Simple, rapid, and cost-effective microextraction by the packed sorbent method for quantifying of urinary free catecholamines and metanephrines using liquid chromatography-tandem mass spectrometry and its application in clinical analysis.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from adrenal and extra-adrenal chromaffin cells. They produce excessive amounts of catecholamines and their metabolites. A newly analytical procedure based on the semi-automated microextraction by packed sorbent (MEPS) technique, using a digitally controlled syringe (eVol) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), was developed to quantify free urinary catecholamines and metanephrines. The important parameters affecting MEPS performance, namely the type of sorbent material (porous graphitized carbon (PGC), polar enhanced polymer (PEP), cation-exchange (CX) and C18), number of extraction cycles, and elution solvent system, were evaluated. The optimal experimental conditions involved the loading of sample mixture in seven extraction cycles through a C18 sorbent in a MEPS syringe, followed by using elution solutions (water/acetonitrile/formic acid, 95/4.75/0.25). The entire sample preparation took about 4 min. Chromatographic separation was well achieved with an HSS PFP column using the gradient elution. The linearity range of the method was 0.167-33.4 ng/mL for epinephrine, 0.650-130 ng/mL for norepinephrine, 1.53-306 ng/mL for dopamine, 1.34-268 ng/mL for metanephrine, 3.43-686 ng/mL for normetanephrine, and 1.33-265 ng/mL for 3-methoxytyramine. The intra- and interassay precisions were ≤ 12.8%, and the respective accuracies were 88.4-112.0% and 89.0-109.5%. The carryover and sample stability without acidification were also investigated. Validation using clinical urine specimens showed that the proposed method had higher sensitivity compared with other urinary biochemical tests. The developed MEPS-LC-MS/MS method was simple, fast, and cost-effective; it helped to obtain information about multiple metabolites. It is applicable in routine clinical laboratories for the screening of PPGL. Graphical abstract.

A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas are notable for a high frequency of inherited cases, many of which present as apparently sporadic tumors. OBJECTIVE: The objective of this study was to establish a comprehensive next generation sequencing (NGS)-based strategy for the diagnosis of patients with pheochromocytoma and paraganglioma by testing simultaneously for mutations in MAX, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. DESIGN: After the methodology for the assay was designed and established, it was validated on DNA samples with known genotype and then patients were studied prospectively. SETTING: The study was performed in a diagnostic genetics laboratory. PATIENTS: DNA samples from 205 individuals affected with adrenal or extraadrenal pheochromocytoma/head and neck paraganglioma (PPGL/HNPGL) were analyzed. A proof-of-principle study was performed using 85 samples known to contain a variant in 1 or more of the genes to be tested, followed by prospective analysis of an additional 120 samples. MAIN OUTCOME MEASURES: We assessed the ability to use an NGS-based method to perform comprehensive analysis of genes implicated in inherited PPGL/HNPGL. RESULTS: The proof-of-principle study showed that the NGS assay and analysis gave a sensitivity of 98.7%. A pathogenic mutation was identified in 16.6% of the prospective analysis cohort of 120 patients. CONCLUSIONS: A comprehensive NGS-based strategy for the analysis of genes associated with predisposition to PPGL and HNPGL was established, validated, and introduced into diagnostic service. The new assay provides simultaneous analysis of 9 genes and allows more rapid and cost-effective mutation detection than the previously used conventional Sanger sequencing-based methodology.

Urapidil in the preoperative treatment of pheochromocytomas: a safe and cost-effective method.

BACKGROUND: Surgery for pheochromocytoma may lead to uncontrolled catecholamine secretion with severe hypertension and cardiac failure. Perioperative α1-receptor-blockade with orally administered phenoxybenzamine or intravenous urapidil therefore is a standard procedure in the treatment regime prior to surgery. METHODS: Medical records of 30 patients who underwent surgery for pheochromocytoma during the years 2002-2011 were retrospectively analyzed. We investigated the difference in the clinical course of patients undergoing surgery for pheochromocytoma with either phenoxybenzamine or urapidil pretreatment with special regard to the intraoperative course and length of hospital stay and costs. RESULTS: Nineteen (16 female, 3 male) patients (63 %) received a preoperative α-block with orally administered phenoxybenzamine. Eleven patients (6 female, 5 male) (37 %) were treated with intravenous urapidil for 3 days prior to surgery. Intraoperative episodes of hypertension or hypotension did not differ significantly. The median total hospital stay in phenoxybenzamine-treated patients was 17 days in contrast to 11 days in the urapidil group (p = 0.0087). Patients who received i.v. pretreatment spent significantly fewer days in the hospital prior to operation [median: 3 days (range: 3-7 days) versus 9 days (range: 3-21 days); p = 0.0001]. The reduction in the number of days in the hospital in the urapidil group led to a significantly elevated revenue per day (637.49/day versus 412.50/day; p = 0.001). CONCLUSIONS: Perioperative treatment with the selective α1 blocker urapidil remains a simple and cost effective method in the treatment regime of patients with pheochromocytoma.

