Is lobectomy sufficient for multifocal papillary thyroid microcarcinoma?

IMPORTANCE: Multifocal papillary thyroid microcarcinoma (PTMC) has been associated with a higher incidence of lymph node involvement, bilateral involvement, and extrathyroidal extension compared to unifocal papillary thyroid cancer (PTC). OBJECTIVE: To describe the incidence and determinants of survival for patients with multifocal PTMC using the Surveillance, Epidemiology, and End Result (SEER) database. DESIGN, SETTING, PARTICIPANTS: The SEER registry was utilized to calculate survival trends for patients with PTMC between 2010 and 2015. Patient data was then analyzed with respect to age, sex, race, multifocality, and types of surgery rendered. MAIN OUTCOMES AND MEASURES: Overall Survival (OS) and Disease Specific Survival (DSS). RESULTS: 22,283 cases of papillary thyroid microcarcinoma (T1a N0 M0) were identified. The cohort was composed of 82.6 % females, and about 82 % of patients were of white race. The mean age at diagnosis was 51.9 years. Multifocal PTMC was present in 32.2 % of the tumors (n = 7186). 73.9 % of patients underwent total thyroidectomy and 23.0 % received lobectomy. OS at 2 and 5 years was 98 % and 95 %, respectively. Multivariate analysis revealed that age, sex, and multifocality were determinants of OS. Only age was a determinant of DSS. Kaplan-Meier survival analysis revealed that multifocal PTMC had similar mean OS between lobectomy and total thyroidectomy patients (69.59 months versus 69.82 months). CONCLUSIONS AND RELEVANCE: PTMC has a good prognosis. Our analysis revealed that age was a determinant of OS and DSS; sex and multifocality were also prognosticators for OS. The type of surgery, whether lobectomy or total thyroidectomy, was not a determinant of survival in multifocal PTMC.

A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.

BACKGROUND: Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS: A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS: Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1ß, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS: The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY: Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.

A sensitive LC-MS assay using derivatization with boron trifluoride to quantify curcuminoids in biological samples.

A procedure is described to measure curcumin (C), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumim (TC) and their glucuronidated metabolites (CG, DMCG, and BDMCG) in plasma, brain, liver and tumor samples. The procedure involves converting the analytes to their boron difluoride derivatives and analyzing them by combined liquid chromatography coupled to an ion trap mass spectrometer operating in the negative ion MSn scan mode. The method has superb limits of detection of 0.01 nM for all curcuminoids and 0.5 nM for TC and the glucuroniated metabolites, and several representative chromatograms of biological samples containing these analytes are provided. In addition, the pharmacokinetic profile of these compounds in one human who daily consumed an over-the-counter curcuminoid product shows the peak and changes in circulating concentrations achieved by this mode of administration.

Laser-Assisted Control of Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Systematic Review.

BACKGROUND AND OBJECTIVES: Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, causes recurrent mucous membrane hemorrhage, especially epistaxis. In this systematic review, we discuss the efficacies of the three most common laser photocoagulation treatments for HHT-related epistaxis. STUDY DESIGN/MATERIALS AND METHODS: A systematic literature search was conducted in PubMed and MEDLINE from database inception to March 2019. Studies reporting epistaxis outcomes following argon, neodymium-doped yttrium aluminum garnet (Nd:YAG), and diode laser photocoagulation for HHT were included. χ2 and Barnard's exact tests were utilized to detect differences in reduced epistaxis frequency and intensity rates. RESULTS: Fifteen out of 157 published studies met our eligibility criteria, spanning a collective 362 patients. Argon, Nd:YAG, and diode laser therapy reduced epistaxis frequency in 90.4%, 88.9%, and 71.1% of patients, respectively, and reduced epistaxis intensity in 87.8%, 87.2%, and 71.1% of patients, respectively. Diode laser photocoagulation significantly underperformed in both outcome measurements when compared with argon (frequency: P = 0.005; intensity: P = 0.034) and Nd:YAG (frequency: P = 0.012; intensity: P = 0.041). There was no significant difference between argon and Nd:YAG in reducing HHT epistaxis frequency (P = 0.434) or intensity (P = 0.969). Categorizing HHT patients by clinical severity demonstrated a higher rate of improvement in the mild-moderate group compared with the severe group in both argon (P < 0.001) and Nd:YAG (P < 0.001) therapeutic methods. While no significant differences were found in rates of improved epistaxis outcomes between argon and Nd:YAG in mild-moderate HHT patients (frequency: P = 0.061; intensity: P = 0.061), Nd:YAG demonstrated greater rates of reduction in epistaxis frequency (P = 0.040) and intensity (P = 0.028) than argon among severe HHT patients. CONCLUSIONS: HHT is a lifelong disease, plaguing patients with debilitating epistaxis. Intranasal laser photocoagulation of telangiectasias using argon or Nd:YAG laser therapy can yield improved epistaxis outcomes compared with diode laser photocoagulation. In severe cases of HHT, Nd:YAG laser therapy provides greater improvements in epistaxis outcomes than argon photocoagulation. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Corticotrophic pituitary carcinoma with cervical metastases: case series and literature review.

