The protective role of postoperative radiation therapy in low and intermediate grade major salivary gland malignancies: A study of the Canadian Head and Neck Collaborative Research Initiative.

BACKGROUND: The objective of this study was to examine the utility of postoperative radiation for low and intermediate grade cancers of the parotid and submandibular glands. METHODS: The authors conducted a retrospective, Canadian-led, international, multi-institutional analysis of a patient cohort with low or intermediate grade salivary gland cancer of the parotid or submandibular gland who were treated from 2010 until 2020 with or without postoperative radiation therapy. A multivariable, marginal Cox proportional hazards regression analysis was performed to quantify the association between locoregional recurrence (LRR) and receipt of postoperative radiation therapy while accounting for patient-level factors and the clustering of patients by institution. RESULTS: In total, 621 patients across 14 tertiary care centers were included in the study; of these, 309 patients (49.8%) received postoperative radiation therapy. Tumor histologies included 182 (29.3%) acinic cell carcinomas, 312 (50.2%) mucoepidermoid carcinomas, and 137 (20.5%) other low or intermediate grade primary salivary gland carcinomas. Kaplan-Meier LRR-free survival at 10 years was 89.0% (95% confidence interval [CI], 84.9%-93.3%). In multivariable Cox regression analysis, postoperative radiation therapy was independently associated with a lower hazard of LRR (adjusted hazard ratio, 0.53; 95% CI, 0.29-0.97). The multivariable model estimated that the marginal probability of LRR within 10 years was 15.4% without radiation and 8.8% with radiation. The number needed to treat was 16 patients (95% CI, 14-18 patients). Radiation therapy had no benefit in patients who had early stage, low-grade salivary gland cancer without evidence of nodal disease and negative margins. CONCLUSIONS: Postoperative radiation therapy may reduce LLR in some low and intermediate grade salivary gland cancers with adverse features, but it had no benefit in patients who had early stage, low-grade salivary gland cancer with negative margins.

Development of a rational strategy for integration of lactate dehydrogenase A suppression into therapeutic algorithms for head and neck cancer.

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 13C-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.

Meta-analysis on the clinical outcomes in patients with intralabyrinthine schwannomas: conservative management vs. microsurgery.

The objective of this review is to compare the symptomatological evolution following conservative management (CM) or microsurgery (MS) in patients with intralabyrinthine schwannomas (ILS). A thorough systematic review of the English and French literature from 1948 to February 2014 was performed using Ovid Medline. An ancestor search was also completed. The major inclusion criterion consisted of a diagnosis of ILS with magnetic resonance imaging. Patients with a classic vestibular schwannoma, cases of incidentaloma during surgery or an autopsy were the main exclusion criteria. Thirty-one studies met our selective criteria. Descriptive data were collected from the articles. Clinical outcomes regarding the hearing loss, tinnitus, vertigo, dizziness and aural fullness were stated as improved, unchanged or worse at the last follow-up. All data were then separated into two different groups according to the management option: CM and MS. The data were analyzed using a Pearson χ (2) test and Fisher's exact test. This meta-analysis suggests that MS has a statistically significant favorable outcome regarding symptom relief compared to CM in patients with ILS suffering from tinnitus, vertigo and dizziness. Hearing level was not compared between treatment groups, as MS leads to anacusis. An indicative bias was the main limitation of this study, as patients suffering from intractable vertigo with moderate-to-severe hearing loss were referred to MS. Therefore, in the presence of a serviceable hearing, we suggest that CM should be the treatment of choice.

Delaying partial stapedectomy for otosclerosis: effects on long-term hearing outcomes following surgery.