A cost-effectiveness analysis of adrenalectomy for nonfunctional adrenal incidentalomas: is there a size threshold for resection?

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare, but aggressive, malignancy. Current American Association of Clinical Endocrinologists (AACE)/American Association of Endocrine Surgeons (AAES) guidelines recommend resection of nonfunctional adrenal neoplasms ≥ 4 cm. This study evaluates the cost-effectiveness of this approach. METHODS: A decision tree was constructed for patients with a nonfunctional, 4-cm adrenal incidentaloma with no radiographic suspicion for ACC. Patients were randomized to adrenalectomy, surveillance per AACE/AAES guidelines, or no follow-up ("sign-off"). Incremental cost-effectiveness ratio (ICER) includes health care costs, including missed ACC. ICER (dollar/life-year-saved [LYS]) was determined from the societal perspective. Sensitivity analyses were performed. RESULTS: In the base-case analysis, assuming a 2.0% probability of ACC for a 4-cm tumor, surgery was more cost-effective than surveillance (ICER $25,843/LYS). Both surgery and surveillance were incrementally more cost-effective than sign-off ($35/LYS and $8/LYS, respectively). Sensitivity analysis demonstrated that the model was sensitive to patient age, tumor size, probability of ACC, mortality of ACC, and cost of hospitalization. The results of the model were stable across different cost and complications related to adrenalectomy, regardless of operative approach. CONCLUSION: In our model, adrenalectomy was cost-effective for neoplasms >4 cm and in patients <65 years, primarily owing to the aggressiveness of ACC. Current AACE/AAES guideline recommendations for the resection of adrenal incidentalomas ≥ 4 cm seem to be cost-effective.

Immediate laparoscopic adrenalectomy versus observation: cost evaluation for incidental adrenal lesions with atypical imaging characteristics.

BACKGROUND: Because of controversy in the management of nonfunctional adrenal masses <6 cm with lipid-poor imaging characteristics, the study was conducted to compare the costs of observation versus immediate laparoscopic adrenalectomy. METHODS: A total of 370 patients who were evaluated for incidental adrenal masses between January 1999 and December 2007 were identified, and 32 (8.7%) patients had lesions with imaging characteristics that were inconsistent with a benign adenoma (ie, atypical appearing). Sixteen patients underwent immediate surgery and 16 had observation with serial imaging and biochemical studies. The associated total costs were subjected to intention-to-treat analysis. RESULTS: In the observation cohort, 7 patients converted and underwent adrenalectomy after a mean of 13.1 months. Initially, costs of immediate surgery exceeded those of observation ($12,015.72 vs $11,601.18, P = .10). After projecting costs of annual surveillance, a cost advantage for immediate surgery was demonstrated after 9 years (P = .02). CONCLUSIONS: In patients with <6 cm atypical-appearing adrenal lesions, the costs of surgery and of observation are initially equal. After 9 years, the costs of surveillance exceed that of initial laparoscopic adrenalectomy.

Adrenal imaging.

The differentiation of adrenal nodules is wide and varies from primary benign neoplasia, through hormone secreting lesions, to primary and secondary malignant masses. With the rapid development of cross-sectional imaging, incidental detection of adrenal nodules has become an everyday practice, leaving clinicians with the necessity of further investigation. In this article, we present the current possibilities of adrenal gland imaging and we propose a diagnostic schema for differential diagnosis of incidentaloma. Non-contrast enhanced computer tomography (CT) is a modality of choice used for the differential diagnosis of adrenal lesions. It allows the detection of 95% of adrenal masses, and the characterisation of most of them. Magnetic resonance imaging (MRI) is a good modality for cases in which CT examination cannot determine the character of an adrenal tumour. Nuclear medicine study with the use of Iodine-131 meta iodobenzylguanidine(MIBG) is helpful in the diagnosis of pheochromocytoma. Positron Emission Tomography-Computed Tomography (PET-CT) is considered a useful method in patients with a known malignancy history. Ultrasound has a low sensitivity for the detection of small lesions and is not capable of reliable characterisation of visualised masses. However, this technique plays an important role in the follow-up of non-hypersecreting adrenal lesions.

