bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation betwen MKK4 expression (exp) and clinicopathological features, KRAS/NRAS mutation in metastatic colorectal cancer (mCRC).
Authors: Dogan Mutlu , Guresci Servet , Kos Fahriye Tugba , Bal Oznur , Ergun Yakup , Bozdogan Onder 
Published: May 2019

e14500 Background: We aimed to evaluate correlation between MKK4 exp & clinicopathological features in mCRC Methods: MKK4 exp was assessed by immunoreactive score (IRS). Staining intensity [0 (no), 1+ (weak), 2+ (moderate), 3+ (strong)] & % of positively stained cells [0 (0%), 1( < 10%), 2 (11-50%), 3 (51-80%), 4 ( > 80%)]. IRS was calculated by this formula (IRS = SI × PP). Cut-offs were explored with ROC analysis. AUC was 0.629 (95%CI:0.419-0.840) & best cut-off value for MKK4 was 2.5 (sensitivity of 68 %). Groups were WIR ('weak'; IRS:0-2) & SIR ('strong'; IRS ≥3). Results: We enrolled 95 patients. Median follow-up was 31.4 months. MKK4 exp strength outcomes are shown in table. K-ras/N-ras mutation rate was 45.2%. WIR patients had longer OS (p: 0.03). In WIR group, metastatic ones at diagnosis had shorter DFS (p:0,05). There was no PFS difference (p: 0,15). In correlation analysis, there was a a negative correlation between MKK4 expression & 1st line treatment resistance, k-ras/n-ras mt, OS, PFS, DFS (r: -0.01; r: -0,06; -0,02; -0,10; -0,06; -0,34) ( p:0,04 for DFS). Conclusions: MKK4 exp inversely correlates with survival outcomes & ras mutation. WIR leads longer DFS & OS. [Table: see text]
High dose apatinib in the reversal of immunosuppressive tumor microenvironment for irradiation therapy in lung carcinoma.
Authors: Liang Lijun , Hu Chenxi , Wen Yixuan , Hui Kaiyuan , Jiang Xiaodong 
Published: May 2019

e14503 Background: The purpose of this study was to investigate the potential systemic anti-tumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma. Methods: Lewis lung cancer cells were injected into C57BL/6 mice in the right hindlimb (primary tumor; irradiated) and in the left flank (secondary tumor; nonirradiated). When both tumors grew to palpable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 100 mg/kg, 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy to the primary tumor or no radiotherapy. Further tumor growth/regression of mice was followed and observed. Results: For the single 15 Gy modality, delays in tumor growth could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growths could be observed, indicating that an abscopal effect had been induced. Mechanism analysis suggested that programmed death ligand-1 expression increased with SABR and was counteracted by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor-antigen-specific immune responses, and the mice were resistant to subsequent tumor rechallenge. Ultimately, long-term survival was improved. Conclusions: Our results suggested that the tumor microenvironment could be managed with high-dose of apatinib, which was effective in eliciting an abscopal effect induced by SABR.
Clinical assessment of tumor angiogenesis and its predictive value for chemotherapy responses of colorectal metastatic hepatic tumors.
Authors: Okamoto Hirotaka , Iino Hiroshi , Shiba Shugo , Sudoh Makoto , Maruyama Suguru , Wakana Hiroyuki , Ichikawa Daisuke , Fujii Hideki 
Published: May 2019

e14505 Background: The treatment of colorectal cancer (CRC) with metastasis is now widely accepted to be systemic chemotherapy of 5-FU base chemotherapy (FOLFOX or FOLFILI) in combination with molecular antibody. The objective of this study was to determine the significance of tumor angiogenesis in metastatic hepatic tumors in relation to the response of systemic chemotherapy. Methods: A total of 48 consecutive CRC patients with hepatic metastasis who had been treated with or without hepatic resection were retrospectively reviewed, and factors, such as metastatic tumor angiogenesis and chemotherapy response, were analyzed. Tumor angiogenesis in association with ring-enhancement (RE) on computed tomography (CT) was also microscopically evaluated by microvessel counting (MVD) in sections stained immunochemically with CD34. Results: The overall response rate after 6 courses of first-line chemotherapy for the liver metastasis with RE on CT was 64% (23/36), whereas the response rate without RE was 25% (3/12), which was significantly different. The survival rate of patients with or without liver resection of all RE-positive tumors was not different, but the survival rate of patients with liver resection was longer than that of patients without liver resection for all RE-negative tumors. Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. Conclusions: The peripheral RE on CT of the metastatic hepatic tumor was associated with tumor angiogenesis and may predict chemotherapy response. A combination of liver resection with chemotherapy improves the survival of patients who have multiple hepatic metastasis.
Tracking endocrine resistance in estrogen-receptor positive breast cancer in ctDNA.
Authors: Meissner Magdalena , Butler Rachel , Casbard Angela Claire , Carucci Margherita , Madden Tracie-Ann , Howell Sacha Jon , Jones Robert Hugh 
Published: May 2019

