AdrenalGuidelines 2009
ENDOCRINE PRACTICE Vol 15 (Suppl 1) July/August 2009 1
AACE/AAES Guidelines
? 2009 AACE.
AmERICAN ASSOCIATION Of ClINICAl ENDOCRINOlOgISTS
AND AmERICAN ASSOCIATION Of ENDOCRINE SuRgEONS
mEDICAl guIDElINES fOR ThE mANAgEmENT
Of ADRENAl INCIDENTAlOmAS
Martha A. Zeiger, MD, FACS, FACE; Geoffrey B. Thompson, MD, FACS, FACE;
Quan-Yang Duh, MD, FACS; Amir H. Hamrahian, MD, FACE;Peter Angelos, MD, PhD, FACS, FACE; Dina Elaraj, MD;
Elliot Fishman, MD; Julia Kharlip, MD
The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas are systematically developed statements to assist health care providers in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and indi -
vidual circumstances.
2 AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1)
WRITING COMMITTEE
Cochairpersons
Martha A. Zeiger, MD, F ACS, F ACE
Geoffrey B. Thompson, MD, F ACS, F ACE
Quan-Yang Duh, MD, F ACS
Amir H. Hamrahian, MD, F ACE
Primary Writers
Martha A. Zeiger, MD, F ACS, F ACE
Geoffrey B. Thompson, MD, F ACS, F ACE
Quan-Yang Duh, MD, F ACS
Peter Angelos, MD, PhD, F ACS, F ACE
Dina Elaraj, MD
Elliot Fishman, MD
Amir H. Hamrahian, MD, F ACE
Julia Kharlip, MD
REVIEWERS
American Association of Clinical Endocrinologists Reviewers
Jeffrey R. Garber, MD, F ACP, F ACE
Jeffrey I. Mechanick, MD, F ACP, F ACE, F ACN
American Association of Endocrine Surgeons Reviewers
Michael J. Demeure, MD, MBA, F ACS, F ACE
William B. Inabnet, MD, F ACS
AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1)
Abbreviations:
AACE = American Association of Clinical Endocrinologists; AAES = American Association of Endocrine Surgeons; ACC = adrenocortical carci-noma; ACE = angiotensin-converting enzyme; ACTH = adrenocorticotropic hormone; APA = aldosterone-producing adenoma; ARBs = angiotensin II recep-tor blockers; ARR = aldosterone-to-renin ratio; A VS = adrenal venous sampling; BEL = “best evidence” rating level; CT = computed tomographic; EL = evi-dence level;FDG= fludeoxyglucose; FNA= fine-needle aspiration; HPA = hypothalamic-pituitary-adre-nal; HU = Hounsfield units; IHA = bilateral idiopathic hyperaldosteronism; MRI = magnetic resonance imag-ing; PAC = plasma aldosterone concentration; PAH = primary adrenal hyperplasia; PET = positron emission tomography; PRA = plasma renin activity; R = rec-ommendation; SCS = subclinical Cushing syndrome; UFC = urine free cortisol
1. INTRODUCTION
The incidence of adrenal incidentaloma, a term coined in reference to the phenomenon of detecting an otherwise unsuspected adrenal mass on radiologic imaging, has been increasing and now approaches the 8.7% incidence reported in autopsy series (1 [evidence level or EL 3], 2 [EL 3]). The definition of incidentaloma excludes patients undergo-ing imaging procedures as part of staging and work-up for cancer. Not only are more incidentalomas being detected by imaging but they are increasingly more likely to be functional because of the more common evaluations for subclinical syndromes (3 [EL 2]). During the evaluation of an adrenal mass, 3 questions need to be addressed: (1) Is the tumor hormonally active? (2) Does it have radio-logic characteristics suggestive of a malignant lesion? and (3) Does the patient have a history of a previous malig-nant lesion? The patient should be tested for evidence of hypercortisolism, aldosteronism (if hypertensive), and the presence of a pheochromocytoma. A summary of the lit-erature revealed that approximately 80% of patients with incidentalomas had a nonfunctioning adenoma, 5% had subclinical Cushing syndrome (SCS), 5% had a pheochro-mocytoma, 1% had an aldosteronoma, <5% had an adre-nocortical carcinoma (ACC), and 2.5% had a metastatic lesion; the remaining incidentalomas were ganglioneuro-mas, myelolipomas, or benign cysts (4 [EL 4], 5 [EL 4]). Before consideration of surgical resection, a high degree of certainty of the diagnosis is critical and can be achieved with a combination of biochemical and radio-graphic studies. Patients who present with an adrenal incidentaloma should be referred to an endocrinologist or endocrine surgeon for assessment. Pheochromocytomas necessitate careful preoperative preparation to avoid intra-operative and postoperative morbidity and mortality. In patients with primary aldosteronism, a thorough evalua-tion should be performed to ensure that they do not have adrenocortical hyperplasia and a nonfunctioning adrenal adenoma. Patients with adrenal Cushing syndrome develop adrenal insufficiency after resection and will require steroid coverage and careful withdrawal. Whether those with SCS require surgical treatment is controversial. Those patients with ACC require preoperative planning in collaboration with an endocrinologist or oncologist because the effec-tiveness of the initial resection can be a major predictor of survival. Finally, nonfunctioning adrenal tumors ≥4 cm (Fig. 1) should be considered for surgical resection. In con-trast, small myelolipomas, benign cysts, or nonfunctioning adenomas can be diagnosed with considerable certainty and usually do not necessitate surgical resection unless symptomatic. Depending on the clinical circumstances, resection may be indicated.
The only previously published clinical practice guide-lines on the management of patients with adrenal inciden-talomas originated from a National Institutes of Health consensus conference and was published in 2002 (6 [EL 4]). This current set of clinical practice guidelines sum-marizes the relevant literature as it pertains to the differ-ential diagnosis, laboratory and radiologic evaluation, and clinical management and includes recommendations (each labeled “R” in the subsequent section) based on the “best evidence” rating level (BEL) of the published sources. 2. ExECUTIVE SUMMARy OF RECOMMENDATIONS
? R1. Patients with an adrenal incidentaloma should undergo evaluation clinically, biochemically, and radio-graphically for signs and symptoms of hypercortisolism, aldosteronism (if hypertensive), the presence of a pheo-chromocytoma, or a malignant tumor (Grade C; BEL 3).
? R2. Patients with adrenal incidentalomas who do not ful-fill the criteria for surgical resection need to have radio-graphic reevaluation at 3 to 6 months and then annually for 1 to 2 years. For all adrenal tumors, hormonal evalu-ation should be performed at the time of diagnosis and then annually for 5 years (Grade C; BEL 3).
? R3. All patients found to have an incidental adrenal mass should be screened for cortisol excess. Although the best strategy for patients with incidentalomas has not been established, the simplest screening test for autono-mous cortisol secretion from an incidentaloma is a 1-mg overnight dexamethasone suppression test. If clinical suspicion is high, such as in patients with hypertension, obesity, diabetes mellitus, or osteoporosis, 3 tests (sali-
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vary cortisol, dexamethasone suppression, and urine free cortisol [UFC]) can be used (Grade C; BEL 3).? R4. After adrenalectomy for a cortisol-producing ade-noma, patients should be treated with exogenous gluco -corticoids until the hypothalamic-pituitary-adrenal (HPA) axis has recovered. This process may take 6 to 18 months after unilateral adrenalectomy (Grade C; BEL 3).? R5. A diagnosis of SCS is made if the serum cortisol level is more than 5.0 m g/dL after a 1-mg dexamethasone sup -pression test, in a patient with an adrenal adenoma and absence of typical physical stigmas of hypercortisolism. A low or suppressed level of adrenocorticotropic hor-mone (ACTH) or a low dehydroepiandrosterone sulfate concentration supports the diagnosis (Grade D; BEL 4). A second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone suppression test, may also be needed to establish the diagnosis of SCS (Grade B; BEL 2).? R6. In patients with SCS, until further evidence is avail-able regarding the long-term benefits of adrenalectomy, surgical resection should be reserved for those with
worsening of hypertension, abnormal glucose tolerance, dyslipidemia, or osteoporosis (Grade D; BEL 4).? R7. Perioperative glucocorticoid therapy and postop-erative assessment of HPA axis recovery are indicated in patients with SCS (Grade C; BEL 3).? R8. Patients thought to have a pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour total urinary metanephrines and fractionated catecholamines (or both plasma and urine studies) (Grade A; BEL 1).? R9. About one-quarter of patients with a pheochromo-cytoma will have associated familial syndromes caused by mutations in the RET gene (multiple endocrine neo-plasia type 2), VHL gene (von Hippel-Lindau disease), or succinate dehydrogenase genes; genetic study and counseling should be performed, especially for young patients or patients with an extra-adrenal pheochromo -cytoma (Grade C; BEL 3).? R10. Surgical resection should be performed for all pheochromocytomas (Grade C; BEL 3)
.
Fig. 1. Algorithm for the evaluation and management of an adrenal incidentaloma. * = Reimage in 3 to 6 months and annually for 1 to 2 years; repeat functional studies annu-ally for 5 years. If mass grows more than 1 cm or becomes hormonally active, then adrenalectomy is recommended. CT = computed tomographic; HU = Hounsfield units; P AC = plasma aldosterone concentration; PRA = plasma renin activity.
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? R11. In all patients with a pheochromocytoma, an α-adrenergic blocking agent should be administered pre-operatively, in an effort to prevent intraoperative hemo-dynamic instability (Grade C; BEL 3).
? R12. In patients who have undergone resection of a pheochromocytoma, long-term follow-up is necessary because 10% to 15% may have recurrence (Grade B; BEL 2).
? R13. Screening for aldosteronism should be performed in patients with an aldosterone-to-renin ratio (ARR) of >20 (Grade C; BEL 3).
? R14. Primary aldosteronism is confirmed in the setting of an adrenal incidentaloma by demonstrating lack of aldosterone suppression (24-hour urine study) with salt loading (Grade C; BEL 3).
? R15. Subtype evaluation should be achieved with high-resolution computed tomographic (CT) scanning in all patients and adrenal venous sampling (A VS) in the majority of patients older than 40 years (Grade C; BEL 3).
? R16. In patients with primary aldosteronism and a uni-lateral source of aldosterone excess, laparoscopic total adrenalectomy is the treatment of choice because it yields excellent outcomes with low associated morbid-ity relative to open approaches (Grade C; BEL 3).
? R17. Patients with bilateral idiopathic hyperaldosteron-ism (IHA) or those not amenable or agreeable to sur-gical intervention should be managed with selective and nonselective mineralocorticoid receptor blockers (Grade A; BEL 1).
? R18. Any adrenal mass with concerning radiographic characteristics and most lesions ≥4 cm should be resected because of increased risk of adrenal cancer (Grade C; BEL 3).
? R19. The presence of pheochromocytoma should be ruled out biochemically before an attempted resection of any adrenal mass (Grade C; BEL 3).
? R20. All patients suspected of having an ACC should undergo biochemical evaluation to identify any poten-tial hormone excess that serves as a tumor marker and to determine whether the patient requires steroid replace-ment perioperatively in cases of hypercortisolism (Grade D; BEL 4).
