Fluorescence guided surgery for pituitary adenomas.

PURPOSE: Resection of pituitary adenomas presents a number of unique challenges in neuro-oncology. The proximity of these lesions to key vascular and endocrine structures as well as the need to interpret neuronavigation in the context of shifting tumor position increases the complexity of the operation. More recently, substantial advances in fluorescence-guided surgery have been demonstrated to facilitate the identification of numerous tumor types and result in increased rates of complete resection and overall survival. METHODS: A review of the literature was performed, and data regarding the mechanism of the fluorescence agents, their administration, and intraoperative tumor visualization were extracted. Both in vitro and in vivo studies were assessed. The application of these agents to pituitary tumors, their advantages and limitations, as well as future directions are presented here. RESULTS: Numerous laboratory and clinical studies have described the use of 5-ALA, fluorescein, indocyanine green, and OTL38 in pituitary lesions. All of these drugs have been demonstrated to accumulate in tumor cells. Several studies have reported the successful use of the majority of the agents in inducing intraoperative tumor fluorescence. However, their sensitivity and specificity varies across the literature and between functioning and non-functioning adenomas. CONCLUSIONS: At present, numerous studies have shown the feasibility and safety of these agents for pituitary adenomas. However, further research is needed to assess the applicability of fluorescence-guided surgery across different tumor subtypes as well as explore the relationship between their use and postoperative clinical outcomes.

Prognostic value of nadir GH levels for long-term biochemical remission or recurrence in surgically treated acromegaly.

CONTEXT: Outcome of acromegaly surgery is assessed by IGF-1 and glucose-suppressed GH, but whether the latter provides additional clinically relevant information when IGF-1 is normal is unclear. The role of GH suppression testing after surgery requires clarification. METHODS: We studied 97 acromegaly patients with normal IGF-1 after surgery by measuring GH after oral glucose longitudinally, initially at ≥ 3 months after surgery and repeated one or more times ≥ 1 year later. Nadir GH was categorized as normal or abnormal relative to the 97.5th percentile of nadir GH in 100 healthy subjects, which were ≤ 0.14 µg/L (DSL IRMA) or ≤ 0.15 µg/L(IDS iSYS). Signs and symptoms scores and insulin resistance were followed longitudinally. RESULTS: Of 68 patients with initial normal GH suppression 63 (93%) remained in remission and of 29 with initial abnormal GH suppression, 9 (31%) recurred. Recurrence was more common in patients with abnormal suppression (P < 0.001). A total of 14 patients recurred, including 5 with normal GH suppression progressing to abnormal and then recurrence. Overall, serial signs and symptoms and insulin resistance assessments did not identify patients with abnormal suppression or recurrence. CONCLUSION: Risk of recurrence after surgery is increased for patients with a normal IGF-1 level, but abnormal GH suppression. We newly find, using both our and others' cut-offs, that while normal suppression predicts long-term remission in most patients, some can progress from normal to abnormal suppression and then recurrence after many years of follow up. Nadir GH levels are of prognostic value in acromegaly patients with normal IGF-1 levels after surgery.

Proinflammatory cytokines remain elevated despite long-term remission in Cushing's disease: a prospective study.

