bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1157: The B-NDG mouse is a perfect tool for immune system humanization and patient derived xenograft transplantation
Authors: Zhang Meiling , Guo Chaoshe , Shen Yuelei , Guo Yanan 
Published: August 2018

Abstract
The B-NDG mice (NOD-Prkdcscid Il2rgtm1/Bcgen), independently developed by Biocytogen, display a severe immunodeficiency phenotype, with no mature T, B or functional NK cells, and deficient in cytokine signaling. The B-NDG mouse is one of the best models for reconstitution of human immune system using peripheral blood mononuclear cells (PBMC) or hematopoietic stem cells (CD34+). Human PBMC reconstituted well in B-NDG mice, with the percentage of hCD45+ cells was over 50% in five weeks. To further analyze the subsets of immune cell composition, we found the majority of human cells were CD8+ T lymphocytes. Other than PBMC, human CD34+ hematopoietic stem cells also demonstrated a high-engraftment efficacy in B-NDG mice. Successful engraftment of CD34+ cells develops all major cell types via myeloid and lymphoid lineage to reconstitute functional human immune system. At 10 weeks post CD34+ cell implantation, the percentage of hCD45+ cells is over 30% with detectable human T, B and NK cells. Therefore, the immuno-humanized B-NDG mice are useful tools for studying hematopoiesis, immunology, infectious disease, and ES/iPS cell research. With barely any rejection to human derived cells, the B-NDG mouse is an ideal host for transplantation of PDX (Patient-Derived Xenograft), and retains the high heterogeneity characteristics of tumor tissues. Each PDX model can be considered as a single tumor patient and fully embodies the patient group characteristics. We have a collection of various PDX models including leukemia, breast cancer, gastric, lung, pancreatic, and colon et al. The humanized PDX model by implantation of PDX on the immuno-humanized B-NDG mice will be a promising tool to evaluate the in vivo efficacy of immune checkpoint antibodies in monotherapy or in combination. Therefore, therapeutic efficacy studies using B-NDG based PDX models are more meaningful and predictive in preclinical drug development and discovery.
Citation Format: Meiling Zhang, Chaoshe Guo, Yuelei Shen, Yanan Guo. The B-NDG mouse is a perfect tool for immune system humanization and patient derived xenograft transplantation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1157.
Abstract 1164: Pdx model of pleural effusion of lung cancer patient for testing on targeted drug sensitivity and resistance
Authors: Zhang Feifei , Zhou Zhen , Long Yuan , Xu Wenhua , Zhao Shizhu , Yang Yang , Liu Hui , Cheng Jijun , Lu Shun , Wen Danyi 
Published: August 2018

Abstract
Advanced lung cancer of late stage patients is selectively sensitive to available targeted therapeutics and often develops resistance to early sensitive drug treatment. Surgery tumor tissues are usually not available to establish patient-derived xenograft (PDX) models which is critical to evaluate drug sensitivity and resistance. We applied CD45 magnet beads to enrich the tumor cell population from pleural effusion specimens of advanced lung cancer. Valuable drug-resistant PDX models were successfully established both from pleural effusion and from routine surgery tissues. Genetic profiling of the PDX models revealed TKI drug-associated EGFR mutations (L858R, T790M, Exon19del, C797S). In particular we successfully established a clinically AZD9291-resistant EGFR triple mutant (Ex19del, T790M, C797S) PDX model. In vivo efficacy results with gefitinib, erlotinib and AZD9291 well matched corresponding gene mutations among the models. Interestingly, we successfully induced AZD9291-resistant clones in vivo using an EGFR double mutant (L858R, T790M) PDX model, and NGS revealed mutations in kinases involved in other signaling pathways, indicating potential therapeutic options against resistance emergence. In conclusion, these precious PDX models provide insight into resistance mechanisms as well as serve as models to test potency of many drugs including current investigational TKIs.
Citation Format: Feifei Zhang, Zhen Zhou, Yuan Long, Wenhua Xu, Shizhu Zhao, Yang Yang, Hui Liu, Jijun Cheng, Shun Lu, Danyi Wen. Pdx model of pleural effusion of lung cancer patient for testing on targeted drug sensitivity and resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1164.
Abstract 1171: Quantitative evaluation of hepatobiliary transporter density with microscopic fluorescence imaging using indocyanine green
Authors: Meng Hui , Gao Yuan , Yin Lin , Ma Xibo , Wang Kun , Tian Jie 
Published: August 2018

