Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

A Novel Preoperative Score to Predict Long-Term Biochemical Remission in Patients with Growth-Hormone Secreting Pituitary Adenomas.

OBJECTIVE: Transsphenoidal surgery (TSS) is considered the treatment of choice in most patients with growth hormone (GH)-secreting pituitary adenomas. Several preoperative factors have been studied to predict postsurgical remission. Our objective was to design a score that could be used in the preoperative setting to identify patients that will achieve long-term biochemical remission after TSS. METHODS: A retrospective analysis of consecutive patients with GH-secreting pituitary adenomas that underwent TSS in our institution from 2000 to 2015 who fulfilled prespecified criteria were included. Logistic regression methods were used to evaluate independent preoperative variables predicting long-term remission. Beta coefficients were used to create a scoring system for clinical practice. RESULTS: Sixty-eight patients were included, with a mean follow-up time of 87 months. Twenty (29%) patients had tumors with a Knosp grade ≥ 3A. Gross-total resection was achieved in 43 (63%) patients. Thirty-three (48%) patients had long-term biochemical remission after TSS. In a multivariate analysis, the following variables were statistically significantly associated with long-term biochemical remission: age, adenoma size (diameter), Knosp grade, GH level, and insulin growth-factor 1index 1 at diagnosis. A score of <3 out of 8 total points was identified as a cutoff associated with long-term remission, with a sensitivity of 91.4% and specificity of 72.7% (AUC 0.867, OR 28.44, 95% CI 6.94-116.47, P = < 0.001). CONCLUSIONS: A novel, simple, easy-to-use scoring system was created to identify patients with the highest chances of long-term biochemical remission following TSS. This scale should be prospectively validated in a multicenter study before widespread adoption.

Postsurgical utility of copeptin for the prediction of postoperative arginine vasopressin deficiency.

OBJECTIVE: Arginine vasopressin deficiency (AVD) following neurosurgical procedures for pituitary disorders is common and can delay discharge. Copeptin, a stable surrogate marker of arginine vasopressin, may predict postoperative AVD. The authors' aim was to assess the optimal postoperative sampling time and cut-point concentration of copeptin to predict the development of postsurgical AVD. METHODS: Adults without preexisting AVD who were undergoing surgery for a pituitary lesion between February 2020 and April 2022 were eligible for study inclusion. Two samples were drawn from each patient postoperatively to assess the copeptin concentration using an immunofluorescent assay. Samples were denoted as "early" (within 6 hours of extubation) or "postoperative day 1" (POD1; within 10-30 hours of extubation). Patients were evaluated for the development of AVD. RESULTS: One hundred ninety-two patients (54.2% female) with a median age of 54.5 years (IQR 39.8-67.0 years) were included in the study. The median copeptin concentration at both time points was significantly lower in those with AVD (transient or permanent; n = 22, 11.5%) than in those without (early: 4.9 vs 18.7 pmol/L, p < 0.001; POD1: 3.4 vs 4.9 pmol/L, p < 0.001) but did not differ in those who developed transient versus permanent AVD. The optimal copeptin cut point for the prediction of AVD was < 8.5 pmol/L for early samples (sensitivity 0.70, specificity 0.80, positive predictive value [PPV] 0.29, negative predictive value [NPV] 0.96) and < 4.3 pmol/L for POD1 samples (sensitivity 0.82, specificity 0.63, PPV 0.22, NPV 0.96). In early samples, a copeptin cutoff of 22.9 pmol/L increased the sensitivity for the detection of AVD to 95% with an NPV of 99%. The proportion of patients who had AVD was higher (60.0% vs 8.8%, p < 0.001) and the copeptin concentration lower (early: 4.3 vs 17.0 pmol/L, p < 0.001; POD1: 2.7 vs 4.9 pmol/L, p < 0.001) among those who had undergone surgery for a craniopharyngeal duct pathology versus a pituitary adenoma. Although copeptin was lower in patients with persistent Cushing's disease than in those in remission, the difference did not reach statistical significance (early p = 0.11, POD1 p = 0.52). Furthermore, the copeptin concentration could not predict the development of syndrome of inappropriate secretion of antidiuretic hormone. Patients without AVD who had received stress dose steroids intraoperatively had lower median early copeptin (11.7 vs 19.1 pmol/L, p = 0.027). CONCLUSIONS: In early postoperative copeptin samples, the optimal copeptin cut point for AVD diagnosis was < 8.5 pmol/L, and a level > 22.9 pmol/L had predicative utility in excluding AVD. Caution should be used when interpreting copeptin results, as patients administered glucocorticoids intraoperatively without AVD had lower median copeptin concentrations.