CONTEXT: Inflammation contributes to the development of metabolic and cardiovascular disease. Cushing's disease (CD), a state of chronic glucocorticoid (GC) excess characterized by visceral obesity and insulin resistance, may be associated with increased systemic inflammation. Cardiovascular mortality in CD remains elevated even after successful remission. It is unclear whether a chronic low-grade inflammatory state persists even after remission of CD, which may account for the increased CVD mortality. PURPOSE: (1) To assess circulating proinflammatory cytokines in patients with active CD and BMI-matched controls; (2) to prospectively follow plasma cytokine concentrations in patients with CD before and after surgical remission; and (3) to assess whether plasma cytokine concentrations correlate with adipose tissue distribution and ectopic lipid content in liver and muscle. METHODS: Plasma cytokines from prospectively enrolled patients with CD (N = 31) were quantified during active disease (v1) vs controls (N = 18) and 19·5 ± 12·9 months after surgical remission (v2). Fasting plasma IL-6, IL-1ß, TNF-α, IL-8, IL-17 and IL-10 were quantified using a multiplex assay. Total and regional fat masses were measured by whole-body MRI. RESULTS: Circulating IL-6 and IL-1ß were elevated in patients with active CD vs controls (P < 0·05) and remained elevated in CD after surgical remission, despite decreases in BMI (P < 0·001), HOMA-IR (P < 0·001), and visceral, hepatic and intermuscular fat (P < 0·001, <0·001 and 0·03, respectively). CONCLUSIONS: Despite long-term remission and improvements in fat distribution and insulin sensitivity, patients with CD may suffer from a state of chronic low-grade inflammation, which could contribute to increased cardiovascular mortality.

A prospective study of appetite and food craving in 30 patients with Cushing's disease.

CONTEXT: Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing's disease (CD), either before or after treatment, and could provide insight into mechanisms of food intake and obesity in these patients. PURPOSE: To examine whether surgical remission of CD changes appetite (prospective consumption, hunger, satisfaction, and fullness) and food cravings (sweet, salty, fatty, and savory); and to identify predictors of appetite and craving in CD remission. METHODS: 30 CD patients, mean age 40.0 years (range 17-70), mean BMI 32.3 ± 6.4, were prospectively studied before and at a mean of 17.4 mo. after remission. At each visit fasting and post-test meal (50% carbohydrate, 35% protein, 15% fat) appetite and craving scores were assessed. RESULTS: Remission decreased prospective consumption, sweet and savory craving (p < 0.05), but did not change hunger, satisfaction, fullness, or fat craving, despite decreases in BMI and fat mass. In CD remission, serum cortisol predicted lower satisfaction and fullness, and masses of abdominal fat depots predicted higher hunger and consumption (p < 0.05). CONCLUSIONS: Chronic GC exposure in CD patients may stimulate the drive to eat by enhancing craving, rather than regulating the sensation of hunger. Continued alterations in appetite regulation due to abdominal fat mass and circulating cortisol could play a role in the cardiovascular and metabolic risk that has been reported in CD patients despite remission.

Predictors of quality of life in 102 patients with treated Cushing's disease.

OBJECTIVE: To identify predictors for quality of life (QoL) in treated Cushing's disease (CD) and quantify patients' assessment of their disease status. CONTEXT: Significant reductions in QoL exist in CD patients despite treatment. Identifying predictors of QoL is paramount to the long-term management of these patents. DESIGN: A cross-sectional study was conducted of patients with treated CD. Patients completed a medical history questionnaire and three validated quality of life assessments: Cushing's QoL Questionnaire (CushingQoL), Hospital Anxiety and Depression Scale (HADS) and Nottingham Health Profile (NHP). PATIENTS: 102 patients (75·7% female, mean time since surgery 7·4 years) with treated CD were included. MEASUREMENTS: Patients were categorized by biochemical and self-identified disease status. Mean CushingQoL, anxiety and depression scores were compared by unpaired t-tests. Multiple linear regressions were performed on the whole cohort to assess for predictors of impaired QoL. RESULTS: Ninety-two per cent of the cohort met criteria for biochemical remission, but only 80·4% felt they had achieved remission. Among those with biochemical remission, those who also self-identified as being in remission had higher CushingQoL scores than those who self-identified as having persistent disease (P = 0·042). Anxiety (P = 0·032) and depression (P = 0·018) scores were lower, and CushingQoL scores were higher (P = 0·05) in patients who self-identified as being in remission compared to persistence. Recovery time, BMI, gender and age were also predictors for QoL. CONCLUSION: Our study identifies the discordance that can exist between biochemical and self-assessed disease status and demonstrates its impact on QoL in patients with CD. These findings highlight the importance of incorporating patients' disease perceptions in their management.

