bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 604: Metabolomics in predicting breast cancer treatment responses
Authors: Barcha Carolina Puyana , Lee Eunkyung , Takita Cristiane , Wright Jean L. , Hu Jennifer 
Published: August 2018

Abstract
Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in American women. Postoperative adjuvant radiotherapy (RT) significantly improve local-regional recurrence and survival. Therefore, there has been increasing usage of adjuvant RT in early-stage breast cancer patients. Although well tolerated by some patients, 48% patients in our study experience RT-induced early adverse skin reactions (EASRs) that negatively impact quality of life. Therefore, we evaluated urine metabolomics in predicting RT-induced EASRs and precision intervention. Based on the pilot data of 478 metabolites in 60 patients, we used the MetaboAnalyst 3.0 (www.metaboanalyst.ca) to conduct metabolomic data analysis, visualization and interpretation. Using KEGG pathway analysis, we have identified 7 pathways that are significantly associated with RT-induced EASRs (i.e., False Discovery Rate (FDR) p less than 0.05). The alanine, aspartate and glutamate metabolism pathway has the most significant FDR p-value and the highest impact value of 0.60 in predicting RT-induced EASRs. In summary, to the best of our knowledge, this is the first study in breast cancer patients associating glutamate metabolism pathway to RT-induced EASRs. Our research will have significant clinical impact because: (i) many tumor cells depend on glutamine-glutamate as energy source for growth and survival, (ii) breast cancer cells secrete high levels of glutamate often metastasize to bone with severe pain issue, (iii) glutaminase inhibitors enhance chemotherapy in triple negative breast cancer, (iv) two thirds of cancer patients receive RT, and (v) glutamate metabolism is associated with RT-induced EASRs. With increasing recent interest in targeting tumor metabolism, we anticipate that glutaminase inhibitors will also have application in preventing RT-induced EASRs in addition to their anticancer activities in triggering metabolic crisis in tumor cells and enhancing chemotherapy.
Citation Format: Carolina Puyana Barcha, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Jennifer Hu. Metabolomics in predicting breast cancer treatment responses [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 604.
Abstract 629: Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments
Authors: Tavernier Jan H. , Cauwels Anje , Lint Sandra Van , Paul Franciane , Garcin Geneviève , Parys Alexander Van , Kley Nikolai , Uzé Gilles 
Published: August 2018

Abstract
An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I interferon (IFN), for instance, has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its optimal clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1000-fold more potent on target cells, allowing specific signaling in selected cell types only. As conventional Dendritic Cells (cDC) are essential for IFN antitumor efficacy, we targeted type I IFN-derived “AcTaferon (AFN)” to Clec9A+ cDC. Clec9A-AFN therapy displayed strong antitumor activity in murine melanoma (B16), breast carcinoma (4T1) and lymphoma models (A20), as well as against human RL lymphoma in immunodeficient NSG mice reconstituted with a human immune system. In sharp contrast to wild-type IFN therapy, the antitumor efficacy of Clec9A-AFN was not accompanied by any detectable toxicity, assessed by body weight and several hematological parameters. Clec9A-AFN effects were lost in CD8-depleted or Batf3-/- mice, and depended on IFN signaling in cDCs but not in T lymphocytes. Combined with α-PDL1 immune checkpoint blockade, Treg-depleting anti-CTLA4 + anti-OX40 therapy, immunogenic chemotherapy, or low-dose TNF, complete tumor regressions and long-lasting tumor immunity (memory) were obtained, still without any adverse effects. Our findings thus indicate that DC-targeted AFN provides a highly efficient, off-the-shelf and safe cancer immunotherapy, with possible application in a broad range of malignancies.
Citation Format: Jan H. Tavernier, Anje Cauwels, Sandra Van Lint, Franciane Paul, Geneviève Garcin, Alexander Van Parys, Nikolai Kley, Gilles Uzé. Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments [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 629.
