[Show abstract][Hide abstract] ABSTRACT: Very low quality (VLQ) evidence translates into very low confidence in the balance of risk and benefits based on the estimates drawn from the body of evidence. Consequently, this assessment highlights gaps in the research evidence, i.e. knowledge gaps, for important clinical questions. In this way, expert guideline panels identify priority knowledge gaps that, arguably, should inform the research agenda and prioritize scarce research economical resources. The extent to which the research agenda reflects the knowledge gaps identified in clinical practice guidelines is unknown.
A systematic evaluation of the Endocrine Society (ES) clinical practice guidelines portfolio from 2008 to 2014 was conducted with the objectives to identify (1) recommendations in the ES clinical practice guidelines based on VLQ evidence reflecting knowledge gaps in endocrinology, and (2) active research designed to address these gaps by searching the clinical trial registry, clinicaltrials.gov, using terms describing patients (diseases), interventions, comparison, and outcomes.
In 25 ES guidelines, we found 660 recommendations, of which 131 (20 %) were supported by VLQ evidence. Clinical trialists are attempting to answer 28 (21 %) of these knowledge gaps by performing 69 clinical trials.
The research enterprise is addressing one in five knowledge gaps identified in clinical practice recommendations in endocrinology. These findings suggest an inefficiency in the allocation of very scarce research economical resources. Linking the research agenda to evidence gaps in clinical practice guidelines may improve both the efficiency of the research enterprise and the translation of evidence into more confident clinical practice.
BMC Medicine 08/2015; 13(1):187. DOI:10.1186/s12916-015-0435-z · 7.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinical features of thymic carcinoid (TC) and bronchial carcinoid (BC) tumors as part of multiple endocrine neoplasia type 1 (MEN1) have been rarely described and their importance in clinical practice is debated. The objective of this study was to describe the clinical presentation and outcome of this uncommon manifestation of MEN1 in a tertiary care center setting. We present the clinical features of patients with MEN1 and either TC or BC evaluated at the Mayo Clinic from 1977 to 2013. A total of 348 patients with MEN1 were evaluated and the prevalence of TC was 2.0 % (n = 7) and of BC 4.9 % (n = 17). The majority of the patients with BC were men (61 %) diagnosed on routine screening (77 %) and BC was not the confirmed cause of death in any patient. In contrast, TC patients were all men and during follow-up 43 % died due to TC complications. We conclude that TC and BC tumors are uncommon, but important components of MEN1. BC were most commonly diagnosed during routine screening and associated with an indolent course. TC were predominantly seen in men and associated with a more aggressive behavior.
Hormones and Cancer 06/2015; DOI:10.1007/s12672-015-0228-z · 0.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Report the prevalence of parathyroid carcinoma (PC) in patients with multiple endocrine neoplasia type 1 (MEN1) and review of the literature.Background
Primary hyperparathyroidism (PHP) is the most common manifestation of MEN1. The occurrence of PC in patients with MEN1 is rare and the literature regarding the clinical manifestations – including the prevalence of the disease – is scarce.ContextSingle tertiary care center experience from 1977 to 2013.DesignElectronic search of the medical records to identify a cohort of patients with MEN1. Literature review based on current case reports.PatientsSingle case of PC in a cohort of 348 patients with MEN1. Ten cases of PC in patients with MEN1 reported in the literature.MeasurementClinical features of PC in patients with MEN1.ResultsThe prevalence of PC in 348 patients with MEN1 was found to be 0.28% (95% CI, 0 - 1.4%). Based on the current published cases of PC in patients with MEN1, 54.5% were women, mean age at diagnosis was 48.3 years, and the serum PTH concentrations at least 4 times the upper limit of the reference range in 73% of the cases.ConclusionPC in patients with MEN 1 is rare with a prevalence of 0.28% and the clinical features are similar to PC in patients without MEN1.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Context:
The most common feature of multiple endocrine neoplasia type 1 (MEN1) is primary hyperparathyroidism (PHP), which occurs in approximately 95% of MEN1 patients. Approximately 40-60% of patients with MEN1 develop recurrent hypercalcemia within 10-12 years after their initial parathyroid surgery and the successful management of recurrent PHP is challenging.