IGF-1 levels across the spectrum of normal to elevated in acromegaly: relationship to insulin sensitivity, markers of cardiovascular risk and body composition.

PURPOSE: Activity of acromegaly is gauged by levels of GH and IGF-1 and epidemiological studies demonstrate that their normalization reduces acromegaly's excess mortality rate. However, few data are available linking IGF-1 levels to features of the disease that may relate to cardiovascular (CV) risk. Therefore, we tested the hypothesis that serum IGF-1 levels relative to the upper normal limit relate to insulin sensitivity, serum CV risk markers and body composition in acromegaly. METHODS: In this prospective, cross-sectional study conducted at a pituitary tumor referral center we studied 138 adult acromegaly patients, newly diagnosed and previously treated surgically, with fasting and post-oral glucose levels of endocrine and CV risk markers and body composition assessed by DXA. RESULTS: Active acromegaly is associated with lower insulin sensitivity, body fat and CRP levels than acromegaly in remission. %ULN IGF-1 strongly predicts insulin sensitivity, better than GH and this persists after adjustment for body fat and lean tissue mass. %ULN IGF-1 also relates inversely to CRP levels and fat mass, positively to lean tissue and skeletal muscle estimated (SM(E)) by DXA, but not to blood pressure, lipids, BMI or waist circumference. Gender interacts with the IGF-1-lean tissue mass relationship. CONCLUSIONS: Active acromegaly presents a unique combination of features associated with CV risk, reduced insulin sensitivity yet lower body fat and lower levels of some serum CV risk markers, a pattern that is reversed in remission. %ULN IGF-1 levels strongly predict these features. Given the known increased CV risk of active acromegaly, these findings suggest that of these factors insulin resistance is most strongly related to disease activity and potentially to the increased CV risk of active acromegaly.

Prospective, longitudinal study of cancer predictors and rates in a New York City cohort of 598 patients with acromegaly.

PURPOSE: Long-term GH/IGF-1 excess could increase risk of cancer in acromegaly, but individual levels of these hormones do not relate to this risk. Therefore, we newly investigated longitudinally-measured IGF-1 levels as a potential predictor of cancer in a large NYC acromegaly cohort. METHODS: We conducted a prospective, longitudinal study of 598 acromegaly (309 men, 289 women) and 292 clinically nonfunctioning pituitary adenoma (CNFPA)(140 women, 152 men) patients from the same underlying population. GH and IGF-1 levels were measured longitudinally and outcomes were observed during long-term follow-up. Cumulative exposure to IGF-1 excess was tested as a predictor of cancer. We compared cancer prevalence in acromegaly and CNFPA cohorts and incidence in each to that expected from SEER data. RESULTS: Cancer prevalence by last follow up was 22.6% in acromegaly and 12.7% in CNFPAs (OR = 1.99 (95% CI, 1.34, 2.97)(P=0.0005). Overall SIR for cancer was 1.78 (1.51, 1.81) in the acromegaly and 1.26 (0.89, 1.70) in the CNFPA cohorts. Cumulative exposure to IGF-1 excess, OR=1.278 (1.060, 1.541)(P = 0.01), years from acromegaly diagnosis to cancer or last follow up, OR= 1.03 (1.004, 1.057)(P=0.024), and age at follow up, OR =1.064 (1.047, 1.082)(P<0.001), were predictors of cancer. CONCLUSIONS: Cancer risk is increased in acromegaly, but not in CNFPA patients. Cumulative exposure to IGF-1 excess is a predictor of cancer in acromegaly. Our data suggest that cancer risk in acromegaly relates to the degree and duration of IGF-1 excess and that full appreciation of this risk requires long-term follow up.

Clinical and Operative Risk Factors Associated With Prolonged Length of Stay After Endoscopic Pituitary Adenoma Resection.

