Real-time intraoperative surgical telepathology using confocal laser endomicroscopy.

OBJECTIVE: Communication between neurosurgeons and pathologists is mandatory for intraoperative decision-making and optimization of resection, especially for invasive masses. Handheld confocal laser endomicroscopy (CLE) technology provides in vivo intraoperative visualization of tissue histoarchitecture at cellular resolution. The authors evaluated the feasibility of using an innovative surgical telepathology software platform (TSP) to establish real-time, on-the-fly remote communication between the neurosurgeon using CLE and the pathologist. METHODS: CLE and a TSP were integrated into the surgical workflow for 11 patients with brain masses (6 patients with gliomas, 3 with other primary tumors, 1 with metastasis, and 1 with reactive brain tissue). Neurosurgeons used CLE to generate video-flow images of the operative field that were displayed on monitors in the operating room. The pathologist simultaneously viewed video-flow CLE imaging using a digital tablet and communicated with the surgeon while physically located outside the operating room (1 pathologist was in another state, 4 were at home, and 6 were elsewhere in the hospital). Interpretations of the still CLE images and video-flow CLE imaging were compared with the findings on the corresponding frozen and permanent H&E histology sections. RESULTS: Overall, 24 optical biopsies were acquired with mean ± SD 2 ± 1 optical biopsies per case. The mean duration of CLE system use was 1 ± 0.3 minutes/case and 0.25 ± 0.23 seconds/optical biopsy. The first image with identifiable histopathological features was acquired within 6 ± 0.1 seconds. Frozen sections were processed within 23 ± 2.8 minutes, which was significantly longer than CLE usage (p < 0.001). Video-flow CLE was used to correctly interpret tissue histoarchitecture in 96% of optical biopsies, which was substantially higher than the accuracy of using still CLE images (63%) (p = 0.005). CONCLUSIONS: When CLE is employed in tandem with a TSP, neurosurgeons and pathologists can view and interpret CLE images remotely and in real time without the need to biopsy tissue. A TSP allowed neurosurgeons to receive real-time feedback on the optically interrogated tissue microstructure, thereby improving cross-functional communication and intraoperative decision-making and resulting in significant workflow advantages over the use of frozen section analysis.

Nationwide Trends in Carotid Endarterectomy and Carotid Artery Stenting in the Post-CREST Era.

Background and Purpose- The CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) demonstrated equivalent composite outcomes between carotid endarterectomy (CEA) and carotid artery stenting (CAS) for treating carotid stenosis. We investigated nationwide trends in these procedures and associated periprocedural stroke, myocardial infarction, death, cost, and readmission rates since CREST outcomes were published. Methods- We queried the Nationwide Readmissions Database to identify patients undergoing CEA and CAS for asymptomatic and symptomatic carotid stenosis from 2010 to 2015. Patients were matched based on demographics, comorbidities, and severity of illness. Results- In total, 378 354 CEA and 57 273 CAS patients were treated during this 6-year period. CEA volume decreased by an average of 2669 procedures annually (P=0.001) with stable CAS volume (P=0.225). After matching, CEA patients had a higher rate of periprocedural stroke than CAS patients, driven by increased stroke risk in symptomatic CEA patients (8.1% versus 5.6%; odds ratio, 1.47 [CI, 1.29-1.68]; P<0.001) but a lower rate of overall inpatient mortality (0.8% versus 1.4%; odds ratio, 0.57 [CI, 0.48-0.68]; P<0.001). CEA patients were less likely to be readmitted within 30 days (7.2% versus 8.0%; odds ratio, 0.90 [CI, 0.84-0.96]; P=0.018) and 90 days (12.3% versus 14.1%; odds ratio, 0.86 [CI, 0.81-0.90]; P<0.001), and mean hospital costs were lower for CEA compared with CAS ($14 433 versus $19 172; P<0.001). Conclusions- The procedural treatment of carotid stenosis has changed dramatically in the post-CREST era. When matched for characteristics and illness severity, patients undergoing CEA had a higher rate of perioperative stroke than patients undergoing CAS, primarily among symptomatic patients. These findings are in contrast to the findings of CREST, which showed nearly twice the risk of stroke in CAS patients compared with CEA patients. CEA was associated with lower procedure cost and readmission rate.

