bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical analysis of cancer associated venous thromboembolism in hospitalized patients with malignant solid tumors in real-world practices.
Authors: Jiang Da , Zhang Xue , Yang Haiying , Zuo Jing , Jin Hui , Li Ying , Huang Fang 
Published: May 2019

e14686 Background: According to previous reports, 1% to 30% patients with malignant tumors developed venous thromboembolism (VTE) and an increased risk of VTE in hospitalized patients. However, real-world clinical analysis of VTE in Chinese hospitalized patients with malignant solid tumors is scarce. Methods: We utilized the collaborative Linkdoc database to retrospectively analyze hospitalized cancer patients in Department of Medical Oncology of the Fourth Hospital of Hebei Medical University from May 2014 to November 2018. Patients who were pathologically confirmed malignant solid tumor, ≥ 18 years of age, ECOG PS 0-4, median overall survival ≥ 1 months, and absence of serious diseases of vital organs such as heart, liver, kidney and blood system or the above chronic diseases in inactive period were included in this study. Results: A total of 3831 patients were enrolled, of whom 180 (4.70%) patients had VTE. The highest incidence of VTE in solid tumors was gynecological cancer (61/1288, 11.90%), followed by gastric cancer (42/701, 5.71%), other cancers (11/206, 5.33%), lung cancer (61/1288, 4.74%), colorectal cancer (18/399, 4.51%), breast cancer (34/903, 3.77%), and esophageal cancer (6/250, 2.40%). Of the enrolled patients, 21.11% (809/3831) underwent relevant imaging examinations to screen for VTE as required by the guidelines of cancer associated VTE. Based on the imaging examinations, the anticoagulant rates of patients with or without VTE were 100% (61/61) and 34.09% (255/748), respectively. Notably, only one patient received the anticoagulant therapy (both anticoagulant dose and time) in lines with the guidelines. Conclusions: This single-center real-world study showed the overall rates of VTE in hospitalized cancer patients was similar with the data previously reported. Referring to the guidelines of cancer associated VTE, the proportion of Chinese cancer patients receiving normative imaging examinations and anticoagulant therapy is seriously low currently, which should be paid more attention to in clinical practices by Chinese medical workers.
A novel CRISPR-directed gene editing method that catalyzes precise gene segment replacement in vitro enabling multiplex site-directed mutagenesis.
Authors: Tarcic Gabi , Sansbury Brett M , Wagner Amanda M , Barth Shaul , Paniri Ester , Kmiec Eric B 
Published: May 2019

e14688 Background: Functional analysis of the multitude of mutations found in tumors is a major goal to better understand their role and to optimize patient treatment. PCR-based site-directed mutagenesis (SDM) techniques are often used to engineer these variants. While these tools are efficient, they are not without significant limitations, most notably off-site mutagenesis, limited scalability and lack of multiplexing capabilities. To overcome many of these limitations, we describe a novel, fast and simple method for the introduction of both simple and complex gene mutations in plasmid DNA by using in vitro CRISPR based DNA editing. Methods: For each mutation, a specifically designed pair of CRISPR/Cas12a ribonucleoprotein complexes are used to execute site-specific double-strand breaks on plasmid DNA enabling the excision of a defined DNA fragment. This is followed by donor DNA replacement and bacterial colony expansion. We term this method, CRISPR-directed DNA Mutagenesis (CDM). Results: Using CDM we have been able to synthesize known oncogenic mutations as well as novel variants in 8 different cancer genes. These mutations have been synthesized with over 60% success rate, compared to about 40% success rate in SDM. More importantly, we show that in the CDM method there were no off-site mutations eliminating the need to sequence large portions of the gene. Conclusions: We have developed a novel multiplex site-directed mutagenesis method that can generate multiple unique mutations simultaneously within plasmids. CDM has proven capable of precise, rapid and robust mutation synthesis, including single base point mutations, site-specific deletions, insertions and duplications within targeted plasmids.
Phenotypic and functional characteristics of patient derived murine xenograft models.
Authors: Kiver Verena Imke Isabel , Wulf-Goldenberg Annika , Schweiger Caroline , Jurmeister Philipp , Brzezicha Bernadette , Gorea Olga , Burock Susen , Kolberg-Liedtke Cornelia , Hoffmann Jens , Blohmer Jens Uwe , Keilholz Ulrich , Denkert Carsten 
Published: May 2019