The management of aldosterone-producing adrenal adenomas--does adrenalectomy increase costs?

BACKGROUND: Most experts agree that primary hyperaldosteronism (PHA) caused by an aldosterone-producing adenoma (APA) is best treated by adrenalectomy. From a public health standpoint, the cost of treatment must be considered. We sought to compare the current guideline-based (surgical) strategy with universal pharmacologic management to determine the optimal strategy from a cost perspective. METHODS: A decision analysis was performed using a Markov state transition model comparing the strategies for PHA treatment. Pharmacologic management for all patients with PHA was compared with a strategy of screening for and resecting an aldosterone-producing adenoma. Success rates were determined for treatment outcomes based on a literature review. Medicare reimbursement rates were calculated to estimate costs from a third-party payer perspective. RESULTS: Screening for and resecting APAs was the least costly strategy in this model. For a reference patient with 41 remaining years of life, the discounted expected cost of the surgical strategy was $27,821. The discounted expected cost of the medical strategy was $34,691. The cost of adrenalectomy would have to increase by 156% to $22,525 from $8,784 for universal pharmacologic therapy to be less costly. Screening for APA is more costly if fewer than 9.6% of PHA patients have resectable APA. CONCLUSION: Resection of APAs was the least costly treatment strategy in this decision analysis model.

Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink?

OBJECTIVE: To assess the performance of current clinical recommendations for the evaluation of an adrenal incidentaloma. DESIGN AND METHODS LITERATURE REVIEW: Electronic databases (Pubmed, Ovid and citation searches from key articles) from 1980 to 2008 were searched. Eligible studies were those deemed most applicable to the clinical scenario of a patient referred to an endocrinologist for assessment of an incidentally detected adrenal mass. Surgical series, histopathological series and oncological series were reviewed and most were excluded. RESULTS: The prevalence of functional and malignant lesions presenting as adrenal incidentaloma was similar to that quoted in most reviews, other than a lower incidence of adrenal carcinoma (1.9 vs 4.7%) and metastases (0.7 vs 2.3%). The development of functionality or malignancy during follow-up was rare (<1% becoming functional and 0.2% becoming malignant). During follow-up, false-positive rates of the recommended investigations are typically 50 times greater than true positive rates. The average recommended computed tomography (CT) scan follow-up exposes each patient to 23 mSv of ionising radiation, equating to a 1 in 430 to 2170 chance of causing fatal cancer. This is similar to the chance of developing adrenal malignancy during 3-year follow-up of adrenal incidentaloma. CONCLUSION: Current recommendations for evaluation of adrenal incidentaloma are likely to result in significant costs, both financial and emotional, due to high false-positive rates. The dose of radiation involved in currently recommended CT scan follow-up confers a risk of fatal cancer that is similar to the risk of the adrenal becoming malignant. This argues for a review of current guidelines.

Role and cost-effectiveness of adrenal imaging and image-guided FNA cytology in the management of incidentally discovered adrenal tumours.

Incidentally discovered adrenal masses (incidentalomas) are relatively frequent and unsuspected incidentalomas (AI) of more than 1 cm in size may be found in 1-5% of patients who have undergone abdominal or chest computed tomography (CT)-scan for unrelated reasons. Once an AI is detected, the two major questions are whether the patient has biochemical evidence of adrenal hyperfunction, and whether the mass is an adrenal metastasis or a malignant adrenal tumour. In most cases (>90%) AI are non-functioning, with a low (<10%) risk of being malignant, and an estimated cumulative risk of malignant transformation of less than 1:1000. However, all patients with non-functioning AI usually undergo several imaging studies, but the impact of imaging techniques and image-guided fine-needle aspiration cytology (FNAC) on the cost-effectiveness in the management of patients is not well established. A single test for disease probabilities is not always more cost-effective than two-test approaches and it has been shown that the cumulative sensitivity and accuracy of both FNAC + magnetic resonance imaging (MRI) and FNAC + norcholesterol adrenal scintigraphy reach 100%, at a similar cost-to-accuracy ratio (7.5 vs. 7.0), whilst the strategy CT-scan + MRI together is less sensitive at a lower cost-to-accuracy ratio. In conclusion, the significance of AI, as well as the optimal management approach to treatment, is still under discussion. However, image-guided FNAC in conjunction with MRI as the exclusive imaging test has the major role and cost-effectiveness in the management of patients with AL, and should be considered the strategy of choice in distinguishing between benign and malignant non-functioning adrenal masses of more than 2 cm in diameter.

