bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2313: Multi-modal deep learning to predict cancer outcomes by integrating radiology and pathology images
Authors: Li Zhe , Jiang Yuming , Li Ruijiang 
Published: March 2024

Abstract
Purpose: Cancer patients routinely undergo radiologic and pathologic evaluation for their diagnostic workup. These data modalities represent a valuable and readily available resource for developing new prognostic tools. Given their vast difference in spatial scales, effective methods to integrate the two modalities are currently lacking. Here, we aim to develop a multi-modal approach to integrate radiology and pathology images for predicting outcomes in cancer patients.
Methods: We propose a multi-modal weakly-supervised deep learning framework to integrate radiology and pathology images for survival prediction. We first extract multi-scale features from whole-slide H&E-stained pathology images to characterize cellular and tissue phenotypes as well as spatial cellular organization. We then build a hierarchical co-attention transformer to effectively learn the multi-modal interactions between radiology and pathology image features. Finally, a multimodal risk score is derived by combining complementary information from two images modalities and clinical data for predicting outcome. We evaluate our approach in lung, gastric, and brain cancers with matched radiology and pathology images and clinical data available, each with separate training and external validation cohorts.
Results: The multi-modal deep learning models achieved a reasonably high accuracy for predicting survival outcomes in the external validation cohorts (C-index range: 0.72-0.75 across three cancer types). The multi-modal prognostic models significantly improved upon single-modal approach based on radiology or pathology images or clinical data alone (C-index range: 0.53-0.71, P&lt;0.01). The multi-modal deep learning models were significantly associated with disease-free survival and overall survival (hazard ratio range: 3.23-4.46, P&lt;0.0001). In multivariable analyses, the models remained an independent prognostic factor (P&lt;0.01) after adjusting for clinicopathological variables including cancer stage and tumor differentiation.
Conclusions: The proposed multi-modal deep learning approach outperforms traditional methods for predicting survival outcomes by leveraging routinely available radiology and pathology images. With further independent validation, this may afford a promising approach to improve risk stratification and better inform treatment strategies for cancer patients.
Citation Format: Zhe Li, Yuming Jiang, Ruijiang Li. Multi-modal deep learning to predict cancer outcomes by integrating radiology and pathology images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2313.
Abstract 2332: Enhanced analysis of CO-Detection by indEXing (CODEX) imaging through a novel image processing technique utilizing two-dimensional Fourier transform for stitching artifact detection
Authors: Jahedi Afrooz , Khan Aliya , Kannan Kasthuri , Bhat Krishna 
Published: March 2024

Abstract
Objective: The objective of this study is to address the challenge of stitching artifacts in CODEX imaging, which hinders the accurate spatial quantification of positive cell locations—a critical step for reliable spatial analysis in computational pathology.
Methods: Our algorithm applies 2D-FT and inverse transformations to process pathological images. We tested the algorithm on 16 different histology images, each containing 5 or more regions. Within these regions, we evaluated 29 protein markers, culminating in the analysis of over 2800 images.
Results: The algorithm demonstrated a recall rate of over 85 percent, indicating a high likelihood of accurately identifying true positive regions with stitching artifacts. However, the precision varied, suggesting further investigation is needed to understand the variability and improve consistency.
Conclusion: The proposed method significantly improves CODEX imaging reliability by detecting and quantifying stitching artifacts. The method's high recall rates are promising, but the variable precision indicates the necessity for ongoing refinement to ensure consistent diagnostic accuracy across diverse and extensive image sets. Keywords: Computational pathology, Fourier transform, Image stitching, CODEX, Spatial analysis, Diagnostic precision, Recall.
Citation Format: Afrooz Jahedi, Aliya Khan, Kasthuri Kannan, Krishna Bhat. Enhanced analysis of CO-Detection by indEXing (CODEX) imaging through a novel image processing technique utilizing two-dimensional Fourier transform for stitching artifact detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2332.
Abstract 2380: The bispecific antibody KA-3004, targeting PD-L1 and 4-1BB, is designed to enhance anti-tumor activity
Authors: Liang Jiabei , Guo Zhengcheng , Peng Hao , Hao Feng , Liu Tongtong , Ning Jinying , Wu Guojin 
Published: March 2024

