Enhanced recovery after brain tumor surgery: pilot protocol implementation in a large healthcare system.

OBJECTIVE: Enhanced recovery after surgery (ERAS) protocols have been used in numerous specialties to improve the safety, efficiency, and cost of surgical interventions. Despite these successes, implementation of ERAS in cranial neurosurgery remains limited. In this study, a comprehensive ERAS protocol was implemented at two pilot sites within the Providence Health & Services system, and groundwork was laid for systemwide adoption. METHODS: An enhanced recovery protocol was developed and implemented through an interdisciplinary team of clinicians, executive leadership, and clinical informatics professionals across preoperative, intraoperative, and postoperative domains. Outcomes including length of stay, discharge destination, and cost were collected through systemwide databases and compared with nonprotocolized sites. RESULTS: During the study period, both pilot sites became top performers across the regional system in all evaluated metrics. The median length of stay for elective craniotomy at site 1 was reduced to 1.25 days, with a home discharge rate of > 90%. The cost per case at the pilot sites was nearly $7000 less on average than that of the nonprotocolized sites. CONCLUSIONS: Implementation of enhanced recovery protocols for brain tumor surgery is feasible and effective, resulting in marked improvements in healthcare efficiency. Future studies, including implementation of the current protocol across the entire Providence system, are needed to maximize the potential benefits of enhanced recovery programs.

Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions: Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. Main Outcomes and Measures: The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. Results: A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Conclusions and Relevance: Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. Trial Registration: ClinicalTrials.gov Identifier: NCT03866174.

Cell-free plasma microRNAs that identify patients with glioblastoma.

Glioblastoma (GBM) is still one of the most commonly diagnosed advanced stage primary brain tumors. Current treatments for patients with primary GBM (pGBM) are often not effective and a significant proportion of the patients with pGBM recur. The effective treatment options for recurrent GBM (rGBM) are limited and survival outcomes are poor. This retrospective multicenter pilot study aims to determine potential cell-free microRNAs (cfmiRs) that identify patients with pGBM and rGBM tumors. 2,083 miRs were assessed using the HTG miRNA whole transcriptome assay (WTA). CfmiRs detection was compared in pre-operative plasma samples from patients with pGBM (n = 32) and rGBM (n = 13) to control plasma samples from normal healthy donors (n = 73). 265 cfmiRs were found differentially expressed in plasma samples from pGBM patients compared to normal healthy donors (FDR < 0.05). Of those 193 miRs were also detected in pGBM tumor tissues (n = 15). Additionally, we found 179 cfmiRs differentially expressed in rGBM, of which 68 cfmiRs were commonly differentially expressed in pGBM. Using Random Forest algorithm, specific cfmiR classifiers were found in the plasma of pGBM, rGBM, and both pGBM and rGBM combined. Two common cfmiR classifiers, miR-3180-3p and miR-5739, were found in all the comparisons. In receiving operating characteristic (ROC) curves analysis for rGBM miR-3180-3p showed a specificity of 87.7% and a sensitivity of 100% (AUC = 98.5%); while miR-5739 had a specificity of 79.5% and sensitivity of 92.3% (AUC = 90.2%). This study demonstrated that plasma samples from pGBM and rGBM patients have specific miR signatures. CfmiR-3180-3p and cfmiR-5739 have potential utility in diagnosing patients with pGBM and rGBM tumors using a minimally invasive blood assay.

Complication avoidance protocols in endoscopic pituitary adenoma surgery: a retrospective cohort study in 514 patients.