The economic implications of three biochemical screening algorithms for pheochromocytoma.

Pheochromocytoma is a rare, life-threatening condition. Using a modeling technique, we studied the economic implications of detection strategies for pheochromocytoma (third-party payer perspective). The diagnostic efficacy of biochemical tests was based on Mayo Clinic Rochester data. In all hypothetical algorithms, positive biochemical tests were followed by abdominal computerized tomography and, if negative, metaiodobenzylguanidine scintigraphy. In each hypothetical algorithm, imaging would be indicated after positive biochemical testing as follows: algorithm A, fractionated plasma metanephrine measurements above the laboratory reference range; or algorithm B, abnormal measurements of 24-h urinary total metanephrines or catecholamines. In algorithm C, subjects with fractions of plasma metanephrine at or above 0.5 nmol/liter or normetanephrine at or above 1.80 nmol/liter would undergo imaging, whereas those with values between the reference range and these cutoffs would undergo 24-h urinary measurements (total metanephrines and fractionated catecholamines) and be imaged if positive. We determined that, if 100,000 hypertensive patients (including 500 patients with pheochromocytoma) were tested, algorithm A (measurement of fractionated plasma metanephrines alone) would detect 489 pheochromocytoma patients at a cost of 56.6 million dollars, whereas B (24-h urinary measurements) would detect 457 pheochromocytoma patients for 39.5 million dollars, and C (combination of measurements of fractionated plasma metanephrines and urines) would detect 478 patients for 28.6 million dollars. None of the screening strategies for pheochromocytoma described are affordable if implemented on a routine basis in extremely low-risk patients. However, algorithm C may be the least costly, and at a reasonable level of sensitivity, for subjects in whom the suspicion of disease is moderate.

Diagnosis and treatment of adrenal incidentaloma. A cost-effectiveness analysis.

Methods of meta-analysis, decision analysis, and cost-effectiveness analysis were applied to the adrenal incidentaloma dilemma. It was shown that the life expectancy of patients with adrenal incidentalomas is decreased by a mean of about 1 year if left undiagnosed and untreated--more in cases of larger incidentalomas. Overall, selective analysis of adrenomedullary hormonal function (by urinary metanephrines) is the most cost-effective strategy. Other strategies, such as more extensive hormonal testing, imaging, and fine needle aspiration cytology may provide better cost-effectiveness in subgroups of patients, identified by signs, symptoms, and incidentaloma morphology. Full adrenal hormonal analysis is indicated in patients with larger (> or = 6 cm) incidentalomas and if the combination of hypertension and hypokalemia suggests Conn's disease. Small or medium-sized adrenal incidentalomas may be ignored if MR imaging or other tests suggest benign pheochromocytoma disorder, or patients are elderly, or both.

Diagnostic evaluation of the adrenal incidentaloma: decision and cost-effectiveness analyses.

