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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

PurposeThere 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.MethodsTwenty 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.ResultsBoth 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

BackgroundFK506 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.MethodsPre-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.ResultsConsistent 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

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.

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 ( β  = 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.

ObjectiveProvide insights into the defective POMC processing and invasive behavior in silent pituitary corticotroph tumors.Design and methodsSingle-cell RNAseq was used to compare the cellular makeup and transcriptome of silent and active corticotroph tumors.ResultsA 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.ConclusionsOur 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.

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.

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.

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

Abstract Silent pituitary corticotroph tumors derive from the Tpit (aka TBX19) pituitary lineage. Accounting for ~ 30% of corticotroph tumors, they are not infrequently clinically aggressive and invade locally into adjacent sellar structures, making complete surgical resection challenging and contributing to their higher recurrence rates. How silent and active corticotroph tumor subtypes differ is not clear although some studies reported that silent corticotroph tumors exhibit reduced PC1 expression causing impaired POMC processing. We used single cell RNAseq to compare the transcriptome between silent (n = 2) and active (n = 4) corticotroph tumors at the single cell level. We obtained an average of 265 million reads, and 24,682 genes per patient with an average of 1,240 genes expressed and 3,5442 unique molecular identifiers (UMIs) detected per cell. We further defined 5 distinct cell populations from a total of 23,269 cells, namely tumor cells (62%), stromal cells (25%), immune cells (7%), progenitor cells (5%), and a minor population of erythrocytes (1%). Tumor cells clustered in an origin-dependent manner and all expressed POMC and TBX19. However, the gene signatures of silent and active corticotroph tumors differed in 3 major aspects. Firstly, and supporting prior studies, a series of hormone processing peptidase genes, including PC1 (aka PCSK1), PDIA3, SEC11C, SPCS1 and CTSB, were reduced in silent corticotroph tumors (p=5.54e-5) compared to active corticotroph tumors. Secondly, genes involved in organization of secretory vesicles such as SCG5, TIMP1, VGF, SYT17, LGALS3 and CALY were also reduced in silent corticotroph tumors, which could further compound their inability to secrete ACTH. Thirdly, the silent corticotroph tumors exhibited several features of endothelial-to-mesenchymal transition (EMT), including increased expression of the mesenchymal genes CDH2 (aka NCAD), COL1A1, PCDH9, FGF5, ID2 (p=8.4e-3), and loss of EPCAM, which regulate cell migration and movement. Upstream analysis suggested that aberrant STAT3 activation may be related to these changes. Consequently, we noted that the stromal content was higher in silent corticotroph tumors (47.5% vs. 18.13%), concordant with the observed EMT de-differentiation of tumor cells. In summary, our scRNAseq analysis provides an unprecedented precise investigation of the transcriptomic features of thousands of heterogenous corticotroph tumor cells simultaneously. We demonstrate that although silent corticotroph tumor cells still express the pituitary lineage markers PITX1 and TBX19, they exhibit EMT, potentially affording increased migratory capacity at the cost of reduced neuroendocrine function with inability to produce and secrete mature ACTH. Our findings provide novel insights into the pathogenesis of silent versus active corticotroph tumor, but may reveal novel molecular targets for treatment of these challenging tumors.

BackgroundCushing 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.MethodsTo 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.FindingsscRNA-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.InterpretationOur 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.FundingThis work was partly funded by NCI P50-CA211015 and the Warley Trust Foundation.

Objectives  Bioabsorbable steroid eluting stents may prevent the stenosis of ostia after sinus surgery. We describe a technique utilizing this technology to prevent the reformation of Rathkes cleft cysts (RCC) after transnasal transsphenoidal surgical drainage. Design  This study is based on retrospective review. Setting  The research took place at Tertiary academic medical center. Participants  Patients who underwent endoscopic marsupialization of RCC with stent placement were participated in this study. Main Outcome Measures  Demographics, surgical history, outcomes, and complications were primary measures of this study. Results  Four patients underwent drainage of a recurrent RCC with subsequent stent placement. All patients consented to off-label use of the stent. The mean age of patients was 42 years old and the number of prior drainage procedures ranged from 1 to 3. The stent was placed directly into the opening of the cyst after drainage with no other tissue placed into the cyst cavity or opening. The stents are bioabsorbable and were not removed after surgery but were evaluated endoscopically at 2 and 6 weeks after surgery. The patients have been followed for a mean of 14 months after surgery with no evidence of recurrence on endoscopic exam or imaging. No patient had cerebrospinal fluid leak during or after the operation or permanent endocrinopathy. Conclusion  The use of a bioabsorbable steroid eluting stent had no unanticipated consequences and all drainage pathways of all the RCCs remain patent. The use of this technology may decrease recurrence rates in revision or complex cases where patients have extensive scarring of the operative field from prior drainage procedures. Further follow-up of the current cases and study in a larger cohort are warranted.

