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Abstract Background and study aims Precise staging in T1 esophageal adenocarcinoma (EAC) is critical in determining candidacy for curative endoscopic resection. High-frequency endoscopic ultrasound (EUS) has demonstrated suboptimal accuracy in T1 EAC staging due to insufficient spatial resolution. Volumetric laser endomicroscopy (VLE) allows for high-resolution wide-field visualization of the esophageal microstructure. We aimed to investigate the role of VLE in staging T1 EAC. Patients and methods Patients undergoing endoscopic mucosal resection (EMR) were prospectively enrolled and only T1 EAC cases were included. EMR specimens were imaged using second-generation VLE immediately after resection. VLE images were analyzed for signal intensity by depth and signal attenuation (dB/mm) in both cross-sectional and en-face orientation. A decision tree model was constructed to combine measured VLE parameters and delineate diagnostic thresholds. Results Thirty EMR scans were obtained – 15 T1a specimens from 9 patients and 15 T1b specimens from 11 patients. T1b specimen VLE scans exhibited higher signal intensity (P < 0.0001) and higher signal attenuation compared to T1a specimens (P = 0.03). A combination of signal attenuation and signal intensity at 150 µm depth yielded optimal diagnostic thresholds and an area under the curve (AUC) of 0.77. VLE signal attenuation was significantly associated with grade of differentiation, irrespective of EAC stage. Conclusions VLE signal intensity and signal attenuation are quantitatively distinct in T1a and T1b EAC and associated with grade of differentiation. This is the first study examining the role of VLE for staging of T1 EAC and demonstrates promising diagnostic performance. With further in vivo validation, VLE may serve a role in staging superficial EAC.

Multinucleate Giant Cell (GC) reaction is a biological response that occurs secondary to infection, an implanted foreign body, tissue injury, or inflammation. In rare instances GC reactions have been reported following tissue ablation. Multinucleate GC reactions and tumefactive fat necrosis both have the ability to mimic cancer recurrence or metastasis and can appear as enhancing masses. We discuss a case of a surgically resected retroperitoneal perinephric mass thought to be recurrent renal cell carcinoma (RCC) that was pathologically confirmed as tumefactive fat necrosis with multinucleate GC reaction 2 years following percutaneous cryoablation of a small renal mass.

Objective Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett’s oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines. Design Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies. Results 594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4–4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI −7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia). Conclusions BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.

Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20–30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.

AbstractBackgroundThe most recent Chicago Classification expanded the criteria for diagnosis of jackhammer esophagus (JHE) to include the distal contractile integral (DCI) of the lower esophageal sphincter (LES). The clinical impact of the manometric inclusion of LES hypercontractility remains unclear. We aimed to analyze the clinical features and long‐term outcomes of measured LES‐dependent (LD‐JHE) and LES‐independent (LI‐JHE) jackhammer esophagus.MethodsPatients meeting diagnostic criteria for JHE were identified at two academic medical centers. High‐resolution esophageal manometry data were re‐analyzed with inclusion and exclusion of the LES DCI. LD‐JHE was defined by falling outside JHE diagnostic criteria with exclusion of the LES. A telephone survey was conducted for follow‐up utilizing the impact dysphagia (IDQ‐10) questionnaire.Key ResultsEighty‐one patients met study inclusion criteria, with 12 (14.8%) classified as LD‐JHE. LD‐JHE patients had a significantly lower mean DCI and fewer swallows with DCI >8000 mm Hg‐s‐cm. Basal LES pressure was higher in patients with dysphagia to solids than those with dysphagia to solids and liquids. Clinical and manometric parameters were otherwise similar between groups. Sixty‐six patients had clinical or phone follow‐up at a median of 46.6 months. Forty‐one patients (62.1%) received therapies directed at JHE. There was no difference in symptom improvement for treated vs untreated patients or for JHE subtype.Conclusions and InferencesOur findings suggest that LD‐JHE and LI‐JHE are clinically indistinguishable and thus support existing diagnostic criteria. Furthermore, our long‐term follow‐up data suggest that JHE, irrespective of LES involvement, may improve without treatment. Further study is needed to clarify which patients merit therapeutic intervention.

