Clinicopathologic and Molecular Analysis of Normal Karyotype Therapy-Related and De Novo Acute Myeloid Leukemia: A Multi-Institutional Study by the Bone Marrow Pathology Group.

PURPOSE: Therapy-related acute myeloid leukemias (t-AML) are a heterogenous group of aggressive neoplasms that arise following exposure to cytotoxic chemotherapy and/or ionizing radiation. Many therapy-related myeloid neoplasms (t-MN) are associated with distinct chromosomal aberrations and/or TP53 alterations, but little is known about the clinicopathologic and molecular features of normal karyotype t-AML (NK-t-AML) and whether this t-MN subtype is distinctly different from NK de novo AML (NK-dn-AML). METHODS: This multi-institutional study by the Bone Marrow Pathology Group retrospectively evaluated clinicopathologic and molecular characteristics of 335 patients with NK-AML, comprising 105 t-AML and 230 dn-AML cases. RESULTS: Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 v 44.2; P < .0001) and relapse-free survival (RFS; median months: 9.1 v 19.2; P = .0018). Frequency of NPM1, FLT3, KRAS, and GATA2 mutations were significantly different in NK-t-AML compared with NK-dn-AML (NPM1 35% v 49%; P = .0493; FLT3 23% v 36%; P = 0494; KRAS 12% v 5%; P = .0465; GATA2 9% v 2% P = .0105), while TP53 mutations were rare. Patients with t-AML more often stratified into intermediate or adverse 2017 ELN genetic risk groups. Favorable ELN risk predicted favorable OS (hazard ratio [HR], 0.4056; 95% CI, 0 to 0.866; P = .020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; P = .006). Among all patients with NK-AML, stem-cell transplant and favorable ELN risk both significantly affected RFS, while therapy-relatedness and age had a borderline significant impact on OS (HR, 1.355; 95% CI, 0.975 to 1.882; P = .070). CONCLUSION: To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations.

Accuracy and Reproducibility of Frozen Section Diagnosis in Ovarian Tumors.

CONTEXT.­: Intraoperative consultation-frozen section diagnosis (FSD)-determines tumor pathology and guides the optimal surgical management of ovarian neoplasms intraoperatively. OBJECTIVE.­: To evaluate the diagnostic accuracy of the FSD and analyze the discrepancy between the FSD and final diagnosis. DESIGN.­: This is a retrospective study of 618 ovarian neoplasm FSDs from 2009 to 2018 at a tertiary health care center. The discrepant cases were reviewed and reevaluated by gynecologic and general surgical pathologists. The outcomes of interest were performing unnecessary procedure, returning for a second surgery, and 30-day postoperative mortality. RESULTS.­: The sensitivity and the positive predictive value of the FSD were lower in borderline tumors than in benign and malignant epithelial ovarian tumors. Major and minor discrepancies were identified in 5.3% (33 of 618) and 12.3% of (76 of 618) cases, respectively. A root cause analysis of the major discrepant cases showed that sampling error accounted for 43% (14 of 33). The discrepancy distributions of gynecologic and general surgical pathologists were statistically similar in the overall cohort (P = .65). The overall κ for diagnostic agreement among gynecologic pathologists, general surgical pathologists, and final diagnosis was 0.18 (0.10-0.26, P < .001), implying only a slight overall agreement. Of the major discrepant cases, only 3 had a clinical implication. One overdiagnosed patient underwent an unecessary procedure, and 2 underdiagnosed patients were recommended to return for a second surgery. No patient had 30-day postoperative mortality. CONCLUSIONS.­: Frozen section diagnosis remains a definitive diagnostic tool in ovarian neoplasms and plays a crucial role in guiding intraoperative surgical management.

Rare Case of 6 cm Right Atrial Myxoma in Patient with Synchronous Endometrial Adenocarcinoma.