PURPOSE: To evaluate the impact of using consistent complication-avoidance protocols in patients undergoing endoscopic pituitary adenoma surgery including techniques for avoiding anosmia, epistaxis, carotid artery injury, hypopituitarism, cerebrospinal fluid leaks and meningitis. METHODS: All patients undergoing endoscopic adenoma resection from 2010 to 2020 were included. Primary outcomes included 90-day complication rates, gland function outcomes, reoperations, readmissions and length of stay. Secondary outcomes were extent of resection, short-term endocrine remission, vision recovery. RESULTS: Of 514 patients, (mean age 51 ± 16 years; 78% macroadenomas, 19% prior surgery) major complications occurred in 18(3.5%) patients, most commonly CSF leak (9, 1.7%) and meningitis (4, 0.8%). In 14 of 18 patients, complications were deemed preventable. Four (0.8%) had complications with permanent sequelae (3 before 2016): one unexplained mortality, one stroke, one oculomotor nerve palsy, one oculoparesis. There were no internal carotid artery injuries, permanent visual worsening or permanent anosmia. New hypopituitarism occurred in 23/485(4.7%). Partial or complete hypopituitarism resolution occurred in 102/193(52.8%) patients. Median LOS was 2 days; 98.3% of patients were discharged home. Comparing 18 patients with major complications versus 496 without, median LOS was 7 versus 2 days, respectively p < 0.001. Readmissions occurred in 6%(31/535), mostly for hyponatremia (18/31). Gross total resection was achieved in 214/312(69%) endocrine-inactive adenomas; biochemical remission was achieved in 148/209(71%) endocrine-active adenomas. Visual field or acuity defects improved in 126/138(91.3%) patients. CONCLUSION: This study suggests that conformance to established protocols for endoscopic pituitary surgery may minimize complications, re-admissions and LOS while enhancing the likelihood of preserving gland function, although there remains opportunity for further improvements.

Minimally invasive surgical treatment of intracranial meningiomas in elderly patients (≥ 65 years): outcomes, readmissions, and tumor control.

OBJECTIVE: Increased lifespan has led to more elderly patients being diagnosed with meningiomas. In this study, the authors sought to analyze and compare patients ≥ 65 years old with those < 65 years old who underwent minimally invasive surgery for meningioma. To address surgical selection criteria, the authors also assessed a cohort of patients managed without surgery. METHODS: In a retrospective analysis, consecutive patients with meningiomas who underwent minimally invasive (endonasal, supraorbital, minipterional, transfalcine, or retromastoid) and conventional surgical treatment approaches during the period from 2008 to 2019 were dichotomized into those ≥ 65 and those < 65 years old to compare resection rates, endoscopy use, complications, and length of hospital stay (LOS). A comparator meningioma cohort of patients ≥ 65 years old who were observed without surgery during the period from 2015 to 2019 was also analyzed. RESULTS: Of 291 patients (median age 60 years, 71.5% females, mean follow-up 36 months) undergoing meningioma resection, 118 (40.5%) were aged ≥ 65 years and underwent 126 surgeries, including 20% redo operations, as follows: age 65-69 years, 46 operations; 70-74 years, 40 operations; 75-79 years, 17 operations; and ≥ 80 years, 23 operations. During 2015-2019, of 98 patients referred for meningioma, 67 (68%) had surgery, 1 (1%) had radiosurgery, and 31 (32%) were observed. In the 11-year surgical cohort, comparing 173 patients < 65 years versus 118 patients ≥ 65 years old, there were no significant differences in tumor location, size, or outcomes. Of 126 cases of surgery in 118 elderly patients, the approach was a minimally invasive approach to skull base meningioma (SBM) in 64 cases (51%) as follows: endonasal 18, supraorbital 28, minipterional 6, and retrosigmoid 12. Endoscope-assisted surgery was performed in 59.5% of patients. A conventional approach to SBM was performed in 15 cases (12%) (endoscope-assisted 13.3%), and convexity craniotomy for non-skull base meningioma (NSBM) in 47 cases (37%) (endoscope-assisted 17%). In these three cohorts (minimally invasive SBM, conventional SBM, and NSBM), the gross-total/near-total resection rates were 59.5%, 60%, and 91.5%, respectively, and an improved or stable Karnofsky Performance Status score occurred in 88.6%, 86.7%, and 87.2% of cases, respectively. For these 118 elderly patients, the median LOS was 3 days, and major complications occurred in 10 patients (8%) as follows: stroke 4%, vision decline 3%, systemic complications 0.7%, and wound infection or death 0. Eighty-three percent of patients were discharged home, and readmissions occurred in 5 patients (4%). Meningioma recurrence occurred in 4 patients (3%) and progression in 11 (9%). Multivariate regression analysis showed no significance of American Society of Anesthesiologists physical status score, comorbidities, or age subgroups on outcomes; patients aged ≥ 80 years showed a trend of longer hospitalization. CONCLUSIONS: This analysis suggests that elderly patients with meningiomas, when carefully selected, generally have excellent surgical outcomes and tumor control. When applied appropriately, use of minimally invasive approaches and endoscopy may be helpful in achieving maximal safe resection, reducing complications, and promoting short hospitalizations. Notably, one-third of our elderly meningioma patients referred for possible surgery from 2015 to 2019 were managed nonoperatively.