? R21. Open adrenalectomy should be performed if ACC is suspected (Grade C; BEL 3).? R22. A metastatic lesion should be suspected in a patient with a history of cancer and an adrenal mass that does not fulfill the criteria for an incidentaloma (Grade C; BEL 3).
? R23.In very rare instances, pathologic confirmation with CT-guided needle biopsy may be required for stag-ing and planning of oncologic treatments (Grade D; BEL 4).
? R24. The presence of pheochromocytoma should be ruled out with biochemical testing before performance of a biopsy (Grade C; BEL 3).
? R25. Patients with bilateral adrenal metastatic lesions should undergo evaluation for adrenal insufficiency (Grade D; BEL 4).
? R26. Adrenal metastasectomy is rarely indicated but should be considered in the case of an isolated adrenal metastatic lesion (Grade C; BEL 3).
3. METHODS FOR DEVELOPMENT OF THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN ASSOCIATION OF ENDOCRINE SURGEONS MEDICAL GUIDELINES FOR THE MANAGEMENT OF ADRENAL INCIDENTALOMAS
In 2004, the American Association of Clinical Endocrinologists (AACE) Protocol for Standardized Production of Clinical Practice Guidelines was published in Endocrine Practice (7 [EL 4]). Those recommenda-tions were used for the preparation of this document. The American Association of Endocrine Surgeons (AAES) and AACE cochairpersons and primary writers are experts in the clinical management of adrenal diseases. After the completion of the first draft created by the primary writers, the chairpersons reviewed the technical assignment of evi-dence levels (inserted in the reference list and in the text) and recommendation grades (in the Executive Summary). The document was subsequently reviewed by the AAES and AACE publication and executive committees and then finally completed by the chairpersons.
4. ADRENAL INCIDENTALOMA
4.1. History and Physical Examination
Patients who have an adrenal incidentaloma identi-fied on CT or magnetic resonance imaging (MRI) need to undergo a thorough clinical evaluation. The history should be aimed at excluding a functional tumor. For patients with hypercortisolism or Cushing syndrome, the investigation should include inquiries about substantial weight gain
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or development of centripetal obesity, easy bruisability, severe hypertension, diabetes, virilization, proximal mus-cle weakness, or fatigue. For patients with pheochromocy-toma, inquiries should address the development of sudden or severe headaches, weight loss, anxiety attacks, sweat-ing, cardiac arrhythmias, or palpitations. For patients with aldosteronism, the clinician should ask about the presence of hypertension, fluid retention, or a history of hypokale-mia. The clinician should inquire about a history of cancer, recent weight loss, and a smoking history because an adre-nal mass may be a metastatic lesion. Physical examination should include measurement of the patient’s blood pres-sure and pulse as well as assessment for evidence of central obesity, ecchymoses, striae, muscle wasting, hirsutism, or other signs of virilization. A review of photographs taken over several years, such as those on a driver’s license, may make changes in appearance obvious.
4.2. Biochemical Evaluation
The detection of an adrenal lesion should prompt biochemical evaluation unless it is an obvious myeloli-poma. Adrenal myelolipomas are of low CT attenuation and also contain fat (-10 to -20 Hounsfield units [HU]); therefore, the diagnosis is generally clear (8 [EL 2]). Any hormonally hyperfunctioning adenoma needs to be surgi-cally resected. Patients are screened for SCS with a 1-mg overnight dexamethasone suppression test. A diagnosis of SCS is suspected if the serum cortisol level exceeds 5.0 m g/dL after a 1-mg dexamethasone suppression test. A low or suppressed level of ACTH or a low dehydroepiandros-terone sulfate concentration further supports the diagnosis.
A second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone suppression test, may be needed to establish the diagnosis of SCS(9 [EL 2]). Patients with hypertension who have a ratio of plasma aldosterone concentration (PAC) (ng/dL) to plasma renin activity (PRA) (ng/mL per hour) of >20 while not taking spironolactone and mineralocorticoid receptor blockers should undergo further assessment for the presence of pri-mary aldosteronism (4 [EL 4], 10 [EL 4]). Finally, elevated plasma free metanephrine and normetanephrine levels and 24-hour total urinary metanephrines and fractionated cat-echolamines suggest the presence of a pheochromocytoma (11 [EL 4], 12 [EL 3]). In general, testing the patient for the production of excess sex hormones is not indicated unless the patient has obvious clinical stigmas.
4.3. Radiologic Imaging
The primary goal of imaging is to distinguish among adrenal adenoma, adrenal carcinoma, pheochromocytoma, and metastatic lesions. It is important to emphasize that imaging cannot reliably distinguish between functioning and nonfunctioning adrenal adenomas. The diagnosis of an adenoma relies on the presence of intracellular lipid in the adrenal lesion, which can be identified by density mea-surement on noncontrast CT or in-phase and out-of-phase MRI. Alternatively, an adenoma can be identified by mea-suring contrast-washout kinetics on CT. Lesions that have an attenuation value below 10 HU on noncontrast CT scan are adenomas (8 [EL 2], 13 [EL 3], 14 [EL 3]). Adenomas constitute about 70% of adrenal masses seen in the clinical setting.
The differential diagnosis can be further delineated by CT scans done immediately after intravenous administra-tion of a contrast agent and then again after a 10- to 15-min-ute delay. Benign adrenal lesions will commonly enhance up to 80 to 90 HU and wash out more than 50% on the delayed scan, whereas lesions such as metastatic tumors, carcinomas, or pheochromocytomas will not (8 [EL 2]). Pheochromocytomas usually show enhancement to more than 100 HU, diagnostically separating them from adeno-mas. On noncontrast CT, some benign adrenal lesions do not have attenuation values of less than 10 HU and may have values of 20 to 40 HU. This result is found in lipid-poor adenomas. In these cases, a washout of >50% will often allow the diagnosis of an adenoma to be made. This observation, however, needs to be confirmed with larger studies.
4.4. Follow-up of Patients With a Nonfunctioning Adrenal Incidentaloma
Patients with adrenal incidentalomas smaller than 4 cm and radiologic characteristics consistent with a benign adenoma need to have radiographic reevaluation at 3 to 6 months and then annually for 1 to 2 years (6 [EL 4], 15 [EL 3], 16 [EL 3]). Hormonal evaluation should be per-formed at the time of diagnosis and then annually for up to 5 years (3 [EL 2]). The risk of the mass enlarging during 1, 2, and 5 years is 6%, 14%, and 29%, respectively, and the risk of the mass becoming hormonally active during those time periods is 17%, 29%, and 47%, respectively (3 [EL 2]). The most common hormonally active lesion in patients with previously inactive adenomas is SCS. The rate of a benign adenoma or hyperplasia developing into an ACC is not well known, but such a change seems to be extremely rare (15 [EL 3], 17 [EL 2], 18-20 [EL 3]). Should the tumor grow more than 1 cm or become hormonally active during follow-up, surgical excision should be considered. Currently, it is unclear what the recommendations should be after 5 years of follow-up for a stable, nonfunctioning adrenal mass.
5. CORTISOL-PRODUCING ADRENAL ADENOMA 5.1. Overview
Adrenocortical adenoma can cause both overt Cushing syndrome and SCS. Those patients with an incidental radiographic finding of the adrenal lesion are more likely than others to have SCS. With better understanding of SCS and more frequent testing for it (4 [EL 4], 21-23 [EL 4]),
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this disease entity is being identified more frequently. Of the hormonally active incidentalomas, this diagnosis con-stitutes the most common form—5.3% of more than 2,000 cases reported in the world literature (4 [EL 4]). Overt clin-ical signs and symptoms of Cushing disease are not always present; thus, biochemical testing is necessary to secure the diagnosis. Overt adrenal Cushing syndrome is character-ized by all the typical stigmas of hypercortisolism.
5.2. History and Physical Examination
Particular attention should be directed at eliciting a history of fatigue, depression, sleep disturbances, weight gain, menstrual irregularities, hypertension, glucose intol-erance, easy bruising, or fracture with minimal trauma. On physical examination, the physician should measure the patient’s blood pressure and pulse and look for central obe-sity, supraclavicular fat accumulation, a dorsocervical fat pad, facial plethora, thinned skin, purple and wide (>1 cm) striae, acne, ecchymoses, hirsutism, and proximal muscle weakness or wasting. Changes on photographs taken over several years (such as those on driver’s licenses) may be of particular help. All these signs and symptoms should raise the level of suspicion for Cushing syndrome. Many patients with mild Cushing syndrome, however, will have only a few of these signs and symptoms present, and many patients without Cushing syndrome may also exhibit one or more of these findings. Therefore, Cushing syndrome cannot be diagnosed on purely clinical grounds, and a care-ful biochemical evaluation is necessary.
5.3. Biochemical Evaluation for Adrenal Cushing Syndrome
Biochemical evaluation for adrenal Cushing syndrome is a 2-step process that first includes screening with 1 or 2 screening tests. If the screening test results are positive, confirmatory tests are then performed. Testing is based on demonstrating 3 pathophysiologic derangements typical of Cushing syndrome: (1) loss of a normal diurnal pattern, with abnormally high late-night cortisol secretion (late-night salivary cortisol test); (2) failure to discontinue the production of cortisol, despite the absence of ACTH stimu-lation (dexamethasone suppression test); and (3) excess production of cortisol (24-hour UFC test).
5.4. Screening Tests
5.4.1. Late-Night Salivary Cortisol
The late-night salivary cortisol test is the most recent assay to be used for screening for Cushing syndrome and is now available through most laboratories. Patients with a regular sleep pattern can collect a specimen of saliva at bedtime at home and then bring or mail the samples to the laboratory for testing. Several investigators have shown that elevated nighttime cortisol levels appear to be the earliest and most sensitive markers for Cushing syndrome (24 [EL 4], 25 [EL 4]), with sensitivity and specificity approaching 90% to 95% (26 [EL 3]).
5.4.2. Overnight 1-mg Dexamethasone Suppression Test
The overnight 1-mg dexamethasone suppression test is performed by administration of 1 mg of dexamethasone at 11 pm and determination of a fasting plasma cortisol level between 8 am and 9 am the following day. Suppression of the plasma cortisol level to <1.8 m g/dL has the best nega-tive predictive value for Cushing syndrome (5 [EL 4]). A positive test result should be followed by further testing, including 24-hour UFC, midnight salivary cortisol, or a 2-day low-dose dexamethasone suppression test.
5.4.3. 24-Hour UFC
Because UFC levels are not affected by factors that influence corticosteroid-binding globulin, UFC is a better reflection of cortisol levels than plasma cortisol levels and is an integrated measure of excess production of cortisol. An elevated UFC level warrants further investigation, and a UFC that is more than 4 times the normal value is con-sidered diagnostic of Cushing syndrome (27 [EL 4]). Up to 3-fold elevation of UFC can be associated with pseudo-Cushing syndrome attributable to chronic anxiety, depres-sion, alcoholism, or obesity or can accompany use of certain medications (24 [EL 4], 28 [EL 3]). Thus, further confirmatory testing is needed in such a case.
No currently available screening test has a 100% sensitivity and thus, when used alone, cannot completely exclude the presence of hypercortisolism. Because these tests target different aspects or pathophysiologic features of Cushing syndrome, they are complementary in the screening process. Although the best diagnostic strategy for patients with incidentalomas has not been established, the simplest screening test for autonomous cortisol secre-tion from an incidentaloma is a 1-mg overnight dexameth-asone suppression test. If clinical suspicion is high, such as in patients with hypertension, obesity, diabetes mellitus, or osteoporosis, all 3 tests (salivary cortisol, dexamethasone suppression, and UFC) can be used.
