The human craniospinal venous system and its influence on postural intracranial pressure: a review.

OBJECTIVE: The cerebral and spinal venous systems have similar functions but unique anatomical and physiological properties. CSF occupies space in the cranial and spinal vaults, is continuously produced, and has many roles, including maintaining a favorable environment for CNS structures. The influence of the cerebrospinal venous system on CSF dynamics has been theorized since the 1940s. Newer studies suggest venous outflow pattern alterations in response to changes in body position. However, the relationship of postural cerebrospinal venous outflow shifts with and their influence on CSF homeostasis is not well understood. METHODS: The authors searched the published literature related to the anatomy and function of vertebral venous plexus (VVP), CSF, and positional cerebral venous flow characteristics. A comprehensive collection of literature was compiled and reviewed, and the relationship between cerebrospinal and venous system changes and alterations in body positions, with an emphasis on the craniocervical system, is discussed. RESULTS: The VVP is a network of valveless veins extending from the sacrum to the cranium that are interconnected with the cranial dural sinuses. The internal VVP occupies space within the extradural spinal canal and functions to return spinal venous blood to the heart, but it has additional properties, including the capability of bidirectional venous flow, an intraspinal dilatory capacity, and a role in cerebral venous outflow. When one rises to the upright position, CSF shifts toward the spinal canal and force vectors change, leading to reduced intracranial CSF pressure; simultaneously, cerebral venous outflow shifts from the jugular vein to the VVP outflow pathway. The venous outflow shift mechanism and its purpose are poorly understood. The authors review the known physiology of the system, identify gaps in knowledge to direct future research, and propose an interpretation of these data, concluding that position-dependent CSF and cerebrospinal venous shifts are part of a complementary positional craniospinal pressure regulation system that must be kept in balance for optimal CNS function. CONCLUSIONS: Current knowledge of the cerebrospinal venous anatomy, dynamic flow characteristics in response to gravity, and the venous system's influence on CSF suggests that the VVP plays a role in influencing CSF pressure, and the authors hypothesize that it plays a role in supporting intracranial pressure in the upright body posture. Further research is needed to better characterize the functional relationship of the VVP to CSF dynamics as well as identify potentially related disease states.

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

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

Comparison of patient-reported outcomes and clinical characteristics among patients with pituitary macroadenomas and giant adenomas.

KEY POINTS: Patients with giant adenomas are more likely to have tumor extension into the paranasal sinuses. Compared to macroadenomas, giant adenomas are not associated with worse preoperative SNOT-22 scores.

Risk Factors Associated with Postoperative CSF Leak in Extrasellar Tumors.

Objective While postoperative cerebrospinal fluid (CSF) leak rates of pituitary tumors have been frequently studied, there are fewer studies examining postoperative CSF leak rates for extrasellar tumors. The purpose of this study was to identify risk factors for the development of postoperative CSF leak in patients undergoing endoscopic surgery for extrasellar tumors. Methods A retrospective chart review was done for patients who underwent endoscopic resection for extrasellar tumors between 2008 and 2020. Age, gender, tumor type, tumor location, tumor size, reconstruction technique, medical comorbidities, and other potential risk factors were identified. Data was analyzed to identify significant risk factors for development of postoperative CSF leak. Results There were 100 patients with extrasellar tumors who developed intraoperative CSF leaks. Seventeen patients (17%) developed postoperative CSF leaks. Leaks occurred at a median of 2 days following surgery (range 0-34 days). Clival tumors had a significantly higher incidence of postoperative leak than those in other sites ( p < 0.05). There were no significant differences in other locations, body mass index, tumor size, reconstruction technique, medical comorbidities, or other factors. There were nearly twice as many intraoperative grade III leaks in those who developed postoperative CSF leak, but this was not statistically significant ( p = 0.12). Conclusion Extrasellar tumors, particularly clival tumors, have a higher rate of postoperative CSF leak than pituitary tumors. Prophylactic lumbar drains can be considered for patients at high risk for developing postoperative CSF leak.