Memory in repeat sports-related concussive injury and single-impact traumatic brain injury.

Background: Repeat sports-related concussive/subconcussive injury (RC/SCI) is related to memory impairment. Objective & Methods: We sought to determine memory differences between persons with RC/SCI, moderate-to-severe single-impact traumatic brain injury (SI-TBI), and healthy controls. MRI scans from a subsample of participants with SI-TBI were used to identify the neuroanatomical correlates of observed memory process differences between the brain injury groups. Results: Both brain injury groups evidenced worse learning and recall in contrast to controls, although SI-TBI group had poorer memory than the RC/SCI group. Regarding memory process differences, in contrast to controls, the SI-TBI group evidenced difficulties with encoding, consolidation, and retrieval, while the RC/SCI group showed deficits in consolidation and retrieval. Delayed recall was predicted by encoding, with consolidation as a secondary predictor in the SI-TBI group. In the RC/SCI group, delayed recall was only predicted by consolidation. MRI data showed that the consolidation index we used mapped onto hippocampal atrophy. Conclusions: RC/SCI is primarily associated with consolidation deficits, which differs from SI-TBI. Given the role of the hippocampus in memory consolidation and the fact that hyperphosphorylated tau tends to accumulate in the medial temporal lobe in RC/SCI, consolidation deficits may be a cognitive marker of chronic traumatic encephalopathy in athletes.

B7H3 regulates differentiation and serves as a potential biomarker and theranostic target for human glioblastoma.

B7H3 (CD276), a co-stimulator molecule of the cell surface B7 protein superfamily, is expressed on glioblastomas (GBM). Recently, B7H3 functions beyond immune costimulation have been demonstrated. However, the mechanisms underlying B7H3 function are diverse and not well understood. GBM tumors contain undifferentiated self-renewing cells, which confound therapeutic attempts. We investigated the role of B7H3 in the regulation of GBM cell differentiation and the regulatory pathways involved. Analysis of public databases (TCGA, Rembrandt, and GEO NCBI) and RNA sequencing were performed to explore the role of B7H3 in GBM. Knockdown and overexpression of B7H3, were used to verify the downstream pathway in vitro. Further studies in vivo were performed to support the new finding. Bioinformatics analysis identified a correlation between the expression of B7H3, the expression of glioma self-renewing cell (GSC)-related genes, and MYC expression. These observations were verified by RNA-sequencing analyses in primary GBM cell lines. In vitro knockdown of B7H3-induced differentiation, associated with downregulation of SMAD6 (a TGF-ß pathway inhibitor) and enhancement of SMAD1 phosphorylation-induced SMAD4 expression. Importantly, activation of the TGF-ß pathway resulted in downregulation of MYC expression. In vivo assays conducted in a human GBM cell line xenograft mouse model demonstrated that B7H3 knockdown decreased MYC expression and inhibited tumor growth. B7H3 knockdown could regulate GBM differentiation by modulating MYC expression. So, B7H3 could serve as a potential theranostic target for the treatment of patients with GBM.

Correction to: Rathke's cleft cysts: a 6-year experience of surgery vs. observation with comparative volumetric analysis.

The original version of this article unfortunately contained errors in legend numbers of Figure 2 caption.

Rathke's cleft cysts: a 6-year experience of surgery vs. observation with comparative volumetric analysis.

