Citations

Objective To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine. Background There is a significant unmet need for novel effective well‐tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation – an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double‐blind, sham‐controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine. Methods This was a randomized, double‐blind, sham‐controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty‐two adults meeting the International Classification of Headache Disorders criteria for migraine with 2‐8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone‐controlled wireless device was applied for 30‐45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non‐painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post‐treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post‐treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain‐free at 2 hours were key secondary endpoints. Results Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI 95% , 15.6‐40.2]; P < .0001), pain‐free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post‐treatment. The pain relief and pain‐free superiority of the active treatment was sustained 48 hours post‐treatment. The incidence of device‐related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499). Conclusions REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non‐pharmacological alternative for acute migraine treatment.

Patients with Crohn’s disease commonly develop ileal and less commonly colonic strictures, containing various degrees of inflammation and fibrosis. While predominantly inflammatory strictures may benefit from a medical anti-inflammatory treatment, predominantly fibrotic strictures currently require endoscopic balloon dilation or surgery. Therefore, differentiation of the main components of a stricturing lesion is key for defining the therapeutic management. The role of endoscopy to diagnose the nature of strictures is limited by the superficial inspection of the intestinal mucosa, the lack of depth of mucosal biopsies and by the risk of sampling error due to a heterogeneous distribution of inflammation and fibrosis within a stricturing lesion. These limitations may be in part overcome by cross-sectional imaging techniques such as ultrasound, CT and MRI, allowing for a full thickness evaluation of the bowel wall and associated abnormalities. This systematic literature review provides a comprehensive summary of currently used radiologic definitions of strictures. It discusses, by assessing only manuscripts with histopathology as a gold standard, the accuracy for diagnosis of the respective modalities as well as their capability to characterise strictures in terms of inflammation and fibrosis. Definitions for strictures on cross-sectional imaging are heterogeneous; however, accuracy for stricture diagnosis is very high. Although conventional cross-sectional imaging techniques have been reported to distinguish inflammation from fibrosis and grade their severity, they are not sufficiently accurate for use in routine clinical practice. Finally, we present recent consensus recommendations and highlight experimental techniques that may overcome the limitations of current technologies.

PurposeThis work aims to develop a new framework of image quality assessment using deep learning‐based model observer (DL‐MO) and to validate it in a low‐contrast lesion detection task that involves CT images with patient anatomical background.MethodsThe DL‐MO was developed using the transfer learning strategy to incorporate a pretrained deep convolutional neural network (CNN), a partial least square regression discriminant analysis (PLS‐DA) model and an internal noise component. The CNN was previously trained to achieve the state‐of‐the‐art classification accuracy over a natural image database. The earlier layers of the CNN were used as a deep feature extractor, with the assumption that similarity exists between the CNN and the human visual system. The PLSR model was used to further engineer the deep feature for the lesion detection task in CT images. The internal noise component was incorporated to model the inefficiency and variability of human observer (HO) performance, and to generate the ultimate DL‐MO test statistics. Seven abdominal CT exams were retrospectively collected from the same type of CT scanners. To compare DL‐MO with HO, 12 experimental conditions with varying lesion size, lesion contrast, radiation dose, and reconstruction types were generated, each condition with 154 trials. CT images of a real liver metastatic lesion were numerically modified to generate lesion models with four lesion sizes (5, 7, 9, and 11 mm) and three contrast levels (15, 20, and 25 HU). The lesions were inserted into patient liver images using a projection‐based method. A validated noise insertion tool was used to synthesize CT exams with 50% and 25% of routine radiation dose level. CT images were reconstructed using the weighted filtered back projection algorithm and an iterative reconstruction algorithm. Four medical physicists performed a two‐alternative forced choice (2AFC) detection task (with multislice scrolling viewing mode) on patient images across the 12 experimental conditions. DL‐MO was operated on the same datasets. Statistical analyses were performed to evaluate the correlation and agreement between DL‐MO and HO.ResultsA statistically significant positive correlation was observed between DL‐MO and HO for the 2AFC low‐contrast detection task that involves patient liver background. The corresponding Pearson product moment correlation coefficient was 0.986 [95% confidence interval (0.950, 0.996)]. Bland–Altman agreement analysis did not indicate statistically significant differences.ConclusionsThe proposed DL‐MO is highly correlated with HO in a low‐contrast detection task that involves realistic patient liver background. This study demonstrated the potential of the proposed DL‐MO to assess image quality directly based on patient images in realistic, clinically relevant CT tasks.