This study sought to evaluate the safety and efficacy of percutaneous ethanol ablation (PEA) for the treatment of recurrent PHP in patients with MEN1. DESIGN, SETTING, PATIENTS, INTERVENTION, OUTCOME MEASURED: We performed an electronic search to identify patients with a billing code for MEN1 who were seen at Mayo Clinic between 1977 and 2013. Patients with recurrent PHP who underwent PEA were identified and their clinical information was collected. We performed t test analyses to compare mean values.
Thirty-seven patients underwent 80 PEA treatments that included 123 sessions of ethanol administration. Twenty-one patients were women (56.8%) and the mean age at diagnosis of PHP was 33.8 years. The mean preprocedure calcium level was 10.7 mg/dl ± 0.57 (SD) and the mean postprocedure calcium level was 9.6 mg/dl ± 0.76 (P < .01). In 14 treatments (18.9%) the postprocedure calcium was greater than 10.1 mg/dl. Postprocedure hypocalcemia occurred in six treatments (8.1%). Normocalcemia was achieved in 54 of the treatment episodes (73%) and the mean duration of normocalcemia was 24.8 months. PEA was safe with transient hoarseness occurring in four of the treatments (5%).
The treatment of recurrent PHP in patients with MEN1 represents a challenge that is associated with increased morbidity. PEA is an effective treatment option for achieving normocalcemia in the majority of the patients with MEN1. PEA is associated with low rates of hypocalcemia and no permanent complications.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Metastatic adrenocortical carcinoma (ACC) is rapidly fatal, with few options for treatment. Patients with metachronous recurrence may benefit from surgical resection. The survival benefit in patients with hematogenous metastasis at initial presentation is unknown.
A review of all patients undergoing surgery (European Network for the Study of Adrenal Tumors) stage IV ACC between January 2000 and December 2012 from two referral centers was performed. Kaplan-Meier estimates were analyzed for disease-free and overall survival (OS).
We identified 27 patients undergoing surgery for stage IV ACC. Metastases were present in the lung (19), liver (11), and brain (1). A complete resection (R0) was achieved in 11 patients. The median OS was improved in patients undergoing R0 versus R2 resection (860 vs. 390 days; p = 0.02). The 1- and 2-year OS was also improved in patients undergoing R0 versus R2 resection (69.9 %, 46.9 % vs. 53.0 %, 22.1 %; p = 0.02). Patients undergoing neoadjuvant therapy (eight patients) had a trend towards improved survival at 1, 2, and 5 years versus no neoadjuvant therapy (18 patients) [83.3 %, 62.5 %, 41.7 % vs. 56.8 %, 26.6 %, 8.9 %; p = 0.1]. Adjuvant therapy was associated with improved recurrence-free survival at 6 months and 1 year (67 %, 33 % vs. 40 %, 20 %; p = 0.04) but not improved OS (p = 0.63). Sex (p = 0.13), age (p = 0.95), and location of metastasis (lung, p = 0.51; liver, p = 0.67) did not correlate with OS after operative intervention. Symptoms of hormonal excess improved in 86 % of patients.
Operative intervention, especially when an R0 resection can be achieved, following systemic therapy may improve outcomes, including OS, in select patients with stage IV ACC. Response to neoadjuvant chemotherapy may be of use in defining which patients may benefit from surgical intervention. Adjuvant therapy was associated with decreased recurrence but did not improve OS.
[Show abstract][Hide abstract] ABSTRACT: Objective: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). Participants: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. Conclusions: The Task Force recommends that initial biochemical testing for PPGLs should include measurements of plasma free or urinary fractionated metanephrines. Consideration should be given to preanalytical factors leading to false-positive or false-negative results. All positive results require follow-up. Computed tomography is suggested for initial imaging, but magnetic resonance is a better option in patients with metastatic disease or when radiation exposure must be limited. (123)I-metaiodobenzylguanidine scintigraphy is a useful imaging modality for metastatic PPGLs. We recommend consideration of genetic testing in all patients, with testing by accredited laboratories. Patients with paraganglioma should be tested for SDHx mutations, and those with metastatic disease for SDHB mutations. All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. Preparation should include a high-sodium diet and fluid intake to prevent postoperative hypotension. We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. Partial adrenalectomy is an option for selected patients. Lifelong follow-up is suggested to detect recurrent or metastatic disease. We suggest personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.