Pregnancy-related hypophysitis revisited.

OBJECTIVE: The aim of the study is to assess the distinguishing features of pregnancy-related hypophysitis (PR-Hy) compared to non-pregnancy autoimmune hypophysitis and to evaluate the changing therapeutic approaches and outcomes in PR-Hy over time. DESIGN: Retrospective analysis of all published cases with PR-Hy and 6 own cases. METHODS: A PubMed search was performed and abstracts screened for publications with information on cases with PR-Hy from which full-text review was performed. Clinical features, diagnostic findings, and outcome in relation to treatment modalities in PR-Hy were assessed. RESULTS: One hundred and forty-eight cases with PR-Hy were identified. PR-Hy was significantly delimited from non-PR-Hy by the frequent occurrence of the chiasmal syndrome (50% vs 13%, P < .0001), higher rate of intrasellar origin (94% vs 74%, P = .0005), lower rate of pituitary stalk involvement (39% vs 86%, P < .0001), and low rate of diabetes insipidus (12% vs 54%, P < .0001). The role of surgery in PR-Hy decreased over time while noninvasive treatment modalities increased. The recurrence rate after high-dose glucocorticoid therapy (33%) was high and exceeded that of surgery (2%) and conservative management (2%). In contrast to initial reports on PR-Hy, recent literature regarding outcome of mother's and child's health was positive. The frequency of spontaneous preterm delivery was not increased. Recurrent PR-Hy in a subsequent pregnancy was reported in only two females. CONCLUSION: PR-Hy has distinct features that delineate the disorder from non-PR-Hy. With increasing experience in diagnosis, availability of adequate replacement therapy, and improved treatment modalities, PR-Hy has lost its threat and the outcome is encouraging.

Hyperphosphatemic Tumoral Calcinosis With Pemigatinib Use.

Background/Objective: Pemigatinib, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, is a novel therapeutic approach for treating cholangiocarcinoma when an FGFR fusion or gene rearrangement is identified. Although the most reported side effect of pemigatinib is hyperphosphatemia, tumoral calcinosis with soft tissue calcifications is not widely recognized as a complication. We report a case of patient with hyperphosphatemic tumoral calcinosis on pemigatinib. Case Report: A 59-year-old woman with progressive metastatic cholangiocarcinoma, despite receiving treatment with cisplatin and gemcitabine for 7 months, was found to have an FGFR2-BICC1 fusion in the tumor on next-generation sequencing. Pemigatinib was, therefore, initiated. Four months into the therapy, multiple subcutaneous nodules developed over the lower portion of her back, hips, and legs. Punch biopsies revealed deep dermal and subcutaneous calcifications. Investigations revealed elevated serum phosphorus (7.5 mg/dL), normal serum calcium (8.7 mg/dL), and elevated intact fibroblast growth factor-23 (FGF23, 1216 pg/mL; normal value <59 pg/mL) levels. Serum phosphorus levels improved with a low-phosphorus diet and sevelamer. Calcifications regressed with pemigatinib discontinuation. Discussion: Inhibition or deficiency of FGF-23 results in hyperphosphatemia and can lead to ectopic calcification. Pemigatinib, a potent inhibitor of FGFR-1-3, blocks the effect of FGF-23 leading to hyperphosphatemia and tumoral calcinosis as observed in our case. Treatment is aimed primarily at lowering serum phosphate levels through dietary restriction or phosphate binders; however, the regression of tumoral calcinosis can occur with pemigatinib cessation, as seen in this case. Conclusion: As the use of FGFR 1-3 inhibitors becomes more prevalent, we aim to raise attention to the potential side effects of tumoral calcinosis.