e14550 Background: Endocrine therapy is the standard of care treatment for patients with estrogen-receptor positive advanced breast cancer, owing to improved tolerability and comparable efficacy to that of cytotoxic chemotherapy. Half of such cancers will progress through first line therapy (primary endocrine resistance) and half will progress after an initial period of disease control (secondary or acquired endocrine resistance). A significant challenge is to test for and identify biomarkers which can guide the likely success of endocrine therapy as a single agent or in combination with small molecule inhibitors.This is particularly challenging where metastatic deposits reside at sites where biopsy is difficult. Potential biomarkers indicative of resistance to endocrine therapy have been identified and can be detected in circulating tumour DNA (ctDNA). CtDNA is shed from tumours and is detectable in a cancer patient’s bloodstream. Information on mutational profiles can guide an oncologist in the selection of targeted therapy in addition to hormonal therapy. Methods: We have analysed formalin-fixed paraffin-embedded(FFPE) tumour samples and longitudinal liquid biopsies from 19 patients who were treated with fulvestrant in combination with a novel inhibitor of the PIK3CA/AKT pathway with next-generation sequencing using a targeted 44-gene panel. Mutations identified using this technique were tracked during the course of treatment using droplet-digital PCR(ddPCR). Results: 57 samples were tested using a 44-gene panel; 19 FFPE tumour samples and matched ctDNA samples were obtained prior therapy and ctDNA samples at disease progression. Mutations detected in PIK3CA, AKT1, ESR1and TP53 genes were trackable in longitudinal ctDNA samples using ddPCR. The association between ctDNA dynamics and outcome will be presented. Conclusions: Multiple mutations that enable the early detection of treatment failure and resistance can be tracked in ctDNA. Investigating the clinical utility of ctDNA is paramount.
Prediction of lesion shrinkage using CT imaging with radiomic and deep learning approaches.
Authors: Ma Junshui , Liu Rongjie , Goldmacher Gregory V. , Baumgartner Richard 
Published: May 2019

e14592 Background: Radiomic features derived from CT scans have shown promise in predicting treatment response (Sun et al 2018, and others). We carried out a proof-of-concept study to investigate the use of CT images to predict lesion-level response. Methods: CT images from Merck studies KEYNOTE-010 (NCT01905657) and KEYNOTE-024 (NCT02142738), were used. Data from each study were evaluated separately and split for training (80%) and validation (20%) in each study. A lesion was classified as “shrinking” if ≥30% size reduction from baseline was seen on any future scan. There were 2004 (613 shrinking vs. 1391 non-shrinking) and 588 (311 vs. 277) lesions in KN10 and KN24, respectively. 130 radiomic features were extracted, followed by random forest to predict lesion response. In addition, end-to-end deep learning was used, which predicts the response directly from ROIs of CT images. Models were trained in two ways: (1) using pre-treatment baseline (BL) only or (2) using both BL and the first post-treatment image (V1) as predictors. Finally, to evaluate the predictive power without relying on initial lesion size, size information was omitted from CT images. Results: Results from the KN10 and KN24 are summarized in Table. Conclusions: The results suggest that the BL CT images alone have little power to predict lesion response, while BL and the first post-baseline image exhibit high predictive power. Although a substantial part of the predictive power can be attributed to change in ROI size, the predictive power does exist in other aspects of CT images. Overall, the radiomic signature followed by random forest produced predictions similar to, if not better than, the deep learning approach. [Table: see text]
A preliminary single institution experience with droplet digital polymerase chain reaction (dd-PCR) liquid biopsy (LB) for therapeutic decision in advanced solid tumors: Personal precision oncology clinic and genetic diagnostics, Brazil.
Authors: Murad Andre Marcio , Rocha Jose Claudio Casali 
Published: May 2019

