bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell-free KRAS in pancreatic cancer as a rapid prognostic marker.
Authors: Saiz-Lopez Patricia , Alcaraz-Ortega Raquel , Lopez Ana Maria , Llorente Beatriz , Diez-Ordoñez Maria Soledad , Pérez Álvarez Juan Carlos , Cáceres Porras Maria José , Palacios Ball Johanna Beatriz , Echevarria-Iturbe Celina , Crespo Guillermo 
Published: May 2020

e15534 Background: KRAS mutations are present over 90% of patients with pancreatic cancer (PC). Liquid biopsies provide the opportunity to genotype alterations in a less invasive way and offer a possibility to monitor the molecular characteristics of a cancer through the course of treatment. We aim to establish an association between the mutational levels of KRAS detected in plasma with patient stage and evolution. Methods: Plasma samples were collected from patients with newly diagnosed PC, before any treatment and during one year. Diagnosis of any previous cancer was an exclusion criterion. Samples were frozen (-80ºC) until analysis of KRAS mutations in cell free DNA (cfDNA) by real time PCR. Specifically, Idylla TM technology was used due to the rapid capacity to report up to 21 KRAS mutations in exon 2, 3, and 4 (LOD = < 5%), without necessity of cfDNA isolation. Mutation was considered present (categorical measurement), taking into account cycle quantification values (Cq) established by the commercial test. Cut-off values for Cq were studied by the ROC curve (receiver operating characteristic) with the Youden's J statistic. Paired tissue samples were analyzed when available. Results: A total of 23 patients were enrolled, median age 65 years old, 57% male, 100% adenocarcinoma, 18 (70%) metastatic. Sixteen patients could also be tested in tissue, being 15 (93.8%) positive for KRAS mutation. Plasma basal mutations were detected in 10 patients (43.5%), all in stage IV (p = 0.046), and interestingly, all with liver involvement (p = 0.003). Moreover, these patients also had metastasis in another organ apart from the liver. The most frequent mutation was G12V (5), followed by G12D (4) and G12R (1). Patients with basal KRAS mutations detected in plasma had a survival of 6.1 months (CI 95%, 3.7-8.5), and non-mutated 11.2 months (95% CI, 7.8-14.7) (p = 0.041). The presence of these cell-free KRAS mutations was more informative for survival than stage IV disease vs III (p = 0.054). Paying attention to KRAS wild type detection in plasma samples used as an internal control of the PCR, we could establish a Cq value cut-off of < 21 Cq for mutant samples, with a sensitivity of 100% (95% CI, 75%-100%) and specificity of 50% (95% CI, 19%-81%), area under ROC curve 0.823 (95% CI, 0.649-0.997). Conclusions: Measurement of cell-free KRAS in plasma samples at diagnosis could be used to quickly predict metastasis and survival in patients with pancreatic adenocarcinoma.
The systemic inflammation response index (SIRI) predicts oncological outcome and correlates with tumor burden in metastatic pancreatic cancer.
Authors: Pacheco Barcia Vilma , France Talya , Asselah Jamil , Mondejar Rebeca , Romero-Laorden Nuria , Zogopoulos George , Serrano Rosario , Donnay Olga , Rogado Revuelta Jacobo , Del Campo Lourdes , Martinez Elia , Martin-Perez Elena , Arlanzón Carmen , Guo Katie , Ochoa Pilar , Alcindor Thierry , Barrena Castello Gabriel , Colomer Ramon 
Published: May 2020