ObjectiveWe evaluated tumor recurrence and regrowth rates following endoscopic transnasal transsphenoidal (TNTS) surgical removal in a consecutive series of clinically nonfunctioning pituitary adenomas (CNFTs).DesignRetrospective chart review of clinical, biochemical, and sellar MRI findings in all TNTS surgeries in patients with CNFT, performed by a single surgeon, between 2008 and 2015 (n = 280).PatientsNinety-three patients met eligibility criteria, with complete clinical, biochemical, and imaging follow-up for a 3-year minimum.ResultsOf 85 patients who were not irradiated, 3-month postsurgical MRI demonstrated no residual tumor in 58 of 85 (68.2%), equivocal findings in 12 of 85 (14.1%), and definite residual tumor in 15 of 85 (17.6%) patients. Six of 85 (7.1%) demonstrated tumor regrowth by 3 years, and 2 further patients demonstrated true tumor recurrence at 3 and 6 years after surgery, respectively, for a total recurrence rate of 9.4% (8 of 85). Eight of the 93 patients were irradiated between 3 months and 4 years after pituitary surgery. In 3 patients with tumor regrowth, 2 exhibited residual tumor and 1 had no residual findings at the 3-month postoperative imaging. Overall, Ki-67 labeling index or Knosp grading did not predict recurrence.ConclusionTumor recurrence at 3 years was low (1 of 58; 1.7%) if the 3-month postoperative MRI showed no residual tumor. The findings support a less frequent imaging schedule for this group. Patients with definite residual tumor visible at 3 months harbor the greatest risk for tumor growth, but regrowth does not occur in all patients (6 of 15; 40%).

Objectives  Bioabsorbable steroid eluting stents may prevent the stenosis of ostia after sinus surgery. We describe a technique utilizing this technology to prevent the reformation of Rathke's cleft cysts (RCC) after transnasal transsphenoidal surgical drainage. Design  This study is based on retrospective review. Setting  The research took place at Tertiary academic medical center. Participants  Patients who underwent endoscopic marsupialization of RCC with stent placement were participated in this study. Main Outcome Measures  Demographics, surgical history, outcomes, and complications were primary measures of this study. Results  Four patients underwent drainage of a recurrent RCC with subsequent stent placement. All patients consented to off-label use of the stent. The mean age of patients was 42 years old and the number of prior drainage procedures ranged from 1 to 3. The stent was placed directly into the opening of the cyst after drainage with no other tissue placed into the cyst cavity or opening. The stents are bioabsorbable and were not removed after surgery but were evaluated endoscopically at 2 and 6 weeks after surgery. The patients have been followed for a mean of 14 months after surgery with no evidence of recurrence on endoscopic exam or imaging. No patient had cerebrospinal fluid leak during or after the operation or permanent endocrinopathy. Conclusion  The use of a bioabsorbable steroid eluting stent had no unanticipated consequences and all drainage pathways of all the RCCs remain patent. The use of this technology may decrease recurrence rates in revision or complex cases where patients have extensive scarring of the operative field from prior drainage procedures. Further follow-up of the current cases and study in a larger cohort are warranted.