e14613 Background: Droplet digital polymerase chain reaction (dd-PCR) is a promising method for analyzing minor amounts of cell-free circulating free nucleic acid (DNA and RNA) due to its high sensitivity, low cost, and fast reading, since it dispenses bioinformatics, making it an appropriate alternative to new generation sequencing (NGS) for the detection of biomarkers to guide molecularly targeted cancer therapy. The assay covers main actionable hotspot alterations across many actionable genes: EGFR(mutations), ALK (fusion, mutations), ROS1(fusion), BRAF(mutations), KRAS (mutations), NRAS(mutations), ERBB2(CNV), ESR1(mutations), KIT(CNV) and PDGFRA(CNV). Methods: We analyzed so far 38 patients with advanced NSCLC: 13(35%), breast: 9(24%), colorectal: 6(16%), pancreatic: 4(10%), ovary: 2(5%), salivary gland: 2(5%), melanoma 1(2.5%), and GIST: 1 (2.5%). ddPCR was performed using the QX200 system (BIO-RAD, Hercules). All samples were tested in duplicate. All assays were performed at Personal Precision Genetic Diagnostics. Belo Horizonte, MG. Brazil. Results: We detected meaningful genomic alterations in 7(18.5%) patients: 4(10.5%) KRAS G12V mutations (all in colorectal cancer), 1(2.6%) EGFR Del19 mutation, 1 EGFR L858R mutation(2.6%), both in NSCLC and 1(2.6%) ERBB2 amplification (in breast cancer). MAF (Mutant Allele Fraction) varied from 0.9% to 24%. In all cases the results were decisive for the indication or the change of a targeted therapy. Conclusions: Our preliminary results suggest that dd-PCR is a highly sensitive method and could be used for a routine laboratory detection of the important genomic variations to determine the targeted therapy in patients with varied advanced solid tumors.
Oncology precision medicine for hepatobiliary and pancreatic cancer: An institutional review.
Authors: Bellini Geoffrey , Godden Jennifer Jo , Weese James L. , Chevinsky Aaron , Papenfuss Wesley Allan , Thompson Michael A. 
Published: May 2019

e14626 Background: Hepatobiliary cancers - hepatocellular carcinoma (HCC), intra or extrahepatic cholangiocarcinoma (I/EC), and gallbladder carcinoma (GB) - and pancreatic adenocarcinoma (PC) remain a leading cause of death with little improvement in long-term outcome. Recent studies have suggested that these cancers harbor actionable mutations to varying degrees. The aim of our study was to examine the number of patients (Pts) with these primary tumors who underwent molecular testing in a large vertically integrated health system. Subsequently, we analyzed the percentage of that population who may be candidates for oncology precision medicine (OPM) directed therapy. Methods: We identified Pts with HCC, IC, EC, GB in an IRB reviewed OPM database of our system over a one year period. Pts who underwent molecular panel testing were selected out, and their molecular alterations were identified and stratified by cancer type. Results: 304 total Pts were identified. 61 (20%) underwent molecular testing broken down as follows: 17/132 (13%) I/EC and HCC, 3/11 (27%) GB, and 41/161 (25%) PC. Quantity not sufficient for testing was in 10/61 (16%), of which 5/10 (50%) were resubmitted and tested successfully. 6/61 (10%) were cancelled or deemed not appropriate. Test recommended potential actionability was 8/17 (47%) of I/EC and HCC, 2/3 (67%) of GB, and 25/41 (61%) of PC. Conclusions: OPM is a dynamic area of increasing testing and learning. We found 13-27% of hepatobiliary and pancreatic Pts had molecular testing, which suggests the potential to increase molecular screening for this difficult group of tumors. Total genetic alterations (TGA) and clinically relevant genomic alterations (CRGA) per patient are similar to Ross et al. ( http://ow.ly/k52a30nBMnU ) for GB. Final interpretation regarding pragmatic actionability (patient on drug) and clinical outcomes are still under investigation.[Table: see text]
A novel mutant-allele capture method for enrichment of low abundant cancer mutants.
Authors: Lin Rui , Pu Yue , Mao Li 
Published: May 2019

