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Abstract Background Treatment-induced neuroendocrine prostate cancer (tNEPC) is an aggressive variant of late-stage metastatic castrate-resistant prostate cancer that commonly arises through neuroendocrine transdifferentiation (NEtD). Treatment options are limited, ineffective, and, for most patients, result in death in less than a year. We previously developed a first-in-field patient-derived xenograft (PDX) model of NEtD. Longitudinal deep transcriptome profiling of this model enabled monitoring of dynamic transcriptional changes during NEtD and in the context of androgen deprivation. Long non-coding RNA (lncRNA) are implicated in cancer where they can control gene regulation. Until now, the expression of lncRNAs during NEtD and their clinical associations were unexplored. Results We implemented a next-generation sequence analysis pipeline that can detect transcripts at low expression levels and built a genome-wide catalogue (n = 37,749) of lncRNAs. We applied this pipeline to 927 clinical samples and our high-fidelity NEtD model LTL331 and identified 821 lncRNAs in NEPC. Among these are 122 lncRNAs that robustly distinguish NEPC from prostate adenocarcinoma (AD) patient tumours. The highest expressed lncRNAs within this signature are H19, LINC00617, and SSTR5-AS1. Another 742 are associated with the NEtD process and fall into four distinct patterns of expression (NEtD lncRNA Class I, II, III, and IV) in our PDX model and clinical samples. Each class has significant (z-scores >2) and unique enrichment for transcription factor binding site (TFBS) motifs in their sequences. Enriched TFBS include (1) TP53 and BRN1 in Class I, (2) ELF5, SPIC, and HOXD1 in Class II, (3) SPDEF in Class III, (4) HSF1 and FOXA1 in Class IV, and (5) TWIST1 when merging Class III with IV. Common TFBS in all NEtD lncRNA were also identified and include E2F, REST, PAX5, PAX9, and STAF. Interrogation of the top deregulated candidates (n = 100) in radical prostatectomy adenocarcinoma samples with long-term follow-up (median 18 years) revealed significant clinicopathological associations. Specifically, we identified 25 that are associated with rapid metastasis following androgen deprivation therapy (ADT). Two of these lncRNAs (SSTR5-AS1 and LINC00514) stratified patients undergoing ADT based on patient outcome. Discussion To date, a comprehensive characterization of the dynamic landscape of lncRNAs during the NEtD process has not been performed. A temporal analysis of the PDX-based NEtD model has for the first time provided this dynamic landscape. TFBS analysis identified NEPC-related TF motifs present within the NEtD lncRNA sequences, suggesting functional roles for these lncRNAs in NEPC pathogenesis. Furthermore, select NEtD lncRNAs appear to be associated with metastasis and patients receiving ADT. Treatment-related metastasis is a clinical consequence of NEPC tumours. Top candidate lncRNAs FENDRR, H19, LINC00514, LINC00617, and SSTR5-AS1 identified in this study are implicated in the development of NEPC. We present here for the first time a genome-wide catalogue of NEtD lncRNAs that characterize the transdifferentiation process and a robust NEPC lncRNA patient expression signature. To accomplish this, we carried out the largest integrative study that applied a PDX NEtD model to clinical samples. These NEtD and NEPC lncRNAs are strong candidates for clinical biomarkers and therapeutic targets and warrant further investigation.

Objective(1) Assess 3‐dimensional volumetric growth of untreated sporadic vestibular schwannomas (VSs) in a large cohort of patients treated with conservative observation. (2) Compare volumetric and conventional linear diameter measurements for detecting tumor growth.Study DesignCase series with chart review.SettingTertiary skull base referral center.Subjects and MethodsPatients with sporadic VS who elected initial conservative treatment with at least 2 serial magnetic resonance imaging (MRI) scans were included. Tumor volume was determined with 3‐dimensional segmentation of MRI sequences. The volumetric threshold for tumor growth was an increase ≥20% from baseline tumor volume. Tumor size based on linear diameter was assessed with the 1995 American Academy of Otolaryngology—Head and Neck Surgery Foundation guidelines for VS outcome reporting, with growth defined as an increase ≥2 mm.ResultsA total of 361 patients were included with a median radiologic follow‐up of 4.1 years (interquartile range [IQR], 2.5‐6.8). At diagnosis, 232 VSs (64%) were purely intracanalicular, and 129 (36%) extended into the cerebellopontine angle. The median baseline tumor volume was 0.161 cm3 (IQR, 0.054‐0.418). Overall, 69% of tumors demonstrated volumetric growth at a median of 1.1 years (IQR, 0.6‐2.1) after initial MRI. In contrast, based on linear measurement assessment, 48% of tumors demonstrated growth at a median of 1.8 years (IQR, 0.8‐3.1) from first MRI scan. Disequilibrium, facial hypoesthesia, aural fullness, initial tumor size, and nonincidental diagnosis were associated with tumor growth.ConclusionThree‐dimensional volumetric assessment of VS provides a more sensitive measure of tumor growth when compared with linear diameter assessment. Through volumetric analysis, the current study revealed that a significant proportion of VSs demonstrate growth during observation.

