Multi-Dynamic-Multi-Echo-based MRI for the Pre-Surgical Determination of Sellar Tumor Consistency: a Quantitative Approach for Predicting Lesion Resectability.

PURPOSE: Pre-surgical information about tumor consistency could facilitate neurosurgical planning. This study used multi-dynamic-multi-echo (MDME)-based relaxometry for the quantitative determination of pituitary tumor consistency, with the aim of predicting lesion resectability. METHODS: Seventy-two patients with suspected pituitary adenomas, who underwent preoperative 3 T MRI between January 2020 and January 2022, were included in this prospective study. Lesion-specific T1-/T2-relaxation times (T1R/T2R) and proton density (PD) metrics were determined. During surgery, data about tumor resectability were collected. A Receiver Operating Characteristic (ROC) curve analysis was performed to investigate the diagnostic performance (sensitivity/specificity) for discriminating between easy- and hard-to-remove by aspiration (eRAsp and hRAsp) lesions. A Mann-Whitney-U-test was done for group comparison. RESULTS: A total of 65 participants (mean age, 54 years ± 15, 33 women) were enrolled in the quantitative analysis. Twenty-four lesions were classified as hRAsp, while 41 lesions were assessed as eRAsp. There were significant differences in T1R (hRAsp: 1221.0 ms ± 211.9; eRAsp: 1500.2 ms ±â€¯496.4; p = 0.003) and T2R (hRAsp: 88.8 ms ± 14.5; eRAsp: 137.2 ms ± 166.6; p = 0.03) between both groups. The ROC analysis revealed an area under the curve of 0.72 (95% CI: 0.60-0.85) at p = 0.003 for T1R (cutoff value: 1248 ms; sensitivity/specificity: 78%/58%) and 0.66 (95% CI: 0.53-0.79) at p = 0.03 for T2R (cutoff value: 110 ms; sensitivity/specificity: 39%/96%). CONCLUSION: MDME-based relaxometry enables a non-invasive, pre-surgical characterization of lesion consistency and, therefore, provides a modality with which to predict tumor resectability.

Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing's syndrome: results from a retrospective multicenter study.

OBJECTIVE: Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as gold standard to differentiate between Cushing´s disease (CD) and ectopic Cushing's syndrome (ECS). However, published data e.g. on the diagnostic value of additional prolactin analysis is controversial. Thus, we evaluated the diagnostic performance of BIPSS with and without prolactin in a multicenter study. DESIGN AND METHODS: Retrospective study in 5 European reference centers. Patients with overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of BIPSS with human corticotropin-releasing hormone stimulation were eligible. Cut-offs for the inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and the normalized ACTH:prolactin IPS:P ratio were calculated via receiver operator characteristics analyses (reference: CD). RESULTS: 156 patients with BIPSS were identified. Of these, 120 patients (92 (77%) females; 106 (88%) CD, 14 (12%) ECS) had either histopathologically confirmed tumors or biochemical remission and/or adrenal insufficiency after surgery; only this subgroup was analyzed by ROC analysis. The optimal cut-offs for the ACTH IPS:P ratio were ≥1.9 at baseline (sensitivity 82.1% (95%CI 73.2-88.6), specificity 85.7% (95%CI 56.2-97.5), AUC 0.86) and ≥2.1 at 5 minutes post-CRH (sensitivity 91.3% (95%CI 83.6-95.7), specificity 92.9%(95%CI 64.1-99.6), AUC 0.96). A subgroup underwent additional prolactin analysis. An optimal cut-off of ≥1.4 was calculated for the normalized ACTH:prolactin IPS:P ratio (sensitivity 96.0% (95%CI 77.7-99.9), specificity 100% (95%CI 56.1-100), AUC 0.99). CONCLUSION: Our study confirms the high accuracy of BIPSS in the differential diagnosis of ACTH-dependent Cushing's syndrome and suggests that the simultaneous measurement of prolactin might further improve the diagnostic performance of this test.

Validation of Myc-Associated Protein X (MAX) regulation in growth hormone secreting and nonfunctional pituitary adenoma.

