Molecular Imaging in the Management of Adrenocortical Cancer: A Systematic Review.

Adrenocortical cancer (ACC) is an uncommon primary neoplasm of the adrenal cortex with dismal prognosis. It often presents with symptoms and signs of adrenal cortical hormone hypersecretion and abdominal mass effect or is incidentally detected as an adrenal mass on imaging performed for other indications. Endocrine evaluation, comprehensive staging, and meticulous resection are crucial to ensure the best possible outcome. Despite extensive initial surgical resection, local and distant metastases are not uncommon with disappointing 5-year survival, although progress is being made at high-volume centers. Accurate restaging of recurrent disease is important to guide further management. Mitotane, external beam radiation and chemotherapy, and newer anticancer systemic treatments are used as adjunctives for inoperable disease and distant metastases. Contrast-enhanced CT and MRI are first-line imaging modalities for evaluation of ACC to characterize adrenal masses and to determine tumor resectability. Emerging literature supports F-FDG PET/CT use to determine the malignant potential of adrenal masses. In patients with a diagnosis of ACC, FDG PET/CT is sensitive for detecting metastatic disease, and its tumor accumulation has been correlated to pathology, Weiss scores, and prognosis. Metomidate, labeled with C for PET or with I for SPECT/CT, allows characterization of an adrenal mass as being of adrenocortical origin with high specificity. Taking advantage of its adrenocortical avidity, metomidate has been labeled with I for radionuclide therapy in a subset of ACC. In this review, we describe how nuclear medicine imaging, and specifically PET, can assist surgical management of ACC.

Parathyroid adenoma localization with 99mTc-sestamibi SPECT/CT: a meta-analysis.

PURPOSE: The aim of the study was to determine the diagnostic utility of parathyroid scintigraphy with technetium-99m (99mTc)-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) for localization of parathyroid adenoma. MATERIALS AND METHODS: We performed a systematic search of medical databases PubMed and Medline/OVID for literature on 99mTc-sestamibi SPECT/CT parathyroid scintigraphy, using the search terms hyperparathyroidism, parathyroid adenoma/hyperplasia, SPECT/CT, and SPECT-CT. Citations for 981 articles and 128 abstracts of full articles were reviewed by two coauthors for relevance. Twenty-four peer-reviewed studies on SPECT/CT parathyroid scintigraphy qualified for inclusion. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality. Meta-analytical techniques were used to obtain pooled estimates of the parathyroid adenoma localization rate using a random-effects model. RESULTS: A total of 24 studies published between January 2003 and March 2014 with 1276 patients (334 men, 762 women, and 180 of unspecified sex) met the inclusion criteria. Data on the test performance of dual-phase 99mTc-sestamibi SPECT/CT showed an estimated pooled sensitivity (per-patient analysis) of 0.86 [confidence interval (CI) 0.81-0.90]. Sensitivity of SPECT/CT was superior to that of SPECT (0.74; CI 0.66-0.82) and planar (0.70; CI 0.61-0.80) techniques. Heterogeneity was present in the reported literature (I2=80.3%). The rate of ectopic parathyroid adenomas ranged between 4 and 20% and SPECT/CT was superior to SPECT and planar imaging for localization of ectopic sites. CONCLUSION: Utilization of SPECT/CT fusion imaging for 99mTc-sestamibi parathyroid scintigraphy improves the test performance compared with planar and SPECT imaging; it assists preoperative planning for a minimally invasive surgical approach for the neck and is of value in subgroups with ectopic glands or coexisting nodular thyroid disease.

Comparing the effectiveness of competing tests for reducing colorectal cancer mortality: a network meta-analysis.

BACKGROUND: Comparative effectiveness data pertaining to competing colorectal cancer (CRC) screening tests do not exist but are necessary to guide clinical decision making and policy. OBJECTIVE: To perform a comparative synthesis of clinical outcomes studies evaluating the effects of competing tests on CRC-related mortality. DESIGN: Traditional and network meta-analyses. Two reviewers identified studies evaluating the effect of guaiac-based fecal occult blood testing (gFOBT), flexible sigmoidoscopy (FS), or colonoscopy on CRC-related mortality. INTERVENTIONS: gFOBT, FS, colonoscopy. MAIN OUTCOME MEASUREMENTS: Traditional meta-analysis was performed to produce pooled estimates of the effect of each modality on CRC mortality. Bayesian network meta-analysis (NMA) was performed to indirectly compare the effectiveness of screening modalities. Multiple sensitivity analyses were performed. RESULTS: Traditional meta-analysis revealed that, compared with no intervention, colonoscopy reduced CRC-related mortality by 57% (relative risk [RR] 0.43; 95% confidence interval [CI], 0.33-0.58), whereas FS reduced CRC-related mortality by 40% (RR 0.60; 95% CI, 0.45-0.78), and gFOBT reduced CRC-related mortality by 18% (RR 0.82; 95% CI, 0.76-0.88). NMA demonstrated nonsignificant trends favoring colonoscopy over FS (RR 0.71; 95% CI, 0.45-1.11) and FS over gFOBT (RR 0.74; 95% CI, 0.51-1.09) for reducing CRC-related deaths. NMA-based simulations, however, revealed that colonoscopy has a 94% probability of being the most effective test for reducing CRC mortality and a 99% probability of being most effective when the analysis is restricted to screening studies. LIMITATIONS: Randomized trials and observational studies were combined within the same analysis. CONCLUSION: Clinical outcomes studies demonstrate that gFOBT, FS, and colonoscopy are all effective in reducing CRC-related mortality. Network meta-analysis suggests that colonoscopy is the most effective test.