Abstract Posterior pilon fractures involve the medial malleolus (MM). Our purpose was to define the characteristics of posterior pilon fractures, and propose a classification system based on fracture morphology and type of management. The records of patients with posterior pilon fractures treated from 2011 to 2015 were retrospectively reviewed. The injury mechanism, fracture morphology, surgical approach, and follow-up results were reviewed and analyzed. This study was approved by the Institutional Review Board of PLA Army General Hospital. Thirty-six patients, 18 males and 18 females (mean age: 48.9 years) were included in the study. Four characteristics were used to define posterior pilon fractures. A simple posterolateral approach or a combined posterolateral and posteromedial approach was used for reduction and fixation in all patients. The mean follow-up time was 28.2 months, and at the end of follow-up, the mean American Orthopedic Foot and Ankle Society Score (AOFAS) was 82.5 points (range: 35–100 points). Based on injury mechanism and fracture morphology, we classified posterior pilon fractures into 3 types that suggest the optimal surgical approach: type I, a single complete fracture fragment; type II, a posterior malleolus fracture with 2 subtypes; type III, a posterior malleolus fracture associated with complete MM fracture with 2 subtypes. The proposed classification system based on injury mechanism and fracture morphology can guide the surgical approach to maximize outcomes.

Patients with severe, treatment-refractory asthma are at risk for death from acute exacerbations. The cytokine IL17A has been associated with airway inflammation in severe asthma, and novel therapeutic targets within this pathway are urgently needed. We recently showed that IL17A increases airway contractility by activating the procontractile GTPase RhoA. Here, we explore the therapeutic potential of targeting the RhoA pathway activated by IL17A by inhibiting RhoA guanine nucleotide exchange factors (RhoGEFs), intracellular activators of RhoA. We first used a ribosomal pulldown approach to profile mouse airway smooth muscle by qPCR and identified Arhgef12 as highly expressed among a panel of RhoGEFs. ARHGEF12 was also the most highly expressed RhoGEF in patients with asthma, as found by RNA sequencing. Tracheal rings from Arhgef12-KO mice and WT rings treated with a RhoGEF inhibitor had evidence of decreased contractility and RhoA activation in response to IL17A treatment. In a house dust mite model of allergic sensitization, Arhgef12-KO mice had decreased airway hyperresponsiveness without effects on airway inflammation. Taken together, our results show that Arhgef12 is necessary for IL17A-induced airway contractility and identify a therapeutic target for severe asthma.

Abstract Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. Hepatitis C virus (HCV) infection is a major risk factor for HCC in the US. HCV infection may cause cancer by suppressing host defense that controls the propagation of repetitive element (RE) sequences, including LINE-1 and Alu, the most representative REs in the human genome. DNA methylation of RE helps stabilize the genome, while reduced RE methylation, also referred as global hypomethylation, leads to genomic instability and is known as a hallmark of cancer. However, current available high-throughput technology for DNA methylation profiling only enables genomewide RE methylation study on a global scale. The role of individual RE methylation in cancer is largely understudied. In this study, using our recently developed and published machine learning algorithm to enhance the RE coverage of the Illumina methylation array platform, we examined the role of individual RE methylation in HCV-induced HCC across the entire genome. We conducted an epigenome-wide association study on 22 HCC, 20 cirrhotic, and 44 normal liver tissues. We included equal numbers of HCV-induced and alcohol-induced HCC/cirrhosis cases. The Illumina 450k array profiled 1939 REs and we computationally predicted 33184 REs; correlations between the overlapping 1541 profiled and predicted RE methylation were &gt; 0.91. Sex, tumor differentiation, and tumor stage were similarly distributed across the HCV and alcohol groups. We adjusted for batch effects and used Benjamini-Hochberg adjusted false discovery rate (FDR) to account for multiple testing. Relative to normal liver tissue, we observed over twice as many differentially methylated (FDR &lt; 0.05) REs in HCV-HCC compared to alcohol-HCC tissue (2911 vs 1304, 749 in common). We validated our results in The Cancer Genome Atlas (TCGA) (325 vs 129, 74 in common) with high correlation (r = 0.90). We also observed that 169 REs were significantly altered in HCV-cirrhosis tissue (compared to none in alcohol-cirrhosis tissue), of which, 17 REs in 13 genes, including PIK3CD, LY9, GCK, NLRC3, and PRKCZ, were consistently hypomethylated in both HCC and cirrhotic liver tissue induced by HCV (r = 0.87). Using TCGA RNA sequencing data, we found that these REs were located in gene body and their hypomethylation was associated with lower expression of their host genes (r &gt; 0.3, p &lt; 0.05). Gene Ontology Enrichment analysis showed that these genes were enriched in T-cell activation & differentiation and cytokine production (FDR &lt; 0.05). Our findings indicate that HCV infection has a more extensive impact on the DNA methylation landscape in RE than alcohol consumption, and that HCV infection may also induce similar hypomethylation in cirrhotic liver. Hypomethylated RE may alter local chromatin environment and disrupt expression of genes involved in immune and inflammatory responses, both of which may promote HCC development. RE hypomethylation in specific genomic locus may serve as early detection biomarker of HCC in patients with HCV-induced cirrhosis. Citation Format: Yinan Zheng, Jimmy Ren, Ryan A. Hlady, Keith D. Robertson, Robert L. Murphy, Lewis R. Roberts, Lifang Hou. DNA methylation of individual repetitive elements in HCV infection-induced HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-235.