AbstractBackgroundThere is limited information about the potential associations of multiple sclerosis (MS) and commonly used household chemicals.MethodsWe performed a case‐control study of exposures to common household chemicals during childhood in children with MS and healthy pediatric controls. Exposures to household products were collected from a comprehensive questionnaire (http://www.usnpmsc.org/Documents/EnvironmentalAssessment.pdf) completed by parents at the time of enrollment in the study. Cases included children diagnosed with MS or clinically isolated syndrome with at least two silent T2 bright lesions on MRI, recruited within 4 years of disease onset from 16 pediatric MS clinics in the USA. Multivariate analyses using logistic regression were adjusted for possible confounders including age, sex, race, ethnicity, mother's highest level of education, and urban versus rural living.ResultsQuestionnaire responses to household chemicals were available for 312 eligible cases (median age 15.7 years, 63% girls) and 490 healthy controls (median age 15.0, 57% girls). Exposure to rodenticides (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.35–3.26, P ≤ 0.001), weed control agents (OR 1.99, 95% CI 1.36–2.92, P ≤ 0.001) and products for plant/tree disease control (OR 2.72, 95% CI 1.54–4.82, P ≤ 0.001) anytime during childhood were associated with an increased risk for pediatric‐onset MS in adjusted and multiple comparisons analyses.ConclusionsOur findings suggest that exposure to specific household chemicals during early childhood is associated with the risk of developing pediatric‐onset MS. Future studies are needed to elucidate a causal relationship and the exact agents involved.

AbstractBackgroundWe previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory.MethodsPediatric MS cases (N = 290) and healthy controls (N = 442) were included as part of an ongoing case–control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk‐Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases.ResultsFine particulate matter (PM2.5), carbon monoxide (CO), sulfur dioxide (SO2), and lead air emissions were associated with increased odds for pediatric MS (P < 0.01) for those residing within 20 miles of an MS center. Most study participants (75%) resided within 5 miles of at least one TRI site; however, the mean total pounds of stack air releases was higher for sites near MS cases (81,000 tons) compared to those near healthy controls (35,000 tons, P = 0.002). Average RSEI scores did not differ significantly between cases and controls.ConclusionOut of several air pollutants examined, we show that fine particulate matter and three other criteria pollutants (SO2, CO, and lead) were statistically associated with higher odds for pediatric MS.

AbstractObjectiveWhile prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections.MethodsCases with pediatric‐onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses‐1 (HSV‐1) and ‐2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA‐DRB1:1501 status.ResultsA total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV‐viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV‐1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA‐DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA‐DRB1*15:01 status.InterpretationEBV seropositivity is strongly associated with pediatric MS, as is HSV‐1 seropositivity in subjects negative for HLA‐DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

Abstract Background Endoscopic mucosal resection (EMR) can be performed en-bloc in Barrett's esophagus (BE) lesions that are ≤2 cm in size. The true size of a BE lesion may be underestimated under white light endoscopy, limiting the rate of en-bloc resection. Volumetric laser endomicroscopy (VLE) provides high-resolution cross-sectional imaging of BE. A greater number of VLE glands are associated with BE dysplasia and may help predict lesion size. The aim of this study was to determine the association between VLE gland count and outcome of resection. Methods EMR specimens from patients with a history of dysplastic BE were imaged with VLE. EMRs performed on BE lesions ≤2cm in size with intent at en-bloc resection were included. Manual quantification of epithelial glands was performed in blinded fashion. Image visualization enhancement software was used to quantify the surface area occupied by epithelial glands on en-face VLE. Histologic en-bloc (R0) and incomplete (R1) resection of the targeted lesion was defined by the absence and presence of dysplasia and/or cancer at the specimen margins respectively. Results The study sample consisted of 37 EMRs from 31 patients. The mean (SD) size of EMRs was 1.04 (0.37) cm. Pathology showed low-grade dysplasia (N = 12), high-grade dysplasia (N = 19), and intramucosal cancer (N = 6). The en-bloc resection rate was 37.8% (R0: N = 14; R1: N = 23). The mean (SD) number of epithelial glands was 13.0 (6.7) and 28.8 (23.9) for R0 and R1 specimens, respectively, with a statistically significant mean difference of 15.8 glands (95% CI: 2–29, P = 0.02) between the two groups. A gland count of 28 or higher per EMR specimen predicted R1 with 100% sensitivity and 39% specificity (ROC: 0.69). The mean (SD) surface area occupied by epithelial glands in R0 and R1 specimens was 0.98 (1.1) mm2 and 2.3 (2.4) mm2, respectively. There was strong correlation between manual gland counts and epithelial gland surface area (R2: 0.81, P < 0.001). Conclusion A higher number of VLE glands in EMR specimens is associated with a lower en-bloc resection rate suggesting that white-light endoscopy underestimates lesion size and that VLE may have a potential role in lesion margin assessment. Disclosure All authors have declared no conflicts of interest.

Objectives Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early‐onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD‐ and schizophrenia (SCZ)‐associated risk variants is associated with an earlier AAO in BD patients. Methods A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn‐Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD‐ and SCZ‐PRSs and AAO were evaluated with regression models. Results BD‐ and SCZ‐PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.