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BackgroundThe feasibility and reproducibility of multifrequency MR elastography (MRE) for diagnosing pancreatic ductal adenocarcinoma (PDAC) have not been reported.PurposeTo determine the feasibility and reproducibility of multifrequency MRE for assessing pancreatic stiffness in healthy and diseased pancreases.Study typeProspective.SubjectsA total of 40 healthy volunteers and 10 patients with PDAC were prospectively recruited between March 2018 and October 2021.Field strength/sequenceA 3.0‐T pancreatic MRE at frequencies in the order of 30, 40, 60, 80, and 100 Hz.AssessmentBody mass index (BMI) and wave distance of the healthy pancreas and PDAC were measured. Image quality was assessed using the image quality score (IQS: 1–4, ≥3 were considered diagnostic quality). Three readers independently performed the pancreatic stiffness and IQS assessments to evaluate reproducibility.Statistical testsLogistic regression analyses were performed to determine variables that influenced IQS. Statistical significance was set at P <0.05. Levels of inter‐ and intrarater agreement were assessed using intraclass correlation coefficients (ICC) and Cohen's kappa coefficient (κ). Good reproducibility was set at ICC and κ ≥ 0.8.ResultsIn logistic regression analysis, a diagnostic IQS in healthy volunteers was independently associated with a lower BMI (odds ratio [OR] = 0.89 kg/m−2), shorter wave distance (OR = 0.70 cm−1), and lower frequency (30 and 40 Hz: OR = 170.01 and 96.02). In PDAC, frequency was the only independent factor for diagnostic IQS (30–60 Hz: OR = 46.18, 46.18, and 17.20, respectively) with 100 Hz as a reference. In healthy volunteers, good reproducibility was observed at 30 and 40 Hz. In PDAC, good reproducibility was observed at 30–60 Hz.Data conclusionMRE at 30 and 40 Hz provides diagnostic wave images and reliable measurements of pancreatic stiffness in healthy volunteers. MRE at 30–60 Hz is acceptable for PDACs (IQS ≥ 3, ICC and κ ≥ 0.80).Evidence Level1Technical EfficacyStage 2

Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P &lt; 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6). In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Our study suggests a limited role of gene–environment interactions in breast cancer risk.

Abstract Reduced age-related terminal duct lobular unit (TDLU) involution has been linked to increased breast cancer risk and triple-negative breast cancer. Associations of TDLU involution levels with race and ethnicity remain incompletely explored. Herein, we examined the association between genetic ancestry and TDLU involution in normal breast tissue donated by 2014 healthy women in the United States. Women of African ancestry were more likely than European women to have increased TDLU counts (odds ratio [OR]trend = 1.36, 95% confidence interval [CI] = 1.07 to 1.74), acini counts per TDLU (OR = 1.47, 95% CI = 1.06 to 2.03), and median TDLU span (ORtrend = 1.44, 95% CI = 1.08 to 1.91), indicating lower involution, whereas East Asian descendants were associated with decreased TDLU counts (ORtrend = 0.52, 95% CI = 0.35 to 0.78) after controlling for potential confounders. These associations are consistent with the racial variations in incidence rates of triple-negative breast cancer in the United States and suggest opportunities for future work examining whether TDLU involution may mediate the racial differences in subtype-specific breast cancer risk.

Abstract Background and study aims Optical coherence tomography (OCT) is a new technology available for evaluation of indeterminate biliary strictures. It allows under-the-surface visualization and preliminary studies have confirmed standardized characteristics associated with malignancy. The aim of this study is to evaluate the first interobserver agreement in identifying previously agreed upon OCT criteria and diagnosing of malignant versus benign disease. Patients and methods Fourteen endoscopists were asked to review an atlas of reference clips and images of eight criteria derived from expert consensus A total of 35 de-identified video clips were then evaluated for presence of the eight criteria and for final diagnosis of malignant versus benign using the atlas as reference Intraclass correlation (ICC) analysis was done to evaluate interrater agreement. Results Clips of 23 malignant lesions and 12 benign lesions were scored. Excellent interobserver agreement was seen with dilated hypo-reflective structures (0.85) and layering effacement (0.89); hyper-glandular mucosa (0.76), intact layering (0.81), and onion-skin layering (0.77); fair agreement was seen with scalloping (0.58), and thickened epithelium (0.4); poor agreement was seen with hyper-reflective surface (0.36). The diagnostic ICC for both neoplastic (0.8) and non-neoplastic (0.8) was excellent interobserver agreement. The overall diagnostic accuracy was 51 %, ranging from 43 % to 60 %. Conclusions Biliary OCT is a promising new modality for evaluation of indeterminate biliary strictures. Interobserver agreement ranged from fair to almost perfect on eight previously identified criteria. Interobserver agreement for malignancy diagnosis was substantial (0.8). Further studies are needed to validate this data.

BackgroundThe standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) is safe and efficacious.MethodsElderly or frail patients with GBM treated with 52.5 Gy in 15 fractions were pooled from 3 phase 1/2 studies and a prospective observational study. Overall survival (OS) and progression‐free survival (PFS) were defined time elapsing between surgery/biopsy and death from any cause or progression of disease.ResultsSixty‐two newly diagnosed patients were eligible for this pooled analysis of individual patient data. The majority (66%) had a Karnofsky performance status (KPS) score <70. The median age was 73 years. The median OS and PFS were 10.3 and 6.9 months, respectively. Patients with KPS scores ≥70 and <70 had a median OS of 15.3 and 9.5 months, respectively. Concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). There was no grade 4/5 toxicity.ConclusionsThis is the only analysis of elderly/frail patients with GBM prospectively treated with a hypofractionated radiation regimen that is isoeffective to the Stupp regimen. Treatment was well tolerated and demonstrated excellent OS and PFS compared with historical studies. This regimen gives the elderly/frail population an alternative to regimens with a lower BED. Randomized trials are needed to validate these results.