PURPOSE: Pituitary tumors are the second most common intracranial tumors, however, pituitary carcinoma is a rare clinical entity which represents only 0.1-0.2% of all pituitary tumors. Diagnosis of pituitary carcinoma requires the presence of metastasis. Early identification of pituitary carcinoma is difficult, and only recently have guidelines been published for the treatment of aggressive pituitary tumors. We present two cases from our institution, with a review of other cases available in literature in order to better characterize this rare disease. METHODS: A retrospective review of two patients with pituitary carcinoma treated at a tertiary medical center was performed. The MEDLINE database was searched for all cases of pituitary carcinoma. Information for age at diagnosis, sex, pituitary tumor type, latency period from pituitary tumor to presentation of carcinoma, sites of metastasis, number of surgical therapies, radiation and chemotherapy, and survival after diagnosis were collected. RESULTS: A total of 69 studies were available for review for a total of 72 unique cases. The average age at diagnosis was 46.3 years. The most common tumors were ACTH-secreting (34.7%), Prolactin-secreting (23.6%), and Null Cell (15.3%). The average latency period from pituitary tumor diagnosis to metastasis was 9 years. All patients underwent surgical therapy during their treatment, with an average of 2.76 procedures. The mortality rate was 54.8% with average time to death after diagnosis of approximately 10 months. CONCLUSIONS: Pituitary carcinoma is a rare disease with high mortality rate and is a diagnostic and treatment challenge. Further study is required but is difficult due to its low incidence.

Human papillomavirus in oropharyngeal cancer: The changing face of a disease.

The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55years, with limited exposure to alcohol and tobacco. This subset of squamous cell carcinoma (SCC) has been found to be associated with human papillomavirus infection (HPV). Other Head and Neck Squamous Cell carcinoma (HNSCC) subtypes include oral cavity, hypopharyngeal, nasopharyngeal, and laryngeal SCC which tend to be HPV negative. HPV associated oropharyngeal cancer has proven to differ from alcohol and tobacco associated oropharyngeal carcinoma in regards to the molecular pathophysiology, presentation, epidemiology, prognosis, and improved response to chemoradiation therapy. Given the improved survival of patients with HPV associated SCC, efforts to de-intensify treatment to decrease treatment related morbidity are at the forefront of clinical research. This review will focus on the important differences between HPV and tobacco related oropharyngeal cancer. We will review the molecular pathogenesis of HPV related oropharyngeal cancer with an emphasis on new paradigms for screening and treating this disease.

