Multicenter Registry of Adenomas of the Pituitary and Related Disorders: Initial Description of Cushing Disease Cohort, Surgical Outcomes, and Surgeon Characteristics.

BACKGROUND AND OBJECTIVES: To address the lack of a multicenter pituitary surgery research consortium in the United States, we established the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). The goals of RAPID are to examine surgical outcomes, improve patient care, disseminate best practices, and facilitate multicenter surgery research at scale. Our initial focus is Cushing disease (CD). This study aims to describe the current RAPID patient cohort, explore surgical outcomes, and lay the foundation for future studies addressing the limitations of previous studies. METHODS: Prospectively and retrospectively obtained data from participating sites were aggregated using a cloud-based registry and analyzed retrospectively. Standard preoperative variables and outcome measures included length of stay, unplanned readmission, and remission. RESULTS: By July 2023, 528 patients with CD had been treated by 26 neurosurgeons with varying levels of experience at 9 academic pituitary centers. No surgeon treated more than 81 of 528 (15.3%) patients. The mean ± SD patient age was 43.8 ± 13.9 years, and most patients were female (82.2%, 433/527). The mean tumor diameter was 0.8 ± 2.7 cm. Most patients (76.6%, 354/462) had no prior treatment. The most common pathology was corticotroph tumor (76.8%, 381/496). The mean length of stay was 3.8 ± 2.5 days. The most common discharge destination was home (97.2%, 513/528). Two patients (0.4%, 2/528) died perioperatively. A total of 57 patients (11.0%, 57/519) required an unplanned hospital readmission within 90 days of surgery. The median actuarial disease-free survival after index surgery was 8.5 years. CONCLUSION: This study examined an evolving multicenter collaboration on patient outcomes after surgery for CD. Our results provide novel insights on surgical outcomes not possible in prior single-center studies or with national administrative data sets. This collaboration will power future studies to better advance the standard of care for patients with CD.

Surgery for Pituitary Tumor Apoplexy Is Associated with Rapid Headache and Cranial Nerve Improvement.

Pituitary tumor apoplexy (PTA) classically comprises sudden-onset headache, loss of vision, ophthalmoparesis, and decreased consciousness. It typically results from hemorrhage and/or infarction within a pituitary adenoma. Presentation is heterologous, and optimal management is debated. The time course of recovery of cranial nerve deficits (CNDs) and headaches is not well established. In this study, a retrospective series of consecutive patients with PTA managed at a single academic institution over a 22-year period is presented. Headaches at the time of surgery were more severe in the early and subacute surgical cohort and improved significantly within 72 h postoperatively (p < 0.01). At one year, 90% of CNDs affecting cranial nerves (CNs) 3, 4, and 6 had recovered, with no differences between early (<4 d), subacute (4−14 d), and delayed (>14 d) time-to-surgery cohorts. Remarkably, half recovered within three days. In total, 56% of CN2 deficits recovered, with the early surgery cohort including more severe deficits and recovering at a lower rate (p = 0.01). No correlation of time-to-surgery and rapidity of recovery of CNDs was observed (p = 0.65, 0.72). Surgery for PTA is associated with rapid recovery of CNDs in the early, subacute, and delayed time frames, and with rapid headache improvement in the early and subacute time frames in 50% or more of patients.

Axis-specific analysis and predictors of endocrine recovery and deficits for non-functioning pituitary adenomas undergoing endoscopic transsphenoidal surgery.