BACKGROUND: This study investigated cerebrospinal fluid (CSF) hydrodynamics using cine phase-contrast MRI in the cerebral aqueduct and the prepontine cistern between three distinct groups: pre-shunt normal pressure hydrocephalus (NPH) patients, post-shunt NPH patients, and controls. We hypothesized that the hyperdynamic flow of CSF through the cerebral aqueduct seen in NPH patients was due to a reduction in cisternal CSF volume buffering. Both hydrodynamic (velocity, flow, stroke volume) and peak flow latency (PFL) parameters were investigated. METHODS: Scans were conducted on 30 pre-treatment patients ranging in age from 58 to 88 years along with an additional 12 controls. Twelve patients also received scans following either ventriculoatrial (VA) or ventriculoperitoneal (VP) shunt treatment (9 VP, 3 VA), ranging in age from 74 to 89 years with a mean follow up time of 6 months. RESULTS: Significant differences in area, velocity, flow, and stroke volume for the cerebral aqueduct were found between the pre-treatment NPH group and the healthy controls. Shunting caused a significant decrease in both caudal and cranial mean flow and stroke volume in the cerebral aqueduct. No significant changes were found in the prepontine cistern between the pre-treatment group and healthy controls. For the PFL, no significant differences were seen in the cerebral aqueduct between any of the three groups; however, the prepontine cistern PFL was significantly decreased in the pre-treatment NPH group when compared to the control group. CONCLUSIONS: Although several studies have quantified the changes in aqueductal flow between hydrocephalic groups and controls, few studies have investigated prepontine cistern flow. Our study was the first to investigate both regions in the same patients for NPH pre- and post- treatment. Following shunt treatment, the aqueductal CSF metrics decreased toward control values, while the prepontine cistern metrics trended up (not significantly) from the normal values established in this study. The opposing trend of the two locations suggests a redistribution of CSF pulsatility in NPH patients. Furthermore, the significantly decreased latency of the prepontine cisternal CSF flow suggests additional evidence for CSF pulsatility dysfunction.

Objectives  Prolactinomas are the most common functional pituitary adenoma. Symptoms of a prolactinoma stem from hormonal causes (menstrual irregularities, galactorrhea, and reduced libido) or from tumor mass effect (visual changes and headache). Gender differences have been noted in prolactinomas, with males presenting with larger tumors and sequelae of mass effect, while females present commonly with hormonal symptoms. The purpose of this study is to evaluate differences in patient and disease characteristics, and outcomes between male and female prolactinoma patients undergoing surgery. Design  This was a retrospective chart review. Setting  This was done at the tertiary medical center. Participants  The medical records of prolactinomas patients who underwent endoscopic endonasal surgery between March 2008 and August 2016 were reviewed. Main Outcome Measures  Demographic information, tumor characteristics, and treatment characteristics and outcomes were collected. Statistical analysis was performed using chi-squared test or Students t -test as applicable. Results  Seventy-nine patients were identified, 22 males and 57 females. The average age for males was 38 years and for females was 35 years. Males were more likely to present with decreased libido ( p

A novel glucose transporter, the sodium glucose cotransporter 2 (SGLT2), has been demonstrated to contribute to the demand for glucose by pancreatic and prostate tumors, and its functional activity has been imaged using a SGLT specific PET imaging probe, α-methyl-4-[F-18]fluoro-4-deoxy-D-glucopyaranoside (Me-4FDG). In this study, Me-4FDG PET was extended to evaluate patients with high-grade astrocytic tumors. Me-4FDG PET scans were performed in four patients diagnosed with WHO Grade III or IV astrocytomas and control subjects, and compared with 2-deoxy-2-[F-18]fluoro-D-glucose (2-FDG) PET and magnetic resonance imaging (MRI) of the same subjects. Immunocytochemistry was carried out on Grade IV astrocytomas to determine the cellular location of SGLT proteins within the tumors. Me-4FDG retention was pronounced in astrocytomas in dramatic contrast to the lack of uptake into the normal brain, resulting in a high signal-to-noise ratio. Macroscopically, the distribution of Me-4FDG within the tumors overlapped with that of 2-FDG uptake and tumor definition using contrast-enhanced MRI images. Microscopically, the SGLT2 protein was found to be expressed in neoplastic glioblastoma cells and endothelial cells of the proliferating microvasculature. This preliminary study shows that Me-4FDG is a highly sensitive probe for visualization of high-grade astrocytomas by PET. The distribution of Me-4FDG within tumors overlapped that for 2-FDG, but the absence of background brain Me-4FDG resulted in superior imaging sensitivity. Furthermore, the presence of SGLT2 protein in astrocytoma cells and the proliferating microvasculature may offer a novel therapy using the SGLT2 inhibitors already approved by the FDA to treat type 2 diabetes mellitus.

