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Background Current methods of amyloid PET interpretation based on the binary classification of global amyloid signal fail to identify early phases of amyloid deposition. A recent analysis of 18F-florbetapir PET data from the Alzheimer’s disease Neuroimaging Initiative cohort suggested a hierarchical four-stage model of regional amyloid deposition that resembles neuropathologic estimates and can be used to stage an individual’s amyloid burden in vivo. Here, we evaluated the validity of this in vivo amyloid staging model in an independent cohort of older people with subjective memory complaints (SMC). We further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimer’s disease (AD). Methods The monocentric INSIGHT-preAD cohort includes 318 cognitively intact older individuals with SMC. All individuals underwent 18F-florbetapir PET scanning and extensive neuropsychological testing. We projected the regional amyloid uptake signal into the previously proposed hierarchical staging model of in vivo amyloid progression. We determined the adherence to this model across all cases and tested the association between increasing in vivo amyloid stage and cognitive performance using ANCOVA models. Results In total, 156 participants (49%) showed evidence of regional amyloid deposition, and all but 2 of these (99%) adhered to the hierarchical regional pattern implied by the in vivo amyloid progression model. According to a conventional binary classification based on global signal (SUVR Cereb  = 1.10), individuals in stages III and IV were classified as amyloid-positive (except one in stage III), but 99% of individuals in stage I and even 28% of individuals in stage II were classified as amyloid-negative. Neither in vivo amyloid stage nor conventional binary amyloid status was significantly associated with cognitive performance in this preclinical cohort. Conclusions The proposed hierarchical staging scheme of PET-evidenced amyloid deposition generalizes well to data from an independent cohort of older people at elevated risk for AD. Future studies will determine the prognostic value of the staging approach for predicting longitudinal cognitive decline in older individuals at increased risk for AD.

This chapter introduces the basic principles of the harmonic shear wave elastography (HSWE). Vibrators typically create a multi‐direction shear wave field in the region of interest (ROI), because of multiple contact locations between the vibrators and the skin. HSWE or external vibration multi‐direction ultrasound shear wave elastography (EVMUSE) uses similar external vibration as time‐harmonic elastography (THE) to create a multi‐direction shear wave field. Directional filters are used to separate shear waves propagating in different directions. For each direction, a two‐dimensional (2D) shear wave speed estimator is used to calculate a local 2D shear wave speedmap. The final shear wave speed map is constructed by compounding the speed maps from all directions. The chapter describes validation of the method ex vivo using phantoms. Finally, it applies HSWE for in vivo liver fibrosis staging in patients with liver diseases.

Epithelial ovarian cancer is the leading cause of gynecologic cancer deaths. Most patients respond initially to platinum-based chemotherapy after surgical debulking, however relapse is very common and ultimately platinum resistance emerges. Understanding the mechanism of tumor growth, metastasis and drug resistant relapse will profoundly impact the therapeutic management of ovarian cancer. Using patient tissue microarray (TMA), in vitro and in vivo studies we report a role of of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme in ovarian carcinoma. We report here that the expression of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme, is common in primary serous ovarian carcinoma. The in vitro effects of CBS silencing can be reversed by exogenous supplementation with the GSH and H2S producing chemical Na2S. Silencing CBS in a cisplatin resistant orthotopic model in vivo by nanoliposomal delivery of CBS siRNA inhibits tumor growth, reduces nodule formation and sensitizes ovarian cancer cells to cisplatin. The effects were further corroborated by immunohistochemistry that demonstrates a reduction of H&E, Ki-67 and CD31 positive cells in si-RNA treated as compared to scrambled-RNA treated animals. Furthermore, CBS also regulates bioenergetics of ovarian cancer cells by regulating mitochondrial ROS production, oxygen consumption and ATP generation. This study reports an important role of CBS in promoting ovarian tumor growth and maintaining drug resistant phenotype by controlling cellular redox behavior and regulating mitochondrial bioenergetics. The present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer.

Separating indolent from aggressive prostate cancer is an important clinical challenge for identifying patients eligible for active surveillance, thereby reducing the risk of overtreatment. The purpose of this study was to assess prostate cancer aggressiveness by metabolic profiling of prostatectomy tissue and to identify specific metabolites as biomarkers for aggressiveness. Prostate tissue samples (n = 158, 48 patients) with a high cancer content (mean: 61.8%) were obtained using a new harvesting method, and metabolic profiles of samples representing different Gleason scores (GS) were acquired by high resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS). Multivariate analysis (PLS, PLS-DA) and absolute quantification (LCModel) were used to examine the ability to predict cancer aggressiveness by comparing low grade (GS = 6, n = 30) and high grade (GS≥7, n = 81) cancer with normal adjacent tissue (n = 47). High grade cancer tissue was distinguished from low grade cancer tissue by decreased concentrations of spermine (p = 0.0044) and citrate (p = 7.73·10(-4)), and an increase in the clinically applied (total choline+creatine+polyamines)/citrate (CCP/C) ratio (p = 2.17·10(-4)). The metabolic profiles were significantly correlated to the GS obtained from each tissue sample (r = 0.71), and cancer tissue could be distinguished from normal tissue with sensitivity 86.9% and specificity 85.2%. Overall, our findings show that metabolic profiling can separate aggressive from indolent prostate cancer. This holds promise for the benefit of applying in vivo magnetic resonance spectroscopy (MRS) within clinical MR imaging investigations, and HR-MAS analysis of transrectal ultrasound-guided biopsies has a potential as an additional diagnostic tool.

