Alaa Al Nofal

The Accuracy of Thyroid Nodule Ultrasound to Predict Thyroid Cancer: Systematic Review and Meta-Analysis

CONTEXT Significant uncertainty remains surrounding the diagnostic accuracy of sonographic features used to predict the malignant potential of thyroid nodules. OBJECTIVE The objective of the study was to summarize the available literature related to the accuracy of thyroid nodule ultrasound (US) in the prediction of thyroid cancer. METHODS We searched multiple databases and reference lists for cohort studies that enrolled adults with thyroid nodules with reported diagnostic measures of sonography. A total of 14 relevant US features were analyzed. RESULTS We included 31 studies between 1985 and 2012 (number of nodules studied 18,288; average size 15 mm). The frequency of thyroid cancer was 20%. The most common type of cancer was papillary thyroid cancer (84%). The US nodule features with the highest diagnostic odds ratio for malignancy was being taller than wider [11.14 (95% confidence interval 6.6-18.9)]. Conversely, the US nodule features with the highest diagnostic odds ratio for benign nodules was spongiform appearance [12 (95% confidence interval 0.61-234.3)]. Heterogeneity across studies was substantial. Estimates of accuracy depended on the experience of the physician interpreting the US, the type of cancer and nodule (indeterminate), and type of reference standard. In a threshold model, spongiform appearance and cystic nodules were the only two features that, if present, could have avoided the use of fine-needle aspiration biopsy. CONCLUSIONS Low- to moderate-quality evidence suggests that individual ultrasound features are not accurate predictors of thyroid cancer. Two features, cystic content and spongiform appearance, however, might predict benign nodules, but this has limited applicability to clinical practice due to their infrequent occurrence.

ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis

CONTEXT The diagnosis of adrenal insufficiency is clinically challenging and often requires ACTH stimulation tests. OBJECTIVE To determine the diagnostic accuracy of the high- (250 mcg) and low- (1 mcg) dose ACTH stimulation tests in the diagnosis of adrenal insufficiency. METHODS We searched six databases through February 2014. Pairs of independent reviewers selected studies and appraised the risk of bias. Diagnostic association measures were pooled across studies using a bivariate model. DATA SYNTHESIS For secondary adrenal insufficiency, we included 30 studies enrolling 1209 adults and 228 children. High- and low-dose ACTH stimulation tests had similar diagnostic accuracy in adults and children using different peak serum cortisol cutoffs. In general, both tests had low sensitivity and high specificity resulting in reasonable likelihood ratios for a positive test (adults: high dose, 9.1; low dose, 5.9; children: high dose, 43.5; low dose, 7.7), but a fairly suboptimal likelihood ratio for a negative test (adults: high dose, 0.39; low dose, 0.19; children: high dose, 0.65; low dose, 0.34). For primary adrenal insufficiency, we included five studies enrolling 100 patients. Data were only available to estimate the sensitivity of high dose ACTH stimulation test (92%; 95% confidence interval, 81-97%). CONCLUSION Both high- and low-dose ACTH stimulation tests had similar diagnostic accuracy. Both tests are adequate to rule in, but not rule out, secondary adrenal insufficiency. Our confidence in these estimates is low to moderate because of the likely risk of bias, heterogeneity, and imprecision.

Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis

BACKGROUND Menopausal hormone therapy is widely used to alleviate climacteric symptoms but may increase the risk of venous and arterial vascular events. OBJECTIVE The objective was to synthesize the evidence about the risk of vascular events in postmenopausal women who use oral estrogen therapy (ET) and transdermal ET. METHODS We searched bibliographical databases through August 2013 for longitudinal comparative studies that enrolled postmenopausal women using either oral or transdermal ET and reported the outcomes of interest: venous thromboembolism (VTE), pulmonary embolism, deep venous thrombosis (DVT), myocardial infarction (MI), and stroke. Two reviewers independently selected and appraised studies. Outcomes were pooled using random effects meta-analysis and were reported as risk ratio (RR) and 95% confidence interval (CI). RESULTS We included 15 observational studies at moderate risk of bias with follow-up of 3 to 20.25 years. When compared to transdermal ET, oral ET was associated with increased risk of a first episode of VTE (RR, 1.63; 95% CI, 1.40-1.90; I(2) = 53%), DVT (RR, 2.09; 95% CI, 1.35-3.23; I(2) = 0 %), and possibly stroke (RR, 1.24; 95% CI, 1.03-1.48; a single case-controlled study), but not MI (RR, 1.17; 95% CI, 0.80-1.71; I(2) = 74%). CONCLUSION Observational evidence warranting low confidence suggests that compared to transdermal ET, oral ET may be associated with increased risk of VTE and DVT, but not MI.