BACKGROUND AND OBJECTIVES: Pituitary adenomas (PAs) are the most common intrasellar tumor. Clinically relevant adenomas have a prevalence of 1 per 1000 in the general population. Transsphenoidal surgery (TSS) is the most common surgical treatment and is the first-line management for most PAs. Most patients fare well postoperatively, but a subset of patients experience a prolonged length of stay (PLOS). In this article, we aim to identify demographic and clinical factors associated with PLOS after TSS for PA. METHODS: Patients with sellar pathologies surgically treated at a single tertiary center from March 1, 2009, to May 31, 2020, were retrospectively reviewed. All patients older than 18 years receiving nonemergent endoscopic TSS for pituitary adenoma were included. Clinical and demographic characteristics were analyzed using χ 2 -tests and student t -tests. For those factors with a P -value less than .01, multivariate logistic regression and negative binomial regression models were constructed to estimate the adjusted odds of PLOS across predictive factors. RESULTS: A total of 301 patients were included in the study. This cohort had an average age of 54.65 ± 15.06 years and an average body mass index of 29.47 ± 6.69. The median length of stay was 54.9 hours [25th-75th percentiles: 43.5-72.9]. Postoperative cerebrospinal fluid leak ( P < .01), postoperative diabetes insipidus (DI) ( P < .01), increased surgery duration ( P = .01), and elevated maximal tumor dimension ( P = .01) were predictive of PLOS in logistic regression. Increased surgery duration, previous pituitary radiation, intraoperative complications, and postoperative DI (all P < .01) were associated with increased rate of PLOS in negative binomial regression. CONCLUSION: Patients undergoing endoscopic TSS for PA resection demonstrate prolonged lengths of stay if they have higher tumor burden, have lengthier surgeries with intraoperative complications, or develop postoperative complications such as cerebrospinal fluid leak or DI. Careful monitoring of these factors will allow for better resource optimization, reducing costs to both the hospital and the patient.

ACTH-producing remnants following apoplexy of an ACTH-secreting pituitary macroadenoma.

Describe a case of apoplexy of an ACTH-producing pituitary adenoma which resulted not only in an empty sella with concurrent hypothyroidism, hypoprolactinemia, and hypogonadism but persistent hypercortisolemia from two distinct extrasellar remnants of the original adenoma. Review the literature to identify other similar cases. The patient's medical history, physical exam, lab data, imaging exams and histopathological results were analyzed and compiled into a case report, and an extensive review of the literature was performed. Endocrinological data revealed hypercortisolism and an elevated ACTH with an otherwise suppressed pituitary axis. A pituitary MRI showed a macroadenoma in the left cavernous sinus in addition to an empty sella. An octreotide scan revealed lesions in the left sella turcica and the right sphenoid sinus. Tissue samples of both lesions stained positive for ACTH and negative for GH, prolactin, FSH, LH, and TSH. The lesions were surgically removed, and the patient treated with radiation and ketoconazole. This resulted in a significant decrease in ACTH and cortisol as well as a marked improvement in blood glucose control. The review of literature revealed the absence of any similar cases in the past. The patient presented with apoplexy of an ACTH-secreting pituitary macroadenoma with two hormonally active extrasellar remnants. Several cases in the literature describe recurrence of Cushing's disease following infarction of ACTH-secreting adenomas. This is the first documented case of infarction of an ACTH-producing adenoma resulting in two distinct ACTH-producing remnants without recurrence of the original adenoma.

Seventy-five years of neurosurgery residency training at The Mount Sinai Hospital.

The Department of Neurosurgery's residency program at The Mount Sinai Hospital was founded in 1946. The department has its origins in 1914 as a division of general surgery, with Charles Elsberg at the helm. Neurosurgery then became a separate department in 1932 under the leadership of Ira Cohen. Dr. Cohen oversaw the creation of the neurosurgery residency training program 75 years ago. Since its inception, the residency program has graduated 120 residents. For more than 100 years, The Mount Sinai Hospital has been a site of clinical excellence, groundbreaking research, and technological innovation in neurosurgery. Currently, the Department of Neurosurgery has 39 clinical faculty members, performs more than 5300 surgeries and endovascular procedures annually, and is in the top 25 neurosurgical departments for NIH funding.

