Tumor T2 signal intensity and stalk angulation correlates with endocrine status in pituitary adenoma patients: a quantitative 7 tesla MRI study.

PURPOSE: Pituitary adenomas are common CNS tumors that can cause endocrine dysfunction due to hormone oversecretion and by mass effect on the normal gland. The study of pituitary adenomas and adjacent sellar anatomy with high-resolution 7 T MRI may further characterize endocrine dysfunction. The purpose of this study was to determine the efficacy of 7 T MRI in identifying radiological markers for endocrine function. METHODS: MR images obtained in 23 patients with pituitary adenomas were reviewed by consensus between three neuroradiologists. Landmarks and criteria were devised to measure radiological features of stalk, tumor, and normal gland. Fischer's exact tests and nominal logistic regression were performed. RESULTS: Mean cross-sectional area of the stalk just below the infundibular recess was 6.3 ± 3.7 mm2. Mean curvature and deviation angles were 34.2° ± 23.2° and 29.7° ± 17.3°, respectively. Knosp scores obtained differed between 7 T and lower field strength scans (P < 0.0001 [right] and P = 0.0006 [left]). Ability to characterize tumor was rated higher at 7 T compared with lower field MRI, P = 0.05. Confidence in visualizing normal gland was also higher using 7 T MRI, P = 0.036. The six hormone-secreting tumors had higher corrected T2 mean SI than non-secreting tumors (2.54 vs. - 0.38, P = 0.0196). Seven patients had preoperative hypopituitarism and had significantly greater stalk curvature angles than patients without hypopituitarism (71.7° vs. 36.55°, P = 0.027). CONCLUSION: Radiological characterization of pituitary adenomas and adjacent native pituitary tissue may benefit with the use of 7 T MRI. Corrected T2 SI of tumor may be a sensitive predictor of hormonal secretion and may be useful in the diagnostic work-up for pituitary adenoma. 7 T MRI may be valuable in identifying markers of endocrine function in patients with pituitary adenomas. Our results indicate that hormone-secreting tumors have higher T2-weighted SI and tumors associated with preoperative hypopituitarism have greater stalk curvature angles.

PREVELENCE OF PRIMARY ALDOSTERONISM IN AN URBAN HYPERTENSIVE POPULATION.

OBJECTIVE: To determine the prevalence of primary aldosteronism (PA) in hypertensive patients presenting to the primary care clinic at The Mount Sinai Hospital, regardless of the degree of hypertension and to identify clinical criteria that should prompt screening for PA. METHODS: An aldosterone:renin ratio (ARR, cutoff ≥20, with plasma aldosterone concentration [PAC] ≥10 and suppressed renin) was used to prospectively screen 296 hypertensive patients (blood pressure [BP] ≥140/90) over the age of 18 from August 2012 through May 2013. Subjects who screened positive then underwent confirmatory oral salt load testing (OSLT). RESULTS: Of the 296 patients, 14 screened positive for PA, an overall prevalence of 4.7%. Six of the 14 cases underwent confirmatory OSLT, upon which 2 were confirmed positive, for a prevalence of 0.7%. Overall, patients with confirmed PA were more likely to have resistant hypertension (42.9% vs. 18.1% (P = .0334)) and require more antihypertensive agents (2.8 ± 1.2 agents vs. 2.1 ± 1.1 agents, P = .0213). There was a trend toward lower potassium values in the cases. CONCLUSION: The prevalence of PA in our clinic is much lower than in reports from certain "at-risk" populations. PA screening is indicated in patients with resistant hypertension, regardless of serum potassium levels. ABBREVIATIONS: ARR = aldosterone:renin ratio ACTH = adrenocorticotropic hormone AVS = adrenal venous sampling BP = blood pressure MRA = mineralocorticoid receptor antagonist OSLT = oral salt load confirmatory test PA = primary aldosteronism PAC = plasma aldosterone concentration PCP = primary care provider PRA = plasma renin activity.

Evaluating Patient-Reported Outcomes in Cushing's Syndrome.

The importance of the patient's perspective on disease has increasingly gained traction among clinical investigators and clinicians. Patient-reported outcomes (PROs) are those which pertain to a patient's health, quality of life, or functional status (associated with health care or treatment) that are reported directly by the patient, without interpretation by a clinician. In this article, we will review PROs as they relate to the signs, symptoms, health-related quality of life, and comorbidities of active Cushing's syndrome (CS), and CS after treatment with surgery, radiotherapy, and medical therapy. We will explore long-term outcomes in the setting of remission, persistence, and recurrence in this population.