Abstract
The sodium-dependent taurocholate cotransporter polypeptide (NTCP) has been identified as a predictive marker for post-surgery survival rate of hepatocellular carcinoma (HCC) patients. Previous studies indicated that the expression of NTCP was associated with tumor differentiation. The ability to quantify protein expression is imperative to ensure successful personalized medicine including treatment stratification and therapeutic monitoring. Current standards for transporter analysis are based on immunohistochemistry and immunofluorescence. These measurements are complicated and too time consuming. Here, we endeavored to identify the expression of NTCP by quantitative microscopic fluorescence imaging (MFI) features, that could be used for investigation of tumor heterogeneity. Quantitative image features including the intensity, texture and wavelet texture were extracted from microscopic fluorescence images. Using multiple xenograft tumor models with varying NTCP expression, we determined the NTCP density in each model with MFI using indocyanine green. The MFI-calculated transporter density was correlated with ex vivo immunohistochemistry. Overall, our results argue that MFI provides a promising measure of transporter expression equivalent to immune-staining, with implications for use in investigation of tumor heterogeneity.
Citation Format: Hui Meng, Yuan Gao, Lin Yin, Xibo Ma, Kun Wang, Jie Tian. Quantitative evaluation of hepatobiliary transporter density with microscopic fluorescence imaging using indocyanine green [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1171.
Abstract 1173: The identification of circulating tumor cells in the cerebrospinal fluid of gastric cancer patients with brain metastasis and the evaluation of intra-patient tumor heterogeneity
Authors: Cho Jang Ho , Kim Sun Young , Kim Kyung , Kim Jusun , Lee Su Jin , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki , Kim Seungtae 
Published: August 2018

Abstract
PURPOSE : The purpose of this study was to identify circulating tumor cells (CTC) and evaluate tumor heterogeneity in cerebrospinal fluid (CSF) of advanced gastric cancer (GC) patients with leptomeningeal seeding. METHOD : We used the DEPArray system to identify and align single enabled CTCs in CSF based on multi-parallel fluorescence analysis. CSF were stained with an antibody cocktail recognizing cytokeratin, EpCAM, and HER2. CTC subpopulations of CSF were quantified as both absolute cell count and relative frequency. Based on the stained morphology of each single CSFTCs, five groups (Group A~E) were categorized.
RESULTS : CSF samples were obtained from a HER2 positive GC patient with leptomeningeal seeding. Each single CTC was collected according to the characteristics of morphology and the difference of marker expression. Group A CTC revealed HER2 positive, CK positive and EpCAM positive cells. The ratio of group A cells to total cells was 56.7%. Although the tumor of patient was HER2 positive cancer, HER2 negative CTCs in CSF (Group D + E) accounted for 21.8% of the total cells. Among CTCs we detected in CSF, there was no CTC revealing HER2 positive, CK negative and EpCAM negative.
CONCLUSIONS : DEPArray analysis might be a novel tool to capture CTC in CSF samples and evaluate the intra-patient's tumor heterogeneity. These findings suggested that DEPArray analysis could be used as a useful tool for the precision medicine.
Characterization of HER2 + CSFTCs on gastric cancer patientHER2CytokeratinEpCamCell#%/total cellGroupPositivePositivePositive13556.7APositivePositiveNegative20.8BPositiveNegativePositive4920.6CPositiveNegativeNegative00.0NegativePositivePositive52.1DNegativePositiveNegative00.0NegativeNegativePositive4719.7E
Citation Format: Jang Ho Cho, Sun Young Kim, Kyung Kim, Jusun Kim, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Seungtae Kim. The identification of circulating tumor cells in the cerebrospinal fluid of gastric cancer patients with brain metastasis and the evaluation of intra-patient tumor heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1173.
Abstract 1175: The establishment of single colorectal cancer organoid clones derived from regional biopsies for studying tumor heterogeneity
Authors: Song Myoung-Hyun , Ku Ja-Lok 
Published: August 2018

