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2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16532-e16532
Author(s):  
Ralph M. Wirtz ◽  
Richard Watts ◽  
Ronny Kellner ◽  
Reinhard Ortmann ◽  
Torsten Horns ◽  
...  

e16532 Background: The objective of the present study was to assess FGFR mutattions and fusions from matched urine and tissue samples from patients suspicious of bladder cancer and undergoing first TURB at the pilot center of the multicentric BRIDGister RealWorld Experience trial Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first TURB of 28 pts participating in the BRIDGister trial and matched urine samples were prospectively collected and analyzed. RNA from FFPE tissues were extracted by commercial kits and analyzed by Therascreen FGFR IVD kit (Qiagen GmbH, Hilden). In addition urine samples were shipped for central isolation of extracellular vesicles and extraction of RNA (exoRNA.Exosome Diagnostics GmbH, Martinsried) and subsequently centrally analyzed by QIAcuity digital PCR (Qiagen, Hilden). Additional urine testing was performed by further technologies including central cytology. Concordance, Kruskal-Wallis, MannWhitney and Sensitivity/Specificity tests were analyzed by JMP 9.0.0 (SAS software). Results: The pilot cohort of the BRIDGister trial consisted of 28 patients (median age: 73, male 71% vs female 29%) of diverse clinical stages (Benign lesions/no tumor 21%, pTa 32%, pT1 21%, pT2 21%) and WHO 1973 grade (G1 7%, G2 43%, G3 21%). Based on FFPE tissue testing using Therascreen FGFR IVD kit 9 out of 28 patients exhibited FGFR alterations (32%). Based on exosomal RNA (exoRNA) and subsequent dPCR testing 8 out of 21 matched urine sampels were FGFR positive (38%). Comparison with tissue testing as probable gold standard revealed 71% sensitivity, 78% specificity, 63% PPV and 85%NPV. There were 3 patients being FGFR positive for exoRNA from urine with no mutation found in the corresponding TUR biopsy. One of these mutations could be validated by independent urine test. Furthermore one tumor harbored two tissue mutations (R248C, Y373C) but three urine mutations (R248C, Y373C, G370C) indicating substantial tumor heterogeneity. One FGFR3-TACC3 fusion was detected from a benign lesion, which was not found by the exosomal urine test. Conclusions: Extraction of exosomal RNA from urine followed by highly sensitive dPCR mutation testing is feasible with good concordance to matched tissue testing. Urine testing bears the potential of detecting additional mutations in a real world setting and might evolve as alternative approach for FGFR3 screening in a non invasive fashion without the need of transurethral biopsy. Discordant cases are further followed up and might reveal validation of mutation status in upcoming recurrences.Further exploration is warranted and includes the potential of monitoring patients with FGFR before and after therapeutic intervention. By the time of the congress an update of the data with approximately 50 matched pairs will be presented.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Matthew H. Larson ◽  
Wenying Pan ◽  
Hyunsung John Kim ◽  
Ruth E. Mauntz ◽  
Sarah M. Stuart ◽  
...  

AbstractCell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We perform the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n = 46], lung [n = 30]) and non-cancer (n = 89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) are not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identify tissue- and cancer-specific genes, defined as “dark channel biomarker” (DCB) genes, that are recurrently detected in individuals with cancer. DCB levels in plasma correlate with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.


2021 ◽  
Author(s):  
Liheng Yang ◽  
Christina Megli ◽  
Carolyn B Coyne

Infections at the maternal-fetal interface can directly harm the developing fetus and compromise the health of the pregnant woman. Innate immune signaling by both fetal-derived placental trophoblasts and the maternal decidua must provide antimicrobial defenses at this critical interface without compromising its integrity. Here, we developed trophoblast and decidua organoids from matched human placentas to define their relative contributions to innate immune defenses at the maternal-fetal interface. We show that trophoblast and decidua organoids recapitulate some, but not all, of the basal cytokine release observed in matched tissue explants. We further show that trophoblast, but not decidua, organoids constitutively release antiviral type III interferons (IFNs) and that fetal and maternal organoids differentially respond to viral infections through the induction of organoid-specific cytokines. These findings define key differences in innate immune signaling generated by fetal-derived trophoblasts and the maternal decidua, which together must protect the fetus from viral infections.


2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Rebecca M. Harman ◽  
Roosheel S. Patel ◽  
Jennifer C. Fan ◽  
Jee E. Park ◽  
Brad R. Rosenberg ◽  
...  