National trends in hospital readmission following transsphenoidal surgery for pituitary lesions.

PURPOSE: Several institutions recently published their experiences with unplanned readmissions rates after transsphenoidal surgery for pituitary lesions. Readmission rates on a national level, however, have not been explored in depth. We investigated nationwide trends in this procedure and associated independent predictors, costs, and causes of 30-day readmission. METHODS: The Nationwide Readmissions Database was queried to identify patients 18 and older who underwent transsphenoidal surgery for pituitary lesion resection (2010-2015). National trends and statistical variances were calculated based on weighted, clustered, and stratified sample means. RESULTS: Of the weighted total of 44,759 patients treated over the 6-year period, 4658 (10.4%) were readmitted within 30 days. Readmission rates did not change across the survey period (P = 0.71). Patients readmitted had a higher prevalence of comorbidities than those not readmitted (82.5% vs. 78.4%, respectively, P < 0.001), experienced more postoperative complications (47.2% vs. 31.8%, P < 0.001), and had a longer length of stay (6.59 vs. 4.23 days, P < 0.001) during index admission. The most common causes for readmission were SIADH (17.5%) and other hyponatremia (16.4%). Average total readmission cost was $12,080 with no significant trend across the study period (P = 0.25). Predictors for readmission identified included diabetes mellitus, psychological disorders, renal failure, and experiencing diabetes insipidus during the index admission. CONCLUSION: Unplanned readmission is an important quality metric. While transsphenoidal pituitary surgery is a relatively safe procedure, 30-day readmission rates and costs have not declined. Future studies on institutional protocols targeting these identified predictors to prevent readmission are necessary to decrease readmission rates on a national scale.

Use of a wrist-mounted device for continuous outpatient physiologic monitoring after transsphenoidal surgery: a pilot study.

PURPOSE: Patients who undergo transsphenoidal surgery can experience hormonal, electrolyte, and fluid disturbances in the postoperative period leading to outpatient readmissions for medical management. Our goal was to determine whether use of a wrist-mounted physiologic tracking device is feasible in this setting and whether changes or trends in these parameters after discharge can help predict aberrant physiology in these patients. METHODS: Wrist-mounted physiologic tracking devices that transmit data via Bluetooth to a mobile device were used to monitor patients. Preoperative baseline data and postoperative data were aggregated daily to compare within-patient and between-patient trends. RESULTS: Of 11 patients enrolled in the study, 1 was readmitted for symptomatic hyponatremia. Device data completeness ranged from 78 to 93% with the exception of oxygen saturation (25% completeness). The patient with hyponatremia had a significantly lower baseline level of activity compared with other patients. Nonreadmitted patient activity variables (steps, calories, and distance) decreased by 48-52% after the operation (P < 0.001). The activity variables for the patient with hyponatremia were statistically unchanged after the operation; however, the patient did experience a significant decrease in heart rate compared with baseline. CONCLUSION: Deployment of a wrist-based physiologic tracking device is feasible for surgical patients in elective clinical practice. Overall, the device was associated with good patient adherence and high patient satisfaction. Patient activity significantly decreased after surgery. A significant decrease in heart rate was detected in a patient with hyponatremia who required readmission, which reflects the known intravascular volume expansion in this state.

Clinical, pathologic, and imaging characteristics of pituitary null cell adenomas as defined according to the 2017 World Health Organization criteria: a case series from two pituitary centers.

PURPOSE: The 2017 World Health Organization classification of pituitary tumors redefined pituitary null cell adenomas (NCAs) by restricting this diagnostic category to pituitary tumors that are negative for pituitary transcription factors and adenohypophyseal hormones. The clinical behavior of this redefined entity has not been widely studied, and this is a major shortcoming of the classification. This study evaluated the imaging and clinical features of NCAs from two pituitary centers and compared them with those of gonadotroph adenomas (GAs). METHODS: Imaging, pathologic, and clinical characteristics of NCAs and GAs were retrospectively reviewed. Tumor immunohistochemistry was performed to confirm absence of adenohypophyseal hormones and pituitary transcription factor expression. RESULTS: Thirty-one NCAs were compared with 38 GAs. NCAs were more likely to invade the cavernous sinus (15/31 [48%] vs. 5/38 [13%], P = .003) and had a higher proliferative index (i.e., MIB-1 > 3%, 11/31 [35%] vs. 5/38 [13%], P = .04). Gross total resection was less likely in the NCA group (19/31 [61%] vs. 33/38 [87], P = .02). Progression-free survival was worse in the NCA cohort (5-year progression-free survival, 0.70 vs. 1.00; P = .011, by log-rank test). CONCLUSIONS: Compared with GAs, NCAs are more invasive at the time of presentation and have a more aggressive clinical course. This study provides evidence that NCAs represent a distinct clinicopathologic entity with behavior that differs adversely from that of GAs. This may inform clinical decision-making, including frequency of postoperative tumor surveillance and timing of adjunctive treatments.

