Single cell view of tumor microenvironment gradients in pleural mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs.

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.

Promoting Surgeon-Scientists in Otolaryngology-Head and Neck Surgery-From Bench to Bedside.

Importance: Surgeon-scientists (defined as principal investigators [PIs] with a Doctor of Medicine [MD] degree or a combined MD and Doctor of Philosophy [PhD] degree) in otolaryngology-head and neck surgery (OHNS) are imperative for achieving clinical translation in the OHNS field. Objective: To (1) raise awareness about the current state of surgeon-scientists in OHNS, (2) contextualize the landscape of surgeon-scientists in OHNS by comparing it to those of neurosurgery and ophthalmology, and (3) identify strategies for attracting and retaining surgeon-scientists in OHNS. Evidence Review: Research funding data from fiscal years 2015 to 2021 among surgeon-scientists in OHNS, neurosurgery, and ophthalmology were obtained from the National Institutes of Health (NIH) Research Portfolio Online Reporting Tools Expenditures and Results and the US Department of Defense (DOD) Congressionally Directed Medical Research Programs awards database. The Association of American Medical Colleges provided the total number of active physicians in each specialty per year and the number and percentage of residents with an MD-PhD degree in each specialty per year. Cohen d was used to express the standardized value of the magnitude of the mean difference between compared groups. Findings: From 2015 to 2021, on average, there were 9566 active physicians in OHNS, 5559.8 in neurosurgery, and 18908.8 in ophthalmology. In OHNS, a greater number of NIH K (research career development) grants were held by surgeon-scientists than by PIs with a PhD degree (21.4 vs 5.1; mean difference, 16.3; 95% CI, 14.3-18.3; Cohen d = 9.6), whereas most NIH R (research) and U (cooperative agreement) grants (144.1 vs 81.6; mean difference, 62.6; 95% CI, 46.3-78.9; Cohen d = 4.5) and DOD grants (9.9 vs 4.1; mean difference, 5.7; 95% CI, 1.0-10.4; Cohen d = 1.4) were held by PIs with a PhD degree. In a comparison of OHNS to neurosurgery and ophthalmology, after the number of R and U grants was scaled by the number of physicians in each field, neurosurgery had a much greater number of grants per surgeon than OHNS (0.02 vs 0.01; mean difference, 0.01; 95% CI, 0.01-0.02; Cohen d = 4.2). Additionally, neurosurgeons received a much larger R and U grant amount per physician than otolaryngologists ($10 630.20 vs $4511.80; mean difference, $6118.40; 95% CI, $2625.90-$9610.80; Cohen d = 2.0). For the R and U grant metrics, there were no meaningful differences between OHNS and ophthalmology. Conclusions and Relevance: Results of this database study showed that from 2015 to 2021, the number of governmental grants held by surgeon-scientists in OHNS increased, but there is room for improvement given the metrics of neurosurgeons, a population smaller than otolaryngologists. Possible strategies include intramural research grants, surgeon-scientist training programs, and partnerships between specialty societies and NIH administering institutes and centers.

Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial.

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2-month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m2 . One hundred and sixty-six participants were randomized to q1m (n = 82) or q2m (n = 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2-month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558).

Major complications after tongue-tie release: A case report and systematic review.

INTRODUCTION: The diagnosis of ankyloglossia, or tongue-tie, and the number of frenotomies performed has increased over 10-fold from 1997 to 2012 in the United States. The sharpest increase has been in neonates. For parents considering frenotomy for their breastfeeding newborn, there is controversy surrounding the evaluation of tongue-tie and the benefit of a frenotomy. Complications from tongue-tie procedures are thought to be low, though it is not well reported nor studied. OBJECTIVES: The aim of this study is to describe a case of a sublingual mucocele after laser frenotomy in a neonate with tongue-tie and to investigate major complications reported after tongue-tie release in pediatric patients through a systematic review of the literature. CASE REPORT: We present a 6-week-old female who underwent a laser frenotomy procedure performed by a dentist who presented with a new cyst under her tongue. MATERIAL AND METHODS: A systematic literature search of articles published from 1965 to April 2020 was conducted in Ovid MEDLINE(R), Ovid EMBASE, and Scopus. Citations were uploaded into a systematic review software program (DistillerSR, Ottawa, ON, Canada), followed by full text screening. RESULTS: 47 major complications were reported in 34 patients, including our patient. Most of the cases were located in the United States and Europe. The most frequent indications for the procedure were breastfeeding problems (n = 18) and speech impediment (n = 4). The procedure was performed by dentists (n = 6), lactation consultants (n = 5), and otolaryngologists (n = 4). The bulk of the major complications after frenotomy included poor feeding (n = 7), hypovolemic shock (n = 4), apnea (n = 4), acute airway obstruction (n = 4), and Ludwig angina (n = 2). CONCLUSIONS: Reporting of complications after frenotomy is lacking. Risks to neonates may be different than risks to older children and adults. Practitioners across different specialties should be monitoring and studying this more rigorously to better guide patients and families on the risks and benefits of this procedure.

Prevalence and significance of cranial nerve imaging abnormalities in patients with hereditary neuropathies: Clinical implications at the skull base.