Revisiting Pituitary Apoplexy.

Pituitary apoplexy (PA) is a rare clinical syndrome due to pituitary hemorrhage or infarction. It is characterized by the sudden onset of one or more of the following: severe headache, visual disturbance, nausea/vomiting, and or altered mental status. Most commonly, PA occurs in an underlying pituitary adenoma. The pathophysiology is not fully understood, but it is thought to involve elements of increased metabolic demand and/or compromise to the vasculature of the pituitary or pituitary tumor. Several risk factors have been described. Stabilization of the patient on presentation, replacement of hormonal deficiencies, and reversal of electrolyte abnormalities are the recommended initial steps in the management of patients with PA. Surgical decompression of the mass effect had been the recommended treatment for patients with PA; however, retrospective studies of patients with PA have demonstrated similar outcomes when a conservative approach is applied. This suggests that in highly selected clinical scenarios (mild visual deficit and improving symptoms), conservative management is possible. Further studies, however, are necessary to better stratify patients but are limited by the rarity of the condition and the acuity.

Long-term outcomes in patients with adult-onset craniopharyngioma.

PURPOSE: Craniopharyngiomas are nonmalignant sellar and parasellar tumors exhibiting a bimodal age distribution. While the outcomes following treatment in patients with childhood-onset craniopharyngiomas are well characterized, similar information in adult-onset craniopharyngiomas is limited. We aimed to describe the long-term outcomes (weight and metabolic parameters, mortality) in patients with adult-onset craniopharyngioma following treatment. METHODS: Patients with adult-onset craniopharyngioma with initial treatment (1993-2017) and >6 months of follow-up at our institution were retrospectively identified. Body mass index (BMI) categories included obese (BMI ≥ 30 kg/m2), overweight (BMI 25-29.9 kg/m2), and normal weight (BMI < 25 kg/m2). RESULTS: For the 91 patients with adult-onset craniopharyngioma (44% women, mean diagnosis age 48.2 ± 18 years) over a mean follow-up of 100.3 ± 69.5 months, weight at last follow-up was significantly higher than before surgery (mean difference 9.5 ± 14.8 kg, P < 0.001) with a higher percentage increase in weight seen in those with lower preoperative BMI (normal weight (20.7 ± 18%) vs. overweight (13.3 ± 18.0%) vs. obese (6.4 ± 15%), P = 0.012). At last follow-up, the prevalence of obesity (62 vs. 40.5%, P = 0.0042) and impaired glucose metabolism (17.4% vs. 34%, P = 0.017) increased significantly. All-cause mortality was 12%, with the average age of death 71.9 ± 19.7 years (average U.S. life expectancy 77.7 years, CDC 2020). CONCLUSION: Patients with adult-onset craniopharyngioma following treatment may experience weight gain, increased prevalence of obesity, impaired glucose metabolism, and early mortality. Lower preoperative BMI is associated with a greater percentage increase in postoperative weight.

Hypophysitis.

OBJECTIVE: Hypophysitis is considered a rare inflammatory disease of the pituitary gland. For a long time, primary autoimmune hypophysitis has stood out as the most relevant type of hypophysitis. However, with the advent of immunotherapy for the treatment of malignancies and identification of hypophysitis as an immune-related adverse event, hypophysitis has garnered increasing interest and recognition. Therefore, awareness, early recognition, and appropriate management are becoming important as the indication for immunomodulatory therapies broaden. METHODS: In this review, we discuss the epidemiology, diagnosis, and treatment of hypophysitis with a focus on recent data and highlight subtypes of particular interest while recognizing the gaps in knowledge that remain. RESULTS: Regardless of cause, symptoms and signs of hypophysitis may be related to mass effect (headache and visual disturbance) and hormonal disruption that warrant prompt evaluation. In the vast majority of cases, a diagnosis of hypophysitis can be made presumptively in the appropriate clinical context with radiologic findings consistent with hypophysitis and after the exclusion of other causes. CONCLUSION: Although subtle differences currently exist in management and outcome expectations between primary and secondary causes of hypophysitis, universally, treatment is aimed at symptom management and hormonal replacement therapy.