PURPOSE: Endoscopic transsphenoidal surgery (ETSS) is a well-established treatment for patients with nonfunctioning pituitary adenomas (NFPAs). Data on the rates of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS and the predictors of endocrine function before and after ETSS are scarce. This study is purposed to analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA. METHODS: A retrospective review of 601 consecutive patients who underwent ETSS between 2010 and 2018 at one institution was performed. Recovery or development of new hypopituitarism was analyzed in 209 NFPA patients who underwent ETSS. RESULTS: Patients with preoperative endocrine deficits (59.8%) in one or more pituitary axes had larger tumor volumes (P = 0.001) than those without preoperative deficits. Recovery of preoperative pituitary deficit occurred in all four axes, with overall mean recovery of 29.7%. The cortisol axis showed the highest recovery whereas the thyroid axis showed the lowest, with 1-year cumulative recovery rates of 44.3% and 6.1%, respectively. Postoperative hypopituitarism occurred overall in 17.2%, most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Axis-specific predictors of post-operative recovery and deficiency were identified. CONCLUSIONS: Dynamic alterations in pituitary hormones were observed in a proportion of patients following ETSS in NFPA patients. Postoperative endocrine vulnerability, recovery, and factors that predicted recovery or loss of endocrine function depended on the hormonal system, necessitating an axis-specific surveillance strategy postoperatively.

Withholding Perioperative Steroids in Patients Undergoing Transsphenoidal Resection for Pituitary Disease: Randomized Prospective Clinical Trial to Assess Safety.

BACKGROUND: Perioperative steroid protocols for patients undergoing transsphenoidal surgery (TSS) for pituitary pathology vary by institution. OBJECTIVE: To assess the safety of withholding glucocorticoids in patients undergoing TSS. METHODS: Patients with an intact hypothalamic-pituitary-adrenal (HPA) axis undergoing TSS for a pituitary tumor at the same academic institution between 2012 and 2015 were randomized to either receive 100 mg of intravenous hydrocortisone followed by 0.5 mg of intravenous dexamethasone every 6 h for 4 doses (STER, n = 23) or to undergo surgery without steroids (NOSTER, n = 20). Postoperative cortisol levels were then used to determine the need for glucocorticoids after surgery. Data regarding postoperative cortisol levels, hospital stay length, and complications were collected. RESULTS: Mean postoperative 8 am cortisol levels were higher in the NOSTER group compared to the STER group (745 ± 359 nmol/L and 386 ± 193 nmol/L, respectively, P = .001) and more patients were discharged on glucocorticoids in the STER group (42% vs 12%, P = .07). There was no difference in the incidence of postoperative complications, including hyperglycemia, diabetes insipidus, or permanent adrenal insufficiency. Permanent adrenal insufficiency occurred in 8% of patients. CONCLUSION: Perioperative steroids can be safely withheld in patients with an intact HPA axis undergoing TSS. Although administration of perioperative glucocorticoids does not appear to increase the risk of complications, it may interfere with assessment of the HPA axis after surgery.

USE OF ELECTRONIC HEALTH RECORDS TO CHARACTERIZE A RARE DISEASE IN THE U.S.: TREATMENT, COMORBIDITIES, AND FOLLOW-UP TRENDS AMONG PATIENTS WITH A CONFIRMED DIAGNOSIS OF ACROMEGALY.

OBJECTIVE: Understanding of acromegaly disease management is hampered in the U.S. by the lack of a national registry. We describe medical management in a population with confirmed acromegaly. METHODS: Inpatient and outpatient electronic health records (EHRs) were used to create a database of de-identified patients assigned the Acromegaly and Gigantism International Classification of Diseases, 9th revision (ICD-9) code and/or an appropriate pituitary procedure code at 1 of 4 regional hospital systems over a 6- to 11-year period. Information regarding demographics, medical history, labs, procedures, and medications was collected and supplemented with a chart review to validate the diagnosis of acromegaly. RESULTS: Of 367 patients with validated acromegaly, available records showed that during the years studied, pituitary surgery was performed on 31%, 4% received radiosurgery, and 22% were prescribed a drug indicated for acromegaly. Insulin-like growth factor-1 (IGF-1) levels were measured in 62% of patients, 83% of whom had at least 1 normal value. Coded comorbidities reflect those reported previously in patients with acromegaly, with the exception of esophageal reflux in 20% of patient records. Fewer data regarding acromegaly-specific medications and testing were available for patients aged 65 and older. CONCLUSION: AcroMEDIC is a U.S. multisite retrospective study of acromegaly that captured medical management in the majority of patients included in the cohort. Chart review highlighted the importance of verification of coded diagnoses. Most of the acromegaly-related comorbidities identified here are known to increase with age and obesity. Patients ≥65 appeared to have less active management/monitoring of their disease. Medical attention should be directed to this population to address evolving needs over time. ABBREVIATIONS: AcroMEDIC = Acromegaly Multisite Electronic Data Innovative Consortium; BMI = body mass index; CCI = Charlson Comorbidity Index; EHR = electronic health record; GH = growth hormone; GHRA = growth hormone receptor antagonist; ICD-9 = International Classification of Diseases, 9th revision; IGF-1 = insulin-like growth factor-1; SSA = somatostatin analogue.