OBJECTIVE: To estimate the prevalence and significance of cranial nerve (CN) imaging abnormalities in patients with hereditary neuropathy and discuss clinical implications. METHODS: We retrospectively analyzed data from patients at four tertiary academic medical centers with hereditary neuropathy diagnoses who had undergone gadolinium-enhanced magnetic resonance imaging (MRI) of the brain or skull base between 2004 and 2018. MRI scans, as well as computed tomography imaging when available, were reviewed and bivariable analysis was performed to identify predictors of CN abnormalities on imaging. RESULTS: Among 39 patients meeting study criteria, 11 had clinical CN deficits (28%) and 8 had CN abnormalities on imaging (21%). Of the patients with CN abnormalities on imaging, half had CN deficits (4/8) and only a quarter had imaging abnormalities of the CNs with the deficits (2/8). Imaging abnormalities were found in varied CNs, including CNs III, V, VII, and the VII/VIII complex in the internal auditory canal. MRI obtained for the purpose of evaluating CN deficits had a statistically significant increased likelihood of containing CN imaging abnormalities. However, CN deficits themselves were not predictive of imaging abnormalities. CONCLUSION: Thickening and enhancement of CNs on MRI may be found in approximately 1/5 of patients with hereditary neuropathies and are inconsistently associated with clinical deficits. These imaging findings should not be mistaken for neoplastic and infectious processes as they may be manifestations of the patients' underlying genetic neuropathy. LEVEL OF EVIDENCE: 4.

Molecular therapy for genetic and degenerative vestibular disorders.

PURPOSE OF REVIEW: The primary purpose of this review is to summarize current literature in the field of vestibular regeneration with a focus on recent developments in molecular and gene therapies. RECENT FINDINGS: Since the discovery of limited vestibular hair cell regeneration in mammals in the 1990s, many elegant studies have improved our knowledge of mechanisms of development and regeneration of the vestibular system. A better understanding of the developmental pathways of the vestibular organs has fueled various biological strategies to enhance regeneration, including novel techniques in deriving vestibular hair cells from embryonic and induced pluripotent stem cells. In addition, the identification of specific genetic mutations responsible for vestibular disorders has opened various opportunities for gene replacement therapy. SUMMARY: Vestibular dysfunction is a significant clinical problem with limited therapeutic options, warranting research on biological strategies to repair/regenerate the vestibular organs to restore function. The use of gene therapy appears promising in animal models of vestibular dysfunction.

Oxidative guanine base damage regulates human telomerase activity.

Changes in telomere length are associated with degenerative diseases and cancer. Oxidative stress and DNA damage have been linked to both positive and negative alterations in telomere length and integrity. Here we examined how the common oxidative lesion 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG) regulates telomere elongation by human telomerase. When 8-oxoG is present in the dNTP pool as 8-oxodGTP, telomerase utilization of the oxidized nucleotide during telomere extension is mutagenic and terminates further elongation. Depletion of MTH1, the enzyme that removes oxidized dNTPs, increases telomere dysfunction and cell death in telomerase-positive cancer cells with shortened telomeres. In contrast, a preexisting 8-oxoG within the telomeric DNA sequence promotes telomerase activity by destabilizing the G-quadruplex DNA structure. We show that the mechanism by which 8-oxoG arises in telomeres, either by insertion of oxidized nucleotides or by direct reaction with free radicals, dictates whether telomerase is inhibited or stimulated and thereby mediates the biological outcome.

Outcomes of chronic frontal sinusitis treated with ethmoidectomy: a prospective study.

BACKGROUND: In medically refractory chronic frontal sinusitis, ethmoidectomy without instrumentation of the frontal ostium may resolve frontal disease. Our aim was to determine the efficacy of ethmoidectomy alone for the treatment of chronic frontal sinusitis. METHODS: Adults with chronic rhinosinusitis prospectively enrolled in a multicenter study who demonstrated frontal sinusitis on computed tomography were divided into 2 groups: (1) endoscopic sinus surgery (ESS) incorporating ethmoidectomy, but excluding frontal sinusotomy; and (2) ESS incorporating frontal sinusotomy. The primary outcome was improvement in 22-item Sino-Nasal Outcome Test (SNOT-22) scores. Secondary outcomes included endoscopic scores and use of corticosteroids and antibiotics. RESULTS: A total of 196 cases undergoing frontal sinusotomy and 30 cases treated with ethmoidectomy without frontal sinusotomy were analyzed and were comparable demographically. The prevalence of nasal polyps, previous ESS, asthma, and aspirin intolerance was more common in the frontal sinusotomy group (p < 0.050). Preoperative endoscopy and computed tomography scores were higher in the frontal sinusotomy group (p ≤ 0.001). Postoperatively, both groups showed comparable SNOT-22 scores with worse endoscopy scores in the frontal sinusotomy group (p = 0.038). Postoperative improvement in SNOT-22 total and subdomain scores was comparable between groups. Nasal endoscopy scores improved to a greater degree in the frontal sinusotomy group (p = 0.023). Duration of postoperative topical steroid use was higher in the frontal sinusotomy group (p = 0.007). Revision surgery was needed in 2.6% of frontal sinusotomy patients and 0% of patients without frontal sinusotomy. CONCLUSION: The treatment of chronic frontal sinusitis through ethmoidectomy is a potential alternative to frontal sinusotomy achieving similar quality of life (QOL) improvements in patients manifesting less severe sinus disease.

Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy.

Mutations in the gene isocitrate dehydrogenase 1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. Arginine 132 (R132) mutations in the enzyme IDH1 result in excess production of the metabolite 2-hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized in vivo spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG noninvasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar brain metabolites, such as glutamate and glutamine. 2HG was also detected using 2D high-resolution magic angle spinning MRS performed ex vivo on a separate set of glioma biopsy samples. 2HG detection by in vivo or ex vivo MRS enabled detailed molecular characterization of a clinically important subset of human gliomas. This has implications for diagnosis as well as monitoring of treatments targeting mutated IDH1.