Primary cardiac tumors are extremely rare. Cardiac myxomas most frequently appear in the left atrium. In this article, we present a case of an asymptomatic 6 cm right atrial mass in a patient undergoing staging for endometrial cancer. The mass was resected, and final pathology was consistent with cardiac myxoma.

Impact of positive cytology in uterine serous carcinoma: A reassessment.

OBJECTIVES: The aim of this study was to evaluate the prognostic value of peritoneal cytology status among other clinicopathological parameters in uterine serous carcinoma (USC). METHODS: A retrospective study of 148 patients diagnosed with uterine serous carcinoma from 1997 to 2016 at two academic medical centers in the Detroit metropolitan area was done. A central gynecologic pathologist reviewed all available slides and confirmed the histologic diagnosis of each case of USC. We assessed the prognostic impact of various clinicopathological parameters on overall survival (OS) and endometrial cancer-specific survival (ECSS). Those parameters included race, body mass index (BMI), stage at diagnosis, tumor size, lymphovascular invasion (LVSI), peritoneal cytology status, receipt of adjuvant treatment, and comorbidity count using the Charlson Comorbidity Index (CCI). We used Cox proportional hazards models and 95% confidence intervals for statistical analysis. RESULTS: Positive peritoneal cytology had a statistically significant effect on OS (HR: 2.09, 95% CI: [1.19, 3.68]) and on ECSS (HR: 2.02, 95% CI: [1.06 - 3.82]). LVSI had a statistically significant effect on both OS (HR: 2.27, 95% CI: [1.14, 4.53]) and ECSS (HR: 3.45, 95% CI: [1.49, 7.99]). Black or African American (AA) race was also found to have a significant effect on both OS (HR: 1.92, 95% CI: [1.07, 3.47]) and ECSS (HR: 2.01, 95% CI: [1.02, 3.98]). Other factors including BMI and tumor size > 1 cm did not show a statistically significant impact on OS or ECSS. CONCLUSIONS: Peritoneal washings with positive cytology and LVSI are important prognostic tools that may have a significant impact on overall survival in USC and can be used as independent negative prognosticators to help guide adjuvant treatment.

p16 positive oropharyngeal small cell cancer: A case report.

Extra-pulmonary small cell carcinomas (EPSCC) are rare malignancies. Like small cell lung cancer (SCLC), they are aggressive malignancies with dismal prognosis. We here report a case of a middle-aged man who presented with odynophagia and cervical lymphadenopathy. Diagnostic workup confirmed the diagnosis of locally-advanced p16-positive oropharyngeal cancer (OPC) with a surprising histology of small cell cancer, suggesting a human papilloma virus (HPV)-related oropharyngeal cancer with small cell differentiation. HPV oropharynx infection is a well-known risk factor for squamous cell carcinoma of the oropharynx, but it is unknown if it may increase the risk of other OPC histology.

Isolation and characterization of a CD34+ sub-clone in B-cell lymphoma.

Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy in the US. Many types remain incurable despite response to initial therapy and achievement of complete remission (CR). Advanced laboratory techniques like multicolor flow cytometry (FCM) and polymerase chain reaction (PCR) have demonstrated persistence of rare malignant cell population post therapy. However, the functional and biological characteristics of this population have not been elucidated. Established B-lymphoma cell lines (B-NHL) and patient-derived samples (PDS) were analyzed using 8-color FCM. CD34+ sub-population was enriched using in vitro exposure to 2-chlorodeoxyadenosine (2-CdA) and by CD34 magnetic beads. Genetic analysis of cell fractions was done by karyotyping and array comparative genomic hybridization (aCGH). Sensitivity to chemotherapy was assayed by short-term in vitro exposure to chemotherapy. Clonogenicity was determined by soft agar colony formation assay, and proliferation was determined using DNA staining with propidium iodide and FCM. FCM demonstrated the presence of a minute sub-clone of monotypic B-cells that express CD34 in B-NHL cell lines (3 of 3) and in PDS (8 of 8). This sub-population enriched up to 50 fold in vitro by exposure to 2-CdA and up to 80% purity by CD34 magnetic bead column isolation. Except for CD34 expression, this population expressed identical phenotype and genotype to parent cells, but was more proliferative, Hoechst 33342-positive, clonogenic, and resistant to chemotherapy compared with the CD34- population. The isolated CD34+ monotypic B-cells may contribute to resistance of certain NHL to treatment and should be targeted by potential new drugs for NHL.