Hyperglycemia induced by pasireotide in patients with Cushing's disease or acromegaly.

PURPOSE: Cushing's disease (CD) and acromegaly are characterized by excessive hormone secretion resulting in comorbidities such as impaired glucose metabolism, diabetes and hypertension. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous [SC] injection formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia-related adverse events (AEs) were frequently observed. This review highlights differences in reported rates of hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia. METHODS: Clinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed. RESULTS: The frequency of hyperglycemia-related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3-67.0 %) than in patients with CD treated with pasireotide SC (68.4-73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia-related AEs (Colao et al. in J Clin Endocrinol Metab 99(3):791-799, 2014, 3.4 %; Gadelha et al. in Lancet Diabetes Endocrinol 2(11):875-884, 2014, 4.0 %) than did patients with CD treated with pasireotide SC (Boscaro et al. in Pituitary 17(4):320-326, 2014, 5.3 %; Colao et al. in N Engl J Med 366(10):914-924, 2012, 6.0 %). Hyperglycemia-related AEs occurred in 40.0 % of patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia. Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively) will address these key safety issues. CONCLUSIONS: Disease pathophysiology, drug formulation, and physician experience potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly. Hyperglycemic effects associated with pasireotide have a predictable pattern, can be managed with antidiabetic agents, and are reversible upon discontinuation.

Need for improved monitoring in patients with acromegaly.

Acromegaly is a rare and insidious disease characterized by the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF1) and is most commonly due to a pituitary adenoma. Patients with acromegaly who experience prolonged exposure to elevated levels of GH and IGF1 have an increased mortality risk and progressive worsening of disease-related comorbidities. Multimodal treatment with surgery, medical therapy, and radiotherapy provides biochemical control, defined by recent acromegaly clinical guidelines from the Endocrine Society as a reduction of GH levels to <1.0 ng/ml and normalization of IGF1 levels, to a substantial proportion of patients and is associated with improved clinical outcomes. Patients with acromegaly, even those without clinical symptoms of disease, require long-term monitoring of GH and IGF1 levels if the benefits associated with biochemical control are to be maintained and the risk of developing recurrent disease is to be abated. However, suboptimal monitoring is common in patients with acromegaly, and this can have negative health effects due to delays in detection of recurrent disease and implementation of appropriate treatment. Because of the significant health consequences associated with prolonged exposure to elevated levels of GH and IGF1, optimal monitoring in patients with acromegaly is needed. This review article will discuss the biochemical assessments used for therapeutic monitoring in acromegaly, the importance of monitoring after surgery and medical therapy or radiotherapy, the consequences of suboptimal monitoring, and the need for improved monitoring algorithms for patients with acromegaly.

Combined high-field intraoperative magnetic resonance imaging and endoscopy increase extent of resection and progression-free survival for pituitary adenomas.