BACKGROUND: Rathke's cleft cysts (RCCs) are common sellar lesions. Their management remains controversial, particularly when small or asymptomatic. Herein we review a consecutive series of RCC patients managed with surgery or observation. METHODS: All patients with a new diagnosis of presumed RCC, based on MRI, from February 2012-March 2018 were retrospectively divided into observational and surgical cohorts based on an intent-to-treat model. The cohorts were compared for clinical presentation, and cyst volume. The observational cohort was followed for change in cyst size. The surgical cohort was followed for changes in endocrinopathy, visual symptoms, headache and recurrence. RESULTS: Of 90 patients (mean age 36.7 ± 19.4 years; 68% female), 60% (n = 54) were in the observational cohort and 40% (n = 36) in the surgical cohort. Average follow-up was 13 ± 23 months in the observational cohort and 24 ± 19 months in the surgical group. In comparing the cohorts, mean ages were similar with more women in the surgical group (81% vs. 56%, p = 0.04). Most patients in the observational cohort had incidentally-discovered RCCs (n = 50, 88%) as opposed to the surgical cohort (n = 6, 17%). The surgical cohort had higher rates of headache (89% vs 26%, p < 0.001), endocrinopathy (36% vs 0%, p < 0.001), and visual dysfunction (19% vs 0%, p = 0.001). Mean cyst volume and maximal cyst dimensions were greater in the surgical cohort (0.94 ± 0.77 cm3 and 14.2 ± 4.1 mm), compared to the observational cohort (0.1 ± 0.14 cm3 and 6.4 ± 3 mm), (p < 0.001). Among the 53% (n = 30/54) of patients in the observational group with follow-up, 3 (10%) had spontaneous RCC shrinkage, 1 (3%) had modest asymptomatic growth (at 10 months from initial MRI), and 87% had stable cyst size. Of the 36 patients recommended to have surgery, 89% (n = 32) did so. Post-operatively, complete or partial resolution of headache, endocrinopathy and visual dysfunction were documented in 90% (n = 28/30), 75% (n = 10/12), and 100% (n = 7/7), respectively. On follow-up MRI, 8 (22%) patients had some cyst reaccumulation, of whom 3 (8%) were symptomatic and underwent uneventful reoperation. No major complications such as hematoma, CSF leak, new endocrinopathy or visual deficits occurred. CONCLUSION: From this consecutive series, a majority (60%) of RCCs do not appear to warrant surgical intervention and have a low risk of cyst progression. However, surgical cyst removal appears to be indicated and safe for patients with larger, symptomatic RCCs. Simple cyst drainage has a high rate of improvement in pituitary gland function, visual function and headache resolution with low complication rates and symptomatic recurrence risk. These findings stress the importance of careful case selection and potential utility of volumetric assessment for patients with RCCs.

Safety of commercial airflight in patients with brain tumors: a case series.

INTRODUCTION: Patients with intracranial masses are often advised to avoid airflight due to concerns of worsening neurological symptoms or deterioration. However, many patients often travel cross-country or internationally to tertiary care centers for definitive care. This study assesses the safety of commercial airflight for brain and skull base tumor patients without severe or progressive neurological deficits. METHODS: Patients that had traveled to our institution for surgery via commercial airflight from 2014 to 2017 were identified. An electronic survey was administered (RedCap) and flight duration, aircraft type, presenting symptoms and new or worsened peri-flight symptoms were queried. Severity was assessed using visual analogue scale (VAS). Significant change of symptoms was determined to be greater than 25%. Demographics and clinical history were obtained from electronic medical records. Providence Health System IRB: 16-168. RESULTS: Of 665 patients operated on for brain tumor, 63 (9.5%) traveled by airflight to our center for surgery and of these, 41 (65%) completed the study (mean age 48.5 ± 16.8 years, 63% female). Pathology included pituitary and other parasellar tumors (58%), meningiomas (22%), metastatic tumors (5%), gliomas (5%), pineal tumor (5%), cerebello-pontine tumor (5%). Average tumor volume was 11.4 cc and average maximal dimension was 2.7 cm. Ten (24.4%) patients developed worsened symptoms during airflight including: headaches 3/19 (15.8%), fatigue 3/14 (21.4%), dizziness 3/5 (60%) and ear pain 3/3 (100%), as well as one patient who had new onset seizures inflight. Seven patients (70%) sustained worsened symptoms after airflight. There were no permanent neurological deficits related to airflight. There was no correlation with tumor size, volume, location or flight duration with development of neurological symptoms. There was an inverse correlation between peri-flight corticosteroid usage and symptom exacerbation (p = 0.048). No patient with completely asymptomatic tumors developed new symptoms during flight. CONCLUSIONS: Most patients with brain and skull base tumors can travel safely via commercial airflight with acceptable symptom exacerbation. However, consideration should be given to administering corticosteroids and possibly anticonvulsants to patients who are symptomatic and/or have relatively large tumors with mass effect and peritumoral edema.