Patient out-of-pocket spending in cranial neurosurgery: single-institution analysis of 6569 consecutive cases and literature review.

OBJECTIVE With drastic changes to the health insurance market, patient cost sharing has significantly increased in recent years. However, the patient financial burden, or out-of-pocket (OOP) costs, for surgical procedures is poorly understood. The goal of this study was to analyze patient OOP spending in cranial neurosurgery and identify drivers of OOP spending growth. METHODS For 6569 consecutive patients who underwent cranial neurosurgery from 2013 to 2016 at the authors' institution, the authors created univariate and multivariate mixed-effects models to investigate the effect of patient demographic and clinical factors on patient OOP spending. The authors examined OOP payments stratified into 10 subsets of case categories and created a generalized linear model to study the growth of OOP spending over time. RESULTS In the multivariate model, case categories (craniotomy for pain, tumor, and vascular lesions), commercial insurance, and out-of-network plans were significant predictors of higher OOP payments for patients (all p < 0.05). Patient spending varied substantially across procedure types, with patients undergoing craniotomy for pain ($1151 ± $209) having the highest mean OOP payments. On average, commercially insured patients spent nearly twice as much in OOP payments as the overall population. From 2013 to 2016, the mean patient OOP spending increased 17%, from $598 to $698 per patient encounter. Commercially insured patients experienced more significant growth in OOP spending, with a cumulative rate of growth of 42% ($991 in 2013 to $1403 in 2016). CONCLUSIONS Even after controlling for inflation, case-mix differences, and partial fiscal periods, OOP spending for cranial neurosurgery patients significantly increased from 2013 to 2016. The mean OOP spending for commercially insured neurosurgical patients exceeded $1400 in 2016, with an average annual growth rate of 13%. As patient cost sharing in health insurance plans becomes more prevalent, patients and providers must consider the potential financial burden for patients receiving specialized neurosurgical care.

National treatment trends, complications, and predictors of in-hospital charges for the surgical management of craniopharyngiomas in adults from 2007 to 2011.

OBJECT: Treatment of craniopharyngiomas is one of the most demanding and controversial neurosurgical procedures performed. The authors sought to determine the factors associated with hospital charges and fees for craniopharyngioma treatment to identify possible opportunities for improving the health care economics of inpatient care. METHODS: The authors analyzed the hospital discharge database of the Nationwide Inpatient Sample (NIS) covering the period from 2007 through 2011 to examine national treatment trends for adults (that is, those older than 18 years) who had undergone surgery for craniopharyngioma. To predict the drivers of in-hospital charges, a multistep regression model was developed that accounted for patient demographics, acuity measures, comorbidities, hospital characteristics, and complications. RESULTS: The analysis included 606 patients who underwent resection of craniopharyngioma; 353 resections involved a transsphenoidal approach (58%) and 253 a transfrontal approach (42%). The mean age (± SD) of patients was 47.7 ± 16.3 years. The average hospital length of stay (LOS) was 7.6 ± 9 days. The mean hospital charge (± SD) was $92,300 ± $83,356. In total, 48% of the patients experienced postoperative diabetes insipidus or an electrolyte abnormality. A multivariate regression model demonstrated that LOS, hospital volume for the selected procedure, the surgical approach, postoperative complications, comorbidities, and year of surgery were all significant predictors of in-hospital charges. The statistical model accounted for 54% of the variance in in-hospital charge. CONCLUSIONS: This analysis of inpatient hospital charges in patients undergoing craniopharyngioma surgery identified key drivers of charges in the perioperative period. Prospective studies designed to evaluate the long-term resource utilization in this complex patient population would be a useful future direction.

hglobal-Index: A Novel Author-Level Measure of the Diffusion of Scientific Ideas Among High-, Low-, and Middle-Income Countries.