Eating, sleeping and sexual function disorders in women with polycystic ovary syndrome (PCOS): A systematic review and meta-analysis.

PURPOSE: We aim to evaluate the association of PCOS with eating, sleeping and sexual function disorders. METHODS: A comprehensive search including MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through 01 August 2018 was conducted for studies reporting the prevalence of any eating, sleep or sexual function disorders in patients with PCOS. Independent reviewers selected studies and extracted data. A random-effects model was utilized to generate pooled odds ratio (OR) and 95% confidence intervals (CI) for binary outcomes, and mean difference (MD) and 95% CI for continuous outcomes. RESULTS: We included 36 studies reporting on 349,529 patients. Compared to women without PCOS, women with PCOS were more likely to have bulimia nervosa (OR 1.37; %CI, 1.17 to 1.60), binge eating (OR 2.95; 95%CI, 1.61 to 5.42), or any eating disorder (OR 1.96; 95% CI 1.18 to 3.24); but not anorexia nervosa (OR 0.92; 95%CI, 0.78 to 1.10). Women with PCOS were more likely to have sleep disorders like hypersomnia (OR 4.39; %CI, 1.07 to 18.07) and obstructive sleep apnoea (OR 10.81; %CI, 2.39 to 48.83). Women with PCOS had lower sexual satisfaction as measured on a visual analogue scale (MD -29.67; 95% CI, -36.97 to -22.37), but no difference in Total Female Sexual Function Index (MD -0.06; 95% CI, -0.51 to 0.38). CONCLUSION: PCOS can be associated with an increased risk of eating and sleeping disorders as well as decreased sexual satisfaction. Screening for these disorders in women with PCOS may allow early intervention and improve quality of life.

High Ki67 proliferation index but not cell-of-origin subtypes is associated with shorter overall survival in diffuse large B-cell lymphoma.

BACKGROUND: CD10, BCL6, and MUM1 are commonly used immunohistochemical stains for classifying diffuse large B-cell lymphoma (DLBCL), which is useful in predicting outcome. Conflicting reports of the prognostic value of other markers such as BCL2, CD23, and Ki67 proliferation index have been reported. Our objective was to correlate these immunostains and Hans classification with response to therapy and overall survival. MATERIALS AND METHODS: A retrospective study of patients diagnosed with DLBCL from 2008-2014 at a tertiary-care cancer hospital. The slides with the IHC stains were reviewed by two independent pathologists. The clinical outcomes--assessed independently--were response to therapy and overall survival. The treatment response evaluation was based on the new Lugano classification. Statistical analyses were conducted using the Fisher's exact test and Kaplan-Meier survival curves. Significance was set at P < 0.05. RESULTS: Forty-one patients were included in the study with a known Hans classification, available clinical data, and at least 5-year follow-up. CD10 immunostain was reported in all patients, whereas CD23 was the least reported in only four patients. No significant association was observed between CD10, BCL6, MUM1, BCL2, and both Response to therapy and overall survival. Owing to few cases reported CD23 immunostain, further analysis of association is not reported. High Ki67 proliferative index of >80% was statistically significantly associated with shorter overall survival and not statistically significant associated with no response to therapy. Hans classification subtypes were not predictive in regard to therapy response. CONCLUSION: High Ki67 expression (>80%) was associated with shorter overall survival in DLBCL. Hans classification subtypes were not predictive.

Comparative assessment of conventional chromosomal analysis and fluorescence in situ hybridization in the evaluation of suspected myelodysplastic syndromes: a single institution experience.