Pregnancy-associated Cushing's disease? An exploratory retrospective study.

PURPOSE: In most clinical series of Cushing's disease (CD), over 80% of patients are women, many of whom are of reproductive age. The year following pregnancy may be a common time to develop CD. We sought to establish the incidence of CD onset associated with pregnancy. METHODS: A retrospective review was conducted for patients with biochemically-proven CD. Demographics, clinical history, biochemistry, imaging, pathology, and outcomes were reviewed. Pregnancy-associated CD was defined as symptom onset within 1 year of childbirth. RESULTS: Over 10 years, 77 patients including 64 women (84%), with CD underwent endonasal surgery. Of the 64 women, 64% were of reproductive age (15-45 years) at the time of diagnosis, and 11 (27%) met criteria for pregnancy-associated CD. Of these 11 women, median number of pregnancies prior to onset of CD was 2 (range 1-4) compared to zero (range 0-7) for 30 other women with CD onset during reproductive age (p = 0.0024). With an average follow-up of 47 ± 34 months, sustained surgical remission rates for woman with pregnancy-associated CD, other women of reproductive age, and women not of reproductive age were 91%, 80% and 83%, respectively. The average lag-time from symptom onset to diagnosis for women with pregnancy-associated CD was 4 ± 2 years. CONCLUSIONS: In this exploratory study, over one quarter of women of reproductive age with CD appeared to have symptomatic disease onset within 1 year of childbirth. This relatively high rate of pregnancy-associated CD suggests a possible causal relationship related to the stress of pregnancy and pituitary corticotroph hyperactivity in the peripartum period. This possible association suggests a heightened degree of clinical suspicion and biochemical testing for CD may be warranted after childbirth. Further study of this possible link between pregnancy and CD is warranted.

Epigenome-wide DNA methylation landscape of melanoma progression to brain metastasis reveals aberrations on homeobox D cluster associated with prognosis.

Melanoma brain metastasis (MBM) represents a frequent complication of cutaneous melanoma. Despite aggressive multi-modality therapy, patients with MBM often have a survival rate of <1 year. Alteration in DNA methylation is a major hallmark of tumor progression and metastasis; however, it remains largely unexplored in MBM. In this study, we generated a comprehensive DNA methylation landscape through the use of genome-wide copy number, DNA methylation and gene expression data integrative analysis of melanoma progression to MBM. A progressive genome-wide demethylation in low CpG density and an increase in methylation level of CpG islands according to melanoma progression were observed. MBM-specific partially methylated domains (PMDs) affecting key brain developmental processes were identified. Differentially methylated CpG sites between MBM and lymph node metastasis (LNM) from patients with good prognosis were identified. Among the most significantly affected genes were the HOX family members. DNA methylation of HOXD9 gene promoter affected transcript and protein expression and was significantly higher in MBM than that in early stages. A MBM-specific PMD was identified in this region. Low methylation level of this region was associated with active HOXD9 expression, open chromatin and histone modifications associated with active transcription. Demethylating agent induced HOXD9 expression in melanoma cell lines. The clinical relevance of this finding was verified in an independent large cohort of melanomas (n = 145). Patients with HOXD9 hypermethylation in LNM had poorer disease-free and overall survival. This epigenome-wide study identified novel methylated genes with functional and clinical implications for MBM patients.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: DIAGNOSIS OF RECURRENCE IN CUSHING DISEASE.