e15537 Background: The SIRI, defined by neutrophil x monocyte/lymphocyte 109/L, has recently emerged as a prognostic factor for pancreatic cancer. However, the association between SIRI values after chemotherapy and tumor response has not been evaluated. Methods: 161 metastatic pancreatic cancer patients were retrospectively analyzed. Associations between overall survival (OS), chemotherapy and SIRI were analyzed. A larger number of patients with pre-treatment SIRI (pre-SIRI) were collected so, post-treatment SIRI (post-SIRI) evaluated after three cycles of chemotherapy, was adjusted for analysis. Results: Median age 66 years. 59 (36%) received gemcitabine + nab-paclitaxel, 40 (24%) gemcitabine, 22 (17%) mFOLFIRINOX, 13 (7%) other regimens. 27 (16%) had not received treatment. Pre-SIRI≥2.3×109/L was an independent, negative predictor of OS compared to pre-SIRI < 2.3×109/L [5 versus 16 months, Hazard Ratio (HR) 2.87, Confidence Interval (CI) 95% 2.02-4.07, P< 0.0001]. In the whole cohort, we observed SIRI values increased after treatment (median pre-SIRI: 1.6×109/L; post-SIRI: 2.3×109/L; P= 0.007). Thus, we analyzed the association between tumor response measured by RECIST and pre-SIRI and post- SIRI values. Patients with progressive disease (PD) showed a higher pre-SIRI than those who had a response to chemotherapy (2.7×109/L versus 1.2×109/L, respectively; P< 0.001). We also observed a statistically significant increase in post-SIRI values for PD compared to tumor response (3.2×109/L versus 1.7×109/L, respectively; P= 0.012). As observed for pre-SIRI, post-SIRI ≥2.3×109/L showed a shorter OS compared to post-SIRI < 2.3×109/L (8 versus 17 months, respectively; P= 0.016). Furthermore, patients with pre-SIRI ≥2.3×109/L were more likely to benefit from mFOLFIRINOX showing a median OS of 17 months compared to 6 and 4 months for gemcitabine + nab-paclitaxel and gemcitabine, respectively ( P< 0.001). Conversely, there was no difference for pre-SIRI < 2.3×109/L: 15.9 months versus 16.5 and 16, respectively. Conclusions: SIRI≥2.3×109/L was a prognostic factor for metastatic pancreatic cancer. An elevated post-SIRI showed an association with disease progression and a negative impact on survival. Therefore, an increase in SIRI could be related to high tumor burden and be useful to appropriately select patients who would benefit of a more intensive first-line chemotherapy regimen.
A novel method for enrichment and detection of the six major subtypes of EGFR exon 19 deletions simultaneously by capturing mutant-alleles.
Authors: Pu Yue , Lin Rui , Wang Tao 
Published: May 2020

e15539 Background: EGFR exon 19 deletions (19DELs) are important precision therapy targets for NSCLC patients. Due to over twenty subtypes of 19DEL mutations, it is usually challenging for detecting different deletion forms in one assay using limited DNA preparation from plasma sample. Methods: Previously we had developed a high sensitivity detection method, namely PEAC, to detect single somatic mutation in one assay. The method used locked¨Cnucleic acid modified short DNA probe to capture mutant fragment under an optimized temperature. In the present study, we have established a multiplexing PEAC approach for simultaneous enrichment and high sensitivity detection of six major subtypes of EGFR 19DELs.The six subtypes overall account for >86% EGFR exon 19 deletions in the patient population. Results: Genomic DNA of EGFR wild-type was mixed with DNA samples of known EGFR 19DEL mutations. The mutation allele fractions of 5%, 1%, and 0.1% for the six 19del subtypes were constructed, which included c.2235-2249del15 p.E746_A750del, c.2236-2250del15 p.E746_A750del, c.2237-2255delinsT p.E746_A752delinsV, c.2235-2249delinsC p.L747_A750delinsP, c.2240-2254del15 p.L747_T751del, and c.2240-2257del18 p.L747_P753delinsS. The mixed DNA samples were sonicated to mimic the fragment distribution of circulating-free DNA (cfDNA) and PCR amplified for exon 19 regions. Multiplexing enrichment using the six specific probes targeted to the 19DEL subtypes were performed to the amplified DNA fragments under the optimal binding conditions. Sanger sequencing all showed detectable variants in the enriched samples starting with 5%, 1%, or 0.1% mutants, which indicated the capacity and high sensitivity of multiplexing PEAC technology. To explore the potential of multiplexing with other EGFR mutants, the 0.1% mixed mutants of 19DEL were PCR amplified for EGFR exon 20 and exon 21 in addition to exon 19, and followed with enrichment and detection of the six 19DEL variants. Sanger sequencing can detect all the six subtypes of 19DELs. Our method is superior to ddPCR in some aspects such as high throughput and low starting DNA amounts. Conclusions: Multiplexing PEAC technology can simultaneously enrich and detect the six major subtypes of EGFR 19 deletions with high sensitivity. It also has potential to multiplex with other EGFR driver mutations such as in exons 18-21. The technology may serve as an attractive method for detecting mutations in liquid biopsies in clinical practice.
Prediction and prognostic validation of colorectal cancer therapeutic effect of WM-S1-030 using pre-clinical CTC animal model.
Authors: Lee Hae Ung , Moon Jai-Hee , Kim Joseph , Kim Seong Keun , Shin Jae Sik , Choi Young Jin , Hong Seung-Woo , Kim Sung Min , Lee Hyun Ho , Park Jae-Chan , Jin Dong-Hoon , Jeon Byung Hee 
Published: May 2020