The purpose of this study is to evaluate hearing outcomes following partial stapedectomy according to age at the time of surgery and evaluate functional hearing at ≥ 10 years' follow-up, and to assess the effect of delay in surgery on overall functional hearing outcomes. Data were collected from patients operated upon for otosclerosis by a single surgeon from 1990 to 1999. Pure-tone air (PTA), pure-tone bone (PTB), air-bone gap (ABG), air-conduction at 8 kHz (AC 8), bone-conduction at 4 kHz (BC4) and speech discrimination score (SDS) were compared between patients <45 and ≥ 45 years old, as well as correlated with overall age preoperatively, short term (4 months) and long term (>10 years), postoperatively. Forty-five patients were included with a mean follow-up of 12.6 years. Mean preoperative ABG and AC 8 values were significantly different between the two age groups (p = 0.002; p = 0.010, respectively). No values remained significantly different between the two age groups at the long-term follow-up. ABG values correlated with age preoperatively (p = 0.001), although no correlation was seen short- and long-term postoperatively (p = 0.980; p = 0.495, respectively). Mean PTA, PTB, and ABG values showed a significant improvement in both groups preoperatively to short-term postoperatively (p < 0.001). Although mean PTA values decreased significantly from short- to long-term follow-ups in both groups (p = 0.033; p = 0.020), the improvement from the preoperative state remained significant (p < 0.001). Regardless of age at the time of surgery, long-term hearing levels will evolve similarly in patients <45 and ≥ 45 years old. Furthermore, no difference will be seen in hearing measurements between the two age groups at ≥ 10 years postoperatively. Delaying a surgery would thus not affect overall long-term hearing outcomes.

Sentinel Lymph Node Biopsy Status Correlates with Postoperative Stimulated Thyroglobulin Levels in Low-risk Papillary Thyroid Cancer Patients.

OBJECTIVE: Radioactive iodine (RAI) remnant ablation in low-risk papillary thyroid cancer (PTC) is controversial. Current patient selection guidelines recommend the use of postoperative stimulated thyroglobulin (stim-Tg), neck dissections, and sonography but fail to include sentinel lymph node biopsy (SLNB). The objective of this study was to evaluate the correlation between SLNB status and postoperative stimulated thyroglobulin as a surrogate marker of clinical outcome. METHODS: Retrospective chart review of low-risk PTC patients who underwent a total thyroidectomy with SLNB at the McGill Thyroid Cancer Center. SLNBs were obtained using methylene blue dye. Biochemical measurements were acquired between 4 and 12 weeks postoperatively. Statistical analyses were performed using logistic regression models and receiver operating characterisitc (ROC) curves. A P-value <.05 was considered significant. RESULTS: Ninety-six patients were included in this study. The positive SLNB rate was 14.6%. The mean postoperative Tg level was 1.41 µg/L. There were no significant correlations between the SLNB and the covariates analyzed (age, gender, histology, tumor size, and thyrotropin levels). Patients with negative SLNB were significantly more likely to have a lower stim-Tg (P<.0001). When postoperative Tg was analyzed as a categorical variable, a threshold of <1 µg/L was significantly associated with a negative SLNB, with a sensitivity and specificity (determined by ROC curves) of 0.86 and 0.88, respectively. CONCLUSION: There exists a correlation between SLNB and postoperative Tg. This creates the possibility of a new approach to RAI administration among low-risk PTC patients incorporating SLNB to the current guidelines.

Superior canal dehiscence syndrome: clinical manifestations and radiologic correlations.

The objective of this study is to describe the superior canal dehiscence syndrome (SCDS) and its vestibule-cochlear manifestations, while analyzing dehiscence size, audiogram and vestibular-evoked myogenic potential (VEMP) changes following dehiscence obliteration. We conducted a prospective study in a tertiary referral center. All Patients diagnosed and surgically treated for SCDS were operated through a middle fossa craniotomy (MFC). Clinical and radiological data were collected. The main outcome measures were Air-bone gaps, Pure-tone average (PTA), speech discrimination scores (SDS) and VEMP thresholds and were correlated to dehiscence size. 28 patients were included in this study with a mean dehiscence size of 4.68 mm. Phonophobia and imbalance were the most debilitating cochlear and vestibular symptoms, respectively. At 2 months postoperatively, low-frequency air-bone gaps showed a statistically significant improvement (p < 0.001). SDS and PTA did not show any statistically significant changes 2 months postoperatively (p = 0.282 and p = 0.295, respectively). VEMP threshold differences between operated and contralateral ears were statistically significant preoperatively (p < 0.001) and non-significant 2 months postoperatively (p = 0.173). Dehiscence size only showed a statistically significant correlation with preoperative total cochlear symptoms, while remaining insignificant with all other variables measured. Air-bone gaps, VEMP and computerized tomography remain essential tools in diagnosing and following SCDS. Dehiscence size is an independent factor in the analysis of SCDS, with cochlear symptomatology being associated to dehiscence sizes. Finally, it is shown that overall symptomatology, audiometric results and VEMP thresholds return to normal values post-obliteration, confirming the continuing success of the MFC approach for SCDS obliteration.

