bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonclinical endpoint assessment utilizing a digital vivarium cloud platform in an ovarian cancer xenograft model.
Authors: Nwagwu Chibueze Dominic , Defensor Erwin , Schaevitz Laura , Carbonell Shawn 
Published: May 2019

e14690 Background: Translation of preclinical data is highly dependent on the validity of the metrics for assessing disease progression and endpoint in mouse oncology models. A digital cloud platform would provide an objective and non-invasive technology allowing real-time assessment of several parameters including motion, breathing, and activity. Here, we hypothesize digital metrics can serve to predict endpoint in an ovarian cancer xenograft model with ascites, thereby improving analysis and interpretation of therapeutic efficacy data and improved adherence to the Three Rs. Methods: Six groups of athymic mice were intraperitoneally inoculated with increasing numbers of ES-2 ovarian cancer cells or control and housed in the Vium Digital Vivarium. Leveraging Vium’s readily accessible videographic and electronic records we retrospectively analyzed night time motion data using the ROC curve on GraphPad Prism and R programming. The following parameters were defined: motion loss post induction (MLPI) and motion loss from endpoint (MLFE). These were in turn compared to the conventional parameters (ie, number of tumor nodules, tumor weight, volume of ascites, and clinical signs) in terms of predicting disease and endpoint. Results: MLPI showed significantly high correlation with endpoint when graphed on a linear regression plot (R2= 0.8671; p< 0.0001), while the conventional metrics showed low correlations with endpoint: number of tumor nodules (R2= 0.1334; p= 0.1133); volume of ascites (R2= 0.2524; p= 0.0240); tumor weight (R2= 0.1162; p= 0.1413). We also showed that MLFE was significantly higher than the days from onset of first clinical sign to endpoint. Analysis of additional digital metrics are underway. Conclusions: The results support the improved ability of a digital platform to predict endpoint over conventional metrics, and earlier than manually-recorded clinical signs. These results are important as they not only provide an objective parameter to enhance study interpretation, but they also reduce the time to humane endpoint. Additionally, the continuously recorded digital metrics increase statistical power, which can be leveraged to potentially reduce the number of animals required per study.
Clinical-relevant model of intraductal papillary mucinous neoplasm induced by ARID1A loss.
Authors: Wei Tao , Chen Qi , Liang Tingbo , Bai Xueli 
Published: May 2019

e14696 Background: Intraductal papillary mucinous neoplasm (IPMN) constitutes a precursor lesion for malignancy of pancreas. Genes encoding subunits of SWI/SNF chromatin-remodeling complexes like ARID1A are collectively mutated in a significant proportion of patients with pancreatic neoplasm. In the present study, we characterize the role of ARID1A in pancreatic tumorigenesis using genetic engineering mouse models. Methods: Various mouse strains were interbred to obtain pancreas-specific Arid1aflox, KrasLSL-G12D/+; Arid1aflox, KrasLSL-G12D/+; Tgfbr2flox; Arid1aflox, and various littermate control animals. Tissue microarrays were used to determine the expression of ARID1A in human pancreatic ductal adenocarcinoma and IPMN. Results: Arid1a loss in pancreas of mice incurred pancreatic duct dilation and development of cystic lesions. Concomitant Kras mutation and Arid1a inactivation accelerated formation of cystic neoplasm resembling human IPMN. These lesions were reminiscent of specific subtype of IPMN given their morphology and expression pattern of mucin proteins. Histological examination further revealed the step-wise progression of these neoplasm from low-grade to high-grade dysplasia and even invasive carcinoma. TGFBR2 deletion promoted the malignant transformation of IPMN to invasive carcinoma in the background of Kras and Arid1a alterations. Analysis of human tissues consistently showed negative or low expression of ARID1A in over half of IPMN patients. Moreover, patients with pancreatic adenocarcinoma also exhibited downregulated ARID1A expression, and reduced expression correlated with worse prognosis. Conclusions: We have established a preclinical mouse model of pancreatic cystic tumor closely resembling human IPMN. This is helpful for the further understanding of biology of IPMN and highlight therapeutic niches for patient tailored treatment in those with altered SWI/SNF function.
Effect of GPR87 on cell proliferation via KRAS signaling pathway in p53-mutant lung cancer cells.
Authors: Nakano Takayuki , Nakashima Nariyasu , Liu Dage , Zhang Xia , Matsuura Natsumi , Tarumi Shintaro , Chang Sung soo , Go Tetsuhiko , Kakehi Yoshiyuki , Yokomise Hiroyasu 
Published: May 2019