A low or suppressed ACTH level would confirm an adrenal origin of Cushing syndrome. The lack of ACTH response during the corticotropin-releasing hormone stim-ulation test may be used in those patients with borderline ACTH levels to distinguish ACTH-dependent from ACTH-independent Cushing syndrome (29 [EL 4]).
5.5. Perioperative Management
In patients with elevated cortisol levels, care should be exercised during the preoperative period to ensure that dia-betes and hypertension, if present, are treated adequately. Because these patients are at increased relative risk for thromboembolic complications, measures must be imple-mented to prevent these complications during the periop-erative period. In the unusual patient with long-standing
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and very high levels of cortisol, the presence of severe immunosuppression must be considered, and prophylactic perioperative antibiotics should be used. Peptic ulcer pro-phylaxis should also be provided.
Patients with Cushing syndrome also have a suppressed HPA axis. Excess cortisol secretion from an adrenocorti-cal adenoma suppresses the production of ACTH by the pituitary. This situation leads to atrophy of the contralateral adrenal gland that is devoid of the trophic effects of ACTH. Once a cortisol-producing adenoma has been removed, physicians must administer glucocorticoid replacement because the remaining adrenal gland is suppressed (30 [EL 3]). High stress doses can usually be weaned to mainte-nance doses of hydrocortisone of approximately 12 to 15 mg/m2 (31 [EL 4]). After an adrenal surgical procedure for Cushing syndrome, physicians should be prepared to treat patients with exogenous glucocorticoids until the HPA axis has recovered. The amount of time for recovery varies from 6 to 18 months after a unilateral adrenalectomy. Doherty et al (32 [EL 2]) reported a median time of 15 months to recover a normal response to the ACTH stimulation test and 19 months (range, 12 to 24) to allow discontinuation of hydrocortisone. During preoperative informed consent discussions, all patients should also be cautioned about the importance of long-term corticosteroid replacement. 6. SUBCLINICAL CUSHING SyNDROME
6.1. Overview
More than 5% of patients with adrenal incidentalo-mas may have SCS (4 [EL 4]). This poorly defined entity may be unique to patients with adrenal incidentalomas. It is characterized by subtle autonomous production of corti-sol by an adrenal tumor, which is usually associated with suppressed production of cortisol from the contralateral gland but no overt clinical features of Cushing syndrome such as atypical fat redistribution, skin fragility, or proxi-mal muscle weakness. Ultimately, the best proof for the presence of this disorder is the development of adrenal insufficiency postoperatively. It has been postulated that long-term exposure to subtle cortisol excess may lead to the metabolic derangements seen in patients with overt Cushing syndrome. Many, although not all, studies found higher prevalences of hypertension, obesity, insulin resis-tance, dyslipidemia, and osteoporosis in patients with SCS (33-36 [EL 3]). Nevertheless, no conclusive evidence exists for a causal relationship between subtle autonomous production of cortisol and such metabolic derangements. In fact, Reincke (37 [EL 4]) theorized that adrenal nod-ules might represent a manifestation of the metabolic syn-drome and develop because of a trophic effect of excess insulin on the adrenal glands. Little information is avail-able about the natural history of this condition. It has been shown that progression to overt Cushing syndrome is a rare event within 1 to 7 years of follow-up (3 [EL 2], 17 [EL 2]). Otherwise, long-term morbidity and mortality data are lacking. Similarly, there are no long-term outcome data for patients who were treated medically with risk factor modi-fication alone versus those who underwent surgical resec-tion of adrenal adenomas.
6.2. Diagnosis
The diagnosis of SCS is made biochemically; however, the variability among diagnostic criteria used in research studies is significant. The 1-mg dexamethasone suppres-sion test is more sensitive than UFC in diagnosing this con-dition (29 [EL 4]). An abnormal result of the dexametha-sone suppression test was the most common biochemical abnormality seen in patients undergoing follow-up by the Study Group on Adrenal Tumors of the Italian Society of Endocrinology (9 [EL 2]) and others who have studied the condition. Consequently, the dexamethasone suppression test is the most frequently used initial screening test, but the appropriate cutoff cortisol level is debated. A cutoff point of 5 m g/dL was associated with a specificity of 100% and a sensitivity of 58% in 1 study, whereas a lower cutoff point of about 1.8 m g/dL had a 75% to 100% sensitivity and a 72% to 82% specificity (38 [EL 3], 39 [EL 3]). Hence, we recommend use of the higher cutoff point (5 m g/dL), which has a higher specificity. In addition, because yearly biochemical reevaluation is recommended for 5 years in patients with nonfunctioning lesions, those patients with false-negative results on the initial evaluation may be iden-tified at later reassessment. A low or suppressed level of ACTH or low dehydroepiandrosterone sulfate concentra-tion supports the diagnosis of SCS. Some investigators have required a second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone sup-pression test, to establish the diagnosis of SCS(9 [EL 2]). A consultation with an endocrinologist experienced in interpreting tests of the HPA axis should be sought (29 [EL 4]).
6.3. Management
At this time, no long-term prospective data are avail-able for guidance in the choice between medical and sur-gical therapy for these patients. Although several studies report improvement in individual cardiovascular risk fac-tors, particularly hypertension, after adrenalectomy, most metabolic derangements persist. Young (40 [EL 4]) has proposed a commonsense strategy to operate on younger patients (<40 years old) with a recent onset or worsening of diabetes, hypertension, or osteoporosis. In older patients with worsening of clinical comorbidities, clinical judg-ment should be used about referral for surgical treatment. In all patients undergoing a surgical procedure for SCS, corticosteroid replacement should be initiated on postop-erative day 1 after a blood sample has been obtained for determination of a morning serum cortisol value, and they should be followed until HPA axis functionality is restored,
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as outlined in the section on Cushing syndrome (see sec-tion 5.5) (41 [EL 3]). There is no need for glucocorticoid replacement intraoperatively in patients with Cushing syn-drome (42 [EL 4], 43 [EL 2]).
7. PHEOCHROMOCyTOMA
7.1. Overview
The presence of a pheochromocytoma should be sus-pected in patients with severe hypertension, tachycardia, palpitations, cardiac arrhythmias, anxiety attacks, weight loss, or sweating. About 15% of patients with a pheochro-mocytoma, however, have no history of hypertension. The management of patients with a pheochromocytoma begins with a biochemical diagnosis. Traditionally, biochemi-cal evidence of the disease has been confirmed with 24-hour fractionated catecholamines, vanillylmandelic acid, and total urinary metanephrines. More recently, because of a high sensitivity rate, plasma free metanephrines and normetanephrines have been measured. Although the urinary measurements have a higher false-negative rate, the plasma levels are associated with a higher false-posi-tive rate. Use of tricyclic antidepressants, decongestants, amphetamines, reserpine, and phenoxybenzamine should be discontinued to eliminate the likelihood of a false-posi-tive result. Review of the literature reveals no level of evi-dence stronger than level 2 to support recommendations for the management of patients with pheochromocytoma (44 [EL 4]).
7.2. History and Physical Examination
The history should be focused on elicitation of the presence of severe hypertension, headaches, weight loss, anxiety attacks, sweating, cardiac arrhythmias, or palpita-tions as well as a family history of syndromes that include pheochromocytomas, such as von Hippel-Lindau disease, multiple endocrine neoplasia type 2, familial paragangli-oma syndrome, or neurofibromatosis syndromes. Physical examination should include measurement of the patient’s blood pressure and pulse, cardiac examination for conges-tive heart failure, and evaluation for excessive sweating, anxiety, and weight loss.
7.3. Biochemical Evaluation
Most pheochromocytomas secrete the catecholamines norepinephrine or epinephrine and, more rarely, dopamine (45 [EL 4]). Traditionally, testing for pheochromocytoma has included a 24-hour urine collection for catecholamines and total or fractionated metanephrines. A 24-hour urine total metanephrine level above 1,800 m g in the appropriate clinical setting is almost always diagnostic for a pheochro-mocytoma, and a plasma metanephrine level exceeding 3 to 4 times normal is highly diagnostic for a pheochromo-cytoma. Reported sensitivities range from 77% to 97%, with specificities from 69% to 98%. Although no single perfect test is available, the measurement of plasma free metanephrines and normetanephrines has the highest sen-sitivity (97% to 100%) and specificity (85% to 89%) and appears to be the best initial test for screening patients for pheochromocytoma (11 [EL 4], 12 [EL 3]).
7.4. Genetic Testing
In light of the association between certain familial syndromes and the development of pheochromocytoma, patients diagnosed with pheochromocytomas at a young age or with multifocal or extra-adrenal disease should be screened with genetic testing for a RET mutation, muta-tions in the VHL gene, and subunits of the succinate dehy-drogenase genes (46 [EL 4], 47 [EL 2], 48 [EL 2]).
7.5. Radiologic Imaging
The sensitivity of CT scanning with use of a contrast agent for the diagnosis of pheochromocytoma is 85% to 95%, with a specificity of 70% to 100%; the sensitivity of MRI exceeds 95%, with a specificity of 100% (49 [EL 3], 50 [EL 3], 51 [EL 4]). Either may be used as the definitive imaging study, depending on availability, cost, and patient preference. High signal intensity on T2-weighted MRI is highly characteristic for pheochromocytoma (52 [EL 4]).
7.6. Malignant Lesion
The diagnosis of a malignant tumor is difficult to establish because there are no reliable radiographic or his-tologic criteria to distinguish benign from malignant pheo-chromocytomas. Malignant pheochromocytoma can be diagnosed if there is extracapsular invasion of the tumor into adjacent structures or if metastatic disease develops. Pheochromocytomas in children, in men, and in patients with familial syndromes are less likely to be malignant (53 [EL 4]). Exceptions would be patients with a family his-tory of malignant pheochromocytoma or with the succinate dehydrogenase B mutation (54 [EL 3]).
7.7. Preoperative Medical Management
Preparation for surgical treatment includes α-adrener-gic blockade for 1 to 3 weeks preoperatively in order to avoid profoundly unstable intraoperative blood pressure. The most commonly used agent is phenoxybenzamine, which is a long-acting α-adrenergic antagonist. Therapy is started at a dosage of 10 mg twice daily, and the dosage is titrated upward to as much as 300 to 400 mg daily in divided doses until the patient becomes normotensive, the hypertension is well controlled, or intolerable side effects develop (orthostatic hypotension, tachycardia, nasal con-gestion, nausea, or abdominal pain) (53 [EL 4], 55 [EL 4]). Other α-adrenergic blocking agents such as doxazo-sin may be used for preoperative preparation of patients with pheochromocytoma (55 [EL 4]). Alpha-methyltyro-sine (metyrosine), which inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, has
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also been used in combination with phenoxybenzamine in the preoperative preparation of patients with pheo-chromocytoma. Small, nonrandomized studies have sug-gested that those patients who receive this combination of drugs experience less hemodynamic instability intraop-eratively in comparison with those given phenoxybenza-mine alone, but this result has not been validated in larger trials (56 [EL 3], 57 [EL 3]). In addition to α-adrenergic blockade, patients are sometimes prepared preoperatively with β-adrenergic blockade. Indications for β-adrenergic blockade, which should be given only after adequate α-adrenergic blockade, include persistent tachycardia, extra-systoles, or arrhythmias. Propranolol is the most common agent used and is administered in dosages of 10 to 40 mg every 6 to 8 hours (53 [EL 4]). Calcium channel blockers have also been used preoperatively and intraoperatively for blood pressure control. Another important component of the preoperative preparation of these patients is encourag-ing liberal fluid and salt intake, inasmuch as the vasocon-stricted state that accompanies pheochromocytomas causes intravascular volume depletion.