INTRODUCTION: Many patients with growth hormone-secreting pituitary adenoma (GHPA) fail to achieve biochemical remission, warranting investigation into epigenetic and molecular signatures associated with tumorigenesis and hormonal secretion. Prior work exploring the DNA methylome showed Myc-Associated Protein X (MAX), a transcription factor involved in cell cycle regulation, was differentially methylated between GHPA and nonfunctional pituitary adenoma (NFPA). We aimed to validate the differential DNA methylation and related MAX protein expression profiles between NFPA and GHPA. METHODS: DNA methylation levels were measured in 52 surgically resected tumors (37 NFPA, 15 GHPA) at ~100,000 known MAX binding sites derived using ChIP-seq analysis from ENCODE. Findings were correlated with MAX protein expression using a constructed tissue microarray (TMA). Gene ontology analysis was performed to explore downstream genetic and signaling pathways regulated by MAX. RESULTS: GHPA had more hypomethylation events across all known MAX binding sites. Of binding sites defined using ChIP-seq analysis, 1,551 sites had significantly different methylation patterns between the two cohorts; 432 occurred near promoter regions potentially regulated by MAX, including promoters of TNF and MMP9. Gene ontology analysis suggested enrichment in genes involved in oxygen response, immune system regulation, and cell proliferation. Thirteen MAX binding sites were within coding regions of genes. GHPA demonstrated significantly increased expression of MAX protein compared to NFPA. CONCLUSION: GHPA have significantly different DNA methylation and downstream protein expression levels of MAX compared to NFPA. These differences may influence mechanisms involved with cellular proliferation, tumor invasion and hormonal secretion.

Does High-Definition 3-Dimensional Imaging Improve Orientation During Endoscopic Transsphenoidal Surgery? A Prospective Trial.

BACKGROUND: Endoscopy has evolved as the standard visualization tool for endonasal transsphenoidal resection of sellar lesions. The most widely used 2-dimensional (2D) endoscopes harbor the problem of limited depth perception. Therefore, 3-dimensional (3D) endoscopes have been developed to enable depth perception through a stereoscopic view. OBJECTIVE: To evaluate the impact of high-definition (HD) 2D vs 3D HD endoscopes on spatial orientation within the sphenoid sinus. METHODS: In this prospective single-center study, 21 patients have been investigated (2021-2022). Eleven standardized anatomic landmarks, which were preoperatively defined on neuronavigation imaging, were intraoperatively targeted with a navigation probe using either 2D HD or 3D HD endoscopes for visualization. RESULTS: Overall, 3D HD endoscopes provided a statistically significant higher accuracy of identification of sphenoid sinus landmarks (median deviation: 5.2 mm vs 4.2 mm, P < .001). In detail: tuberculum sellae (3.0 mm vs 4.3 mm, P = .047), most anterior point of sella (3.3 mm vs 4.8 mm, P = .049), and clivus indentation (3.8 mm vs 5.3 mm, P = .035). Anatomic variations such as a complex sphenoid sinus configuration had no influence on identifying sphenoid sinus landmarks. CONCLUSION: According to our data, stereoscopic 3D HD endoscopy enhances intraoperative orientation by improved depth perception within the sphenoid sinus. This may add to the safety of endoscopic skull base procedures, especially in extended approaches and cases with distorted anatomy.

Elevated EMMPRIN Serum Levels Indicate Plaque Vulnerability in Patients With Asymptomatic High Grade Carotid Stenosis.

OBJECTIVE: Carotid atherosclerosis is an important cause of cerebral ischaemic stroke. Sonographic plaque characteristics are inappropriate for exact prediction of possible future ischaemic events. Additional markers are needed to predict the clinical outcome in high grade carotid stenosis. This study aimed to test extracellular matrix metalloproteinase inducer (EMMPRIN), due to its involvement in plaque formation and destabilisation, as a potential marker of high risk vulnerable plaques. METHODS: EMMPRIN was analysed in pre-operative serum samples from patients with symptomatic and asymptomatic carotid artery stenosis by a specific ELISA. Pre-operative duplex sonography classified the atherosclerotic plaque due to echogenicity. Histopathological analysis of vulnerable and non-vulnerable plaques was based on the American Heart Association (AHA) classification. RESULTS: The study included 265 patients undergoing carotid endarterectomy: 90 (m:f, 69:21) patients with symptomatic and 175 (m:f, 118:57) with asymptomatic disease. Analysis of circulating EMMPRIN revealed significantly higher levels in patients with echolucent plaques (4 480; IQR 3 745, 6 144 pg/mL) compared with echogenic plaques (4 159; IQR 3 418, 5 402 pg/mL; p = .025). Asymptomatic patients with vulnerable plaques had significantly higher levels of EMMPRIN (4 875; IQR 3 850, 7 016 pg/mL) compared with non-vulnerable plaques (4 109; IQR 3 433, 5 402 pg/mL; p < .001). In logistic regression analysis, duplex sonography combined with age, gender, and clinical risk factors predicted vulnerable plaques in asymptomatic patients with an AUC of 0.71 (95% CI 0.61 - 0.80). EMMPRIN significantly improved the AUC in asymptomatic patients (AUC 0.79; 95% CI 0.71 - 0.87; p = .014). CONCLUSION: Patients with high risk plaques according to ultrasound and histopathological characteristics demonstrated increased serum EMMPRIN levels. EMMPRIN on top of clinical risk factors, including age, gender, and duplex sonography may be used for pre-operative risk stratification in asymptomatic patients.