e15557 Background: CTC (Circulating tumor cells) has the advantage of being able to effectively investigate non-invasive diagnosis, prediction, and prognosis for non-surgical carcinoma or tissue sample collection. We have developed WM-S1-030 (WMBIO) as a novel inhibitor for mtRTK (mutant receptor tyrosine kinase) identified important targets for cancer progression and metastasis in various cancers, including colorectal cancer, and have tried to prove the possibility of CTC diagnosis, prediction and prognosis of WM-S1-030 using tumor animal models. Methods: Six of colon cancer cell lines expressing mtRTK (pTyr-mtRTK) were transplanted into Balb.c nude mice and NSG mice to collect peripheral blood when the tumor size reached 1000 mm3. CTCs were quantified in peripheral blood using the Smart Biopsy cell isolator (Cytogen). The expression of pTyr-mtRTK in CTCs was analyzed via the Smart Biopsy Image Analyzer (Cytogen). Colon cancer cell lines expressing pTyr-mtRTK were transplanted into NSG mice and we examined the tumor suppression, the enumeration of CTCs and pTyr-mtRTK expression in CTCs after administration of WM-S1-030. We also identified CTCs in peripheral blood of colon cancer patients and analyzed expression of pTyr-mtRTK in CTCs through Smart Biopsy system. Results: As results of the enumeration of CTCs after tumor transplantation into Balb.c nude mice and NSG mice, the number of CTC was 8 ~ 20 times higher peripheral blood in the NSG model, which indicates innate immune responses are critical for the survival of CTCs. Half of CTCs isolated from the blood expressed pTyr-mtRTK. The tumor size, the number of CTCs, and the expression of pTyr-mtRTK in CTCs were examined after the administration of WM-S1-030. The volume of tumor decreased by 67% in the WM-S1-030 group compared to the vehicle. The number of CTCs was reduced by approximately three times after the treatment of WM-S1-030 and also the number of CTCs expressing pTyr-mtRTK was significantly decreased. CTC detection and pTyr-mtRTK expression analysis in the peripheral blood of colon cancer patients detected 9 CTCs per 10 ml of peripheral blood, of which 11 % of CTCs representing pTyr-mtRTK were confirmed. Conclusions: WM-S1-030 was developed and confirmed in the CTC-based animal model, which implies that the analysis of CTCs is the powerful tool for predicting/ prognosing WM-S1-030 in the pre-clinical analysis. Currently, we are conducting clinical diagnostic validation using CTC in the blood of colorectal cancer patients and preparing for clinical trial of WM-S1-030.
ROS new function for ECT imaging observation of sustained 99mTC-labeled cytarabine in liver cancer patient with hydrogen peroxide.
Authors: Zheng Guoqin , Han Yan , Zhang Jian , Li Bian , Chen Dong , Zhao Ming , Fu Qiang , Wu Yanfei , Yu Baofa ,   Shandong Baofa Cancer Therapeutics, Inc.
Published: May 2020