7.8. Intraoperative Management of Pheochromocytoma
Close intraoperative monitoring of patients with pheo-chromocytoma is imperative, and anesthetic drugs that precipitate catecholamine secretion should be avoided. An arterial line is used to monitor blood pressure continuously, and a central venous line is used to monitor the intravascu-lar volume status. Occasionally, a pulmonary arterial line may be necessary in patients with clinically significant car-diac disease. Inhaled anesthetics that have the least cardiac depressant effects are generally preferred. Hypertension can be controlled with nitroprusside, nicardipine, nitro-glycerin, or phentolamine. Tachyarrhythmia is treated with a β-adrenergic blocking agent (esmolol), and ventricular arrhythmia is treated with lidocaine. Once the pheochro-mocytoma has been removed, the patient may have severe hypotension that necessitates use of large volumes of intra-venously administered fluid and α-adrenergic agonists. Because of the considerable intraoperative hemodynamic changes that can occur, it is important that an anesthesi-ologist experienced in the management of pheochromocy-tomas be available. During the immediate postoperative period, patients should be monitored for hypotension and hypoglycemia.
7.9. Postoperative Management and Follow-up
The postoperative management of patients with pheo-chromocytoma will depend on whether the tumor is benign or malignant as well as whether the tumor has been com-pletely resected or just debulked. Because there are no definitive diagnostic criteria for malignant pheochromocy-toma, patients with an apparently benign pheochromocy-toma who have undergone a complete surgical resection should have at least annual follow-up postoperatively. One large study found that, in 29 of 176 patients (16%) with an apparently benign tumor, recurrent disease developed dur-ing long-term follow-up with biochemical testing (58 [EL 3]). Patients in whom the tumor was incompletely resected, or those whose primary tumor was resected but who have known metastatic disease, should continue their α-adrener-gic blockade therapy postoperatively for symptom control. Antihypertensive agents should be withheld after resection of localized benign-appearing pheochromocytomas and used only if the patient appears to have underlying essen-tial hypertension. If long-term treatment with a β-adrener-gic blocking agent has been used, it should not be stopped abruptly, especially in older patients with ischemic heart disease.
8. ALDOSTERONOMA
8.1. Overview
One percent of adrenal incidentalomas are associated with autonomous production of aldosterone (59 [EL 3]). Drug resistance and refractory hypertension (need for >3 antihypertensive agents) are common hallmarks of primary aldosteronism attributable to an aldosteronoma, along with spontaneous hypokalemia (serum potassium <3.5 mEq/L) or severe (<3 mEq/L) diuretic-induced hypokalemia. Of note, most patients with primary aldosteronism do not have hypokalemia (60 [EL 3]). Muscle cramping and weakness, headaches, intermittent or periodic paralysis, polydipsia, polyuria, and nocturia are less common symptoms and are generally attributable to the degree of hypokalemia (61 [EL 3], 62 [EL 3]).
In addition to an aldosteronoma, other important rare causes of primary aldosteronism in the setting of an adre-nal incidentaloma include primary (unilateral) adrenal hyperplasia and pure aldosterone-secreting ACC (63 [EL 3], 64 [EL 3], 65 [EL 4]). Primary unilateral adrenal hyper-plasia is an important entity because its proper recognition and surgical treatment can lead to cure of or considerable improvement in hypertension. These variations demon-strate a continuum between adrenal adenoma and hyper-plasia, emphasizing the importance of A VS for subtype evaluation (66-68 [EL 3]).
8.2. Pathology
Adenomas are usually solitary but, on rare occasions, may be bilateral. They are usually less than 2.0 cm in diam-eter, with a mean diameter ranging from 1.5 to 2.0 cm (69 [EL 4]). Typically, primary unilateral adrenal hyperplasia is characterized by micronodular or macronodular hyper-plasia and may confound the diagnosis in older patients, inasmuch as nonfunctioning cortical incidentalomas occur with increasing frequency in patients older than 40 years.
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8.3. Diagnosis and Screening
Determining the ratio of PAC (ng/dL) to PRA (ng/mL per hour) has become the accepted screening modality for primary aldosteronism (65 [EL 4], 70-73 [EL 2], 74-76 [EL 4]). The addition of elevated PAC to a high ARR has increased its specificity as a screening test for primary aldosteronism (4 [EL 4], 10 [EL 4]). One study found that an ARR of more than 30 in conjunction with a PAC value greater than 20 ng/dL had a sensitivity and specificity of 90% and 91%, respectively (73 [EL 2]). Investigators at the Mayo Clinic (4 [EL 4], 10 [EL 4], 77 [EL 2]) found that an ARR greater than 20 in association with a PAC of more than 15 ng/dL was highly sensitive (Fig. 2); however, others have reported lower aldosterone levels in patients with primary aldosteronism (78 [EL 4], 79 [EL 2], 80 [EL 2]). Ratios can be laboratory dependent. Before screening, it is necessary to withhold spironolactone and eplerenone (mineralocorticoid receptor blockers) for 4 to 6 weeks. Diuretics often lead to hypokalemia, and inhibition of the renin-angiotensin system is seen with angiotensin-convert-ing enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). A low PRA in the setting of an ARB or ACE inhibitor should alert one to the possibility of autono-mous aldosterone excess. Thiazide diuretics, calcium chan-nel blockers (dihydropyridines), ACE inhibitors, and ARBs can actually improve the diagnostic discriminatory power of the ARR; in contrast, β-adrenergic blocking agents and clonidine suppress PRA and thus may cause false-positive results. The ARR is most sensitive when blood samples are collected in the morning, after patients have been out of bed for at least 2 hours and have been seated for 5 to 15 minutes.
8.3.1. Confirmation of Primary Aldosteronism
The presence of primary aldosteronism can be con-firmed by demonstrating lack of suppression of aldosterone levels after salt loading. This can be done in 1 of the fol-lowing ways: (1) patients are instructed to add 1 flat tea-spoon of salt to their daily food intake and to consume salty foods (for example, potato chips, pretzels, and pickles) for 72 hours or (2) performance of the saline suppression test: isotonic saline is infused at a rate of 300 to 500 mL/h for 4 hours (caution should be exercised in patients with severe hypertension, those receiving multiple antihypertensive medications, or those with heart failure). A PAC is then determined in the seated patient; a nonsuppressed PAC exceeding 10 ng/dL is confirmatory of primary aldoste-ronism (81 [EL 3]). During the third day, a 24-hour urine collection is performed for aldosterone, sodium, and creati-nine measurement (the latter 2 to verify adequate salt load-
Fig. 2. Algorithm showing use of plasma renin activity (PRA) and plasma aldo-sterone concentration (P AC) and their ratio (P AC/PRA) for diagnosing aldosteron-ism in patients with resistant hypertension, hypokalemia, or both. Modified with permission from Young et al (77 [EL 2]).
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ing [>200 mEq of sodium per 24 hours] and an adequate [true 24-hour] urine collection). In some medical centers, the potassium supplement is withheld at the beginning of the salt-loading test. The measurement of potassium in the urine during salt loading further supports the diagnosis by demonstrating inappropriate potassium excretion: >30 mmol/d. Failure to suppress 24-hour urinary aldosterone levels to less than 12 m g is confirmatory of primary aldo-steronism (10 [EL 4], 65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]).
8.3.2. Aldosterone-Producing Adenoma Versus Idiopathic Hyperplasia
The distinction between aldosterone-producing ade-noma (APA) and primary adrenal hyperplasia (PAH) is crit-ical in evaluating a patient with confirmed primary aldoste-ronism and an adrenal tumor. These 2 entities account for more than 95% of all cases of primary aldosteronism (one-third APA and two-thirds PAH). The distinction is critical because APA is often successfully managed surgically with unilateral adrenalectomy (82 [EL 2]) (Fig. 3), whereas PAH is best managed medically with mineralocorticoid receptor antagonists. This distinction, however, is clouded by a physiologic and pathologic continuum that includes solitary unilateral APAs, bilateral or double APAs, primary unilateral hyperplasia, bilateral micronodular or mac-ronodular hyperplasia, and PAH in conjunction with one or more nonfunctioning adrenal incidentalomas (65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]). Patients with APA are often younger, have more severe hypertension and hypokalemia, and demonstrate higher PAC and urinary aldosterone levels (65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]). Patients with APA often respond better to spironolactone than do those with PAH. Unfortunately, none of these observations is specific enough for subtype evaluation.
8.4. Imaging and Localization
The ability to lateralize the source of aldosterone excess considerably facilitates the selection of patients for surgical treatment who have the greatest likelihood for cure. Although enhanced CT imaging reduces the number of false-negative studies, it clearly increases the number of studies with false-positive results that could lead to either inappropriate withholding of surgical intervention or surgi-cal removal of the wrong gland. This challenge becomes more important with advancing age as the incidence of adrenal incidentalomas increases. A young patient (less
Fig. 3. Algorithm for confirmation of primary aldosteronism. AP A = aldoste-rone-producing adenoma; AVS = adrenal venous sampling; CT = computed tomographic; P AH = primary adrenal hyperplasia. Modified with permission from Young (82 [EL 2]).
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than 40 years) with primary aldosteronism who has an adrenal adenoma larger than 1 cm (uniform, hypodense, no enhancement with an intravenously administered contrast agent) and a morphologically normal contralateral adrenal gland needs no further imaging or evaluation and should be referred for operative intervention. Older patients, patients with bilateral morphologically abnormal glands, or those with a unilateral microadenoma (or microadenomas) need to be considered for bilateral A VS to distinguish APA from PAH and referred to a medical center familiar with this procedure. Patients too infirm for surgical management, those with a limited life expectancy, and those comfortable with medical therapy utilizing mineralocorticoid receptor blockers need no further evaluation (65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]). Patients should discon-tinue the use of spironolactone for 6 weeks and eplerenone for 4 weeks before A VS.