Comparative effectiveness of elastographic and B-mode ultrasound criteria for diagnostic discrimination of thyroid nodules: a meta-analysis.

OBJECTIVE: The purpose of this article is to present, through systematic review of recent literature, a comparative effectiveness analysis of ultrasound elastography versus B-mode ultrasound features for differentiating thyroid nodules. MATERIALS AND METHODS: We conducted an extensive literature search of PubMed and other medical and general purpose databases from January 1966 through March 2012. Eligible studies were published in English, reported diagnostic performance of elastography (using elasticity score or strain ratio) with or without B-mode ultrasound in differentiation of thyroid nodules, and used histology or cytology as the reference standard. Summary diagnostic performance measures were assessed for each of the elasticity measuring methods and ultrasound features by means of a bivariate random effects model. RESULTS: Twenty-four studies provided relevant information on more than 2624 patients and 3531 thyroid nodules (927 malignant and 2604 benign). Six ultrasound features (echogenicity, calcifications, margins, halo sign, shape, and color Doppler flow pattern) were compared with elasticity score and strain ratio. The respective sensitivities and specificities were as follows: elasticity score, 82% and 82%; strain ratio, 89% and 82%; hypoechogenicity, 78% and 55%; microcalcifications, 50% and 80%; irregular margins, 66% and 81%; absent halo sign, 56% and 57%; nodule vertical development, 46% and 77%; and intranodular vascularization, 40% and 61%. CONCLUSION: Evaluation of thyroid nodules with ultrasound elastography appears to be both more sensitive and specific than each of the ultrasound features. The former is a safe and effective technique that warrants further rigorous investigation or use in the clinical diagnosis of thyroid nodules.

Impact of breast mass size on accuracy of ultrasound elastography vs. conventional B-mode ultrasound: a meta-analysis of individual participants.

OBJECTIVES: To conduct an individual patient data meta-analysis comparing the diagnostic performance of ultrasound elastography (USE) versus B-mode ultrasound (USB) across size ranges of breast masses. METHODS: An extensive literature search of PubMed and other medical/general purpose databases from inception through August 2011 was conducted. Corresponding authors of published studies that reported a direct comparison of the diagnostic performance of USE using the elasticity score versus USB for characterisation of focal breast masses were contacted for their original patient-level data set. Summary diagnostic performance measures were compared for each test within and across three mass size groups (<10 mm, 10-19 mm, and >19 mm). RESULTS: The patient-level data sets were received from five studies, providing information on 1,412 breast masses. For breast masses <10 mm (n = 543; 121 malignant), the sensitivity/specificity of USE and USB were 76 %/93 % and 95 %/68 %, respectively. For masses 10-19 mm of size (n = 528; 247 malignant), sensitivity/specificity of USE and USB were 82 %/90 % and 95 %/67 %, respectively. For masses >19 mm of size (n = 325; 162 malignant), sensitivity/specificity of USE and USB were 74 %/94 % and 97 %/55 %, respectively. CONCLUSION: Regardless of the mass size, USE has higher specificity and lower sensitivity compared to USB in characterising breast masses. The performance of each of these two tests does not vary significantly by mass size.

Accuracy of quantitative ultrasound elastography for differentiation of malignant and benign breast abnormalities: a meta-analysis.