e15568 Background: To investigate the sustaining time of 99mTc labeled cytarabine in the tumor of liver cancer patients by ROS under ECT imaging instrument. Methods: A liver cancer patient with 2 lesions in the liver was enrolled in this study. After obtaining informed consent and excluding relevant contraindications, two tumors in the liver of the patient were guided by single photon emission computed tomography (ECT). Injecting the drug, the tumor was injected with 99m TC-labeled cytarabine solution as control, the tumor was injected with 99m TC-labeled cytarabine + hydrogen peroxide solution (ROS) as experimental, and the two tumor masses were detected by ECT imaging, with an intensity of 1h as background. The drug retention rate was calculated by caculated of deduction of the baseline (minus background) at 1h, 3h, and 23h. Results: The patient was detected by ECT on the right laid down position. The area of the region of interest was 679 account by Gama detector, and the background level of the liver was 494 account. The acquisition time was about 400 seconds as a standard acquisition. The ECT imaging showed that the labeling rate of 99mTC-labeled cytarabine was about 100%. The drug of 99mTC-labeled cytarabineretentionrates in tumor lesions with ROS at 1 hours, 3 hours, and 23 hours were 97.83%, 81.63%, and 60.72%, respectively; the drug retention rates in tumor lesions without ROS at 1 hours, 3 hours, and 23 hours were 44.74%, 15.87%, and 0, respectively. Conclusions: The ROS can hold drug in the tumor long time after the intratumoral injection of drugs with ROS whichoxidant with the extracellular matrix and interstitial of the tumor to cause degeneration and deformation so that drug of Ara-C sustaining in tumor for a long time, and the tumor cells are also degenerated and necrotic and died, so that high concentrations of cytarabine are embedded between the denatured tumor tissues and cells. The drug slowly released from the inside to the outside to kill tumor cells. IT is further confirmed that the ROS is a sustained release agent intratumorally injection and it can significantly increase the residence time of 99mTc-labeled cytarabine in the tumor, prolong the drug action time of cytarabine, and improve the effect of killing tumor cells.
Effect of hydrogen peroxide on the sustained release of 99mTc-labeled cytarabine in melanoma of C57 mice by ECT imaging pharmacology.
Authors: Han Yan , Fu Qiang , Yu Baofa ,   Shandong Baofa Cancer Therapeutics, Inc.
Published: May 2020

e15569 Background: To investigate the residence time of 99mTc-labeled cytarabine in mouse tumors under ECT imaging. Methods: The subcutaneous solid tumor model of mice was established by injection of melanoma cell suspension into the left forelimb of C57 mice. The tumor-bearing mice were divided into treatment group and control group when the longest diameter of the tumor was 5-8 mm. Group 3 only. The mice in the control group were given intratumoral injection of 0.1 ml of 99mTc-labeled cytarabine solution, and the mice in the treatment group were given intratumoral injection 0.1 ml 99mTc labeled cytarabine combined with hydrogen peroxide solution at 0.25 h, 0.5 h, 1 h. After 2 hours and 19 hours of administration, the radioactivity intensity values were observed by SPECT Apx-409 ECT phenomenon equipment. Results: The T/W values of ECT imaging in 3 mice in the treatment group were higher than those in the control group at 0.25 h, 0.5 h, 1 h, 2 h and 19 h. The T/W values of ECT imaging decreased in the treatment group at different time points. The amplitude was lower, and the T/W values in each period were higher than those in the control group. Conclusions: The sustained release agent hydrogen peroxide can significantly increase the residence time of 99mTc-labeled cytarabine in the tumor. It is speculated that hydrogen peroxide has a positive effect on prolonging the drug action time of cytarabine and improving the effect of killing tumor cells. It showed that H2O2 can hold the Ara-C for a long time in tumor.
IL-6 influences PD-L1 expression in monocytes and macrophages by effecting protein tyrosine phosphatase receptor type O expression in-human breast cancer.
Authors: Chen Lin , Tang Jinhai 
Published: May 2020

e15570 Background: We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human breast cancer (BC). Methods: The expression and correlation of all the indices were explored in monocytes and tumor infiltrating macrophages within both human and mice BC. The mechanic regulations were studied by using both in vitro and in vivo studies. Results: We found a significant decrease in PTPRO in BC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in BC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with BC and were associated with increased T cell exhaustion (Tim3+ T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25-3p axis. Monocytes and TAMs showed significantly increased miR-25-3p expression, which could target the 3' untranslated region of PTPRO. The miR-25-3p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in BC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25-3p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25-3p–modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1–induced immunosuppression in breast tumor model. Conclusions: Increased serum IL-6 downregulated PTPRO expression in BC monocytes and macrophages by activating STAT3/c-MYC/miR-25-3p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.
Use of real-world clinical lab data to reveal Asian NTRK fusion test availability patterns.
Authors: Eckstein Markus , Bloom Kenneth Joel , Fosvig Susanne Munksted , Hoefsmit Marieke , Clark Jordan 
Published: May 2020