Objectives/Hypotheses  To assess quality of life (QOL) after transnasal, endoscopic pituitary surgery using the 36-item short form (SF-36) instrument. Design  Retrospective review was used for this study. Setting  The study was conducted in a tertiary academic medical center. Participants  Patients who underwent endoscopic, transnasal, transsphenoidal surgery for pituitary adenomas between January 1, 2007 and July 1, 2016 and completed preoperative and postoperative SF-36 surveys. Main Outcome Measures  SF-36 survey data as measured by its eight domains (physical functioning, physical role functioning, emotional role functioning, energy/fatigue, emotional well-being, social functioning, pain, and general health). Results  There were 18 preoperative, 13 short-term (2 weeks or less after surgery) postoperative, and 14 longer term (>2 weeks after surgery) postoperative surveys. There was no significant difference between preoperative and long-term postoperative SF-36 scores across domains ( p  > 0.05). In comparing short-term postoperative and preoperative scores, tumor size was positively associated with emotional well-being ( p  = 0.049) and general health scores ( p  = 0.031), while visual changes preoperatively were positively associated with general health scores ( p  = 0.046). Compared with standard U.S. general population summary data, these patients scored lower preoperatively in all domains except for emotional role functioning and pain ( p

Objectives/Hypotheses  The endoscopic endonasal approach (EEA) is the workhorse endoscopic procedure for sellar and parasellar pathology. Various reconstruction techniques have been reported following EEA surgery, ranging from no reconstruction to vascularized flaps. We review our institutions experience with sellar reconstruction following EEA and propose an evidence-based algorithm. Design  Retrospective review. Setting  Tertiary academic medical center. Participants  Patients who underwent endoscopic EEA surgery for sellar or parasellar pathology between March 1, 2013 and August 31, 2016. Main Outcome Measures  Patient demographic and clinicopathologic data were collected. Outcome measures included intraoperative and postoperative cerebrospinal fluid (CSF) leak rates and extent of resection (gross or subtotal). Results  Three hundred consecutive patients were included. Depending on the presence and grade of intraoperative CSF leak, cases were reconstructed using either a free mucosal graft (FMG) or nasoseptal flap (NSF). Intraoperative and postoperative CSF leak rates were 30.7% and 2.3%, respectively. Multivariable logistic regression found that intraoperative CSF leak was associated with recurrent disease (odds ratio [OR] 2.47, p  = 0.004), with no apparent predictors of postoperative CSF leak. Conclusions  Based on this large series, we propose the following algorithm for sellar reconstruction: FMG for no CSF leak; fat graft + FMG ± rigid fixation for low-grade leaks; and fat graft + NSF ± rigid fixation for high-grade leaks.

Objectives/Hypotheses  The endoscopic endonasal approach (EEA) is the workhorse endoscopic procedure for sellar and parasellar pathology. Various reconstruction techniques have been reported following EEA surgery, ranging from no reconstruction to vascularized flaps. We review our institution's experience with sellar reconstruction following EEA and propose an evidence-based algorithm. Design  Retrospective review. Setting  Tertiary academic medical center. Participants  Patients who underwent endoscopic EEA surgery for sellar or parasellar pathology between March 1, 2013 and August 31, 2016. Main Outcome Measures  Patient demographic and clinicopathologic data were collected. Outcome measures included intraoperative and postoperative cerebrospinal fluid (CSF) leak rates and extent of resection (gross or subtotal). Results  Three hundred consecutive patients were included. Depending on the presence and grade of intraoperative CSF leak, cases were reconstructed using either a free mucosal graft (FMG) or nasoseptal flap (NSF). Intraoperative and postoperative CSF leak rates were 30.7% and 2.3%, respectively. Multivariable logistic regression found that intraoperative CSF leak was associated with recurrent disease (odds ratio [OR] 2.47, p  = 0.004), with no apparent predictors of postoperative CSF leak. Conclusions  Based on this large series, we propose the following algorithm for sellar reconstruction: FMG for no CSF leak; fat graft + FMG ± rigid fixation for low-grade leaks; and fat graft + NSF ± rigid fixation for high-grade leaks.

Objectives/Hypotheses Functioning pituitary adenomas may produce endocrinopathies such as acromegaly and Cushing syndrome. Both conditions lead to characteristic anatomic variations as a result of hormonally induced abnormal soft tissue deposition. We evaluate the anatomic differences between acromegalics and Cushing disease patients and compare these dimensions to controls. Design Radiographic review of preoperative magnetic resonance images (MRI) of the pituitary gland. Setting Tertiary academic medical center. Participants Patients who underwent transnasal, transsphenoidal surgery for pituitary adenomas found to have acromegaly or pituitary Cushing between January 1, 2007 and September 1, 2015. A total of 15 patients with similar MRIs and no history of pituitary or sinonasal disease were selected as controls. Main Outcome Measures Dimensions assessed were intercarotid distance; carotid canal width; piriform aperture width; distance from the piriform aperture to the anterior face of the sphenoid; sphenoid sinus height, width, and length; angle from anterior nasal spine to anteroinferior face of sphenoid sinus; choanal height; and nasal cavity height at the level of the vertical segment of the middle turbinate. Sphenoid sinus pneumatization patterns were recorded. Results There were 30 acromegalics and 31 Cushing disease patients. When compared with controls, both acromegalics and Cushing disease patients had significantly wider piriform apertures and a longer distance from the piriform aperture to the anterior face of the sphenoid sinus (p

