bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5372: HER2 expression on tumor-derived extracellular vesicles and circulating tumor cells in metastatic breast cancer
Authors: Nanou Afroditi , Zeune Leonie L. , Bidard Francois-Clement , Pierga Jean-Yves , Terstappen Leon W. 
Published: September 2020

Abstract
Tumor-derived extracellular vesicles (tdEVs) and circulating tumor cells (CTCs) in blood of metastatic cancer patients associate with poor outcome. In this study, we explored the human epidermal growth factor receptor 2 (HER2) expression on CTCs and tdEVs of metastatic breast cancer patients.
Blood samples from 98 patients (IC 2006-04 study) were originally processed with the CellSearch® system using the CTC kit and anti-HER2 as an additional marker in the staining cocktail. CTCs and tdEVs were automatically enumerated from the generated CellSearch image datasets using the open-source ACCEPT software. The HER2 status of the tissue was assessed by fluorescence in situ hybridization (FISH).
The inclusion of anti-HER2 increased the percentage of informative samples with ≥1 detectable CTC and tdEV from 89% and 99% to 95 and 100%, respectively. CTCs and tdEVs were subdivided based on their cytokeratin (CK) and HER2 phenotype into CK+HER2-, CK-HER2+ and CK+HER2+. Inter- and intra- patient heterogeneity was found regarding the phenotype of CTCs and tdEVs with the majority of patients having all different subclasses present. CK- CTCs and tdEVs correlated equally well with clinical outcome as CK+ CTCs and tdEVs. Use of ≥7% HER2+CK+ tdEVs can predict HER2 expression of the tissue with 74% sensitivity and specificity, whereas the respective use of ≥23% HER2+CK+ CTCs leads to 65% sensitivity and 66% specificity.
HER2 can be detected on CTCs and tdEVs not expressing CK, which have similar clinical relevance to CTCs and tdEVs expressing CK. tdEVs perform better than CTCs in predicting the HER2 status of the tissue.
Funded by the NWO Applied and Engineering Sciences Cancer-ID project #14190, the EUFP7 CTCTrap project #305341 and the EU IMI CANCER-ID project # 115749-1.
Citation Format: Afroditi Nanou, Leonie L. Zeune, Francois-Clement Bidard, Jean-Yves Pierga, Leon W. Terstappen. HER2 expression on tumor-derived extracellular vesicles and circulating tumor cells in metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5372.
Abstract 5374: Rapid microfluidic isolation and detection of circulating tumor cells/clusters with zero sample preparation
Authors: Zhou Jian , Liu Bin , Luan Qiyue , Mallisetty Apurva , Hulbert Alicia , Papautsky Ian 
Published: September 2020

Abstract
Background: Circulating tumor cells (CTCs) and clusters of liquid biopsy permits continual access to phenotypic and genotypic landscape of primary and metastatic tumors for optimized personalized therapy. In addition, it holds the promise of deciphering the tumor heterogeneity which is one of the major sources of treatment resistance. Due to the extreme rarity of CTCs in peripheral blood, rapid and reliable isolation remains challenging amid new technologies being tested. Herein, we developed and demonstrated a novel microfluidic approach capable of direct isolation of CTCs and clusters from untreated whole blood within 20 min.
Methods: Our microfluidic approach takes advantages of the intrinsic strong cell-cell interactions when whole blood flows in a microchannel, which leads to faster lateral migration of larger cells and thus label-free isolation of CTCs based on size. Our biochip integrates cell isolation and cell immobilization units and allows processing of untreated whole blood at high throughput (2 mL in 20 min). Immobilized CTCs and clusters were subsequently characterized onchip by immunocytochemistry as CD45-, CK+ and DAPI+.
Results: Blood samples of 9 deidentified patients diagnosed with non-small-cell-lung cancer (NSCLC) were directly processed through our microfluidic biochip. 2 mL whole blood of each sample were used without pretreatment. Immunofluorescence assay identified at least 1 CTC in the blood samples from all patients (100%). CTC count ≥ 5 was found in 8/9 samples (89%). The median of CTC count was 9 per 2 mL blood. A maximum of 38 CTCs per 2 mL whole blood was found in the sample of a late stage patient. Grape-like CTC cluster was also detected in one of the nine samples (11%).