Persistent vs Recurrent Cushing's Disease Diagnosed Four Weeks Postpartum.

Background: Cushing's disease (CD) recurrence in pregnancy is thought to be associated with estradiol fluctuations during gestation. CD recurrence in the immediate postpartum period in a patient with a documented dormant disease during pregnancy has never been reported. Case Report. A 30-year-old woman with CD had improvement of her symptoms after transsphenoidal resection (TSA) of her pituitary lesion. She conceived unexpectedly 3 months postsurgery and had no symptoms or biochemical evidence of recurrence during pregnancy. After delivering a healthy boy, she developed CD 4 weeks postpartum and underwent a repeat TSA. Despite repeat TSA, she continued to have elevated cortisol levels that were not well controlled with medical management. She eventually had a bilateral adrenalectomy. Discussion. CD recurrence may be higher in the peripartum period, but the link between pregnancy and CD recurrence and/or persistence is not well studied. Potential mechanisms of CD recurrence in the postpartum period are discussed below. Conclusion: We describe the first report of recurrent CD that was quiescent during pregnancy and diagnosed in the immediate postpartum period. Understanding the risk and mechanisms of CD recurrence in pregnancy allows us to counsel these otherwise healthy, reproductive-age women in the context of additional family planning.

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.

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.

Epidemiology of anesthesia-related complications in labor and delivery, New York State, 2002-2005.

BACKGROUND: Epidemiologic data on anesthesia-related complications occurring during labor and delivery are essential for measuring and evaluating the safety and quality of obstetric anesthesia care but are lacking. We aimed to fill this research gap by exploring the epidemiologic patterns and risk factors of anesthesia-related complications in a large sample of women giving birth in New York hospitals. METHODS: Using the Healthcare Cost and Utilization Project State Inpatient Databases files, we identified all discharge records for labor and delivery from New York hospitals between 2002 and 2005. We then identified women who experienced any recorded anesthesia-related complication during labor and delivery as determined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. The incidence of anesthesia-related complications was calculated by demographic and clinical characteristics. Multivariate logistic regression was performed to assess risk factors of anesthesia-related complications. RESULTS: Of the 957,471 deliveries studied, 4438 (0.46%) had at least one anesthesia-related complication. The majority (55%) of anesthesia-related events occurring during labor and delivery were spinal complications, followed by systemic complications (43%) and overdose or adverse effects (2%). Multivariate logistic regression revealed five risk factors of anesthesia-related complications: cesarean delivery (odds ratio [OR] 2.51, 95% confidence interval [CI] 2.36-2.68), rural area (OR 1.33, 95% CI 1.21-1.46), Charlson-Deyo Comorbidity Index >or=1 (OR 1.47, 95% CI 1.28-1.69), Caucasian race (OR 1.37, 95% CI 1.24-1.52), and scheduled admission (OR 1.10, 95% CI 1.03-1.18). Anesthesia-related complications were associated with about a one-day increase in the average length of stay (3.89 +/- 3.69 [mean +/- SD] days vs 2.92 +/- 2.38 days for deliveries without anesthesia-related complications, P < 0.0001) and a 22-fold increased risk of maternal mortality (OR 22.26, 95% CI 11.20-44.24). CONCLUSION: The incidence of anesthesia-related complications during labor and delivery seems to be low but remains a cause of concern, particularly in women undergoing cesarean delivery, living in rural areas, or having preexisting medical conditions.

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.

Primary aldosteronism: emerging trends.

Primary aldosteronism (PA) is the most common etiology of endocrine hypertension (HTN), and recent prevalence studies suggest that it may be under-diagnosed. Indications for screening have been expanded with recognition that many patients with PA do not have hypokalemia and that the disease may be familial. The aldosterone:renin ratio (ARR) is the preferred screening test for PA. The ARR can be interpreted in patients on most anti-hypertensive agents, and can be used to guide medical therapy of HTN even in patients without PA. Once PA is confirmed, adrenal venous sampling (AVS) should be performed to determine if PA is due to bilateral disease or a unilateral adenoma, if surgery is being considered. Targeted medical or surgical therapy improves patient outcomes.