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Clinically nonfunctional pituitary adenomas cause hypopituitarism or compression of regional structures. Unlike functional tumors, there is no available medical treatment or specific imaging technique for these tumors. We have recently discovered that both folate receptor (FR)alpha mRNA and protein are uniquely overexpressed in nonfunctional pituitary tumors, but not in functional adenomas. We hypothesized that FRalpha may hold significant promise for medical treatment by enabling novel molecular imaging and targeted therapy. Here, we used murine pituitary tumor cell line alphaT3-1 as a model to investigate the biological significance of FRalpha and its mutant FR67. We demonstrate that overexpression of FR facilitated tumor cell growth and anchorage-independent growth in soft agar. More colonies were observed in FR overexpressing cells than in mutant FR67 clones in soft agar. Cell proliferation rate was increased, the percentage of cells in S-phase was increased, and high PCNA staining was detected in cells overexpressing the receptor. In alphaT3-1 cells transfected with mutant FR67, cell proliferation rate was reduced, the percentage of cells residing in S-phase was slightly decreased, and low PCNA staining was observed. By real-time quantitative PCR, the genes involved in NOTCH3 pathway including NOTCH3, HES-1, and TLE2 were altered; the mRNA expression of FGFR1 was upregulated, and ERbeta mRNA was downregulated in FR overexpressing cells. Our findings suggest that FRalpha plays a role in pituitary tumor formation, and this effect may in part be due to its regulation of the NOTCH3 pathway. [ABSTRACT FROM AUTHOR]

Acromegaly is a disease that occurs secondary to high levels of GH, most often from a hormone-secreting pituitary adenoma, with multisystem adverse effects. Diagnosis includes serum GH and IGF-1 levels, and obtaining an MRI pituitary protocol to assess for a functional pituitary adenoma. Attempted gross total resection of the GH-secreting adenoma is the gold standard in treatment for patients with acromegaly for a goal of biochemical remission. Medical and radiation therapies are available when patients do not achieve biochemical cure after surgical therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bray, Mannam, Rindler, Quillin and Oyesiku.)

Background: Adjuvant radiotherapy (RT) can help achieve local control (LC) and reduce hormonal overexpression for pituitary adenomas (PAs). Prior reports involved Gamma Knife or older linear accelerator (LINAC) techniques. The aim of this study was to report long-term outcomes for modern LINAC RT., Methods: Institutional retrospective review of LINAC RT for PAs with minimum 3 years of magnetic resonance imaging follow-up was performed. Hormonal control was defined as biochemical remission in absence of medications targeting hormone excess. LC defined using Response Evaluation Criteria in Solid Tumors on surveillance magnetic resonance imaging. Progression-free survival defined as time alive with LC without return of or worsening hormonal excess from secretory PA. Kaplan-Meier and Cox proportional hazard models used., Results: From 2003 to 2017, 140 patients with PAs (94 nonsecretory, 46 secretory) were treated with LINAC RT (105 fractionated RT, 35 radiosurgery) with median follow-up of 5.35 years. Techniques included fixed gantry intensity-modulated radiotherapy (51.4%), dynamic conformal arcs (9.3%), and volumetric modulated arc therapy (39.3%). Progression-free survival at 5 years was 95.3% for secretory tumors and 94.8% for nonsecretory tumors. Worse progression-free survival was associated with larger planning target volume on multivariable analysis (hazard ratio 2.87, 95% confidence interval 1.01-8.21, P = 0.049). Hormonal control at 5 years was 50.0% and associated with higher dose to tumor (hazard ratio 1.05, 95% confidence interval 1.02-1.09, P = 0.005) and number of surgeries (hazard ratio 1.74, 95% confidence interval 1.05-2.89, P = 0.032). Patients requiring any pituitary hormone replacement increased from 57.9% to 70.0% after RT., Conclusions: Modern LINAC RT for patients with PAs was safe and effective for hormonal control and LC. No difference in LC was noted for functional versus nonfunctional tumors, possibly owing to higher total dose and daily image guidance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cushing disease is a disorder of hypercortisolemia caused by hypersecretion of adrenocorticotropic hormone by a pituitary adenoma and is a rare diagnosis. Cushing disease presents with characteristic clinical signs and symptoms associated with excess cortisol, but diagnosis is difficult and often relies on repeated and varied endocrinologic assays and neuroradiologic investigations. Gold standard treatment is surgical resection of adrenocorticotropic hormone-secreting pituitary adenoma, which is curative. Patients require close endocrinologic follow-up for maintenance of associated neuroendocrine deficiencies and surveillance for potential recurrence. Medications, radiation therapy, and bilateral adrenalectomy are alternative treatments for residual or recurrent disease., Competing Interests: Disclosure of funding Dr. David P. Bray is partly supported by the Nell W. and William S. Elkin Research Fellowship in Oncology, Winship Cancer Institute, Emory University Hospital, Atlanta, GA and supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UL1TR002378 and TL1TR002382., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Crooke cell adenomas (CCAs) are rare, potentially aggressive pituitary adenomas. Data regarding prevalence and clinical course are sparse., Methods: We performed a retrospective review of 59 consecutive functioning corticotroph adenomas operated on between October 2017 and November 2020 and a literature review of CCA publications since 1991., Results: The prevalence of CCAs among functioning corticotroph adenomas at our institution was 8.5% (5/59). In the 4 other surgical case series, prevalence of CCAs was 0%-6.8%. Our patients (4 women and 1 man, mean age 46 ± 11 years) presented with hypercortisolism (3/5), with vision loss (1/5), and incidentally (1/5). All patients had elevated adrenocorticotropic hormone (151 ± 54 pg/mL) and urinary free cortisol (830 ± 796.5 μg/day). Radiologically, 3 tumors were macroadenomas and 2 had cavernous sinus invasion. All patients achieved biochemical remission at 3 months postoperatively. One patient with a giant pituitary adenoma underwent fractionated radiation for residual tumor. During follow-up (range, 3.1-31.0 months), no patients had evidence of radiological or biochemical recurrence. The literature review identified 22 functioning corticotroph adenomas with outcome data. Additional treatments included reoperation (50%), radiation (59%), bilateral adrenalectomy (23%), and temozolomide (36%)., Conclusions: We found a higher CCA prevalence among functioning adrenocorticotropic hormone adenomas after implementation of the 2017 World Health Organization classification. In our series and the literature, most CCAs were macroadenomas with high adrenocorticotropic hormone levels. Postoperative outcomes were excellent in our series, while some cases from the literature were refractory to standard treatments. Larger clinical and molecular studies are needed to identify patients at risk., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective  The purpose of this study was to evaluate pituitary tumor patient satisfaction with telemedicine, patient preference for telemedicine, potential socioeconomic benefit of telemedicine, and patients' willingness to proceed with surgery based on a telemedicine visit alone. Method  In total, 134 patients who had pituitary surgery and a telemedicine visit during the coronavirus disease 2019 (COVID-19) pandemic (April 23, 2020-March 4, 2021) were called to participate in a 13-part questionnaire. Chi-square, ANOVA, and Wilcoxon Rank Sum tests were used to determine significance. Result  Of 134 patients contacted, 90 responded (67%). Ninety-five percent were "satisfied" or "very satisfied" with their telemedicine visit, with 62% stating their visit was "the same" or "better" than previous in-person appointments. Eighty-two percent of the patients rated their telemedicine visit as "easy" or "very easy." On average, patients saved 150 minutes by using telemedicine compared with patient reported in-person visit times. Seventy-seven percent of patients reported the need to take off from work for in-person visits, compared with just 12% when using telemedicine. Forty-nine percent of patients preferred in-person visits, 34% preferred telemedicine, and 17% had no preference. Fifty percent of patients said they would feel comfortable proceeding with surgery based on a telemedicine visit alone. Patients with both initial evaluation and follow-up conducted via telemedicine were more likely to feel comfortable proceeding with surgery based on a telemedicine visit alone compared with patients who had only follow-up telemedicine visits ( p  = 0.051). Conclusion  Many patients are satisfied with telemedicine visits and feel comfortable proceeding with surgery based on a telemedicine visit alone. Telemedicine is an important adjunct to increase access to care at a Pituitary Center of Excellence., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Purpose: Surgical workflow analysis seeks to systematically break down operations into hierarchal components. It facilitates education, training, and understanding of surgical variations. There are known educational demands and variations in surgical practice in endoscopic transsphenoidal approaches to pituitary adenomas. Through an iterative consensus process, we generated a surgical workflow reflective of contemporary surgical practice., Methods: A mixed-methods consensus process composed of a literature review and iterative Delphi surveys was carried out within the Pituitary Society. Each round of the survey was repeated until data saturation and > 90% consensus was reached., Results: There was a 100% response rate and no attrition across both Delphi rounds. Eighteen international expert panel members participated. An extensive workflow of 4 phases (nasal, sphenoid, sellar and closure) and 40 steps, with associated technical errors and adverse events, were agreed upon by 100% of panel members across rounds. Both core and case-specific or surgeon-specific variations in operative steps were captured., Conclusions: Through an international expert panel consensus, a workflow for the performance of endoscopic transsphenoidal pituitary adenoma resection has been generated. This workflow captures a wide range of contemporary operative practice. The agreed "core" steps will serve as a foundation for education, training, assessment and technological development (e.g. models and simulators). The "optional" steps highlight areas of heterogeneity of practice that will benefit from further research (e.g. methods of skull base repair). Further adjustments could be made to increase applicability around the world., (© 2021. The Author(s).)