Abstract 633: Application of a novel analytical metric that quantifies copy number alterations in low-coverage, genome-wide sequencing of cell-free DNA to monitor and differentiate response to immunotherapy in cancer patients
Authors: Jensen Taylor J. , Goodman Aaron M. , Ellison Christopher K. , Kato Shumei , Daniels Gregory A. , Tran Lisa , Nakashe Prachi , McCarthy Erin , Mazloom Amin R. , McLennan Graham , Grosu Daniel S. , Ehrich Mathias , Kurzrock Razelle 
Published: August 2018

Abstract
Inhibitors of the PD-1/PD-L1/CTLA4 immune checkpoint pathway have transformed the cancer treatment paradigm. It has been observed that even some patients with advanced, refractory malignancies achieve durable responses; however, only a minority of patients benefit, demonstrating the importance of developing new biomarkers to predict patient outcome. The most commonly used biomarkers for predicting response to checkpoint inhibitors are the expression of PD-1/PD-L1, microsatellite instability, and tumor mutational burden. While these markers have been shown to have varying degrees of predictive power, they have not been used to monitor and differentiate response during treatment and require invasive procedures. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising noninvasive method for monitoring response. We describe the use of low-coverage (~0.3X) genome-wide sequencing of cfDNA, validated extensively for detecting chromosomal abnormalities in non-invasive prenatal testing (NIPT) and previously shown to enable incidental detection of occult maternal malignancies, to detect tumor-specific copy number alterations; and the development of a new metric–the genome instability number (GIN)–to monitor response to these drugs. Using a series of more than 450 plasma aliquots taken from more than 75 patients throughout their treatment, we demonstrate how the GIN can be used to discriminate clinical response from progression, differentiate progression from pseudoprogression, and identify hyperprogressive disease, as early as 4-6 weeks after treatment initiation. Finally, we provide evidence for a delayed therapeutic response to checkpoint inhibitors relative to targeted therapies. While this study is still ongoing, these initial data provide proof of concept for using this method for monitoring treatment outcome in cancer patients receiving immunotherapy.
Citation Format: Taylor J. Jensen, Aaron M. Goodman, Christopher K. Ellison, Shumei Kato, Gregory A. Daniels, Lisa Tran, Prachi Nakashe, Erin McCarthy, Amin R. Mazloom, Graham McLennan, Daniel S. Grosu, Mathias Ehrich, Razelle Kurzrock. Application of a novel analytical metric that quantifies copy number alterations in low-coverage, genome-wide sequencing of cell-free DNA to monitor and differentiate response to immunotherapy in cancer patients [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 633.
Abstract 64: Macrophage perceive tumor-intrinsic glutamine metabolism and orchestrate immunosuppression through IL-23 inclear cell renal cell carcinoma
Authors: Fu Qiang 
Published: August 2018

Abstract
The signaling mechanisms between renal cancer cell metabolism and infiltrating immune cells may illuminate novel therapeutic approaches. Here, we showed the idiomatic glutamine metabolism of clear cell renal cell carcinoma (ccRCC) suppress immune surveillance through nonautonomous IL-23. Through analyzing multiple ccRCC clinical cohorts and human tumor samples, we uncovered SLC1A5 (solute carrier family 1 member 5) promotes ccRCC consumption of extrinsic glutamine, predicts patient prognostication, and associates with reduction of cytotoxic T cells and NK cells in the tumor microenvironment. Specifically, the immune surveillance suppression of tumor-intrinsic SLC1A5 is considerably conducted by IL-23, which could directly induce intratumoral accumulation of T helper 17 cells and regulatory T cells. Intriguingly, we identified macrophages as the major source of intratumoral IL-23, and macrophages secrete large amount of IL23 under low glutamine condition, as the consequence of tumor-driven glutamine consumption. Furthermore, blocking IL-23 using specific antibody in syngeneic mice tumor model prolonged their survival, and blocking IL-23 in an in vitro culture model of human tumors promote anti-tumoral T and NK cells reaction. Our results demonstrate that macrophage-secreting IL-23 is a key immune effector as the response to tumor-driving glutamine metabolism, and IL-23 profoundly facilitate an immunosuppressive microenvironment which suggest it as a promising target for cancer immunotherapy in ccRCC.