Outcome of Dopamine Agonist Therapy Withdrawal in Children with Prolactinomas.

BACKGROUND: Prolactinomas are rare in children and adolescents. As in adults, dopamine agonists (DAs) are the treatment of choice in the majority of patients. However, at what point children should be taken off of therapy and what the recurrence risk of hyperprolactinemia is following treatment withdrawal is not well described. OBJECTIVE: Our objective was to systematically review our experience with DA treatment withdrawal in children and adolescents with prolactinomas. METHODS: A retrospective review of patients followed for prolactinomas during the last 12 years was conducted. Variables analyzed included age, gender, initial serum prolactin levels, tumor characteristics, cabergoline dose, and results of treatment withdrawal. Clinical characteristics of patients who met eligibility criteria for DA withdrawal were compared with those who did not. Patients who underwent surgery were excluded. RESULTS: Of 47 patients identified, 42 were included in the study. Of those, DA withdrawal was attempted in 13 (31%) and was initially successful in 3 (21%). Patients who did not meet eligibility criteria for treatment withdrawal had higher baseline prolactin levels (p = 0.018) as well as larger (p = 0.03) and more invasive (p = 0.002) tumors. CONCLUSIONS: Less than half of our patients were eligible for DA treatment withdrawal and less than one-fourth achieved remission of hyperprolactinemia following cessation of therapy. This suggests that the overall recurrence rate of prolactinomas in pediatric patients may be higher than has been reported in adults.

Outcomes of Initial Management Strategies in Patients With Autoimmune Lymphocytic Hypophysitis: A Systematic Review and Meta-analysis.

CONTEXT: Lymphocytic hypophysitis (LyHy) is characterized by inflammation of the pituitary and or neuroinfundibulum and is uncommon. Treatment options include observation, high-dose glucocorticoids (HD-GCs) or surgery. Optimal first-line management strategy, however, remains unknown. OBJECTIVE: This work aimed to assess response to first-line treatment options (observation, HD-GCs, or surgery) of clinically relevant outcomes (symptomatic, hormonal, and radiographic improvement) among patients with LyHy. METHODS: A systematic review was conducted in 6 databases through 2020. Meta-analysis was conducted when feasible using a random-effects model. RESULTS: We included 33 studies reporting on 591 patients (423 women, 72%) with LyHy. Improvement/resolution of anterior pituitary dysfunction was highest when HD-GCs was first-line treatment. Surgery was associated with the greatest proportion of patients who had regression on imaging. Subgroup analysis comparing HD-GCs to observation showed the odds of anterior pituitary hormone recovery (OR 3.41; 95% CI, 1.68-6.94) or radiographic regression (OR 3.13; 95% CI, 1.54-6.36) were higher with HD-GCs, but so was the need for additional forms of treatment (OR 4.37; 95% CI, 1.70-11.22). No statistically significant difference was seen in recovery of diabetes insipidus (OR 0.9; 95% CI, 0.26-3.10). Certainty in these estimates was very low. CONCLUSION: Observation and use of HD-GCs both are successful first-line management strategies in LyHy. Although use of HD-GCs was associated with increased recovery of anterior pituitary hormone deficit, it also was associated with greater likelihood of additional treatment after withdrawal. Optimal dosing and duration of HD-GCs remains unknown.

Insulin-Like Growth Factor 1 in the Early Postoperative Assessment of Acromegaly.

OBJECTIVES: Assessment of surgical outcome in acromegaly is typically recommended at 3 to 6 months following surgery. The purpose of this study was to determine if insulin-like growth factor 1 (IGF-1) concentrations at 6 weeks were equally predictive of surgical outcomes compared with IGF-1 concentrations at 3 to 6 months postoperatively applying newer IGF-1 assays. METHODS: Retrospective review of patients with newly diagnosed acromegaly who had surgery between 2013 and 2020 and had postoperative IGF-1 measured by 6 weeks and 3 to 6 months. RESULTS: At 6 weeks, 20 (35%) of the total 57 had normal IGF-1 and became abnormal in 1 at 3 to 6 months, whereas 37 (65%) of 57 had abnormal IGF-1 concentrations at 6 weeks, which normalized in 1 patient by 3 to 6 months. In patients who changed clinical status, IGF-1 at 6 weeks was within ±0.1-fold of normal. Although a difference was seen between median IGF-1 concentrations (286 vs 267 ng/mL, P = .009) at 6 weeks and 3 to 6 months, the mean reduction was small (-19.9 ng/mL). CONCLUSIONS: Compared with 3 to 6 months, use of IGF-1 at 6 weeks was associated with a change in clinical status in 3.5% of patients. Therefore, in most patients, IGF-1 at 6 weeks can be used to assess clinical outcome via newer assays.