USP8 and TP53 Drivers are Associated with CNV in a Corticotroph Adenoma Cohort Enriched for Aggressive Tumors.

CONTEXT: Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropin (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. OBJECTIVE: To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. DESIGN: Whole-exome sequencing of patient-matched corticotroph tumor and normal deoxyribonucleic acid (DNA) from a patient cohort enriched for tumors at risk for aggressive behavior. SETTING: Tertiary care center. PATIENTS: Twenty-seven corticotroph tumors from 22 patients were analyzed. Twelve tumors were macroadenomas, of which 6 were silent ACTH tumors, 2 were Crooke's cell tumors, and 1 was a corticotroph carcinoma. INTERVENTION: Whole-exome sequencing. MAIN OUTCOME MEASURE: Somatic mutation genomic biomarkers. RESULTS: We found recurrent somatic mutations in USP8 and TP53 genes, both with higher allelic fractions than other somatic mutations. These mutations were mutually exclusive, with TP53 mutations occurring only in USP8 wildtype (WT) tumors, indicating they may be independent driver genes. USP8-WT tumors were characterized by extensive somatic copy number variation compared with USP8-mutated tumors. Independent of molecular driver status, we found an association between invasiveness, macroadenomas, and aneuploidy. CONCLUSIONS: Our data suggest that corticotroph tumors may be categorized into a USP8-mutated, genome-stable subtype versus a USP8-WT, genome-disrupted subtype, the latter of which has a TP53-mutated subtype with high level of chromosome instability. These findings could help identify high risk corticotroph tumors, namely those with widespread CNV, that may need closer monitoring and more aggressive treatment.

MRI assessment of lean and adipose tissue distribution in female patients with Cushing's disease.

OBJECTIVE: Chronic hypercortisolemia due to Cushing's disease (CD) results in abnormal adipose tissue (AT) distribution. Whole-body magnetic resonance imaging (MRI) was used to examine lean and AT distribution in female patients with CD to further understand the role of glucocorticoid excess in the development of abnormal AT distribution and obesity. DESIGN: Cross-sectional and case-control study. PATIENTS: Fifteen women with CD and 12 healthy controls. MEASUREMENTS: Mass of skeletal muscle (SM) and AT in the visceral (VAT), subcutaneous (SAT), and intermuscular (IMAT) compartments from whole-body MRI and serum levels of insulin, glucose, and leptin were measured. RESULTS: CD patients had leptin values that correlated to total AT (TAT) and SAT (P < 0.05) but not to VAT. CD patients had higher VAT/TAT ratios (P < 0.01) and lower SAT/TAT ratios (P < 0.05) compared to controls. TAT, VAT, and trunk SAT (TrSAT) were greater in CD patients (P < 0.01). SM was less in CD (P < 0.001) but IMAT was not different. CONCLUSIONS: TAT, VAT, trSAT, and the proportion of AT in the visceral depot were greater in CD although the proportion in the subcutaneous depot was less. SM was less but IMAT was not different. These findings have implications for understanding the role of cortisol in the abnormal AT distribution and metabolic risk seen in patients exposed to chronic excess glucocorticoids.

Features at diagnosis of 324 patients with acromegaly did not change from 1981 to 2006: acromegaly remains under-recognized and under-diagnosed.