Background Non-coding RNAs have been drawing increasing attention in recent years as functional data suggest that they play important roles in key cellular processes. N-BLR is a primate-specific long non-coding RNA that modulates the epithelial-to-mesenchymal transition, facilitates cell migration, and increases colorectal cancer invasion. Results We performed multivariate analyses of data from two independent cohorts of colorectal cancer patients and show that the abundance of N-BLR is associated with tumor stage, invasion potential, and overall patient survival. Through in vitro and in vivo experiments we found that N-BLR facilitates migration primarily via crosstalk with E-cadherin and ZEB1. We showed that this crosstalk is mediated by a pyknon, a short ~20 nucleotide-long DNA motif contained in the N-BLR transcript and is targeted by members of the miR-200 family. In light of these findings, we used a microarray to investigate the expression patterns of other pyknon-containing genomic loci. We found multiple such loci that are differentially transcribed between healthy and diseased tissues in colorectal cancer and chronic lymphocytic leukemia. Moreover, we identified several new loci whose expression correlates with the colorectal cancer patients’ overall survival. Conclusions The primate-specific N-BLR is a novel molecular contributor to the complex mechanisms that underlie metastasis in colorectal cancer and a potential novel biomarker for this disease. The presence of a functional pyknon within N-BLR and the related finding that many more pyknon-containing genomic loci in the human genome exhibit tissue-specific and disease-specific expression suggests the possibility of an alternative class of biomarkers and therapeutic targets that are primate-specific.

Genistein has been shown to inhibit cancers both in vitro and in vivo, by altering the expression of several microRNAs (miRNAs). In this study, we focused on tumor suppressor miRNAs regulated by genistein and investigated their function in prostate cancer (PCa) and target pathways. Using miRNA microarray analysis and real-time RT-PCR we observed that miR-574-3p was significantly up-regulated in PCa cells treated with genistein compared with vehicle control. The expression of miR-574-3p was significantly lower in PCa cell lines and clinical PCa tissues compared with normal prostate cells (RWPE-1) and adjacent normal tissues. Low expression level of miR-574-3p was correlated with advanced tumor stage and higher Gleason score in PCa specimens. Re-expression of miR-574-3p in PCa cells significantly inhibited cell proliferation, migration and invasion in vitro and in vivo. miR-574-3p restoration induced apoptosis through reducing Bcl-xL and activating caspase-9 and caspase-3. Using GeneCodis software analysis, several pathways affected by miR-574-3p were identified, such as 'Pathways in cancer', 'Jak-STAT signaling pathway', and 'Wnt signaling pathway'. Luciferase reporter assays demonstrated that miR-574-3p directly binds to the 3' UTR of several target genes (such as RAC1, EGFR and EP300) that are components of 'Pathways in cancer'. Quantitative real-time PCR and Western analysis showed that the mRNA and protein expression levels of the three target genes in PCa cells were markedly down-regulated with miR-574-3p. Loss-of-function studies demonstrated that the three target genes significantly affect cell proliferation, migration and invasion in PCa cell lines. Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa.

Introduction In the majority of US institutions, gastrectomy specimens are sent for pathologic examination without surgeon assessment or standardized technique of lymph node (LN) assessment for gastric cancer. We conducted a quality improvement project at a US cancer center utilizing surgeon assessment of gastric LNs, and created a video to illustrate a technique of standardized lymph node assessment. Methods Convenience sampling was employed among patients with gastric adenocarcinomas who underwent curative-intent D2 gastrectomy between July 2016 and June 2017. For each patient, a surgeon assessed gastric LNs by harvesting individual LNs, followed by conventional evaluation by a pathologist. Results We enrolled 17 patients for this quality improvement project. Eight patients underwent total gastrectomy, and nine patients underwent subtotal gastrectomy. Twelve patients underwent preoperative chemoradiation therapy, three underwent preoperative chemotherapy alone, and two underwent upfront surgery. The median number of examined LNs was 43. All patients had ≥ 16 LNs examined, and 88% of patients had ≥ 30 LNs examined. Conclusion Surgeon assessment of gastric LN specimens was feasible and effective to provide high-quality pathologic LN assessment after gastrectomy in gastric adenocarcinoma patients. Standardization of the technical methods for gastric LN evaluation is needed to improve the accuracy and quality of gastric cancer staging in the US. The provided video can help inform standardization of gastric LN assessment.