Sinonasal quality of life outcomes following laser treatment of epistaxis related to hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder which manifests as recurrent, episodic, and potentially debilitating epistaxis. In this study, we aim to (1) characterize baseline sinonasal symptoms for HHT patients and to (2) analyze changes in sinonasal symptoms before and after laser surgical treatment for HHT. We performed a retrospective chart review of sinonasal outcome test-22 (SNOT-22) scores before and after one or more laser surgical treatments for HHT-related epistaxis between January 1, 2010 and December 1, 2015 at a tertiary academic medical center with an HHT Foundation-approved Center of Excellence. Preoperative and all subsequent postoperative SNOT-22 scores (short-term, <45 days and long-term, ≥45 days) were compared. Twenty consecutive HHT patients underwent 51 laser surgeries for recurrent epistaxis. Mean preoperative, short-term postoperative, and long-term postoperative SNOT-22 scores were 34.6 ± 5.4, 33.9 ± 5.5, and 18.8 ± 4.6, respectively. When analyzing subcategory scores, there was a significant improvement in the rhinologic domain from short-term to long-term postoperatively (13.5 vs. 7.3; p = 0.004), in the non-rhinologic otolaryngic domain from short-term to long-term postoperatively (2.8 vs. 1.7; p = 0.014), and in the psychological domain from preoperative and short-term postoperative to long-term postoperatively (12.2 and 10.0 vs. 6.0; p = 0.015 and 0.01, respectively). Following laser surgery for HHT-related epistaxis, patients' rhinologic symptoms worsened on the short run postoperatively but improved over time. The main benefit of laser treatment appears to be long-term improvement in psychological factors. This study once again underscores the important role of the otolaryngologist in managing sinonasal manifestations of HHT.

Treatment outcomes in veterans with HPV-positive head and neck cancer.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) caused by the human papilloma virus (HPV) has an improved prognosis relative to HPV-negative tumors. Patients with HPV-positive disease may benefit from different treatment modalities in order to optimize survival and quality of life. We sought to investigate HPV-positive HNSCC within the military veteran population, and analyze the role of treatment modality in outcomes of patients with HPV-positive and HPV-negative tumors. METHODS: Patients diagnosed with HNSCC between January 1, 2010 and December 31, 2014 at one regional veterans health center were retrospectively examined. Pathologic specimens underwent testing for HPV subtype and p16 expression. Demographic and clinical factors, including treatment modality, were analyzed for their impact on the primary outcome of overall survival. RESULTS: There were 209 patients with primary tumor sites including larynx (25.4%), oral tongue (19.6%), oral cavity (13.4%), oropharynx (17.2%), tonsil (17.2%), unknown primary (2.9%), nasopharynx (1.9%), and multiple sites (2.4%). Patients had HPV-positive (n=82, 39.2%), HPV-negative (n=89, 42.6%) or unknown HPV status (n=38, 18.2%). Primary treatment modalities were chemoradiation (n=124, 59.3%), surgery (n=39, 18.7%), radiation therapy (n=37, 17.7%), or no treatment (n=9, 4.3%). Survival analysis with Cox proportional hazards model demonstrated significant associations with T classification (T4 3.61, P=0.005), N classification (N3 3.52, P=0.0159), M classification (M1 2.8, P=0.0209), and HPV status (HPV-positive 0.43, P=0.0185), but no relation with primary treatment modality (primary surgery vs. primary chemoradiation 1.01, P=0.9718). CONCLUSION: HPV-positive HNSCC in the veteran population has a significantly improved prognosis relative to similarly staged patients with HPV-negative disease. This study demonstrates that the primary treatment modality - chemoradiation, radiation therapy, or surgery - does not impact overall survival among veterans with HPV-positive HNSCC.

A review of gigaxonin mutations in giant axonal neuropathy (GAN) and cancer.

Gigaxonin, the product of GAN gene localized to chromosome 16, is associated with the early onset neuronal degeneration disease giant axonal neuropathy (GAN). Gigaxonin is an E3 ubiquitin ligase adaptor protein involved in intermediate filament processing in neural cells, and vimentin filaments in fibroblasts. Mutations of the gene cause pre-neural filaments to accumulate and form giant axons resulting in the inhibition of neural cell signaling. Analysis of the catalog of somatic mutations in cancer, driver DB and IDGC data portal databases containing 21,000 tumor genomic sequences has identified GAN patient mutations in cancer cell lines and primary tumors. The database search has also shown the presence of identical missense and nonsense gigaxonin mutations in GAN and colon cancer. These mutations frequently occur in the domains associated with protein homodimerization and substrate interaction such as Broad-Complex, Tramtrack and Bric a brac (BTB), BTB associated C-terminal KELCH (BACK), and KELCH repeats. Analysis of the International HapMap Project database containing 1200 normal genomic sequences has identified a single nucleotide polymorphism (SNP), rs2608555, in exon 8 of the gigaxonin sequence. While this SNP is present in >40 % of Caucasian population, it is present in less than 10 % of Japanese and Chinese populations. Although the role of gigaxonin polymorphism is not yet known, CFTR and MDR1 gene studies have shown that silent mutations play a role in the instability and aberrant splicing and folding of mRNAs. We believe that molecular and functional investigation of gigaxonin mutations including the exon 8 polymorphism could lead to an improved understanding of the relationship between GAN and cancer.