Context: Acromegaly (ACM) and Cushing's disease (CD) are caused by functioning pituitary adenomas secreting growth hormone and ACTH respectively., Objective: To determine the impact of race on presentation and postoperative outcomes in adults with ACM and CD, which has not yet been evaluated., Methods: This is a retrospective study of consecutive patients operated at a large-volume pituitary center. We evaluated (1) racial distribution of patients residing in the metropolitan area (Metro, N = 124) vs 2010 US census data, and(2) presentation and postoperative outcomes in Black vs White for patients from the entire catchment area (N = 241)., Results: For Metro area (32.4% Black population), Black patients represented 16.75% ACM ( P  = .006) and 29.2% CD ( P  = .56). Among the total 112 patients with ACM, presentations with headaches or incidentaloma were more common in Black patients (76.9% vs 31% White, P  = .01). Black patients had a higher prevalence of diabetes (54% vs 16% White, P  = .005), significantly lower interferon insulin-like growth factor (IGF)-1 deviation from normal ( P  = .03) and borderline lower median growth hormone levels ( P  = .09). Mean tumor diameter and proportion of tumors with cavernous sinus invasion were similar. Three-month biochemical remission (46% Black, 55% White, P  = .76) and long-term IGF-1 control by multimodality therapy (92.3% Black, 80.5% White, P  = .45) were similar. Among the total 129 patients with CD, Black patients had more hypopituitarism (69% vs 45% White, P  = .04) and macroadenomas (33% vs 15% White, P  = .05). At 3 months, remission rate was borderline higher in White (92% vs 78% Black, P  = 0.08), which was attributed to macroadenomas by logistic regression., Conclusion: We identified disparities regarding racial distribution, and clinical and biochemical characteristics in ACM, suggesting late or missed diagnosis in Black patients. Large nationwide studies are necessary to confirm our findings., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Cushing's disease (CD) is defined as hypercortisolemia caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (corticotroph PA) that afflicts humans and dogs. In order to map common aberrant genomic features of CD between humans and dogs, we performed genomic sequencing and immunostaining on corticotroph PA., Methods: For inclusion, humans and dog were diagnosed with CD. Whole exome sequencing (WES) was conducted on 6 human corticotroph PA. Transcriptome RNA-Seq was performed on 6 human and 7 dog corticotroph PA. Immunohistochemistry (IHC) was complete on 31 human corticotroph PA. Corticotroph PA were compared with normal tissue and between species analysis were also performed., Results: Eight genes (MAMLD1, MNX1, RASEF, TBX19, BIRC5, TK1, GLDC, FAM131B) were significantly (P < 0.05) overexpressed across human and canine corticotroph PA. IHC revealed MAMLD1 to be positively (3+) expressed in the nucleus of ACTH-secreting tumor cells of human corticotroph PA (22/31, 70.9%), but absent in healthy human pituitary glands., Conclusions: In this small exploratory cohort, we provide the first preliminary insights into profiling the genomic characterizations of human and dog corticotroph PA with respect to MAMLD1 overexpression, a finding of potential direct impact to CD microadenoma diagnosis. Our study also offers a rationale for potential use of the canine model in development of precision therapeutics., (© 2021. The Author(s).)

Acromegaly is a rare disease associated with comorbidities that are common in the general population. Most patients undergo screening for classic phenotypical (CP) or mass effect manifestations. By retrospective review of pituitary tumor surgeries performed between 1994 and 2016 (1836), we identified patients with acromegaly (112). Main presentations were: CP (43%), mass effect (26%), incidentally detected (ID) tumors (17%), and other (14%). We compared the ID and CP groups regarding prevalence, clinical, biochemical, radiological and histopathological characteristics, and postoperative outcomes. The prevalence of ID among all surgeries increased after 2011 from 0.6% to 1.9% (p=0.01), while prevalence of CP remained stable (2.8% and 2.33%, p=0.65). Almost half of ID (47.4%) presented with otolaryngological manifestations. The ID and CP groups were similar regarding age, gender, comorbidities (hypertension, diabetes, hypopituitarism), tumor diameter and cavernous sinus invasion. Median insulin-like growth factor (IGF-1) and growth hormone (GH) levels were lower in the ID than CP (p<0.05 and p=0.07). Patients younger than 40 had smaller tumors in the ID than CP, while the opposite was true for older patients. The 3-month biochemical remission rates were similar (68% ID and 58% CP). A similar number of patients had normal IGF-1 at last follow-up (89.5% ID and 81.25% CP) after surgery alone and multimodality treatment. In conclusion, an increased number of patients with GH-secreting adenomas were ID in recent years. Education of physicians other than endocrinologists regarding presentation and comorbidity clustering may lead to an earlier diagnosis of acromegaly and improved outcomes., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