Introduction Variability in surgical and pathological techniques in Western centers may lead to inconsistency in lymph node staging in patients with gastric adenocarcinoma. We hypothesize that ex vivo dissection (EVD) after gastrectomy for adenocarcinoma increases lymph node yield. Methods We retrospectively reviewed 222 consecutive patients who underwent gastrectomy with curative intent for adenocarcinoma between November 2010 and June 2014. In August of 2012, we began performing EVD of nodes in surgical specimens (EVD group, N  = 111), as opposed to submitting specimens en bloc with lymph node basins attached to the specimen (No EVD group, N  = 111). Primary end point was lymph node yield. Results The median number of lymph nodes procured was significantly higher in the EVD compared to that in the No EVD group (30 vs. 21 lymph nodes, respectively; P  < 0.0001). Moreover, 28 % of the No EVD group were not adequately staged (defined by ≤15 nodes), compared to 5 % of the EVD group ( P  < 0.0001). Stage-for-stage overall survival was not significantly different. Conclusion EVD may be a useful tool to maximize lymph node yield. However, this had no impact on staging or survival. This is an interesting finding that warrants further investigation.

Objective This study aimed to investigate the use of in vivo dose validation during post-breast-conserving radiation for early breast cancer, the impact of image guidance on validation outcomes, and the role of inter- and intra-fractional variations on dose distribution. Methods Twenty-six patients undergoing post-breast-conserving radiotherapy for early-stage breast cancer were selected for in-treatment in vivo dose validation. The target area and organs at risk were re-defined using the image-guided images to quantitatively evaluate the impact of inter- and intra-fractional differences on the dose distribution. The retrospective analysis examined the in vivo dose validation outcomes. Results The 3%3 mm/5%3 mm 2Dγ-pass (gamma pass) rates in the image-guided radiotherapy(IGRT) group were significantly higher than those in the non-IGRT(N-IGRT) group for both left and right breast cancer ( p  < 0.05). Furthermore, the 5%3 mm 2Dγ-pass rate of the fan-beam CT(FBCT) group was higher than that of the IGRT group and was statistically significant ( p  < 0.05). The target area parameters primary gross tumor volume (PGTV) D95, PGTV D2, planning target volume (PTV) D95, PTV D90, heart Dmean and V5, lung V5, and inter-fractional differences were statistically significant ( p  < 0.05) in patients with left breast cancer. The effects of intra-fractional differences on dose distribution were statistically significant except for cardiac Dmean ( p  < 0.05). Similarly, the dose distribution of measures including PGTV D95, PGTV D2, PTV D95, PTV D90, Heart Dmean, and Lung V5 was strongly impacted by inter-fractional variances in patients with right breast cancer. The influence of intra-fractional differences on dose distribution was statistically significant for all parameters ( p  < 0.05), and they were statistically significant ( p  < 0.05). Conclusion When paired with fan-beam CT image guidance, electronic portal imaging device (EPID) in vivo dose validation provides a precise real-time dose delivery evaluation for patients undergoing radiation therapy for breast cancer.

Circulating tumor cells (CTCs) constitute a useful approach for personalized medicine. Nevertheless, the isolation of these cells remains very challenging because they rarely circulate in the blood. Another current problem is the cancer-specific characterization of these cells, which requires a method that allows for the molecular and immunocytochemical profiling of all captured cells. The purpose of our proof of concept study was to investigate the use of a medical wire (CellCollector, GILUPI) to isolate CTCs in the blood of prostate cancer (PCa) patients, which allowed CTCs to be counted and molecularly characterized. Forty-three PCa patients in different stages and 11 control subjects were studied. Some randomized samples were used to detect tumor-associated transcripts, such as prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA) and epidermal growth factor receptor (EGFR), in the isolated CTCs. The mean CTC counts were 4.6 CTCs [range, 0-8] in patients with localized PCa, 16.8 CTCs [range, 10-25] in patients with locally advanced PCa, and 26.8 CTCs [range, 0-98] in patients with metastatic PCa. The median follow-up time was 24 months, and there was a significant difference in the cancer-specific survival rates. Patients with CTC counts under 5 CTCs lived significantly longer (p = 0.035) than patients with more than 5 CTCs. We also demonstrated that the captured CTCs could be molecularly characterized. We detected tumor-associated transcripts of EGFR and PSMA in patients with metastatic PCa in 42.8% and 14.3% of the analyzed samples, respectively. Our results indicate that the sensitive isolation and molecular characterization of CTCs can be achieved ex vivo using the wire. Patients with more than 5 CTCs had a mortality risk that was 7.0 times greater that of those with fewer than 5 CTCs (hazard ratio 7.0 95%, CI 1.1-29.39). This proof of concept was required for the approval of the use of the CellCollector in a clinical study for the in vivo isolation of CTCs from the blood stream of PCa patients by the Federal Institute for Drugs and Medical devices (Germany, BfArM).