear Pain of equal/greather than 1 was reported in 39/131 CRS patients compared to 33/251 control patients. Following ESS, mean Ear Fullness and Ear Pain scores decreased to 1.17 and 0.73, respectively. CONCLUSION: Symptoms suggestive of ET dysfunction are frequent in CRS, and for most patients the symptoms will decrease post-ESS to a level comparable with a non-CRS population. Patients whose ET symptoms do not respond to ESS may represent a target population for emerging therapeutic options for ET dysfunction.

Background Superior canal dehiscence (SCD) is a benign condition in which a surgical treatment may be considered depending on the patients’ tolerance of their symptoms. In this study, we aim to identify driving factors behind the patients’ choice of a surgical management over watchful waiting. Methods Sixty-two patients with cochlear and/or vestibular symptoms and a temporal bone high-resolution CT (HRCT) scan showing SCD were included in the study. All patients have been offered either surgical management or watchful waiting. Results Of these, 28 elected surgery and 34 declined it. The operated group showed more cochlear (6.6 vs. 2.4) symptoms than the non-operated group (P < 0.001) except for hypoacousis, but no significant difference (P = 0.059) was found for the number of vestibular symptoms between both groups (3.4 vs. 1.1). Footstep and eating hyperacousis were both present in 57.1% of operated vs. 3% of non-operated patients (P < 0.001). Oscillopsia with effort and with walking was found in 50% and 35.7% of operated patients, respectively, but none in the non-operated group (P < 0.001). Hearing tuning fork at malleolus and Valsalva and pneumatic speculum induced vertigo showed a statistically significant difference between the two groups (P = 0.003, P < 0.001, P = 0.010 respectively). Cervical vestibular-evoked myogenic potential (cVEMP) thresholds, air and bone conduction thresholds, and mean air-bone gap (ABG) were similar in the two populations (P > 0.05). The average dehiscence size was 4.7 mm (2.0 - 8.0 mm) and 3.8 mm (1.3 - 7.7 mm) in the operated and non-operated patients, respectively (P = 0.421). Conclusions The natures of cochleovestibular signs and symptoms were shown to be key factors in patients’ choice of a surgical management whereas paraclinical tests seem to be less significant in the patients’ decision for a surgical treatment.