[Show abstract][Hide abstract] ABSTRACT: The original 4 patients with Cushing syndrome who underwent bilateral adrenalectomy for primary pigmented nodular adrenocortical disease were followed up for an average of 31 years to determine whether they or any of their primary relatives had developed Carney complex or its components. None had. Three of the patients were alive and well; the fourth had died of an unrelated condition. All the adrenal glands contained multiple small, black or brown cortical nodules, up to 4 mm in diameter. The extracapsular extension of the micronodules was limited to the immediate pericapsular adipose tissue and was not considered evidence of low-grade malignancy. Immunocytochemically, the nodules were positive for synaptophysin, inhibin-A, and melan A and negative for vimentin and CD56. Ki-67 antibody stained the cytoplasm of cells in the micronodules but not that of the atrophic cortical cells. The 4 patients had the PRKAR1A deletion that has been associated with the isolated form of primary pigmented nodular adrenocortical disease.
The American journal of surgical pathology 05/2014; 38(9). DOI:10.1097/PAS.0000000000000220 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: The accurate distinction between unilateral and bilateral adrenal disease in patients with primary aldosteronism (PA) guides surgical management. Adrenal venous sampling (AVS), the criterion standard localization procedure, is not readily available at many centers throughout the world. Objective: To determine factors most consistent with surgically curable PA. Design: A retrospective observational study Setting: Mayo Clinic, Rochester, a tertiary referral center Patients: All patients who underwent unilateral adrenalectomy for treatment of PA between January 1993 and December 2011. Intervention: Unilateral adrenalectomy Main outcome measures: Variables associated with prediction of unilateral disease Results: Over 19 years, 263 patients underwent unilateral adrenalectomy for the treatment of PA. Long-term postoperative follow-up was obtained in 143 patients (54.4%). The overall effective cure rate of PA was 95.5% in those patients sent for adrenalectomy for presumptive unilateral disease. In patients with cured PA, defined as resolution of autonomous aldosterone secretion, hypertension was cured in 53 (41.7%) and improved in 59 (46.5%) patients. PA was not cured with unilateral adrenalectomy in 6 (4.2%) patients. Adrenal imaging and AVS were concordant to the surgically documented side in 58.6% and 97.1% of the patients, respectively. Although there was no statistically significant difference in mean age between the inaccurate versus the accurate adrenal imaging group, we found that the minimum age in the former was 35.1 years. Conclusions: Using adrenal imaging and AVS, the effective surgical cure rate for PA was 95.5%. Although the overall accuracy of CT or MRI in detecting unilateral adrenal disease was poor at 58.6%, adrenal imaging performed well in those patients less than 35 years of age.
The Journal of Clinical Endocrinology and Metabolism 05/2014; 99(8):jc20134146. DOI:10.1210/jc.2013-4146 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PurposeThe distinction between corticotropin (ACTH)-producing pituitary adenomas and occult ectopic ACTH neoplasms is a challenge and frequently complicated by the detection of nonfunctioning pituitary adenomas on dynamic magnetic resonance imaging (DMRI). Herein, we explored quantitative differences in DMRI measures from ACTH-producing pituitary adenomas.Materials and Methods
Fifty-five patients with pathology confirmed ACTH-producing and 44 with nonfunctioning pituitary adenomas were analyzed in this retrospective pilot study. The intensities of adenomas and of adjacent pituitary tissue were measured by drawing a region of interest. Time–intensity curves were then constructed and quantitative analysis included: enhancement time, enhancement peak, and pre-peak slope (PPS). Multivariable logistic analysis and receiver operating characteristic curves (ROC) were used to evaluate the parameters.ResultsQuantitative analysis showed that tumor PPS in ACTH-producing adenomas was markedly lower than that in nonfunctioning adenomas (P=0.0042) and that, the PPS of the adjacent pituitary gland were not different (P=0.2441). The PPS was > 3.0 in 59.1% of nonfunctioning adenomas and ≤ 3.0 in 69.1% of ACTH-producing adenomas (P=0.0049). Logistic analysis revealed lower tumor PPS levels (P=0.0123, OR 1.24, 95% CI: 1.05-1.52) were associated with ACTH-producing adenomas. The optimal PPS cutoff determined by ROC analysis was 2.89, with a sensitivity of 69% and specificity of 70%. No significant difference was found between the two groups in enhancement time or enhancement peak.Conclusion
Enhancement parameters in DMRI can help distinguishing ACTH-producing from nonfunctioning pituitary adenomas, which could be useful in the differential diagnosis between ACTH-producing pituitary adenomas and ectopic ACTH syndrome complicated with nonfunctioning pituitary adenoma.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Introduction
Neuroendocrine tumors (NE) commonly afflict patients with MEN1. It is thought that patients with MEN1 have improved survival compared to individuals with analogous lesions. The role of metastasectomy of NE tumors in MEN1 patients is not clearly defined.