BACKGROUND: Traditionally, acromegaly evaded diagnosis until in its clinically obvious later stages when treatment is more difficult. Over the last 25 years diagnostic tests have improved, but whether clinical disease detection also improved was unknown, so we tested if disease severity at diagnosis had changed from 1981 to 2006. METHODS: Data on 324 consecutive acromegaly patients presenting from 1981 to 2006 at two New York City hospitals were collected by retrospective review (n = 324) and by interview (n = 200). The main complaint, acromegaly associated comorbidities, signs, symptoms, healthcare providers visited, preoperative GH and IGF-I levels and pituitary tumour size at diagnosis were compared in patients presenting in the earlier vs. later halves of the time period. RESULTS: Times from symptom onset to diagnosis were 5.9 year (early) vs. 5.2 year (late; P = NS). At diagnosis, 96% of early and late groups had facial feature changes and/or hand/foot enlargement. Comorbidities included hypertension 37% (early) vs. 36% (late), carpal tunnel syndrome (24%vs. 24%), sleep apnoea (13%vs. 29%; P < 0.01), osteoarthritis (25%vs. 23%) and diabetes mellitus (18%vs. 15%); each patient had 1.2 (early) vs. 1.3 (late; P = 0.53) comorbidities. Groups were similar in signs, symptoms, tumour size, GH and IGF-I. CONCLUSIONS: Clinical, biochemical and tumour size characteristics at diagnosis of acromegaly patients were unchanged from 1981 to 2006. Most patients still have marked manifestations of acromegaly at diagnosis, suggesting that acromegaly remains clinically under-recognized. Healthcare professionals should more commonly consider acromegaly, which can lead to earlier diagnosis and better treatment outcome.

RECURRENT PITUITARY APOPLEXY IN AN ADENOMA WITH SWITCHING PHENOTYPES.

OBJECTIVE: To describe an unusual presentation of a patient with recurrent pituitary apoplexy of an adenoma that switched phenotypes from a nonfunctioning, or silent gonadotroph adenoma (SGA), to a silent corticotroph adenoma (SCA). We discuss the potential etiologies of both recurrent pituitary apoplexy and phenotype switching of pituitary tumors. METHODS: The presented case includes clinical and biochemical findings, surgical outcomes, and pathologic reports related to the treatment of our patient who presented with recurrent pituitary apoplexy. RESULTS: A 56-year-old man presented for evaluation of decreased libido and was found to have a low testosterone level. A pituitary magnetic resonance image demonstrated an 8-mm pituitary adenoma. He underwent transsphenoidal surgery (TSS) to remove the tumor and pathology demonstrated an SGA immunopositive for luteinizing hormone and follicle-stimulating hormone with evidence of apoplexy. Eight years later, the patient underwent another TSS after developing acute-onset headache, vomiting, and a cranial nerve palsy. Pathology at this time showed a necrotic tumor consistent with apoplexy with negative immunostains for all pituitary tumors. Three years after this, the tumor recurred and after another TSS the tumor stained positive for adrenocorticotropic hormone but was negative for luteinizing hormone and follicle-stimulating hormone with hemorrhage consistent with apoplexy. A few years afterward, he again developed acute-onset headache and cranial nerve palsies and had another TSS. On pathology, the tumor demonstrated extensive necrosis consistent with apoplexy and again stained positive for adrenocorticotropic hormone. The patient was then referred for radiation therapy and was subsequently lost to follow up. CONCLUSION: Recurrent pituitary apoplexy in the same patient has only been described 3 times in the literature. There have been no case reports of a pituitary adenoma that switched phenotypes from an SGA to SCA. We suggest that pituitary apoplexy may recur multiple times due to a tumor with particularly fragile vessel walls and increased vascularization. We review the literature that suggests clinical and molecular similarities between SGAs and SCAs. Further studies are needed to determine the etiologies of recurrent apoplexy and pituitary adenomas with switching phenotypes.

Presenting Features in 269 Patients With Clinically Nonfunctioning Pituitary Adenomas Enrolled in a Prospective Study.