The emerging landscape of salivary diagnostics.

Saliva contains a variety of biomolecules, including DNA, coding and noncoding RNA, proteins, metabolites and microbiota. The changes in the salivary levels of these molecular constituents can be used to develop markers for disease detection and risk assessment. Use of saliva as an early-detection tool is a promising approach because collection of saliva is easy and noninvasive. Here, we review recent developments in salivary diagnostics, accomplished using salivaomics approaches, including genomic, transcriptomic, proteomic, metabolomic and microbiomic technologies. Additionally, we illustrate the mechanisms of how diseases distal from the oral cavity can lead to the appearance of discriminatory biomarkers in saliva, and discuss the relevance of these markers for translational and clinical applications.

HIGH PREVALENCE OF AGENT ORANGE EXPOSURE AMONG THYROID CANCER PATIENTS IN THE NATIONAL VA HEALTHCARE SYSTEM.

OBJECTIVE: Thyroid cancer is the most common endocrine malignancy and the most rapidly increasing cancer in the U.S. Little is known regarding the epidemiology and characteristics of patients with thyroid cancer within the national Veterans Health Administration (VHA) integrated healthcare system. The aim of this study was to further understand the characteristics of thyroid cancer patients in the VHA population, particularly in relation to Agent Orange exposure. METHODS: This is a descriptive analysis of the VA (Veterans Affairs) Corporate Data Warehouse database from all U.S. VHA healthcare sites from October1, 1999, to December 31, 2013. Information was extracted for all thyroid cancer patients based on International Classification of Diseases-ninth revision diagnosis codes; histologic subtypes of thyroid cancer were not available. RESULTS: There were 19,592 patients (86% men, 76% white, 58% married, 42% Vietnam-era Veteran) in the VHA system with a diagnosis of thyroid cancer within this 14-year study period. The gender-stratified prevalence rates of thyroid cancer among the Veteran population during the study period were 1:1,114 (women) and 1:1,023 (men), which were lower for women but similar for men, when compared to the U.S. general population in 2011 (1:350 for women and 1:1,219 for men). There was a significantly higher proportion of self-reported Agent Orange exposure among thyroid cancer patients (10.0%), compared to the general VHA population (6.2%) (P<.0001). CONCLUSION: Thyroid cancer patients, in this sample, have a higher prevalence of self-reported Agent Orange exposure compared to the overall national VA patient population. ABBREVIATIONS: T4 = thyroxine TCDD = 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin TSH = thyroid-stimulating hormone VA = Veterans Affairs VHA = Veterans Health Administration.

p16 Protein and gigaxonin are associated with the ubiquitination of NFκB in cisplatin-induced senescence of cancer cells.

The molecular mechanism of p16-mediated senescence in cisplatin-treated cancer cells is not fully understood. Here we show that cisplatin treatment of head and neck cancer cells results in nuclear transport of p16 leading to a molecular modification of NFκB. Chromatin immunoprecipitation assays show that this modification is associated with the inhibition of NFκB interacting with its DNA binding sequences, leading to decreased expression of NFκB-transcribed proteins. LCMS proteomic analysis of LAP-TAP-purified proteins from HeLa cells containing a tetracycline-inducible GFP-S peptide-NFκB expression system identified gigaxonin, an ubiquitin E3 ligase adaptor, as an NFκB-interacting protein. Immunoblotting and siRNA studies confirmed the NFκB-gigaxonin interaction and the dependence of this binding on p16-NFκB binding. Using gel shift assays, we have confirmed p16-NFκB and gigaxonin-NFκB interactions. Furthermore, we have observed increased NFκB ubiquitination with cisplatin treatment that is abolished in the absence of p16 and gigaxonin expression. Analysis of 103 primary tumors has shown that increased nuclear p16 expression correlates with enhanced survival of head and neck cancer patients (p < 0.0000542), indicating the importance of nuclear p16 expression in prognosis. Finally, p16 expression is associated with reduced cytokine expression and the presence of human papilloma virus in chemoradiation-sensitive basaloid tumors. However, the absence of p16 expression is associated with enhanced cytokine expression and the absence of human papilloma virus in aggressive tumors. These results clearly demonstrate that nuclear p16 and gigaxonin play an important role in chemosensitivity of head and neck cancers through ubiquitination of NFκB.