Flexible in-cavity MRI receiving coil for ultra-high-resolution imaging of the pituitary gland.

OBJECTIVE: The objective of this study was the preclinical design and construction of a flexible intrasphenoid coil aiming for submillimeter resolution of the human pituitary gland. METHODS: Sphenoid sinus measurements determined coil design constraints for use in > 95% of adult patients. Temperature safety parameters were tested. The 2-cm-diameter coil prototype was positioned in the sphenoid sinus of cadaveric human heads utilizing the transnasal endoscopic approach that is used clinically. Signal-to-noise ratio (SNR) was estimated for the transnasal coil prototype compared with a standard clinical head coil. One cadaveric pituitary gland was explanted and histologically examined for correlation to the imaging findings. RESULTS: With the coil positioned directly atop the sella turcica at a 0° angle of the B0 static field, the craniocaudal distance (21.2 ± 0.8 mm) was the limiting constraint. Phantom experiments showed no detectable change in temperature at two sites over 15 minutes. The flexible coil was placed transnasally in cadaveric specimens using an endoscopic approach. The image quality was subjectively superior at higher spatial resolutions relative to that with the commercial 20-channel head coil. An average 17-fold increase in the SNR was achieved within the pituitary gland. Subtle findings visualized only with the transnasal coil had potential pathological correlation with immunohistochemical findings. CONCLUSIONS: A transnasal radiofrequency coil feasibly provides a 17-fold boost in the SNR at 3 T. The ability to safely improve the quality of pituitary imaging may be helpful in the identification and subsequent resection of small functional pituitary lesions.

Multi-nuclear sodium, diffusion, and perfusion MRI in human gliomas.

PURPOSE: There is limited knowledge about the associations between sodium and proton MRI measurements in brain tumors. The purpose of this study was to quantify intra- and intertumoral correlations between sodium, diffusion, and perfusion MRI in human gliomas. METHODS: Twenty glioma patients were prospectively studied on a 3T MRI system with multinuclear capabilities. Three mutually exclusive tumor volumes of interest (VOIs) were segmented: contrast-enhancing tumor (CET), T2/FLAIR hyperintense non-enhancing tumor (NET), and necrosis. Median and voxel-wise associations between apparent diffusion coefficient (ADC), normalized relative cerebral blood volume (nrCBV), and normalized sodium measurements were quantified for each VOI. RESULTS: Both relative sodium concentration and ADC were significantly higher in areas of necrosis compared to NET (P = 0.003 and P = 0.008, respectively) and CET (P = 0.02 and P = 0.02). Sodium concentration was higher in CET compared to NET (P = 0.04). Sodium and ADC were higher in treated compared to treatment-naïve gliomas within NET (P = 0.006 and P = 0.01, respectively), and ADC was elevated in CET (P = 0.03). Median ADC and sodium concentration were positively correlated across patients in NET (r = 0.77, P < 0.0001) and CET (r = 0.84, P < 0.0001), but not in areas of necrosis (r = 0.45, P = 0.12). Median nrCBV and sodium concentration were negatively correlated across patients in areas of NET (r=-0.63, P = 0.003). Similar associations were observed when examining voxel-wise correlations within VOIs. CONCLUSION: Sodium MRI is positively correlated with proton diffusion MRI measurements in gliomas, likely reflecting extracellular water. Unique areas of multinuclear MRI contrast may be useful in future studies to understand the chemistry of the tumor microenvironment.

An Algorithm for the Use of Free Tissue Graft Reconstruction in the Endoscopic Endonasal Approach for Pituitary Tumors.