OBJECTIVE: To describe an intuitive and useful method for measuring the global impact of a medical scholar's research ideas by examining cross-border citations (CBCs) of peer-reviewed neurosurgical publications. METHODS: Publication and citation data for a random sample of the top 50 most academically productive neurosurgeons were obtained from Scopus Application Programming Interface. We characterized an author-level global impact index analogous to the widely used h-index, the hglobal-index, defined as the number of published peer-reviewed manuscripts with at least the same number of CBCs. To uncover socioeconomic insights, we explored the hglobal-index for high-, middle-, and low-income countries. RESULTS: The median (interquartile range) number of publications and CBCs were 144 (62-255) and 2704 (959-5325), respectively. The median (interquartile range) h-index and hglobal-index were 42 (23-61) and 32 (17-38), respectively. Compared with neurosurgeons in the random sample, the 3 global neurosurgeons had the highest hglobal-indices in low-income countries at 17, 13, and 9, despite below-average h-index scores of 33, 38, and 19, respectively. CONCLUSION: This intuitive update to the h-index uses CBCs to measure the global impact of scientific research. The hglobal-index may provide insight into global diffusion of medical ideas, which can be used for social science research, author self-assessment, and academic promotion.

A proposed clinical classification for pituitary neoplasms to guide therapy and prognosis.

No comprehensive classification system that guides prognosis and therapy of pituitary adenomas exists. The 2022 WHO histopathology-based classification system can only be applied to lesions that are resected, which represent few clinically significant pituitary adenomas. Many factors independent of histopathology provide mechanistic insight into causation and influence prognosis and treatment of pituitary adenomas. We propose a new approach to guide prognosis and therapy of pituitary adenomas by integrating clinical, genetic, biochemical, radiological, pathological, and molecular information for all adenomas arising from anterior pituitary cell lineages. The system uses an evidence-based scoring of risk factors to yield a cumulative score that reflects disease severity and can be used at the bedside to guide pituitary adenoma management. Once validated in prospective studies, this simple manageable classification system could provide a standardised platform for assessing disease severity, prognosis, and effects of therapy on pituitary adenomas.

Intraoperative in vivo confocal laser endomicroscopy imaging at glioma margins: can we detect tumor infiltration?

OBJECTIVE: Confocal laser endomicroscopy (CLE) is a US Food and Drug Administration-cleared intraoperative real-time fluorescence-based cellular resolution imaging technology that has been shown to image brain tumor histoarchitecture rapidly in vivo during neuro-oncological surgical procedures. An important goal for successful intraoperative implementation is in vivo use at the margins of infiltrating gliomas. However, CLE use at glioma margins has not been well studied. METHODS: Matching in vivo CLE images and tissue biopsies acquired at glioma margin regions of interest (ROIs) were collected from 2 institutions. All images were reviewed by 4 neuropathologists experienced in CLE. A scoring system based on the pathological features was implemented to score CLE and H&E images from each ROI on a scale from 0 to 5. Based on the H&E scores, all ROIs were divided into a low tumor probability (LTP) group (scores 0-2) and a high tumor probability (HTP) group (scores 3-5). The concordance between CLE and H&E scores regarding tumor probability was determined. The intraclass correlation coefficient (ICC) and diagnostic performance were calculated. RESULTS: Fifty-six glioma margin ROIs were included for analysis. Interrater reliability of the scoring system was excellent when used for H&E images (ICC [95% CI] 0.91 [0.86-0.94]) and moderate when used for CLE images (ICC [95% CI] 0.69 [0.40-0.83]). The ICCs (95% CIs) of the LTP group (0.68 [0.40-0.83]) and HTP group (0.68 [0.39-0.83]) did not differ significantly. The concordance between CLE and H&E scores was 61.6%. The sensitivity and specificity values of the scoring system were 79% and 37%. The positive predictive value (PPV) and negative predictive value were 65% and 53%, respectively. Concordance, sensitivity, and PPV were greater in the HTP group than in the LTP group. Specificity was higher in the newly diagnosed group than in the recurrent group. CONCLUSIONS: CLE may detect tumor infiltration at glioma margins. However, it is not currently dependable, especially in scenarios where low probability of tumor infiltration is expected. The proposed scoring system has excellent intrinsic interrater reliability, but its interrater reliability is only moderate when used with CLE images. These results suggest that this technology requires further exploration as a method for consistent actionable intraoperative guidance with high dependability across the range of tumor margin scenarios. Specific-binding and/or tumor-specific fluorophores, a CLE image atlas, and a consensus guideline for image interpretation may help with the translational utility of CLE.