A Patient-Specific Reference Tracker for Noninvasive Electromagnetic Navigation of Endoscopic Skull Base Surgery.

BACKGROUND: Owing to the possibility of nonrigid head fixation, electromagnetic navigation (EM) is a mainstay for endoscopic skull base surgery. The currently available dynamic reference trackers (RTs) are invasive or inaccurate. OBJECTIVE: To investigate the feasibility and stability of this innovative oral tracker (OT), which is adhesive to the hard palate in comparison with a commercially available skin adhesive tracker (ST). METHODS: A prospective series of 31 patients with intrasellar lesions who underwent surgery between 2019 and 2021 using a pure endoscopic transsphenoidal approach were evaluated. A patient-specific palatal mold was designed from preoperative computed tomography data. The OT was cast using a biocompatible algin with an integrated EM tracker assembly. In comparison with a skull-mounted RT, which served as a gold standard, the deviations of OT vs those of the ST with the RT were continuously assessed. RESULTS: The OT showed significantly lower deviations from the RT than the ST during the surgical steps: start of endoscopic surgery (OT vs ST: 0.62 mm, IQR 0.36-0.89 vs 1.65 mm, IQR 1.35-2.32, P < .001), drilling phase (OT vs ST: 0.81 mm, IQR 0.51-1.32 vs 1.89 mm, IQR 1.6-2.74, P < .001), and end of endoscopic surgery (OT vs ST: 1.1 mm, IQR 0.68-1.64 vs 1.9 mm, IQR 1.6-2.72, P < .001). CONCLUSION: The OT showed significantly higher intraoperative stability than the ST. Therefore, this noninvasive and patient-specific tool could be used to achieve accurate EM guidance during endoscopic skull base surgeries.

Diagnostic criteria of small sellar lesions with hyperprolactinemia: Prolactinoma or else.

Objective: To evaluate the combined predictive value of MRI criteria with the prolactin-volume-ratio (PVR) to differentiate prolactinoma from non-prolactinoma, in small sellar lesions with hyperprolactinemia. Methods: Retrospective analysis of 55 patients with sellar lesions of ≤15 mm diameter on MRI and hyperprolactinemia of ≤150 ng/mL, surgically treated between 2003 and 2020 at the Medical University of Vienna, with a conclusive histopathological report. Serum prolactin levels, extent of pituitary stalk deviation, size and volume of the lesion were assessed. The PVR was calculated by dividing the preoperative prolactin level by tumor volume. Results: Our study population consisted of 39 patients (71%) with a prolactin-producing pituitary adenoma (group A), while 16 patients (29%) had another type of sellar lesion (group B). Patients in group A were significantly younger (p=0.012), had significantly higher prolactin levels at diagnosis (p<0.001) as well as smaller tumor volume (p=0.036) and lower degree of pituitary stalk deviation (p=0.009). The median PVR was significantly higher in group A (243 ng/mL per cm3) than in group B (83 ng/mL per cm3; p=0.002). Furthermore, the regression operating characteristics analysis revealed a PVR >100 ng/mL per cm3 to be predictive for distinguishing prolactin-producing lesions from other small sellar lesions. Conclusion: In patients with small sellar lesions, Prolactin-Volume-Ratios >100 represents a possible predictive marker for the diagnosis of prolactin-producing pituitary adenomas.

5-Aminolevulinic acid-enhanced fluorescence-guided treatment of high-grade glioma using angled endoscopic blue light visualization: technical case series with preliminary follow-up.