Guideline familiarity predicts variation in self-reported use of routine surveillance PET/CT by physicians who treat head and neck cancer.

BACKGROUND: Use of routine surveillance testing beyond guideline recommended levels is common in many oncologic disciplines, including head and neck cancer. The impact of guideline familiarity and other physician characteristics on surveillance imaging use are not well understood. METHODS: A cross-sectional national survey was performed of physicians responsible for surveillance of patients with head and neck squamous cell carcinoma (HNSCC). The primary outcome was self-reported use of routine surveillance PET/CT in asymptomatic patients. A secondary outcome was familiarity with guideline recommendations. Using multivariable regression, the impact of guideline familiarity and other physician characteristics on PET/CT use was examined. RESULTS: Of the 502 responders, 79% endorsed ever using PET/CT scans for routine surveillance imaging, and 39% were high imaging users (used PET/CT scans on more than half of their asymptomatic patients); 76% were familiar with the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers recommending against routine surveillance PET/CT scans. Although guideline familiarity was associated with being a low imaging user or a never-user, among those who were familiar with guidelines, 31% were nonetheless high imaging users and 73% endorsed ever using PET/CT scans. In multivariable analysis controlling for physician characteristics, guideline familiarity was the strongest predictor of PET/CT use. CONCLUSIONS: Familiarity with the NCCN Guidelines predicts self-reported routine surveillance PET/CT use among physicians who treat patients with HNSCC. However, given the observed variation and high levels of imaging even among physicians who are familiar with the guidelines, further research should examine the reasons physicians choose to use surveillance PET/CT scans.

Empty nose syndrome.

Empty nose syndrome (ENS) is a rare, late complication of turbinate surgery. The most common clinical symptoms are paradoxical nasal obstruction, nasal dryness and crusting, and a persistent feeling of dyspnea. Little is known about the pathogenesis of ENS, though it is speculated that anatomical changes leading to alterations in local environment, disruption of mucosal cooling, and disruption of neurosensory mechanisms are strongly implicated. The diagnosis is clinical, though often difficult to make due to the poor correlation between subjective and objective findings. Medical therapies include mucosal humidification, irrigations, and emollients. Surgical therapy should be reserved for refractory cases and may involve turbinate reconstruction, most commonly using implantable biomaterials. Ultimately, prevention of this feared complication through turbinate-sparing techniques is essential.

Acromegaly: otolaryngic manifestations following pituitary surgery.

OBJECTIVES: Acromegalics present with a wide range of otolaryngic symptoms, including rhinosinusitis, changes in facial appearance, obstructive sleep apnea (OSA), and voice disturbances. Treatment typically involves transnasal-transsphenoidal (TNTS) resection of the offending pituitary adenoma. In this study, we identify the prevalence of otolaryngic symptoms of acromegalic patients, and evaluate Sinonasal Outcome Test (SNOT-22) scores preceding and following pituitary resection. DESIGN: Retrospective chart review. SETTING: Tertiary academic medical center. PARTICIPANTS: Patients diagnosed with acromegaly who underwent surgical resection of a growth-hormone secreting pituitary adenoma between August 2010 and September 2013. MAIN OUTCOME MEASURES: Subjects were asked to complete questionnaires detailing otolaryngic symptoms as well as SNOT-22 surveys before and after TNTS surgery. A Student's t-test was used to compare preoperative and postoperative SNOT-22 scores. RESULTS: Twenty-five patients underwent pituitary surgery for acromegaly. Acromegalic patients were found to have macroglossia (60%), OSA or sleep-disordered breathing (52%), thyroid neoplasia (20%), hearing loss/tinnitus (20%), sinonasal symptoms (16%), and parathyroid pathology (8%). Differences in preoperative and postoperative SNOT-22 scores were not statistically significant. CONCLUSION: Acromegalics present with assorted otolaryngic complaints. Routine screening of all acromegalics with sleep evaluations (for both surgical and perioperative planning), thyroid ultrasound, and audiologic testing should be strongly considered.