BACKGROUND: Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic neoplasms, roughly half of which harbor cytogenetic abnormalities with diagnostic, prognostic, and therapeutic significance. Fluorescence in situ hybridization (FISH) for the most commonly seen abnormalities (5/5q, -7/7q, +8, and -20/20q-) is routinely performed alongside conventional cytogenetics (CC) in the evaluation of suspected MDS despite conflicting reports of its relative contribution compared to CC alone. OBJECTIVES: To assess the additional diagnostic and prognostic value of performing concurrent FISH versus CC alone in cases of suspected MDS. MATERIALS AND METHODS: A total of 127 bone marrow samples submitted to our cytogenetic laboratory with a presumptive diagnosis of MDS were evaluated by concurrent CC and an MDS FISH panel. RESULTS: CC was used as the gold standard method with 100% sensitivity in detecting suspected MDS-associated cytogenetic abnormalities. FISH alone had a sensitivity of 76%, whereas CC alone achieved a sensitivity of 97%. The addition of FISH did not change the diagnosis nor change the Revised International Prognostic Scoring System score in any patient. Moreover, in 12 cases identified as positive by both CC and FISH, CC identified multiple chromosomal aberrations of clinical significance not interrogated by the FISH probe panel. CONCLUSION: CC alone is sufficiently sensitive in detecting suspected MDS-associated cytogenetic abnormalities that influence clinical decision-making. Routine FISH testing does not provide a significant increase in test sensitivity when an adequate karyotype is obtained. Therefore, FISH testing is best reserved for suspected MDS cases lacking sufficient metaphases.

Effect of digitalis level on readmission and mortality rate among heart failure reduced ejection fraction patients.

INTRODUCTION: Digitalis has been used for over 200 years to treat patients with heart failure, and evidence supports its use to improve clinical symptoms and quality of life, but not survival. The objective of this retrospective study was to evaluate the effects of digitalis on readmission and mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were receiving current guideline recommended medical therapy. METHODS: We reviewed medical record data from a retrospective cohort study of 1047 patients admitted to the hospital from 2005 to 2014 with decompensated HFrEF. 244 received digitalis, at some point during patient trajectory, and 803 never received digitalis. The primary outcomes of interest were the length of stay in hospital, readmission rates after discharge at 1, 6, 12, and 24 months and the overall mortality rate, at the same time points. RESULTS: We studied the effects of digitalis after adjusting for age, sex, race, potentially confounding comorbidities, and prescription medications. Digitalis treatment is associated with decreases in EF in patients with HFrEF (OR = -2.83, P < 0.001) and was associated with an increased readmission rate for any reason after discharge from the hospital at 6, 12, and 24 months, 53%, 34%, and 35%, respectively. No statistically significant difference was found between patients who received digitalis and those who did not (referent group) for the length of hospital stay and overall mortality rate. CONCLUSION: Digitalis use is associated with increased re-admission rates for any reason following discharge from the hospital at 6, 12, and 24 months.

Genital Reconstructive Surgery in Females With Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis.

Background: Females with congenital adrenal hyperplasia (CAH) and atypical genitalia often undergo complex surgeries; however, their outcomes remain largely uncertain. Methods: We searched several databases through 8 March 2016 for studies evaluating genital reconstructive surgery in females with CAH. Reviewers working independently and in duplicate selected and appraised the studies. Results: We included 29 observational studies (1178 patients, mean age at surgery, 2.7 ± 4.7 years; mostly classic CAH). After an average follow-up of 10.3 years, most patients who had undergone surgery had a female gender identity (88.7%) and were heterosexual (76.2%). Females who underwent surgery reported a sexual function score of 25.13 using the Female Sexual Function Index (maximum score, 36). Many patients continued to complain of substantial impairment of sensitivity in the clitoris, vaginal penetration difficulties, and low intercourse frequency. Most patients were sexually active, although only 48% reported comfortable intercourse. Most patients (79.4%) and treating health care professionals (71.8%) were satisfied with the surgical outcomes. Vaginal stenosis was common (27%), and other surgical complications, such as fistulas, urinary incontinence, and urinary tract infections, were less common. Data on quality of life were sparse and inconclusive. Conclusion: The long-term follow-up of females with CAH who had undergone urogenital reconstructive surgery shows variable sexual function. Most patients were sexually active and satisfied with the surgical outcomes; however, some patients still complained of impairment in sexual experience and satisfaction. The certainty in the available evidence is very low.