CONTEXT: Clinically nonfunctioning pituitary adenomas (CNFPAs) typically remain undetected until mass effect symptoms develop. However, currently, head imaging is performed commonly for many other indications, which may increase incidental discovery of CNFPAs. Since current presentation and outcome data are based on older, retrospective series, a prospective characterization of a contemporary CNFPA cohort was needed. OBJECTIVE: To determine the prevalence of incidental presentation and hypopituitarism and its predictors in a CNFPA cohort that spanned 6 to 9 mm micro- to macroadenoma included observational and surgical therapy. METHODS: At enrollment in a prospective, observational study, 269 patients with CNFPAs were studied by history, examination, blood sampling, and pituitary imaging analysis and categorized into incidental or symptoms presentation groups that were compared. RESULTS: Presentation was incidental in 48.7% of patients and due to tumor symptoms in 51.3%. In the symptoms and incidental groups, 58.7% and 27.4% of patients had hypopituitarism, respectively, and 25% of patients with microadenomas had hypopituitarism. Many had unappreciated signs and symptoms of pituitary disease. Most tumors were macroadenomas (87%) and were larger in the symptoms than incidental and hypopituitary groups than in the eupituitary groups. The patients in the incidental group were older, and males were older and had larger tumors in both the incidental and symptoms groups. CONCLUSIONS: Patients with CNFPAs commonly present incidentally and with previously unrecognized hypopituitarism and symptoms that could have prompted earlier diagnosis. Our data support screening all large micro and macro-CNFPAs for hypopituitarism. Most patients with CNFPAs still have mass effect signs at presentation, suggesting the need for more awareness of pituitary disease. Our ongoing, prospective observation of this cohort will assess outcomes of these CNFPA groups.

The historical evolution of transsphenoidal surgery: facilitation by technological advances.

Over the past century, pituitary surgery has undergone multiple evolutions in surgical technique and technological advancements that have resulted in what practitioners now recognize as modern transsphenoidal surgery (TSS). Although the procedure is now well established in current neurosurgical literature, the historical maze that led to its development continues to be of interest because it allows a better appreciation of the unique contributions by the pioneers of the technique, and of the innovative spirit that continues to fuel neurosurgery. The early events in the history of TSS have already been well documented. This paper therefore summarizes the major early transitions along the timeline, and then further concentrates on some of the more recent advancements in TSS, such as the surgical microscope, fluoroscopy, endoscopy, intraoperative imaging, and frameless guidance. The account of each of these innovations is unique because they were each developed as a response to certain historical needs by the surgeon. An understanding of these more recent contributions, coupled with the early history, provides a more complete perspective on modern TSS.

Selective use of bilateral inferior petrosal sinus sampling in patients with adrenocorticotropin-dependent Cushing's syndrome prior to transsphenoidal surgery.

CONTEXT: Few data are available on the selective use of bilateral inferior petrosal sinus sampling (BIPSS) in the presurgical evaluation of patients with ACTH-dependent Cushing's syndrome, so we investigated whether its use only in patients without a clear adenoma on magnetic resonance imaging and/or inconsistent biochemical testing affected remission and long-term outcome after surgery in patients with Cushing's disease (CD). SETTING: This was a retrospective review of patients treated for CD by one pituitary neurosurgeon at tertiary medical centers in New York City. PATIENTS: A total of 193 consecutive adult patients who underwent initial transsphenoidal surgery (TS) for presumed CD between 1987 and 2005 were included. MAIN OUTCOME MEASURES: We examined preoperative pituitary imaging and biochemical data, results of BIPSS and surgical pathology, and outcome based on biochemical tests after initial TS and long term after subsequent therapies. RESULTS: Remission rate after the first TS was 80.8% overall, 79.1% in the BIPSS group (n = 105), and 83.0% in the No-BIPSS group (n = 88). Recurrences occurred in 13.5% after the first TS at a mean of 4.8 +/- 3.5 yr (range, 0.7-12.4 yr) with no difference between BIPSS and No-BIPSS groups. Long-term remission was achieved after surgeries and radiotherapy in 85% (86.7% of BIPSS group, 83.0% of No-BIPSS group). CD was ultimately confirmed in all but one patient in each group. CONCLUSIONS: Selective use of BIPSS in the preoperative evaluation of patients with presumed CD did not lead to misdiagnosis in the No-BIPSS group or adversely affect remission rates or long-term outcome.