Objectives Rathkes cleft cysts (RCC) are benign cystic lesions of the sella resulting from incomplete obliteration of Rathkes cleft. Symptomatic lesions often require surgical decompression, which is often amenable to a transnasal, transsphenoidal (TNTS) approach. We report our experience with marsupialization of RCC and describe a novel technique to promote re-epithelization of the cyst cavity. Design Retrospective review. Setting Tertiary academic medical center. Participants Patients who underwent TNTS for RCC between 2007 and 2015. Main Outcome Measures Demographics, lesion characteristics, and reconstruction and treatment outcomes. Results In total, 52 patients were identified. The mean age was 41 ± 18 years. The mean RCC size was 13 ± 5 mm. Intraoperative cerebrospinal fluid (CSF) leak was encountered in 14 (27%) patients; all were repaired. There were six complications (12%) and no deaths. Mean follow-up was 20 ± 18 months, with five (10%) recurrences. RCC size was associated with intraoperative CSF leak (p = 0.04). In 12 patients, the marsupialized cyst cavity was lined with a free mucosal graft (FMG) to promote healing and re-epithelialization. Conclusions The TNTS approach is safe and effective in surgical decompression of RCC. Lining the exposed cyst cavity with an FMG is a simple intervention without added morbidity that may promote formation of an epithelialized tract. Level of Evidence Not applicable.

Objectives The nasoseptal flap (NSF) has become the workhorse for reconstruction in endoscopic endonasal skull-base surgery. The NSF, though useful in reconstruction, may lead to significant donor site morbidity. Published techniques to reduce the donor site morbidity, free mucosal grafts, and septal rotational flaps have shown to reduce crusting and remucosalization times. We present a novel technique utilizing posterior septal mucosa as a free mucosal graft for reconstruction of the anterior septal donor site. The septal mucosal graft is taken from the mucosa overlying the posterior septectomy site of the endonasal approach to skull base tumors. Design Retrospective chart review. Setting Single tertiary academic medical center. Participants All patients who underwent endoscopic endonasal skull-base surgery between November 1, 2014 and August 30, 2015 with free mucosal graft reconstruction of the NSF donor site. Main Outcome Measures Postoperative graft success. Results Fifteen patients underwent septal reconstruction using a septal free mucosal graft. There was a 100% graft success rate with near complete remucosalization by 6 weeks postoperatively. Conclusions The posterior septal free mucosal graft is a simple, reliable method for reconstructing the NSF donor site. The advantages of this technique include utilization of native septal mucosal tissue and middle turbinate preservation.

Objectives Bilateral anterior skull base (ASB) defects following endoscopic endonasal tumor resection are most commonly repaired utilizing multilayered reconstruction with a vascularized mucosal flap. Single-layer closure of large ASB defects has been described in the literature but this technique has yet to gain a widespread use. We report our experience with a series of patients who underwent reconstruction of large ASB defects using a single-layer intradural graft, without nasoseptal flaps. We also compared the use of acellular dermal matrix (AlloDerm, LifeCell, Branchburg, New Jersey, United States) or collagen matrix xenograft (Duramatrix, Stryker, Kalamazoo, Michigan, United States) as the graft biomaterial. Design A retrospective case series. Setting Tertiary academic medical center. Main Outcome Measures Postoperative cerebrospinal fluid leak, the number of postoperative debridements, the number of postoperative infections, and time to remucosalization. Results Two patients were reconstructed with AlloDerm and three with Duramatrix, with all patients receiving postoperative external beam radiation. There were no postoperative cerebrospinal fluid leaks identified in these patients during follow-up. The AlloDerm group showed increased postsurgical crusting, the number of clinically apparent postoperative infections, and an increased time to remucosalization. Conclusions Single-layer repair without a vascularized mucosal flap is a viable method of skull base repair for large ASB defects. We found repair with Duramatrix was superior, with less graft crusting and infection, requiring fewer debridements.