We present a case of a 28-year-old woman with a history of severe headaches and pituitary insufficiency. She was found to have a large, enhancing, sellar mass consistent with a pituitary adenoma. The patient's surgical care was delayed due to the coronavirus disease 2019 (COVID-19) pandemic, and follow-up imaging revealed spontaneous involution of the sellar mass. Spontaneous involution of pituitary masses has been described but not often encountered in clinical practice. This case highlights that follow-up imaging is necessary when scheduling elective surgeries during the COVID-19 pandemic., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Background: The association between spontaneous skull base cerebrospinal fluid (CSF) leaks and idiopathic intracranial hypertension (IIH) has been suggested, but its significance remains unclear., Objective: To estimate the prevalence of IIH in spontaneous skull base CSF leak patients., Methods: Systematic collection of demographics, neuro-ophthalmic and magnetic resonance imaging evaluation of spontaneous skull base CSF leak patients seen pre- and post-leak repair in one neuro-ophthalmology service. Patients with preexisting IIH were diagnosed with definite IIH if adequate documentation was provided; otherwise, they were categorized with presumed IIH. Classic radiographic signs of intracranial hypertension and bilateral transverse venous sinus stenosis were recorded., Results: Thirty six patients were included (age [interquartile range]: 50 [45;54] years; 94% women; body mass index: 36.8 [30.5;39.9] kg/m2), among whom six (16.7%, [95% confidence interval, CI]: [6.4;32.8]) had a preexisting diagnosis of definite or presumed IIH. Of the remaining 30 patients, four (13.3%, 95%CI: [3.8;30.7]) had optic nerve head changes suggesting previously undiagnosed IIH, while one was newly diagnosed with definite IIH at initial consultation. One out of 29 patients with normal findings of the optic nerve head at presentation developed new onset papilledema following surgery (3.4%, 95%CI: [0.1;17.8]) and was ultimately diagnosed with definite IIH. Overall, the prevalence of definite IIH was 19.4% (95%CI: [8.2;36.0])., Conclusion: Striking demographic overlap exists between IIH patients and those with spontaneous CSF leak. Definite IIH was present in approximately 20% of our patients. However, its true prevalence is likely higher than identified by using classic criteria. We therefore hypothesize that an active CSF leak serves as an auto-diversion for CSF, thereby "treating" the intracranial hypertension and eliminating characteristic signs and symptoms at initial presentation.

Purpose: This comparative survey of surgical practice patterns between 2010 and 2020 aims to elicit trends in practice patterns for transsphenoidal surgery and to identify areas for improvement., Methods: Web-based surveys were sent to the International Society of Pituitary Surgeons via a membership listserv in 2010 and 2020. These 33-item surveys collected information on demographics, surgical approach, perceived advantages and disadvantages, and recommendations for improvements. Statistical analyses were conducted using the Mann-Whitney U test for continuous variables and Fisher's exact test for categorical variables., Results: There were 51 respondents in 2010 and 82 respondents in 2020. The majority were full-time academic surgeons from the United States or Europe. Preference for a purely endoscopic technique increased from 43% in 2010 to 87% in 2020. Preference for routinely working with an otolaryngologist or second neurosurgeon increased from 35 to 51%. Most surgeons (74%) reported that they were more likely to achieve a greater extent of resection with the endoscope, though 51% noted increased operating time. The most commonly rated advantage (34%) of endoscopic TSS was fewer postoperative nasoseptal perforations; the most commonly (34%) rated disadvantage was more postoperative complications, including cerebrospinal fluid leak. Respondents were divided on whether microscopic TSS should continue to be taught in residency. Many (32%) advocated for improved endoscopic instrumentation and team training., Conclusion: Endoscopic TSS is now the clearly preferred method for surgery amongst a cohort of higher-volume academic neurosurgeons. This trend is likely to continue, and this provides guidelines for future training.

Background: Endoscopic endonasal approaches pose the potential risk of olfactory loss. Loss of olfaction and potentially taste can be permanent and greatly affect patients' quality of life. Treatments for olfactory loss have had limited success. Omega-3 supplementation may be a therapeutic option with its effect on wound healing and nerve regeneration., Objective: To evaluate the impact on olfaction in patients treated with omega-3 supplementation following endoscopic skull base tumor resection., Methods: In this multi-institutional, prospective, randomized controlled trial, 110 patients with sellar or parasellar tumors undergoing endoscopic resection were randomized to nasal saline irrigations or nasal saline irrigations plus omega-3 supplementation. The University of Pennsylvania Smell Identification Test (UPSIT) was administered preoperatively and at 6 wk, 3 mo, and 6 mo postoperatively., Results: Eighty-seven patients completed all 6 mo of follow-up (41 control arm, 46 omega-3 arm). At 6 wk postoperatively, 25% of patients in both groups experienced a clinically significant loss in olfaction. At 3 and 6 mo, patients receiving omega-3 demonstrated significantly less persistent olfactory loss compared to patients without supplementation (P = .02 and P = .01, respectively). After controlling for multiple confounding variables, omega-3 supplementation was found to be protective against olfactory loss (odds ratio [OR] 0.05, 95% CI 0.003-0.81, P = .03). Tumor functionality was a significant independent predictor for olfactory loss (OR 32.7, 95% CI 1.15-929.5, P = .04)., Conclusion: Omega-3 supplementation appears to be protective for the olfactory system during the healing period in patients who undergo endoscopic resection of sellar and parasellar masses., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Even in ideal circumstances, the performance of safe and effective endoscopic transsphenoidal pituitary surgery requires complicated orchestration of care amongst multiple medical and surgical teams in the preoperative, intraoperative, and postoperative settings. The current COVID-19 pandemic further complicates this highly orchestrated effort. Healthcare systems around the globe are working to adapt to the rapidly changing healthcare landscape as information about the SARS-CoV-2 virus is discovered and disseminated. The nature of the transsphenoidal corridor exposes the pituitary surgery team to increased risk of virus exposure., Competing Interests: None

Purpose: To evaluate the impact of gender and year at surgery on clinical presentation and postoperative outcomes in acromegaly., Methods: Retrospective review of patients operated between 1994 and 2016 to compare presentation and outcomes in groups defined by gender and year of surgery. Kaplan-Meier survival analyses with a composite endpoint (recurrence, reoperation, and radiation) were used for gender comparison and Youden indices for biochemical remission rates changes during study period., Results: Primary indications for evaluation were phenotype, neurological symptoms, incidentaloma, hypogonadism, and galactorrhea. At surgery, men (N = 54) were younger (43.6 ± 12.7 years) than women (N = 58, 48.7 ± 12.3, P = 0.04). Male:female ratios before and after age 50 were 1.4 and 0.6 respectively. Men had higher mean IGF-1 levels (874 ± 328 vs 716 ± 296, P < 0.01) and smaller tumors (1.8 ± 1.3 cm vs 2.3 ± 1.5, P = 0.04). Postoperative remission rates were comparable (51% men, 56% women) and inversely associated with cavernous sinus invasion and GH levels. Women had longer mean follow-up (5.2 ± 3.4 years vs 3.6 ± 3.6 men, P = 0.02) and longer endpoint-free survival (P < 0.01). At last follow-up, 89.6% women and 70% men had normal IGF-1 levels (P = 0.03). Postoperative remission rates were higher in patients operated after February 15, 2011 (67.35 vs 43.5% previously, P = 0.01). In late vs early surgery group, physical changes as main indication for screening decreased (54 vs 30%, P < 0.01), while incidentaloma and hypogonadism increased. Median GH levels were lower in late vs early surgery group (P = 0.03)., Conclusion: We demonstrate gender-specific characteristics and an evolving spectrum of clinical presentation with implications for earlier diagnosis and personalized management of acromegaly.

Background: The association between cerebrospinal fluid (CSF) leaks at the skull base and raised intracranial pressure (ICP) has been reported since the 1960s. It has been suggested that spontaneous CSF leaks might represent a variant of idiopathic intracranial hypertension (IIH). We review the evidence regarding the association between spontaneous CSF leaks and IIH, and the role of ICP in the pathophysiology of nontraumatic skull base defects. We also discuss the management of ICP in the setting of CSF leaks and IIH., Evidence Acquisition: References were identified by searches of PubMed from 1955 to September 2018 with the terms "idiopathic intracranial hypertension" and "cerebrospinal fluid leak." Additional references were identified using the terms "pseudotumor cerebri," "intracranial hypertension," "benign intracranial hypertension," and by hand search of relevant articles., Results: A CSF leak entails the egress of CSF from the subarachnoid spaces of the skull base into the surrounding cavitary structures. Striking overlaps exist regarding demographic, clinical, and radiological characteristics between IIH patients and those with spontaneous CSF leaks, suggesting that some (if not most) of these patients have IIH. However, determining whether a patient with spontaneous CSF leak may have IIH may be difficult, as signs and symptoms of raised ICP may be obviated by the leak. The pathophysiology is unknown but might stem from progressive erosion of the thin bone of the skull base by persistent pulsatile high CSF pressure. Currently, there is no consensus regarding the management of ICP after spontaneous CSF leak repair when IIH is suspected., Conclusions: IIH is becoming more widely recognized as a cause of spontaneous CSF leaks, but the causal relationship remains poorly characterized. Systematic evaluation and follow-up of patients with spontaneous CSF leaks by neuro-ophthalmologists will help clarify the relation between IIH and spontaneous CSF leaks.