OBJECTIVE: 5-Aminolevulinic acid (5-ALA)-enhanced fluorescence-guided resection of high-grade glioma (HGG) using microscopic blue light visualization offers the ability to improve extent of resection (EOR); however, few descriptions of HGG resection performed using endoscopic blue light visualization are currently available. In this report, the authors sought to describe their surgical experience and patient outcomes of 5-ALA-enhanced fluorescence-guided resection of HGG using primary or adjunctive endoscopic blue light visualization. METHODS: The authors performed a retrospective review of prospectively collected data from 30 consecutive patients who underwent 5-ALA-enhanced fluorescence-guided biopsy or resection of newly diagnosed HGG was performed. Patient demographic data, tumor characteristics, surgical technique, EOR, tumor fluorescence patterns, and progression-free survival were recorded. RESULTS: In total, 30 newly diagnosed HGG patients were included for analysis. The endoscope was utilized for direct 5-ALA-guided port-based biopsy (n = 9), microscopic to endoscopic (M2E; n = 18) resection, or exoscopic to endoscopic (E2E; n = 3) resection. All endoscopic biopsies of fluorescent tissue were diagnostic. 5-ALA-enhanced tumor fluorescence was visible in all glioblastoma cases, but only in 50% of anaplastic astrocytoma cases and no anaplastic oligodendroglioma cases. Gross-total resection (GTR) was achieved in 10 patients in whom complete resection was considered safe, with 11 patients undergoing subtotal resection. In all cases, endoscopic fluorescence was more avid than microscopic fluorescence. The endoscope offered the ability to diagnose and resect additional tumor not visualized by the microscope in 83.3% (n = 10/12) of glioblastoma cases, driven by angled lenses and increased fluorescence facilitated by light source delivery within the cavity. Mean volumetric EOR was 90.7% in all resection patients and 98.8% in patients undergoing planned GTR. No complications were attributable to 5-ALA or blue light endoscopy. CONCLUSIONS: The blue light endoscope is a viable primary or adjunctive visualization platform for optimization of 5-ALA-enhanced HGG fluorescence. Implementation of the blue light endoscope to guide resection of HGG glioma is feasible and ergonomically favorable, with a potential advantage of enabling increased detection of tumor fluorescence in deep surgical cavities compared to the microscope.

Demographic-Dependent Risk of Developing Severe Novel Psychiatric Disorders after Concussion.

Current guidelines for patients experiencing a concussion or mild traumatic brain injury (mTBI) often focus on conservative care and observation. However, mTBI may increase the risk of severe novel psychiatric disorders (NPDs) within 180 days, and long-term management of mTBI should include psychiatric evaluation in patient populations. Retrospective cohort analysis was conducted using 8 years of the Nationwide Readmission Database. All individuals who were admitted for concussion and were readmitted within 180 days were queried. This cohort was then subdivided based on age, sex, and whether they experienced loss of consciousness (LOC) to control for demographic-dependent confounding. A binary decision tree provided recommendations for patients who may be at risk of developing severe NPDs. Analysis included 12,080 patients who experienced concussion. Males and females with LOC had higher rates of depression in all age quartiles within 180 days (p < 0.05). Young females with LOC had increased rates of suicidal ideation (p < 0.01), and those >25 years of age had increased rates of anxiety (p < 0.005). Adult males with LOC had increased rates of suicidal ideation (p < 0.002) and males >75 years of age had increased rates of anxiety at readmission (p < 0.05). Males without LOC had increased rates of depression (p < 0.005), with men in the second quartile also at higher risk of developing anxiety (p < 0.05). Females without LOC showed the fewest number of NPDs at readmission. Concussion may be associated with increased rates of NPDs in the first 6 months following discharge. We use these data to develop recommendations for psychiatric screening of patients with mTBI.

Treatment strategies for giant pituitary adenomas in the era of endoscopic transsphenoidal surgery: a multicenter series.

OBJECTIVE: Given the anatomical complexity and frequently invasive growth of giant pituitary adenomas (GPAs), individually tailored approaches are required. The aim of this study was to assess the treatment strategies and outcomes in a large multicenter series of GPAs in the era of endoscopic transsphenoidal surgery (ETS). METHODS: This was a retrospective case-control series of 64 patients with GPAs treated at two tertiary care centers by surgeons with experience in ETS. GPAs were defined by a maximum diameter of ≥ 4 cm and a volume of ≥ 10 cm3 on preoperative isovoxel contrast-enhanced MRI. RESULTS: The primary operation was ETS in all cases. Overall gross-total resection rates were 64% in round GPAs, 46% in dumbbell-shaped GPAs, and 8% in multilobular GPAs (p < 0.001). Postoperative outcomes were further stratified into two groups based on extent of resection: group A (gross-total resection or partial resection with intracavernous remnant; 21/64, 33%) and group B (partial resection with intracranial remnant; 43/64, 67%). Growth patterns of GPAs were mostly round (11/14, 79%) in group A and multilobular (33/37, 89%) in group B. In group A, no patients required a second operation, and 2/21 (9%) were treated with adjuvant radiosurgery. In group B, early transcranial reoperation was required in 6/43 (14%) cases due to hemorrhagic transformation of remnants. For the remaining group B patients with remnants, 5/43 (12%) underwent transcranial surgery and 12/43 (28%) underwent delayed second ETS. There were no deaths in this series. Severe complications included stroke (6%), meningitis (6%), hydrocephalus requiring shunting (6%), and loss or distinct worsening of vision (3%). At follow-up (mean 3 years, range 0.5-16 years), stable disease was achieved in 91% of cases. CONCLUSIONS: ETS as a primary treatment modality to relieve mass effect in GPAs and extent of resection are dependent on GPA morphology. The pattern of residual pituitary adenoma guides further treatment strategies, including early transcranial reoperation, delayed endoscopic transsphenoidal/transcranial reoperation, and adjuvant radiosurgery.