Survival Outcomes of Temporal Bone Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

OBJECTIVE: Temporal bone squamous cell carcinoma (TBSCC) is a rare malignancy with poor prognosis, and optimal treatment for advanced cases is uncertain. Our systematic literature review aimed to assess 5-year survival outcomes for advanced TBSCC across different treatment modalities. DATA SOURCES: EMBASE, Medline, PubMed, and Web of Science. REVIEW METHODS: A systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for articles published between January 1989 and June 2023. RESULTS: The review yielded 1229 citations of which 31 provided 5-year survival data for TBSCC. The final analysis included 1289 patients. T classification data was available for 1269 patients and overall stage for 1033 patients. Data for 5-year overall survival (OS) was 59.6%. Five-year OS was 81.9% for T1/2 and 47.5% for T3/4 (P < .0001). OS for T1/T2 cancers did not significantly differ between surgery and radiation (100% vs 81.3%, P = .103). For advanced-stage disease (T3/T4), there was no statistical difference in OS when comparing surgery with postoperative chemoradiotherapy (CRT) (OS 50.0%) versus surgery with postoperative radiotherapy (XRT) (OS 53.3%) versus definitive CRT (OS 58.1%, P = .767-1.000). There was not enough data to assess the role of neoadjuvant CRT. CONCLUSION: Most patients will present with advanced-stage disease, and nodal metastasis is seen in nearly 22% of patients. This study confirms the prognostic correlation of the current T classification system. Our results suggest that OS did not differ significantly between surgery and XRT for early stage disease, and combined treatment modalities yield similar 5-year OS for advanced cancers.

Checkpoint Inhibition in Addition to Dabrafenib/Trametinib for BRAFV600E-Mutated Anaplastic Thyroid Carcinoma.

Background: The dabrafenib plus trametinib combination (DT) has revolutionized the treatment of BRAFV600E-mutated anaplastic thyroid carcinoma (BRAFm-ATC). However, patients eventually develop resistance and progress. Single-agent anti-PD-1 inhibitor spartalizumab has shown a median overall survival (mOS) of 5.9 months. Combination of immunotherapy with BRAF/MEK inhibitors (BRAF/MEKi) seems to improve outcomes compared with BRAF/MEKi alone, although no direct comparison is available. BRAF-targeted therapy before surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared with current standard-of-care DT alone as an initial treatment, as well as in the neoadjuvant setting. Methods: Retrospective single-center study of patients with BRAFm-ATC treated with first-line BRAF-directed therapy between January 2014 and March 2023. Three groups were evaluated: DT, DTP (pembrolizumab added upfront or at progression), and neoadjuvant (DT before surgery, and pembrolizumab added before or after surgery). The primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT versus DTP as initial treatments, and the exploratory endpoint was mOS in the neoadjuvant group. Results: Seventy-one patients were included in the primary analysis: n = 23 in DT and n = 48 in DTP. Baseline demographics were similar between groups, including the presence of metastatic disease at start of treatment (p = 0.427) and prior treatments with surgery (p = 0.864) and radiation (p = 0.678). mOS was significantly longer with DTP (17.0 months [confidence interval CI, 11.9-22.1]) compared with DT alone (9.0 months [CI, 4.5-13.5]), p = 0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [CI, 7.0-15.0]) compared with DT alone (4.0 months [CI, 0.7-7.3]), p = 0.049. Twenty-three patients were in the exploratory neoadjuvant group, where mOS was the longest (63.0 months [CI, 15.5-110.5]). No grade 5 adverse events (AEs) occurred in all three cohorts, and 32.4% had immune-related AEs, most frequently hepatitis and colitis. Conclusions: Our results show that in BRAFm-ATC, addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival. Surgical resection of the primary tumor after initial BRAF-targeted therapy in selected patients may provide further survival benefit. However, conclusions are limited by the retrospective nature of the study. Additional prospective data are needed to confirm this observation.

Canadian French Translation and Validation of the Neck Dissection Impairment Index: A Quality of Life Measure for the Surgical Oncology Population.