OBJECTIVE: To identify factors associated with successful use of free tissue grafting versus vascularized reconstruction after resection of pituitary tumors. METHODS: A retrospective chart review of 2 tertiary academic medical centers over 3.5 years was conducted. Variables assessed included age, sex, body mass index, pathology, extent of surgical exposure, cavernous sinus or suprasellar extension, intraoperative cerebrospinal fluid (CSF) leak, grade of leak, previous radiation, and previous surgery. Reconstructive techniques were divided into no reconstruction, free tissue grafts, and vascularized flaps. RESULTS: A total of 485 patients were included. Free grafts were used in 299/485 cases (61.6%) and were more commonly used with smaller approaches (P < 0.001). Larger exposure size and CSF leak grades 2 and 3 were associated with vascularized flap use (P < 0.001 and P = 0.012, respectively). Using multivariate regression, type of reconstruction could be predicted by increasing extent of approach, intraoperative CSF leak grade, and suprasellar extension (odds ratio [OR], 2.014, P < 0.001, 95% confidence interval [CI], 1.335-3.039; OR, 1.636, P = 0.025, 95% CI, 1.064-2.517; OR, 1.975, P < 0.001, 95% CI, 1.554-2.510, respectively). Postoperative CSF leak occurred in 9 of 173 patients (5.2%) with intraoperative leak and was not associated with any factors on analysis. CONCLUSIONS: We propose an algorithm whereby grade 1 CSF leaks in sellar and parasellar resections can be successfully reconstructed with a free graft. Vascularized flaps may be reserved for grade 2 or 3 intraoperative CSF leaks, extended approaches, or tumors with suprasellar extension.

Endoscope-Assisted Pedicled Maxillary Artery to Middle Cerebral Artery Bypass: An Anatomic Feasibility Study.

BACKGROUND: Extracranial to intracranial bypass is used to augment and/or replace the intracranial circulation for various pathologies. The superficial temporal artery is the mainstay donor for pedicled bypasses to the anterior circulation but can be limited by its variable size, low native flow rates, and potential scalp complications. Interposition grafts such as the radial artery or greater saphenous vein are alternatives but are sometimes limited by size mismatch, length needed to reach the extracranial circulation, and loss of inherent vascular elasticity. Interposition grafts between the maxillary artery (IMA) and middle cerebral artery (MCA) address these limitations. OBJECTIVE: To explore the feasibility of harvesting the IMA through an endoscopic transnasal, transmaxillary approach to perform a direct IMA to MCA bypass. METHODS: Combined transcranial and endoscopic endonasal dissections were performed in embalmed human cadavers to harvest the IMAs for intracranial transposition and direct anastomosis to the MCA. Donor and recipient vessel calibers were measured and recorded. RESULTS: A total of 8 procedures were performed using the largest and distal-most branches of the IMA (the sphenopalatine branch and the descending palatine branch) as pedicled conduits to second division of middle cerebral artery (M2) recipients. The mean diameter of the IMA donors was 1.89 mm (SD ± 0.42 mm), and the mean diameter of the recipient M2 vessels was 1.90 mm (SD ± 0.46 mm). CONCLUSION: Endoscopic harvest of the IMA using a transnasal, transmaxillary approach is a technically feasible option offering an excellent size match to the M2 divisions of the MCA and the advantages of a relatively short, pedicled donor vessel.

Circulating FK506 binding protein 51 mRNA expression in patients with pituitary adenomas.

Background: FK506 binding protein 51 (FKBP5) is a co-chaperone regulator of the glucocorticoid receptor (GR). Recent studies have reported increased FKBP5 mRNA in the circulation from patients with Cushing disease (CD) which returned to comparable levels seen in healthy controls following successful trans-nasal trans-sphenoidal (TNTS) surgical corticotroph tumor removal. However, the expression of circulating FKBP5 mRNA levels in other pituitary tumor subtypes and its specificity to corticotroph tumors is unknown. Methods: Pre-operative blood was collected from consecutive patients undergoing TNTS for pituitary tumors (n = 57) at our center between 2015 and 2019. Total RNA was isolated from whole blood using RiboPure blood RNA isolation kit and real-time qPCR was used to quantitate circulating FKBP5 mRNA expression. Results: Consistent with the prior report, higher circulating FKBP5 mRNA levels were observed in 20 patients with CD prior to surgical tumor removal, compared to 21 healthy controls (p < 0.0005) and compared to 8 patients harboring gonadotroph pituitary tumors (p < 0.05) and 6 patients with silent corticotroph pituitary tumors (p < 0.05). However, circulating FKBP5 mRNA levels were higher in 10 patients with prolactin (PRL)-secreting pituitary tumors compared to healthy controls (p < 0.05), and did not differ between patients with CD and patients with growth hormone secreting tumors (GH-omas). Conclusions: Although we confirm that circulating FKBP5 mRNA is higher in patients with corticotroph tumors compared to healthy subjects, measurement of circulating FKBP5 does not appear to be helpful to distinguish corticotroph tumors from other pituitary tumor sub-types.