Development of a miniaturized robotic guidance device for stereotactic neurosurgery.

OBJECTIVE: Consistently high accuracy and a straightforward use of stereotactic guidance systems are crucial for precise stereotactic targeting and a short procedural duration. Although robotic guidance systems are widely used, currently available systems do not fully meet the requirements for a stereotactic guidance system that combines the advantages of frameless surgery and robotic technology. The authors developed and optimized a small-scale yet highly accurate guidance system that can be seamlessly integrated into an existing operating room (OR) setup due to its design. The aim of this clinical study is to outline the development of this miniature robotic guidance system and present the authors' clinical experience. METHODS: After extensive preclinical testing of the robotic stereotactic guidance system, adaptations were implemented for robot fixation, software usability, navigation integration, and end-effector application. Development of the robotic system was then advanced in a clinical series of 150 patients between 2013 and 2019, including 111 needle biopsies, 13 catheter placements, and 26 stereoelectroencephalography (SEEG) electrode placements. During the clinical trial, constant modifications were implemented to meet the setup requirements, technical specifications, and workflow for each indication. For each application, specific setup, workflow, and median procedural accuracy were evaluated. RESULTS: Application of the miniature robotic system was feasible in 149 of 150 cases. The setup in each procedure was successfully implemented without adding significant OR time. The workflow was seamlessly integrated into the preexisting procedure. In the course of the study, procedural accuracy was improved. For the biopsy procedure, the real target error (RTE) was reduced from a mean of 1.8 ± 1.03 mm to 1.6 ± 0.82 mm at entry (p = 0.05), and from 1.7 ± 1.12 mm to 1.6 ± 0.72 mm at target (p = 0.04). For the SEEG procedures, the RTE was reduced from a mean of 1.43 ± 0.78 mm in the first half of the procedures to 1.12 ± 0.52 mm (p = 0.002) at entry in the second half, and from 1.82 ± 1.13 mm to 1.57 ± 0.98 mm (p = 0.069) at target, respectively. No healing complications or infections were observed in any case. CONCLUSIONS: The miniature robotic guidance device was able to prove its versatility and seamless integration into preexisting workflow by successful application in 149 stereotactic procedures. According to these data, the robot could significantly improve accuracy without adding time expenditure.

Dumbbell-shaped pituitary adenomas: prognostic factors for prediction of tumor nondescent of the supradiaphragmal component from a multicenter series.

OBJECTIVE: Dumbbell-shaped pituitary adenomas (DSPAs) are a subgroup of macroadenomas with suprasellar extension that are characterized by a smaller diameter at the level of the diaphragma sellae opening compared with the supradiaphragmal tumor component (SDTC). Hence, DSPAs may be particularly prone to a nondescending suprasellar tumor component and risk for residual tumor or postoperative bleeding. METHODS: A multicenter retrospective cohort analysis of 99 patients with DSPA operated on via direct endoscopic endonasal transsphenoidal approach between 2011 and 2020 was conducted. Patient recruitment was performed at two tertiary care centers (Medical University of Vienna and University of Southern California) with expertise in endoscopic skull base surgery. DSPA was defined as having a smaller diameter at the level of the diaphragma sellae compared with the SDTC. RESULTS: On preoperative MRI, all DSPAs were macroadenomas (maximum diameter range 17-71 mm, volume range 2-88 cm3). Tumor descent was found in 73 (74%) of 99 patients (group A), and nondescent in 26 (26%) of 99 patients (group B) intraoperatively. DSPAs in group A had a significantly smaller diameter (30 vs 42 mm, p < 0.001) and significantly smaller volume (10 vs 22 cm3, p < 0.001) than those in group B. The ratio of the minimum area at the level of the diaphragmal opening in comparison with the maximum area of the suprasellar tumor component ("neck-to-dome area") was significantly lower in group A than in group B (1.7 vs 2.7, p < 0.001). Receiver operating characteristic curve analysis revealed an area under the curve of 0.75 (95% CI 0.63-0.87). At a cutoff ratio of 1.9, the sensitivity and specificity for a nondescending suprasellar tumor component were 77% and 34%, respectively. CONCLUSIONS: In the present study, the neck-to-dome area ratio was of prognostic value for prediction of intraoperative tumor nondescent in DSPAs operated on via a direct endonasal endoscopic approach. Pituitary adenoma SDTC nondescent carried the inherent risk of hemorrhagic transformation in all cases.

