Citations

Archival data were used to examine the feasibility of a 5-day, clinic-based, intensive exposure–based cognitive-behavioral group therapy for childhood anxiety disorders (CADs) and obsessive-compulsive disorder (OCD). Participants were 143 children (82 girls) aged 6 to 19 years ( M = 13.93 years, SD = 2.9 years) with CADs or OCD (or both) in 28 consecutive groups. Repeated-measures ANOVA in the subsample ( n = 57) with complete treatment data indicated positive change on all variables from pretreatment to posttreatment with few differences between CADs and OCD patients. Effect sizes were moderate to large for anxiety symptoms (parent reported = 0.74, child reported = 0.65) and impairment (parent reported = 1.02, child reported = 0.69). The intensive group protocol required fewer sessions and 36% fewer therapist-hours per patient than the individually administered protocol. The program increased treatment availability for families from diverse geographic areas ( M distance traveled to clinic = 407 miles, SD = 786.4 miles). These findings support further, well-controlled examination of the 5-day intensive group treatment protocol’s efficacy and potential to increase availability of evidence-based exposure therapy.

AbstractAimPersistent or recurrent wheezing is a common indication for flexible bronchoscopy, as anatomic and infectious or inflammatory changes are highly prevalent. We sought to evaluate the prevalence of anatomic, infectious, and inflammatory disease in a cohort of children undergoing flexible bronchoscopy for wheezing or poorly controlled asthma.MethodsWe retrospectively reviewed all children <18 years old who underwent flexible bronchoscopy at our center from October 29, 2012‐December 31, 2016 for the primary or secondary indication of wheezing (persistent, frequently recurring, or atypical) or poorly controlled asthma.ResultsA total of 101 procedures were identified in 94 patients, aged 3 months to 18 years. Potential anatomic causes for wheezing identified in 45.7% of patients and inflammatory changes in 49.5% of procedures. This included the identification of a laryngeal cleft in 17% for which half required medical or surgical management. Tracheobronchomalacia was the most commonly identified anatomic lesion. Thirty children from this cohort had poorly controlled asthma. Among this subgroup, 54% had increased neutrophils on BAL and 30% had an anatomic contributor to wheezing, including one with a laryngeal cleft. Based on findings from flexible bronchoscopy, management changes made in 63.8% of patients. This included medication changes in 54 and surgical intervention in 9.DiscussionWe conclude that transnasal flexible bronchoscopy has high yield in children with recurrent, persistent, or atypical wheezing and those with poorly controlled asthma. Laryngeal cleft has a reasonably high prevalence that warrants specific evaluation in this population.

AbstractIn hemophilia B (HB), factor IX gene (F9) genotyping is used for molecular confirmation of affected individuals, for carrier testing, to facilitate the identification of those at risk for anaphylaxis/inhibitors (associated with large deletions), and to assist in assigning disease severity. Owing to test costs, optimal test utilization involves pre/post-test counseling and appropriate patient and test selection (e.g., mutation screening [F9MS] vs. known mutation [F9KM] testing). This article aims to review the trends and outcomes of F9-genotyping orders and describe the spectrum of variants identified in a sample of individuals in our reference laboratory. We performed a retrospective review of consecutive orders submitted to the Special Coagulation DNA Diagnostic Laboratory, Mayo Clinic, between 2012 and 2015. A total of 133 orders (38%) were identified for men: 118 (88%) were F9MS and 15 (12%) were F9KM. Thirteen orders (10%) were cancelled. A total of 209 orders were identified for women: 178 (85%) were F9MS and 31 (15%) were F9KM. Thirty-seven orders (18%) were cancelled and 30% of the tests performed yielded negative results. A total of 164 samples (47%) were received without clinical information. Seventeen previously unreported variants were identified. F9 genotyping provides useful information for HB management; however, 18% of our orders were cancelled and almost half were received without relevant clinical information, thus reaffirming the need for ongoing scrutiny of submitted orders. Optimal patient and test selection is important as is the accurate interpretation of variants identified. Most of the pathogenic variants identified were point mutations, with very few large deletions, consistent with the literature.

Abstract Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

This pilot study examined the functional impact of computerized versus compensatory calendar training in cognitive rehabilitation participants with mild cognitive impairment (MCI). Fifty-seven participants with amnestic MCI completed randomly assigned calendar or computer training. A standard care control group was used for comparison. Measures of adherence, memory-based activities of daily living (mADLs), and self-efficacy were completed. The calendar training group demonstrated significant improvement in mADLs compared to controls, while the computer training group did not. Calendar training may be more effective in improving mADLs than computerized intervention. However, this study highlights how behavioral trials with fewer than 30–50 participants per arm are likely underpowered, resulting in seemingly null findings.

Abstract Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 &gt;10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

AbstractBackgroundObservational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium‐chain triglyceride (MCT) treatment of long‐chain fatty acid oxidation disorders (LC‐FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven‐carbon fatty acid triglyceride, to trioctanoin (C8), an eight‐carbon fatty acid triglyceride, in patients with LC‐FAODs.MethodsA double blinded, randomized controlled trial of 32 subjects with LC‐FAODs (carnitine palmitoyltransferase‐2, very long‐chain acylCoA dehydrogenase, trifunctional protein or long‐chain 3‐hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis.ResultsPatients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p = 0.046) while experiencing a 20% (p = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate‐intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups.ConclusionsC7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC‐FAODs.Clinical Trial Registration: Clinicaltrials.gov NCT01379625.

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. (Hepatology2018;67:401‐421).

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; I 2 = 0%) and of waitlist dropout from all causes (RR, 0.38; 95% CI, 0.060‐2.370; I 2 = 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. (H epatology 2018;67:381‐400).