The Need for Patient-centered Education Among Patients Newly Diagnosed With a Pituitary Tumor.

OBJECTIVES: Brain tumors, including pituitary adenomas (PA), cause anxiety and distress, with a high unmet need for information correlating with increased anxiety. Condition-specific education may alleviate anxiety. We explored patients' experience around the diagnosis of a PA and piloted a patient education intervention to address peridiagnostic anxiety in adults diagnosed with PA. METHODS: Anxiety, patient satisfaction, patient knowledge, and need for information were measured prior to, immediately after, and 1 month following the appointment in this multimethods study. A phone interview to explore patient diagnostic and intervention experiences was analyzed using qualitative methods. RESULTS: A total of 17 patients participated in the study; 15 completed the interview. The baseline need for information was high. Disease-specific anxiety decreased, and patient knowledge and satisfaction increased significantly after the initial visit. Interview analysis identified 3 main themes: (1) the importance of communication; (2) the need for information; and (3) the impact of the diagnosis on patient experience. CONCLUSIONS: For patients with newly diagnosed PA, the diagnostic experience was associated with high levels of anxiety. Patients expressed a need for information. Information delivery reduced anxiety and had a positive impact on patient satisfaction. PRACTICE IMPLICATIONS: The study findings suggest a need for a streamlined diagnostic process with readily accessible information.

Diagnosis and Management of Neuroendocrine Disorders of Survivors of Brain Tumors.

Advances in the treatment of brain tumors have led to an increase in the number of survivors of this disease. Consequently, the long-term complications associated with past and current treatments are becoming more apparent. Of relevance to patients who receive treatment of brain tumors are the potential neuroendocrine complications that develop either acutely or several years following treatment. Presentation may differ between adults and children (e.g., short stature or adult growth hormone deficiency) but in both settings can complicate treatment and impact quality of life. The risk for the development of these complications depends on the location of the tumor (proximity to the pituitary/hypothalamus) and/or the treatment delivered (chemotherapy/surgery/radiation). Given the potential overlap in symptoms attributable to the underlying brain tumor and neuroendocrine dysfunction, a high level of suspicion, appropriate investigation, and administration of treatment may reduce morbidity and mortality for patients with brain tumors experiencing neuroendocrine dysfunction.

Mifepristone as Bridge or Adjunct Therapy in the Management of Challenging Cushing Disease Cases.

Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical heterogeneity, initiating effective treatment to control the effects of hypercortisolism, and managing recurrence are challenging disease aspects to address. Mifepristone is a competitive glucocorticoid receptor antagonist that is approved in the US by the Food and Drug Administration to control hyperglycemia secondary to endogenous hypercortisolism (Cushing syndrome) in patients who have glucose intolerance or type 2 diabetes mellitus and have failed surgery or are not candidates for surgery. Herein, we describe 6 patients with CD who received mifepristone as adjunct/bridge therapy in the following clinical settings: to assess clinical benefits of treatment for suspected recurrent disease, to control hypercortisolism preoperatively for severe disease, to control hypercortisolism during the COVID-19 pandemic, and to provide adjunctive treatment to radiation therapy. The patients were treated at multiple medical practice settings. Mifepristone treatment in each of the described cases was associated with clinical improvements, including improvements in overall glycemia, hypertension, and weight loss. In addition, in one case where biochemical and radiological evidence of disease recurrence was uncertain, clinical improvement with mifepristone pointed toward likely disease recurrence. Adverse events associated with mifepristone reported in the 6 cases were consistent with those previously reported in the pivotal trial and included cortisol withdrawal symptoms, antiprogesterone effects (vaginal bleeding), hypothyroidism (treated with levothyroxine), and hypokalemia (treated with spironolactone). These cases show how mifepristone can potentially be utilized as a therapeutic trial in equivocal cases of CD recurrence; as a presurgical treatment strategy, particularly during the COVID-19 pandemic; and as bridge therapy, while awaiting the effects of radiation.