Menopausal Hormone Therapy and Mortality: A Systematic Review and Meta-Analysis

OBJECTIVES The objective was to assess the effect of menopausal hormonal therapy (MHT) on all-cause and cause-specific mortality. METHODS We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus) from inception until August 2013. We included randomized controlled trials (RCTs) of more than 6 months of duration comparing MHT with no treatment. Pairs of independent reviewers selected trials, assessed risk of bias and extracted data. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using the random-effects model. RESULTS We included 43 RCTs at moderate risk of bias. Meta-analysis showed no effect on mortality (RR 0.99 [95% CI, 0.94-1.05]), regardless of MHT type or history of preexisting heart disease. No association was found between MHT and cardiac death (RR 1.04 [95% CI 0.87-1.23]) or stroke (RR 1.49 [95% CI 0.95-2.31]). Estrogen plus progesterone use was associated with a likely increase in breast cancer mortality (RR 1.96 [95% CI 0.98-3.94]), whereas estrogen use was not. MHT use was not associated with mortality of other types of cancer. In 5 trials, MHT was likely started at a younger age: 2 RCTs with mean age less than 60 and 3 RCTs with MHT started less than 10 years after menopause. Meta-analysis of these 5 RCTs showed a reduction of mortality with MHT (RR 0.70 [95% CI 0.52-0.95]). CONCLUSION The current evidence suggests that MHT does not affect the risk of death from all causes, cardiac death and death from stroke or cancer. These data may be used to support clinical and policy deliberations about the role of MHT in the care of symptomatic postmenopausal women.

PREDICTORS OF BIOCHEMICAL REMISSION AND RECURRENCE AFTER SURGICAL AND RADIATION TREATMENTS OF CUSHING DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVE We conducted a systematic review and meta-analysis to synthesize the evidence about predictors that may affect biochemical remission and recurrence after transsphenoidal surgery (TSS), radiosurgery (RS), and radiotherapy (RT) in Cushing disease. METHODS We searched multiple databases through December 2014 including original controlled and uncontrolled studies that enrolled patients with Cushing disease who received TSS (first-line), RS, or RT. We extracted data independently, in duplicates. Outcomes of interest were biochemical remission and recurrence. A meta-analysis was conducted using the random-effects model to estimate event rates with 95% confidence intervals (CIs). RESULTS First-line TSS was associated with high remission (76% [95% CI, 72 to 79%]) and low recurrence rates (10% [95% CI, 6 to 16%]). Remission after TSS was higher in patients with microadenomas or positive-adrenocorticotropic hormone tumor histology. RT was associated with a high remission rate (RS, 68% [95% CI, 61 to 77%]; RT, 66% [95% CI, 58 to 75%]) but also with a high recurrence rate (RS, 32% [95% CI, 16 to 60%]; RT, 26% [95% CI, 14 to 48%]). Remission after RS was higher at short-term follow-up (≤2 years) and with high-dose radiation, while recurrence was higher in women and with lower-dose radiation. Remission was after RT in adults who received TSS prior to RT, and with lower radiation doses. There was heterogeneity (nonstandardization) in the criteria and cutoff points used to define biochemical remission and recurrence. CONCLUSION First-line TSS is associated with high remission and low recurrence, while RS and RT are associated with reasonable remission rates but important recurrence rates. The current evidence warrants low confidence due to the noncomparative nature of the studies, high heterogeneity, and imprecision.

Accuracy of thyroid nodule sonography for the detection of thyroid cancer in children: Systematic review and meta-analysis

Thyroid ultrasound (US) is a widely used tool for evaluating thyroid nodules. Various US features have been suggested as predictors of thyroid cancer in children.

Thiazide Diuretics in the Management of Young Children with Central Diabetes Insipidus.

OBJECTIVE To report our experience in treating infants and toddlers with central diabetes insipidus (DI) with thiazide diuretics. STUDY DESIGN A retrospective chart review of all infants and toddlers who were treated with thiazide diuretics for central DI at the Mayo Clinic between 1996 and 2014. RESULTS Our cohort consisted of 13 patients. The median age at the start of therapy was 6 months (IQR, 1-14 months). Eight patients were given chlorothiazide at a starting dose of 5-10 mg/kg/day, and 5 patients were treated with hydrochlorothiazide at a starting dose of 1-2 mg/kg/day. The median age at the cessation of thiazide therapy was 18 months (IQR, 11.5-39 months). The main reason for stopping was the lack of continued response, in addition to hypernatremia. There was no hospitalization secondary to hyponatremia and only 1 hospitalization secondary to hypernatremia while receiving thiazide therapy. Calcium was checked periodically in 7 of the 13 patients, and 2 of these 7 patients had persistent hypercalcemia. CONCLUSION Thiazide diuretics appear to be safe and effective in treating infants with central DI. They can be continued after the introduction of solid food, and until a lack of response is observed.