To sense and to respond to mechanical stimuli is a fundamental process of cardiomyocytes during both heart development and diseases. However, how mechanical stimuli control cardiomyocyte size remains elusive. Here, we report a novel inhibitory mechanotransductive response suggested by loss-of-functions studies of α-Actinin2 (Actn2), a predominant sarcomeric Z-disc protein. During zebrafish cardiogenesis, depletion of Actn2 results in a defective Z-disc, while other sarcomeric substructures remain normal. As a consequence, ventricle chamber size is severely reduced. Interestingly, this chamber size reduction can be rescued by the cessation of heart contraction, suggesting the involvement of an inhibitory mechanotransductive reponse. At the molecular level, both tcapa and tcapb, two zebrafish tcap homologues that are transcriptionally responsive to stretch, are transcriptionally activated in actn2 knockdown embryos while activation of these gene results in smaller cardiomyocytes. Depletion of either gene rescues the reduced cardiomyocyte size in actn2 knockdown embryos. Consistent to embryonic studies, tcaps are transcriptionally activated during pathogenesis of anemia-induced cardiomyopathy, while over expression of tcapa via transgenics exerts a cardioprotective effect. Together, we conclude that transcriptional regulation of tcaps conveys a novel inhibitory mechanotransductive response that modulates cardiomyocyte size during both zebrafish cardiogenesis and adult cardiac remodeling.

Introduction: Arteriovenous fistulas (AVFs) used for hemodialysis vascular access will fail because of venous neointimal hyperplasia (VNH) that causes stenosis formation at the venous outflow tract. As a result, only 60% of all AVFs are patent at 1-year. There are several factors which have been hypothesized to contribute to VNH including shear stress, hypoxia, and both local and systemic inflammation. Mesenchymal stem cells (MSCs) have been demonstrated to reduce inflammation while having antiproliferitive properties that aid abrogating vascular injury. Hypothesis: We hypothesized that adventitial transplantation of human adipose derived MSCs to the outflow vein of AVF created in CD1-FoxN1 would attenuate VNH failure by reducing pro-inflammatory mediators including tissue necrosis factor alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), and interleukin-1 beta (IL-1β). Methods: Adventitial transplantation of human MSC was performed in CD1-FoxN1 mice. A carotid artery to ipsilateral jugular AVF was placed and animals were divided into three groups: MSCs (M), CorMatrix ECM scaffold (S, CorMatrix Scaffold, Roswell, GE), or scaffold embedded with 250,000 MSCs (S+M) which were delivered to the adventitia. The mice were then sacrificed at 7 and 28 days post AVF placement and the outflow veins were harvested for histomorphometric and qPCR expression analysis. Results: The average lumen vessel area was significantly increased in the outflow veins removed from the S + M group compared to S or M alone at days 7 and 21 (both, P<0.05). The average area of neointima was significantly decreased in the S+M group when compared to S or M groups (P<0.05) while cell density and Ki-67 index were also significantly decreased at day 7 between S and S+M groups (P<0.05). RNA expression analysis revealed that MCP-1, IL-1β, and TNF-α were all significantly decreased in the outflow vein removed from the S+M group when compared to the S or M group (P<0.05). Conclusion: Adventitial transplantation of MSCs to the outflow vein of the AVF at the time of placement attenuates VNH mediated through a reduction of MCP-1, IL-1β, and TNF-α.

Purpose: The majority of patients with end stage renal disease who require hemodialysis use a arteriovenous fistula (AVF) for their vascular access. However, only 40% of AVFs are clinically usable after 1 year. Arteriovenous fistulas fail because of venous neointimal hyperplasia (VNH) that develops in the proximal outflow vein. The immediate early gene, IEX-1 (IER-3), is increased in response to shear stress and hypoxia and both factors contribute to VNH. IEX-1 expression was increased in stenotic venous stenoses removed from patients with hemodialysis vascular access compared to controls. We hypothesized that reducing the expression of IEX-1 using a knockout mouse model with chronic kidney disease (CKD) and AVFs would have decreased VNH compared to wild type (WT) mice. Methods: CKD was induced by performing a nephrectomy. Four weeks later, an AVF was placed to connect the carotid artery to ipsilateral jugular vein. The mice were sacrificed 3 and 28 days after fistula creation and outflow veins were harvested for gene expression and histomorphometric analyses. Results: By day 3, the average gene expression of vascular endothelial growth factor-A (VEGF-A) was significantly lower in the IEX-1 KO vs. WT mice (average reduction: 40%, P<0.05). At day 28, the average lumen vessel area was increased significantly (average increase: 133%, P<0.05, IEX-1 KO vs. WT, respectively) while the average area of the neointima was significantly decreased (average reduction: 20%, IEX-1 KO vs. WT, respectively). Accompanied with this, there was a significant decrease in α-SMA staining and Ki-67 proliferation while the average TUNEL staining was significantly increased (all P<0.05, IEX-1 KO vs. WT). Finally, there was a significant decrease in the average staining intensity for VEGF-A and matrix metalloproteinase-9 (MMP-9) in the KO vs. WT mice (both, P<0.05). Conclusion: A reduction in IEX-1 gene expression results in positive vascular remodeling accompanied with a reduction in proliferation and α-SMA density mediated through a VEGF-A/MMP-9 pathway. Taken collectively, these findings indicate that reducing IEX-1 expression is protective for VNH formation and provide a rationale for use of anti-IEX-1 therapies aimed at prolonging AVF function.