A Prospective, Multicenter, Observational Study of Surgical vs Nonsurgical Management for Pituitary Apoplexy.

CONTEXT: Pituitary apoplexy (PA) has been traditionally considered a neurosurgical emergency, yet retrospective single-institution studies suggest similar outcomes among patients managed medically. OBJECTIVE: We established a multicenter, international prospective registry to compare presentation and outcomes in PA patients treated with surgery or medical management alone. METHODS: A centralized database captured demographics, comorbidities, clinical presentation, visual findings, hormonal status, and imaging features at admission. Treatment was determined independently by each site. Key outcomes included visual, oculomotor, and hormonal recovery, complications, and hospital length of stay. Outcomes were also compared based on time from symptom onset to surgery, and from admission or transfer to the treating center. Statistical testing compared treatment groups based on 2-sided hypotheses and P less than .05. RESULTS: A total of 100 consecutive PA patients from 12 hospitals were enrolled, and 97 (67 surgical and 30 medical) were evaluable. Demographics, clinical features, presenting symptoms, hormonal deficits, and imaging findings were similar between groups. Severe temporal visual field deficit was more common in surgical patients. At 3 and 6 months, hormonal, visual, and oculomotor outcomes were similar. Stratifying based on severity of visual fields demonstrated no difference in any outcome at 3 months. Timing of surgery did not affect outcomes. CONCLUSION: We found that medical and surgical management of PA yield similar 3-month outcomes. Although patients undergoing surgery had more severe visual field deficits, we could not clearly demonstrate that surgery led to better outcomes. Even without surgery, apoplectic tumor volumes regress substantially within 2 to 3 months, indicating that surgery is not always needed to reduce mass effect.

Predictors of Durable Remission After Successful Surgery for Cushing Disease: Results From the Multicenter RAPID Registry.

BACKGROUND AND OBJECTIVE: Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated. METHODS: Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses. RESULTS: Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm3 vs 0.49 ± 1.17 cm3, P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis. CONCLUSION: This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes.

Multicenter Registry of Adenomas of the Pituitary and Related Disorders: Initial Description of Cushing Disease Cohort, Surgical Outcomes, and Surgeon Characteristics.

BACKGROUND AND OBJECTIVES: To address the lack of a multicenter pituitary surgery research consortium in the United States, we established the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). The goals of RAPID are to examine surgical outcomes, improve patient care, disseminate best practices, and facilitate multicenter surgery research at scale. Our initial focus is Cushing disease (CD). This study aims to describe the current RAPID patient cohort, explore surgical outcomes, and lay the foundation for future studies addressing the limitations of previous studies. METHODS: Prospectively and retrospectively obtained data from participating sites were aggregated using a cloud-based registry and analyzed retrospectively. Standard preoperative variables and outcome measures included length of stay, unplanned readmission, and remission. RESULTS: By July 2023, 528 patients with CD had been treated by 26 neurosurgeons with varying levels of experience at 9 academic pituitary centers. No surgeon treated more than 81 of 528 (15.3%) patients. The mean ± SD patient age was 43.8 ± 13.9 years, and most patients were female (82.2%, 433/527). The mean tumor diameter was 0.8 ± 2.7 cm. Most patients (76.6%, 354/462) had no prior treatment. The most common pathology was corticotroph tumor (76.8%, 381/496). The mean length of stay was 3.8 ± 2.5 days. The most common discharge destination was home (97.2%, 513/528). Two patients (0.4%, 2/528) died perioperatively. A total of 57 patients (11.0%, 57/519) required an unplanned hospital readmission within 90 days of surgery. The median actuarial disease-free survival after index surgery was 8.5 years. CONCLUSION: This study examined an evolving multicenter collaboration on patient outcomes after surgery for CD. Our results provide novel insights on surgical outcomes not possible in prior single-center studies or with national administrative data sets. This collaboration will power future studies to better advance the standard of care for patients with CD.