The pituitary stalk effect: is it a passing phenomenon?

Most patients with large pituitary tumors do not exhibit hyperprolactinemia as a result of pituitary lactotroph disinhibition (stalk effect). Studies have demonstrated that increased intrasellar pressure is associated with both "stalk effect" hyperprolactinemia and pituitary insufficiency. Our primary hypothesis was that, despite continued disinhibition, lactotroph failure is responsible for normoprolactinemia in patients with large macroadenomas. As a corollary, we proposed that the hyperprolactinemia phase, which presumably would precede the insufficiency/normoprolactinemic state, would more likely be discovered in premenopausal females and go unnoticed in males. Prospective, consecutive surgical series of 98 patients of clinically nonfunctional pituitary adenomas. Lactotroph insufficiency was inferred by the coexistence of insufficiency in another pituitary axis. The existence of pre-operative lactotroph disinhibition was inferred based on comparison of pre- versus post-operative prolactin levels. 87 % of patients with tumor size >20 mm and normoprolactinemia had pituitary insufficiency. Pre-operative prolactin in patients with pituitary insufficiency were lower than those with intact pituitary function. Prolactin levels dropped in nearly all patients, including patients with normoprolactinemia pre-operatively. Premenopausal women had smaller tumors and higher pre-operative prolactin levels compared to males. No premenopausal female exhibited evidence of pituitary insufficiency. Our study provides suggestive evidence that the "stalk effect" pathophysiology is the norm rather than the exception, and that the finding of normoprolactinemia in a patient with a large macroadenoma is likely a consequence of lactotroph insufficiency. In males, the hyperprolactinemia window is more likely to be missed clinically due to an absence of prolactin-related symptoms.

Assessing the cost of contemporary pituitary care.

OBJECT: Knowledge of the costs incurred through the delivery of neurosurgical care has been lagging, making it challenging to design impactful cost-containment initiatives. In this report, the authors describe a detailed cost analysis for pituitary surgery episodes of care and demonstrate the importance of such analyses in helping to identify high-impact cost activities and drive value-based care. METHODS: This was a retrospective study of consecutively treated patients undergoing an endoscopic endonasal procedure for the resection of a pituitary adenoma after implementation and maturation of quality-improvement initiatives and the implementation of cost-containment initiatives. RESULTS: The cost data pertaining to 27 patients were reviewed. The 2 most expensive cost activities during the index hospitalization were the total operating room (OR) and total bed-assignment costs. Together, these activities represented more than 60% of the cost of hospitalization. Although value-improvement initiatives contributed to the reduction of variation in the total cost of hospitalization, specific cost activities remained relatively variable, namely the following: 1) OR charged supplies, 2) postoperative imaging, and 3) use of intraoperative neuromonitoring. These activities, however, each contributed to less than 10% of the cost of hospitalization. Bed assignment was the fourth most variable cost activity. Cost related to readmission/reoperation represented less than 5% of the total cost of the surgical episode of care. CONCLUSIONS: After completing a detailed assessment of costs incurred throughout the management of patients undergoing pituitary surgery, high-yield opportunities for cost containment should be identified among the most expensive activities and/or those with the highest variation. Strategies for safely reducing the use of the targeted resources, and related costs incurred, should be developed by the multidisciplinary team providing care for this patient population.

Fungal and Bacterial Microbiome in Sinus Mucosa of Patients with and without Chronic Rhinosinusitis.