Background: Personalized postoperative management of patients with pituitary adenomas requires an early risk stratification system., Methods: We reviewed 501 cases operated between 10/27/2011 and 5/5/2016 by a single neurosurgeon. We determined biochemical remission and tumor resection at 3 months, and biochemical recurrence, tumor recurrence, radiation and reoperation during follow-up. We considered age, gender, tumor diameter, cavernous sinus invasion (CSI) by MRI, diagnostic category (clinical, biochemical and immunohistochemical), and proliferation markers in a Cox proportional hazards model. We built predictive models with the significant parameters and used Kaplan-Meier survival curves for time-dependent analyses., Results: The 501 cases comprised 141 functional and 360 nonfunctional adenomas. Tumor diameter, CSI, and ki-67 index predicted long-term events. Model 1 (CSI, diameter ≥ 2.9 cm and ki-67 > 3%) identified 18 (3.6%) adenomas and predicted persistent hypersecretory syndrome and residual tumor with 98.7% specificity (OR 8.6; CI 3.0-24.7). Model 2 (ki-67 > 3% and CSI) identified 48 (9.6%) adenomas and had 93.1% specificity (OR 3.3; CI 1.8-6.0). Model 3 (ki-67 > 3%, mitoses and p53, former "atypical" adenoma) identified 26 (5.2%) adenomas and had 96.0% specificity (OR 2.3; CI 1.0-5.0). Model 1 best predicted the long-term event-free survival and was strengthened when Knosp 3-4 CSI grades were used. Model 2 better identified the smaller adenomas at risk. Among the WHO 2017 special PA subtypes, patients with silent corticotroph adenoma had a lower event-free survival than ACTH-negative nonfunctional adenomas., Conclusion: Use of CSI, ki-67 and tumor diameter in prediction models facilitates tailored surveillance and management of patients with pituitary adenomas.

Endoscopic endonasal transsphenoidal approach to the sella (EES) for pituitary adenomas has become standard of care because of its promising outcomes, minimal invasiveness, and popularity among surgeons. Three-dimensional (3D) endoscope technology represents the next step in improving visualization and understanding of surgical anatomy, allowing surgeons to mirror the view offered by a traditional 3D microscope. This article discusses the history and development of 3D endoscopes, addresses theoretic advantages and disadvantages of using these devices for EES, reviews recent studies of EES for adenoma outcomes using 3D endoscopes, examines possible implications for neurosurgical training, and discusses personal experience with 3D devices., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: When distinct pituitary hypersecretory manifestations coexist, the differential diagnosis includes plurihormonal or double pituitary adenomas. We describe a rare case of hypercortisolemia and hyperprolactinemia caused by 2 noncontiguous adenomas that required 2 surgeries., Case Description: A 37-year-old woman presented with 6 months of weight gain, amenorrhea, joint pain, leg swelling, and skin changes. She received prednisone for possible systemic lupus erythematosus. Four months later, she presented with headaches and new-onset diabetes with glucose >1000 mg/dL. Work-up revealed a right-sided 1.1-cm pituitary adenoma and prolactin level of 152.9 ng/mL (normal: 3-27 ng/mL). She was advised to stop the prednisone, start bromocriptine, and see a pituitary specialist. Examination revealed centripetal obesity, supraclavicular and dorsocervical fat pads, violaceous wide striae, bilateral leg edema, and galactorrhea. Workup confirmed adrenocorticotrophic hormone-dependent Cushing syndrome, with a central-to-peripheral gradient on inferior petrosal sinus sampling bilaterally. Transsphenoidal adenenomectomy yielded an adenoma diffusely positive for prolactin. Postoperatively prolactin normalized, hypercortisolemia persisted, and magnetic resonance imaging findings raised suspicion for a 2-mm microadenoma. The patient underwent a second operation when an adrenocorticotrophic hormone-positive adenoma was identified. After 4 years, both hypersecretory syndromes remain in biochemical remission., Conclusions: A complete clinical and biochemical evaluation is necessary in patients with pituitary adenomas. Repeat surgery may be necessary for noncontiguous double adenomas., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Contrast-enhanced (CE) Constructive Interference in Steady State (CISS) and Volumetric Interpolated Breath-hold Examination (VIBE) are MRI sequences used to improve the detection of pituitary adenomas and adjacent cranial nerves. The purpose of this study was to assess image quality and identify imaging predictors of postoperative hormonal remission of functioning pituitary adenomas using CE-T1 weighted image (WI), T2WI, CE-CISS, and CE-VIBE MRI sequences., Materials and Methods: Patients with pre-operative CE-T1WI, T2WI, CE-CISS, and CE-VIBE pituitary MRI sequences were included in this institutional retrospective review. Three raters independently reviewed randomized sequences in a blinded fashion for adenoma characteristics and parasellar invasion. Subgroup analysis of hormonal remission was performed., Results: A total of 34 functioning pituitary adenoma patients were included (average age 39.3 ± 12.2; female n = 27), 30 of which had post-operative hormonal remission (n = 34; 88.2%). Compared to CE-T1WI, CE-CISS has significantly higher number of sequences rated "good" image quality (p = 0.02). Hormone remission was associated with decreased degrees of pre-operative internal carotid artery (ICA) contact and Knosp score (p ≤ 0.02) on all sequences except for Knosp score on T2WI. On receiver operating characteristic analysis, the area under curve for differentiating endocrine remission ranged from 0.88 to 0.92 for Knosp score and 0.85-0.93 for ICA contact, depending on sequence., Conclusion: Extent of pituitary adenoma cavernous sinus invasion as measured by degrees of ICA contact and Knosp score is associated with postoperative endocrine outcomes. Given improved image quality, inclusion of CE-CISS may be helpful for pre-surgical planning., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Endoscopic endonasal surgery of the skull base requires expert knowledge of the anatomy and a systematic approach. The vidian canal is regarded as a reliable landmark to localize the petrous internal carotid artery (pICA) near the second genu, which can be used for orientation in deep skull base approaches. There is controversy about the relationship between the vidian canal and the pICA., Objective: To further establish the vertical relationship between the vidian canal and the pICA to aid in surgical approaches to the skull base., Methods: We utilized a collection of institutional review board-approved computed tomographic (CT) angiograms (CTAs). Fifty CTAs were studied bilaterally for 100 total sides. The vidian canal was visualized radiographically to determine whether it terminates below, at, or above the level of the pICA., Results: Sixty-six of 100 vidian canals terminated inferior to the pICA (66%), which was the most common relationship observed. The average distance inferior to the pICA was 1.01 mm on the right, 1.18 mm on the left, and 1.09 mm of the total 66 sides. Less commonly, the vidian canal terminated at the level of the pICA canal in 34 sides (34%). The vidian canal was not observed to terminate superior to the pICA in any of the 50 CTAs studied., Conclusion: The vidian canal terminates inferior to the pICA most commonly, but often terminates at the level of the pICA. Careful drilling clockwise inferior to superior around the vidian canal should allow for safe pICA localization in most cases.