Endoscopic Endonasal Transsphenoidal Approach to Repair Cerebrospinal Fluid Rhinorrhea After an Anterior Clinoidectomy for Aneurysm Clipping: Series of 4 Cases.

BACKGROUND: Cerebrospinal fluid (CSF) rhinorrhea through a pneumatized optic strut is a known potential complication after an anterior clinoidectomy that is used to microsurgically clip a proximal internal carotid artery aneurysm. The original craniotomy site can be reopened to repair the skull base defect, but this technique has disadvantages. OBJECTIVE: To avoid a repeat craniotomy and address the limitations of a transcranial approach, a straightforward alternative was used for skull base repair-the binostril endoscopic endonasal transsphenoidal approach. METHODS: This retrospective case series describes the use of endoscopic transsphenoidal repair and outcomes for patients with CSF leaks after anterior clinoidectomy for aneurysm repair between January 1, 2015, and December 31, 2019. RESULTS: Four adult patients (3 women and 1 man) with a mean age of 59.5 years were reviewed. Skull base repair occurred on average 24 days (range, 4-75 days) after the index operation. After demucosalization of the parasellar sphenoid sinus, the fistula in the pneumatized optic strut was reconstructed with a free nasal mucosal graft with or without an autologous muscle graft. None of the patients developed a recurrent CSF leak at a mean follow-up of 12.5 months (range, 8-22 months), and none experienced complications. CONCLUSION: The endoscopic endonasal transsphenoidal approach was safe and effective for skull base repair in 4 patients with CSF rhinorrhea after an anterior clinoidectomy for aneurysm clipping.

Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators.

Cushing's disease (CD) is a serious endocrine disorder attributed to an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that that subsequently leads to chronic hypercortisolemia. PitNET regression has been reported following treatment with the investigational selective glucocorticoid receptor (GR) modulator relacorilant, but the mechanisms behind that effect remain unknown. Human PitNET organoid models were generated from induced human pluripotent stem cells (iPSCs) or fresh tissue obtained from CD patient PitNETs (hPITOs). Genetically engineered iPSC derived organoids were used to model the development of corticotroph PitNETs expressing USP48 (iPSCUSP48) or USP8 (iPSCUSP8) somatic mutations. Organoids were treated with the GR antagonist mifepristone or the GR modulator relacorilant with or without somatostatin receptor (SSTR) agonists pasireotide or octreotide. In iPSCUSP48 and iPSCUSP8 cultures, mifepristone induced a predominant expression of SSTR2 with a concomitant increase in ACTH secretion and tumor cell proliferation. Relacorilant predominantly induced SSTR5 expression and tumor cell apoptosis with minimal ACTH induction. Hedgehog signaling mediated the induction of SSTR2 and SSTR5 in response to mifepristone and relacorilant. Relacorilant sensitized PitNET organoid responsiveness to pasireotide. Therefore, our study identified the potential therapeutic use of relacorilant in combination with somatostatin analogs and demonstrated the advantages of relacorilant over mifepristone, supporting its further development for use in the treatment of Cushing's disease patients.

Intraoperative confocal laser endomicroscopy: prospective in vivo feasibility study of a clinical-grade system for brain tumors.