Diagnosis of Pituitary Adenoma Biopsies by Ultrahigh Resolution Optical Coherence Tomography Using Neuronal Networks.

Objective: Despite advancements of intraoperative visualization, the difficulty to visually distinguish adenoma from adjacent pituitary gland due to textural similarities may lead to incomplete adenoma resection or impairment of pituitary function. The aim of this study was to investigate optical coherence tomography (OCT) imaging in combination with a convolutional neural network (CNN) for objectively identify pituitary adenoma tissue in an ex vivo setting. Methods: A prospective study was conducted to train and test a CNN algorithm to identify pituitary adenoma tissue in OCT images of adenoma and adjacent pituitary gland samples. From each sample, 500 slices of adjacent cross-sectional OCT images were used for CNN classification. Results: OCT data acquisition was feasible in 19/20 (95%) patients. The 16.000 OCT slices of 16/19 of cases were employed for creating a trained CNN algorithm (70% for training, 15% for validating the classifier). Thereafter, the classifier was tested on the paired samples of three patients (3.000 slices). The CNN correctly predicted adenoma in the 3 adenoma samples (98%, 100% and 84% respectively), and correctly predicted gland and transition zone in the 3 samples from the adjacent pituitary gland. Conclusion: Trained convolutional neural network computing has the potential for fast and objective identification of pituitary adenoma tissue in OCT images with high sensitivity ex vivo. However, further investigation with larger number of samples is required.

Morpho-Molecular Metabolic Analysis and Classification of Human Pituitary Gland and Adenoma Biopsies Based on Multimodal Optical Imaging.

Pituitary adenomas count among the most common intracranial tumors. During pituitary oncogenesis structural, textural, metabolic and molecular changes occur which can be revealed with our integrated ultrahigh-resolution multimodal imaging approach including optical coherence tomography (OCT), multiphoton microscopy (MPM) and line scan Raman microspectroscopy (LSRM) on an unprecedented cellular level in a label-free manner. We investigated 5 pituitary gland and 25 adenoma biopsies, including lactotroph, null cell, gonadotroph, somatotroph and mammosomatotroph as well as corticotroph. First-level binary classification for discrimination of pituitary gland and adenomas was performed by feature extraction via radiomic analysis on OCT and MPM images and achieved an accuracy of 88%. Second-level multi-class classification was performed based on molecular analysis of the specimen via LSRM to discriminate pituitary adenomas subtypes with accuracies of up to 99%. Chemical compounds such as lipids, proteins, collagen, DNA and carotenoids and their relation could be identified as relevant biomarkers, and their spatial distribution visualized to provide deeper insight into the chemical properties of pituitary adenomas. Thereby, the aim of the current work was to assess a unique label-free and non-invasive multimodal optical imaging platform for pituitary tissue imaging and to perform a multiparametric morpho-molecular metabolic analysis and classification.

Improved surgeon performance following cadaveric simulation of internal carotid artery injury during endoscopic endonasal surgery: training outcomes of a nationwide prospective educational intervention.