Association Between Prolactinoma and Body Mass Index.

OBJECTIVE: Obesity is increasing worldwide, and certain endocrine disorders may contribute to weight gain. While several studies have examined the association between weight gain and prolactinomas, the results are conflicting. Therefore, this study aimed to determine if body mass index (BMI) is higher among those with prolactinomas than those without. METHODS: We identified patients ≥18 years of age referred to an endocrine clinic between 2008 and 2018 with newly diagnosed prolactinomas. We extracted the relevant information, and comparative data was obtained from the 2015-2016 National Health and Nutrition Examination Survey. RESULTS: In total, 34 cases met the inclusion criteria. One third of the patients described weight gain at presentation. Those with prolactinomas had a significantly higher BMI than the National Health and Nutrition Examination Survey population (median BMI, 29.8 kg/m2 vs 28.3 kg/m2, P = .0048). When stratified by sex, only men with prolactinomas had an increased BMI compared with the controls. Moreover, those with prolactinomas had a higher prevalence of class II obesity (BMI ≥ 35 kg/m2) than the survey population (35% vs 18%, P = .01). Among the prolactinoma patients, a correlation was observed between BMI and log-transformed prolactin levels (R2 = 0.4, P = .0002). CONCLUSION: Weight gain can be a presenting symptom for patients with newly diagnosed prolactinomas. Those with prolactinomas have a higher BMI and an increased prevalence of class II obesity. These findings suggest that patients should be counseled regarding weight issues related to prolactinomas at presentation and should be a consideration in the investigative and treatment algorithm of prolactinomas.

Clinical, biological, radiological, and pathological comparison of sparsely and densely granulated somatotroph adenomas: a single center experience from a cohort of 131 patients with acromegaly.

PURPOSE: Growth hormone-producing pituitary adenomas are divided into two clinically relevant histologic subtypes, densely (DG-A) and sparsely (SG-A) granulated. Histologic subtype was evaluated in a large cohort of patients with acromegaly, separating DG-A and SG-A, and correlated with clinicopathological characteristics. METHODS: Patients with acromegaly undergoing surgery as initial therapy between 1995 and 2015 were identified. Histologic subtype was determined by keratin expression pattern with CAM5.2 and correlated with clinical and imaging parameters, somatostatin receptor subtype 2 (SST2) expression, post-surgical remission rate, and application of a prognostic scoring system incorporating proliferation and invasiveness. RESULTS: One hundred thirty-one patients were included. Tumors were classified as DG-A (75, 57.3%), SG-A (29, 22.1%), intermediate (I-A) (9, 6.9%), and unclassified (18, 13.7%) when CAM5.2 was negative. DG-A and I-A were combined for analysis (DG/I-A) and compared to SG-A. Age, gender, proliferation, and post-surgical remission did not differ. SG-A were larger [2 vs. 1.5 cm (median), p = 0.03], more frequently invasive [65.5% vs. 32.9%, p = 0.004], associated with higher MRI T2-weighted signal ratio [1.01 vs. 0.82 (median), p = 0.01], showed lower SST2 expression (p < 0.0001), and scored higher in the prognostic classification (p = 0.004). Surgical remission occurred in 41.7% DG/I-A and 41.4% SG-A (p = 1.0). On multivariate analysis, absence of invasion (p = 0.009) and lower pre-operative IGF-1 index (p = 0.0002) were associated with post-surgical remission. CONCLUSION: CAM5.2 allowed distinction between DG/I-A and SG-A in most but not all cases. Histologic subtype did not predict surgical outcome. Absence of invasion and lower pre-operative IGF-1 index were the only significant predictors of post-surgical remission in this cohort.

Prevalence of Opioid-Induced Adrenal Insufficiency in Patients Taking Chronic Opioids.