Abstract Background The efficacy of mesenchymal stromal cell (MSC) therapy is thought to depend on the intrinsic heterogeneity of MSC cultures isolated from different tissue sources as well as individual MSCs isolated from the same tissue source, neither of which is well understood. To study this, we used MSC cultures isolated from horses. The horse is recognized as a physiologically relevant large animal model appropriate for translational MSC studies. Moreover, due to its large size the horse allows for the simultaneous collection of adequate samples from multiple tissues of the same animal, and thus, for the unique collection of donor matched MSC cultures from different sources. The latter is much more challenging in mice and humans due to body size and ethical constraints, respectively. Methods In the present study, we performed single-cell RNA sequencing (scRNA-seq) on primary equine MSCs that were collected from three donor-matched tissue sources; adipose tissue (AT), bone marrow (BM), and peripheral blood (PB). Based on transcriptional differences detected with scRNA-seq, we performed functional experiments to examine motility and immune regulatory function in distinct MSC populations. Results We observed both inter- and intra-source heterogeneity across the three sources of equine MSCs. Functional experiments demonstrated that transcriptional differences correspond with phenotypic variance in cellular motility and immune regulatory function. Specifically, we found that (i) differential expression of junctional adhesion molecule 2 (JAM2) between MSC cultures from the three donor-matched tissue sources translated into altered cell motility of BM-derived MSCs when RNA interference was used to knock down this gene, and (ii) differences in C-X-C motif chemokine ligand 6 (CXCL6) expression in clonal MSC lines derived from the same tissue source correlated with the chemoattractive capacity of PB-derived MSCs. Conclusions Ultimately, these findings will enhance our understanding of MSC heterogeneity and will lead to improvements in the therapeutic potential of MSCs, accelerating the transition from bench to bedside.


2020 ◽  
Vol 31 ◽  
pp. S134-S135
Author(s):  
S. Khakoo ◽  
S. Moorcraft ◽  
A. Pacis ◽  
M. Munter ◽  
M. Lathrop ◽  
...  

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1050-1050
Author(s):  
Ethan Sokol ◽  
Smruthy Sivakumar ◽  
Dexter Jin ◽  
Natalie Danziger ◽  
Kimberly McGregor ◽  
...  

1050 Background: Liquid biopsy-based comprehensive genomic profiling (CGP) is a minimally invasive approach to potentially identify truncal driver alterations and mechanisms of acquired resistance. However, there are limited data comparing solid tissue and plasma biopsies from the same patient in breast cancer. Methods: CGP was performed on matched tumor tissue and plasma samples from 444 patients with breast cancer (Foundation Medicine, Inc.) to identify short variant mutations and rearrangements in at least 62 genes. ER/PR/HER2 status was abstracted for a subset of patients (n = 273). Patients were primarily ER+/HER2- (58%) with fewer HER2+ (16%) and TNBC (25%). Results: Samples were temporally heterogeneous with a median time between matched tissue-plasma collection of 276 days (interquartile range 45 - 650). Positive percent agreement (PPA) to tissue biopsy was 81.5% with higher PPA for collection interval ≤1y v > 1y (82.5% v 76.5%). PPA was highest in known truncal driver genes ( AKT1, PTEN, BRCA2, BRCA1, TP53, PIK3CA: 85-89% PPA). PPA of tissue to liquid biopsy was 50.5% with strong time dependence (62.4% ≤1y, 37.9% > 1y), presumably due to intervening therapies. Acquired alterations in liquid biopsy were primarily known resistance mechanisms ( ESR1, NF1, ERBB2, PIK3CA, PTEN, TP53, BRCA1, and BRCA2), were often polyclonal, associated with longer collection intervals, and exhibited higher prevalence in the ER+/HER2- subtype (62% ER+/HER2-, 33% HER2+, 42% TNBC). Acquired alterations significantly enriched in ER+ cases included ESR1, NF1, ERBB2 and TP53. For PIK3CA, a PPA of 84.6% was observed with solid as baseline and 79.1% with liquid as baseline; prevalence was similar (36.5% solid, 35.6% liquid). Alpelisib companion diagnostic alterations (CDx) had a similar PPA (84.0% solid, 83.3% liquid). Overall percent agreement (OPA) for PIK3CA CDx in paired samples was 91.4% (406/444). When acquired PIK3CA alterations are observed they tend to be subclonal, co-occur with shared PIK3CA alterations, and consist of rare alterations (E726K, E453K, M1043I). Conclusions: While high PPA to tissue was observed for alterations in truncal driver genes, acquired alterations observed in plasma were frequently polyclonal, often identify potential mechanisms of therapeutic resistance and are, in part, a function of time and intervening treatments relative to tissue CGP. These results demonstrate high PPA to tissue suggesting that liquid biopsy has clinical validity in identifying truncal alterations and can also identify acquired alterations in breast cancer.


Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Ian Yu Lee ◽  
Thais Sabedot ◽  
Tathiane Malta ◽  
James Snyder ◽  
Michael Wells ◽  
...  

Abstract INTRODUCTION Genome-wide DNA methylation profiling has shown that epigenetic abnormalities are biologically important in glioma and can be used to classify these tumors into distinct prognostic groups. Thus far, DNA profiling has required surgically resected glioma tissue; however, gliomas release tumoral material into biofluids providing an opportunity for a minimally invasive testing. While prior studies have shown that molecular markers can be detected in liquid biopsy (LB), there has been low sensitivity for tumor-specific markers. We hypothesize that the low sensitivity is due to the targeted assay methods. METHODS Genome-wide CpG methylation levels in DNA of tumor tissue and cell-free DNA serum of glioma patients. RESULTS We defined glioma-specific and IDH-specific epigenetic LB (eLB) signatures (Glioma-eLB and IDH-eLB, respectively) from serum cell-free DNA from patients diagnosed with glioma (N = 15 IDH mutant and N = 7 IDH wildtype) and with epilepsy (N = 3). The epigenetic profiles of the matched tissue demonstrate that these eLB signatures reflected the signature of the tumor. Through cross-validation we show that Glioma-eLB can accurately predict a patient's glioma from those with other neoplasias (N = 6 Colon; N = 14 Pituitary; N = 3 Breast; N = 4 Lung), non-neoplastic immunological conditions (N = 22 sepsis; N = 9 pancreatic islet transplantation), and from healthy individuals (sensitivity: 98%; specificity: 99%). Finally, IDH-eLB includes promoter methylated markers associated with genes known to be involved in glioma tumorigenesis (PVT1 and CXCR6). CONCLUSION The application of the noninvasive eLB signature discovered in this study has the potential to complement the standard of care for patients harboring glioma.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tian An ◽  
Tao Fan ◽  
Xin Qing Zhang ◽  
Yu-Fei Liu ◽  
Jiangpinghao Huang ◽  
...  

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16036-e16036 ◽  
Author(s):  
Jean-Michel Lavoie ◽  
Gillian Vandekerkhove ◽  
Matti Annala ◽  
Nora Sundahl ◽  
Takeshi Sano ◽  
...  

e16036 Background: Patients (pts) with metastatic urothelial cancer (mUC) now have access to many different treatment options. This creates an incentive for molecular profiling of their tumors, with the aim of developing biomarkers. Genomic profiling may leverage the presence of circulating tumor DNA (ctDNA), but it has not been shown whether this recapitulates the findings from tissue samples. Methods: Whole blood samples were collected for next-generation sequencing of leukocyte and cell-free DNA (cfDNA). Deep targeted sequencing was performed across a UC-specific custom 50-gene panel (median depth of 986x). Matched archival tissue was profiled using the same assay for 65 pts. Results: Between 11/2011 and 12/2017, 90 pts developed mUC (87 evaluable). Baseline characteristics: median age 67, 83% male, 14% upper-tract disease, 17% stage IV at initial presentation. Treatments delivered: 76% platinum-based chemotherapy, 47% PD-1/PD-L1 inhibitor. At a median follow-up of 12.8 mo., 45% remain alive. We found ctDNA fractions above 2% in at least one blood collection in 81% of cases. For 17 pts, matched metastatic biopsies and cfDNA collection were available; in those cases 82% of coding somatic mutations identified in tissue were independently detected in cfDNA. Half of discordant findings could be attributed to low ctDNA fraction. Most (89%) mutations detected in primary tissue (cystectomy or nephrectomy) were present in later cfDNA collections. ctDNA detected mutations in TP53 and ARID1A in 64% and 29% of pts, respectively. A tumor mutation burden ≥25 mutation per Mb was observed in 27% of cases. Conclusions: There is a high concordance between genomic findings from ctDNA and matched tissue of pts with mUC. This supports the use of liquid biopsies to study potential biomarkers in this disease.


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