Citations

AbstractBackgroundIrritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, diagnosed on symptom‐based criteria. Many have reported discrepancies between formal Rome criteria and diagnoses made in clinical practice. The aim of the study was to explore whether a quantitative version of the Rome criteria would better represent a clinical diagnosis of IBS than the current dichotomous criteria for symptom measure.MethodsAs part of a large, case‐control study, participants completed a validated bowel disease questionnaire. Rome criteria were analyzed based on 15 individual symptoms. Penalized logistic regression model with stepwise selection was used to identify significant symptoms of IBS which were independently associated with case‐control status.Key ResultsIn cases with a clinical diagnosis of IBS, 347 (70%) met Rome criteria for IBS. Increasing number of Rome symptoms were found related to the odds of being diagnosed with IBS. Nearly half of the Rome‐negative case group experienced infrequent symptoms suggesting milder disease. Five of 15 Rome symptoms were associated with predicting case‐control status in the final model, with 96% correctly classified among Rome‐positive cases, 76% for Rome‐negative cases, and 91% for controls.Conclusions and InferencesIrritable bowel syndrome appears to be a spectrum disorder. Quantifying individual symptoms of Rome criteria has greater utility than the current application in representing the degree of IBS affectedness and appears to better reflect a clinical diagnosis of IBS applied by physicians. The use of a quantitative diagnostic Rome “score” may be helpful in clinical practice and research studies to better reflect the degree an individual is affected with IBS.

During contrast-enhanced ultrasound (CEUS) imaging of tumor microvascular perfusion, nearby arteriole enhancement can be a dominant feature of the wash-in kinetics that obscures the perfusion characteristics of the capillary bed. This presentation demonstrates that statistical wash-in curves generated using our compound CEUS speckle model1 exhibit two distinct phases corresponding to “fast-flow” and “slow-flow” enhancement that can be detected by fitting a linear combination of two monoexponential functions with different time constants. CEUS cine loops were acquired from a patient-derived xenograft model of renal cell carcinoma, where fresh tumor fragments were engrafted into the chicken embryo chorioallantoic membrane. Subharmonic CEUS images were acquired at 18 MHz using a destruction-replenishment protocol. Enhancement of manually segmented tumor cross-sections was analyzed offline in MATLAB. The CEUS cine loops from this xenograft model frequently exhibited in-plane arteriole enhancement. The two-phase fit discriminated a slow-flow component in 26.6% of time-intensity wash-in curves and 62.9% of the statistical wash-in curves, leading to a decrease in estimated tumor blood volume by 22.1% and 24.7%, respectively, compared to a simple monoexponential fit. These results suggest that conventional CEUS processing may frequently overestimate capillary blood volume. 1M.R. Lowerison et al., Med. Phys. 44, 99-111 (2017).

Background: Long-QT syndrome (LQTS), an inherited cardiac repolarization disorder, is an important cause of fetal and neonatal mortality. Detecting LQTS prenatally is challenging. A fetal heart rate (FHR) less than third percentile for gestational age is specific for LQTS, but the sensitivity is only ≈50%. Left ventricular isovolumetric relaxation time (LVIRT) was evaluated as a potential diagnostic marker for fetal LQTS. Methods and Results: LV isovolumetric contraction time, LV ejection time, LVIRT, cycle length, and FHR were measured using pulsed Doppler waveforms in fetuses. Time intervals were expressed as percentages of cycle length, and the LV myocardial performance index was calculated. Single measurements were stratified by gestational age and compared between LQTS fetuses and controls. Receiver-operator curves were performed for FHR and normalized LVIRT (N-LVIRT). A linear mixed-effect model including multiple measurements was used to analyze trends in FHR, N-LVIRT, and LV myocardial performance index. There were 33 LQTS fetuses and 469 controls included. In LQTS fetuses, the LVIRT was prolonged in all gestational age groups ( P <0.001), as was the N-LVIRT. The best cutoff to diagnose LQTS was N-LVIRT ≥11.3 at ≤20 weeks (92% sensitivity, 70% specificity). Simultaneous analysis of N-LVIRT and FHR improved the sensitivity and specificity for LQTS (area under the curve=0.96; 95% confidence interval, 0.82–1.00 at 21–30 weeks). N-LVIRT, LV myocardial performance index, and FHR trends differed significantly between LQTS fetuses and controls through gestation. Conclusions: The LVIRT is prolonged in LQTS fetuses. Findings of a prolonged N-LVIRT and sinus bradycardia can improve the prenatal detection of fetal LQTS.

AbstractAtopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high‐level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for “the Agency's current thinking on a particular subject.” Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices).