Objectives Rathke's cleft cysts (RCC) are benign cystic lesions of the sella resulting from incomplete obliteration of Rathke's cleft. Symptomatic lesions often require surgical decompression, which is often amenable to a transnasal, transsphenoidal (TNTS) approach. We report our experience with marsupialization of RCC and describe a novel technique to promote re-epithelization of the cyst cavity. Design Retrospective review. Setting Tertiary academic medical center. Participants Patients who underwent TNTS for RCC between 2007 and 2015. Main Outcome Measures Demographics, lesion characteristics, and reconstruction and treatment outcomes. Results In total, 52 patients were identified. The mean age was 41 ± 18 years. The mean RCC size was 13 ± 5 mm. Intraoperative cerebrospinal fluid (CSF) leak was encountered in 14 (27%) patients; all were repaired. There were six complications (12%) and no deaths. Mean follow-up was 20 ± 18 months, with five (10%) recurrences. RCC size was associated with intraoperative CSF leak (p = 0.04). In 12 patients, the marsupialized cyst cavity was lined with a free mucosal graft (FMG) to promote healing and re-epithelialization. Conclusions The TNTS approach is safe and effective in surgical decompression of RCC. Lining the exposed cyst cavity with an FMG is a simple intervention without added morbidity that may promote formation of an epithelialized tract. Level of Evidence Not applicable.

Latino Americans are a rapidly growing ethnic group in the United States but studies of glioblastoma in this population are limited. We have evaluated characteristics of 21,184 glioblastoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. This SEER data from 2001 to 2011 draws from 28% of the U.S.PopulationLatinos have a lower incidence of GBM and present slightly younger than non-Latino Whites. Cubans present at an older age than other Latino sub-populations. Latinos have a higher incidence of giant cell glioblastoma than non-Latino Whites while the incidence of gliosarcoma is similar. Despite lower rates of radiation therapy and greater rates of sub-total resection than non-Latino Whites, Latinos have better 1 and 5 year survival rates. SEER does not record chemotherapy data. Survivals of Latino sub-populations are similar with each other. Age, extent of resection, and the use of radiation therapy are associated with improved survival but none of these variables are sufficient in a multivariate analysis to explain the improved survival of Latinos relative to non-Latino Whites. As molecular data is not available in SEER records, we studied the MGMT and IDH status of 571 patients from a UCLA database. MGMT methylation and IDH1 mutation rates are not statistically significantly different between non-Latino Whites and Latinos. For UCLA patients with available information, chemotherapy and radiation rates are similar for non-Latino White and Latino patients, but the latter have lower rates of gross total resection and present at a younger age.

We recently demonstrated that the orphan nuclear receptor testicular receptor 4 (TR4) is a potent regulator of corticotroph tumor growth and hormone secretion. The Ras/Raf/MEK/ERK pathway is commonly overactivated in human tumors and we have demonstrated that corticotroph tumor TR4 is activated by ERK1/2-mediated phosphorylation. We evaluated effects of MEK-162, a selective, non-ATP-competitive allosteric inhibitor of MEK1/2, on murine and human in vitro and in vivo corticotroph tumor proliferation and adrenocorticotrophic hormone (ACTH) secretion. MEK-162 treatment dose-dependently inhibited corticotroph tumor proliferation, induced apoptosis, reduced pro-opiomelanocortin (POMC) mRNA levels and inhibited ACTH secretion in vitro. Similar findings were obtained in human corticotroph tumor primary cultures (n = 5). These actions of MEK-162 were augmented in the presence of TR4 overexpression, suggesting that TR4 levels may serve as a predictive biomarker of MEK-162 corticotroph tumor responsiveness. Additionally, MEK-162 treatment reduced TR4 protein expression and blocked recruitment of TR4 to bind its consensus site on the POMC promoter (-854bp to -637bp), elucidating multiple mechanisms to control TR4 corticotroph tumor actions. In a murine corticotroph tumor in vivo model of Cushing's disease, MEK-162 treatment inhibited tumor growth and reduced tumor-derived circulating plasma ACTH, and corticosterone levels. These results demonstrate the potent actions of MEK-162 to inhibit corticotroph tumor growth and hormone secretion in vitro and in vivo via TR4-dependent and independent mechanisms, and raise the possibility of MEK-162 as a novel therapy for Cushing's disease.