e14713 Background: GPR87 is a member of the cell surface molecular G protein-coupled receptors (GPCRs) family and suggested to contribute to the viability of human tumor cells including lung cancer cell. The mechanism of GPR87 in promote cell proliferation is still not yet well understand. p53 was reported to take an important role in keeping cell viability of GPR87-expressing cells. However, most of lung cancer cells possess p53 mutation. In the present study, several reported signal pathway were investigated in lung cancer cells. Methods: Two p53 mutant GPR87-overexpressing lung cancer cell H358 and PC9 lung cancer cell was investigated. An adenoviral vector that encoded a short hairpin siRNA targeting the GPR87 gene (Ad-shGPR87) was constructed. Real-time RT-PCR was performed to evaluate gene expressions and westen blotting analysis for protein expression. MTT assay was used to evaluate the cell viability. Results: Ad-shGPR87 effectively inhibited the GPR87 expression and significantly reduced the percentage of viable cells in GPR87-overexpression H358 and PC9 cell. Regading the signal pathway, there was no p53 expression in H358 cell and no changes in PC9 cell. However, both cells showed a significant decrease in KRAS and c-Myc gene expression 5 days after Ad-shGPR87 transfection. On the other hand, after Ad-shGPR87 transfection, Akt and Cyclin-D1gene expression decrease slightly in H358, but not in the PC9 cell. Conclusions: Theses result show that GPR87 may promoting cell proliferation through several signaling pathways and that the active in p53 mutant cell may linked to KRAS pathway in lung cancer cell.
Targeting EGFR Ex20 mutant lung cancer with the wild type sparing kinase inhibitor PRB001.
Authors: Sos Martin L. , Tumbrink Hannah Lea , Schultz-Fademrecht Carsten , Lategahn Jonas , Keul Marina , Niggenaber Janina , Heimsoeth Alena , Baumann Matthias , Werr Lisa Hanna , Degenhart Carsten , Menninger Sascha , Heuckmann Johannes M , Thomas Roman K. , Rauh Daniel , Klebl Bert 
Published: May 2019

e14718 Background: The majority of EGFR mutant tumors can be effectively treated with targeted drugs. Lung adenocarcinoma patients with EGFR Ex20 insertion mutations, however, lack safe and potent treatment options. These genetic alterations share homology with HER2 Ex20 insertion mutations and perturb the ATP binding pocket in a way that limits accessibility through currently available tyrosine kinase inhibitors. Second-generation EGFR inhibitors are partially active in EGFR Ex20 mutant models but their potent activity against wild type (WT) EGFR and the resulting adverse effects largely prohibit the clinical use of these drugs. To address this medical need, we developed PRB001, a novel EGFR kinase inhibitor. Methods: We facilitated protein X-ray crystallography to guide the development of small molecule inhibitors with high potency against EGFR/HER2 Ex20 mutant kinases and low activity against WT EGFR. Iterative compound optimization involved biochemical profiling concerning inhibition and binding kinetics, cellular profiling as well as mouse pharmacokinetic and mouse efficacy studies. Results: PRB001 exhibits potent activity against EGFR/HER2 Ex20 insertion mutations, in genetically engineered Ba/F3 cell line models and patient derived cell lines. At the same time, PRB001 exhibits a 10-100 fold lower activity against WT EGFR in several cellular models. Our data indicate that PRB001 and its derivatives display a therapeutic window for an effective treatment of EGFR Ex20 mutant tumors with a limited toxicity profile. Mouse xenograft experiments support these results, showing that, in contrast to second-generation EGFR inhibitors, PRB001 does not inhibit WT EGFR and does not lead to loss of weight of treated animals at effective doses of 90 mg/kg daily. Conclusions: Our data support the notion that PRB001 effectively kills a wide range of EGFR Ex20 mutant cellular models and together with its safety profile builds a basis for the development of a mutant-selective and clinically effective tyrosine kinase inhibitor.
Urinary excretion of components of the renin-angiotensin-aldosterone system in patients having localized renal cancer.
Authors: Osokin Roman , Kit Oleg Ivanovich , Komarova Ekaterina , Aboyan Igor , Komarova Elizaveta 
Published: May 2019