GLUCOCORTICOID REPLACEMENT REGIMENS IN CHRONIC ADRENAL INSUFFICIENCY: A SYSTEMATIC REVIEW AND META-ANALYSIS

OBJECTIVE Various glucocorticoid (GC) regimens have been used in the treatment of patients with adrenal insufficiency, yet the differences between such regimens on health outcomes are unclear. We performed a systematic review and meta-analysis to compare the effects of GC regimens on quality of life (QoL), bone density, incidence of adrenal crisis, and death. In pediatric studies, we also searched for final adult height. METHODS We searched 6 databases through July 2016. Studies were selected and appraised by independent reviewers. Data were pooled using the profile likelihood random-effects model. RESULTS We included 34 studies. We found no difference in QoL scores between higher (≥30 mg/day of hydrocortisone [HC] equivalence) vs. lower daily doses (<30 mg/day of HC equivalence) (P = .15) or based on frequency of daily dosing (once, twice or thrice daily). Extended-release (1 study), dual-/modified-release (3 studies), and continuous subcutaneous (3 studies) forms of GCs were associated with higher QoL scores. There was no significant association between dose and type of GC and the incidence of adrenal crises. The effect on bone mineral density was heterogeneous. No data were available on mortality or final adult height in children. The quality of evidence was low due to increased risk of bias, imprecision, and heterogeneity. CONCLUSION Extended-/dual-release, and continuous subcutaneous forms of GC may be associated with higher QoL scores. However, this is derived from short-term and imprecise evidence, warranting low confidence. ABBREVIATIONS AI = adrenal insufficiency BMD = bone mineral density GC = glucocorticoids HC = hydrocortisone QoL = quality of life RCT = randomized controlled trial.

ORAL VERSUS TRANSDERMAL ESTROGEN IN TURNER SYNDROME: A SYSTEMATIC REVIEW AND META-ANALYSIS

OBJECTIVE To conduct a systematic review and meta-analysis comparing transdermal estrogens (TDEs) versus oral estrogens (OEs) in Turner syndrome (TS). METHODS Randomized trials and observational comparative studies with a minimal follow-up of 6 months for skeletal and metabolic outcomes and serum hormone changes were included. Outcomes were pooled with a random effects model and are reported as mean differences between OE and TDE groups and 95% confidence intervals (CIs). RESULTS Of 845 candidate references, 4 studies were included. Both OEs and TDEs were associated with an increase in whole-body bone mineral density (BMD) z-score, with TDE therapy displaying a greater increase. OEs were associated with higher fasting glucose and total cholesterol. Both OEs and TDEs reduced low-density lipo-protein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C), with OEs providing a more favorable effect. The use of 17-β estradiol was associated with a higher total cholesterol and lower LDL-C than TDE. No statistically significant difference was found between OEs and TDEs in body mass index, fat mass, fat free mass, insulin-like growth factor 1, insulin-like growth factor binding protein 3, fasting insulin, triglycerides, estradiol, or estrone levels. CONCLUSION In girls with TS, TDEs may be associated with a more beneficial effect on fasting glucose, cholesterol, and whole-body BMD. However, OEs have a more favorable impact on LDL-C and HDL-C. 17-β estradiol has a more favorable effect on LDL-C. ABBREVIATIONS BMI = body mass index BMD = bone mineral density CI = confidence interval HDL-C = high density lipo-protein-cholesterol IGF-1 = insulin-like growth factor 1 IGF-BP3 = insulin-like growth factor binding protein 3 LDL-C = low density lipoprotein-cholesterol MD = mean difference OE = oral estrogen RCT = randomized controlled trial TDE = transdermal estrogen TS = Turner syndrome.

Ultrasonography and the American Thyroid Association Ultrasound-Based Risk Stratification Tool: Utility in Pediatric and Adolescent Thyroid Nodules

Background: Pediatric thyroid nodules are more likely to be malignant compared to those in adults and may have different concerning ultrasound (US) features. Recent adult guidelines stratify malignancy risk by US features. Our aim is to (1) describe and confirm US features that predict pediatric malignancy, and (2) apply the Adult American Thyroid Association (ATA) Risk Stratification Guidelines to a large pediatric cohort. Methods: We identified 112 children with 145 thyroid nodules from 1996 to 2015. Two blinded pediatric radiologists independently read all US images, described multiple features, and reported their overall impression: benign, indeterminate, or malignant. Each nodule was assigned an ATA risk stratification category. Radiologists’ impressions and ATA risk stratification were compared to histology and cytology results. Results: Multiple US features including a solid composition, presence of microcalcifications, irregular margins, increased blood flow, and hypoechogenicity were associated with increased odds of malignancy. ATA risk stratification correlated with the radiologists’ overall impression (p < 0.001). The sensitivity for detecting malignancy was comparable between both ATA stratification (91%) and the radiologists’ overall impression (90%). The specificity of the radiologists’ malignant overall impression (80%) was better compared to the ATA high risk stratification (54%). Conclusions: At our institution, pediatric radiologists’ overall impressions had similar sensitivity but better specificity for detecting malignancy than the ATA risk stratification tool by our convention. However, neither US-based methods perfectly discriminated benign from malignant nodules, supporting the continued need for fine needle aspiration for suspicious nodules. Further work is needed to develop an US-based scoring system specific to pediatric patients.