bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA39: Explaining the obesity paradox in cancer: The role of muscle
Authors: Caan Bette 
Published: February 2019

Abstract
Although overweight and obesity, assessed by body mass index (BMI), are reliably related to an increased risk of cancer, data on the relationship between BMI and cancer prognosis are inconsistent. An emerging literature suggests that the relationship between BMI and cancer survival is often U-shaped and that overweight, and in some cases mild obesity, may not increase risk and might even offer protection. This is termed the “obesity paradox” and has been demonstrated in patients with lymphoma, leukemia, colorectal, endometrial, thyroid, and renal cancers.
Reasons provided to explain the obesity paradox in cancer include methodologic biases such as reverse causality, confounding, detection bias, or collider bias. Yet others posit that the association reflects true benefits of a higher BMI, including extra nutritional reserves, greater muscle mass, a lower likelihood of dose-limiting toxicity, and less aggressive tumors, each of which may be independently associated with better prognosis.
We will present evidence of the obesity paradox in breast and colorectal cancer. We will also present data on the importance of adequate muscle reserves to optimal cancer outcomes and explain how muscle may explain the U-shaped relationship between BMI and survival in these cancers. We will show that BMI is not an accurate measure of either adiposity or muscle, especially among cancer survivors. We will illustrate that when BMI is used to measure body size, an obesity paradox can emerge because “overweight” patients often have higher levels of protective muscle but lack adiposity levels sufficient to increase their risk of mortality.
Citation Format: Bette Caan. Explaining the obesity paradox in cancer: The role of muscle [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA39.
Abstract A12: Non-small cell lung tumor-derived autoantibodies can distinguish benign from malignant pulmonary nodules
Authors: Lastwika Kristin J. , Kargl Julia , Zhang Yuzheng , Zhu Xiaodong , Shelley David , Lo Edward , Wu Wei , Pipavath Sudhakar N. , Kinahan Paul E. , Houghton A. McGarry , Lampe Paul D. 
Published: February 2019

Abstract
High-risk smokers are currently being screened with low-dose CT imaging after the National Lung Screening Trial demonstrated a 20% reduction in lung cancer mortality. Unfortunately, small pulmonary nodules are a common finding in smokers (present in 25-50%), with very few (&lt;2.5%) nodules ultimately determined to be cancer. We observed a 4-fold increase in lung tumor-associated B cells compared to normal lung and hypothesized that lung-tumor derived autoantibodies could be useful biomarkers for malignant nodule diagnosis. We first discovered 13 IgG or IgM autoantibodies found in both non-small cell lung tumor and peripheral plasma (n=10) on a large (~17,000) protein array. These autoantibodies were predominantly absent in plasma from patients with benign nodules (n=10). In the plasma from an expanded nodule positive cohort (n=250) we validated 3/13 autoantibodies on a targeted protein array and 5/13 autoantibodies on a high-density antibody array. By using both antibody arrays (to measure antigen-autoantibody complexes) and protein arrays (to measure free autoantibody), we obtained a comprehensive picture of malignant nodule-associated autoantibodies. When we combine our top two autoantibodies (one free and one complexed with antigen) with two features from CT images, they yield an AUC = 0.92 (72% sensitivity at 90% specificity). These observations indicate that our noninvasive autoantibody biomarkers can increase the diagnostic accuracy of pulmonary nodules identified by CT imaging.
Citation Format: Kristin J. Lastwika, Julia Kargl, Yuzheng Zhang, Xiaodong Zhu, David Shelley, Edward Lo, Wei Wu, Sudhakar N. Pipavath, Paul E. Kinahan, A. McGarry Houghton, Paul D. Lampe. Non-small cell lung tumor-derived autoantibodies can distinguish benign from malignant pulmonary nodules [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A12.
Abstract A18: Diagnostic and prognostic utility of urinary creatine riboside for early stage non-small cell lung cancer
Authors: Oike Takahiro , Kanke Yasuyuki , Parker Amelia , Haznadar Majda , Krausz Kristopher W. , Bowman Elise D. , Robles Ana I. , Gonzalez Frank J. , Harris Curtis C. 
Published: February 2019