Citation Format: Qiang Fu. Macrophage perceive tumor-intrinsic glutamine metabolism and orchestrate immunosuppression through IL-23 inclear cell renal cell carcinoma [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 64.
Abstract 648: Digital PCR in genetic diagnosis of NUT midline carcinoma
Authors: Okumura Shunsuke , Chiba Shin-ichi , Sado Masatoshi , Takahashi Nana , Sasaki Takaaki , Kitada Masahiro , Ohsaki Yoshinobu 
Published: August 2018

Abstract
Background; NUT midline carcinoma (NMC) is a rare, highly aggressive tumor with t(15;19) translocation involving NUT midline carcinoma family member 1 (NUTM1) gene. NMC is genetically defined and diagnosed by RNA sequencing or by immunohistochemistry for NUT protein expression instead. However, it can be challenging to perform these assays on small biopsy specimens. We, here, report the utility of digital PCR (dPCR) assay for diagnosis of NMC. Methods; The QuantStudio 3D dPCR system (Thermo Fisher Scientific) was used. We designed optimal dPCR probes for the BRD4-NUT fusion gene and evaluated the dPCR method using NMC cell lines (HCC2429 and Ty82) and clinical samples. Total RNA was extracted from the cell lines and FFPE tissue samples from patients with thoracic tumors (RecoverAll total nucleic acid isolation kit, Thermo Fisher Scientific). cDNA was synthesized with SuperScript VILO cDNA kit (Thermo Fisher Scientific). PCR was performed using ProFlex PCR system (Thermo Fisher Scientific). Data was analyzed with QuantStudio 3D AnalysisSuite Cloud Software (Thermo Fisher Scientific). Results; We identified the BRD4-NUT fusion gene in HCC2429 and Ty82 cells using the dPCR system, which allowed us to detect the fusion gene at a prevalence &lt; 0.1%. The fusion genes were detected in the clinical samples, and we successfully found NMC patients using the dPCR assay. Conclusion; We conclude the dPCR assay is an appropriate method for diagnosis of NMC.
Citation Format: Shunsuke Okumura, Shin-ichi Chiba, Masatoshi Sado, Nana Takahashi, Takaaki Sasaki, Masahiro Kitada, Yoshinobu Ohsaki. Digital PCR in genetic diagnosis of NUT midline carcinoma [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 648.
Abstract 649: Development of a novel RNA sequencing approach that identifies aberrant splicing in cancer predisposing genes
Authors: Jansen Anne M. , Klift Heleen M. van der , Eendenburg Jaap D. van , Tops Carli M. , Wijnen Juul T. , Hes Frederik J. , Goel Ajay , Morreau Hans , Wezel Tom van 
Published: August 2018

Abstract
Background: High-throughput sequencing efforts in molecular tumor diagnostics detect increased numbers of novel genetic variants, including the ones that are predicted to affect splicing. Current approach for predicting whether a specific variant may result in aberrant RNA transcripts often consists of in-silico prediction using bioinformatics prediction tools, which is sometimes followed by RT-PCR analysis of the RNA extracted from blood, or functional splicing reporter assays. Although high-quality patient RNA analysis is usually preferred, such RNA is not always available, or the analysis is hampered due to degradation of aberrant transcripts through nonsense-mediated decay. To overcome this issue, we investigated the possibility of analyzing RNA isolated from formalin-fixed paraffin-embedded (FFPE) tissues, with the underlying hypothesis that formalin fixation may inhibit RNA degradation, enabling the detection of aberrant RNA products. Methods: RNA analysis was performed for 13 canonical splice site variants predicted or known to affect splicing in the cancer predisposition genes MLH1, MSH2, MSH6, APC and BRCA1. Of 11 variants, total nucleic acid was obtained from FFPE tumor tissues. For two variants, no FFPE material was available, but EBV-transformed B-cells carrying a splice variant were cultured. Primers were designed to amplify the exon-exon boundary predicted to be affected. Housekeeping gene expression was assessed to determine presence of RNA. Results: Total nucleic acid was successfully isolated for 10 variants from eight FFPE tumor tissues and two EBV-transformed B-cell lines. Aberrant splicing was confirmed in all six variants known to result in splicing. Of one known splice variant, present in the B-cell line, the known aberrant splice product could only be detected after formalin fixation of the cells, suggesting that formalin fixation possibly inhibited RNA degradation. Conclusion: Aberrant splicing was successfully identified in all known splice variants and three of four variants predicted to affect splicing, of which the splice effect was previously unknown. Using a RNA sequencing approach, somatic splice variants could be easily and rapidly analyzed, enabling retrospective analysis of variants predicted to result in splicing when only FFPE material is available in clinical settings.