Objective Chordomas are locally aggressive, highly recurrent tumors requiring adjuvant radiotherapy following resection for successful management. We retrospectively reviewed patients treated for intracranial chordomas with adjuvant stereotactic radiosurgery (SRS) and stereotactic radiation therapy (SRT). Methods A total of 57 patients underwent 83 treatments at the UCLA Medical Center between February 1990 and August 2011. Mean follow-up was 57.8 months. Mean tumor diameter was 3.36 cm. Overall, 8 and 34 patients received adjuvant SRS and SRT, and the mean maximal dose of radiation therapy was 1783.3 cGy and 6339 cGy, respectively. Results Overall rate of recurrence was 51.8%, and 1- and 5-year progression-free survival (PFS) was 88.2% and 35.2%, respectively. Gross total resection was achieved in 30.9% of patients. Adjuvant radiotherapy improved outcomes following subtotal resection (5-year PFS 62.5% versus 20.1%; p = 0.036). SRS and SRT produced comparable rates of tumor control (p = 0.28). Higher dose SRT (> 6,000 cGy) (p = 0.013) and younger age (< 45 years) (p = 0.03) was associated with improved rates of tumor control. Conclusion Adjuvant radiotherapy is critical following subtotal resection of intracranial chordomas. Adjuvant SRT and SRS were safe and improved PFS following subtotal resection. Higher total doses of SRT and younger patient age were associated with improved rates of tumor control.

ImportanceLymphocytic hypophysitis (LH) is a poorly understood autoimmune disorder of the pituitary gland. Symptoms include headache, pituitary dysfunction, visual disturbances, and neurological deficits. The diagnosis can be made based on clinical and biochemical findings, but for atypical presentations, no circulatory diagnostic biomarkers exist, and a pituitary biopsy is necessary for diagnosis.ObjectivesWe used high-resolution human leukocyte antigen (HLA) screening assays to investigate a relationship between specific HLA markers and LH.DesignThis was a retrospective analysis.SettingThe study was conducted at a tertiary referral center.SubjectsFifteen patients with sporadic LH, 4 patients with melanoma who developed hypophysitis after administration of cytotoxic T lymphocyte antigen 4 (CTLA4) antibodies, and 1 patient with sarcoid-associated hypophysitis were evaluated.InterventionClinical data, including endocrine function, were assessed, and HLA typing was performed in all 20 patients with hypophysitis, 50 control patients with other sellar abnormalities, and 4 CTLA4 antibody-treated patients without hypophysitis.ResultsTwo major histocompatibility class II HLA markers, DQ8 and DR53, were found in 13 of 15 (87%) and 12 of 15 (80.0%) patients with sporadic LH, respectively. In contrast, none of the 4 patients who developed hypophysitis after administration of the CTLA4 antibodies exhibited the HLA-DQ8 marker and only 1 of 4 (25%) exhibited the HLA-DR53 marker. In a parallel group of 50 control subjects with sellar masses and 4 CTLA4 antibody-treated patients who did not develop evidence of pituitary failure, the candidate HLA subtypes were found in ∼20% for DQ8 and ∼48% for DR53, respectively.Conclusion and relevanceThe HLA markers, DQ8 and DR53, were found to be commonly present in patients with LH. The odds ratio of a patient with LH expressing the HLA-DQ8 marker is 23.1-fold higher than that of a patient with another sellar mass. HLA-DQ8 testing may assist in diagnosis and avoid unnecessary biopsies in patients with atypical LH.

Objectives To profile the clinical presentation and treatment results of esthesioneuroblastomas at the University of California, Los Angeles (UCLA), from 2002 to 2013. Design Retrospective review. Setting Tertiary academic institution. Participants Forty-one patients with esthesioneuroblastomas treated at UCLA. Main Outcome Measures Overall survival (OS) and recurrence-free survival (RFS). Results Thirty-six patients were included with a mean age of 50.1 years and a median duration of follow-up of 33 months. The 5-year RFS and OS were 54% and 82%, respectively. Modified Kadish stage was the only factor identified to affect OS. Multivariate analysis demonstrated that tumor grade was the only factor that had an independent impact on RFS. There was no statistical difference in survival among the surgical approaches chosen. Conclusions The updated data on the UCLA experience reveals that all three surgical approaches chosen provide comparable survival, although longer follow-up will be needed to ascertain if these findings hold true. The endoscopic approach had a statistically significant decrease in length of hospital stay and a trend toward reduced blood loss, intensive care unit admission, and complications. The modified Kadish staging was the only factor identified to predict OS. Multivariate analysis revealed that tumor grade was an independent predictor of recurrence; therefore, its importance should be emphasized in future staging systems.