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR02) of the Conference Proceedings.
Citation Format: Takahiro Oike, Yasuyuki Kanke, Amelia Parker, Majda Haznadar, Kristopher W. Krausz, Elise D. Bowman, Ana I. Robles, Frank J. Gonzalez, Curtis C. Harris. Diagnostic and prognostic utility of urinary creatine riboside for early stage non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A18.
Abstract B05: Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma
Authors: Chung Chaeuk , Lee Daehye 
Published: February 2019

Abstract
Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered the most important medical breakthroughs in lung cancer treatment. Nowadays, third-generation EGFR TKI is widely used for T790M positive first and second EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy-resistant patients. It also has changed the concept of conventional anticancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung
Citation Format: Chaeuk Chung, Daehye Lee. Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B05.
Abstract B06: Targeted radiopeptide therapy re188-P2045 to treat neuroendocrine lung cancer
Authors: Adams Chris , Shinto Ajit , Saif Wasif 
Published: February 2019

Abstract
Background: Despite the recent success of checkpoint inhibitors, there continues to be a significant medical need for lung cancer therapies that can be directed to the patients most likely to respond. Somatostatin receptor subtype 2 (SSTR2) is the most widely upregulated subtype in both small and non-small cell lung cancers and is also expressed in tumoral (but not mature) blood vessels. Peptide-targeted radiotherapy has advantages over traditional targeted therapies in that targeted tumor cells as well as surrounding cancer cells and supporting stroma are selectively killed. This study was conducted to determine the ability of Rhenium Re 188 P2045, a radiolabeled somatostatin analog specific for SSTR2 to both image (to select the most appropriate patients) and treat lung and neuroendocrine cancer patients who overexpress somatostatin receptors.
Methods: In an open-label, single-arm study, refractory lung cancer and metastatic neuroendocrine patients to standard-of-care therapy were identified by image analysis using Rhenium Re 188 P2045, a radiolabeled somatostatin analog. Twenty-five patients received the imaging dose of 10uCi of Re188 and 265ng of peptide by intravenous injection. Three patients were selected based on high SSTR expression levels to receive 30uCi of Re188 P2045 as a therapeutic dose 14 days after imaging. Patients were followed for 8 weeks post treatment.
Results: The imaging study revealed a high density of expression of the somatostatin receptor in the lungs of patients. Patients in the imaging and therapeutic treatment groups reported no adverse advents or signs of toxicity. The image analysis using Re188 P2045 was compared to CT images and demonstrated accurate detection of lung and neuroendocrine tumor lesions. The patients who received R188 P2045 at the therapeutic dose had a 25% reduction in tumor mass based on image analysis versus typical results of stable disease from standard of care. The images obtained using Re188 P2045 were of sufficiently high quality to enable identification of receptor expression at the tumor site as shown in Figures 1 and 2 (figures not available).
Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung and neuroendocrine cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach, and this highly targeted patient therapy may significantly improve treatment of tumors that overexpress somatostatin receptors.
Citation Format: Chris Adams, Ajit Shinto, Wasif Saif. Targeted radiopeptide therapy re188-P2045 to treat neuroendocrine lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B06.
Abstract B09: Evaluating transcription factor networks as targets for the treatment of small cell lung cancer
Authors: Pozo Karine , Kollipara Rahul K. , Minna John D. , Gazdar Adi F. , Johnson Jane E. 
Published: February 2019