e14725 Background: The aim of the study was exploring the content of components of the renin-angiotensin-aldosterone system (RAAS) in the urine of renal cancer (RC) patients depending on the clinical and morphological characteristics. Methods: In the urine of patients having localized renal cancer Т1N0M0 (the main group, n = 40) the level of angiotensinII (ATII), angiotensin-converting enzymes (ACE and ACE2) was studied by the ELISA with excretable creatinine taken into account in order to eliminate the differences of diuresis. The control group was made up of 35 healthy donors. Results: In patients of the main group, the content of ATP in the urine is 71,5% higher (р = 0,003) than in the healthy donors. In 50% of the patients, the range of fluctuations of ATI in the urine from the lower to the upper quartile amounts to 4,2-9,8 pg/µmol of creatinine against 2,1-5,2 pg/µmol of creatinine in the healthy ones.The level of ACE and ACE2 in the patients as compared to the healthy donors is also 35,4% and 24,5% higher, respectively (at p < 0,05). The proportion of increment ΔATII/ΔACE in the patients amounted to 2,2±0,1as compared to the healthy donors, that of ΔATII/ΔACE2 – to3,2±0,2. Meanwhile, ΔACE/ΔACE2 was 1,6±0,1, which confirms the predominance of the activity of ACE. In patients of the main group, no statistically valid difference of the urinary excretion value of ATII, ACE and ACE2 has been identified between the subgroups depending on the RC stage T1a, Т1bas well as on dimensions of the tumor nodes. However, in case of the RC with G2 tumor differentiation grade as compared to the G1, the content of ATII, ACE and ACE2 in the urine is 3,5; 2,5 and 2,1 times higher, respectively (p < 0,05). Conclusions: In patients having localized renal cancer, increased urinary excretion of components of the renin-angiotensin-aldosterone system has been found. The content of angiotensin II in the urine exceeds the activity of angiotensin-converting enzymes, which may be related to the alternative ways of its formation under tumor growth. The content of the RAAS components in the urine in patients having localized renal cancer does not depend on the stage and dimensions of the tumor but it correlates with the differentiation grade.
ALK resistance mutations (muts) developed in different ALK fusion types.
Authors: Zhao Jun , Liu Caixia , Chen Jianhua , Chen Likun , Ai Xinghao , Fan Zaiwen , Wu Yifen , Chen Rongrong , Xia Xuefeng 
Published: May 2019