Psychiatric disorders in women with polycystic ovary syndrome: a systematic review and meta-analysis.

PURPOSE: Polycystic ovary syndrome (PCOS) is a common disorder affecting up to 15% of women in the reproductive age. Prior studies suggest that PCOS can be associated with mood and psychiatric disorders. The purpose of this study is to examine the prevalence of any psychiatric disorder in women with PCOS. METHODS: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through February 08, 2017 for studies that examined the prevalence of any psychiatric disorder in adolescents or adults with a clinical or biochemical diagnosis of PCOS. We used a random-effects model to generate pooled estimates and 95% confidence intervals (CI). RESULTS: We included 57 studies reporting on 172,040 patients. The majority of studies addressed depression and anxiety. Studies had fair methodological quality although most estimates were unadjusted. Women with PCOS were more likely to have a clinical diagnosis of depression (odds ratio (OR), 2.79; 95% CI, 2.23-3.50), anxiety (OR, 2.75; 95% CI, 2.10-3.60), bipolar disorder (OR, 1.78; 95% CI, 1.43-2.23) and obsessive compulsive disorder (OCD) (OR, 1.37; 95% CI 1.22-1.55), but not social phobia or panic disorder. Using various scales, the severity of symptoms of depression, anxiety, obsessive compulsive disorder, and somatization disorders were higher compared to women without PCOS. CONCLUSIONS: PCOS is associated with an increased risk of diagnosis of depression, anxiety, bipolar disorder, and obsessive compulsive disorder. It is associated with worse symptoms of depression, anxiety, OCD, and somatization. Screening for these disorders to allow early intervention may be warranted.

Treatment Effect in Earlier Trials of Patients With Chronic Medical Conditions: A Meta-Epidemiologic Study.

OBJECTIVE: To determine whether the early trials in chronic medical conditions demonstrate an effect size that is larger than that in subsequent trials. METHODS: We identified randomized controlled trials (RCTs) evaluating a drug or device in patients with chronic medical conditions through meta-analyses (MAs) published between January 1, 2007, and June 23, 2015, in the 10 general medical journals with highest impact factor. We estimated the prevalence of having the largest effect size or heterogeneity in the first 2 published trials. We evaluated the association of the exaggerated early effect with several a priori hypothesized explanatory variables. RESULTS: We included 70 MAs that had included a total of 930 trials (average of 13 [range, 5-48] RCTs per MA) with average follow-up of 24 (range, 1-168) months. The prevalence of the exaggerated early effect (ie, proportion of MAs with largest effect or heterogeneity in the first 2 trials) was 37%. These early trials had an effect size that was on average 2.67 times larger than the overall pooled effect size (ratio of relative effects, 2.67; 95% CI, 2.12-3.37). The presence of exaggerated effect was not significantly associated with trial size; number of events; length of follow-up; intervention duration; number of study sites; inpatient versus outpatient setting; funding source; stopping a trial early; adequacy of random sequence generation, allocation concealment, or blinding; loss to follow-up or the test for publication bias. CONCLUSION: Trials evaluating treatments of chronic medical conditions published early in the chain of evidence commonly demonstrate an exaggerated treatment effect compared with subsequent trials. At the present time, this phenomenon remains unpredictable. Considering the increasing morbidity and mortality of chronic medical conditions, decision makers should act on early evidence with caution.

Therapies for advanced stage hepatocellular carcinoma with macrovascular invasion or metastatic disease: A systematic review and meta-analysis.