Abstract
Achaete-scute homolog 1 (ASCL1) is a transcription factor that is highly expressed in most small cell lung cancer (SCLC) tumors and cell lines and is critical for their proliferation. Inhibiting ASCL1 transcriptional activity may thus be a valid therapeutic strategy for SCLC. However, transcription factors (TFs) have been historically difficult to target. Given that TFs belong to complex regulatory networks, we propose to identify and target multiple components within an ASCL1-transcriptional network rather than ASCL1 alone. We have previously detected ASCL1-bound genomic regions associated with the active chromatin epigenetic mark, H3K27Ac in SCLC cells. Here we report the identification of an ASCL1-containing transcriptional network in SCLC cells and evaluate its targeting by the transcriptional inhibitor, mithramycin. We conducted chromatin immunoprecipitation (ChIP) by immunoprecipitating the H3K27Ac chromatin mark from NCI-H2107 and NCI-H69 SCLCs (5X107 cells) nuclear lysates with10 μg H3K27Ac antibodies (Abcam-Ab4729), and sequenced ChIP libraries on an Illumina High-Seq2000. Further characterization using siRNA transfections, immunoblotting and MTS-cell proliferation assays were conducted following standard procedures. We found 82 overlapping TF genes, including lineage-specific TF genes for ASCL1, Forkhead box protein A2 (FOXA2), and nuclear factor 1 B-type (NFIB), associated with the active chromatin epigenetic marks H3K27Ac in SCLC cell lines. This suggests that ASCL1, FOXA2, and NFIB may belong to the same transcriptional network. siRNA-mediated knockdown of ASCL1 leads to decreased FOXA2 levels, but it has no effect on NFIB levels, implicating ASCL1 as a transcriptional regulator of FOXA2 but not NFIB. Mithramycin stops cell proliferation and reduces ASCL1, FOXA2 but not NFIB protein levels. In conclusion, our studies identify the beginning of a transcriptional network necessary for SCLC proliferation in which ASCL1 regulates FOXA2. Targeting multiple TFs within a network with mithramycin can stop cell proliferation and as such suggests a therapeutic strategy for SCLC. Because of the importance of NFIB in mediating metastatic behavior of SCLC, these data indicate that approaches other than targeting ASCL1 and use of mithramycin will be needed to target NFIB.
Citation Format: Karine Pozo, Rahul K. Kollipara, John D. Minna, Adi F. Gazdar, Jane E. Johnson. Evaluating transcription factor networks as targets for the treatment of small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B09.
Abstract IA24: Are tumors predictable? Inherited immune variation constrains tumor evolution
Authors: Marty Rachel , Kaabinejadian Saghar , Rossel David , Slifker Michael J. , Haar Joris Van de , Engin Hattice Billur , Prisco Nicola de , Ideker Trey , Hildebrand William H. , Font-Burgada Joan , Carter Hannah 
Published: February 2019

Abstract
Recent studies have characterized the extensive somatic alterations that arise during cancer, and various studies have probed rare inherited mutations that lead to early-onset cancer syndromes. However, little is understood about the role of genetic background in “sporadic” adulthood cancers. The somatic evolution of a tumor may be significantly affected by inherited polymorphisms carried in the germline. The region encoding the Major Histocompatibility Complex Class I (MHC-I) is one of the most variable regions in the human population. MHC-I is a molecule that exposes the intracellular protein content of a cell on the cell surface, allowing T cells to detect mutated or foreign peptides. Each individual carries six MHC-I alleles that define the set of peptides that can be effectively presented for immune surveillance. We hypothesized that individual variation in MHC-I could create personal gaps in immune surveillance, generating individual-specific susceptibility for cells to acquire specific oncogenic mutations. We tested this hypothesis through the development and application of a residue-centric patient presentation score to 1,018 recurrent oncogenic mutations in 9,176 cancer patients. This analysis found that cancer-causing mutations were more likely to be observed when a patient’s genotype-based scores suggested poor MHC-I based presentation of those mutations. Mutations that were poorly presented by most patients were also more likely to reach high frequency among tumors. Thus the landscape of oncogenic mutations observed in clinically diagnosed tumors is shaped by MHC-I genotype-restricted immunoediting during tumor formation, and individual MHC-I genotype provides information about the mutations likely to emerge in tumors that develop later in life.
Citation Format: Rachel Marty, Saghar Kaabinejadian, David Rossel, Michael J. Slifker, Joris Van de Haar, Hattice Billur Engin, Nicola de Prisco, Trey Ideker, William H. Hildebrand, Joan Font-Burgada, Hannah Carter. Are tumors predictable? Inherited immune variation constrains tumor evolution [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA24.
Abstract IA29: Circulating Tumor Cells: A liquid biopsy for SCLC with multiple applications
Authors: Dive Caroline 
Published: February 2019