e14741 Background: Patients (pts) treated with ALK inhibitors (ALKi) inevitably develops resistance. Diverse mutations (muts) confer resistance to ALKis, which may be related to the diverse types of ALK fusion. The objective of this study is to see whether the resistance mechanisms developed during ALKi therapy are ALK fusion types dependent. Methods: The mutation profiles of 38 pts with known ALK fusion partners and positions, who ordered NGS test in our institution after progressed on ≥ 1 ALKis, were analyzed. Results: Resistant muts in ALK kinase domain ( ALK resistant muts) were detected in 53% (20/38) of the resistant pts. 100% (1/1) of the EML4-ALK V5’ variant (V5’), 81% (13/16) of the EML4-ALK V3 variant (V3), 60% (3/5) of the non- EML4-ALK, 23% (3/13) of EML4-ALK V1 variant (V1), and 0% (0/3) of the EML4-ALK V2 variant (V2) had ALK resistant muts. ALK G1202R was detected in 29% of the pts. 100% (1/1) of the V5’, 50% (8/16) of the V3, 20% (1/5, HIP1-ALK) of the non- EML4-ALK, and none of the V1 (0/13) and V2 (0/3) had G1202R. Amplification and gain of function muts in oncogenes and loss of function muts in tumor suppressor gene were detected in 16% (6/38) of the pts, namely 4 V1, 1 V2, and 1 V3. On average, pts treated with 3rd generation ALKis had significantly more muts in ALK (7.5 vs. 3.6, p = 0.0008) and in all targeted regions (9.1 vs. 4.3, p = 0.0005) than pts treated with only 1st and 2nd generation ALKis. Conclusions: The type of resistance mechanisms developed during ALKi therapy may depend on the ALK fusion type of the pt. ALK resistant muts, especially G1202R, developed most frequently in V3/V5’, followed by non- EML4-ALK, and V1/V2, while amplification and grain of function muts in oncogenes and loss of function muts in tumor suppressor genes developed more often in V1/V2 than in V3/V5’. The 3rd generation ALKi may increase the genomic alterations in treated pts.
Differential copy number alteration profiles among gynecological malignancies.
Authors: Romero Ignacio , López-Reig Raquel , Fernandez-Serra Antonio , Garcia-Casado Zaida , Illueca Carmen , Zorrero Cristina , Poveda Andres , Lopez-Guerrero Jose Antonio 
Published: May 2019

e14744 Background: Copy number alterations (CNA) constitutes a genomic hallmark that defines specific outcomes in gynecological neoplasms, as evidenced by the integrated analysis of the high-grade serous ovarian carcinoma (HGSOC) and endometrial carcinomas (EC) performed by the TCGA Consortium. The purpose of this study is to set up an NGS-based technology to obtain CNA profiles on formalin-fixed paraffin-embedded (FFPE) samples with clinical utility. Methods: FFPE blocks from 14 EC and 12 HGSOC were analyzed using a SureSelectXT custom panel plus OneSeq backbone, interrogating 147.000 SNPs (Agilent). CNA groups were defined in EC with a RF algorithm based on genotyping data as previously reported (Romero, ASCO 2018) and in HGSOC Homologous recombination deficiency (HRD) was determined by sequencing a serie of 35 HR genes. saasCNV pipeline was used to perform CNA calling. Results: Ten (38.50 %) of our cases were classified as CN Low (CNL), 8 as CN high (CNH)-RF (30.75 %) and 8 CNH-HRD (30.75 %). CNL profiles from EC and OC are homogenous in terms of genomic stability. CNH-RF and CNH-HRD cases harbor the highest percentage of genomic instability (p = 0.012) with distinct patterns of CNA. CNH-HRD is characterized by a higher ratio of genomic losses (p = 0.023). However, CNH-RF is mainly defined by gains (p = 0.011) (Table). Conclusions: Our NGS-based approach represents a FFPE clinically available procedure to define CNA alterations in gynecological cancer with distinct CNH patterns with prognostic potential.[Table: see text]
A large subtype of squamous cell carcinoma enriched for TrkB-T1 mRNA.
Authors: Zhou Yalu , Schwartz Joel L. , Sinha Saurabh , Shergill Ardaman , Adami Guy 
Published: May 2019