Audit of Postoperative Readmissions and Patient Messages following Endoscopic Transnasal Transsphenoidal Surgery.

Objectives The aim of this study was to identify the reasons for patient messages, phone calls, and emergency department (ED) visits prior to the first postoperative visit following discharge after endoscopic transnasal transsphenoidal (eTNTS) surgery. Design This is a retrospective review of patients at a tertiary care academic center who underwent eTNTS for resection of a sellar region tumor between May 2020 and August 2021. Patient, tumor, and surgical characteristics were collected, along with postoperative, postdischarge, and readmission information. Regression analyses were performed to investigate risk factors associated with postdischarge phone calls, messages, ED visits, and readmissions. Main Outcome Measures The main outcomes were the number of and reasons for phone calls, patient messages, and ED visits between hospital discharge and the first postoperative visit. We additionally determined whether these reasons were addressed in each patient's discharge instructions. Results A total of 98 patients underwent eTNTS during the study period. The median length of hospital stay was 2 days (interquartile range [IQR]: 1-4 days), at which point most patients (82%) were provided with eTNTS-specific discharge instructions. First postoperative visit took place 9 days after discharge (IQR: 7-10 days). Within that time, 54% of patients made at least one phone call or sent at least electronic message and 17% presented to the ED. Most common reasons for call/message were nasal care, appointment scheduling, and symptom and medication questions. Conclusion Through this work, we highlight the most common reasons for resource utilization via patient phone calls, messages, and ED visits among our cohort to better understand any shortfall or gap in the discharge process that may reduce these events.

Sinonasal Symptom Outcomes following Endoscopic Anterior Cranial Base Surgery in the Pediatric Population.

Objective This study aimed to evaluate the impact of endoscopic anterior cranial base (ACB) surgery on sinonasal symptoms in the pediatric population utilizing the Sino-Nasal Outcome Test (SNOT)-22 questionnaire. Design This is a retrospective review. Setting The study was conducted at a tertiary academic medical center. Participants Thirty-four consecutive patients, age 6 to 17 years, M:F 14:20, who underwent endoscopic ACB surgery from July 2008 to August 2019. Ten patients had baseline and a minimum of two subsequent postoperative SNOT-22 questionnaires available for analysis. Main Outcome Measures Baseline and postoperative SNOT-22 scores were compared. The mean change from baseline sinonasal symptom scores in the pediatric and historical adult cohorts was compared. Results The mean baseline SNOT-22 score for our 10 patient cohort was 0.46 out of 5 for each of the first 10 sinonasal-specific questions. This worsened to 1.69 at 1 month and returned to near baseline, 0.7, at 3 months postoperatively. The mean quality-of-life score improved to 0.91 at 1 month and 0.6 at 3 months postoperatively. The mean change from baseline for the following items: need to blow nose, runny nose, postnasal discharge, thick nasal discharge, wake up at night, reduced concentration, and frustrated/restless/irritable were similar to those in our historical adult cohort at 3 months postoperatively. Conclusion Endoscopic ACB surgery in the pediatric population results in increased sinonasal symptom morbidity in the early postoperative period; however, symptoms return to near baseline by ∼3 months, and quality-of-life scores progressively improve in the postoperative period. These trends were similar to those seen in our historic adult cohort.