Citation Format: Anne M. Jansen, Heleen M. van der Klift, Jaap D. van Eendenburg, Carli M. Tops, Juul T. Wijnen, Frederik J. Hes, Ajay Goel, Hans Morreau, Tom van Wezel. Development of a novel RNA sequencing approach that identifies aberrant splicing in cancer predisposing genes [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 649.
Abstract 65: Impact of tumor-infiltrating dendritic cells in esophageal squamous cell carcinoma treated with neoadjuvant chemotherapy
Authors: Nishimura Junya , Tanaka Hiroaki , Yamakoshi Yoshihito , Hiramatsu Soichiro , Tamura Tatsuro , Toyokawa Takahiro , Muguruma Kazuya , Hirakawa Kosei , Ohira Masaichi 
Published: August 2018

Abstract
Background: Tumor-infiltrating CD8+T cells have been found to be associated with favorable outcome of patients in many cancers including esophageal squamous cell carcinoma (ESCC). Dendritic cells (DCs) are the most potent antigen-presenting cells to induce CD8+T cells. Several investigators have shown that tumor infiltrating mature DCs (mDCs) were associated with favorable prognosis of cancer patients. We showed that mDCs were associated with favorable prognosis of ESCC patients who had not received preoperative treatment. Neoadjuvant chemotherapy (NAC) is the standard treatment for Stage II/ III thoracic esophageal carcinoma in Japan. The effect of chemotherapy on tumor infiltrating DCs remains unclear.
Purpose: The aim of this study was to examine the correlation of efficacy of NAC and locally infiltrating DCs in ESCC patients.
Object and Methods: Formalin-fixed, paraffin-embedded blocks of primary lesions were collected from 50 patients with ESCC who underwent surgical treatment after NAC at Osaka City University Hospital. Immunohistochemical analysis using anti-LAMP-3 antibody and CD8 antibody was used to evaluate tumor infiltrating DCs and CD8+T cells. The number of LAMP-3+DCs and CD8+T cells were counted at ×400 magnification. We divided the 50 cases into two groups according to the median number of tumor infiltrating DCs and CD8+T cells to examine the correlation of efficacy of NAC and locally infiltrating DCs.
Results: LAMP-3+DCs were predominantly observed in peritumoral area and sparsely found in intratumoral area, whereas CD8+T cells distributed between both peritumoral and intratumoral areas. LAMP-3+DCs infiltrated the peritumoral space from 0 to 19.0 (median 6.0) and the intratumoral space from 0 to 3.8 (median 0.0). Patients with histological effect (≧Grade 1a) had higher infiltration of mDCs than Grade 0. Patients with high infiltration of mDCs had better prognosis than those with low. The number of mDCs had positive correlation with the number of tumor infiltrating CD8+T cells.
Conclusions: Our results suggested that increase of tumor infiltrating mDCs was associated with histological effect of NAC and favorable prognosis in ESCC.
Citation Format: Junya Nishimura, Hiroaki Tanaka, Yoshihito Yamakoshi, Soichiro Hiramatsu, Tatsuro Tamura, Takahiro Toyokawa, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Impact of tumor-infiltrating dendritic cells in esophageal squamous cell carcinoma treated with neoadjuvant chemotherapy [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 65.