Hepatocellular carcinoma (HCC) is a complex disease most commonly arising in the background of chronic liver disease. In the past two decades, there has been a significant increase in our understanding of both the clinical and molecular heterogeneity of HCC. There has been a robust increase in clinical trial activity in patients with poor prognostic factors, such as macrovascular invasion and extrahepatic spread (EHS). We aimed to synthesize the evidence for the treatment of patients with advanced HCC based on these baseline characteristics, including patients with both Child-Pugh (CP) scores of A and B. A comprehensive search of several databases from each database inception to February 15, 2016 any language was conducted. We included 14 studies (three randomized controlled studies [RCTs] and 11 observational studies). We included studies that compared sorafenib, transarterial bland embolization/transarterial chemoembolization, yttrium-90/radiation therapy, ablation (or combination), and no therapy. Two RCTs comparing sorafenib to best supportive care demonstrated a consistent improvement in overall survival (OS) for patients with advanced HCC and metastatic vascular invasion (MVI) and/or EHS and CP A liver disease (hazard ratio, 0.66 [95% confidence interval, 0.51-0.87]; I2 = 0%). Several observational studies evaluated locoregional therapies alone or in combination with other treatments and were limited by very-low-quality of evidence. This was true for both patients with EHS and MVI. CONCLUSION: In patients with advanced HCC and CP A liver function, sorafenib is the only treatment that has been shown to improve OS in randomized studies. High-quality data supporting the use of other treatment modalities in this setting, or in the setting of patients with less compensated (CP B) liver disease, are lacking. (Hepatology 2018;67:422-435).

Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: A systematic review and meta-analysis.

Patients with hepatocellular carcinoma (HCC) who are listed for liver transplantation (LT) are often treated while on the waiting list with locoregional therapy (LRT), which is aimed at either preventing progression of HCC or reducing the measurable disease burden of HCC in order to receive increased allocation priority. We aimed to synthesize evidence regarding the effectiveness of LRT in the management of patients with HCC who were on the LT waitlist. We conducted a comprehensive search of multiple databases from 1996 to April 25, 2016, for studies that enrolled adults with cirrhosis awaiting LT and treated with bridging or down-staging therapies before LT. Therapies included transcatheter arterial chemoembolization, transarterial radioembolization, ablation, and radiotherapy. We included both comparative and noncomparative studies. There were no randomized controlled trials identified. For adults with T1 HCC and waiting for LT, there were only two nonrandomized comparative studies, both with a high risk of bias, which reported the outcome of interest. In one series, the rate of dropout from all causes at 6 months in T1 HCC patients who underwent LRT was 5.3%, while in the other series of T1 HCC patients who did not receive LRT, the dropout rate at median follow-up of 2.4 years and the progression rate to T2 HCC were 30% and 88%, respectively. For adults with T2 HCC awaiting LT, transplant with any bridging therapy showed a nonsignificant reduction in the risk of waitlist dropout due to progression (relative risk [RR], 0.32; 95% confidence interval [CI], 0.06-1.85; I2 = 0%) and of waitlist dropout from all causes (RR, 0.38; 95% CI, 0.060-2.370; I2 = 85.7%) compared to no therapy based on three comparative studies. The quality of evidence is very low due to high risk of bias, imprecision, and inconsistency. There were five comparative studies which reported on posttransplant survival rates and 10 comparative studies which reported on posttransplant recurrence, and there was no significant difference seen in either of these endpoints. For adults initially with stage T3 HCC who received LRT, there were three studies reporting on transplant with any down-staging therapy versus no downstaging, and this showed a significant increase in 1-year (two studies, RR, 1.11; 95% CI, 1.01-1.23) and 5-year (1 study, RR, 1.17; 95% CI, 1.03-1.32) post-LT survival rates for patients who received LRT. The quality of evidence is very low due to serious risk of bias and imprecision. CONCLUSION: In patients with HCC listed for LT, the use of LRT is associated with a nonsignificant trend toward improved waitlist and posttransplant outcomes, though there is a high risk of selection bias in the available evidence. (Hepatology 2018;67:381-400).