e14694 Background: Generation of patient-derived models for breast cancer has been difficult. In other histologies, success was higher in refractory disease. With the goal to develop a protean resource for testing novel compounds and combinations for treatment refractory breast cancer, we establish patient-derived murine xenograft models (PDX) from tumors clinically unresponsive to at least anthracyclin, platin and taxane. Here we report phenotypic and drug testing data of our established breast cancer models. Methods: On immunodeficient NOG mice, PDX were engrafted from breast cancer tissue samples. The tissues were obtained from patients with disease progression after chemotherapy with three to four drugs. The established PDX were characterized by immunohistochemistry and the PDX and primary tumor are currently undergoing exome and transcriptome sequencing. The PDX were tested for response to all standard chemotherapy agents. The drug testing included platin, taxane, anthracycline, 5-FU, Everolimus, Eribulin and depending on the subtype tamoxifen, olaparib, and a CDK4/6 Inhibitor. Results: Since May 2017 30 breast cancer samples have been processed under rapid and stringent conditions. Currently five models, three TNBC and two hormone receptor positive PDX, have been fully engrafted, phenotypically compared and drug tested. The immunohistochemistry (estrogen/progesterone/androgen/Her2 receptor, Ki-67, CK5/6) of original tumor and PDX were correlative. All patients had shown clinical resistance to platin, anthracyclines, and taxanes in the neoadjuvant or palliative setting. Concordant with the clinical resistance, the PDX models showed only limited or transient sensitivity to single agents. Six more PDX, three TNBC, two HR+ and one Her2+, are currently in various states of engraftment and testing. Conclusions: With our stringent approach, we successfully generated PDX models in 15%, which may rise to 30% with the ongoing models. Phenotype between patient tumors and PDX was consistent. The minor differences in responsiveness to chemotherapy may be due to differences in stromal factors. In summary, the PDX of refractory tumors are a versatile resource for preclinical studies of novel treatment approaches.
Sorafenib as a postoperative adjuvant therapy in patients with hepatocellular carcinoma and microvascular invasion: A propensity score matching analysis.
Authors: Zhang Xiu-Ping , Chai Zong-Tao , Gao Yu-Zhen , Ding Jin , Cong Wen-Ming , Lau Wan Yee , Cheng Shuqun 
Published: May 2019

e14707 Background: There is an unmet need for the postoperative adjuvant therapy in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI), which is associated with early recurrence after curative resection. This study aimed to investigate the role of Sorafenib as a postoperative adjuvant therapy in HCC patients with MVI after R0 liver resection (LR). Methods: Consecutive HCC patients with pathologically confirmed MVI who underwent R0 LR between January 2009 and December 2016 at the Eastern Hepatobiliary Surgery Hospital were retrospectively reviewed. Patients in the LR+sorafenib group (n = 581) received oral sorafenib (400 mg/d) at 1 weeks after R0 LR, while patients in the LR group (n = 147) only underwent R0 LR. Propensity score matching (PSM) was performed to balance the baseline characteristics between the two groups. Overall survival (OS) and recurrence-free survival (RFS) were followed up, and multivariate Cox regression analysis was performed. Results: After PSM, there were 113 patients in each group. The LR+sorafenib group demonstrated improved OS (median, 43.3 vs. 34.9 months; 1-year, 85% vs. 65%; 3-year, 66% vs. 51%; 5-year, 57% vs. 37%; log-rank P = 0.007) and RFS (median, 32.0 vs. 15.0 months; 1-year, 72% vs. 55%; 3-year, 47% vs. 36%; 5-year, 39% vs. 19%; log-rank P = 0.001) compared with the LR group after PSM. Multivariate Cox regression analysis indicated that R0 LR with postoperative sorafenib therapy was associated with better OS and PFS ( P < 0.001). On subgroup analysis, similar survival benefits were observed for sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) 0-A, BCLC B and Child-Pugh A stages of disease. Conclusions: Sorafenib used as a postoperative adjuvant therapy in HCC patients with MVI after R0 LR was associated with significantly better survival outcomes than LR alone.
Multiplatform molecular profiling: Observational study to determine the effect of treatment selection in advanced or refractory metastatic solid tumors.
Authors: Khan Faraz A. , EL Khoury Maroun , Safar Thalia , Tareen Mona , Sayed Kadriya 
Published: May 2019