OBJECTIVE: Internal carotid artery injury (ICAI) is a rare, life-threatening complication of endoscopic endonasal approaches that will be encountered by most skull base neurosurgeons and otolaryngologists. Rates of surgical proficiency for managing ICAI are not known, and the role of simulation to improve performance has not been studied on a nationwide scale. METHODS: Attending and resident neurosurgery and otorhinolaryngology surgeons (n = 177) were recruited from multicenter regional and national training courses to assess training outcomes and validity at scale of a prospective educational intervention to improve surgeon technical skills using a previously validated, perfused human cadaveric simulator. Participants attempted an initial trial (T1) of simulated ICAI control using their preferred technique. An educational intervention including personalized instruction was performed. Participants attempted a second trial (T2). Task success (dichotomous), time to hemostasis (TTH), estimated blood loss (EBL), and surgeon heart rate were measured. RESULTS: Participant rating scales confirmed that the simulation retained face and construct validity across eight instructional settings. Trial success (ICAI control) improved from 56% in T1 to 90% in T2 (p < 0.0001). EBL and TTH decreased by 37% and 38%, respectively (p < 0.0001). Postintervention resident surgeon performance (TTH, EBL, and success rate) was superior to preintervention attending surgeon performance. The most improved quartile of participants achieved 62% improvement in TTH and 73% improvement in EBL, with trial success improvement from 25.6% in T1 to 100% in T2 (p < 0.0001). Baseline surgeon confidence was uncorrelated with T1 success, while posttraining confidence correlated with T2 success. Tachycardia was measured in 57% of surgeon participants, but was attenuated during T2, consistent with development of resiliency. CONCLUSIONS: Prior to training, many attending and most resident surgeons could not manage the rare, life-threatening intraoperative complication of ICAI. A simulated educational intervention significantly improved surgeon performance and remained valid when deployed at scale. Simulation also promoted the development of favorable cognitive skills (accurate perception of skill and resiliency). Rare, life-threatening intraoperative complications may be optimal targets for educational interventions using surgical simulation.

Neural network modeling for prediction of recurrence, progression, and hormonal non-remission in patients following resection of functional pituitary adenomas.

PURPOSE: Functional pituitary adenomas (FPAs) cause severe neuro-endocrinopathies including Cushing's disease (CD) and acromegaly. While many are effectively cured following FPA resection, some encounter disease recurrence/progression or hormonal non-remission requiring adjuvant treatment. Identification of risk factors for suboptimal postoperative outcomes may guide initiation of adjuvant multimodal therapies. METHODS: Patients undergoing endonasal transsphenoidal resection for CD, acromegaly, and mammosomatotroph adenomas between 1992 and 2019 were identified. Good outcomes were defined as hormonal remission without imaging/biochemical evidence of disease recurrence/progression, while suboptimal outcomes were defined as hormonal non-remission or MRI evidence of recurrence/progression despite adjuvant treatment. Multivariate regression modeling and multilayered neural networks (NN) were implemented. The training sets randomly sampled 60% of all FPA patients, and validation/testing sets were 20% samples each. RESULTS: 348 patients with mean age of 41.7 years were identified. Eighty-one patients (23.3%) reported suboptimal outcomes. Variables predictive of suboptimal outcomes included: Requirement for additional surgery in patients who previously had surgery and continue to have functionally active tumor (p = 0.0069; OR = 1.51, 95%CI 1.12-2.04), Preoperative visual deficit not improved after surgery (p = 0.0033; OR = 1.12, 95%CI 1.04-1.20), Transient diabetes insipidus (p = 0.013; OR = 1.27, 95%CI 1.05-1.52), Higher MIB-1/Ki-67 labeling index (p = 0.038; OR = 1.08, 95%CI 1.01-1.15), and preoperative low cortisol axis (p = 0.040; OR = 2.72, 95%CI 1.06-7.01). The NN had overall accuracy of 87.1%, sensitivity of 89.5%, specificity of 76.9%, positive predictive value of 94.4%, and negative predictive value of 62.5%. NNs for all FPAs were more robust than for CD or acromegaly/mammosomatotroph alone. CONCLUSION: We demonstrate capability of predicting suboptimal postoperative outcomes with high accuracy. NNs may aid in stratifying patients for risk of suboptimal outcomes, thereby guiding implementation of adjuvant treatment in high-risk patients.

Prevalence Rate of Coexisting Rathke Cleft Cysts and Pineal Cysts: A Multicenter Cross-Sectional Study.