Recurrence of hypercortisolemia after initial treatment of Cushing disease (CD) is more common than previously thought, with a third of patients suffering a recurrence over their lifetime. Awareness of this high rate and delayed timeline (sometimes decades) of potential recurrence is critical and patients with CD should be monitored at regular intervals throughout their lives. In this manuscript, we review the complex evaluation needed for defining CD remission versus persistent disease after surgery, and focus on challenges in diagnosing early recurrent hypercortisolemia. Late night salivary cortisol appears to be an earlier predictor of recurrence when compared with urinary free cortisol (UFC) excretion. We also review the criteria suggested to define recurrence of hypercortisolemia in patients treated with medical therapy. Further research is needed to determine the optimal way to evaluate a patient with CD recurrence as well as the riskbenefit ratio of treatment in early, mild recurrent disease. ABBREVIATIONS: ACTH = adrenocorticotropic hormone AI = adrenal insufficiency CD = Cushing disease CDDT = coupled dexamethasone desmopressin test CR = circadian rhythm CRH = corticotropin-releasing hormone GC = glucocorticoid GCR = global clinical response HPA = hypothalamic-pituitary-adrenal LDDST = low-dose dexamethasone suppression test LNSC = late-night salivary cortisol ODST = overnight dexamethasone suppression test TSS = trans-sphenoidal surgery.

Impact of selective pituitary gland incision or resection on hormonal function after adenoma or cyst resection.

OBJECTIVE: With the resection of pituitary lesions, the anterior pituitary gland often obstructs transsphenoidal access to the lesion. In such cases, a gland incision and/or partial gland resection may be required to obtain adequate exposure. We investigate this technique and determine the associated risk of post-operative hypopituitarism. METHODS: All patients who underwent surgical resection of a pituitary adenoma or Rathke cleft cyst (RCC) between July 2007 and January 2013 were analyzed for pre- and post-operative hormone function. The cohort of patients with gland incision/resection were compared to a case-matched control cohort of pituitary surgery patients. Total hypophysectomy patients were excluded from outcome analysis. RESULTS: Of 372 operations over this period, an anterior pituitary gland incision or partial gland resection was performed in 79 cases (21.2 %). These include 53 gland incisions, 12 partial hemi-hypophysectomies and 14 resections of thinned/attenuated anterior gland. Diagnoses included 64 adenomas and 15 RCCs. New permanent hypopituitarism occurred in three patients (3.8 %), including permanent DI (3) and growth hormone deficiency (1). There was no significant difference in the rate of worsening gland dysfunction nor gain of function. Compared to a control cohort, there was a significantly lower incidence of transient DI (1.25 vs. 11.1 %, p = 0.009) but no significant difference in permanent DI (3.8 vs. 4.0 %) in the gland incision group. CONCLUSION: Selective gland incisions and gland resections were performed in over 20 % of our cases. This technique appears to minimize traction on compressed normal pituitary gland during removal of large lesions and facilitates better visualization and removal of cysts, microadenomas and macroadenomas.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: A NEUROENDOCRINE APPROACH TO PATIENTS WITH TRAUMATIC BRAIN INJURY.

OBJECTIVE: Traumatic brain injury (TBI) is now recognized as a major public health concern in the United States and is associated with substantial morbidity and mortality in both children and adults. Several lines of evidence indicate that TBI-induced hypopituitarism is not infrequent in TBI survivors and may contribute to the burden of illness in this population. The goal of this article is to review the published data and propose an approach for the neuroendocrine evaluation and management of these patients. METHODS: To identify pertinent articles, electronic literature searches were conducted using the following keywords: "traumatic brain injury," "pituitary," "hypopituitarism," "growth hormone deficiency," "hypogonadism," "hypoadrenalism," and "hypothyroidism." Relevant articles were identified and considered for inclusion in the present article. RESULTS: TBI-induced hypopituitarism appears to be more common in patients with severe TBI. However, patients with mild TBI or those with repeated, sports-, or blast-related TBI are also at risk for hypopituitarism. Deficiencies of growth hormone and gonadotropins appear to be most common and have been associated with increased morbidity in this population. A systematic approach is advised in order to establish the presence of pituitary hormone deficiencies and implement appropriate replacement therapies. CONCLUSION: The presence of traumatic hypopituitarism should be considered during the acute phase as well as during the rehabilitation phase of patients with TBI. All patients with moderate to severe TBI require evaluation of pituitary function. In addition, symptomatic patients with mild TBI and impaired quality of life are at risk for hypopituitarism and should be offered neuroendocrine testing.

Role of Endoscopic Skull Base and Keyhole Surgery for Pituitary and Parasellar Tumors Impacting Vision.