e14730 Background: To assess the clinical benefit of treatment in advanced and refractory solid tumors utilizing evidence-guided molecular profiling (MP) of tumors in routine clinical practice. Methods: This retrospective observational study was conducted on patients with advanced or refractory metastatic solid tumors, whose tumor biopsy samples were referred for profiling using a multi-platform tumor profiling service (Caris Molecular Intelligence) between January 2014 and April 2017. Specific testing was performed per physician’s request and included a combination of next-generation sequencing (NGS), protein expression (IHC), gene amplification (CISH or FISH), and/or RNA fusion analysis. Results: Data of twenty five patients with solid tumors was analyzed (median age of 58 years, range 25-82 years). Patients had received a median of 2 prior lines of therapy (range 0-6). In evaluable patients, 1 (4%) patient had a complete response, 10 (46%) patients had a partial response, 5 (23%) had stable disease and 6 (27%) had progressive disease, giving a disease control rate of 73%. The majority of patients received chemotherapy (CT) alone (13; 56%). Five patients received CT combined with targeted therapy (TT), 2 received TT alone, 2 received TT combined with hormone therapy (HT), 2 have received immunotherapy and 1 received HT alone. Two patients were not evaluable for response. In responding patients, median duration of response was 7 months (3-18 months). Conclusions: The result of this study show that treatment based on Broad tumor profiling in a select group of advanced and refractory solid tumors was associated with a high disease control rate.
The impact of androgen receptor (AR) expression on the prognosis of ductal carcinoma in situ (DCIS).
Authors: Lee Choong Man , Kim Jisun , Jo Hwi Gyeong , Park Hye Jin , Lee Sae Byul , Chung Il Yong , Yu Jong Han , Kim Hee Jeong , Ko Beom Seok , Lee Jong Won , Sohn Byung Ho , Ahn Sei-Hyun 
Published: May 2019

e14731 Background: Ductal carcinoma in situ (DCIS) display favorable outcome while little is known about the factors associated with invasive recurrence. To identify better prognostic biomarkers we performed gene expression analysis followed by immunohistochemistry (IHC) staining validation. Methods: Differential gene expression analysis of 29 pure DCIS patients was performed using nanostring platform. RNA was extracted from paraffin blocks from age/size matched 11 recurrence-free and 18 invasive-recurrence cases (disease free interval > 5 years). Gene annotation enrichment analysis was done for differentially expressed genes (DEG) using DAVID. Eighty-two pure DCIS cases were selected for external validation by IHC staining. Allred score cutoff 1 was used for survival analysis. Results: Ninety-nine differentially expressed genes were found statistically significant (p-value < 0.05). Androgen receptor (AR) gene, which encodes a transcription factor AR, has recently been highlighted as a favorable prognostic marker and a therapeutic target in invasive tumor (fold change = - 1.35, p < 0.001). AR protein expression was externally validated by IHC staining of 82 pure DCIS cases (24 invasive-recurrence versus 58 recurrence-free). Similar to gene expression analysis result, patients with invasive recurrence showed lower AR staining score than recurrence-free patients (p = 0.007). Cox regression analysis showed lower AR level as an independent risk factor of long-term invasive recurrence (HR 7.43, 95%CI 1.50 – 36.62). Gene enrichment analysis revealed enrichment of kinase pathway and cell cycle pathway in recurred cases (Enrichment Score = 2.43, 2.41 respectively). Conclusions: DEG pattern was observed among pure DCIS cases. AR may serve as a prognostic biomarker and targeting kinase, cell proliferation may be effective for higher risk DCIS patients.
Changes in TROP2 expression in lung cancer patients receiving anticancer treatments.
Authors: Omori Shota , Kenmotsu Hirotsugu , Muramatsu Koji , Kawata Takuya , Kobayashi Haruki , Nakashima Kazuhisa , Wakuda Kazushige , Ono Akira , Naito Tateaki , Murakami Haruyasu , Sugino Takashi , Takahashi Toshiaki 
Published: May 2019