BACKGROUND: Rathke cleft cysts (RCCs) are benign sellar lesions originating from remnants of primitive ectoderm. They have not been previously linked to other cystic lesions, such as pineal cysts (PCs). Our objective was to perform a multicenter cross-sectional neuroimaging study to examine prevalence rates of coexisting RCC and PC. METHODS: We retrospectively queried prospectively maintained, institutional review board-approved, databases from the authors' centers. All patients undergoing transsphenoidal surgery for RCC between the years of 2011 and 2020 were included for analysis. Preoperative magnetic resonance imaging was reviewed to identify the coexistence of a PC. Patient demographics and neuroimaging characteristics were recorded. A control cohort comprised of 100 age- and sex-matched patients with nonfunctional pituitary adenoma (NFPA) who also underwent surgical intervention was utilized. RESULTS: Eighty-four patients with RCC were identified for analysis. A coexistent PC was identified in 40.5% (n = 34) of patients with RCC compared with 14.3% (n = 12) in the NFPA cohort (P < 0.001). There was no significant difference in PC size between patients with RCC and PA (8 vs. 8.8 mm, respectively; P = 0.77). Although the majority (85.7%; n = 72) of the RCC cohort were female patients, there was no sex predominance with respect to coexisting PC in either the RCC or PA cohort. CONCLUSIONS: This is the first study to report an increased prevalence of coexisting PC and RCC, possibly because of an embryologic link or other propensity for intracranial cyst formation. Additional studies in more generalizable populations can further explore the relation between RCC and PC, or other cyst formation.

Safety and Effectiveness of the Direct Endoscopic Endonasal Approach for Primary Sellar Pathology: A Contemporary Case Series of More Than 400 Patients.

BACKGROUND: The direct endoscopic endonasal approach (EEA) has become the primary technique used for resection of sellar pathology, meriting investigation into the risk factors for complications and predictors of postoperative outcomes after direct EEA. METHODS: We retrospectively analyzed the patient and tumor characteristics from 404 patients who had undergone direct EEA for sellar pathology at the USC Pituitary Center from September 2011 to December 2019. RESULTS: Of the 404 pathologic entities included, 349 (86%) were pituitary adenomas (PAs), 29 (7%) were Rathke cleft cysts, and 26 (6%) were other sellar lesions. The mean lesion diameter was 2.3 cm, with 34 microadenomas (10%) and 315 macroadenomas (90%). Cavernous sinus invasion was present in 39% of the PAs. No patient died. The surgical complications included internal carotid artery injury without neurological sequelae (0.2%), vision loss (0.7%), meningitis (0.7%), cerebrospinal fluid leak (4%), epistaxis (4%), sinusitis (1%), transient cranial nerve paresis (0.5%), and postoperative abscess (0.25%). New hypopituitarism developed in 3%. Gross total resection was achieved in 208 PA cases (58%). Clinical improvement of headaches and visual deficits were reported for 67% and 76% of cases, respectively. Hormonal remission was achieved in 82% of patients with functional PAs. The median hospital stay was 2 days, with 34 patients (8%) readmitted within 30 days and 10 (3%) undergoing early reoperation. Disease recurrence or progression developed in 10% and was less likely in the case of gross total resection and apoplexy. CONCLUSION: In the present, large, consecutive, mostly single-surgeon series, the patients experienced clinical improvement in most preoperative symptoms and had low rates of perioperative morbidity. We have demonstrated that direct EEA can be efficiently, safely, and successfully performed by a neurosurgical team.

Acute and Life-threatening Complications in Cushing Syndrome: Prevalence, Predictors, and Mortality.

CONTEXT: Cushing syndrome (CS) results in significant morbidity and mortality. OBJECTIVE: To study acute and life-threatening complications in patients with active CS. METHODS: We performed a retrospective cohort study using inpatient and outpatient records of patients with CS in a tertiary center. A total of 242 patients with CS were included, including 213 with benign CS (pituitary n = 101, adrenal n = 99, ectopic n = 13), and 29 with malignant disease. We collected acute complications necessitating hospitalization, from appearance of first symptoms of hypercortisolism until 1 year after biochemical remission. Mortality data were obtained from the national registry. Baseline factors relating to and predicting acute complications were tested using uni- and multivariate analysis. RESULTS: The prevalence of acute complications was 62% in patients with benign pituitary CS, 40% in patients with benign adrenal CS, and 100% in patients with ectopic CS. Complications observed in patients with benign CS included infections (25%), thromboembolic events (17%), hypokalemia (13%), hypertensive crises (9%), cardiac arrhythmias (5%), and acute coronary events (3%). Among these patients, 23% had already been hospitalized for acute complications before CS was suspected, and half of complications occurred after the first surgery. Glycated hemoglobin (HbA1c) and 24-hour urinary free cortisol positively correlated with the number of acute complications per patient. Patients with malignant disease had significantly higher rates of acute complications. Mortality during the observation period was 2.8% and 59% in benign and malignant CS, respectively. CONCLUSIONS: This analysis highlights the whole spectrum of acute and life-threatening complications in CS, and their high prevalence even before disease diagnosis and after successful surgery.