Imaging for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis.

Multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) are both used for noninvasive diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. To determine if there is a relative diagnostic benefit of one over the other, we synthesized evidence regarding the relative performance of CT, extracellular contrast-enhanced MRI, and gadoxetate-enhanced MRI for diagnosis of HCC in patients with cirrhosis. We also assessed whether liver biopsy versus follow-up with the same versus alternative imaging is best for CT-indeterminate or MRI-indeterminate liver nodules in patients with cirrhosis. We searched multiple databases from inception to April 27, 2016, for studies comparing CT with extracellular contrast-enhanced MRI or gadoxetate-enhanced MRI in adults with cirrhosis and suspected HCC. Two reviewers independently selected studies and extracted data. Of 33 included studies, 19 were comprehensive, while 14 reported sensitivity only. For all tumor sizes, the 19 comprehensive comparisons showed significantly higher sensitivity (0.82 versus 0.66) and lower negative likelihood ratio (0.20 versus 0.37) for MRI over CT. The specificities of MRI versus CT (0.91 versus 0.92) and the positive likelihood ratios (8.8 versus 8.1) were not different. All three modalities performed better for HCCs ≥2 cm. Performance was poor for HCCs <1 cm. No studies examined whether adults with cirrhosis and an indeterminate nodule are best evaluated using biopsy, repeated imaging, or alternative imaging. Concerns about publication bias, inconsistent study results, increased risk of bias, and clinical factors precluded support for exclusive use of either gadoxetate-enhanced or extracellular contrast-enhanced MRI over CT. CONCLUSION: CT, extracellular contrast-enhanced MRI, or gadoxetate-enhanced MRI could not be definitively preferred for HCC diagnosis in patients with cirrhosis; in patients with cirrhosis and an indeterminate mass, there were insufficient data comparing biopsy to repeat cross-sectional imaging or alternative imaging. (Hepatology 2018;67:401-421).

A systematic review of surveillance after endovascular aortic repair.

OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the optimal modality and frequency of surveillance after endovascular aortic repair (EVAR) in adult patients with abdominal aortic aneurysms. METHODS: We searched for studies of post-EVAR surveillance in MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Scopus through May 10, 2016. The outcomes of interest were endoleaks, mortality, limb ischemia, renal complications, late rupture, and aneurysm-related mortality. Outcomes were pooled using a random-effects model and were reported as incidence rate and 95% confidence interval. RESULTS: Of 1099 candidate references, we included 6 meta-analyses and 52 observational studies. Complication rates were common after EVAR, particularly in the first year. Magnetic resonance imaging had a higher detection rate of endoleaks than computed tomography angiography. Doppler ultrasound had lower diagnostic accuracy, whereas contrast-enhanced ultrasound was likely to be as sensitive as computed tomography angiography. The highest endoleak detection rates were in surveillance approaches that used combined tests. There were no studies that compared different surveillance intervals to determine optimal intervals; however, most studies reported detection rates of patient-important outcomes at 1, 6, 12, 24, 36, 48, and 60 months. Data were insufficient to provide comparative inferences about the best strategy to reduce the risk of patient-important outcomes, such as mortality, limb ischemia, rupture, and renal complications. CONCLUSIONS: Several tests with reasonable diagnostic accuracy are available for surveillance after EVAR. The available evidence suggests a high complication rate, particularly in the first year, and provides a rationale for surveillance.

The Diagnostic Accuracy of Fractional Exhaled Nitric Oxide Testing in Asthma: A Systematic Review and Meta-analyses.