Stereotactic radiosurgery (SRS) is commonly used in the treatment of brain metastases, benign tumors, and arteriovenous malformations (AVM). Single-fraction radiosurgery, though ubiquitous, is limited by lesion size and location. In these cases, hypofractionated radiosurgery (hfSRS) offers comparable efficacy and toxicity. We review the recent literature concerning hfSRS in the treatment of brain metastases, benign tumors, and AVMs that are poorly suited for single-fraction SRS. Published retrospective analyses suggest that local control rates for brain metastases and benign tumors, as well as the rates of AVM obliteration, following hfSRS treatment are comparable to those reported for single-fraction SRS. Additionally, the toxicities from hypofractionated treatment appear comparable to those seen with single-fractioned SRS to small lesions.

Purpose: To report patients with sellar tumors and chiasmal compression with normal visual fields, who demonstrate damage to the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) on optical coherence tomography (OCT)., Methods: Seven patients with sellar tumors causing mass effect on the optic chiasm without definite visual field defect, but abnormal GCC are described. GCC/RNFL analyses using Cirrus-OCT were classified into centiles based on the manufacturer's reference range., Results: In seven patients with radiologic compression of the chiasm by a sellar tumor, OCT-GCC thickness detected compressive chiasmopathy before visual defects became apparent on standard automated visual field testing. Without OCT, our patients would have been labelled as having normal visual function and no evidence of compressive chiasmopathy. With only OCT-RNFL analysis, 3/7 patients would still have been labelled as having no compression of the anterior visual pathways., Conclusions: These patients show that OCT-GCC analysis is more sensitive than visual field testing with standard automated perimetry in the detection of compressive chiasmopathy or optic neuropathy. These cases and previous studies suggest that OCT-GCC analysis may be used in addition to visual field testing to evaluate patients with lesions compressing the chiasm.

Preclinical evidence suggests angiotensin blockade therapy (ABT) decreases late radiation toxicities. This study aims to investigate the association between ABT and symptomatic radiation necrosis (SRN) following stereotactic radiosurgery (SRS). Resected brain metastases (rBM) and arteriovenous malformation (AVM) patients treated with SRS from 2002 to 2015 were identified. Patients in the ABT cohort were on therapy during SRS and at 1-month follow up. Kaplan Meier method and cumulative incidence model were used to analyze overall survival (OS) and intracranial outcomes. 228 consecutive patients were treated with SRS: 111 with rBM and 117 with AVM. Overall, 51 (22.4%) patients were in the ABT group: 32 (28.8%) in the rBM and 19 (16.2%) in AVM cohorts. Baseline characteristics were similar, except for higher Graded Prognostic Analysis (3-4) in the rBM (ABT: 25.0% vs. non-ABT: 49.0%, p = 0.033) and median age in the AVM (ABT: 51.4 vs. non-ABT: 35.4, p < 0.001) cohorts. In both populations, OS and intracranial efficacy (rBM-local control; AVM-obliteration rates) were statistically similar between the cohorts. ABT was associated with lower 1-year SRN rates in both populations: rBM, 3.1 versus 25.3% (p = 0.003); AVM, 6.7 vs. 14.6% (p = 0.063). On multivariate analysis, ABT was a significant predictive factor for rBM (HR: 0.17; 95% CI 0.03-0.88, p = 0.035), but did not reach statistical significance for AVM (HR: 0.36; 95% CI 0.09-1.52, p = 0.165). ABT use appears to be associated with a reduced risk of SRN following SRS, without detriment to OS or intracranial efficacy. A prospective trial to validate these findings is warranted.

Context: Acromegaly has been associated with calcium-phosphate and bone turnover alterations. Controlled studies of these interactions are sparse., Objective: To evaluate calcium and bone metabolism in active and treated acromegaly., Design/setting/patients: We conducted a controlled, prospective study at a tertiary referral center. We studied 22 patients with acromegaly referred for surgical or medical therapy (ACM) and 22 with nonfunctioning pituitary adenomas referred for surgery (control)., Main Outcome Measures: Calcium (serum and urine), phosphorus, parathyroid hormone (PTH), 25-hydroxy- and 1,25-dihydroxy-vitamin D, bone turnover markers [serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP)], and cytokines [receptor activator of nuclear factor κB ligand (RANK-L) and osteoprotegerin (OPG)] at baseline and 3 to 6 months after treatment., Results: At baseline, the ACM group had lower PTH levels than controls (36.3 ± 13.9 pg/mL vs 56.0 ± 19.9 pg/mL) and higher phosphorus (4.34 ± 0.71 mg/dL vs 3.55 ± 0.50 mg/dL) (P < 0.01). Groups had similar levels of serum and urine calcium and 25-hydroxy- and 1,25-dihydroxy-vitamin D. The ACM group had higher bone turnover markers than control; P1NP and CTX were strongly correlated (r2 = 0.82, P < 0.05). CTX was dependent on age and disease group but not on sex or gonadal status. After treatment of acromegaly, serum calcium (9.52 ± 0.43 mg/dL to 9.26 ± 0.28 mg/dL), phosphorus (4.34 ± 0.71 mg/dL to 3.90 ± 0.80 mg/dL), and CTX (0.91 ± 0.75 ng/mL to 0.63 ± 0.68 ng/mL) decreased, while PTH increased (36.3 ± 13.9 pg/mL to 48.9 ± 16.7 pg/mL) (P < 0.01). 25-hydroxy-vitamin D, P1NP, and RANK-L/OPG ratio did not change significantly., Conclusion: Acromegaly patients exhibited PTH-independent calcium-phosphate alterations and enhanced coupled bone formation and resorption. Within 6 months of treatment, bone resorption decreased, whereas RANK-L/OPG changes were inconsistent., (Copyright © 2017 Endocrine Society)

Background: Sphenoid wing meningiomas (SWMs) can encase arteries of the circle of Willis, increasing their susceptibility to intraoperative vascular injury and severe ischemic complications., Objective: To demonstrate the effect of circumferential vascular encasement in SWM on postoperative ischemia., Methods: A retrospective review of 75 patients surgically treated for SWM from 2009 to 2015 was undertaken to determine the degree of circumferential vascular encasement (0°-360°) as assessed by preoperative magnetic resonance imaging (MRI). A novel grading system describing "maximum" and "total" arterial encasement scores was created. Postoperative MRIs were reviewed for total ischemia volume measured on sequential diffusion-weighted images., Results: Of the 75 patients, 89.3% had some degree of vascular involvement with a median maximum encasement score of 3.0 (2.0-3.0) in the internal carotid artery (ICA), M1, M2, and A1 segments; 76% of patients had some degree of ischemia with median infarct volume of 3.75 cm 3 (0.81-9.3 cm 3 ). Univariate analysis determined risk factors associated with larger infarction volume, which were encasement of the supraclinoid ICA ( P < .001), M1 segment ( P < .001), A1 segment ( P = .015), and diabetes ( P = .019). As the maximum encasement score increased from 1 to 5 in each of the significant arterial segments, so did mean and median infarction volume ( P < .001). Risk for devastating ischemic injury >62 cm 3 was found when the ICA, M1, and A1 vessels all had ≥360° involvement ( P = .001). Residual tumor was associated with smaller infarct volumes ( P = .022). As infarction volume increased, so did modified Rankin Score at discharge ( P = .025)., Conclusion: Subtotal resection should be considered in SWM with significant vascular encasement of proximal arteries to limit postoperative ischemic complications., (Copyright © 2017 by the Congress of Neurological Surgeons)