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Cushing's disease (CD) is caused by pituitary corticotroph adenomas that secrete excess adrenocorticotropic hormone (ACTH). In these tumors, somatic mutations in the gene USP8 have been identified as recurrent and pathogenic and are the sole known molecular driver for CD. Although other somatic mutations were reported in these studies, their contribution to the pathogenesis of CD remains unexplored. No molecular drivers have been established for a large proportion of CD cases and tumor heterogeneity has not yet been investigated using genomics methods. Also, even in USP8-mutant tumors, a possibility may exist of additional contributing mutations, following a paradigm from other neoplasm types where multiple somatic alterations contribute to neoplastic transformation. The current study utilizes whole-exome discovery sequencing on the Illumina platform, followed by targeted amplicon-validation sequencing on the Pacific Biosciences platform, to interrogate the somatic mutation landscape in a corticotroph adenoma resected from a CD patient. In this USP8-mutated tumor, we identified an interesting somatic mutation in the gene RASD1, which is a component of the corticotropin-releasing hormone receptor signaling system. This finding may provide insight into a novel mechanism involving loss of feedback control to the corticotropin-releasing hormone receptor and subsequent deregulation of ACTH production in corticotroph tumors.

Day of Surgery Impacts Outcome: Rehabilitation Utilization on Hospital Length of Stay in Patients Undergoing Elective Meningioma Resection.

OBJECTIVE/BACKGROUND: Meningiomas account for approximately one third of all brain tumors in the United States. In high-volume medical centers, the average length of stay (LOS) for a patient is 6.8 days compared with 8.8 days in low-volume centers with median total admission charges equaling approximately $55,000. To our knowledge, few studies have evaluated day of surgery and its effect on hospital LOS. Our primary goal was to analyze patient outcome as a direct result of surgical date, as well as to characterize the individual variables that may impact their hospital course, early access to rehabilitation, and long-term functional status. METHODS: A retrospective database was generated for cranial meningioma patients who underwent elective surgical resection at our institution over a 3-year study period (2011-2014). Inclusion criteria included any patient who underwent elective meningioma resection and was discharged either home or to a rehabilitation facility with at least 6 months of follow-up. Exclusion criteria included any patient who was not discharged after resection (i.e., expired). Each patient's medical record was evaluated for a subset of demographics and clinical variables. Given that patients who undergo surgical resection of meningiomas have a national median LOS of 6 days, we subdivided the patients into 2 cohorts: early discharge (LOS < 3) and late discharge (LOS ≥ 3). Statistical analysis was performed using SPSS 21.0 to assess the significance of the results. RESULTS: We identified 139 (25 male, 114 female) meningioma patients who underwent surgical resection. Seventy of these patients had surgery during the early week (defined as Monday-Wednesday), and 69 had surgery in the later week (Thursday-Friday). The median age for both early and late groups was 58, and the median diameter of the tumor was 3.1 cm and 3.3 cm, respectively. Overall, 55% of the patients had public insurance and 43% had private insurance, with no significant variation between the early and late groups. The median LOS for the early and late populations was 3 and 4 days, respectively. Physical therapy recommendations for rehabilitation facility were made in 26% of early-week patients and in 42% of late-week patients. Additionally, we found a statistically significant decreased LOS (<3 days) in those patients who underwent surgery during the early week (Monday-Wednesday), as opposed to those who received surgery in the later week (Thursday, Friday) (P = 0.045, Mann-Whitney test). CONCLUSION: Day of surgery may play a significant role in LOS for meningioma patients. Clinicians should remain aware of those factors that may delay optimal patient discharge and early access to rehabilitation facilities. Further studies will need to be performed to assess the social variables that may affect LOS, as well as the financial implications for such extended hospital courses.