OBJECTIVES: Dysbiosis of the sinonasal microbiome has been implicated in the pathogenesis of chronic rhinosinusitis (CRS). However, the mycobiome remains largely understudied, and microbial alterations associated with specific CRS subtypes have yet to be delineated. The objective of this study is to investigate the fungal and bacterial microbiome of sinus mucosa in CRS patients with and without nasal polyposis (CRSwNP and CRSsNP) versus healthy controls. METHODS: Sinus mucosa was obtained from 92 patients (31 CRSsNP, 31 CRSwNP, and 30 controls) undergoing endoscopic sinus/skull base surgery. Data regarding demographics, Lund-MacKay scores, and histopathology were collected. Fungal and bacterial microbiome analysis was performed utilizing internal transcribed spacer amplicon and 16S rRNA sequencing. RESULTS: Beta diversity of the sinonasal mycobiome differed significantly between CRS and controls (p = 0.001) and between CRSwNP and controls (p = 0.049), but not between CRSwNP and CRSsNP (p = 0.32) nor between CRSsNP and controls (p = 0.06). With respect to the bacterial microbiome, significantly lower alpha diversity was observed between CRS and controls (p < 0.001), CRSwNP versus controls (p < 0.001), and CRSsNP versus controls (p < 0.001). Beta diversity was also significantly different at the genus level between CRSwNP and CRSsNP (p = 0.019), CRSwNP and controls (p = 0.002)), and CRSsNP and controls (p < 0.001). However, alpha and beta diversity did not differ significantly between CRS patients with/without eosinophils or correlate with Lund-MacKay scores. CONCLUSIONS: Differences in mycobiota diversity in CRS patients in comparison with controls suggest that alterations in the mycobiome may contribute to disease pathogenesis. Our findings also confirmed that diminished diversity among bacterial communities is associated with CRS and that significant differences are present in microbial composition between CRSwNP and CRSsNP. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1054-1062, 2024.

Cabergoline targets multiple pathways to inhibit PRL secretion and increases stromal fibrosis.

OBJECTIVE: Unravel the potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumors and neighboring stromal and immune cells. DESIGN AND METHODS: Five surgically resected prolactinomas (PRLomas) from 3 cabergoline (CBG)-treated patients and 2 treatment-naive patients were analyzed by using single-cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape. RESULTS: Six major cell populations, namely tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%), were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components such as perforin and the granzymes GZMB, GNLY, and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from the CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in the CBG-treated samples. CONCLUSIONS: Our scRNA-seq studies revealed key differences in the transcriptomic features of CBG-treated and CBG-untreated PRLomas in both tumor and microenvironment cellular constituents, and for the first time, describe the previously unknown activation of CD8+ T cells following CBG treatment, which may play a role in the tumoricidal actions of CBG.

Decreases in Rhinology Care Utilization by People with Cystic Fibrosis on Highly Effective Modulator Therapy.

BACKGROUND: Many people with cystic fibrosis (PwCF) have chronic rhinosinusitis (CRS). CRS requires additional management beyond that of pulmonary disease and leads to increased utilization of healthcare resources. Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective modulator therapy that has been shown to improve CRS in PwCF. However, the impact of ETI on rhinologic healthcare utilization is understudied. OBJECTIVE: To compare rates of rhinologic healthcare utilization and procedures among PwCF prior to and after initiating ETI therapy. METHODS: A single-center, cohort study investigating adult PwCF was performed in January 2023. Demographics, clinical characteristics, and data related to CF treatment were retrospectively abstracted. Characteristics of the cohort were compared over 2 periods: the 12-months prior to ETI initiation and the 12-months after ETI initiation. Post-ETI data were linearly extrapolated if a subject had not yet completed the full 12 months of ETI. Paired t-testing, Wilcoxon signed rank testing, and regression analysis were performed. RESULTS: Of 126 PwCF, 98 (77.8%) were on ETI therapy and 35 (27.7%) were both on ETI and concurrently followed by the rhinology service (ETI-ENT). Rhinology clinic visits (P = .007) and frequency of obtaining nasal cultures (P = .046) decreased for the ETI-ENT cohort after initiating ETI treatment. There were no significant changes in the number of endoscopic sinus surgeries (P = .452) performed. Beyond ETI use, regression analysis did not identify any factors associated with changes in utilization. CONCLUSION: Aspects of rhinology healthcare utilization by PwCF decreased after initiation of ETI therapy. Additional studies are needed to determine rhinologic healthcare requirements for PwCF who remain on ETI for the long-term and to evaluate larger cohorts of PwCF on ETI.