Background: The impact of failed cerebrospinal fluid leak (CSF) leak repair in endoscopic skull base surgery has not been adequately studied., Methods: In this investigation we reviewed patients who had undergone endoscopic skull base surgery between 2002 and 2014 at 7 international centers. Demographic variables, comorbidities, tumor characteristics, and repair techniques were evaluated to determine association with successful repair of CSF leak. Postoperative complications and length of stay were compared among groups., Results: Data were collected on 2097 patients who were divided into 3 groups: (1) those with no intraoperative leak (n = 1533); (2) those with successful repair of their intraoperative leak (n = 452); and (3) those with failed repair (n = 112). Compared with successful repair, failed repair was associated with an increased risk of intracranial infection (odds ratio [OR], 5.6; 95% confidence interval [CI], 5.3-13.15), pneumocephalus (OR, 16; 95% CI, 5.8-44.4), 30-day readmission (OR, 8.4; 95% CI, 5.3-13.5), reoperation (OR, 115.4; 95% CI, 56.3-236.8), and prolonged hospital stay (14.9 vs 7.0 days, p < 0.01). Outcomes in patients who had successful repairs of intraoperative leaks were similar to those who never had leakage. Intraoperative use of pedicled nasoseptal flaps was associated with successful repair (OR, 0.60; 95% CI, 0.34-0.92)., Conclusion: Intraoperative CSF leaks are a frequent and expected occurrence during endoscopic skull base surgery. Failed CSF leak repair has a significant impact on patient outcomes, with increased rates of postoperative pneumocephalus, intracranial infections, reoperation, deep vein thrombosis, readmission, and prolonged hospital stay. Recognition and repair of intraoperative CSF leaks reduces postoperative complications. Use of pedicled nasoseptal flaps improves outcomes in reconstructing defects at higher risk for postoperative leak., (© 2016 ARS-AAOA, LLC.)

Background: In patients undergoing transnasal endoscopic sellar surgery, an analysis of risk factors and predictors of intraoperative and postoperative cerebrospinal fluid leak (CSF) would provide important prognostic information., Methods: A retrospective review of patients undergoing endoscopic sellar surgery for pituitary adenomas or craniopharyngiomas between 2002 and 2014 at 7 international centers was performed. Demographic, comorbidity, and tumor characteristics were evaluated to determine the associations between intraoperative and postoperative CSF leaks. Correlations between reconstructive and CSF diversion techniques were associated with postoperative CSF leak rates. Odds ratios (OR) were identified using a multivariate logistic regression model., Results: Data were collected on 1108 pituitary adenomas and 53 craniopharyngiomas. Overall, 30.1% of patients had an intraoperative leak and 5.9% had a postoperative leak. Preoperative factors associated with increased intraoperative leaks were mild liver disease, craniopharyngioma, and extension into the anterior cranial fossa. In patients with intraoperative CSF leaks, postoperative leaks occurred in 10.3%, with a higher postoperative leak rate in craniopharyngiomas (20.8% vs 5.1% in pituitary adenomas). Once an intraoperative leak occurred, craniopharyngioma (OR = 4.255, p = 0.010) and higher body mass index (BMI) predicted postoperative leak (OR = 1.055, p = 0.010). In patients with an intraoperative leak, the use of septal flaps reduced the occurrence of postoperative leak (OR = 0.431, p = 0.027). Rigid reconstruction and CSF diversion techniques did not impact postoperative leak rates., Conclusion: Intraoperative CSF leaks can occur during endoscopic sellar surgery, especially in larger tumors or craniopharyngiomas. Once an intraoperative leak occurs, risk factors for postoperative leaks include craniopharyngiomas and higher BMI. Use of septal flaps decreases this risk., (© 2016 ARS-AAOA, LLC.)

Background: Nonfunctioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. Due to the lack of hormonal hypersecretion, posttreatment follow-up evaluation of NFPAs is challenging., Objective: To create evidence-based guidelines in an attempt to formulate guidance for posttreatment follow-up in a consistent, rigorous, and cost-effective way., Methods: An extensive literature search was performed. Only clinical articles describing postoperative follow-up of adult patients with NFPAs were included. To ascertain the class of evidence for the posttreatment follow-ups, the authors used the Clinical Assessment evidence-based classification., Results: Twenty-three studies met the inclusion criteria with respect to answering the questions on the posttreatment radiologic, endocrinologic, and ophthalmologic follow-up. Through this search, the authors formulated evidence-based guidelines for radiologic, endocrinologic, and ophthalmologic follow-up after surgical and/or radiation treatment., Conclusion: Long-term radiologic, endocrinologic, and ophthalmologic surveillance monitoring after surgical and/or radiation therapy treatment of NFPAs to evaluate for tumor recurrence or regrowth, as well as pituitary and visual status, is recommended. There is insufficient evidence to make a recommendation on the duration of time of surveillance and its frequency. It is recommended that the first radiologic study to evaluate the extent of resection of the NFPA be performed ≥3 months after surgical intervention. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter&#95;8., Abbreviation: NFPA, nonfunctioning pituitary adenoma.

Background: Pituitary apoplexy (PA) often presents with acute headache and neuro-ophthalmic manifestations, including ocular motility dysfunction (OMD) from cranial nerve palsies (CNPs). Our goal was to describe the epidemiology and outcomes of OMD in a large, single-center series of patients with PA., Methods: We conducted a retrospective chart review of all patients with PA seen in our pituitary center between January 1995 and December 2012. Presenting neuro-ophthalmic, endocrine, and radiologic data, as well as neuro-ophthalmology follow-up data, were collected., Results: We identified 235 patients with PA, 59 of whom (25%) had OMD. Twenty-seven of those 59 patients underwent neuro-ophthalmic evaluation. Preoperatively, 23 of these 27 patients had unilateral OMD, 18 (78%) with a single CNP and 5 (22%) with multiple CNPs. Bilateral OMD was present in 4 of the 27 patients. Postoperatively, 24 of the 27 patients with OMD had follow-up (median duration, 7 months; interquartile range [IQR], 3-17 months). At the last postoperative follow-up, 7 of these 24 patients (29%) had OMD (5 unilateral, 2 bilateral). OMD resolved in 3 of the 24 patients (12%) within 1 month, in 13 of 21 patients (62%) within 6 months (3 lost to follow-up), and in 17 of 19 patients (89%) within 1 year (2 lost to follow-up). Surgery was performed at ≤14 days after presentation in 16 of 18 (89%) resolved cases and in 4 of 6 (67%) unresolved cases. Patients with OMD were more likely than those without OMD to have larger tumors (2.6 vs. 2.0 cm; P < 0.001), panhypopituitarism (31% vs. 14%; P = 0.005), and necrosis (58% vs. 37%; P = 0.03)., Conclusions: OMD from CNPs is common in PA, occurring in one-quarter of patients, and is frequently associated with certain radiologic, endocrinologic, and pathological features. The prognosis is excellent, with 90% of cases of OMD resolving by 1 year after early pituitary surgery., Competing Interests: The authors report no conflict of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The authors reviewed published articles pertaining to the preoperative imaging evaluation of nonfunctioning pituitary adenomas (NFPAs) and formulated recommendations., Objective: To provide an exhaustive review of published articles pertaining to the preoperative imaging evaluation of nonfunctioning pituitary adenomas., Methods: The MEDLINE database was queried for studies investigating imaging for the preoperative evaluation of pituitary adenomas., Results: From an initial search of 5598 articles, 122 articles were evaluated in detail and included in this article. Based on analysis of these articles, the recommendations are as follows: (1) High-resolution magnetic resonance imaging (level II) is recommended as the standard for preoperative assessment of nonfunctioning pituitary adenomas, but may be supplemented with CT (level III) and fluoroscopy (level III). (2) Although there are promising results suggesting the utility of magnetic resonance spectroscopy, magnetic resonance perfusion, positron emission tomography, and single-photon emission computed tomography, there is insufficient evidence to make formal recommendations pertaining to their clinical applications., Conclusion: The authors identified 122 articles that form the basis of recommendations for preoperative imaging evaluation of nonfunctioning pituitary adenomas. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter&#95;2., Abbreviations: CT, computed tomographyDWI, diffusion-weighted imagingMRI, magnetic resonance imagingNFPA, nonfunctioning pituitary adenoma.