BACKGROUND: Neck dissections (ND) are a routine procedure in head and neck oncology. Given the postoperative functional impact that some patients experience, it is imperative to identify and track quality of life (QoL) symptomatology to tailor each patient's therapeutic needs. To date, there is no validated French-Canadian questionnaire for this patient-population. We therefore sought to translate and validate the Neck Dissection Impairment Index (NDII) in Canadian French. METHODS: A 3-phased approach was used. Phase 1: The NDII was translated from English to Canadian French using a "forward and backward" translational technique following international guidelines. Phase 2: A cognitive debriefing session was held with 10 Canadian 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 Canadian French. Cronbach's alpha revealed high internal consistency (0.92, lower 95% confidence limit 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 Canadian 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 multisite clinical trials requiring the NDII as an outcome measure.

Decreasing utilization for postoperative radiation therapy in locoregionally advanced medullary thyroid cancer.

BACKGROUND: Use of postoperative radiation therapy (PORT) in locoregionally advanced medullary thyroid cancer (MTC) remains controversial. The objective was to evaluate the effect of PORT on locoregional control (LRC) and overall survival (OS). METHODS: Retrospective cohort study of 346 MTC patients separated into PORT and no-PORT cohorts. Relative indications for PORT, as well as changes in patterns of treatment, were recorded. RESULTS: 49/346 (14%) received PORT. PORT was associated with worse OS; adjusted HR = 2.0 (95%CI 1.3-3.3). PORT was not associated with improved LRC, even when adjusting for advanced stage (Stage III p = 0.892; Stage IV p = 0.101). PORT and targeted therapy were not associated with improved OS compared to targeted therapy alone; adjusted HR = 1.2 (95%CI 0.3-4.1). CONCLUSIONS: Use of PORT in MTC has decreased and its indications have become more selective, coinciding with the advent of effective targeted therapies. Overall, PORT was not associated with improved LRC or OS.

Initial Management of BRAF V600E-Variant Anaplastic Thyroid Cancer: The FAST Multidisciplinary Group Consensus Statement.

Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease. Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making. Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.

Patterns of loco-regional progression and patient outcomes after definitive-dose radiation therapy for anaplastic thyroid cancer.

BACKGROUND: The aim of this study is to characterize the patterns of loco-regional progression (LRP) and outcomes after definitive-dose intensity modulated radiation therapy (IMRT) for anaplastic thyroid cancer (ATC) with macroscopic neck disease at the time of IMRT. METHODS: Disease/treatment characteristics and outcomes for patients with unresected or incompletely resected ATC who received IMRT (≥45 Gy) were retrospectively reviewed. For those with LRP after IMRT, progressive/recurrent gross tumor volumes (rGTV) were contoured on diagnostic CTs and co-registered with initial planning CTs using deformable image registration. rGTVs were classified based on established spatial/dosimetric criteria. RESULTS: Forty patients treated between 2010-2020 formed the cohort. Median IMRT dose was 66 Gy (45-70 Gy); altered fractionation (AF) was used in 24 (60 %). All received concurrent chemotherapy. In addition to areas of gross disease, target volumes (TVs) commonly included: central compartment/upper mediastinum (levels VI/VII), neck levels II-V in an involved, and levels III-IV in an uninvolved lateral neck. Median overall survival was 7.1 m. Median progression free survival was 7.4 m for patients with locoregional disease and 1.8 m for patients with distant metastasis at the time of IMRT. Twenty-one patients (53 %) developed LRP at median of 10.9 m; freedom from LRP at 3 m and 12 m was 71 % (95 %CI 58-87 %) and 47 % (95 %CI 32-68 %). Forty-one individual rGTVs were identified and most occurred within the high dose (HD) TVs: Type A/central HD (n = 29, 71 %) and B/peripheral HD (n = 3, 7 %). CONCLUSIONS: Despite an intensive treatment schedule, including AF and concurrent chemotherapy, classic radio-resistant and rapid Type A failures predominated; isolated extraneous dose failures were rare. While these findings support the IMRT and TV delineation strategies described herein, they highlight the importance of identifying novel strategies to further improve LRC for patients with unresectable disease without targetable mutations for contemporary neo-adjuvant strategies.