The success of A VS is very much dependent on the operator’s experience; thus, A VS should be relegated to medical centers with a busy interventional radiologist ded-icated to this particular procedure (66-68 [EL 3], 83 [EL 2]). Cannulation of the small right adrenal vein can be a formidable task. On the basis of a review of 47 reports, the success rate for cannulation of the right adrenal vein in 384 patients was 74% (69 [EL 4]). In more than 200 patients with primary aldosteronism treated (during 1990 to 2003) at a major referral center, the success of bilateral adrenal venous catheterization, as demonstrated by high adrenal vein cortisol-to-systemic cortisol levels (under continuous cosyntropin infusion), was approximately 95% (83 [EL 2]). Associated morbidity, including minor bleeding, hema-toma, dissection, and adrenal infarction, is exceedingly rare. Cortrosyn stimulation also augments the aldosterone/ cortisol ratio in patients with APA. Aldosterone/cortisol ratios are used to account for the dilutional effect on the left side due to mixing of blood from the inferior phrenic vein. Corrected aldosterone/cortisol ratios (aldosterone/cortisol ratio of one side to aldosterone/cortisol ratio of the other side) of greater than 4 to 1 are indicative of a unilateral source of aldosterone excess, likely to be responsive to uni-lateral adrenalectomy. Some medical centers perform A VS in all patients who have the diagnosis of primary aldo-steronism, whereas others advocate its selective use (for example, A VS likely not needed in patients younger than age 40 years with a solitary adenoma on CT scan) (83 [EL 2], 84 [EL 3]). If A VS had not been used and CT alone was used to determine laterality in a cohort of 203 patients, 42 patients or 21% would have been inappropriately excluded as candidates for adrenalectomy and 25% might have had an unnecessary or inappropriate adrenalectomy (83 [EL 2], 85 [EL 4], 86 [EL 3]. Thus, selective A VS should be considered as an essential step in distinguishing APA and primary unilateral hyperplasia from PAH in the majority of the patients (68 [EL 3], 84 [EL 3]).8.5. Definitive Therapy
Definitive therapy is essential for patients with pri-mary aldosteronism. Excess plasma aldosterone levels are deleterious, even when hypertension and hypokalemia are adequately controlled. If left untreated or unblocked, aldo-sterone excess can lead to myocardial fibrosis, left ventricu-lar hypertrophy, increased mortality from congestive heart failure, more ischemic events, and increased vascular and clotting abnormalities (87-89 [EL 1], 90-95 [EL 2], 96-99 [EL 3]). Patients who are too old or too ill, those with IHA, and those refusing surgical intervention should be treated with spironolactone (along with other classes of antihyper-tensive agents as needed) or with eplerenone (65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]). Eplerenone is a recently added, corticosteroid-based competitive min-eralocorticoid receptor antagonist. Unlike spironolactone, it has little androgen receptor antagonist activity that often leads to untoward side effects in men (gynecomastia and impotence) and menstrual irregularities in women (71 [EL 2], 100 [EL 3], 101 [EL 3], 102 [EL 2], 103 [EL 1], 104 [EL 1]).
In patients with unequivocal evidence of a unilateral source of aldosterone excess and primary aldosteronism, unilateral laparoscopic adrenalectomy is the treatment of choice. The laparoscopic approach is well suited to patients with primary aldosteronism because the tumors are usually small and benign (105-108 [EL 3], 109 [EL 4], 110 [EL 4]). Although cortex-sparing or partial adrenalectomy has been performed successfully in selected cases, this should be undertaken with caution in patients with a unilateral source of aldosterone excess. Pathologic specimens often demon-strate additional nodules in the same gland of patients with a dominant nodule. Theoretically, the dominant nodule may be nonfunctioning; leaving the other nodules intact could result in a surgical failure. Little long-term morbidity has been noted in patients undergoing a complete unilateral adrenalectomy for primary aldosteronism.
Physiologic outcomes are identical whether laparo-scopic or open adrenalectomy is performed (111 [EL 3]). Patients with a unilateral source of aldosterone excess, as determined by A VS, can expect a 100% cure of hypoka-lemia. More than 90% of patients will show substantial improvement in hypertension, as evidenced by a decrease in the number of and dosing of antihypertensive medi-cations. Approximately 30% to 60% of patients will be able to discontinue all medications; most often, these are younger patients with a shorter clinical course (65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]). Long delays in diagnosis can result in secondary renal changes, eventu-ating in sustained but improved hypertension. In addition, women seem to fare better than men, and a positive family history of hypertension seems to be a negative predictor for long-term control of hypertension (111 [EL 3]). An excel-lent response to spironolactone is often predictive of a suc-
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cessful result from adrenalectomy (67 [EL 3], 112-114 [EL 3]).
Laparoscopic adrenalectomy has advantages over open posterior and anterior adrenalectomy, including shorter operative time, briefer recovery period, less postoperative pain, less blood loss, and diminished overall long-term morbidity (T12 nerve injury, hernias) (106 [EL 3], 108 [EL 3], 115-117 [EL 3]). If laparoscopic transperitoneal adre-nalectomy cannot be accomplished because of an exten-sive prior upper abdominal surgical procedure, a posterior endoscopic or open approach can be used (118 [EL 3]), the former being preferable when expertise with this technique is available. Large aldosterone-secreting tumors (>6 cm) with noncontrast CT attenuation values >10 HU should be suspected of being ACCs and should be managed accord-ingly with an open surgical approach.
8.6. Preparation for Surgical Procedure and Postoperative Care
In preparation for surgical treatment, most patients are given a mineralocorticoid receptor antagonist, along with other necessary antihypertensive and cardiac medications. Potassium stores are repleted cautiously in patients receiv-ing mineralocorticoid receptor antagonists. Postoperatively, potassium chloride replacement is continued until normoka-lemia can be maintained. Mineralocorticoid receptor antag-onists are stopped, and antihypertensive agents are withheld unless blood pressure remains elevated. Antihypertensive medications are added back or weaned in accordance with blood pressure measurements. Normotension without use of any medications may take weeks to months to achieve or may not be possible (65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]). During the perioperative period, β-adrenergic blocking agents should not be abruptly discon-tinued, and they may necessitate continued use in patients receiving long-term therapy for ischemic heart disease.
9. ADRENOCORTICAL CARCINOMA
9.1. Overview
Patients with ACC, a rare malignant lesion, have a poor prognosis. Two determinants of long-term survival are the tumor stage at presentation and curative resection by an experienced surgeon (119 [EL 3]). The goal of an adrenal incidentaloma screening protocol is to identify all patients with ACC (4 [EL 4], 6 [EL 4], 40 [EL 4]). Nevertheless, definitive preoperative diagnosis of ACC is impossible by means of biochemical or cytologic testing. Because the risk of ACC is determined by the radiographic phenotype of a lesion, the strategy is to operate on all patients considered at risk on the basis of the radiographic appearance of the incidentaloma. In a pooled analysis from 26 international studies, ACC constituted <5% of all adrenal incidentalomas (120 [EL 3]). Clearly, however, ACC prevalence depends on the size of the tumor, accounting for 2% of lesions ≤4 cm, 6% of lesions from 4.1 to 6 cm, and 25% of lesions larger than 6 cm (6 [EL 4]).
Two-thirds of all ACCs are hormonally active (121-123 [EL 3]) and tend to manifest with hypercortisolism and virilization (and, rarely, aldosteronism and feminization). In general, however, the ACCs manifesting as radiographic incidentalomas are clinically nonfunctioning tumors.
An incidentaloma with >10 HU attenuation on non-contrast CT is concerning for an ACC, most of which have an attenuation >30 HU (14 [EL 3]). The differential diag-nosis essentially includes pheochromocytoma, metastatic lesion, lipid-poor adenoma, or ACC. Biochemical evalu-ation will exclude a pheochromocytoma and may provide clues to the presence of a hormonally active ACC, although these lesions are typically obvious clinically. The distinc-tion between a metastatic lesion and a primary ACC can be difficult, although radiographic features can occasion-ally be of help in distinguishing between the 2. Most com-monly, metastatic disease manifests in patients with a prior history of a malignant tumor during evaluation (often in consultation with a patient’s oncologist) for a recurrent primary lesion or evidence of other metastatic disease. Judicious use of a biopsy may be helpful after the diagno-sis of a pheochromocytoma has been excluded; however, a CT-guided fine-needle aspiration (FNA) may not distin-guish ACC from a benign adenoma. If metastatic disease is unlikely, an open adrenalectomy for a suspected ACC should be performed (124 [EL 3]).
9.2. Clinical Evaluation
A paucity of clinical symptoms is frequently a fea-ture of a hormonally inactive, albeit large, ACC inciden-tally found radiographically. Some causes of ACC may manifest with flank pain, vague abdominal discomfort, and occasionally fever due to hemorrhage within the tumor. In contrast, hormonally active lesions manifest with dramatic and rapidly progressive symptoms of hypercortisolism, virilization, or, less frequently, feminization or aldoste-ronism. Typically, these lesions are suspected clinically. The initial manifestations of hormonally inactive tumors may be abdominal pressure or fullness attributable to mass compression of adjacent structures.
9.3. Biochemical Evaluation
Detailed hormonal evaluation is critical before sur-gical resection in a patient suspected of having an ACC. Even in patients without clinical stigmas, high circulating levels of steroid precursors may be found. Patients with cortisol-producing ACC are at risk of postoperative adrenal insufficiency attributable to suppression of the HPA axis and will require postoperative corticosteroid replacement. Moreover, any hormonal markers identified before resec-tion will serve as tumor markers during postoperative sur-veillance. Patients need to undergo biochemical evaluation for Cushing syndrome and aldosteronism (if hypertensive),
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as we already described. Clinicians can test for sex steroids and steroid precursors, including androstenedione, testos-terone, dehydroepiandrosterone sulfate, and 17β-estradiol (in postmenopausal women and men only) (119 [EL 3]).
9.4. Radiographic Evaluation
The size of the lesion can be a major predictor of an ACC in an incidentaloma with >10 HU attenuation on non-contrast CT. Multiple studies have addressed this relation-ship (125 [EL 3]). In a recent study of 81 patients, accord-ing to a receiver operating characteristic curve analysis, the cutoff value of tumor size to distinguish between a malig-nant tumor and a benign lesion was 4.75 cm, with a sen-sitivity of 90% and a specificity of 58% (16 [EL 3]). The National Italian Study Group on Adrenal Tumors (125 [EL
3]) determined that the cutoff of 4 cm was associated with
a 93% sensitivity and a specificity of 24%. In addition to HU, other features that cause concern for a malignant lesion include irregular shape and an inhomogeneous pattern of enhancement due to central areas of necrosis. Invasion into surrounding tissues, especially the inferior vena cava, or thrombosis makes the presence of ACC highly likely. For intraoperative planning, a magnetic resonance angiogram may be useful.
9.5. Operative Management
Open adrenalectomy by an experienced surgeon is the procedure of choice. Patients with ACC should undergo en bloc resection of the involved adrenal gland and surrounding tissues (kidney, liver, inferior vena cava). Lymphadenectomy is required as well. Leaving the cap-sule intact during resection reduces the possibility of local recurrence (119 [EL 3]).
Several published reports of laparoscopic adrenalec-tomies have included ACC; most were smaller lesions that were unrecognized as ACC preoperatively. Increased risk of early local recurrence, peritoneal dissemination, and port entry site seeding has been observed (126-129 [EL 3]). On the basis of this evidence, it is prudent to convert to open resection if ACC is suspected intraoperatively.
Adjuvant mitotane treatment may be considered post-operatively in selected patients who have undergone a complete resection of their ACC and have poor prognostic features (130 [EL 4]).