Background: Nonfunctioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. Visual symptoms from NFPAs are common and include visual field defects, loss of central vision, and motility problems resulting in diplopia., Objective: To create evidence-based guidelines in an attempt to formulate guidance for preoperative ophthalmologic evaluation of NFPA patients., Methods: An extensive literature search was performed. Only clinical articles describing preoperative ophthalmologic evaluation of adult patients with NFPA were included. To ascertain the class of evidence for the posttreatment follow-up, the authors used the Clinical Assessment evidence-based classification., Results: Six studies met the inclusion criteria with respect to the questions regarding the preoperative ophthalmologic evaluation of NFPA patients. Based on the studies located through the search, the authors formulated evidence-based recommendations as they pertain to the necessity of ophthalmologic evaluation before surgical treatment., Conclusion: Preoperative ophthalmologic evaluation is recommended. Such evaluation can provide prognostic factors for recovery and, when paired with postoperative evaluation, documents postoperative change. In addition to formal ophthalmologic examination, tests of value include automated static perimetry and optical coherence tomography. Older patients and patients with longer duration (>4 months) of vision loss should be counseled regarding the reduced chance of postoperative vision improvement. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter&#95;4., Abbreviations: NFPA, nonfunctioning pituitary adenomaOCT, optical coherence tomography.

Background: Nonfunctioning pituitary adenomas (NFPAs) are among the most common pituitary lesions and may present clinically with vision loss and hypopituitarism., Objective: To characterize the existing literature as it pertains to the initial management of NFPAs., Methods: A systematic literature review was conducted to identify and screen articles assessing primary treatment options (surgical, medical, radiation based, or observation) for NFPAs. Outcomes assessed included vision-, endocrine-, and headache-related symptoms, as well as tumor response to therapy. Twenty-five studies met inclusion criteria for analysis., Results: A considerable amount of class II evidence (14 studies) was identified supporting primary surgical intervention in patients with symptomatic NFPA macroadenomas, resulting in immediate tumor volume reduction in nearly all patients and a residual tumor rate of 10% to 36%. One prospective, observational cohort study and multiple retrospective studies showed improved visual function in 75% to 91% of surgically treated patients and improved hypopituitarism in 35% to 50% of patients. Limited class II evidence showed inconsistent benefits for observation alone (1 study), primary radiation-based treatment (3 studies), or primary medical treatment (8 studies) for improving vision, headaches, hypopituitarism, or tumor volume. One retrospective study implementing observation alone showed tumor progression in 50% of patients and a requirement for surgery in 21% of patients. Eight studies assessing primary medical therapy for NFPAs showed inconsistent tumor response rates using somatostatin analogs (12%-40% response rate), dopamine agonist therapy (0%-61% response rate), or combination therapy (60% response rate). Three studies reporting primary radiosurgery for NFPAs showed decreased tumor size in 38% to 60% of patients., Conclusion: Multiple retrospective and some prospective studies have demonstrated consistent effectiveness of primary surgical resection of symptomatic NFPAs with acceptable morbidity rates. Limited and inconsistent reports are available for alternative treatment strategies, including radiation, medical treatment, and observation alone; these modalities may, however, play a valid role in patients who are not surgical candidates. Based on the available evidence, the authors recommend surgical resection as the preferred primary intervention for symptomatic NFPAs. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter&#95;5., Abbreviation: NFPA, nonfunctioning pituitary adenoma.

Background: Nonfunctioning pituitary adenomas (NFPAs) are among the most common pituitary lesions and may present with hypopituitarism and/or hyperprolactinemia., Objective: To review the existing literature as it pertains to preoperative endocrine assessment in the workup for NFPAs., Methods: A systematic review methodology was utilized to identify and screen articles assessing the role and results of preoperative laboratory assessment in patients with NFPAs. The prevalence of individual pituitary hormonal axis deficiencies was reviewed., Results: Twenty-nine studies met inclusion criteria for analysis. No class I evidence was available, and all studies met criteria for class II evidence. Baseline serum laboratory assessment showed a prevalence of overall hypopituitarism in 37% to 85% of patients. The most common hormonal axis deficiency was growth hormone deficiency, prevalent in 61% to 100% of patients. The next most common deficit was hypogonadism, seen in 36% to 95% of patients. Adrenal insufficiency was diagnosed in 17% to 62% of patients. Finally, hypothyroidism was seen in 8% to 81% of patients. Hyperprolactinemia was seen in 25% to 65% of patients, with a mean level of 39 ng/mL and with a minority of patients exceeding a serum prolactin level of 200 ng/mL. No evidence supporting routine biomarker testing (eg, α-subunit or chromogranin A) or genetic testing in patients with sporadic NFPAs was available., Conclusion: Despite a paucity of class I evidence, multiple retrospective studies have demonstrated a high prevalence of hypopituitarism in patients with NFPAs. Routine endocrine analysis of all anterior pituitary axes to assess for hypopituitarism is recommended, with prolactin and insulin-like growth factor 1 evaluation also valuable to assess for hypersecretion states that might not be clinically suspected. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter&#95;3., Abbreviations: GH, growth hormoneIGF-1, insulin-like growth factor 1NFPA, nonfunctioning pituitary adenoma.

Background: Despite the advancement of microsurgical and endoscopic techniques, some nonfunctioning pituitary adenomas (NFPAs) can be difficult to cure. Tumor recurrence or incomplete resection may occur in some patients with NFPAs, and management strategies for these NFPAs remain unclear., Objective: To review the existing literature as it pertains to the management of postsurgical residual or recurrent NFPAs., Methods: A systematic review of the treatment options for residual or recurrent NFPAs was performed. In this review, the authors critically evaluated the evidence to support the options of repeat microsurgical resection, stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT), and fractionated radiation therapy (XRT)., Results: Forty-nine studies met the inclusion criteria for analysis: outcome of repeat surgical resection (n = 4), radiosurgery (ie, single-session or hypofractionated SRS; n = 24), or fractionated radiotherapy (ie, conventional XRT, proton beam radiotherapy, intensity-modulated radiotherapy, SRT; n = 21). No class I evidence was available; 6 studies met criteria for class II evidence; and other studies provided class III evidence. A meta-analysis of 5 class II studies with recurrence rates for both adjuvant radiation therapy and observation demonstrated that XRT for residual/recurrent NFPAs offered a lower rate of recurrence (odds ratio = 0.04; 95% confidence interval, 0.01-0.20; P < .001). The analysis also demonstrated significant heterogeneity between the included studies (χ = 20.70; P = .003; I = 81%)., Conclusion: Repeat resection, SRS, SRT, and XRT play a role in the management of patients with recurrent or residual NFPAs. SRS or some type of radiation therapy is typically performed for patients with residual tumor or tumor recurrence after resection. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter&#95;7., Abbreviations: NFPA, nonfunctioning pituitary adenomaSRS, stereotactic radiosurgerySRT, stereotactic radiotherapyXRT, fractionated radiation therapy.