A review of MEN1 patients undergoing surgery for NE tumors from 1994-2010 at a single tertiary care center was performed. Tumor function, extent of metastasis, R0 resection and survival were analyzed.
We identified 30 patients who underwent resection including synchronous and metachronous metastasectomy. Synchronous metastases were identified in 19 (63%) while 11 (37%) had metachronous disease. R0 resection was achieved in 93% of patients. Estimated 10y survival is 86.4% (95% CI, 60%-100%) with no factors predictive of OS. The disease free interval at 1, 5 and 10y was 89%, 50% and 19% with recurrence occurring at a median of 5.4 y (95% CI, 77.7%-100%). Synchronous metastasis (p=0.0072, HR 3.4) and non-functioning tumors (p=0.014, HR3.3) were more likely to recur while age (p=0.09, HR1.5), gender (p=0.49, HR 1.3), and site of metastasis (p=0.81, HR1.1) did not influence recurrence.
Patients with MEN1 benefit from resection of metastatic NE disease. Despite a high recurrence rate, survival and DFI is favorable vs. patients without MEN1.
[Show abstract][Hide abstract] ABSTRACT: Adrenocortical cancer (ACC) recurs despite apparent complete resection. We examined the survival and palliative benefit of resection for recurrent ACC.
A review of all patients undergoing operation for ACC between 1980 and 2010 at our institution was performed in which we compared resection with nonoperative therapy.
Overall, 164 patients underwent operation for ACC, 125 of whom underwent a complete resection (R0). Recurrence occurred in 93 R0 patients (median, 15 months; range, 1.5-150 months). Symptoms at recurrence were present in 71% (66/93), including pain (34%) and hormone excess (43%). There were 67 patients who underwent reoperation for recurrence. Forty-eight of 67 patients underwent R0 resection for recurrence. Operative patients had a greater overall operative versus nonoperative management or no therapy (65 months vs 6 months, P < .01). Median survival for nonoperatively managed patients (226 days) and those undergoing no therapy (179 days) was less than for debulking (1,272 days, P = .002). R0 for recurrence (P = .005) and a disease-free interval >6 months (P < .001) were associated with survival after operation, whereas original tumor size (P = .47), grade (P = .8), and stage (P = .23) were not. Pain and hormonal symptoms improved in 84% of operative patients versus 29% of nonoperatively managed patients (P = .005). Debulking had similar symptomatic improvement to R0 resection (P = .52).
Patients with recurrent ACC can benefit from operative intervention with improvement in survival and symptoms. Patients with a disease-free interval >6 months and complete resection are likely to benefit from resection of the recurrence, but the near universal improvement in symptoms may expand the criteria for operation in recurrent ACC.
Surgery 12/2013; 154(6):1292-9. DOI:10.1016/j.surg.2013.06.033 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adrenal venous sampling is recommended by current guidelines to identify surgically curable causes of hyperaldosteronism but remains markedly underused. Key factors contributing to the poor use of adrenal venous sampling include the prevailing perceptions that it is a technically challenging procedure, difficult to interpret, and can be complicated by adrenal vein rupture. In addition, the lack of uniformly accepted standards for the performance of adrenal venous sampling contributes to its limited use. Hence, an international panel of experts working at major referral centers was assembled to provide updated advice on how to perform and interpret adrenal venous sampling. To this end, they were asked to use the PICO (Patient or Problem, Intervention, Control or comparison, Outcome) strategy to gather relevant information from the literature and to rely on their own experience. The level of evidence/recommendation was provided according to American Heart Association gradings whenever possible. A consensus was reached on several key issues, including the selection and preparation of the patients for adrenal venous sampling, the procedure for its optimal performance, and the interpretation of its results for diagnostic purposes even in the most challenging cases.