Conclusions: These “proof of concept” results suggest that our novel, label-free microfluidic technology is capable of rapid isolation and detection of CTCs and clusters directly from patient peripheral blood without sample pretreatment. It completely spares the need of costly, time-consuming and laborious sample pretreatment required by other methods. Further validation studies with cases and controls using patient lung tumor compared to the obtained CTC from our microfluidic approach are required before its implementation in the real-world practice.
Citation Format: Jian Zhou, Bin Liu, Qiyue Luan, Apurva Mallisetty, Alicia Hulbert, Ian Papautsky. Rapid microfluidic isolation and detection of circulating tumor cells/clusters with zero sample preparation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5374.
Abstract 5407: Novel imipridone combination therapies targeting oncohistone H3K27M mutant diffuse midline glioma (DMG)
Authors: Borsuk Robyn , Zhou Lanlan , Lulla Rishi , El-Deiry Wafik 
Published: September 2020

Abstract
Malignant glioma including diffuse midline glioma (DMG) is the leading cause of cancer related death in children. Recent advances in sequencing have identified the oncohistone H3K27M mutation in ~80% of pediatric DMG, which represents a target for new therapeutics. ONC201 is a first-in-class small molecule which upregulates TNF-related apoptosis inducing ligand (TRAIL) and its proapoptotic receptor DR5, independent of p53, selecting for apoptosis/growth arrest of many different tumor types including H3K27M mutant DMG. While single agent ONC201 along with RT is currently being tested in clinical trials for newly diagnosed and refractory DMG, there is an urgent need to evaluate ONC201 and other imipridone analogs in combination with other agents. Patient derived H3K27M mutant DMG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SU-DIPG-36, and SF8628), were grown in culture and exposed to imipridones (ONC201, ONC206 and ONC212) alone, and in combination with other chemotherapeutic agents that have demonstrated pre-clinical activity against DMG (HDAC inhibitors and etoposide). Response to treatment was determined by Cell Titer-Glo cell viability assays as well as Western Immunoblotting for evidence of apoptosis and integrated stress response (ISR) activation. All H3K27M-mutant DMG cell lines tested to date exhibit a dose-dependent response to imipridone therapy. Mean IC50 values were significantly lower with the imipridone analogs ONC206 (0.11 µM) and ONC212 (0.03 µM) as compared to ONC201 (1.46 µM) when used as a single agent. ONC206 and ONC212 were associated with robust induction of apoptosis evidenced by increased expression of cleaved PARP, and ISR by increased expression ATF4. In the SU-DIPG-IV cell line, combination studies of ONC201 and panobinostat demonstrated a synergistic effect of both agents, as calculated by CompuSyn software. Combination indices below one were observed at concentrations of 0.003 - 0.05 µM of panobinostat with ONC201 at 0.156 - 5 µM, with the best combination index of 0.22. We similarly observed synergy between either ONC201 or ONC206 with Etoposide. Additional combination testing and synergy analysis is ongoing and will be presented. Our findings suggest that H3K27M DMG cells demonstrate increased sensitivity to imipridones ONC206 and ONC212 as single agents and combinational strategies with HDAC inhibitors and etoposide, and provide insights into novel therapies for further clinical testing.
Citation Format: Robyn Borsuk, Lanlan Zhou, Rishi Lulla, Wafik El-Deiry. Novel imipridone combination therapies targeting oncohistone H3K27M mutant diffuse midline glioma (DMG) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5407.