OBJECTIVE The morbidity of gross-total resection of jugular paraganglioma (JP) is often unacceptable due to the potential for irreversible lower cranial neuropathy. Stereotactic radiosurgery (SRS) has been used at the authors’ institution since 1990 for the treatment of JP and other benign intracranial tumors. Conventional means of assessing tumor progression using linear measurements or elliptical approximations are imprecise due to the irregular shape and insinuating growth pattern of JP. The objective of this study was to assess long-term tumor control in these patients by using slice-by-slice 3D volumetric segmentation of serial MRI data. METHODS Radiographic data and clinical records were reviewed retrospectively at a single, tertiary-care academic referral center for patients treated from 1990 to 2017. Volumetric analyses by integration of consecutive tumor cross-sectional areas (tumor segmentation) of serial MRI data were performed. Tumor progression was defined as volumetric growth of 15% or greater over the imaging interval. Primary outcomes analyzed included survival free of radiographic and clinical progression. Secondary outcomes included new or worsened cranial neuropathy. RESULTS A total of 85 patients were treated with Gamma Knife radiosurgery (GKRS) for JP at the authors’ institution over the last 27 years. Sixty patients had pretreatment and serial posttreatment contrast-enhanced MRI follow-up suitable for volumetric analysis. A total of 214 MR images were analyzed to segment tumor images in a slice-by-slice fashion to calculate integral tumor volume. The median follow-up duration was 66 months (range 7–202 months). At 5 years the tumor progression-free survival rate was 98%. Three tumors exhibited progression more than 10 years after GKRS. Estimated survival free of radiographic progression rates (95% confidence interval [CI]; n = number still at risk) at 5, 10, and 15 years following radiosurgery were 98% (95% CI 94%–100%; n = 34), 94% (95% CI 85%–100%; n = 16), and 74% (95% CI 56%–98%; n = 6), respectively. One patient with tumor progression required treatment intervention using external beam radiation therapy, constituting the only case of clinical progression. Two patients (3%) without preexisting lower cranial nerve dysfunction developed new ipsilateral vocal fold paralysis following radiosurgery. CONCLUSIONS SRS achieves excellent long-term tumor control for JP without a high risk for new or worsened cranial neuropathy when used in primary, combined modality, or recurrent settings. Long-term follow-up is critical due to the potential for late radiographic progression (i.e., more than 10 years after SRS). As none of the patients with late progression have required salvage therapy, the clinical implications of this degree of tumor growth have yet to be determined.

Evidence from animal studies indicates that hyperinsulinemia, without changes in glucose, increases ventilation via a carotid body-mediated mechanism. However, whether insulin elevates ventilation in humans independently of changes in glucose remains unclear. Therefore, we tested the hypothesis that insulin increases ventilation in humans during a hyperinsulinemic-euglycemic clamp in which insulin was elevated to postprandial concentrations while glucose was maintained at fasting concentrations. First, in 16 healthy young men ( protocol 1), we retrospectively analyzed respiration rate and estimated tidal volume from a pneumobelt to calculate minute ventilation during a hyperinsulinemic-euglycemic clamp. In addition, for a direct assessment of minute ventilation during a hyperinsulinemic-euglycemic clamp, we retrospectively analyzed breath-by-breath respiration rate and tidal volume from inspired/expired gasses in an additional 23 healthy young subjects ( protocol 2). Clamp infusion elevated minute ventilation from baseline in both protocols ( protocol 1: +11.9 ± 4.6% baseline, P = 0.001; protocol 2: +9.5 ± 3.8% baseline, P = 0.020). In protocol 1, peak changes in both respiration rate (+13.9 ± 3.0% baseline, P < 0.001) and estimated tidal volume (+16.9 ± 4.1% baseline, P = 0.001) were higher than baseline during the clamp. In protocol 2, tidal volume primarily increased during the clamp (+9.7 ± 3.7% baseline, P = 0.016), as respiration rate did not change significantly (+0.2 ± 1.8% baseline, P = 0.889). Collectively, we demonstrate for the first time in humans that elevated plasma insulin increases minute ventilation independent of changes in glucose.

Abstract Physician burnout, a work‐related syndrome involving emotional exhaustion, depersonalization and a sense of reduced personal accomplishment, is prevalent internationally. Rates of burnout symptoms that have been associated with adverse effects on patients, the healthcare workforce, costs and physician health exceed 50% in studies of both physicians‐in‐training and practicing physicians. This problem represents a public health crisis with negative impacts on individual physicians, patients and healthcare organizations and systems. Drivers of this epidemic are largely rooted within healthcare organizations and systems and include excessive workloads, inefficient work processes, clerical burdens, work–home conflicts, lack of input or control for physicians with respect to issues affecting their work lives, organizational support structures and leadership culture. Individual physician‐level factors also play a role, with higher rates of burnout commonly reported in female and younger physicians. Effective solutions align with these drivers. For example, organizational efforts such as locally developed practice modifications and increased support for clinical work have demonstrated benefits in reducing burnout. Individually focused solutions such as mindfulness‐based stress reduction and small‐group programmes to promote community, connectedness and meaning have also been shown to be effective. Regardless of the specific approach taken, the problem of physician burnout is best addressed when viewed as a shared responsibility of both healthcare systems and individual physicians. Although our understanding of physician burnout has advanced considerably in recent years, many gaps in our knowledge remain. Longitudinal studies of burnout's effects and the impact of interventions on both burnout and its effects are needed, as are studies of effective solutions implemented in combination. For medicine to fulfil its mission for patients and for public health, all stakeholders in healthcare delivery must work together to develop and implement effective remedies for physician burnout.