10. METASTATIC DISEASE
10.1. Overview
Metastatic disease to the adrenal glands is rarely found in patients without any history of a known malig-nant lesion. Two pooled analyses of international studies reported a 2.1% to 2.5% prevalence of metastatic lesions among incidentalomas (4 [EL 4], 120 [EL 3]). Even in patients who are undergoing assessment for a suspected malignant tumor, an adrenal metastatic lesion is rarely found at diagnosis. In a series of 1,639 patients suspected of having an occult malignant lesion, an adrenal mass was the initial manifestation in only 5.8% of cases (131 [EL 3]). Lung, breast, stomach, and kidney cancers and mela-nomas and lymphomas most commonly metastasize to the adrenal glands (132 [EL 2]). The majority of adrenal lesions found in a patient with a history of any of these malignant conditions will prove to be a metastatic growth. Pheochromocytomas should be ruled out with biochemi-cal testing in each patient (133 [EL 3]). Another cause of adrenal lesions is ACC; other primary adrenal tumors are less frequent in this group. In the series reported by Lenert et al (133 [EL 3]), only 3 patients (4%) had an ACC.
The process of distinction between a metastatic lesion and a primary adrenal tumor is aided by the knowledge of a past cancer type in a specific patient. Targeted evalua-tion for locoregional recurrence and other metastatic sites should be planned in consultation with an oncologist. In addition to cancer-specific tests, this investigation typically includes contrast-enhanced CT of the chest, abdomen, and pelvis. Fludeoxyglucose (FDG)-positron emission tomog-raphy (PET)/CT is frequently being used in restaging pro-tocols for FDG-avid malignant tumors and can be helpful in documenting other extra-adrenal metastatic lesions. If a definitive diagnosis is needed for oncologic treatment plan-ning, CT-guided FNA can be performed—but only after the diagnosis of pheochromocytoma has been excluded.
10.2. Clinical Evaluation
The history should focus on eliciting a personal history of prior malignant lesions, weight loss, unexplained fevers, adherence to an age-appropriate cancer screening program, family history of malignant conditions, and smoking his-tory. Physical examination may reveal lymphadenopathy or may suggest the presence of a lung mass, breast mass, or skin lesion suspicious for melanoma as well as other cancer-specific findings.
10.3. Radiographic Evaluation
Documentation of radiologic criteria for an adenoma can exclude the presence of a malignant tumor. Metastatic lesions are heterogeneous with irregular margins and are bilateral in 10% to 15% of cases (131 [EL 3], 132 [EL 2], 134 [EL 3]). The size of a metastatic lesion varies widely from 0.8 to 20 cm (131 [EL 3], 132 [EL 2], 135 [EL 3]). Other metastatic disease or lymphadenopathy is present in up to one-third of cases (133 [EL 3]). The role of FDG-PET in metastatic disease is in evolution. It does not distin-guish between an adrenal metastatic growth and an ACC, both of which are FDG-avid lesions. It does, however, have a role in detecting extra-adrenal metastatic disease both in patients with ACC and in those with a history of an FDG-avid malignant tumor (for example, lung or breast cancer) (135 [EL 3]).
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10.4. Further Preoperative Evaluation
All patients with bilateral adrenal involvement should undergo evaluation for adrenal insufficiency (4 [EL 4], 132 [EL 2]). Patents suspected of having a metastatic lesion from a previously treated cancer should undergo evalua-tion, with the assistance of an oncologist, with tumor-spe-cific markers and global imaging (contrast-enhanced CT of the chest, abdomen, and pelvis, site-specific MRI or FDG-PET/CT [or both], and bone scanning) to search for other sites of metastatic involvement.
If metastatic disease is likely and ACC is unlikely on the basis of biochemical, clinical, and radiographic find-ings, FNA biopsy can be used to confirm the diagnosis of metastatic disease. This technique allows distinction between adrenal and nonadrenal tissue (metastatic growth, infection). The risks of FNA are well described and include adrenal hematoma or abscess, abdominal pain, hematuria, pancreatitis, pneumothorax, and tumor recurrence in the biopsy track (40 EL 4]). The patient should undergo bio-chemical evaluation for pheochromocytoma before biopsy, in light of the risk of fatal hypertensive crisis during FNA (136 [EL 3], 137 [EL 3]). Cross-sectional imaging 2 weeks before the planned surgical procedure should be done for suspected metastatic lesions, inasmuch as these can grow rapidly. If there are signs of locoregional invasion or development of disease at other sites, surgical intervention should be canceled.
10.5. Operative Management
Resection of an adrenal metastatic lesion can be per-formed for symptomatic palliation. Surgical resection can improve disease-free survival in a very select group of patients with good control of their extra-adrenal disease and a good performance status (132 [EL 2], 133 [EL 3]). Unfortunately, most patients with adrenal metastatic dis-ease have a poor overall prognosis, with a mean duration of survival of 3 months (132 [EL 2]). DISCLOSURE
Cochairpersons/Primary Writers
Dr. Martha A. Zeiger reports that she does not have any relevant financial relationships with any commercial interests.
Dr. Geoffrey B. Thompson reports that he does not have any relevant financial relationships with any commer-cial interests.
Dr. Quan-Yang Duh reports that he has received advi-sory board honoria from Covidien.
Dr. Amir H. Hamrahian reports that he does not have any relevant financial relationships with any commercial interests.Primary Writers
Dr. Peter Angelos reports that he has received faculty honoraria from Ethicon Endo-Surgery, Inc.
Dr. Dina Elaraj reports that she does not have any relevant financial relationships with any commercial interests.
Dr. Elliot Fishman reports that he has received research grant support from GE Healthcare and Siemens AG.
Dr. Julia Kharlip reports that she does not have any relevant financial relationships with any commercial interests.
American Association of Clinical Endocrinologists Reviewers
Dr. Jeffrey R. Garber reports that he does not have any relevant financial relationships with any commercial interests.
Dr. Jeffrey I. Mechanick reports that he does not have any relevant financial relationships with any commercial interests.
American Association of Endocrine Surgeons Reviewers
Dr. Michael J. Demeure reports that he does not have any relevant financial relationships with any commercial interests.
Dr. William B. Inabnet reports that he has received research grant support from Covidien. REFERENCES
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成人本科学位英语统一考试真题及答案
2017年11月北京成人学士学位英语考试真题及答案 Part I Reading Comprehension (30%) Directions: There are three passages In this part Each passage is followed by some questions or unfinished statements. For each of them there are four choices marked A, B, C and D. You should decide on the best choice and blacken the corresponding letter on the Answer Sheet. Passage 1 Questions 1 to 5 are based on the following passage: In 2014, older Americans fell 29 million times, leading to 7 million injuries, according to a report published last week. About million cases were treated in emergency department, and approximately 800,000 seniors went on to be hospitalized. More than 27,000 falls led to death. (76) And the problem is getting more and more serious. “Older adult falls are increas ing and, sadly, often indicate the end of independence,” said Dr. Tom Frieden. The fallsare preventable, Frieden stressed. He said individuals, families and health care providers can take steps to resist the trend.
列车时刻表计算
第一题 某同学买了一张列车时刻表．他注意到在北京和上海间往返的D31和D32次动车的运行时刻表如下： 他了解了D31次列车由北京开往上海，D32次列车由上海开往北京．这两次列车每天各发一趟．自北京到上海铁路长1463km．根据列车时刻表回答下列问题： （1）你从列车时刻表所列各项内容可以获得哪些信息（写出两条） （2）计算说明D31、D32次列车运行时间差为多少？ （3）计算D39次列车由北京开往上海的平均速度是多少km/h？ 第二题 在火车站，通常可见到列车运行时刻表，其中T114次列车时刻表可知，列车从上海至蚌埠 第三题 下表是T721次空调特快列车的运行时刻表。求：列车全程的运行时间和全程的平均速度分别是多少？在哪两个城市间行驶最快？当天16：00列车的瞬时速度多大？ 第四题 根据如表所示的列车时刻表，计算该次列车从北京南站到上海虹桥站运行的平均速度，以及从曲阜东站到常州北站运行的平均速度． 某次列车的时刻表
火车由南京驶往上海，（1）实际运动的时间是多少？全程的平均速度是多少？（2）火车运行所花时间最多的路段是哪一段？此路段火车的平行速度最小吗？（3）火车运行路程最长的路程是哪一段？此路段火车的平行速度最大吗？ 第六题 第七题 下表是某次列车的运行时刻表，列车准点运行时，由曲靖到安顺这段路程的平均速度为
第八题 根据右边列车时刻表计算出火车-直达特快Z51从北京到南通所需要的时间，如果从北京到南通火车行驶的距离是1325km，请计算出这列火车行驶的平均速度是多少km/h（结果保留整数） 第九题 根据图中的列车时刻表，计算D5次列车从葫芦岛北到沈阳的平均速度．（时间和路程的单位分别用h和km） 第十题 下表是从北京到杭州和从杭州到北京的T31、T32列车时刻表，请你根据表中信息求解下列问题：
1操作系统试题及答案
操作系统试题及答案 一、选择题 1、操作系统的主要功能是管理计算机系统中的（）。 A．程序库 B．数据 C．文件 D．资源 2、在操作系统中，（）是竞争和分配计算机系统资源的基本单位。 A．程序 B．进程 C．作业 D．用户 3、在操作系统中，并发性是指若干个事件（）发生。 A，在同一时刻 B。一定在不同时刻 C．某一时间间隔内 D。依次在不同时间间隔内 4、产生死锁的基本原因是（）和进程推进顺序非法。 A．资源分配不当B．系统资源不足C．作业调度不当D．进程调度不当 5、文件系统采用多级目录结构的目的是（） A．系统开销B．节省存储空间C．解决命名冲突D．缩短传送时间 6、位示图方法可用于（） A．盘空间的管理 B．盘的驱动调度 C．文件目录的查找 D．页式虚拟存储管理中的页面调度 7、下列算法中用于磁盘移臂调度的是( ) A．时间片轮转法 B． LRU算法 C．最短寻找时间优先算法 D．优先级高者优先算法 8、存放在磁盘上的文件，（）。 A．即可随机访问，又可顺序访问 B。只能随机访问 C．只能顺序访问 D。只能读/写不能访问 9、一作业8：00到达系统，估计运行时间为1小时，若10：00开始执行该作业，其响应比是（）A．2 B．1 C．3 D．0.5 10、进程和程序的本质区别是（）。 A．内存和外存 B。动态和静态特征 C。共享和独占使用计算机资源D。顺序和非顺序执行机器指令 11、对于硬盘上存放的信息，物理上读写的最小单位是一个（）。 A．二进位 B。字节 C。物理块 D。逻辑记录 12、多道程序设计是指（） A．在实时系统中并发运行多个程序 B．在分布系统中同一时刻运行多个程序 C．在一台处理机上同一时刻运行多个程序 D．在一台处理机上并发运行多个程序 13、进程从运行状态进入就绪状态的原因可能是（） A．被选中占有处理机 B．等待某一事件 C．等待的事件已发生 D．时间片用完 14、由于系统无法预先知道一个作业未来访问页面的情况，所以（）在实际上是无法实现的。 A．先进先出淘汰算法 B。最近最少使用淘汰算法 C．最优淘汰算法 D。最不常用页面淘汰算法 15、文件系统为每个文件另建立一张指示逻辑记录和物理块之间的对应关系表，由此表和文件本身构成的文件是（）。
学位英语考试真题-文档
2017 年4 月成人高等教育本科毕业生申请学士学位 外国语水平考试广东) A 英语试卷一 Part I Dialogue completion (15 points) Part II Reading Comprehension (40 points) Part III Vocabulary and Structure (20 points) Part IV Cloze (10 points) 考生须知 1.本试卷分试卷一和试卷二两部分，试卷一满分85分，试卷二满分15分，考试时间共 120分钟。 2. 本试卷一为A型试卷，请将答案用2B铅笔填涂在A型试卷一答题卡上，答在试卷或其他类型答题卡上的无效。答题前请核对试卷一答题卡是否为A型卡，若不是，请要求监考人员予以更换。 3. 答题卡上正确的填涂方法为：在代表答案的字母上划线，如[A] [B] [C] [D] Part I Dialogue Completion (l5 points) Directions: There are I5 short in complete dialogues in this part, each followed by four choices marked A, B, C and D. Choose the one that best complete the dialogue and mark your answer on the ANSWER Sheet. 1.Speaker A: ______ I guess I’m addicted to the Internet. Speaker B: So you’d better quit surfing the Net deep into the night. A.I knew it. B. Why, it’s a pity! C. I can't help it. D. What seems to be the problem? 2. Speaker A: Don't be sad, I'm sure things will change for the better soon. Speaker B: ______. A. That sounds awful. B. Yes you're probably right. C. I hope not! D. You are welcome! 3. Speaker A: Can I get some information about the training program here? Speaker B: _______ A. Yes, you do B. Go ahead C. You certainly can D. That's fun 4. Speaker A: Tom, would you like to go to a party this Saturday? SpeakerB:______ What kind of party? Speaker A: It's a birthday party. A. Sounds good B. Looks nice C. Seems all right D. Feels OK 5. Waiter: ______? Customer: Yes, I'll have a steak, medium rare, with French fries. A. What do you want to eat B. Have you decided what to do yet C. Excuse me, are you ready to order now D. Sorry, but who'd like to order
历年学位英语试题及答案
广东省学位英语历年真题及答案 - 百度文库 百度文库 搜索文档或关键词 普通分享 > 广东省学位英语历年真题及答案 VIP专享文档 2020-05-09 66页 用App免费查看 I. 会话技能15道15分15分钟 II. 阅读理解20道40分40分钟 III. 词汇和语法40道20分25分钟 IV. 完形填空10道10分10分钟 V . 短文写作100～120个词15分30分钟 考试总时间：120分钟 2011年广东学位英语考试试题及答案 PartⅠ Vocabulary and Structure (25 points, 30 minutes) Directions: There are 50 incomplete sentences in this part. For each sentence there are four choices marked A), B), C) and D). Choose the ONE answer that best completes the sentence. Then mark the corresponding letter on the Answer Sheet with a single line through the center. 1. By 1929, Mickey Mouse was as popular ____ children as Coca Cola. A) for B) with C) to D) in 2. When you buy anything expensive, never forget to ask for the ____ from the shop. A) receipt B) trust C) render D) tale 3. The financial support is decided not only according to your GRE score, but also according to your ____ in college. A) intelligence B) policy C) performance D) statement 4. Professor Smith is also the ____ of the international program office. If you have any problem when you study here, you may go to him for help. A) detective B) president C) manager D) director 5. We do not have a ____ school in our institute. The highest degree we provide for the students is a B. A. and a B. S. .