Abstract 5415: Profiling cancer testis antigens in osteosarcomas
Authors: Zhang Zhongting , Wang Yifei , Zhang Wendong , Xu Zhaohui , Zhou Xin , Roth Michael , Gill Jonathan , Harrison Douglas , Hingorani Pooja , Jusu Sylvester , Kannan Sankar , Tian Xiangjun , Wang Jing , Lazcano Rossana N Segura , Lazar Alexander , Gorlick Richard 
Published: September 2020

Abstract
Cancer testis antigens (CTA) are reported to have restricted expression in placenta and testis, but they are also known to be expressed in some malignant tumors. Immunotherapy targeting CTAs in melanomas and certain types of soft tissue sarcomas have shown potential therapeutic value. However, the expression pattern of CTAs in osteosarcoma (OS) has not been fully elucidated. To characterize the CTA landscape of OS, we compared RNA sequencing data from 40 high-risk OS patients treated at MD Anderson Cancer Center and 111 OS patients available through a public online database. All of these tumor data are subsequently compared with testis/placenta and other normal tissue RNA-sequencing data from the NIH Genotype-Tissue Expression (GTEx) database as well as an online dataset which includes normal bone tissue. 53 genes that are significantly highly expressed in OS and testis/placenta (log fold change tumor versus normal &gt;1.0 for each tissue, p &lt; 0.01) are selected. Of those, 11 genes have been annotated in the Cancer Testis Database (CTdatabase) such as MAGEA3/A6 and LY6K. We also identified 42 genes that are not annotated in the CTdatabase. The co-expression pattern of CTAs in OS was also investigated by unsupervised hierarchical cluster analysis. The expression of selected CTAs was validated by IHC staining with an OS tissue microarray from 100 patients, and western blot using PDX models and patient-derived cell lines. Interestingly, the results demonstrated that multiple CTAs such as MAGEA3, LY6K and PAGE5 are also highly expressed in normal bone tissue. The current results suggest further development of immunotherapy approaches targeting CTAs in OS.
Citation Format: Zhongting Zhang, Yifei Wang, Wendong Zhang, Zhaohui Xu, Xin Zhou, Michael Roth, Jonathan Gill, Douglas Harrison, Pooja Hingorani, Sylvester Jusu, Sankar Kannan, Xiangjun Tian, Jing Wang, Rossana N Segura Lazcano, Alexander Lazar, Richard Gorlick. Profiling cancer testis antigens in osteosarcomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5415.
Abstract 5423: Multimodal prediction of diagnosis for cancers of unknown primary
Authors: Michuda Jackson , Leibowitz Benjamin , Amar-Farkash Shlomit , Bevis Crystal , Breschi Alessandra , Kapilivsky Joshuah , Igartua Catherine , Bell Joshua S. , Beauchamp Kyle A. , White Kevin , Stumpe Martin , Beaubier Nike , Taxter Timothy 
Published: September 2020

Abstract
Background: Tumors of unknown origin account for up to 5% of newly diagnosed cancers and the average survival time is 9 to 12 months from diagnosis. Establishing tumor type and subtype guides standard of care treatment for several NCCN targeted therapy guidelines.
Methods: Targeted DNA sequencing for more than 500 cancer-associated genes and exome-capture RNA sequencing was carried out in more than 25,000 fresh frozen or paraffin embedded tumor samples, including both primary and metastatic tumors. Mutations, copy number variants, and viral sequences were detected from DNA sequencing while gene expression and fusion events were determined from RNA sequencing. We aimed to predict cancer type by utilizing multiple machine learning models trained on individual data types and harmonize predictions across multiple data types.
Results: The transcriptome model predicts more than 60 unique diagnoses covering both solid and hematological cancers with &gt;90% overall accuracy on a held-out test set. Of note, the model can accurately predict 10 subtypes of sarcoma and 6 subtypes of neuroendocrine tumors. Gene expression and splicing were the most informative data types, but a performant DNA-only model was also evaluated for application when only DNA data is available. Finally, we evaluated the model on an unlabeled cohort of poorly differentiated samples with inconclusive diagnosis.
Conclusions: The incorporation of multiple modes of omics data can improve the interpretability and robustness of machine learning models to predict cancer diagnosis.