Recent advances in anaplastic thyroid cancer management.

PURPOSE OF REVIEW: To summarize recent developments in the diagnosis and management of patients with anaplastic thyroid cancer (ATC). RECENT FINDINGS: An updated edition of the Classification of Endocrine and Neuroendocrine Tumors was released by the World Health Organization (WHO), in which squamous cell carcinoma of the thyroid are now a subtype of ATC. Broader access to next generation sequencing has allowed better understanding of the molecular mechanisms driving ATC and improved prognostication. BRAF-targeted therapies revolutionized the treatment of advanced/metastatic BRAFV600E -mutated ATC, offering significant clinical benefit and allowing better locoregional control of disease through the neoadjuvant approach. However, inevitable development of resistance mechanisms represents a major challenge. Addition of immunotherapy to BRAF/MEK inhibition has shown very promising results and significant improvement in survival outcomes. SUMMARY: Major advancements took place in the characterization and management of ATC in recent years, especially in patients with a BRAF V600E mutation. Still, no curative treatment is available, and options are limited once resistance to currently available BRAF-targeted therapies develops. Additionally, there is still a need for more effective treatments for patients without a BRAF mutation.

Carotid blowout into the trachea: unusual entity with unexpected management outcome.

We present a case report of a patient with a history of aggressive thyroid cancer managed by surgery, chemotherapy, and radiation to the neck. A year later, he presented with hemoptysis. Endobronchial ultrasound showed a pulsatile vessel; however, a CT scan and conventional angiogram were negative. Three days later, a repeat angiogram revealed a pseudoaneurysm arising from the right common carotid artery. Carotid sacrifice was performed after passing balloon test occlusion. Three years later the patient presented with coil herniation into the trachea. The carotid stump was closed with a vascular plug to prevent rebleeding from coil removal. Four months later the patient experienced an intractable cough and underwent laryngoscopy-assisted removal of the residual coil mass. This case report discusses the rare scenario of a carotid blowout into the trachea and the subsequent course of events.

Genetically engineered mouse models of head and neck cancers.

The head and neck region is one of the anatomic sites commonly afflicted by cancer, with ~1.5 million new diagnoses reported worldwide in 2020 alone. Remarkable progress has been made in understanding the underlying disease mechanisms, personalizing care based on each tumor's individual molecular characteristics, and even therapeutically exploiting the inherent vulnerabilities of these neoplasms. In this regard, genetically engineered mouse models (GEMMs) have played an instrumental role. While progress in the development of GEMMs has been slower than in other major cancer types, several GEMMs are now available that recapitulate most of the heterogeneous characteristics of head and neck cancers such as the tumor microenvironment. Different approaches have been employed in GEMM development and implementation, though each can generally recapitulate only certain disease aspects. As a result, appropriate model selection is essential for addressing specific research questions. In this review, we present an overview of all currently available head and neck cancer GEMMs, encompassing models for head and neck squamous cell carcinoma, nasopharyngeal carcinoma, and salivary and thyroid gland carcinomas.

Utilization of Transcriptomic Profiling to Identify Molecular Markers Predicting Successful Recovery Following Endoscopic Sinus Surgery for Chronic Rhinosinusitis.

OBJECTIVES: Successful recovery from chronic rhinosinusitis (CRS) following endoscopic sinus surgery (ESS) can be characterized by minimal presence of symptoms and absence of disease on endoscopy. However, molecular markers of surgical success remain to be characterized. These could allow for better tailoring of perioperative therapy. This study aims to identify novel molecular markers associated with surgery responsive patient. STUDY DESIGN: Prospective cohort study. SETTING: Single academic hospital center. METHOD: One hundred eighteen consecutive patients with CRS at high risk of recurrence after surgery were followed prospectively following ESS in an academic medical center. Symptomatic and endoscopic outcomes were assessed at 4 months, with success rigorously defined subjectively as minimal or no symptoms (no symptom greater than 1 on an ordinal scale of 0-3) and objectively by the absence of nasal polyposis on sinus cavity endoscopy and Lund-Kennedy endoscopic edema score no greater than 1. Samples were obtained at the time of surgery and at 4-month postoperatively. Changes associated with surgery were determined by gene expression profiling using Affymetrix's Clariom S Human HT arrays. RESULTS: Successful ESS was characterized by a mild upregulation in Type 1 inflammation, upregulation of cell cycle progression, and epithelial barrier and proliferation-associated genes and pathways. ESS failure was associated to very high levels of Type 1 inflammation along with downregulation of epithelial barrier function and regeneration genes and pathways. CONCLUSION: Successful recovery from ESS involves restoration of epithelial function and regulated activation of Type 1 inflammation. Excessively elevated Type 1 inflammation is associated with epithelial barrier dysfunction.