(完整word)路程速度时间应用题(三年级)
路程速度时间应用题 解决路程、速度、时间这类问题，我们必须要理清这三者之间的数量关系： 路程=速度×时间；时间＝路程÷速度；速度＝路程÷时间。 例1. 一辆大巴车从张村出发，如果每小时行驶60千米，4小时就可以到达李庄。结果只用了3个小时就到达了。这辆汽车实际平均每小时行驶多少千 米？ 试一试： 一列火车，提速前平均每小时行驶71千米，从秦皇岛到邯郸用12小时，提速后平均每小时行驶95千米，提速后从秦皇岛开往邯郸大约需要几小时？ 例2. 石家庄到承德的公路长是546千米。红红一家从石家庄开车到承德游览避暑山庄，如果平均每小时行驶78千米，上午8时出发，那么几时可以到 达？ 试一试： 一辆从北京到青岛的长途客车，中途经过天津和济南。北京到天津137km；天津到济南360km；济南到青岛393km。早晨6：30从北京发车，平均每小时行驶85千米，大约何时可以到达青岛？
例3.从小明家到济南共360千米，爸爸开车上午10时从家出发，平均每小时行驶110千米，他下午1时能到达济南吗？ 试一试： 小楠家到学校的路程长302米，他下午1时56分从家出发，2时1分到达学校。小楠平均每分钟大约走多少米？ 课外作业 1.从甲地到乙地936千米，一辆车3小时走216千米，照这样的速度， 从甲地出发经过几小时后可以到达乙地？ 2.汽车以72千米/时的速度从甲地到乙地，到达后立即以48千米/时的 速度返回甲地，求该车的平均速度 3. 一辆大巴车从深圳出发开往广西，原计划每小时行驶60千米，8小时 就可以到达目的地。结果只用了6个小时就到达了。这辆汽车实际平 均每小时行驶多少千米？
计算机操作系统试题库完整
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广东省学士学位英语历年真题 附答案
2009年广东学士学位英语历年真题考试附答案 Paper One 试卷一90 minutes Part I Dialogue Completion (15 points) Directions: There are 15 short incomplete dialogues in this part, each followed by 4 choices marked A, B, C and D. Choose the best one to complete the dialogue and mark your answer on the ANSWER SHEET with a single line through the center. 1. Jenny: Shall I go and tell Mr. Fairbanks about our proposal? Jackie: ___________. A. Yes, you go B. Yes, go C. Yes, let’s D. Yes, please 2. Mori: It’s a plea sure to meet you here. Kaco: __________. A. Pleased to meet you, too B. Thank you so much C. I didn’t expect to see you here D. You’re too hospitable 3. Williams: Excuse me. I’m looking for a present for my son. I have no idea what to get him, Can you help me? Sales girl: ____________. A. Of course I can
3 操作系统真题
16、CPU执行完一条指令后检查是否有中断事件发生，若有则硬件进行中断向量的交换工 作，以完成B A、中断扫描 B、中断响应 C、中断处理 D、中断请求 17、下列哪一因素对时间片大小的设置没有影响？D A、系统响应时间 B、就绪进程数目 C、CPU能力 D、进程就绪时间 18、在采用多线程技术的系统中，下列关于线程的描述哪些是正确的？C I．每个线程有自己的标识符II.每个线程拥有系统分配给它的独立使用的地址空间 III.线程有状态及状态转换 A、仅I和II B、仅II和III C、仅I和III D、都正确 19、若系统中有若干进程共享5个R类资源，下列哪一种情况不可能发生死锁？A A、系统中有6个进程，每个进程需要1个资源 B、系统中有5个进程，每个进程需要2个资源 C、系统中有4个进程，每个进程需要3个资源 D、系统中有3个进程，每个进程需要4个资源 20、在硬件进行地址映射的过程中，通过检查页表中的哪一项确定所需页面没有调入内存？A A、驻留位 B、访问位 C、修改位 D、保护位 21、下列关于快表的叙述中，哪些是正确的？D I．快表的内容是页表的子表 II．对快表的查找是按内容并行进行的 III．当切换进程时，要刷新快表 A、仅I和II B、仅II和III C、仅I和III D、都正确 22、使用文件前要先打开文件。在执行完打开文件系统调用后，系统会返回用户一个C A、文件长度 B、内存地址 C、文件描述符 D、文件打开方式 23、设计文件系统时应尽量减少访问磁盘的次数，以提高文件系统的性能。下列各种措施中，哪些可以提高文件系统的性能？D I．块高速缓存II.磁盘的驱动调度III.目录项分解 A、仅I和II B、仅II和III C、仅I和III D、都可以 24、下列关于操作系统设备管理的叙述中，哪一条是不正确的？B A、通过“设备类、相对号”可以指定独占设备 B、静态分配策略可以提高设备利用率 C、磁盘是典型的共享设备 D、SPOOLING技术是一种虚设备技术 填空题 6、创建一个进程的主要任务是为它分配内存空间和建立一个【进程控制块】 7、进程运行时，在一段时间内，其程序的执行往往呈现出高度的局部性，包括时间局部性和【空间】局部性 8、在一个多层次的树形文件目录中，查找一个文件可以从根目录开始，也可以从【当前】目录采用相对路径名开始查找。 答案 BDCAA DCDB 填空题：6、进程控制块7、空间8、当前
学位英语考试真题答案 完整版
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C. I think I do. D. what else? Dialogue Two Speaker A: I just recently moved into the neighborhood. Speaker B: __5__ How recently? Speaker A: Just last week. Speaker B: What kinds of things have you been doing out there? Speaker A: __6__ Speaker B: why not? Speaker A: I don't know what to do. Speaker B: There're all sort of things to do. Speaker A: __7__ Speaker B: Shopping, or seeing a movie, or even going to the beach. Speaker A: That sounds great. A. I haven't been doing much. B. Really? C. How are you doing? D. Like what? Dialogue Three
2015年11月1日学位英语考试真题答案(完整版)
2015年11月1日学位英语考试真题答案（完整版） Part ⅠDialogue completion (10 points) Dialogue one Tom: Do you go to college? Mike: Yes. __1__ Tom: What college do you go to? Mike: I go to Pasadena City College. Tom: Do you like it? Mike: Oh, yes. __2__ Tom: why do you like it? Mike: Because it has great teachers. Tom: __3__ Mike: I like all my classmates, too. Tom: Anything else? Mike: Yes. __4__ A. It’s not expensive! B. You bet. C. I think I do. D. what else? Dialogue Two Speaker A: I just recently moved into the neighborhood. Speaker B: __5__ How recently? Speaker A: Just last week. Speaker B: What kinds of things have you been doing out there? Speaker A: __6__ Speaker B: why not? Speaker A: I don't know what to do. Speaker B: There're all sort of things to do. Speaker A: __7__ Speaker B: Shopping, or seeing a movie, or even going to the beach. Speaker A: That sounds great. A. I haven't been doing much. B. Really? C. How are you doing? D. Like what? Dialogue Three George: Did you hear about the robbery? Johnny: No, I didn't hear about it.