OBJECTIVE: To evaluate the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) measurement in individuals with suspected asthma. METHODS: We searched MEDLINE, EMBASE, PsycINFO, Cochrane databases, and SciVerse Scopus from the databases' inception through April 4, 2017, for studies that enrolled patients aged 5 years and older with suspected asthma and evaluated FeNO diagnostic accuracy. Independent reviewers selected studies and extracted data. We used the symmetric hierarchical summary receiver operating characteristic models to estimate test performance. RESULTS: We included 43 studies with a total of 13,747 patients. In adults, using FeNO cutoffs of less than 20, 20 to 29, 30 to 39, and 40 or more parts per billion, FeNO testing had sensitivities of 0.80, 0.69, 0.53, and 0.41, respectively, and specificities of 0.64, 0.78, 0.85, and 0.93, respectively. In children, using FeNO cutoffs of less than 20 and 20 to 29 parts per billion, FeNO testing had sensitivities of 0.78 and 0.61, respectively, and specificities of 0.79 and 0.89, respectively. Depending on the FeNO cutoff, the posttest odds of having asthma with a positive FeNO test result increased by 2.80- to 7.00-fold. Diagnostic accuracy was modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the overall population. CONCLUSION: Fractional exhaled nitric oxide measurement has moderate accuracy to diagnose asthma in individuals aged 5 years and older. Test performance may be modestly better in corticosteroid-naive asthmatics, children, and nonsmokers than in the general population with suspected asthma. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42016047887.

Comparative Effectiveness and Safety of Cognitive Behavioral Therapy and Pharmacotherapy for Childhood Anxiety Disorders: A Systematic Review and Meta-analysis.

Importance: Childhood anxiety is common. Multiple treatment options are available, but existing guidelines provide inconsistent advice on which treatment to use. Objectives: To evaluate the comparative effectiveness and adverse events of cognitive behavioral therapy (CBT) and pharmacotherapy for childhood anxiety disorders. Data Sources: We searched MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and SciVerse Scopus from database inception through February 1, 2017. Study Selection: Randomized and nonrandomized comparative studies that enrolled children and adolescents with confirmed diagnoses of panic disorder, social anxiety disorder, specific phobias, generalized anxiety disorder, or separation anxiety and who received CBT, pharmacotherapy, or the combination. Data Extraction and Synthesis: Independent reviewers selected studies and extracted data. Random-effects meta-analysis was used to pool data. Main Outcomes and Measures: Primary anxiety symptoms (measured by child, parent, or clinician), remission, response, and adverse events. Results: A total of 7719 patients were included from 115 studies. Of these, 4290 (55.6%) were female, and the mean (range) age was 9.2 (5.4-16.1) years. Compared with pill placebo, selective serotonin reuptake inhibitors (SSRIs) significantly reduced primary anxiety symptoms and increased remission (relative risk, 2.04; 95% CI, 1.37-3.04) and response (relative risk, 1.96; 95% CI, 1.60-2.40). Serotonin-norepinephrine reuptake inhibitors (SNRIs) significantly reduced clinician-reported primary anxiety symptoms. Benzodiazepines and tricyclics were not found to significantly reduce anxiety symptoms. When CBT was compared with wait-listing/no treatment, CBT significantly improved primary anxiety symptoms, remission, and response. Cognitive behavioral therapy reduced primary anxiety symptoms more than fluoxetine and improved remission more than sertraline. The combination of sertraline and CBT significantly reduced clinician-reported primary anxiety symptoms and response more than either treatment alone. Head-to-head comparisons were sparse, and network meta-analysis estimates were imprecise. Adverse events were common with medications but not with CBT and were not severe. Studies were too small or too short to assess suicidality with SSRIs or SNRIs. One trial showed a statistically nonsignificant increase in suicidal ideation with venlafaxine. Cognitive behavioral therapy was associated with fewer dropouts than pill placebo or medications. Conclusions and Relevance: Evidence supports the effectiveness of CBT and SSRIs for reducing childhood anxiety symptoms. Serotonin-norepinephrine reuptake inhibitors also appear to be effective based on less consistent evidence. Head-to-head comparisons between various medications and comparisons with CBT represent a need for research in the field.