Objectives Health disparities between individuals of African and European ancestry are well documented. The disparities in bipolar disorder may be driven by racial bias superimposed on established factors contributing to misdiagnosis, including: evolving empirically based diagnostic criteria (International Classification of Diseases [ ICD ], Research Diagnostic Criteria [ RDC ] and Diagnostic and Statistical Manual [ DSM ]), multiple symptom domains (i.e. mania, depression and psychosis), and multimodal medical and additional psychiatric comorbidity. Methods For this paper, we reviewed the phenomenological differences between bipolar individuals of African and European ancestry in the context of diagnostic criteria and clinical factors that may contribute to a potential racial bias. Results Published data show that bipolar persons of African ancestry, compared with bipolar persons of non‐African ancestry, are more often misdiagnosed with a disease other than bipolar disorder (i.e. schizophrenia). Additionally, studies show that there are disparities in recruiting patients of African ancestry to participate in important genomic studies. This gap in biological research in this underrepresented minority may represent a missed opportunity to address potential racial differences in the risk and course of bipolar illness. Conclusion A concerted effort by the research community to increase inclusion of diverse persons in studies of bipolar disorder through community engagement may facilitate fully addressing these diagnostic and treatment disparities in bipolar individuals of African ancestry.

Abstract The trend toward precision-based therapeutic approaches dictated by molecular alterations offers substantial promise for men with metastatic castration-resistant prostate cancer (mCRPC). However, current approaches for molecular characterization are primarily tissue based, necessitating serial biopsies to understand changes over time and are limited by the challenges inherent to extracting genomic material from predominantly bone metastases. Therefore, a circulating tumor cell (CTC)-based assay was developed to determine gene expression across a panel of clinically relevant and potentially actionable prostate cancer–related genes. CTCs were isolated from the whole blood of mCRPC patients (n = 41) and multiplex qPCR was performed to evaluate expression of prostate cancer–related target genes (n = 78). A large fraction of patients (27/41, 66%) had detectable CTCs. Increased androgen receptor (AR) expression (70% of samples) and evidence of Wnt signaling (67% of samples) were observed. The TMPRSS2:ERG fusion was expressed in 41% of samples, and the aggressive prostate cancer–associated long noncoding RNA SChLAP1 was upregulated in 70%. WNT5a [HR 3.62, 95% confidence interval (CI), 1.63–8.05, P = 0.002], AURKA (HR 5.56, 95% CI, 1.79–17.20, P = 0.003), and BMP7 (HR 3.86, 95% CI, 1.60–9.32, P = 0.003) were independently predictive of overall survival (FDR &lt; 10%) after adjusting for a panel of previously established prognostic variables in mCRPC (Halabi nomogram). A model including Halabi, WNT5a, and AURKA expression, termed the miCTC score, outperformed the Halabi nomogram alone (AUC = 0.89 vs. AUC = 0.70). Understanding the molecular landscape of CTCs has utility in predicting clinical outcomes in patients with aggressive prostate cancer and provides an additional tool in the arsenal of precision-based therapeutic approaches in oncology. Implications: Analysis of CTC gene expression reveals a clinically prognostic “liquid biopsy” signature in patients with metastatic castrate-resistance prostate cancer. Mol Cancer Res; 16(4); 643–54. ©2018 AACR.

Background— In severe asymptomatic primary mitral valve regurgitation without risk factors, surgery strategy is controversial. We sought to clarify whether being symptomatic corresponds to the hemodynamic burden and reduced exercise capacity. A better understanding of this may contribute to optimize timing of surgery. Methods and Results— Subjects with asymptomatic (New York Heart Association functional class I, n=29) or symptomatic (New York Heart Association functional class II and III, n=28) significant primary mitral valve regurgitation (effective regurgitant orifice, ≥0.30 cm 2 ; left ventricular ejection fraction, >60%) were included. Right heart catheterization during rest and exercise, echocardiography, magnetic resonance imaging, and peak oxygen consumption test was performed. Symptomatic subjects had significantly higher pulmonary capillary wedge pressure at rest (14±4 versus 11±3 mm Hg; P =0.003) and at maximal exercise (30±6 versus 25±7 mm Hg; P =0.02) and higher mean pulmonary artery pressure (PAP) at rest (22±7 versus 18±4 mm Hg; P =0.005) and maximal exercise (46±8 versus 39±7 mm Hg; P =0.005) than asymptomatic subjects. Among asymptomatic subjects with normal resting value, exercise testing revealed a systolic PAP >60 mm Hg in 34%. Also the reverse response with minimal increase in pulmonary capillary wedge pressure and mean PAP during exercise was seen, especially in asymptomatic subjects. Among symptomatic subjects, we found a significant inverse correlation between resting mean PAP and left ventricular ejection fraction ( r =−0.52; P =0.02) and right ventricular ejection fraction ( r =−0.67; P <0.01). Peak oxygen consumption was equal and normal in both groups and correlated with left ventricular stroke volume but not with pulmonary capillary wedge pressure. Conclusions— Symptoms in patients with severe mitral valve regurgitation relate to congestion (pulmonary capillary wedge pressure and PAP), but not to peak oxygen consumption, which is determined by forward left ventricular stroke volume. Exercise testing reveals a higher mitral valve regurgitation burden in apparently asymptomatic patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02961647.

Abstract Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (&gt; 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p&lt;0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-08.