e14751 Background: A large subtype of squamous cell carcinoma enriched for TrkB-T1 mRNA. Background The NTRK2 genetic locus encodes neurotrophin membrane receptors that play an important role in normal neural tissue plasticity, growth, and survival. One NTRK2-encoded protein is TrkB-FL, which can regulate multiple pathways relevant to cancer. A second NTRK2 gene mRNA isoform encodes TrkB-T1, a receptor that has a different cytoplasmic domain and is encoded in a mRNA with a unique 3’ terminal exon. Methods: Tumors from The Cancer Genome Atlas (TCGA) and other studies were classified according to the expression of a single form of NTRK2 mRNA that of TrkB-T1. Analysis of differentially expressed genes in TrkB-T1 high expressers was done to determine if tumors enriched for TrkB-T1 were a uniform group independent of anatomic site. Results: The mRNA for TrkB-T1 is the most abundant NTRK2 gene mRNA in all squamous cell carcinomas (SCCs). Comparison of oral SCC (OSCC) high TrkB-T1 RNA expressers to low expressers (n = 284) revealed gene expression differences consistent with the high TrkB-T1 tumors being more neural-like. The upregulated genes in the TrkB-T1 RNA high expressers also showed enrichment of pathways involved in retinol metabolism, hedgehog signaling, and the Nfe2l2 response, among other pathways. An examination of larynx, esophagus, and lung SCCs (n = 100, 100, 540) showed induction of the same pathways among the tumors that expressed high levels of TrkB-T1 mRNA.. Surprisingly, the relationship of high level TrkB-T1 expression to patient outcomes was SCC anatomic site specific. High TrkB-T1 mRNA levels in laryngeal SCC correlated with poor survival, but the opposite was true for lung SCC. This may be because pathways enriched in the TrkB high expressers, like those regulated by Nfe2l2, Pik3ca, and Sox2, are known to have SCC anatomic site-specific effects on progression. Conclusions: High level TrkB-T1 mRNA serves as a marker of a distinct SCC subtype. These tumors share the enrichment of at least 3 pathways relevant to tumor progression, Nfe2l2 response, retinol metabolism, and hedgehog signaling.
Somatic mutations in non-small cell lung cancer and their correlation with overall survival, tumor mutation burden, and programmed-death cell ligand-1 (PD-L1) status.
Authors: Dotson Jennifer , Jamil Muhammad 
Published: May 2019

e14752 Background: In recent years, treatments for non-small cell lung cancer (NSCLC) have expanded to include targeted therapies and immune checkpoint inhibitors in addition to traditional treatments. These newer modalities of treatment require testing with next-generation sequencing (NGS) testing, which offers testing for hundreds of somatic mutations, both with known and unknown significance. Tumor mutation burden (TMB), which is the number of mutations per coding sequence, is also reported on NGS. Patients with targetable mutations or a high TMB have been found to have improved survival and higher responses to immunotherapy, respectively. We wanted to investigate whether the total number of mutations (both with known and unknown significance) had any association with PD-L1 status, TMB and overall survival. Methods: This was a single institution, retrospective study of 51 patients with stage I-IV NSCLC. Results: In our study, we found that there was a significant correlation between the number of mutations and TMB in all patients with NSCLC (p = 0.001), including adenocarcinoma (p = 0.005). We found that the number of known mutations, mutations of unknown significance and total overall mutations did not have a significant correlation with survival (p = 0.708, p = 0.808, and p = 0.639, respectively) or PD-L1 status (p = 0.214). In a subset analysis of patients with metastatic NSCLC, there was also no correlation between the total number of mutations and overall survival (p = 0.821). Conclusions: In our study, we determined that there was a positive correlation between TMB and higher number of mutations, though the number of mutations did not correlate with PD-L1 status or overall survival. As TMB is associated with higher immunogenic responses, this data may have future therapeutic implications. Additional investigation of the most frequent mutations is ongoing.
Targeted-sequencing in rare cancers and the impact on patient treatment.
Authors: Okuma Hitomi Sumiyoshi , Kubo Takashi , Ichikawa Hitoshi , Kohno Takashi , Mizuno Takaaki , Kojima Yuki , Sunami Kuniko , Shimomura Akihiko , Iwasa Satoru , Kondo Shunsuke , Fujiwara Yutaka , Yonemori Kan , Tamura Kenji , Yamamoto Noboru 
Published: May 2019