Abstract
Checkpoint inhibitors (CPI) have transformed the treatment landscape for advanced solid tumors; however, a majority of cancers still do not respond to immune checkpoint therapy. In this study, we developed a bispecific antibody (BsAb) named KA-3004, targeting PD-L1 and human 4-1BB, with the aim of enhancing the functionality and survival of stimulated CD8+ T cells in the tumor microenvironment. This antibody was designed using our nanobody antibody discovery platform. KA-3004, in IgG1 format, incorporates mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. It features two identical nanobodies at the C-terminal against 4-1BB to stimulate 4-1BB signaling in T cells and binds to PD-L1 with two Fabs at the N-terminal. KA-3004 binds to PD-L1 with high affinity, blocking the interaction of PD-1 and PD-L1. It also binds to 4-1BB expressed on 293T cells and activated human T cells. In the presence of a low concentration of CD3 antibody to stimulate T cell activation, co-culture of tumor cells expressing PD-L1 with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3004 effectively suppresses the growth of NCI-H292 tumors expressing PD-L1. Additionally, KA-3004 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and KA-3004 shows neither aggregation nor degradation. In conclusion, the BsAb KA-3004, developed with our nanobody antibody discovery platform, stands out as a promising pre-clinical candidate drug for the treatment of solid cancers.
Citation Format: Jiabei Liang, Zhengcheng Guo, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning, Guojin Wu. The bispecific antibody KA-3004, targeting PD-L1 and 4-1BB, is designed to enhance anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2380.
Abstract 242: Development of organoids-bacteria co-cultures for medium-to-high throughput screening
Authors: Valle-Encinas Eider , Doorn Mayke , Pourfarzad Farzin , Mateo Lani San , Gokare Prashanth , Pocalyko David , Boj Sylvia F. , Verissimo Carla S. 
Published: March 2024

Abstract
HUB patient derived organoids, (HUB-OrganoidsTM or PDOs) are self-organized epithelial cell structures with near-physiological features, extensively used to model aspects of cancer initiation and progression. Microinjection of colibactin-producing pks+ E. coli into the lumen of PDOs resulted in the appearance of two co-occurring mutational signatures identified in a subset of colorectal cancer (CRC) patients, demonstrating that pks+ E. coli plays a causative role in CRC development. The scalability of PDO bacteria microinjection is, however, limited and represent a bottleneck in the screening of preventive therapies for these patients. Here we develop a bacteria-PDO co-culture system (PDO-fragment exposure model), alternative to PDO microinjection, that is compatible with medium-to-high throughput screening methods. We validated the genotoxicity of colibactin-producing bacteria and showed the potential of the PDO fragment exposure model for the screening of drugs targeting colibactin-dependent genotoxicity.
Citation Format: Eider Valle-Encinas, Mayke Doorn, Farzin Pourfarzad, Lani San Mateo, Prashanth Gokare, David Pocalyko, Sylvia F. Boj, Carla S. Verissimo. Development of organoids-bacteria co-cultures for medium-to-high throughput screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 242.
Abstract 2459: ADT-030 is a novel dual-acting RAS/β-catenin inhibitor that potentiates antitumor immunity
Authors: Gazi Md Yeashin , Okoko Ogacheko , Wang Xin , Brandle Caitlin , Chen Xi , Fadlalla Khalda , Keeton Adam , Maxuitenko Yulia , Hedrick Catherine , Shi Huidong , Piazza Gary , Zhou Gang 
Published: March 2024