Azithromycin Mechanisms of Action in CRS Include Epithelial Barrier Restoration and Type 1 Inflammation Reduction.

OBJECTIVE: Previous in vitro transcriptomic profiling suggests azithromycin exerts its effects in patients with chronic rhinosinusitis (CRS) via modulation of type 1 inflammation and restoration of epithelial barrier function. We wished to verify these postulated effects using in vitro models of epithelial repair and in vivo transcriptional profiling. STUDY DESIGN: Functional effects of azithromycin in CRS were verified using in vitro models of wounding. The mechanism of the effect of azithromycin was assessed in vivo using transcriptomic profiling. SETTING: Academic medical center. METHODS: Effects of azithromycin on the speed of epithelial repair were verified in a wounding model using primary nasal epithelial cells (pNEC) from CRS patients. Nasal brushings collected pre-and posttreatment during a placebo-controlled trial of azithromycin for CRS patients unresponsive to surgery underwent transcriptomic profiling to identify implicated pathways. RESULTS: Administration of azithromycin improved the wound healing rates in CRS pNECs and prevented the negative effect of Staphylococcus aureus on epithelial repair. In vivo, response to azithromycin was associated with downregulation in pathways of type 1 inflammation, and upregulation of pathways implicated in the restoration of the cell cycle. CONCLUSION: Restoration of healthy epithelial function may represent a major mode of action of azithromycin in CRS. In vitro models show enhanced epithelial repair, while in vivo transcriptomics shows downregulation of pathways type 1 inflammation accompanied by upregulation of DNA repair and cell-cycle pathways. The maximal effect in patients with high levels of type 1-enhanced inflammation suggests that azithromycin may represent a novel therapeutic option for surgery-unresponsive CRS patients.

Prior Thyroid and Nonthyroid Cancer History Do Not Significantly Alter Overall Survival in Patients Diagnosed with Anaplastic Thyroid Cancer.

Background: A history of thyroid and nonthyroid malignancies has traditionally been an exclusion criterion in patients with anaplastic thyroid cancer (ATC) seeking to enroll in clinical trials. In this study, we examined the impact of prior malignancies on overall survival (OS) in patients diagnosed with ATC. Methods: In our retrospective cohort study, we identified 451 patients with ATC treated at MD Anderson between 2000 and 2019. Clinical and pathological information was obtained through chart review. Survival analyses were conducted using the Kaplan-Meier method and multivariable Cox proportional hazard models. Results: A history of clinically documented differentiated thyroid cancer (DTC) was reported in 14% of patients with ATC (n = 62), most commonly papillary thyroid cancer (81%, n = 50). The median time from diagnosis of prior DTC to ATC diagnosis was 3.5 years (range: 6 months to 35 years). Concomitant DTC was found on pathology in a higher proportion of patients (52%, n = 234). A history of nonthyroid cancer was reported in 23% of patients (n = 102), where 19% (n = 87) had one, 2% (n = 10) had two, and 1% (n = 5) had three prior cancers. The median time from diagnosis of prior nonthyroid cancer to ATC diagnosis was 8 years (range: 3 months to 53 years). The most common prior nonthyroid cancers were nonmelanoma skin (28.4%), prostate (19.6%), and breast cancers (16.7%). In a subgroup analysis performed in patients with available tumor mutation information (n = 183), the frequency of detected tumor driver mutations (BRAF, RAS, TP53) was not significantly different between patients with ATC with and without a history of nonthyroid cancer. On multivariate analysis after adjusting for age and overall stage, prior DTC, concomitant DTC, and prior nonthyroid cancers, all had no significant impact on OS. Conclusions: The presence of prior malignancy does not significantly impact OS in patients with ATC. Revision of eligibility criteria for enrollment of patients with ATC into clinical trials is warranted.