e15574 Background: The development and launch of first-generation tropomyosin receptor kinase (TRK) inhibitors, such as larotrectinib and entrectinib, has brought targeted treatment options to neurotrophic tropomyosin-related kinase (NTRK) fusion–positive adult and pediatric cancer patients who may have been out of treatment options. Widespread adoption of NTRK fusion testing is needed to support successful selection of patients for these TRK inhibitors as well as other targeted therapies. The objective of this study was to investigate global availability of NTRK fusion testing, with a specific focus on Asia. Methods: For this study, real-world clinical pathology laboratory data, derived from Diaceutics’ proprietary Global Diagnostic Index (GDI) of more than 2500 labs, were investigated to assess the current footprint of NTRK fusion testing in Asia. Availability of clinical routine testing was analyzed in selected cohorts of laboratories across different regions, comparing Asia to the US and Europe. Laboratories were included based on their large volume of testing or on their importance (e.g., large academic and large commercial laboratories). Results: Data on availability of NTRK fusion testing by clinical laboratories reveal different patterns of NTRK fusion test adoption in Asia, depending on the region under study. In China and similarly in the US, Italy, and France clinical NTRK fusion testing is already being performed by the majority of laboratories from the selected cohort. In Japan, physicians have limited access to testing, with only a few laboratories from the selected cohort performing testing for NTRK fusions. Conclusions: NTRK fusion testing is essential for identifying patients eligible for first-generation TRK-inhibitors. Various laboratories across selected cohorts of labs in China and Japan lack the capability to initiate clinical NTRK fusion testing in-house, denying some patients the potential benefit from these breakthrough therapies. Consequently, patient outcomes will be suboptimal due to lack of testing infrastructure. The readiness of Asian markets to support patient selection successfully can affect the rate of testing and the impact of these innovative therapies on patients’ lives. [Table: see text]
Baseline radiomics features (RF) in metastatic colorectal cancer (mCRC): Correlation with m site and clinical-pathological characteristics.
Authors: Vivolo Raffaella , Boldrini Luca , Lenkowicz Jacopo , Caliolo Gianluca , Camarda Floriana , Anghelone Annunziato , Di Stefano Brunella , Calegari Maria Alessandra , Pozzo Carmelo , Basso Michele , Liguori Carolina , De Gaetano Anna Maria , Dinapoli Nicola , Manfredi Riccardo , Valentini Vincenzo , Tortora Giampaolo , Salvatore Lisa 
Published: May 2020

e15589 Background: R is an emerging field of research based on the extraction of a large amount of F from biomedical images and on computed analysis algorithms of tumour architecture. Few data regarding mCRC are available, in particular no correlation of baseline RF both with m sites and clinical-pathological characteristics was so far investigated. Methods: Baseline chest-abdomen CT scans of mCRC patients (pts) were retrospectively analysed. RF were extracted from Regions of Interest (ROI) delineated on CT scan from each m sites, including primary tumor, when on site. The association of specific F and disease site (liver, lung, nodes, peritoneum and on-site primary tumor) was investigated. Sites similarity was assessed with Principal Component Analysis, an unsupervised learning technique to identify patterns and clusters. Then RFs were tested individually for correlation with clinical-pathological covariates of interest (gender, CEA level, synchronous disease, RAS/BRAF status, mucinous histology, grading, number of m site, primary tumor site). Wilcoxon-Mann-Whitney test was used for this purpose (significance level set at 0.05). Results: After RF extraction from the different ROIs, the dataset was composed of 433 observations of 236 variables. Observations referred to the number (N) of pts = 89 and the N of ROIs = 18. RF classes were divided in statistical F (grey-level histogram) (N of F = 10); morphological F (N = 14); texture F GLCM (grey level co-occurrence matrix) (N = 100); texture F GLRLM (grey level run length matrix) (N = 66); texture F GLSZM (grey level size zone matrix) (N = 32). Regarding the association of RF with m sites, an homogenous distribution with liver, nodes, peritoneum and primary tumor was detected, while lung metastases showed a different pattern for all the RF classes. A significant correlation of specific RF with clinical-pathologic characteristics was shown, in particular with gender, CEA level, synchronous disease, mucinous histology, RAS/BRAF status. Conclusions: Despite its retrospective nature and the limited number of pts, this is the first experience demonstrating I) a different pattern of RF for lung m versus an homogeneous RF distribution for the other m sites; and II) a significant association of specific RF with few clinical-pathologic characteristics. Our results, if confirmed in a prospective validation set, may represent an hypothesis generator regarding the different behaviour of lung metastases and a possible R signature able to identify different prognostic subgroups of pts.