e14632 Background: High sensitivity detection of cancer mutants can facilitate cancer diagnosis, treatment selection, and disease monitoring. Improved methods to detect low abundance of cancer driver mutants are needed. Methods: We developed a novel method, termed PEAC, with a super high sensitivity to detect low abundant mutant from cancer driver genes through mutant capturing followed by Sanger sequencing. Circulating free DNA (cfDNA) standards containing 20 ng of 5%, 1%, 0% (wild-type), or 40 ng of 0.1% cancer driver mutants were used to establish the method. After pre-amplification of both wild-type and mutant alleles, mutant fragments were specifically bound by biotin-labelled, locked–nucleic acid modified probes, enriched by streptavidin beads, amplified through PCR and sequenced using Sanger for detection. Results: The wild-type standard did not show any mutation signal either with or without PEAC, nor did the standards with 5%, 1%, or 0.1% mutants prior to PEAC enrichment. However, after PEAC enrichment, 5%, 1%, and 0.1% of cancer driver mutants ( EGFR L858R, EGFR T790M, and BRAF V600E) predicting sensitivities to target therapies were enriched to ~90%, ~80% and 30-40% abundance, respectively. In addition to the application for point mutations, PEAC methodology was also used to enrich deletion mutant; 5%, 1%, and 0.1% of EGFR exon 19 deletion, E746_A750del, were all enriched to 90-100% frequency after PEAC. To address the limit of detection of PEAC technology, 100 ng of cfDNA standard containing 0.01% EGFR L858R and EGFR exon 19 deletion mutant were enriched to 15% and 50%, respectively, after PEAC, which indicates up to 5000-fold enrichment for EGFR exon 19 deletion by PEAC technology. Conclusions: PEAC technology can enrich very low abundance of key cancer driver mutants predicting sensitivities to tyrosine kinase inhibitors. PEAC enrichment in combination with Sanger sequencing may guide the application of cancer target therapy and represent a useful technology in the era of precision medicine.
The chick embryo chorioallantoic membrane assay: In ovo model for personalized assessment and evaluation of the most effective therapeutic approach in cancer therapy.
Authors: Shapira Shiran , Bogin Oren , Kazanov Dina , Bedny Faina , Hershkovizh Dov , Izhaki Ayelet , Brazowski Eli , Bernstein Ezra , Wolf Ido , Arber Nadir 
Published: May 2019

e14634 Background: "Personalized medicine,” is the tailoring of medical treatment to a single person aiming to maximize efficacy and minimize toxicity. Currently there is no good prediction for response to therapy. The Chick Chorioallantoic Membrane (CAM) is naturally immuno-deficient and rich in vascularity therefore an ideal system, allowing generate 3D cancerous “organoids” in a very efficient, reproducible and cost-effective manner and translates basic research to the clinic. Aims: Generate a “personalized” HTP system for a quick, reliable and effective evaluation of different therapeutic options using 3D tumors in a "humanized egg" instead of mouse PDX model. Methods: Fertilized eggs were incubated until day 3 (37°C, 75-90% humidity). Then, 2ml of albumin was pulled out to separate the CAM from the eggshell and a small window in the eggshell has been made. To destroy the chicken immune system development, the eggs were irradiated at day 5 and human immune cells were then inoculated onto the CAM. On day 7, single cells suspension or tissues, derived from cancer patients, were transplanted onto the CAM and visible tumors were performed ("CAM-PDX"). Drugs, mAbs and chemotherapy, were applied via the yolk sac. Tumor growth was measured, weighted and monitored by caliper and IVIS fluorescent imaging platform. IHC was performed and confirmed the response of the particular specimens to the tested regiment. Results: Histology and IHC analysis confirmed that the established tumors retained their characteristics. Positive Ki-67 staining confirmed that cancer cells proliferate while the treated tumors showed reduced staining. Anti-CD24 mAb, FOLFOX, cetuximab, Foflorinox and Gemcitabine, given as single agent or combinations, successfully inhibited CR and pancreatic tumors (by 70-75%). Detection of active caspase 3 confirmed those results. Biopsies from human specimens, were successfully established and expanded by serial passages allows generation of bio-bank. The stimulated human PBMCs demonstrated enhanced proliferation in vitro and in ovo, even after 5 days in the egg. Irradiated eggs showed no functional immune system even after 2 weeks of development. Conclusions: The CAM is an ideal, effective, economical and powerful avatar-based precision medicine approach to predict the best protocol for cancer therapy.
Non-inferiority of a new advanced dry plasma thawing system compared to leading standard method: Preservation of coagulation and anticoagulation proteins necessary for use in the clinic.
Authors: Bischoff Farideh Z. , Davey Will , Read Brian , Deleon Tess , Laba Rebequec , Thacher Fred , Shavit Moni 
Published: May 2019