Abstract
ADT-030 is a novel indene identified from a screening campaign and chemically optimized for drug-like properties that acts as a dual inhibitor of RAS and β-catenin signaling. Here we demonstrate that ADT-030 binds RAS with high affinity and inhibits MAPK/AKT signaling with high potency and selectivity in KRAS mutant cells to inhibit proliferation and induce apoptosis. ADT-030 also inhibits phosphodiesterase 10A (PDE10) that is overexpressed in cancer cells to selectively activate cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling, which induces phosphorylation and degradation of the oncogenic pool of β-catenin. ADT-030 exhibited cytotoxicity to a variety of murine cancer cell lines in vitro, and inhibited tumor growth in syngeneic immunocompetent mice when orally administered. The antitumor activity of ADT-030 was diminished in mice that were immunodeficient or depleted of CD8+ T cells, indicating a critical role of the host immune system. In a metastatic breast tumor mouse model (4T1), ADT-030 not only delayed the growth of the primary tumor but also reduced tumor colonization in the lungs, leading to increased survival. CyTOF and scRNAseq analyses provided a plethora of information revealing the impact of ADT-030 on the immune milieu in the tumor microenvironment. Notably, ADT-030 selectively induced apoptosis of myeloid-derived suppressor cells (MDSCs) while CD8+ T cells were not affected. Consequently, ADT-030 treatment resulted in a marked reduction of MDSCs, which was accompanied by increased tumor infiltration of effector CD8+ T cells. ADT-030 treatment of cancer cells led to immunogenic cell death and enhanced dendritic cell activation. Furthermore, the ability of ADT-030 to augment the antitumor activity of immune checkpoint blockade therapy underlines its potential as a desirable immune-potentiating agent to improve the outcome of cancer immunotherapy. ADT-030 represents a development candidate ready for IND-enabling safety assessment.
Citation Format: Md Yeashin Gazi, Ogacheko Okoko, Xin Wang, Caitlin Brandle, Xi Chen, Khalda Fadlalla, Adam Keeton, Yulia Maxuitenko, Catherine Hedrick, Huidong Shi, Gary Piazza, Gang Zhou. ADT-030 is a novel dual-acting RAS/β-catenin inhibitor that potentiates antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2459.
Abstract 2514: Adjuvant chemotherapy drug response-related gene detection using JASPAC01 pancreatic cancer resection cohort
Authors: Okamura Yukiyasu , Otsu Tomohisa , Hayashi Masamichi , Ashida Ryo , Uesaka Katsuhiko 
Published: March 2024

Abstract
Background of Purpose: Although various multidisciplinary treatments have been attempted for pancreatic cancer, sufficient improvement in prognosis has not been achieved. It is necessary to establish biomarkers that can predict the malignant potential for each patient and the therapeutic effect of chemotherapy in order to select the optimal treatment for each individual case.This study was designed as a companion study to the phase III comparative study (JASPAC 01 of gemcitabine (GEM) and S-1 therapy as adjuvant chemotherapy after pancreatectomy. Among the 22 candidate biomarker genes that have been reported to be involved in pancreatic cancer treatment prognosis, we focused on E2F transcription factor 7 (E2F7), which is associated with a significantly poor overall survival rate when highly expressed. E2F7 is one of the target proteins of p53 and has been reported to be involved in cell cycle regulation. We examined the possibility of E2F7 expression in pancreatic cancer surgery and the effect of adjuvant chemotherapy.
Patients and Methods: After optimizing the E2F7 imunostaining protocol, we scored E2F7 protein expression using the slides from excised tissues from JASPAC 01 registered cases. We investigated the relationship between malignancy and treatment efficacy using the case cohort treatment allocation information, clinicopathological information, and prognosis data.
Results: Immunostaining was performed on approximately 330 resected pancreatic cancer specimens from 24 facilities nationwide. Of the 311 patients for whom E2F7 protein expression could be scored, 202 patients who completed the assigned treatment were included in the analysis. In 88 cases with high E2F7 expression, no significant difference in clinicopathological factors was observed between the S-1 treatment group and the GEM treatment group, but the S-1 treatment group showed better recurrence-free survival (RFS, P=0.066) and overall survival (OS, P=0.015) were observed. On the other hand, in the 114 patients with low E2F7 expression, there was no significant difference in clinicopathological factors between the two groups (RFS, P=0.168, OS: P=0.276). High E2F7 expression in pancreatic cancer tissues may affect S-1 sensitivity, GEM resistance, or both.
Conclusions: It is considered that high expression E2F7 in pancreatic cancer may affect the therapeutic efficacy of GEM and S-1, which are frequently used in adjuvant chemotherapy for pancreatic cancer.
Citation Format: Yukiyasu Okamura, Tomohisa Otsu, Masamichi Hayashi, Ryo Ashida, Katsuhiko Uesaka. Adjuvant chemotherapy drug response-related gene detection using JASPAC01 pancreatic cancer resection cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2514.
Abstract 2555: Real-world data analysis of comprehensive genomic profiling using plasma samples from non-small cell lung cancer patients
Authors: Morishita Momoko , Fujii Koki , Ueki Michiko , Ikushima Hiroaki , Isago Hideaki , Watanabe Kousuke , Oda Katsutoshi , Kage Hidenori 
Published: March 2024