Citation Format: Jackson Michuda, Benjamin Leibowitz, Shlomit Amar-Farkash, Crystal Bevis, Alessandra Breschi, Joshuah Kapilivsky, Catherine Igartua, Joshua S. Bell, Kyle A. Beauchamp, Kevin White, Martin Stumpe, Nike Beaubier, Timothy Taxter. Multimodal prediction of diagnosis for cancers of unknown primary [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5423.
Abstract 5431: Subungual melanoma: It may be a distinct entity
Authors: Holman Blair N. , Van Gulick Robert J. , Amato Carol , Couts Kasey , Robinson William A. 
Published: September 2020

Abstract
Subungual melanoma (SUM) is a type of malignant melanoma that arises beneath the nails of the hands and feet. Subungual melanomas represent a small subset of melanoma patients and have not been well characterized by current molecular techniques. In most studies they have been included in the category of acral melanoma (AM), but there are numerous reasons to believe that they may be different. New effective melanoma treatments rely on both clinical and molecular data to select therapy. In this study, we reviewed characteristics in 29 patients with subungual melanomas seen at our institution in an attempt to provide better understanding and treatment. The median age was 56, almost equally distributed between males and females, with a higher percentage of non-Caucasians than seen in cutaneous melanoma. The most common sites were the thumb (28%), big toe (21%), and index finger (17%). Most were deep at diagnosis (mean Breslow depth 4.21 mm), and 72% had, or developed, metastases and responded poorly to therapy of all kinds. In 12 of the 29 cases, molecular testing via targeted sequencing through Foundation Medicine was done on either a primary or metastatic lesion. These 12 cases were compared to 20 cases of AM seen at our institution. One BRAF mutation was found (1/12, 4%) in SUM, whereas BRAF mutations occurred in about 20% of patients with AM. No patients with SUM had an NRAS mutation, compared to a 45% mutation rate in AM. Two SUM patients had KRAS mutations (2/12, 17%), whereas no patients with AM had a KRAS mutation. Three SUM patients had mutations in KIT (3/12, 25%) compared to one (1/20, 5%) in AM. In addition, 3 patient tumors had a recurrent variant (K587R) in the tuberous sclerosis related gene TSC-1, which has not been described in patients with AM. While our profile of subungual melanoma has some similarities with non-subungual acral melanomas, the high number of KRAS, KIT and TSC1 mutations and lack of BRAF and NRAS mutations suggests that these melanoma may have unique characteristics, different causation, and need specific therapy different from acral melanomas.
Citation Format: Blair N. Holman, Robert J. Van Gulick, Carol Amato, Kasey Couts, William A. Robinson. Subungual melanoma: It may be a distinct entity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5431.
Abstract 5434: Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract
Authors: Kim Isaac E. , Amin Ali , Wang Li Juan , Cheng Liang , Perrino Carmen M. 
Published: September 2020

Abstract
Introduction
Clinical guidelines including the American Urological Association (AUA) state that neoadjuvant chemotherapy should be administered prior to surgery in cases of muscle invasive urinary bladder small cell neuroendocrine carcinoma. Although the recently described marker insulinoma-associated protein 1 (INSM1) has been reported to be sensitive and specific for neuroendocrine differentiation in neuroendocrine tumors at several sites, its efficacy as a marker in urinary bladder small cell carcinoma has not been well established. This study aims to examine the immunohistochemical expression pattern of INSM1 on whole tissue sections of urinary bladder small cell neuroendocrine carcinoma and compare INSM1 expression to those of established markers of neuroendocrine differentiation.
Methods
Archived tissue from 32 cases of urinary bladder small cell neuroendocrine carcinoma were obtained from Rhode Island Hospital and The Miriam Hospital. Immunohistochemical stains for CD56, INSM1, synaptophysin, and chromogranin were performed. Staining was scored for intensity (0: no staining; 1: weak; 2: moderate; 3: strong) and proportion of cells stained (0: 0%; 1: &gt;0 to 25%; 2: &gt;25 to 50%; 3: &gt;50 to 75%; 4: &gt;75 to 100%).