The purpose of this study was to systematically review recent literature on diagnostic performance of strain ratio and length ratio, two different strain measurements in ultrasound elastography, for differentiating benign and malignant breast masses. A literature search of PubMed and other medical and general purpose databases from inception through January 2012 was conducted. Published studies that evaluated the diagnostic performance of ultrasound elastography alone reporting either strain ratio or length ratio for characterization of focal breast lesions and using cytology (fine needle aspiration) or histology (core biopsy) as a reference standard were included. Summary diagnostic performance measures were assessed using bivariate generalized linear mixed modeling. Nine studies reported strain ratio for 2,087 breast masses (667 cancers, 1,420 benign lesions). Summary sensitivity and specificity were 88 % (95 % Credible Interval (CrI), 84-91 %), and 83 % (95 % CrI, 78-88 %), respectively. The positive and negative likelihood ratios (LR) were 5.57 (95 % CrI, 3.85-8.01) and 0.14 (95 % CrI, 0.09-0.20), respectively. The inconsistency index for heterogeneity was 6 % (95 % CrI, 1-22 %) for sensitivity and 8 % (95 % CrI, 3-24 %) for specificity. Analysis of three studies reporting length ratio for 450 breast masses demonstrated sensitivity and specificity of 98 % (95 % CrI, 93-99 %) and 72 % (95 % CrI, 31-96 %), respectively. Strain ratio and length ratio have good diagnostic performance for distinguishing benign from malignant breast masses. Although, this performance may not be incrementally superior to that of breast imaging reporting and data system (BIRADS) in B-mode ultrasound, the application of USE using strain ratio or length ratio in combination with USB may have the potential to benefit the patients, and this requires further comparative effectiveness and cost-effectiveness analyses.

Utility of pretreatment mean apparent diffusion coefficient and apparent diffusion coefficient histograms in prediction of outcome to chemoradiation in head and neck squamous cell carcinoma.

PURPOSE: This study aimed to evaluate pretreatment whole-tumor mean apparent diffusion coefficient (ADC) and ADC histogram as predictors of outcome to chemoradiation in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Patients with HNSCC underwent pretreatment 3-T diffusion-weighted magnetic resonance imaging with calculation of mean ADC and ADC histograms. Outcomes were determined 2 years after chemoradiation. Positive outcome was defined as no abnormal 18-fluoro deoxy glucose uptake on posttherapy computed tomography-positron emission tomography (or abnormal uptake that was proven benign), no locoregional recurrence or metastatic disease, and no requirement for salvage surgery. Negative outcome was defined as residual abnormal 18-fluoro deoxy glucose avidity that was proven malignant, salvage surgery requirement, locoregional recurrence or metastatic disease, death, or a combination of these. A 2-sample t test was used to compare the mean ADC between patients with positive and negative outcomes. The ADC cut point for dividing the groups was determined by looking at its distribution. A Kaplan-Meier plot was produced, and a log-rank test was conducted with calculation of sensitivity, specificity, and positive and negative predictive values. RESULTS: Nine patients showed positive and 8 showed negative outcomes. Significant difference (P = 0.03) was seen in mean ADC (in 10 mm/s) between patients showing positive and negative outcomes (1.18 and 1.43, respectively). According to the log-rank test, tumors with greater than 45% of their volume below the ADC threshold of 1.15 × 10 mm/s were more likely to have a positive outcome (accuracy, 77%). CONCLUSIONS: Patients with HNSCC demonstrating lower pretreatment ADC and with greater than 45% of volume below ADC threshold of 1.15 × 10 mm/s may have better outcome to chemoradiation at 2 years.

Ultrasonographic differentiation of malignant from benign breast lesions: a meta-analytic comparison of elasticity and BIRADS scoring.

There has been controversy regarding the accuracy of breast ultrasound elastography (USE) compared to conventional B-mode Ultrasound (USB). The purpose of this study was to conduct a direct comparative effectiveness analysis of USB versus USE or their combination in differentiating breast lesions through systematically reviewing recent literature. An extensive literature search of PubMed and other medical and general purpose databases from inception through August 2011 was conducted. Published studies that reported a direct comparison of the diagnostic performance of USE, using elasticity score versus USB, using breast imaging reporting and data system (BIRADS) for characterization of focal breast lesions were included. Summary diagnostic performance measures were assessed for each of the tests and their combination using bivariate generalized linear mixed modeling. The two tests were combined as: (1) conjunctive, where the outcome of the combination of tests is positive only if both test results are positive; (2) disjunctive, where the outcome of a combination of tests is negative only if both tests are negative. Twenty nine studies provided relevant information on 5,511 breast masses (2,065 cancers, 3,446 benign lesions). Sensitivity of USB, USE, and their conjunctive and disjunctive combinations were 96% (95% credible interval (CrI), 93-98%), 79% (95% CrI, 74-83%), 73% (95% CrI, 67-78%), and 99% (95% CrI, 98-99%), respectively. Specificity of USB, USE, and their conjunctive and disjunctive combinations were 70% (95% CrI, 55-83%), 88% (95% CrI, 82-92%), 97% (95% CrI, 95-99%), and 56% (95% CrI, 43-69%), respectively. The application of USE as a single test is not superior to USB alone. However, in low risk patients it is recommended to perform an USE following a positive USB result to decrease the rate of unnecessary biopsies.