Perioperative Antibiotic Use in Endoscopic Endonasal Skull Base Surgery.

Introduction Improved evidence-based guidelines on the optimal type and duration of antibiotics for patients undergoing endoscopic endonasal transsphenoidal surgery (EETS) are needed. We analyze the infectious complications among a large cohort of EETS patients undergoing a standardized regimen of cefazolin for 24 hours, followed by cephalexin for 7 days after surgery (clindamycin if penicillin/cephalosporin allergic). Methods A retrospective review of 132 EETS patients from 2018 to 2020 was conducted. Patient, tumor, and surgical characteristics were collected, along with infection rates. Multivariate logistic regression determined the variable(s) independently associated with infectious outcomes. Results Nearly all patients (99%) received postoperative antibiotics with 78% receiving cefazolin, 17% receiving cephalexin, 3% receiving clindamycin, and 2% receiving other antibiotics. Fifty-three patients (40%) had an intraoperative cerebrospinal fluid (CSF) leak, and three patients (2%) developed a postoperative CSF leak requiring surgical repair. Within 30 days, no patients developed meningitis. Five patients (4%) developed sinusitis, two patients (3%) developed pneumonia, and one patient (1%) developed cellulitis at a peripheral intravenous line. Two patients (2%) developed an allergy to cephalexin, requiring conservative management. After adjustment for comorbidities and operative factors, presence of postoperative infectious complications was independently associated with increased LOS ( ß = 3.7 days; p = 0.001). Conclusion Compared with reported findings in the literature, we report low rates of infectious complications and antibiotic intolerance, despite presence of a heavy burden of comorbidities and high intraoperative CSF leak rates among our cohort. These findings support our standardized 7-day perioperative antibiotic regimen.

Single-cell RNA sequencing in silent corticotroph tumors confirms impaired POMC processing and provides new insights into their invasive behavior.

Objective: Provide insights into the defective POMC processing and invasive behavior in silent pituitary corticotroph tumors. Design and methods: Single-cell RNAseq was used to compare the cellular makeup and transcriptome of silent and active corticotroph tumors. Results: A series of transcripts related to hormone processing peptidases and genes involved in the structural organization of secretory vesicles were reduced in silent compared to active corticotroph tumors. Most relevant to their invasive behavior, silent corticotroph tumors exhibited several features of epithelial-to-mesenchymal transition, with increased expression of mesenchymal genes along with the loss of transcripts that regulate hormonal biogenesis and secretion. Silent corticotroph tumor vascular smooth muscle cell and pericyte stromal cell populations also exhibited plasticity in their mesenchymal features. Conclusions: Our findings provide novel insights into the mechanisms of impaired POMC processing and invasion in silent corticotroph tumors and suggest that a common transcriptional reprogramming mechanism simultaneously impairs POMC processing and activates tumor invasion.

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures.

Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurologic diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurologic disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. These data provide powerful new insights into human astrocyte biology in several biologically relevant states that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENT Astrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurologic diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

Opiate Use After Endoscopic Endonasal Transsphenoidal Surgery.