Results
INSM1 was positive (intensity 1-3 or proportion 1-4) in 87% (28/32) of small cell neuroendocrine carcinoma cases (20 with intensity 2-3, 17 with proportion 3-4). CD56, synaptophysin, and chromogranin were positive in 75% (24/32), 60% (19/32), and 44% (14/32) of cases, respectively. While the rate of positivity was high, INSM1 was negative (n=4) or only showed weak intensity staining (n=7) in 34% (11/32) of cases.
Conclusion
INSM1 is a sensitive marker of small cell neuroendocrine differentiation of the urinary bladder. However, the findings in this study suggest that optimal utilization of INSM1 would be in a limited panel of stains rather than as a stand-alone screening marker given that it is negative or only shows weak intensity staining in a significant proportion of cases.
StainNegative [n (%)]Positive [n (%)]INSM14 (13)28 (87)CD568 (25)24 (75)Synaptophysin13 (40)19 (60)Chromogranin18 (56)14 (44)
Citation Format: Isaac E. Kim, Ali Amin, Li Juan Wang, Liang Cheng, Carmen M. Perrino. Insulinoma-associated protein 1 (INSM1) expression in small cell neuroendocrine carcinoma of the urinary tract [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5434.
Abstract 5439: Distinct genomic profile in H. pylori associated gastric cancer
Authors: Wang Ao , Bao Hua , Hu Pengfei , Wu Yong , Zhang Jinfeng , Wu Xue , Wang Xiaonan , Shao Yang 
Published: September 2020

Abstract
Background: Gastric cancer is one of the most common and deadly cancer types. Currently 4 subtypes have been identified with unique molecular alterations: Epstein-Barr virus (EBV)-positive, microsatellite instability (MSI), chromosomal instability (CIN), and genomic stable (GS) tumors. However, many gastric tumors are associated with the bacterium Helicobacter pylori but the genomic landscape of this subgroup of tumors remains largely unknown.
Methods: Targeted-sequencing covering 425 genes were performed retrospectively on 1759 gastric tumor tissues and matched normal blood samples. The mean sequencing depth of tumors was 1159X. Nonsynonymous mutations, copy-number variation (CNV) and MSI status were called from human DNA reads; non-human DNA reads were mapped to NCBI microbial reference genome using Kraken and significant species were identified.
Results: Overall, 37 (2.67%) samples were EBV-positive, 200 (11.37%) samples were H. pylori-positive, and 10 (0.57%) samples were positive for both. Other notable species identified in tumor samples were E. coli and C. acnes. No bacteria or viral reads were found in normal blood. Among the rest, 59 (3.35%) samples were MSI, 380 (21.6%) were CIN, and 1017 (57.82%) were GS. H. pylori-positive samples tend to be GS (85.5%, p &lt; 0.001) and microsatellite stable (95%, p = 0.04). The most common mutations identified in H. pylori-positive tumors were TP53 (47%), CDH1 (12%) and ARID1A (8.5%). The top CNV events were amplification in MCL1 (14.5%), TERC (9%), CCNE1 (8.5%), PTPRD (8.5%), and MYC (7.5%). Compared to other GS tumors, mutation in AKT3 (p = 0.002) and amplification of TERC (p = 0.008) as well as MCL1 (p = 0.0.029) were significantly enriched in H. pylori-positive tumors. There was no difference in patients' sex or age among subtypes (p &gt;= 0.05).
Conclusion: This study characterized the genomic landscape of H. pylori positive gastric tumors using targeted-sequencing, which allowed direct comparison with other subtypes of gastric cancer. Identification of DNA reads from infectious agents in the tumor samples indicates that deep sequencing platform has promising utility in uncovering the characteristics of microbial environment of tumor. Co-infection between H. pylori and EBV occurred at a low frequency. H. pylori-positive tumors were GS and microsatellite stable with unique molecular features. Future study examining difference in treatment response among these subtypes of gastric cancer are warranted.
Citation Format: Ao Wang, Hua Bao, Pengfei Hu, Yong Wu, Jinfeng Zhang, Xue Wu, Xiaonan Wang, Yang Shao. Distinct genomic profile in H. pylori associated gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5439.