UNLABELLED: The goal of this study was to examine the clinical and economic outcomes of alternative diagnostic strategies for differentiating benign from malignant adrenal masses. METHODS: We used cost-effectiveness assessment derived from decision analysis and the economic perspective of the payer of health care services. One-time evaluation with fine-needle aspiration (FNA) and combinations of chemical-shift MRI, noncontrast CT, 131I-6beta-iodomethylnorcholesterol (NP-59) scintigraphy, with or without FNA, in a hypothetical cohort of 1000 patients with incidentally discovered unilateral, nonhypersecretory adrenal masses. We calculated and compared the diagnostic effectiveness, costs and cost-effectiveness of the alternative strategies based on estimates from published literature and institutional charge data. RESULTS: At an assumed baseline malignancy rate of 0.25, diagnostic utility varied from 0.31 (CT0) to 0.965 (NP-59) and diagnostic accuracy from 0.655 [noncontrast CT using a cut-off attenuation value of > or = 0 (CT0)] to 0.983 (NP-59). The average cost per patient per strategy ranged from $746 (NP-59) to $1745 (MRI +/- FNA). The best and worst potential cost-to-diagnostic utility ratios were 773 (NP-59) and 2839 (CT0) and 759 (NP-59) and 1982 (MRI +/- FNA) for cost and diagnostic accuracy, respectively. The NP-59 strategy was the optimal choice regardless of the expected outcome examined: cost, diagnostic utility, diagnostic accuracy or cost-effectiveness. Varying the prevalence of malignancy did not alter the cost-effectiveness advantage of NP-59 over the other diagnostic modalities. CONCLUSION: Based on available estimates of reimbursement costs and diagnostic test performance and using reasonable clinical assumptions, our results indicate that the NP-59 strategy is the most cost-effective diagnostic tool for evaluating adrenal incidentalomas over a wide range of malignancy rates and that additional clinical studies are warranted to confirm this cost-effectiveness advantage.

Laparoscopic adrenalectomy compared to open adrenalectomy for benign adrenal neoplasms.

BACKGROUND: Laparoscopic adrenalectomy has recently been used for removing a variety of adrenal neoplasms. The purpose of the present study was to compare results and outcomes in patients who underwent either laparoscopic or open adrenalectomy at our institution from 1988 to the present. STUDY DESIGN: The records of 66 consecutive patients with benign adrenal neoplasms who underwent adrenalectomy from 1988 through 1995 were retrospectively reviewed. Patients were divided into three groups based on the operative approach: group I (n = 25), open anterior transabdominal approach; group II (n = 17), open posterior retroperitoneal approach; and group III (n = 24), laparoscopic transabdominal flank approach. Various parameters were compared and statistical analyses were performed. RESULTS: The three groups were similar in age, gender, American Society of Anesthesiologists class, and distribution of unilateral compared with bilateral adrenalectomy. Mean tumor size was slightly larger in group I (3.4 +/- 1.4 cm) than in group II (2.4 +/- 1.4 cm) or group III (2.7 +/- 1.4 cm) (p = NS). Mean operative times for unilateral adrenalectomy were 142 +/- 38 minutes in group I, 136 +/- 34 minutes in group II, and 183 +/- 35 minutes in group III (p < 0.001, groups I and II compared with group III). For bilateral adrenalectomy, mean operative times were 205 +/- 71 minutes (group I), 328 +/- 11 minutes (group II), and 422 +/- 77 minutes (group III). Patients who underwent laparoscopic adrenalectomy had significantly less operative blood loss (mean, 104 mL compared to 408 mL in group I and 366 mL in group II, p < 0.001) and a lower incidence of perioperative blood transfusion. Laparoscopic adrenalectomy was also associated with significantly reduced parenteral pain medication requirements (p < or = 0.001) and more rapid resumption of a regular diet (p < or = 0.01) compared to open adrenalectomy. Postoperative length of stay was significantly longer in group I (8.7 +/- 4.5 days) and in group II (6.2 +/- 3.9 days) after open adrenalectomy than after laparoscopic adrenalectomy (3.2 +/- 0.9 days) (p < 0.01). Total hospital charges were similar for groups II and III but somewhat higher for group I. Patients were able to resume 100 percent activity an average of 10.6 +/- 4.9 days after laparoscopic adrenalectomy and returned to work a mean of 16.0 +/- 6.1 days postoperatively. CONCLUSIONS: Laparoscopic adrenalectomy is a safe and effective procedure and has several advantages over open adrenalectomy. Laparoscopic adrenalectomy should become the preferred operative approach for the treatment of patients with small, benign adrenal neoplasms.

Preoperative endocrine tumor localization utilizing a cost-effective approach.

Endocrine tumors commonly produce characteristic clinical signs, and laboratory tests lead to accurate diagnosis in a high percentage of cases. The successful management of these tumors usually requires complete surgical resection. A large number of preoperative localization procedures to facilitate the operative management of these tumors have been developed. This report reviews the recent contributions to this literature, with a particular emphasis on cost-effective use of these procedures.