CONTEXT: Chronic opioid use may lead to adrenal insufficiency because of central suppression of the hypothalamic-pituitary-adrenal axis. However, the prevalence of opioid-induced adrenal insufficiency (OIAI) is unclear. OBJECTIVE: To determine the prevalence of OIAI and to identify predictors for the development of OIAI in patients taking opioids for chronic pain. DESIGN: Cross-sectional study, 2016-2018. SETTING: Referral center. PATIENTS: Adult patients taking chronic opioids admitted to the Pain Rehabilitation Center. MAIN OUTCOME MEASURE: Diagnosis of OIAI was considered if positive case detection (cortisol < 10 mcg/dL, ACTH < 15 pg/mL, and dehydroepiandrosterone sulfate < 25 mcg/dL), and confirmed after endocrine evaluation. Daily morphine milligram equivalent (MME) was calculated. RESULTS: In 102 patients (median age, 53 years [range, 22-83], 67% women), median daily MME was 60 mg (3-840), and median opioid therapy duration was 60 months (3-360). Abnormal case detection testing was found in 11 (10.8%) patients, and diagnosis of OIAI was made in 9 (9%). Patients with OIAI were on a higher daily MME (median, 140 [20-392] mg vs 57 [3-840] mg, P = 0.1), and demonstrated a 4 times higher cumulative opioid exposure (median of 13,440 vs 3120 mg*months, P = 0.03). No patient taking  20 mg); however, specificity of MME cutoff >20 mg was only 19%. After opioid discontinuation, 6/7 patients recovered adrenal function. CONCLUSION: The prevalence of OIAI was 9%, with MME cumulative exposure being the only predictor for OIAI development. Patients on MME of 20 mg/day and above should be monitored for OIAI.

The Impact of Insulin-Like Growth Factor Index and Biologically Effective Dose on Outcomes After Stereotactic Radiosurgery for Acromegaly: Cohort Study.

BACKGROUND: Stereotactic radiosurgery (SRS) is a safe and effective treatment for acromegaly. OBJECTIVE: To improve understanding of clinical and dosimetric factors predicting biochemical remission. METHODS: A single-institution cohort study of nonsyndromic, radiation-naïve patients with growth hormone-producing pituitary adenomas (GHA) having single-fraction SRS between 1990 and 2017. Exclusions were treatment with pituitary suppressive medications at the time of SRS, or <24 mo of follow-up. The primary outcome was biochemical remission-defined as normalization of insulin-like growth factor-1 index (IGF-1i) off suppression. Biochemical remission was assessed using Cox proportional hazards. Prior studies reporting IGF-1i were assessed via systematic literature review and meta-analysis using random-effect modeling. RESULTS: A total of 102 patients met study criteria. Of these, 46 patients (45%) were female. The median age was 49 yr (interquartile range [IQR] = 37-59), and the median follow-up was 63 mo (IQR = 29-100). The median pre-SRS IGF-1i was 1.66 (IQR = 1.37-3.22). The median margin dose was 25 Gy (IQR = 21-25); the median estimated biologically effective dose (BED) was 169.49 Gy (IQR = 124.95-196.00). Biochemical remission was achieved in 58 patients (57%), whereas 22 patients (22%) had medication-controlled disease. Pre-SRS IGF-1i ≥ 2.25 was the strongest predictor of treatment failure, with an unadjusted hazard ratio (HR) of 0.51 (95% CI = 0.26-0.91, P = .02). Number of isocenters, margin dose, and BED predicted remission on univariate analysis, but after adjusting for sex and baseline IGF-1i, only BED remained significant-and was independently associated with outcome in continuous (HR = 1.01, 95% CI = 1.00-1.01, P = .02) and binary models (HR = 2.27, 95% CI = 1.39-5.22, P = .002). A total of 24 patients (29%) developed new post-SRS hypopituitarism. Pooled HR for biochemical remission given subthreshold IGF-1i was 2.25 (95% CI = 1.33-3.16, P < .0001). CONCLUSION: IGF-1i is a reliable predictor of biochemical remission after SRS. BED appears to predict biochemical outcome more reliably than radiation dose, but confirmatory study is needed.