Objective To review our experience in a series of patients who underwent revision endoscopic pituitary surgery. Methods Retrospective chart review. Results A total of 27 patients were included in the study. Of the 21 patients who required nasoseptal flap reconstruction, a left-sided nasoseptal flap was successfully used in 13 patients. Gross total or near-total resection of tumor was achieved in 74.1%. Cavernous sinus invasion and presentation with residual disease were identified as factors limiting extent of resection (p = 0.002 and 0.009, respectively). A statistically significant difference (p = 0.027) was noted between mean largest tumor dimension in patients with gross total resection and those with near-total or subtotal resection. Complications occurred in 22% and included postoperative temporary diabetes insipidus (n = 2), postoperative hypotension (n = 2), new anterior pituitary insufficiency (n = 1), and right-sided abducens palsy (n = 1). Conclusions Revision endoscopic pituitary surgery is advantageous but technically challenging. Cavernous sinus invasion and presentation with residual disease were significant factors limiting extent of resection. Suprasellar extension was not a factor limiting extent of resection and may prove to be an advantage over microscopic speculum-based approaches. Because of the right-sided scarring from prior surgery, a left-sided nasoseptal flap is reliable and advantageous.

Here, we report on the development and evaluation of novel unobstructing magnetic microactuators for maintaining the patency of implantable ventricular catheters used in hydrocephalus application. The treatment of hydrocephalus requires chronic implantation of a shunt system to divert excess cerebrospinal fluid from the brain. These shunt systems suffer from a high failure rate (>40%) within the first year of implantation, often due to biological accumulation. Previously, we have shown that magnetic microactuators can be used to remove biological blockage. The new cantilever-based magnetic microactuator presented in this paper improves upon the previous torsional design using a bimorph to induce a postrelease out-of-plane deflection that will prevent the device from occluding the pore at rest. The mechanical evaluations (i.e., postrelease deflection, static and dynamic responses) of fabricated devices are reported and compared with theoretical values.

Background/Objective Our institution previously showed that patients experience significant postoperative sinonasal symptoms for the first few months after endoscopic transnasal transsphenoidal skull base surgery (eTNTS). Since our initial study we have modified our technique, discontinuing routine resection of the middle turbinate, maxillary antrostomies, and nasoseptal flaps. In this study, we analyze whether these technical modifications decrease postoperative sinonasal morbidity after eTNTS. Methods A retrospective review was performed of 93 consecutive patients who underwent eTNTS at a tertiary academic medical center from August 2011 to August 2012. Main Outcome Measures  Sino-Nasal Outcome Test (SNOT)-20 and SNOT-22 scores preoperatively and after surgery. Results Compared with our previous study, our new cohort experienced a significant improvement (p

This article discusses the use of different techniques for skull base reconstruction in endoscopic pituitary surgery and their association with cerebrospinal fluid (CSF) leaks. The Hadad-Bassagasteguy nasoseptal flap (NSF) has been effective in reducing CSF leaks, but there is limited data on the appearance of different reconstruction techniques on MRI and their relationship to CSF leak rates. The study reviewed patient data and imaging to compare the vascularization patterns of free mucosal grafts (FMG) and NSF, and found that patients with NSF reconstruction had higher rates of intraoperative CSF leaks. However, there was no association between patterns of flap enhancement on MRI and CSF leaks. FMGs showed a predictable change in enhancement pattern over 3 months, while NSFs without flap enhancement at 1 week still demonstrated neovascularization without increased risk of complications. [Extracted from the article]

Abstract Background The waveform morphology of intracranial pressure pulses (ICP) is an essential indicator for monitoring, and forecasting critical intracranial and cerebrovascular pathophysiological variations. While current ICP pulse analysis frameworks offer satisfying results on most of the pulses, we observed that the performance of several of them deteriorates significantly on abnormal, or simply more challenging pulses. Methods This paper provides two contributions to this problem. First, it introduces MOCAIP++, a generic ICP pulse processing framework that generalizes MOCAIP (Morphological Clustering and Analysis of ICP Pulse). Its strength is to integrate several peak recognition methods to describe ICP morphology, and to exploit different ICP features to improve peak recognition. Second, it investigates the effect of incorporating, automatically identified, challenging pulses into the training set of peak recognition models. Results Experiments on a large dataset of ICP signals, as well as on a representative collection of sampled challenging ICP pulses, demonstrate that both contributions are complementary and significantly improve peak recognition performance in clinical conditions. Conclusion The proposed framework allows to extract more reliable statistics about the ICP waveform morphology on challenging pulses to investigate the predictive power of these pulses on the condition of the patient.