Significant advances over the last 2 decades in imaging technology, instrumentation, anatomical knowledge, and reconstructive techniques have resulted in the endonasal endoscopic approach becoming an integral part of modern skull base surgery. With growing use and greater experience, surgical outcomes continue to incrementally improve across many skull base pathologies, including those tumors that impact vision and ocular motility. The importance of the learning curve and use of a multi-disciplinary approach is critical to maximizing success, minimizing complications, and enhancing quality of life in these patients. Realizing the limits of the endonasal route and reasonable use of transcranial approaches such as the supraorbital eyebrow craniotomy, it may br appropriate to consider nonsurgical therapy including various forms of radiotherapy [corrected] and medical treatment options.

Sellar Masses that Present with Severe Hyponatremia.

OBJECTIVE: Hyponatremia is a known but underrecognized presentation of sellar lesions. Herein, we present a series of patients who presented with single or multiple episodes of hyponatremia. METHODS: Over 5 years, patients undergoing endonasal surgery for a de novo sellar mass with hyponatremia as an initial presentation were included. Pathology, sodium levels, pituitary hormonal status, and treatment course were documented. RESULTS: Of 282 patients, 16 (5.7%) (9 males, 7 females, age 32 to 84 years) presented with severe hyponatremia, with a mean serum sodium level of 115 ± 6 mmol/L (range, 101 to 125 mmol/L), and 3 patients had 2 or more episodes. Severe hyponatremia was a presenting sign in 0, 4.1, 14.3, and 37.5% of patients with craniopharyngiomas (n = 10), pituitary adenomas (n = 243), Rathke's cleft cysts (RCCs) (n = 21), and sellar arachnoid cysts (n = 8), respectively (P<.01). Half of the patients presenting with hyponatremia, including 6 of 10 patients with adenomas and 2 of 3 patients with RCCs, had pituitary apoplexy or cyst rupture. All patients had anterior pituitary gland dysfunction, including 81% with hypoadrenalism and 69% with hypothyroidism. Following surgery, hormonal status was unchanged or improved in 15 patients (median follow-up, 14 months). No patient had tumor/cyst recurrence or recurrent hyponatremia. CONCLUSION: Severe hyponatremia was a presenting sign in 5.7% of patients with sellar pathology, most frequently in patients with arachnoid cysts, RCCs, and pituitary apoplexy. Patients with new-onset severe hyponatremia and no obvious pharmacologic or systemic cause should undergo pituitary hormonal evaluation and brain imaging. Surgical resection and correction of hormonal deficiencies are associated with resolution of recurrent hyponatremic episodes.

Avoidance of postoperative epistaxis and anosmia in endonasal endoscopic skull base surgery: a technical note.

BACKGROUND: Most endoscopic transsphenoidal approaches jeopardize the sphenopalatine artery and septal olfactory strip (SOS), increasing the risk of postoperative anosmia and epistaxis while precluding the ability to raise pedicled nasoseptal flaps (NSF). We describe a bilateral "rescue flap" technique that preserves the mucosa containing the nasal-septal vascular pedicles and the SOS. This approach can reduce the risk of postoperative complications, including epistaxis and anosmia. METHODS: A retrospective analysis was conducted of all patients who underwent endoscopic transsphenoidal surgery with preservation of both sphenopalatine vascular pedicles and SOS. In a recent subset of patients, olfactory assessment was performed. RESULTS: Of 174 consecutive operations performed in 161 patients, bilateral preservation of the sphenopalatine vascular pedicle and SOS was achieved in 139 (80 %) operations, including 31 (22 %) with prior transsphenoidal surgery. Of the remaining 35 operations, 18 had a planned formal NSF and 17 had prior surgery or extensive lesions precluding use of this technique. Of pituitary adenomas, RCCs or sellar arachnoid cysts, 118 (94 %) underwent this approach, including 91 % of patients who had prior surgery. Preoperative olfaction function was maintained in 97 % of patients that were tested. None of the patients had postoperative arterial epistaxis. CONCLUSION: Preservation of bilateral sphenopalatine vascular pedicles and the SOS is feasible in over 90 % of patients undergoing endonasal endoscopic surgery for pituitary adenomas and RCCs. This approach, while not hindering exposure or limiting instrument maneuverability, preserves the nasoseptal vasculature for future NSF use if needed and appears to minimize the risks of postoperative arterial epistaxis and anosmia.