Abstract
Circulating Tumor Cells (CTCs) are relatively prevalent in SCLC compared to other tumor types and present several research opportunities in a disease where tumor biopsy is challenging, and notably so when repeated sampling is required.
Pre-treatment CTC number by the CellSearch platform (CS-CTCs) is prognostic for overall survival and in most patients decreases significantly after cycle 1 of platinum-based chemotherapy. The prevalence and wide dynamic range of CS-CTC numbers makes them an ideal pharmacodynamic biomarker, and their prevalence affords assay development and implementation as a predictive biomarker in upcoming trials of novel treatments. Recently we showed that chemotherapy response could be predicted via single CTC sequencing to generate a CTC copy number signature (Carter et al., Nat Med 2017).
SCLC patients’ CTCs are also highly tumorigenic in immune-compromised mice (Hodgkinson et al., Nat Med 2014). CDX mirror patient tumor histology and chemotherapy response. The resultant CTC-derived explant models (CDX) can be generated not only at baseline but also from the same patient at disease progression, allowing studies of the almost universal acquired chemotherapy resistance and insights into the rapid evolution of this dismal disease. CDX are used for therapy testing and biomarker development that can be translated to CTC-based biomarkers in the clinic. CDX allow exploration of SCLC biology as we recently exemplified by the identification of vasculogenic mimicry and its likely role in metastasis (Williamson et al., Nat Commun 2016). CDX tumors can be disaggregated and propagated in culture for more rapid treatment screening and can be genetically manipulated for function testing hypotheses ex vivo and in vivo. Finally, SCLC CTCs can now be cultured directly from the patient sample, offering the potential for real-time treatment testing. In summary, SCLC CTC research can now make a valuable contribution to the worldwide efforts to molecularly profile this recalcitrant tumor at all stages of disease progression and to discover, develop, and implement new treatments for much-needed improved patient outcomes.
Citation Format: Caroline Dive. Circulating Tumor Cells: A liquid biopsy for SCLC with multiple applications [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA29.
Abstract A008: Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update
Authors: Gupta Shilpa , Weight Christopher J. , Agarwal Neeraj , Gupta Sumati , Konety Badrinath , Gibb Ewan , Davicioni Elai , Thyagarajan Bharat , Sonpavde Guru 
Published: February 2019

Abstract
Background: Cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). Immunotherapy with checkpoint inhibitors has improved outcomes in advanced bladder cancer and immunotherapy is synergistic with chemotherapy. Our ongoing trial is aimed at studying the efficacy and safety of nivolumab (N)with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC (NCT03294304). Methods: This is a single-arm, multicenter phase II study for patients with MIBC eligible for neoadjuvant GC and planned for RC. Forty-one patients will be treated with N+ GC every 21 days for 4 treatment cycles over 12 weeks followed by RC. The primary endpoint is PaR. Key inclusion criteria are presence of MIBC (predominantly urothelial carcinoma) with clinical stage T2-T4a and N≤1 disease (solitary lymph node measuring &lt; 2 cm) and M0 and deemed eligible for radical cystectomy, ECOG PS of 0 or 1, Cr Cl ≥ 50 ml/min, adequate organ function, eligible to receive GC and no contraindications to receiving N. Patients will receive C (70mg/m2) IV on D1, G (1000mg/m2) on D1,D8 and N (360 mg) IV on D8 every 21 days for 4 cycles followed by radical cystectomy within 6-8 weeks. Secondary objectives are to determine safety of combination of N+GC in pts with MIBC prior to RC and PFS. The correlative objectives include: 1) correlation of whole-genome sequencing (WGS) of the pre-treatment bladder cancer biopsy with PaR; 2) correlation of molecular subtypes of bladder cancer using Genomedx to evaluate whether addition of N alters the response to neoadjuvant GC; 3) correlation of PD-L1 expression in tumor tissue at baseline with PaR; 4) Nanostring pancan immune panel gene expression will be studied at baseline and at RC. At the time of submission of this abstract, 12/41 pts. have been enrolled and the combination has not resulted in any added toxicities or immune-related AEs so far. There were no delays in RC. PaR and correlative analysis is ongoing in enrolled pts. and further enrollment is ongoing.
Citation Format: Shilpa Gupta, Christopher J. Weight, Neeraj Agarwal, Sumati Gupta, Badrinath Konety, Ewan Gibb, Elai Davicioni, Bharat Thyagarajan, Guru Sonpavde. Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A008.