PURPOSE: The clinical benefit of combined intraoperative magnetic resonance imaging (iMRI) and endoscopy for transsphenoidal pituitary adenoma resection has not been completely characterized. This study assessed the impact of microscopy, endoscopy, and/or iMRI on progression-free survival, extent of resection status (gross-, near-, and sub-total resection), and operative complications. METHODS: Retrospective analyses were performed on 446 transsphenoidal pituitary adenoma surgeries at a single institution between 1998 and 2012. Multivariate analyses were used to control for baseline characteristics, differences during extent of resection status, and progression-free survival analysis. RESULTS: Additional surgery was performed after iMRI in 56/156 cases (35.9%), which led to increased extent of resection status in 15/156 cases (9.6%). Multivariate ordinal logistic regression revealed no increase in extent of resection status following iMRI or endoscopy alone; however, combining these modalities increased extent of resection status (odds ratio 2.05, 95% CI 1.21-3.46) compared to conventional transsphenoidal microsurgery. Multivariate Cox regression revealed that reduced extent of resection status shortened progression-free survival for near- versus gross-total resection [hazard ratio (HR) 2.87, 95% CI 1.24-6.65] and sub- versus near-total resection (HR 2.10; 95% CI 1.00-4.40). Complication comparisons between microscopy, endoscopy, and iMRI revealed increased perioperative deaths for endoscopy versus microscopy (4/209 and 0/237, respectively), but this difference was non-significant considering multiple post hoc comparisons (Fisher exact, p = 0.24). CONCLUSIONS: Combined use of endoscopy and iMRI increased pituitary adenoma extent of resection status compared to conventional transsphenoidal microsurgery, and increased extent of resection status was associated with longer progression-free survival. Treatment modality combination did not significantly impact complication rate.

Pharmacologic amelioration of severe hypoglycemia-induced neuronal damage.

Hypoglycemia is a common complication for insulin treated people with diabetes. Severe hypoglycemia, which occurs in the setting of excess or ill-timed insulin administration, has been shown to cause brain damage. Previous pre-clinical studies have shown that memantine (an N-methyl-d-aspartate receptor antagonist) and erythropoietin can be neuroprotective in other models of brain injury. We hypothesized that these agents might also be neuroprotective in response to severe hypoglycemia-induced brain damage. To test this hypothesis, 9-week old, awake, male Sprague-Dawley rats underwent hyperinsulinemic (0.2 U kg(-1)min(-1)) hypoglycemic clamps to induce severe hypoglycemia (blood glucose 10-15 mg/dl for 90 min). Animals were randomized into control (vehicle) or pharmacological treatments (memantine or erythropoietin). One week after severe hypoglycemia, neuronal damage was assessed by Fluoro-Jade B and hematoxylin and eosin staining of brain sections. Treatment with both memantine and erythropoietin significantly decreased severe hypoglycemia-induced neuronal damage in the cortex by 35% and 39%, respectively (both p<0.05 vs. controls). These findings demonstrate that memantine and erythropoietin provide a protective effect against severe hypoglycemia-induced neuronal damage.

Recurrent moderate hypoglycemia ameliorates brain damage and cognitive dysfunction induced by severe hypoglycemia.

OBJECTIVE: Although intensive glycemic control achieved with insulin therapy increases the incidence of both moderate and severe hypoglycemia, clinical reports of cognitive impairment due to severe hypoglycemia have been highly variable. It was hypothesized that recurrent moderate hypoglycemia preconditions the brain and protects against damage caused by severe hypoglycemia. RESEARCH DESIGN AND METHODS: Nine-week-old male Sprague-Dawley rats were subjected to either 3 consecutive days of recurrent moderate (25-40 mg/dl) hypoglycemia (RH) or saline injections. On the fourth day, rats were subjected to a hyperinsulinemic (0.2 units x kg(-1) x min(-1)) severe hypoglycemic ( approximately 11 mg/dl) clamp for 60 or 90 min. Neuronal damage was subsequently assessed by hematoxylin-eosin and Fluoro-Jade B staining. The functional significance of severe hypoglycemia-induced brain damage was evaluated by motor and cognitive testing. RESULTS: Severe hypoglycemia induced brain damage and striking deficits in spatial learning and memory. Rats subjected to recurrent moderate hypoglycemia had 62-74% less brain cell death and were protected from most of these cognitive disturbances. CONCLUSIONS: Antecedent recurrent moderate hypoglycemia preconditioned the brain and markedly limited both the extent of severe hypoglycemia-induced neuronal damage and associated cognitive impairment. In conclusion, changes brought about by recurrent moderate hypoglycemia can be viewed, paradoxically, as providing a beneficial adaptive response in that there is mitigation against severe hypoglycemia-induced brain damage and cognitive dysfunction.