e14675 Background: Cancer can affect the bone marrow, cause anemia and internal or excess bleeding, requiring blood or plasma transfusion. Fresh frozen plasma (FFP) should be thawed before transfusing to patients but it must be monitored closely to avoid contamination, uncontrolled or prolonged thawing which may subsequently lead to plasma protein denaturation. In this study, we compared and evaluated the effect of two different thawing methods on clotting factor activities as well as factors such as throughput and turnaround time. Methods: Over a period of approximately one month, November 6 to December 3, 2018, our testing laboratory at the UCSD School of Medicine received three sets of samples for a total of 197 freshly collected (pre-freeze) or freshly thawed plasma samples (standard commercial thawing device and the new dry ZipThaw device) that had been collected and processed in accordance with a San Diego Blood Bank protocol described elsewhere. The Lab conducted over 1,782 tests on these plasma for the following factors: Prothrombin time (PT), International Normalized Ratios (INR), Activated Partial Thromboplastin time (aPTT) Factor VIII activity, Factor V activity, Protein C activity, Protein S antigen, Von Willebrand activity and Thrombin Antithrombin Complex (TAT) concentration. The assays were carried out on an ACL TOP 700 Hemostasis Analyzer (Instrumentation Laboratory, Bedford, MA, USA) using manufacturer’s reagents and automated protocols. The ACL TOP 700 has validated precision CV of 5- 10%. All assays were completed within 4 hours of collection or, if frozen, within 4 hours of thawing. The statistical analysis method employed is two-tailed, student t-test. Results: We observed 100% concordance with no statistically significant differences between the pre-freeze group and the two different post thaw groups, except for a slight increase in the mean TAT complex concentration. Overall, the means of all three groups were well within the normal range defined by the assay kits (1-10 ng/ml). Further, the increased mean TAT is more notable with standard method (33%, p = 0.004) than with the ZipThaw (18%, p = 0.054). Conclusions: We report for the first time non-inferiority between the new ZipThaw device and the leading commercial predicate in plasma thawing while preserving coagulation and anticoagulation proteins and minimizing activation of clotting cascade. The results provide support for the use of ZipThaw device in clinical settings.
Effect of therapeutic GAS6/AXL inhibition of tumor and stromal cells on DNA damage and response to chemotherapy in ovarian cancer.
Authors: Mullen Mary M , Lomonosova Elena , Noia Hollie M , Guo Lei , Kuroki Lindsay Midori , Hagemann Andrea M , McCourt Carolyn K. , Thaker Premal H. , Mutch David Gardner , Powell Matthew A. , Fuh Katherine Cynthia 
Published: May 2019

e14676 Background: Ovarian cancer is the leading cause of death due to gynecologic malignancy. Biomarkers to predict chemoresponse and novel therapies to target these proteins would be practice changing. We aim to establish serum and tissue GAS6 as a predictive biomarker of chemoresponse and to determine if AXL inhibition through sequestration of its ligand, GAS6, with AVB-S6-500 (AVB) can improve chemoresponse. Methods: AVB was supplied by Aravive Biologics. High grade serous ovarian cancer (HGSOC) tumor samples were obtained pre- and post-neoadjuvant chemotherapy. AXL and GAS6 expression were evaluated by immunohistochemistry and serum concentration. In vitro viability and clonogenic assays were performed on chemoresistant tumor (OVCAR8, OVCAR5, COV62, and POV71-hTERT) and stromal cells (CAF86) treated with chemotherapy +/- AVB. Mouse models (OVCAR8, PDX, OVCAR5) were used to determine if the combination of chemotherapy + AVB reduced tumor burden. Immunofluorescent assays targeting ɣH2AX were used to evaluate DNA damage. Results: Patients with high pretreatment tumor GAS6 expression ( > 85%, n = 7) or serum GAS6 concentrations ( > 25ng/mL, n = 13) were more likely to be resistant to neoadjuvant chemotherapy than those with low tumor GAS6 expression ( < 45%, n = 4) (P = 0.010) or low serum GAS6 concentrations ( < 15ng/mL, n = 5) (P = 0.002). Carboplatin plus AVB (2µM, 5µM) and paclitaxel plus AVB (1µM) resulted in decreased cell viability and clonogenic growth compared to chemotherapy alone (p < 0.05) in all tumor and stromal cell lines. Synergism was seen between carboplatin+AVB and paclitaxel+AVB with a weighted combination index < 1. In vivo tumor mouse models treated with chemotherapy+AVB had significantly smaller subcutaneous and intraperitoneal (IP) tumors than those treated with chemotherapy alone (3.1mg vs 64mg, P = 0.003 OVCAR8; 62mg vs 157mg, P = 0.0108 PDX subcutaneous model; 0.05mg vs 0.3669mg, P < 0.001 OVCAR5 IP model). Increased DNA damage was noted in tumor and stromal cells treated with carboplatin+AVB compared to carboplatin alone (OVCAR8, COV362, CAF86 P < 0.001). Conclusions: High GAS6 is associated with lack of neoadjuvant chemoresponse in HGSOC patients. The combination of chemotherapy with AVB decreases tumor cell viability, tumor growth, and an increase in DNA damage response.