e14732 Background: Human trophoblast cell surface glycoprotein (TROP2) is expressed on the cell surface of trophoblasts and various solid cancer cells. Recently, an antibody-drug conjugate (ADC) targeting TROP2 has been developed. The objective of this retrospective study is to evaluate the prevalence of TROP2 expression in the specimen of lung cancer and its changes during anticancer treatments. Methods: TROP2 expression was evaluated prior to and following anticancer treatment by immunohistochemical (IHC) analysis using an anti-TROP2 antibody (SP295). IHC scores were graded from 0 to 3 and grade ≥2 was considered to be positive. Pre- and post-treatment IHC scores of TROP2 expression were compared by Wilcoxon signed rank test. Results: Among 160 patients with evaluable tissue samples, median age was 65 (range, 39-89) years with 69% in stage III-IV. Histological diagnosis included 81% adenocarcinoma (Ad), 12% squamous cell carcinoma (Sq), 5% neuroendocrine carcinoma (NEC), and others. Among 130 Ad patients, 59% had EGFR mutations. Anticancer treatments included cytotoxic chemotherapy (77%), targeted therapy (42%), and radiotherapy (19%). TROP2 was expressed in 143 (89%) and 139 (87%) in pre- and post-treatment samples, respectively. Pre-treatment TROP2 positive expression were more frequently observed in Ad (92%) or Sq (100%) than NEC histology (25%, p < 0.001). There was no significant change in TROP2 expression after treatment (p = 0.509). Conclusions: TROP2 was commonly observed in the specimen of lung cancer especially in non-NEC histology regardless of anticancer treatments. TROP2-targeted ADC might have a therapeutic potential to be tested in TROP2-expressing lung cancer. [Table: see text]
Morphologic and genomic characterization of circulating tumor cells in patients with metastatic colorectal cancer treated with combinational treatment of andecaliximab, bevacizumab and chemotherapy.
Authors: Shishido Stephanie , Kuhn Peter 
Published: May 2019

e14753 Background: The liquid biopsy is a noninvasive route to evaluate circulating tumor cells (CTCs) during the course of treatment to gain understanding of tumor biology, with potential prognostic utility. CTCs could serve as a predictive biomarker while aiding in the identification of resistance mechanisms to treatment through single cell genomic and proteomic analysis providing a longitudinal snapshots of tumor heterogeneity. Methods: Through the use of the high definition single cell assay (HD-SCA) workflow, we characterized the rare circulating cells to determine prognostic value of the liquid biopsy in monitoring the efficacy of andecaliximab in a combinational treatment as 1st or 2nd line therapy in patients with metastatic colorectal cancer (mCRC). 174 samples from 95 patients were analyzed to determine the significance of CTCs during treatment. Results: HD-CTCs were detected in 31% of samples, with 41 (43%) patients being CTC positive in at least 1 timepoint during the study. Patients receiving 1st line therapy presented with a median of 0 (range 0-346.04) and a mean of 9.49 (±14.06) HD-CTC/mL at baseline (BL). At initiation of 2nd line therapy, patients presented with a median of 0 HD-CTC/mL (range 0-277.37) and a mean of 10.94 (±15.32). There was no association between BL HD-CTC/mL and response, but for the 20 patients with > 1 HD-CTC at BL, there was a trend toward response for higher HD-CTC/mL (non-response: mean 2.8, n = 12; response: mean 89.7, n = 8; p = .04). The 3 patients with > 10 HD-CTC/mL at BL had undetectable HD-CTC on-treatment, which accompanied radiologic partial response; however, the 2 patients with complete radiological response had no HD-CTC detected at BL. In case studies, treatment pressure led to an observable change in HD-CTC morphology and genomic instability (single cell CNV analysis), suggesting these parameters may inform prognosis. Conclusions: Characterization of CTCs from patients with mCRC is feasible and may provide prognostic information to guide clinical decision making. Further evaluation of CTCs for pharmacodynamics and clinical monitoring in patients with mCRC is warranted.
Association of co-occuring mutations in exosomal DNA and clinical outcomes of patients with metastatic colorectal cancer.
Authors: Zhao Chuanhua , Chang Lianpeng , Cui Cong , Tan Zhaoli , Jia Ru , Wang Yan , Liu Rongrui , Zhang Yun , Liu Jianzhi , Xu Jian-Ming 
Published: May 2019