Characterization of adrenal masses by using FDG PET: a systematic review and meta-analysis of diagnostic test performance.

PURPOSE: To perform a systematic review and meta-analysis of published data to determine the diagnostic utility of adrenal fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) for distinguishing benign from malignant adrenal disease. MATERIALS AND METHODS: Data on FDG PET assessment in MEDLINE and other electronic databases (from inception to November 2009) and in subject matter-specific journals were evaluated and compared with histologic diagnoses and/or established clinical and imaging follow-up results. Methodologic quality was assessed by using Quality Assessment of Diagnostic Accuracy Studies criteria. Bivariate random-effects meta-analytical methods were used to estimate summary and subgroup-specific sensitivity, specificity, and receiver operating characteristic curves and to investigate the effects of study design characteristics and imaging procedure elements on diagnostic accuracy. RESULTS: A total of 1391 lesions (824 benign, 567 malignant) in 1217 patients from 21 eligible studies were evaluated. Qualitative (visual) analysis of 841 lesions (in 14 reports) and quantitative analyses based on standardized uptake values (SUVs) for 824 lesions (in 13 reports) and standardized uptake ratios (SURs) for 562 lesions (in eight reports) were performed. Resultant data were highly heterogeneous, with a model-based inconsistency index of 88% (95% confidence interval [CI]: 79%, 98%). Mean sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio values for differentiating between benign and malignant adrenal disease were 0.97 (95% CI: 0.93, 0.98), 0.91 (95% CI: 0.87, 0.94), 11.1 (95% CI: 7.5, 16.3), 0.04 (95% CI: 0.02, 0.08), and 294 (95% CI: 107, 805), respectively, with no significant differences in accuracy among the visual, SUV, and SUR analyses. CONCLUSION: Meta-analysis of combination PET-computed tomography (CT) reports revealed that FDG PET was highly sensitive and specific for differentiating malignant from benign adrenal disease. Diagnostic accuracy was not influenced by the type of imaging device (PET vs PET/CT), but specificity was dependent on the clinical status (cancer vs no cancer).

The prognostic power of the NOD2 genotype for complicated Crohn's disease: a meta-analysis.

OBJECTIVES: Crohn's disease is often purely inflammatory at presentation, but most patients develop strictures and fistulae over time (complicated disease). Many studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2) mutations are associated with a varying but increased risk of complicated disease. An accurate and sufficiently powerful predictor of complicated disease could justify the early use of biological therapy in high-risk individuals. We performed a systematic review and meta-analysis to obtain accurate estimates of the predictive power of the identified mutations (such as p.R702W, P.G908R, and p.Leu1007fsX1008) in NOD2 for the risk of complicated disease. METHODS: An electronic search of MEDLINE, Embase, and Web of Science identified 917 relevant papers. Inclusion required specification of genetic mutations at the individual level and disease phenotypes by Vienna classification (inflammatory (B1), stricturing (B2), and fistulizing (B3)). A total of 49 studies met these criteria, which included 8,893 subjects, 2,897 of whom had NOD2 mutations. Studies were weighted by median disease duration. Studies not providing duration data were weighted at the level of the study with the shortest disease duration (3.9 years). RESULTS: The relative risk (RR) of the presence of any NOD2 mutant allele for complicated disease (B2 or B3) was 1.17 (95% confidence interval (95% CI) 1.10-1.24; P<0.001). P.G908R was associated with an RR of complicated disease of 1.33 (95% CI 1.11-1.60; P=0.002). NOD2 did not predict perianal disease (P=0.4). The RR of surgery was 1.58 (95% CI 1.38-1.80; P<0.001). There was substantial heterogeneity across all studies (I(2)=66.7%). On the basis of logistic regression of these data, the sensitivity of any mutation in predicting complicated disease was 36% and specificity was 73%, with the area under the receiver operating characteristic curve 0.56. CONCLUSIONS: The presence of a single NOD2 mutation predicted an 8% increase in the risk for complicated disease (B2 or B3), and a 41% increase with 2 mutations. Surgery risk is increased by 58% with any NOD2 mutation, whereas perianal disease was unchanged. The predictive power associated with a single NOD2 mutation is weak. The RR of any NOD2 mutations for complicated disease was only 17% across 36 studies. However, the presence of two NOD2 mutations had 98% specificity for complicated disease. These data provide insufficient evidence to support top-down therapy based solely on single NOD2 mutations, but suggest that targeted early-intensive therapy for high-risk patients with two NOD2 mutations might be beneficial, if prospective trials can demonstrate changes in the natural history in this subset of patients.