Abstract
Nowadays, there is a spotlight on organoid culture, which is cultivated in 3D by using specimens derived from human or another mammalian. In addition, in the process of testing and screening anticancer drugs in vitro, the limitations of 2D culture have been pointed out because homogenous culture condition does not sufficiently represent the real environment in human body. Simultaneously, there has been consensus that 3D models such as spheroids and organoids are more physiologically similar to in vivo system when compared to 2D. In fact, tumor tissue grows in 3D and in heterogenous environment including extra-cellular matrix, immune cells and various lineage of cells differentiated from stem cells. To further comprehend complex in vivo tumor development pathway, new experimental model for mimicking real three-dimensional biopsy has been required and successfully become a part of biological field. Accordingly, organoid culture technic as an emerging next generation ex-vivo model has drawn tremendous attention for its advantages in lots of experimental and therapeutic application. Thus, we have established organoid (3D) lines by isolating tumor epithelium from colon cancer patient tissue and to look into the heterogenous environment of human intestine as well as investigating sensitivity in response to various stimulations such as anti-cancer reagents treatment and irradiation (professors Seung-Yong Jeong and Ji-Won Park contributed this work). And in particular, six to eight single organoids were isolated from the primary passage in each regional biopsy. 4 tumor tissues and 6 to 8 single organoids were obtained from a patient and each biopsy, respectively. In sum, more than 30 organoid lines from one patient were established and cultured to confirm both heterogeneity among regional biopsies and single organoids derived from each biopsy. Each single organoid was successfully isolated by using micromanipulator and micropipette without contamination. Then, we confirmed whether single clones were solely isolated. Furthermore, during the process of expansion of each organoid population, we observed differences in morphology and proliferation rate among organoid lines. However, distinct mechanisms that mainly influences on the tumor heterogeneity are still not fully understood. The technic of single organoid clone isolation could give insights for further studies on investigating heterogeneity among regional tumor biopsies.
Citation Format: Myoung-Hyun Song, Ja-Lok Ku. The establishment of single colorectal cancer organoid clones derived from regional biopsies for studying tumor heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1175.
Abstract 1179: PAM50 subtype admixture in individual breast cancers and the relationship of this intratumoral heterogeneity to clinical variables
Authors: Gann Peter H. , Kumar Neeraj , Zhao Dan , Sethi Amit 
Published: August 2018