Primary care physicians' decisions about discharging patients from their practices.

OBJECTIVE: There are few data available about factors which influence physicians' decisions to discharge patients from their practices. To study general internists' and family medicine physicians' attitudes and experiences in discharging patients from their practices. DESIGN: A cross-sectional mailed survey was used. PARTICIPANTS: One thousand general internists and family medicine physicians participated in this study. MEASUREMENTS AND MAIN RESULTS: We studied the likelihood physicians would discharge 12 hypothetical patients from their practices, and whether they had actually discharged such patients. The effect of demographic data on the number of scenarios in which patients were likely to be discharged, and the number of patients actually discharged were analyzed via ANOVA and multiple logistic regression analysis. Of 977 surveys received by subjects, 526 (54%) were completed and returned. A majority of respondents were willing to discharge patients in 5 of 12 hypothetical scenarios. Eighty-five percent had actually discharged at least one patient from their practices. Most respondents (71%) had discharged 10 or fewer patients, but 14% had discharged 11 to 200 patients. Respondents who were in private practice (p < 0.000001) were more likely to discharge both hypothetical and actual patients from their practices. Older physicians (> or =48 years old) were more likely to discharge actual patients from their practices (p = 0.005) as were physicians practicing in rural settings (p = 0.003). CONCLUSIONS: Most physicians in our sample were willing to discharge actual and hypothetical patients from their practices. This tendency may have significant implications for the initiation of pay-for-performance programs. Physicians should be educated about the importance of the patient-physician relationship and their fiduciary obligations to the patient.

Continuity clinic satisfaction and valuation in residency training.

BACKGROUND: Internal Medicine residency training in ambulatory care has been judged inadequate, yet how trainees value continuity clinic and which aspects of clinic affect attitudes are unknown. OBJECTIVES: To determine the value that Internal Medicine residents place on continuity clinic and how clinic precepting, operations, and patient panels affect its valuation. DESIGN AND MEASUREMENTS: A survey on ambulatory care was developed, including questions on career choice and the value of clinical training experiences. Independent variables were Likert-scale ratings (1 = disagree strongly/no value; 3 = neutral; 5 = agree strongly/high value) on preceptors, patients, operations, and resident characteristics. Odds ratios and stepwise multivariate logistic regression with clustering were used to evaluate associations between clinic valuation and independent variables. SUBJECTS: Internal medicine residents at 3 residency programs. RESULTS: 218 of 260 residents (83.8%) completed the survey. Resident ratings were highest on diversity of illness seen (4.1), medical record systems used (4.1), and contact with preceptors who were receptive to questions (4.8). Resident ratings were lowest on economic diversity of patients (2.7), interruptions from inpatient wards (3.1), and contact with preceptors who taught history and physical exam skills (3.5). High ratings on all precepting issues and nearly all operational issues were associated with valuing clinic. With multivariate analysis, high ratings of preceptors as role models were most strongly associated with valuing clinic (corrected relative risk 3.44). A planned career in general Internal Medicine was not associated with valuing clinic. CONCLUSIONS: Satisfaction with preceptors, particularly as role models, and clinic operations correlate with the value residents place on continuity clinic.