Solitary pulmonary nodules and masses: a meta-analysis of the diagnostic utility of alternative imaging tests.

The purpose was to assess the clinical utility of diagnostic tests for identifying malignancy within a solitary pulmonary nodule (SPN), and to create a nomogram or "look-up" table using clinical data and non-invasive radiology (positive) test results to estimate post-test probability of malignancy. Studies that examined computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the evaluation of SPN. Two reviewers independently abstracted data and assessed study quality. Study-specific and overall positive likelihood ratios (LRs) for each diagnostic test confirming a diagnosis of malignancy and negative LR for each diagnostic test excluding a diagnosis of malignancy within an SPN were calculated. Forty-four of 242 articles were included. Positive LRs for diagnostic tests were: CT 3.91 (95% confidence interval 2.42, 5.40), MRI 4.57 (3.03, 6.1), PET 5.44 (3.56, 7.32) and SPECT 5.16 (4.03, 6.30). Negative LRs were: CT 0.10 (0.03, 0.16), MRI 0.08 (0.03, 0.12), PET 0.06 (0.02, 0.09) and SPECT 0.06 (0.04, 0.08). Differences in performance for all tests were negligible; therefore, the clinician may confidently use any of the four tests presented in further evaluating an SPN. Given the low cost and prevalence of the technology, SPECT appears to be the leading choice for additional testing in SPN evaluation.

Solitary pulmonary nodules: meta-analytic comparison of cross-sectional imaging modalities for diagnosis of malignancy.

PURPOSE: To perform a meta-analysis to estimate the diagnostic accuracy of dynamic contrast material-enhanced computed tomography (CT) and magnetic resonance (MR) imaging, fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and technetium 99m ((99m)Tc) depreotide single photon emission computed tomography (SPECT) for evaluation of solitary pulmonary nodules (SPNs). MATERIALS AND METHODS: Data sources were studies published in PubMed between January 1990 and December 2005. The selected investigations were comparative and noncomparative diagnostic cohort studies to examine the operating characteristics of the four imaging modalities for evaluation of SPNs, involving at least 10 enrolled participants with histologic confirmation and having sufficient data to calculate contingency tables. A random coefficient binary regression model with disease probability conditioned on test results was used to summarize test performance and construct summary receiver operating characteristic (ROC) curves. Sensitivities, specificities, predictive values, diagnostic odds ratios, and areas under the ROC curve were calculated. RESULTS: Forty-four studies--10 dynamic CT, six dynamic MR, 22 FDG PET, and seven (99m)Tc-depreotide SPECT--met the inclusion criteria. (One study was included in both the FDG PET and SPECT groups.) Sensitivities, specificities, positive predictive values, negative predictive values, diagnostic odds ratios, and areas under the ROC curve were, respectively, 0.93 (95% confidence interval [CI]: 0.88, 0.97), 0.76 (95% CI: 0.68, 0.97), 0.80 (95% CI: 0.74, 0.86), 0.95 (95% CI: 0.93, 0.98), 39.91 (95% CI: 1.21, 81.04), and 0.93 (95% CI: 0.81, 0.97) for dynamic CT; 0.94 (95% CI: 0.91, 0.97), 0.79 (95% CI: 0.73, 0.86), 0.86 (95% CI: 0.83, 0.89), 0.93 (95% CI: 0.90, 0.96), 60.59 (95% CI: 5.56, 115.62), and 0.94 (95% CI: 0.83, 0.98) for dynamic MR; 0.95 (95% CI: 0.93, 0.98), 0.82 (95% CI: 0.77, 0.88), 0.91 (95% CI: 0.88, 0.93), 0.90 (95% CI: 0.85, 0.94), 97.31 (95% CI: 6.26, 188.37), and 0.94 (95% CI: 0.83, 0.98) for FDG PET; and 0.95 (95% CI: 0.93, 0.97), 0.82 (95% CI: 0.78, 0.85), 0.90 (95% CI: 0.83, 0.97), 0.91 (95% CI: 0.84, 0.98), 84.50 (95% CI: 34.28, 134.73), and 0.94 (95% CI: 0.83, 0.98) for (99m)Tc-depreotide SPECT. CONCLUSION: Dynamic CT and MR, FDG PET, and (99m)Tc-depreotide SPECT are noninvasive and accurate in distinguishing malignant from benign SPNs; differences among these tests are nonsignificant.