OBJECTIVE: The authors evaluated the feasibility of using the first clinical-grade confocal laser endomicroscopy (CLE) system using fluorescein sodium for intraoperative in vivo imaging of brain tumors. METHODS: A CLE system cleared by the FDA was used in 30 prospectively enrolled patients with 31 brain tumors (13 gliomas, 5 meningiomas, 6 other primary tumors, 3 metastases, and 4 reactive brain tissue). A neuropathologist classified CLE images as interpretable or noninterpretable. Images were compared with corresponding frozen and permanent histology sections, with image correlation to biopsy location using neuronavigation. The specificities and sensitivities of CLE images and frozen sections were calculated using permanent histological sections as the standard for comparison. A recently developed surgical telepathology software platform was used in 11 cases to provide real-time intraoperative consultation with a neuropathologist. RESULTS: Overall, 10,713 CLE images from 335 regions of interest were acquired. The mean duration of the use of the CLE system was 7 minutes (range 3-18 minutes). Interpretable CLE images were obtained in all cases. The first interpretable image was acquired within a mean of 6 (SD 10) images and within the first 5 (SD 13) seconds of imaging; 4896 images (46%) were interpretable. Interpretable image acquisition was positively correlated with study progression, number of cases per surgeon, cumulative length of CLE time, and CLE time per case (p ≤ 0.01). The diagnostic accuracy, sensitivity, and specificity of CLE compared with frozen sections were 94%, 94%, and 100%, respectively, and the diagnostic accuracy, sensitivity, and specificity of CLE compared with permanent histological sections were 92%, 90%, and 94%, respectively. No difference was observed between lesion types for the time to first interpretable image (p = 0.35). Deeply located lesions were associated with a higher percentage of interpretable images than superficial lesions (p = 0.02). The study met the primary end points, confirming the safety and feasibility and acquisition of noninvasive digital biopsies in all cases. The study met the secondary end points for the duration of CLE use necessary to obtain interpretable images. A neuropathologist could interpret the CLE images in 29 (97%) of 30 cases. CONCLUSIONS: The clinical-grade CLE system allows in vivo, intraoperative, high-resolution cellular visualization of tissue microstructure and identification of lesional tissue patterns in real time, without the need for tissue preparation.

The anterior skull base nasal inventory (ASK nasal inventory): a clinical tool for evaluating rhinological outcomes after endonasal surgery for pituitary and cranial base lesions.

The goal of this project was to develop a prospectively-validated, site-specific patient quality of life survey for assessing nasal outcomes following endonasal pituitary and skull base surgery. (ClinicalTrials.gov #NCT01322945) An 9-item patient survey (the ASK Nasal Inventory) focusing on the most common postoperative complaints, such as crusting, sinusitis, pain, and ease of breathing, was developed by the anterior skull base team at the Barrow Neurological Institute. Content was validated in structured patient interviews and by four subject matter experts. This survey was self-administered before and 3 months after surgery to 94 patients (52 endonasal surgery and 42 controls) between October 2010 and June 2011. Standard methods for psychometric evaluation were applied. Cronbach's alpha was 0.83 indicating good internal consistency. Test-retest reliability was excellent in both groups (r = 0.87 and 0.95; P < 0.001). Discriminant validity was determined by comparing mean scores at 3 months in the endonasal and control groups and the difference was significant (13.5 vs. 17.2, P = 0.001). Standardized response mean was 0.17 suggesting that the scale was sensitive to clinical change. Concurrent validity was determined by mean ASK Nasal score for each level of self-reported overall functioning at 3 months (P = 0.001). Preliminary psychometric evaluation of the performance of the ASK Nasal Inventory suggests that it meets criteria as a clinical and research instrument in endonasal surgery. This study also suggests modifications to the instrument, which will serve as key quality of life endpoint in an ongoing multicenter nasal outcomes study.

The journey of discovering skull base anatomy in ancient Egypt and the special influence of Alexandria.

The field of anatomy, one of the most ancient sciences, first evolved in Egypt. From the Early Dynastic Period (3100 BC) until the time of Galen at the end of the 2nd century ad, Egypt was the center of anatomical knowledge, including neuroanatomy. Knowledge of neuroanatomy first became important so that sacred rituals could be performed by ancient Egyptian embalmers during mummification procedures. Later, neuroanatomy became a science to be studied by wise men at the ancient temple of Memphis. As religious conflicts developed, the study of the human body became restricted. Myths started to replace scientific research, squelching further exploration of the human body until Alexander the Great founded the city of Alexandria. This period witnessed a revolution in the study of anatomy and functional anatomy. Herophilus of Chalcedon, Erasistratus of Chios, Rufus of Ephesus, and Galen of Pergamon were prominent physicians who studied at the medical school of Alexandria and contributed greatly to knowledge about the anatomy of the skull base. After the Royal Library of Alexandria was burned and laws were passed prohibiting human dissections based on religious and cultural factors, knowledge of human skull base anatomy plateaued for almost 1500 years. In this article the authors consider the beginning of this journey, from the earliest descriptions of skull base anatomy to the establishment of basic skull base anatomy in ancient Egypt.