Abstract
Classification of breast cancers by PAM50 gene profiling assigns each cancer to one of five intrinsic subtypes. However, individual cancers vary in their adherence to the assigned prototype, and some may exhibit expression patterns that indicate admixture with other subtypes. The prevalence of this intratumoral heterogeneity phenomenon and the relationship of subtype admixture to clinical endpoints has not been extensively studied. We obtained microarray data on 1,460 cases from the public Gene Expression Omnibus and processed the data to normalize and log-transform expression levels and control for batch effects. For each case, we extracted levels for PAM50 genes and computed the Mahalanobis distance in multidimensional space for each case from all five centroids, including the one assigned. This metric obtains the standardized distance from a centroid for a single case while accounting for correlation between genes. We then discriminated pure from admixed cases by setting criteria for distance from the assigned centroid as well as distance from nonassigned centroids. Using the criteria that pure cases are those within the 75th percentile of distance from the assigned centroid, while being greater than the 75th percentile from any other centroid, we found that 59% of basal cases were categorized as pure, versus luminal A 31%, luminal B 35%, HER2 34% and normal 27%. We used t-Distributed Stochastic Neighbor Embedding (t-SNE) plots to visualize these admixtures in two dimensions. This confirmed that basal cancers were more heterogeneous than the other types, and that LumA, LumB and normal were more frequently admixed than other combinations. Pure LumA cases were less likely to be high-grade than LumA cases admixed with LumB, basal, HER2 or null cases not near any other centroid (18.5% vs. 7.2%, P &lt; 0.01). Pure basal cases were more likely to be high-grade than basal cases admixed with any other subtype. Kaplan-Meier curves for metastasis-free survival for pure LumA were very similar to admixed cases for the first 5 years, but then diverged, with worse survival when LumA was admixed with worse subtypes. These results support the hypothesis that subtype admixture, or at least the tendency for some breast cancers to exhibit this form of intratumoral heterogeneity, can be identified and that it should be explored for clinical consequences, including failure to respond to subtype-specific therapy.
Citation Format: Peter H. Gann, Neeraj Kumar, Dan Zhao, Amit Sethi. PAM50 subtype admixture in individual breast cancers and the relationship of this intratumoral heterogeneity to clinical variables [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1179.
Abstract 1183: Targeted sequencing of cell-free DNA data enables comprehensive profiling of tumor copy number landscape from blood
Authors: Barbacioru Catalin , Collisson Eric , Chudova Darya , Odegaard Justin , Lanman Richard , Talasaz AmirAli 
Published: August 2018

Abstract
Background: The evolution of cancer genomes within a single tumor creates mixed cell populations with divergent somatic mutational architectures. Inference of tumor subpopulations has been disproportionately focused on the assessment of somatic point mutations, whereas computational methods targeting copy number alterations (CNA) in targeted sequencing data remain underdeveloped.
Methods: Using a large database of clinical cell-free DNA (cfDNA) sequencing data (Guardant Health, CA), we developed a coverage-based probabilistic model to simultaneously normalize molecular coverage, segment the genome, predict copy number alterations, and estimate the tumor content in cfDNA samples, while accounting for mixtures of cell populations. This model was technically validated using tissue fluorescence in situ hybridization (FISH) data and then applied to a unique set of cfDNA sequencing data from &gt;5,000 normal and clinical samples spanning multiple cancer types, where model predictions were compared to the observed allelic frequencies of somatic driver mutations and heterozygous germline SNPs.
Results: Technical validation against FISH-derived tissue copy number estimates demonstrated high concordance with model estimates. Analysis of clinical samples demonstrated a wide range of copy number architectures, including prevalent copy number neutral loss-of-heterozygosity, large chromosomal deletions, and high focal amplifications, all of which are not easily detected and/or differentiated with standard sequencing analysis approaches on highly-fragmented cfDNA.
Conclusion: Our results show that probabilistic modeling of coverage data generated from targeted cfDNA sequencing can detect and differentiate heterogeneous tumor populations with diverse somatic variations, CNA, and LOH landscape. This method may enable improvements in CNA detection accuracy, sensitivity, and specificity and provides more precise interrogation of tumor fraction and clonal architecture.
Citation Format: Catalin Barbacioru, Eric Collisson, Darya Chudova, Justin Odegaard, Richard Lanman, AmirAli Talasaz. Targeted sequencing of cell-free DNA data enables comprehensive profiling of tumor copy number landscape from blood [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1183.
Abstract 1186: Intratumoral heterogeneity in small cell carcinoma of the lung: An evolutionary and ecologic process
Authors: Peacock Craig D. , Gopal Priyanka , Petty Aaron , Rogacki Kevin , Abazeed Mohamed E. 
Published: August 2018