[Show abstract][Hide abstract] ABSTRACT: The Carney triad is the combination of gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma. Herein, we describe the clinical, imaging, pathologic, and follow-up findings from 14 patients for a fourth component of the syndrome, adrenal adenoma. The adrenal neoplasm was asymptomatic and usually a late finding. Results of adrenocortical function tests were normal. Computed tomography revealed low-density adrenal masses that were consistent with adenomas. Bilateral lesions were present in 4 patients. In 13 of the 14 patients who underwent surgery, resected adrenal glands and biopsy specimens featured 1 or more circumscribed, yellow tumors, up to 3.5 cm in diameter, composed of well-differentiated polygonal cells with clear vacuolated cytoplasm and a smaller component of eosinophilic cells. The extratumoral cortex had combinations of normal histologic features, discrete clear cell micronodules, zonal clear cell hypertrophy, and marked atrophy. The lesion in the 14th patient was different, grossly and microscopically resembling the usual sporadic cortisol-secreting adenoma. After the tumor was excised, the patient required glucocorticoid support. None of the tumors recurred or metastasized. Fourteen additional patients had unilateral or bilateral adrenal tumors consistent with adenomas detected by imaging studies.
The American journal of surgical pathology 05/2013; 37(8). DOI:10.1097/PAS.0b013e318285f6a2 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context:Pituitary stalk lesions have various etiologies, often not clinically apparent. Pathological samples from these lesions are rarely obtained, because of the critical location and function of the hypophyseal stalk.Objectives:The purpose of this study was to characterize the etiological spectrum of pituitary stalk lesions seen at Mayo Clinic Rochester over 20 years and to determine whether specific magnetic resonance imaging (MRI) characteristics could provide clinician guidance with regard to the etiology of infundibular lesions.Design:A retrospective review of patients with pituitary stalk lesions seen at Mayo Clinic Rochester between 1987 and 2006 was conducted. Demographic, clinical presentation, imaging, laboratory, operative, and pathology data were reviewed and are reported using descriptive statistics.Results:Of the 152 pituitary stalk lesions included, 49 (32%) were neoplastic, 30 (20%) were inflammatory, 13 (9%) were congenital anomalies, and 60 (39%) were of unclear etiology. Diabetes insipidus was diagnosed in 43 (28%) of the 152 patients, and 49 (32%) patients had at least one anterior pituitary hormone deficit. Secondary hypogonadism was the most common endocrine deficiency. Eleven of 13 congenital lesions were round in appearance and 5 of 7 patients with neurosarcoidosis confirmed by pathology had a uniformly thickened pituitary stalk on MRI. There were no statistically significant correlations between hypopituitarism and the pattern of enhancement or size of the lesion.Conclusions:Findings on MRI remain key in guiding the diagnosis of pituitary stalk lesions, particularly when used in conjunction with other clinical clues. There are no good imaging predictors for hypopituitarism, making clinical evaluation of all patients with pituitary stalk lesions crucial.
The Journal of Clinical Endocrinology and Metabolism 03/2013; 98(5). DOI:10.1210/jc.2012-4171 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Described in this article is the massive enlargement of both adrenal glands in 3 newborns-2 girls and 1 boy. Two had hemihypertrophy and other congenital abnormalities but no identified genetic mutation; the third had genetically proven Beckwith-Wiedemann syndrome. Two had severe Cushing syndrome, the third had hypercortisolemia but no clinical Cushing syndrome. Bilateral adrenalectomy cured Cushing syndrome in the 2 with severe symptoms; total adrenal weight in these patients was 44 and 53 g, respectively. Unilateral adrenalectomy was performed in the third patient: the gland weighed 52 g; postoperatively, the patient's hypercortisolemia normalized, and, concomitantly, the enlarged contralateral adrenal gland had a 5-fold decrease in size with slight enlargement 6 years postoperatively. Microscopically, the 3 patients had similar pathology: massive adrenal enlargement due to a combination of cytomegaly, persistence of the transient cortex, and hyperplasia of the permanent cortex. The pathologic findings were most likely the result of the genetic mutation identified in 1 patient and of an unknown mutation in the remaining 2 patients.
The American journal of surgical pathology 10/2012; 36(10):1452-63. DOI:10.1097/PAS.0b013e31825d538b · 5.15 Impact Factor