Background: Numerous technological adjuncts are used during transsphenoidal surgery for nonfunctioning pituitary adenomas (NFPAs), including endoscopy, neuronavigation, intraoperative magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) diversion, and dural closure techniques., Objective: To generate evidence-based guidelines for the use of NFPA surgical techniques and technologies., Methods: An extensive literature search spanning January 1, 1966, to October 1, 2014, was performed, and only articles pertaining to technological adjuncts for NFPA resection were included. The clinical assessment evidence-based classification was used to ascertain the class of evidence., Results: Fifty-six studies met the inclusion criteria, and evidence-based guidelines were formulated on the use of endoscopy, neuronavigation, intraoperative MRI, CSF diversion, and dural closure techniques., Conclusion: Both endoscopic and microscopic transsphenoidal approaches are recommended for symptom relief in patients with NFPAs, with the extent of tumor resection improved by adequate bony exposure and endoscopic visualization. In select cases, combined transcranial and transsphenoidal approaches are recommended. Although intraoperative MRI can improve gross total resection, its use is associated with an increased false-positive rate and is thus not recommended. There is insufficient evidence to recommend the use of neuronavigation, CSF diversion, intrathecal injection, or specific dural closure techniques. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter&#95;6., Abbreviations: CSF, cerebrospinal fluidNFPA, nonfunctioning pituitary adenoma.

Background: Stereotactic radiosurgery (SRS) is an increasingly common modality used with surgery for resectable brain metastases (BM)., Objective: To present a multi-institutional retrospective comparison of outcomes and toxicities of preoperative SRS (Pre-SRS) and postoperative SRS (Post-SRS)., Methods: We reviewed the records of patients who underwent resection of BM and either Pre-SRS or Post-SRS alone between 2005 and 2013 at 2 institutions. Pre-SRS used a dose-reduction strategy based on tumor size, with planned resection within 48 hours. Cumulative incidence with competing risks was used to determine estimated rates., Results: A total of 180 patients underwent surgical resection for 189 BM: 66 (36.7%) underwent Pre-SRS and 114 (63.3%) underwent Post-SRS. Baseline patient characteristics were balanced except for higher rates of performance status 0 (62.1% vs 28.9%, P < .001) and primary breast cancer (27.2% vs 10.5%, P = .010) for Pre-SRS. Pre-SRS had lower median planning target volume margin (0 mm vs 2 mm) and peripheral dose (14.5 Gy vs 18 Gy), but similar gross tumor volume (8.3 mL vs 9.2 mL, P = .85). The median imaging follow-up period was 24.6 months for alive patients. Multivariable analyses revealed no difference between groups for overall survival (P = .1), local recurrence (P = .24), and distant brain recurrence (P = .75). Post-SRS was associated with significantly higher rates of leptomeningeal disease (2 years: 16.6% vs 3.2%, P = .010) and symptomatic radiation necrosis (2 years: 16.4% vs 4.9%, P = .010)., Conclusion: Pre-SRS and Post-SRS for resected BM provide similarly favorable rates of local recurrence, distant brain recurrence, and overall survival, but with significantly lower rates of symptomatic radiation necrosis and leptomeningeal disease in the Pre-SRS cohort. A prospective clinical trial comparing these treatment approaches is warranted., Abbreviations: BM, brain metastasesCI, confidence intervalCTV, clinical target volumeDBR, distant brain recurrenceGTV, gross tumor volumeLC, local controlLMD, leptomeningeal diseaseLR, local recurrenceMVA, multivariable analysisOS, overall survivalPost-SRS, postoperative stereotactic radiosurgeryPre-SRS, preoperative stereotactic radiosurgeryPTV, planning target volumeRN, radiation necrosisSRN, symptomatic radiation necrosisSRS, stereotactic radiosurgeryWBRT, whole-brain radiation therapy.

Purpose: To present a single-center 20-year experience with operated thyrotropinomas, including prevalence, clinical, biochemical and histological characteristics, and postoperative outcomes., Methods: Retrospective series of histopathologically-proven thyrotropinomas (1993-2013), divided in two groups: A (active, central hyperthyroidism) and B (silent, no hyperthyroidism)., Results: Of 1628 operated pituitary adenomas, 20 were β-TSH-positive (1.2%). In increments of 5 years, proportion of thyrotropinomas was 1, 1, 0.04 and 1.77% respectively. Median follow-up was 10.4 months (1.2-150). Group A: 6 patients (5 men), age 41 ± 12 years presented with hyperthyroidism (3), pituitary incidentaloma (2) and acromegaly (1). Tumor diameter was 2.1 ± 1.2 cm, FT4 2.68 ± 2.73 ng/dL; TSH 6.50 ± 3.68 µIU/mL. Glycoprotein alpha subunit (GSU) was uniformly elevated. Two patients had biochemical evidence of acromegaly. Tumors were plurihormonal (5 GH-positive); none atypical. Postoperative euthyroidism was achieved in 4 of 6 patients (66%). Group B: 14 patients (7 men), age 47 ± 14 years presented with acromegaly (6), mass effect (4), incidentaloma (3) and galactorrhea (1). Tumor diameter was 2.0 ± 1.0 cm. Free T4 (1.00 ± 0.24 ng/dL) and TSH (2.02 ± 1.65 mIU/L) were lower than in group A (p < 0.01). GSU was elevated in all tested cases. Nine patients had biochemical evidence of acromegaly. Tumors were plurihormonal (12 GH-positive); none atypical. Gross total resection was achieved in 12 of 14 (86%), and 1 (7%) recurred., Conclusion: In our series, more thyrotropinomas were operated in recent years. These tumors were often plurihormonal with heterogenous clinical presentation and frequent GH co-secretion. Surgical outcomes were good but long-term follow up is necessary.

Objective: Transsphenoidal adenomectomy (TSA) is first-line treatment for acromegaly. Our aim was to determine the impact of pre-operative biochemical parameters on the outcomes of surgery., Methods: Retrospective case series of 79 consecutive acromegalics operated between 1994 and 2013. Inclusion criteria were: first TSA, pathology-confirmed growth hormone (GH) adenoma, and follow-up >3 months. Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) without adjuvant therapy during follow-up., Results: Median follow-up was 35.4 months (range, 3 to 187 months). Logistic regression analysis showed that the best model to predict long-term remission included the following pre-operative markers: GH, tumor diameter, and cavernous sinus invasion (CSI) (area under the curve, 0.933). A threshold GH of 40 ng/mL was associated with long-term remission (sensitivity, 97%; specificity, 42%). Group A (GH >40 ng/mL) comprised 19 patients (9 men); age, 43 ± 13 years; tumor diameter, 2.7 ± 1.0 cm; 73.7% with CSI; and pre-operative median GH, 77.8 ng/mL (interquartile range [IQR], 66.7 to 107.0 ng/mL). Three patients (15%) in group A achieved remission at 3 months, but 2 patients recurred during follow-up. Group B (GH ≤40 ng/mL) comprised 60 patients (25 men); age, 47 ± 13 years; tumor diameter, 1.6 ± 1.0 cm; 35% with CSI, preoperative median GH, 6.9 ng/mL (IQR, 3.4 to 16.9 ng/mL). Thirty-five patients (58%) in group B achieved remission at 3 months without recurrence during follow-up. Group A had larger tumors and a higher proportion of tumors with CSI (P<.05)., Conclusion: Both GH and IGF-1 should be measured pre-operatively, as highly elevated GH levels negatively impact long-term surgical remission. This strategy allows early identification of patients who require adjuvant therapy and may decrease time to biochemical control.

Neurosurgery journals have played an active role in improving the quality of the neurosurgical literature. This role has expanded to improve the quality of care by incorporating an evidence-based view of neurosurgery practice. Neurosurgery journals have facilitated the organization of knowledge into clinically useful forms via the publication of meta-analyses and dissemination of clinical practice guidelines. Peer review continues to be a core feature of neurosurgery publishing, with attendant ethical and procedural safeguards. Finally, neurosurgery journals have spearheaded innovative responses to cultural and technological changes, including initiatives to deliver high-quality research in electronic formats and support the education of future neurosurgery investigators., (Copyright © 2015 Elsevier Inc. All rights reserved.)