Abstract
It is increasingly apparent that tumors represent dynamic structures in which cell populations, defined by genetic, epigenetic and non-genetic variation, compete for space and resources, while attempting to evade host defenses, resist therapeutic interventions and colonize new environments. Yet, the extent of this intratumoral genetic heterogeneity and the rules governing this ecosystem remain largely unknown. Using a large inventory of patient-derived xenograft models and an ex vivo culture system that maintains the transcriptional fidelity of the primary tumors, we have interrogated small cell lung cancer (SCLC) as a tractable model system for studying tumor evolution. In the process, we have identified at least three morphologically distinct intratumoral subpopulations across several samples: (i) suspended aggregates of small cells (neuroendocrine or NE), (ii) larger, pleomorphic cells with visible cytoplasm and spindle-like membrane extensions growing as a monolayer (mesenchymal or MS) and (iii) pre-suspension aggregates that are nested above mesenchymal-like cells (proneural or PN). Moreover, we have shown that these subpopulations are functionally distinct as measured by cellular proliferation, migration/invasion ability and sensitivity to chemotherapy/radiation. Intriguingly, distinct inter-tumoral transcriptional states assembled from earlier analyses of SCLC gene expression values across 53 and 71 cell lines and primary tumors, respectively, were preserved in the three intratumoral subpopulations within our examined SCLC lines. The proportion of each well-defined subpopulation varied across samples, suggesting sample-specific fractional setpoints. Finally, we have identified transcription factors that function as central nodes in the gene expression networks of each population and have used computational tools to nominate and functionally confirm biological processes within each population. Namely, we have shown that ASCL1 marks the rapidly proliferating NE population, NEUROD1 marks the primitive PN population and YAP1 marks the slow-growing MS population. We posit that understanding the SCLC ecosystem will provide substantial insight into its biological and clinical behavior and advance therapeutic possibilities in this recalcitrant disease.
Citation Format: Craig D. Peacock, Priyanka Gopal, Aaron Petty, Kevin Rogacki, Mohamed E. Abazeed. Intratumoral heterogeneity in small cell carcinoma of the lung: An evolutionary and ecologic process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1186.
Abstract 1204: Incidences of malignant primary soft-tissue sarcomas regardless of primary site: A nationwide population-based study in Taiwan
Authors: Hung Giun-Yi , Horng Jiun-Lin , Yen Chueh-Chuan 
Published: August 2018

Abstract
Population-based studies on soft tissue sarcomas (STS) incidence beyond extremities and trunk wall are lacking in Asia. In this study, we aimed to report the incidences of STS arise in any part of the body. The data of primary STS registered in the population-based Taiwan Cancer Registry during 2007 and 2013 was acquired via the Health and Welfare Data Science Center, Taiwan. Histologic subtype-, age-, and gender-specific STS incidence rates of all sites were analyzed. A total of 11393 subjects were identified, with an age-standardized incidence rate of 5.62 (95% CI, 5.51-5.73) per 100,000 person-years. Approximately 30% of STS occurred in soft tissues (ICD-O-3 topography codes of C47, C49), and 70% occurred in all other primary sites (ICD-O-3 topography codes of C00-C80 except C47, C49, C40 and C41). The three most common primary sites other than soft tissues were stomach (15.9%), skin (14.3%) and small intestine (10.5%). Gastrointestinal stromal tumor (GIST) was the most common subtype, accounting for 29.2% of STS, followed by liposarcoma (11.5%) and leiomyosarcoma (9.7%). For overall STS, no significant incidence trend was identified during 2007-2013. However, a significant declining trend in incidence rate of undifferentiated pleomorphic sarcoma was found (annual percentage change, APC, -7.8%). By contrast, a significant upward trend was identified in other specified sarcomas (APC, 7.3%). For the first time, this analysis demonstrated that STS incidence varied by histologic subtype, gender, age, and primary site in Asians. In the future, more population-based studies should be performed in Asians for comparison with the results from Western countries to better clarification if racial variation exists in any subtype-specific incidence rates of STS.
Citation Format: Giun-Yi Hung, Jiun-Lin Horng, Chueh-Chuan Yen. Incidences of malignant primary soft-tissue sarcomas regardless of primary site: A nationwide population-based study in Taiwan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1204.