Abstract 660: Integration of radiomics with "omic" analyses to predict survival in newly diagnosed IDH-1 wild-type glioblastoma
Authors: Daniel Paul M. 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most commonly diagnosed glioma and has the poorest median survival of all brain tumours at only 14 months. Despite intensive characterisation of this disease through ‘omic' investigations which has led to the identification of critical molecular drivers of malignancy, only a limited selection of biomarkers have proven to be clinically relevant in predicting patient survival. One reason for this lack of success is the existence of intratumoural heterogeneity, where individual tumours can harbour spatially separated molecular and phenotypic diversity, thereby limiting the insight which ‘omic' analysis of small biopsy specimens can impart. Radiomics involves high-throughput mining of quantitative image features via image acquisition, region of interest segmentation and feature extraction from standard MRI scans and relating extracted feature values to molecular, phenotypic and clinical properties. Notably, radiomics derives features from the whole tumour mass and therefore overcomes limitations associated with intratumoural heterogeneity. As such, we sought to investigate the ability for radiomics to describe tumour characteristics and integrate radiomics alongside genomics and transcriptomics to derive a prognostic model for IDH1 wild-type GBM. We observed 2 radiomic clusters in IDH1-wild-type GBM which each had an equivalent distribution of each of the four molecular subtypes. Whilst radiomic clusters themselves were not predictive of survival, three radiomic features were able to separate patients into long and short survival groups. Integration of genomic and transcriptomic features alongside radiomic analysis increased the predictive strength of our model. Finally, we found an association between longer survival in patients with IDH1 wild-type GBM and increased expression of the complement system. Our observations suggest that integration of radiomics alongside ‘omic' investigations offer a greater ability to predict survival in IDH1 wild-type GBM and suggests a role for the innate immune system in driving patient outcome.
Citation Format: Paul M. Daniel. Integration of radiomics with "omic" analyses to predict survival in newly diagnosed IDH-1 wild-type glioblastoma [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 660.
Abstract 662: IMA_Detect: Mass spectrometry guided development and clinical application of a companion diagnostic for adoptive cellular therapy against tumor associated HLA peptides
Authors: Fritsche Jens , Satelli Arun , Hörzer Helen , Rakitsch Barbara , Hoffgaard Franziska , Hilf Norbert , Schoor Oliver , Singh-Jasuja Harpreet , Toni Weinschenk 
Published: August 2018

Abstract
Adoptive cellular therapy (ACT) has dramatically changed the landscape of cancer immunotherapy. ACTolog® and ACTengine® are actively personalized ACT approaches employing T-cell receptor products based on a warehouse of human leucocyte antigen (HLA)-bound peptide targets. Selecting the relevant target candidates requires the establishment of biomarkers predictive for HLA peptide presentation and their development into companion diagnostic devices.
Here we describe the development of IMA_Detect, a diagnostic test based on gene expression analysis of primary patient tumor material by qPCR which is predictive for presentation of a target peptide by HLA. To establish mRNA expression levels which indicate actual peptide presentation, data of Immatics' XPRESIDENT® target discovery platform was used by integrating quantitative immunopeptidomics data (label-free LC-MS) with paired transcriptomics data (RNA-Seq). The peptide-specific correlation between peptide presentation and expression of the coding exons was verified for each target individually. The resulting RNA-Seq thresholds were mapped to qPCR thresholds using calibration curves followed by validation of the qPCR assay.
The IMA_Detect test is performed in a CLIA/CAP approved setting and is currently being applied in the phase I ACT trials IMA101-101 and IMA201-101 to determine whether a patient's tumor expresses any of the tested targets at levels considered sufficient for potential benefit from the administered T-cell therapy. IMA101-101 uses autologous T-cell products (ACTolog®) for patients with solid cancers while IMA201-101 is based on TCR-engineered T Cells (ACTengine®) in NSCLC and HNSCC patients. We will present first results of the patient screening and the personalized target selection.
Citation Format: Jens Fritsche, Arun Satelli, Helen Hörzer, Barbara Rakitsch, Franziska Hoffgaard, Norbert Hilf, Oliver Schoor, Harpreet Singh-Jasuja, Weinschenk Toni. IMA_Detect: Mass spectrometry guided development and clinical application of a companion diagnostic for adoptive cellular therapy against tumor associated HLA peptides [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 662.