Comparative Analysis of Endoscope Obscuration With Utilization of an Endonasal Access Guide for Endonasal Skull Base Surgery.

BACKGROUND AND OBJECTIVES: In endoscopic endonasal approaches (EEAs) for skull base pathologies, endoscope view obscuration remains a persistent, time-consuming, and distracting issue for surgeons and may result in increased operative time. The endonasal access guide (EAG) has been demonstrated as a possible adjunct to minimize these events. However, to date, there have been no comparative studies performed and the potential time savings by using EAGs have yet to be quantified. This cohort study aimed to determine the operative efficiency benefits of the EAG in EEA operations. METHODS: Analysis of EEA operative videos from an EAG cohort (n = 20) and a control cohort (n = 20) was performed, assessing 12-minute segments in the first, middle, and last third of each operation. The first segment in each cohort was selected before EAG placement, serving as an internal control. Every endoscope lens soiling instance was counted (measured as cleaning actions per minute), timed (obscuration time %), and identified as a withdrawal, irrigation, or other cleaning action. Perioperative variables including skull base repair and postoperative cerebrospinal fluid leakage were assessed. RESULTS: Within the EAG cohort, obscuration time was reduced in the middle and last third compared with the first third (3.73% [CI: 2.39-5.07] vs 12.97% [CI: 10.24-15.70], P < .001; 4.19% [CI: 2.83-5.55] vs 12.97% [CI: 10.24-15.70], P < .001) and cleaning actions were also significantly reduced by EAG (0.69/min [CI: 0.39-0.99] vs 1.67/min [CI: 1.34-2.00], P = .001; 0.66/min [CI: 0.35-0.97] vs 1.67/min [CI: 1.34-2.00], P < .001). Between the control and EAG cohorts, there was no significant difference between obscuration time and cleaning actions in the first third (9.33% vs 12.97%, P = .086; 1.34/min vs 1.67/min, P = .151) or in the middle third (6.24% vs 3.73%, P = .140; 0.80/min vs 0.69/min, P = .335), but there was a significant difference in the last third (9.25% [CI: 6.95-11.55] vs 4.19% [CI: 2.83-5.55], P < .001; 0.95/min [CI: 0.73-1.17] vs 0.66/min [CI: 0.35-0.97], P = .018). CONCLUSION: EAG significantly reduces lens obscurations and cleaning events, particularly during the intradural portion of operations. This technology may offer a greater time-saving impact with patients undergoing long EEA operations.

A phase I dose-escalation study of pulsatile afatinib in patients with recurrent or progressive brain cancer.

Background: Afatinib (BIBW2992; Gilotrif®) is a selective and irreversible inhibitor of the epidermal growth factor receptor (ErbB; EGFR) family. It inhibits EGFR, HER2, and HER4 phosphorylation, resulting in tumor growth inhibition and regression. This phase I dose-escalation trial of pulsatile afatinib examined the safety, drug penetration into the central nervous system, preliminary antitumor activity, and recommended phase II dose in patients with progressive or recurrent brain cancers. Methods: Afatinib was taken orally once every 4 days or once every 7 days depending on dose cohort, until disease progression or unacceptable toxicity. Results: A total of 24 patients received the investigational agent and were evaluable for safety analyses, and 21 patients were evaluable for efficacy. Dosing was administered at 80 mg every 4 days, 120 mg every 4 days, 180 mg every 4 days, or 280 mg every 7 days. A recommended phase II dose of pulsatile afatinib was established at 280 mg every 7 days as there were no dose-limiting toxicities in any of the dosing cohorts and all toxicities were deemed manageable. The most common drug-related toxicities were diarrhea, rash, nausea, vomiting, fatigue, stomatitis, pruritus, and limb edema. Out of the 21 patients evaluable for efficacy, 2 patients (9.5%) exhibited partial response based on Response Assessment in Neuro-Oncology criteria and disease stabilization was seen in 3 patients (14.3%). Conclusions: Afatinib taken orally was safe and well-tolerated up to 280 mg every 7 days in brain cancer patients.