e15001 Background: Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Compared with cell-free DNA (cfDNA) derived from apoptotic cells, exosomal nucleic acids (exoNAs) released from living cells, which include more complete DNA, RNA and protein component, can better reflect underlying cancer biology. However, little evidence supports the clinical relevance of such a biomarker in metastatic colorectal cancer (mCRC). Methods: From May 2013 to July 2016, patients with mCRC received chemotherapy with or without molecular targeted drugs were enrolled in the Fifth Medical Center, General Hospital of PLA. Clinical response was evaluated using RECIST 1.1. Serial blood samples were collected and used to extract exosomal DNA. Targeted amplicon ultradeep sequencing was employed to analyze mutations in exosomal DNA with a customized-designed 10-genes panel including prognostic-related and cetuximab-resistant genes of CRC. Results: 91 patients were enrolled in this study, and median follow-up time was 11.7 months. In total of 82 pretreatment samples, 58% were detected to harboring mutations in designed targeted regions. The most frequent mutant genes were TP53 (56%), KRAS (54%), and PIK3CA (33%). Co-occuring genes were detected in 25 (31%) patients, including 16 patients with mutation in both KRAS and TP53 gene. Patients with co-occurring TP53/KRAS mutations showed significantly poor outcome (median OS=9.23m ), than those without co-occuring in these two genes (median OS=18.75m; P=.0141). Further analysis showed progress disease with new metastasis was enriched in patients with co-occurring KRAS/TP53-mutant patients (p=.0016). Of 23 samples from progressed patients received cetuximab, 39% were detected with acquired cetuximab-resistance related mutations in KRAS (26%), PIK3CA (17%), NRAS (4%) and BRAF (4%). In addition, exosomal DNA abundance increased was observed at or before disease progression (mean leading time = 8.90 weeks). Conclusions: This study provided clinical evidence for exosomal DNA as a potential biomarker of prognosis and cetuximab-resistant mechanism of mCRC.
Clinical significance of ZHX2 in colitis and colorectal carcinogenesis.
Authors: Bao Yonghua , Guo Yongchen , Yang Wancai 
Published: May 2019

e15010 Background: Colorectal cancer (CRC) is one of the most common malignancies. Mechanistic studies have revealed that the malignant transformation of chronic colitis is one of the major causes besides the activation of Wnt/beta-catenin signaling. Our preliminary data have shown that ZHX2 is a common target of the miRNAs and is associated with colitis malignant transformation. This study aimed to explore the changes of ZHX2 in colitis-CRC tissues and their clinical significance, and to reveal the underlying mechanism. Methods: ZHX2 protein expression levels were analyzed by immunohistochemical staining in a CRC tissue microarray containing 400 cases of CRC and matched normal mucosa; mRNA levels were analyzed in fresh tissues by qRT-PCR. ZHX2 functional studies were conducted in ZHX2 transgenic mouse model and in vitro; Protein regulation was assayed by proteomic analysis using iTRAQ and RNA changes were assayed by RNA-sequence. Results: Protein and mRNA levels of ZHX2 were significantly increased in CRC and was associated with poor outcomes and recurrence, the copy numbers were also elevated in CRC. Intestine-specific transgenic Zhx2 mouse model showed chronic inflammation in the intestine at early age and intestinal carcinogenesis at late ages. Intestinal epithelial cell RNA sequence assay showed differential expression of genes and signaling pathways, compared to the wild-type mice. Biological functional studied showed that increasing ZHX2 in CRC cells enhanced cell proliferation, motility and migration, and suppressed cell apoptosis. Proteomic analysis showed that ZHX2 and HMGA1 were synergistic during tumorigenesis; mi-RNA regulatory study showed that miR-150 targeted ZHX2 and suppressed ZHX2 expression, but ZHX2 could regulate Wnt/beta-catenin and Serine family member PRSS8. Conclusions: This study has revealed the critical roles of ZHX2 in chronic colitis and its malignant transformation and underlying molecular mechanism, identifying a novel target for CRC prevention and therapy.