列车时刻表
榆林始发列车： 1、榆林（始发站）——延安——上海（到达站） 榆林（快速K8163次）8:00开车，11:47到达延安，延安（快速K559次）12:40开车，次日14:35到达上海。 途经站点：榆林——绥德——子长——延安——西安——渭南——灵宝——三门峡——洛阳——郑州——开封——商丘——徐州——蚌埠——南京——镇江——常州——无锡——苏州——昆山——上海 2、榆林（始发站）——西安（到达站） 榆林（快速K8157/6次）20:00开车，次日6:12到达西安。（原来是17:54开车，次日6:12到达西安） 途经站点：榆林——米脂——绥德——清涧——子长——延安北——延安——富县东——蒲城东——阎良——三原——咸阳——西安 3、榆林（始发站）——西安（到达站） 榆林（普客7005次）7:20开车，20:20到达西安。（原来8:00开车，21:25到达） 途经站点：榆林——闫庄则——鱼河——镇川——米脂——绥德——田庄镇——清涧——子长——蟠龙镇——延安北——延安——甘泉北——甘泉——道镇——富县——明义沟——督河村——洛川——弥家河——黄陵——刘家沟——生芝渠——贺家河——蔡河——张家船——狄家河——洞子崖——韩家河——坡底村——苏家坡——孙镇——杜赵——蒲城——集北——钟家村——张桥——新丰镇V场——临潼——西安 榆林火车站过往列车： 1、包头（始发站）——榆林——北京西（到达站） 包头（直快K1117/6次）17:10开车，21:45到达榆林，21:49榆林开车，次日11:58到达北京西。 途经站点：包头——榆林——绥德——吕梁——汾阳——清徐——太原——阳泉北——石家庄北——晋州——辛集——衡水——肃宁——任丘——霸州——黄村——北京西 2、包头（始发站）——榆林——邯郸（到达站） 包头（快速K219/8/9次）19:24开车，23:57到达榆林，0:10榆林开车，次日11:09到达邯郸。 途经站点：包头——榆林——绥德——吕梁——文水——太原——阳泉北——石家庄——邢台——邯郸 3、呼和浩特（始发站）——榆林——西安（到达站） 呼和浩特（快速K1673次）21:35开车，次日5:05到达榆林，5:09榆林开车，13:50到达西安。 途经站点：呼和浩特——察素齐——包头东——包头——榆林——米脂——绥德——延安——蒲城东——西安 4、包头（始发站）——榆林——西安（到达站） 包头（快速K1675次）14:45开车，19:41到达榆林站，19:47榆林开车，次日6:02到达西安。 途经站点：包头——榆林——米脂——绥德——清涧——子长——延安北——延安——甘泉北——富县东——蒲城东——张桥——西安 5、包头——榆林——太原 包头（直快2863/2次）21:47开车，次日2:23到达榆林站，2:25榆林开车，8:15到达太原
操作系统试题及答案
操作系统试题一 一、单选题（每小题1分，共20分） 1、操作系统中采用多道程序设计技术提高CPU和外部设备的【A 】。 A、利用率 B、可靠性 C 、稳定性D、兼容性 2、如果分时操作系统的时间片一定，那么【C】，则响应时间越短。 A、内存越少 B、内存越多 C、用户数越少 D、用户数越多 3、若把操作系统看作资源管理者，下列的【C】不属于操作系统所管理的资源。 A、CPU B、内存 C、中断 D、程序 4、操作系统是通过【D 】感知进程存在的。 A、程序名 B、进程的状态 C、中断 D、进程控制块 5、当【B 】时，进程从执行状态变为就绪状态。 A、进程被进程调度程序选中 B、时间片用完 C、等待某一事件 D、等待的事件发生 6、以下的进程状态变化中，不可能发生的变化是【D 】。 A、执行状态到就绪状态 B、等待状态到就绪状态 C、执行状态到等待状态 D、等待状态到执行状态 7、若P、V操作的信号量S初值为2，当前值为-3，则表示有【D】
个等待进程。 A、0个 B、1个 C、2个 D、3个 8、P、V操作是【A】 1 / 22 A、两条低级进程通信原语 B、两条高级进程通信原语 C、两条系统调用命令 D、两组不同的机器指令 9、用V操作唤醒一个等待进程时，被唤醒的进程状态变为【B 】。 A、等待 B、就绪 C、执行 D、完成 0、资源的有序分配策略破坏【D 】条件，是一种死锁预防策略。 A、互斥条件 B、保持和请求条件 C、不剥夺条件 D、环路等待条件 1、银行家算法是一种【B 】算法。 A、死锁预防 B、死锁避免 C、死锁检测 D、死锁解除 2、某系统中有同类资源10个，每个进程的资源需求量为3个，则不会发生死锁的最大并发进程数为【C】 A、2 B、、4 D、5 3、分区管理中采用首次适应分配算法时，应把空闲区按【C】次序进行管理。 A、大小递增 B、大小递减 C、地址递增 D、地址递减 4、很好地解决了内存碎片问题的存储管理方案是【C 】。
学位英语试题和答案
考试须知 1、本次考试试卷有试题册（试卷一）和答题纸（Answer Sheet)两种，答题时间 为120分钟。 2、请考生用钢笔在Answer Sheet上写上、学号、专业班级。 3、请考生在Answer Sheet上答题，写在试题册上的答案一律作废。 4、选择题每题只能选一个答案，多选作废。选定答案后，在Answer Sheet中找到相应题号，将答案对应字母（A\B\C\D）填写在题号后的括号里。注意保持字迹清晰工整，容易识别。由于字迹潦草、答案模棱两可甚至无法识别者，一律判为0分，责任由考生本人负责。 5、简答题、翻译和作文等主观题部分的答题请考生用钢笔书写在Answer Sheet 指定位置上。 6、考试结束，考生不得将试题册和答题纸带出考场。请把试题册和答题纸分别 上交监考老师。 Test 15 Part I. Situational Conversations (10%) Directions:In this part, there are ten short incomplete dialogues between two speakers, each followed by four choices marked A, B, C and D. Choose the one that most appropriately suits the conversational context and best completes the dialogue. Mark your answer on the ANSWER SHEET with a single line through the center of the corresponding letter． 1. Vivian: Christina! I haven’t seen you for ages. How are you? Christina: Fine. And you? Vivian: Pretty good. How’s Christopher? Christina: Oh, don’t you know? We got divorced two years ago. Vivian: __________ A. Hope you’ll be better. B. It is really a problem. C. What a pity! D.Oh, I’m sorry. 2. Richard: How much is it to rent an economy car? Tina: $15.00 a day or $95.00 a week, unlimited mileage. Richard: Could I have one for tomorrow morning? Tina: ___________________________ Richard: Sure. Here it is.
操作系统试题
操作系统试题 课程代码：02326 第一部分选择题(共30分) 一、单项选择题(本大题共20小题，每小题1分，共20分) 在每小题列出的四个备选项中只有一个是符合题目要求的，请将其代码填写在题后的括号内。错选、多选或未选均无分。 1．设计分时操作系统的主要目标是（） A．吞吐量和周转时间B．交互性和响应时间 C．灵活性和可适应性D．可靠性和完整性 2．用户通常利用键盘命令、系统调用命令请求操作系统服务，有时也会用（） A．宏指令B．汇编语言 C．作业控制语言D．计算机高级语言 3．操作系统中的中断处理程序很大部分是处理（）中断的。 A．程序B．访管 C．I/O D．外部 4．用作业控制语言编写作业控制说明书主要用在（）系统。 A．分时B．实时 C．批处理D．多CPU 5．采用多道程序设计能（） A．增加平均周转时间B．发挥且提高并行工作能力 C．缩短每道程序执行时间D．降低对处理器调度的要求 6．程序状态字反映了（）状态。 A．进程调度B．作业调度 C．与处理器有关的系统D．主存储器分配 7．为了对紧急进程或重要进程进行调度，调度算法应采用（） A．先来先服务B．轮转法 C．优先权调度D．短执行时间优先调度 8．单个分区的存储管理不适用于（） A．个人计算机B．专用计算机 C．单道程序系统D．多道程序系统 9．页式管理中的地址结构分页号和页内地址两部分，它（） A．仍是线性地址B．是个二维地址 C．是个三维地址D．是个四维地址 10．把逻辑文件存放到存储介质上时，如果组织成（）文件，则逻辑记录可以按任意次序存放在不相邻的存储块中。 A．流式B．记录式 C．顺序D．链接 11．为了保证存取文件的可靠性，用户要求读一个文件前应首先请求系统执行（）文件操作。 A．打开B．建立 C．关闭D．删除 12．计算机系统中往往对每一台设备确定一个编号以识别各台设备，这些编号称为设备的（）号。 A．绝对B．相对 C．逻辑D．类 13．Spool技术是一种实现虚拟（）的技术。
学位英语考试练习题(四)
学位英语考试练习题（四） Part I Reading Comprehension A teddy bear is delivered to No. 10 Downing Street after the birth of Prime Minister Tony Blair and wife Cherie’s fourth child. Britain’s baby alert is over-Cherie Blair gave birth to a boy. Mrs. Blair, 45, wife of Prime Minister Tony Blair, had the baby this morning. The baby will be named Leo after the prime minister’s father, his office announced, the baby weighed in at 6 pounds, 12 ounces. Mother, father and the baby boy returned to 10 Downing Street-the prime minister’s official residence-after the birth, a spokesman said. The baby is the couples’ fourth child. “Cherie and the baby are absolutely fine,” Blair said today outside his Downing Street residence. “He is a gorgeous little boy. They are resting right now.” Blair, dressed casually in an open shirt, appeared emotional about the birth, the first of his four children whose birth he has been at from beginning to end. “this is the first time I’ve seen the whole thing though,” he said. “it was quite a struggl e, really, for Cherie.” The switchboard was reportedly lit up with calls from world leaders wishing them well, including a call from Hillary Colliery Clinton. Former prime minister John Major was the first public figure to get through on the phone at 7 a.m. on Saturday. The baby came after a 12-year gap from the Blairs other three children-Euan, 16, Nicky, 14, and Kathryn. He is the first to be born to a serving Buitish prime minister in over 150 years. News of the pregnancy took Cherie and the rest of the nation by surprise when it was announced last year. After decades of much older occupants at No.10 Downing Street, the Blairs’ arrival at the prime minister’s residence with their children and assorted toys in tow was hailed as a breath of fresh air.
邯郸到保定火车时刻表
邯郸到保定火车时刻表-邯郸到保定火车票价查询 序号车次 始发站- 终点站 出发 站 出发时 间 到达 站 到达时 间 运行时 长 里 程 硬 座 软 座 硬卧 下 软卧 下 1 K590重庆-北 京西 邯郸00:15 保定03:26 03时 11分 296 44 - 107 162 2 1364成都-北 京西 邯郸00:36 保定04:08 03时 32分 296 39 - 101 154 3 K118攀枝花- 北京西 邯郸00:47 保定03:56 03时 09分 296 44 - 107 162 4 2165/2164长治北- 北京西 邯郸00:53 保定04:48 03时 55分 296 39 - 101 154 5 K270洛阳-北 京西 邯郸01:01 保定04:16 03时 15分 296 44 - 107 162 6 K402周口-北 京西 邯郸01:09 保定04:25 03时 16分 296 44 - 107 162 7 K158湛江-北 京西 邯郸01:17 保定04:31 03时 14分 296 44 - 107 162 8 1482/1483南昌-包 头 邯郸02:03 保定06:35 04时 32分 296 39 - 101 154 9 K750信阳-北 京西 邯郸02:14 保定06:59 04时 45分 296 44 - 107 162 10 K186衡阳-北 京西 邯郸04:13 保定07:55 03时 42分 296 44 - 107 162 11 K472/K473昆明-北 京西 邯郸04:21 保定09:06 04时 45分 296 44 - 107 162 12 T232西安-北 京西 邯郸04:41 保定07:42 03时 01分 296 44 - 107 162 13 T233/T232延安-北 京西 邯郸04:41 保定07:42 03时 01分 296 44 - 107 162 14 K184南阳-北 京西 邯郸05:01 保定09:12 04时 11分 296 44 - 107 162 15 K268怀化-北 京西 邯郸05:13 保定08:47 03时 34分 296 44 - 107 162 16 T56宝鸡-北 京西 邯郸05:32 保定08:31 02时 59分 296 44 - 107 162 17 T147/T146南昌-北 京西 邯郸05:59 保定08:45 02时 46分 296 44 - 107 162
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