Abstract Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Consistent with this carcinogenic exposure, cytogenetic analyses have identified multiple recurrent structural chromosomal abnormalities in this malignancy, but more recent high-throughput sequencing evaluations of point mutations suggest that there is a low mutational burden in mesothelioma. Since tumor mutational burden has been correlated with responses to treatment with immune checkpoint inhibitors such as nivolumab, it was not consistent that patients with mesothelioma and low mutation burdens would have similar response rates in clinical trials with immune checkpoint inhibitors as patients with non-small cell lung cancer which is associated with a high mutation burden. In order to reconcile these differences, and given the potential for an improved understanding of the molecular pathogenesis of mesothelioma to improve therapeutic options, we used mate-pair sequencing (MPseq) and RNA sequencing (RNAseq) to understand how structural variants affect the transcriptome. MPseq differs from standard next generation sequencing approaches by tiling the whole genome with larger fragments (2-5kb) to reliably detect structural variants such as insertions, deletions and rearrangements. Amongst 22 mesothelioma specimens there were 1535 chromosomal rearrangements (median 41, range 3-298 per specimen), that resulted in junctions or novel fusions of non-coding DNA or genes. Six-hundred thirty-seven of these rearrangements (median 22, range 5-103 range per specimen) resulted in novel fusions of genes. Many of these inter- or intra-chromosomal rearrangements were consistent with a pattern of chromoanagesis such as chromoplexy or chromothripsis. Chromosomal rearrangements detected by MPseq were used to guide analysis of RNAseq data and revealed that these chromosomal junctions resulted in the expression of 179 novel amino acid sequences (median 5, 0-51 range per specimen). To determine whether transcription of chromosomal rearrangement-related junctions have neoantigenic potential, we used in silico tools to determine whether any of the expressed junctions contained peptides that could be presented by patient-specific HLA molecules. The top candidate rearrangement-related peptides with neoantigenic potential bound patient-specific HLA molecules nearly as well or as well as a positive control in competitive binding assays. Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel therapeutic strategies, the selection of patients to receive immunotherapy, and blood-based treatment monitoring strategies. Citation Format: Aaron S. Mansfield, Tobias Peikert, James B. Smadbeck, Julia B. Udell, Farhad Kosari, Stephen J. Murphy, Hongzheng Ren, Vishnu V. Serla, Janet L. Schaefer Klein, Giannoula Karagouga, Faye R. Harris, Carlos Sosa, Sarah H. Johnson, Wendy Nevala, Svetomir N. Markovic, Aaron O. Bungum, Eric S. Edell, Haidong Dong, John C. Cheville, Marie Christine Aubry, Jin Jen, George Vasmatzis. Rearrangement-related peptides with neoantigenic potential in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5726.

Objective: To determine whether the association between overall survival (OS) and response to neoadjuvant chemotherapy (NACT) in breast cancer patients varies with tumor subtype and anatomic extent of pathologic complete response (pCR). Background: pCR after NACT predicts improved OS in breast cancer, but it is unclear whether pCR limited to the breast or axilla is also associated with OS. Methods: Women with cT1-3/cN0-1 breast cancer diagnosed in 2010 to 2014 who underwent surgery following NACT were identified in the NCDB and divided into 4 subtypes based on reported hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Kaplan-Meier curves and Cox proportional hazards models were used to estimate OS. Multivariate logistic regression was used to identify factors associated with post-NACT response, defined as upstage (yp stage>clinical stage); no change (clinical stage = yp stage); overall (breast+axilla, ypT0N0), breast-only (ypT0N1/N1mic), or node-only (ypT1-3N0) pCR. Results: Of 33,162 identified patients, 20,265 experienced overall pCR (n = 6370, 19.2%), breast-only pCR (n = 494, 1.5%), node-only pCR (n = 1133, 3.4%), no stage change (n = 9641, 29.1%), or upstage (n = 2627, 7.9%). Compared with no stage change, breast-only pCR was associated with improved OS in triple-negative disease [hazard ratio = 0.58, 95% confidence interval (95% CI) = 0.37–0.89], and node-only pCR was associated with improved OS in both triple-negative (hazard ratio = 0.55,95% CI = 0.39–0.76) and HR+/HER2− disease (hazard ratio = 0.54, 95% CI = 0.33–0.89). For patients achieving overall (breast+axilla) pCR, unadjusted 5-year OS was 0.94 (95% CI = 0.93–0.95), with no difference between patients who were cN0 (hazard ratio = 0.95, 95% CI = 0.93–0.96) or cN1 (hazard ratio = 0.94, 95% CI = 0.92–0.96) at diagnosis. Conclusions: In node-positive patients, pCR limited to either the breast or axilla predicts survival for select receptor subtypes. In patients achieving pCR in both the breast and axilla, survival is driven by response to NACT rather than presenting cN stage.