BACKGROUND: The literature on opiate use after endoscopic endonasal transsphenoidal surgery (EETS) is limited. OBJECTIVE: To determine the risk factors for higher opiate use following EETS and the quantity of opiates used after discharge. METHODS: A retrospective review of 144 patients undergoing EETS from July 2018 to July 2020 was conducted. Patient, tumor, and surgical factors were documented. Pain scores and medications used on postoperative days (POD) 0 and 1, and discharge prescriptions, were recorded. Opiate use was quantified using morphine milligram equivalents (MME) dose. Multiple linear regression determined risk factors independently associated with POD0 to 1 opiate use. RESULTS: On POD 0 to 1, mean pain score was 4.9/10 (standard deviation [SD] ± 2.0). Mean acetaminophen use was 3.4 tablets (SD ± 1.6; 650 mg per tablet). Mean opiate use was 35.6 MME (SD ± 36.3), equivalent to 4.7 tablets (SD ± 4.8) of oxycodone 5 mg. Multiple linear regression showed that current smokers required an additional 37.1 MME (P = .011), and patients with grade 3 intraoperative cerebrospinal fluid leaks required an additional 36.7 MME (P = .046) on POD0 to 1. On discharge, mean opiate prescription was 117.7 MME (SD ± 102.1), equivalent to 15.7 tablets (SD ± 13.6) of oxycodone 5 mg. Thirty-nine patients (27.1%) did not require prescriptions. Only 10 patients (6.9%) required opiate refill(s) within 30 days after surgery. CONCLUSION: Patients undergoing EETS have higher opiate needs compared to those undergoing endoscopic sinus surgery, although the overall requirements are still considered low. Independent risk factors associated with higher opiate use in the immediate postoperative period included current smokers and grade 3 intraoperative cerebrospinal fluid leaks.

Sinonasal Quality of Life Outcomes after Endoscopic Endonasal Transsphenoidal Surgery with Posterior Septum Free Mucosal Graft Reconstruction.

Objective Quality of life (QoL) outcomes following endoscopic endonasal transphenoidal surgery (EETS) across a variety of reconstructive methods improve by 2 to 6 months. An option for sellar reconstruction, in the absence of a significant intraoperative cerebrospinal fluid (CSF) leak, is a free mucosal graft (FMG) from the posterior septum. We analyze sinonasal QoL outcomes in patients undergoing EETS with FMG reconstruction. Study Design This study was a retrospective review. Setting This study was conducted at tertiary care academic center. Participants This study group consisted of patients undergoing EETS for pituitary adenomas from 2013 to 2018. Main Outcome Measures Tumor and surgical factors were included, along with postoperative complications. Patients completed Sinonasal Outcome Test-22 (SNOT-22) questionnaires. Pre- and postoperative scores were compared among the entire cohort using linear multilevel regression. A subcohort analysis was performed among patients who completed questionnaires during the preoperative visit and two postoperative visits (within 1 month and between 2 and 3 months, respectively); pre- and postoperative total and individual domain SNOT-22 scores were compared using paired t -tests. Results A total of 243 patients underwent EETS with FMG reconstruction. Four patients (1.6%) developed a postoperative CSF leak requiring reoperation. Among the entire cohort, SNOT-22 scores increased at the first postoperative visit ( p < 0.01) but returned to baseline by the second, third, and fourth postoperative visits ( p = 0.27, p = 0.18, and p = 0.21). Among 48 patients who completed both preoperative and two postoperative questionnaires, scores increased within the first month ( p < 0.01) but returned to baseline at 2 to 3 months ( p = 0.67). Conclusion Posterior septum FMG reconstruction of sellar defects is an effective option, demonstrating early recovery of baseline sinonasal QoL by 2 to 3 months.

A human ACTH-secreting corticotroph tumoroid model: Novel Human ACTH-Secreting Tumor Cell in vitro Model.

BACKGROUND: Cushing disease (CD), although rare, is a life-threatening disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, which leads to excess adrenal-derived cortisol. Efficacious and safe medical therapies that control both hormonal hypersecretion and pituitary corticotroph tumor growth remain an unmet need in the management of CD. Translational research in pituitary tumors has been significantly hampered by limited quantities of surgically resected tissue for ex vivo studies, and unavailability of human pituitary tumor cell models. METHODS: To characterize human corticotroph tumors at the cellular level, we employed single cell RNA-sequencing (scRNA-seq) to study 4 surgically resected tumors. We also used microarrays to compare individualized paired consecutive culture passages to understand transcriptional shifts as in vitro cultures lost ACTH secretion. Based on these findings, we then modified our in vitro culture methods to develop sustained ACTH-secreting human corticotroph tumoroid cultures. FINDINGS: scRNA-seq identified 4 major cell populations, namely corticotroph tumor (73.6%), stromal (11.2%), progenitor (8.3%), and immune cells (6.8%). Microarray analysis revealed striking changes in extracellular matrix, cell adhesion and motility-related genes concordant with loss of ACTH secretion during conventional 2D culture. Based on these findings, we subsequently defined a series of crucial culture nutrients and scaffold modifications that provided a more favorable trophic and structural environment that could maintain ACTH secretion in in vitro human corticotroph tumor cultures for up to 4 months. INTERPRETATION: Our human corticotroph tumoroid model is a significant advance in the field of pituitary tumors and will further enable translational research studies to identify critically needed therapies for CD. FUNDING: This work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation.

Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease.

CONTEXT: Cushing disease (CD) is a life-threatening disorder. Therapeutic goals include symptom relief, biochemical control, and tumor growth inhibition. Current medical therapies for CD by and large exert no action on tumor growth. OBJECTIVE: To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth. DESIGN: High throughput screen employing a novel "gain of signal" ACTH AlphaLISA assay. SETTING: Academic medical center. PATIENTS: Corticotroph tumor tissues from patients with CD. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Potent inhibitors of corticotroph tumor ACTH secretion and growth. RESULTS: From a kinase inhibitor library, we identified the dual PI3K/HDAC inhibitor CUDC-907 as a potent inhibitor of murine and human corticotroph tumor ACTH secretion (median effective concentration 1-5 nM), and cell proliferation (median inhibitory concentration 5 nM). In an in vivo murine corticotroph tumor xenograft model, orally administered CUDC-907 (300 mg/kg) reduced corticotroph tumor volume (TV [cm3], control 0.17 ± 0.05 vs CUDC-907 0.07 ± 0.02, P < .05) by 65% and suppressed plasma ACTH (ACTH [pg/mL] control 206 ± 27 vs CUDC-907 47 ± 7, P < .05) and corticosterone (corticosterone [ng/mL] control 180 ± 87 vs CUDC-907 27 ± 5, P < .05) levels by 77% and 85% respectively compared with controls. We also demonstrated that CUDC-907 acts through HDAC1/2 inhibition at the proopiomelanocortin transcriptional level combined with its PI3K-mediated inhibition of corticotroph cell viability to reduce ACTH secretion. CONCLUSIONS: Given its potent efficacy in in vitro and in vivo models of CD, combined with proven safety and tolerance in clinical trials, we propose CUDC-907 may be a promising therapy for CD.

United States Medical Licensing Examination step 2 scores do not predict American Board of Neurological Surgery scores: A single-institution experience.

OBJECTIVES: The neurosurgery residency match is becoming increasingly competitive, with numerous factors being considered as part of the application. We aim to determine whether USMLE Step 2 scores were a significant predictor of neurosurgery board performance. PATIENTS AND METHODS: Residents who entered a neurological surgery residency program at a single academic institution during 2000-2017 provided scores for all ABNS attempts, USMLE Step 1 and Step 2 scores. Data were deidentified and analyzed for correlation and regression. Pearson's correlation coefficients were determined. RESULTS: USMLE Step 1, Step 2, and maximum ABNS scores were all normally distributed. Step 1 and Step 2 scores were less variable than ABNS scores. USMLE Step 2 and residents' best ABNS written examination scores were not correlated (Pearson Correlation of 0.228 with a 2-tailed significance of 0.272). No outliers were present. When comparing USMLE Step 2 scores with year in residency at which residents scored over 300 on the ABNS written examination, Pearson correlation was -0.500 (p = .015). A simple linear regression was calculated using Step 2 scores to predict the passing year of ABNS written examination (F(1,14) = 6.984, p = .015, R2 = 0.25). CONCLUSION: Although other studies have found correlations between USMLE Step 2 scores and performance before graduating medical school and during residency for other specialties, this is the first study comparing USMLE Step 2 scores with the ABNS written examination scores of neurosurgical residents. Our data showed that USMLE Step 2 was not a reliable predictor of ABNS written examination scores.