e14755 Background: Rare cancers lack standard or investigational therapeutic options. Next-generation sequencing (NGS) has provided new insight into personalized medicine. We sought to catalog genetic alterations detected from tissue NGS in rare cancers and to assess their clinical utility. Methods: This was a single-center series with patients (pts) who had been referred to the National Cancer Center Hospital (Tokyo, Japan). Patients with a metastatic/unresectable disease who underwent comprehensive genomic profiling of their tumor for the purpose of precision treatment were first identified (approved by the NCCH institutional review board). Among them, pts diagnosed as rare cancers, defined as an incidence of < 6/100,000 pts/year, were included in this study. Prospectively consentedpts had tissue NGS testing (NCC Oncopanel) for point mutations, select indels, copy number amplifications, fusions. Alterations were assessed for incidence according to cancer type, functional impact, therapeutic implications. Results: Between July 2013 to April 2016, 289 pts were enrolled. 217 pts with sufficient tissue sample succeeded in sequencing. 78% (169/217) had a least one alteration most likely pathogenic. Most common alterations were TP53, PIK3CA, BRCA2, KRAS, MYC, ERBB2, RB1, CCND1, and ARID1A. 114/289 pts (39%) were classified as rare cancers: gynecological cancers (44 pts), cholangiocarcinoma (20), sarcomas (16), NET (9), thymic carc. (6), mesothelioma (3), CUP (2), urachal carc. (2), GIST (1), thyroid carc. (1), other super-rare cancers (10). 86 pts succeeded in sequencing; 72 % (62/86) had a variant most likely pathogenic. Most common alterations were TP53, KRAS, BRCA2, FBXW7, NF1, PIK3CA, ALK, BRCA1, and CCND1. 23 pts (27%) of rare cancer pts received a targeted drug of which 9 (10%) were “matched” to a detected alteration. Response rate to the “matched” therapy was CR/PR/SD/PD = 0/1/5/3 (ORR 11%). Conclusions: Genomic alterations were equally detected in rare cancers as well as common cancers, however showed different alteration profiles. Rare cancer pts receiving “matched” therapy and the response rate to those remain low, suggesting a need for a more efficient treatment development platform. Clinical trial information: UMIN000011141.
Fruquintinib or regorafenib as the third-line treatments for metastatic colorectal cancer based on CONCUR and FRESCO trials: A cost-effectiveness analysis.
Authors: Li Qiu , Zhang Mengxi 
Published: May 2019

e15011 Background: Survival benefit of regorafenib and fruquintinib as third-line agents have been respectively demonstrated in patients with treatment-refractory metastatic colorectal cancer. This study tries to explore the cost-effectiveness of the two agents. Methods: A Markov model was performed based on two phase 3 trials, FRESCO and CONCUR. Health outcomes were measured with quality-adjusted life-years (QALYs). The key outcome was incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity and one-way sensitivity analysis were performed to estimate the impact of essential variables on the results of the analysis. Results: No statistical differences were observed in the baseline patient characteristics, except that the CONCUR trial enrolled older patients and higher ratios of prior use of VEGF or EGFR antibodies in comparison with the FRESCO trial.Treatment with fruquintinib was estimated to cost $25,550.15 with an effectiveness gain of 0.54 QALYs, whereas regorafenib resulted in 0.53 QALY at a mean cost of $29,681.52, yielding ICER of $-413,137.00 per QALY. By using treble the Chinese Gross Domestic Product per Capita as willingness-to-pay threshold, the probability for fruquintinib being cost-effective was higher than regorafenib in the probabilistic sensitivity analysis. Conclusions: Fruquintinib provides a more cost-effective option for metastatic colorectal patients compared with regorafenib in the third line treatment.[Table: see text]