Abstract
Introduction: Comprehensive genomic profiling (CGP) tests which use plasma samples can detect driver mutations and are recommended when tissue samples are unavailable. Multiple studies have shown that plasma CGP tests can result in genomically matched treatment for cancer patients, especially in gastrointestinal cancer. However, data for non-small cell lung cancer (NSCLC) remain limited.
Methods: We searched the database of the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), which comprised 99.7% of the CGP data under insurance coverage in Japan. NSCLC patients analyzed with FoundationOne Liquid CDx (F1LCDx) between August 1 2021 to July 31 2023 were included, all of whom were previously treated.
Result: 694 patients with NSCLC underwent liquid biopsy. Among them, 572 cases were adenocarcinoma, and 71 were squamous cell carcinoma. The median age was 68 years (range: 24-93), and 423 patients were male. Pathogenic or likely pathogenic EGFR mutations, ALK rearrangements, ROS1 rearrangements, MET exon 14 skipping mutations, BRAF V600E, RET fusions, ERBB2 mutations, and KRAS G12C were detected in 174 cases (25.1%), 18 cases (2.6%), 2 cases (0.3%), 9 cases (1.3%), 3 cases (0.4%), 7 cases (1.0%), 26 cases (3.7%) and 17 cases (2.4%), respectively. Among the 499 patients without known driver mutations, driver mutations were detected by F1LCDx in 60 patients (12.0%). The detection rate of each driver oncogene is shown in Table 1. Conversely, among the 174, 20, 9 and 3 patients with known EGFR, ALK, ROS1, or BRAF V600E alterations, F1LCDx showed false negative results in 48 (27.6%), 10(50.0%), 8 (88.9%), and 3 cases (100%) (EGFR/BRAF vs. ALK/ROS1, p = 0.001), respectively.
Conclusion: In patients without known driver oncogenes, mutations associated with approved therapeutic implications were detected in 12.0%. The detection of gene rearrangements using liquid biopsy may be limited compared with genetic mutations.
Genomic profiling detected by FoundationOne Liquid CDx Cases (%) EGFR, known EGFR, unknown ALK, known ALK, unknown ROS1, known ROS1, unknown BRAF V600E, known BRAF V600E, unknown Detected by F1LCDx 126 (72.4) 48 (9.2) 10 (50.0) 8 (1.2) 1 (11.1) 1 (0.15) 0 3 (0.43) Undetected by F1LCDx 48 (27.6) 472 (90.8) 10 (50.0) 666 (98.8) 8 (88.9) 684 (99.9) 3 (100) 688 (99.6) Total 174 520 20 674 9 685 3 691
Citation Format: Momoko Morishita, Koki Fujii, Michiko Ueki, Hiroaki Ikushima, Hideaki Isago, Kousuke Watanabe, Katsutoshi Oda, Hidenori Kage. Real-world data analysis of comprehensive genomic profiling using plasma samples from non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2555.
Abstract 2611: Non-specific elimination of tumor-associated neutrophils by antibody-drug conjugates boosts anti-tumor immunity for PD-1 immunotherapy
Authors: Yao Shili , Sun Lu , Zhu Xiu , Xie Hanfei , Yang Tong , Guo Peng , Tang Huarong , Zhu Tao 
Published: March 2024

Abstract
Background: Antibody-drug conjugates (ADCs) play a key role in targeted therapy of solid tumors. However, few studies have examined the impact of ADCs on the tumor microenvironment (TME), particularly on innate immune cells. To elucidate this, this study focuses on investigating the comprehensive impacts of ICAM1-DXd on the tumor microenvironment, especially on tumor-associated neutrophils (TAN) and its synergistic effect with PD-1 immunotherapy.
Methods: Firstly, the efficacy and prognosis of ICAM1-DXd, a potent ADC for cervical cancer, were determined in pre-clinical tumor models, providing crucial transcriptomic and biological function information by using RNA-seq. Then, pathological studies were performed to evaluate the abundance and location of TAN (Ly6G+/MPO+) in TME post-ADC treatment. The interaction between TAN and ICAM1-DXd and subsequent impacts on adaptive immune cells (e.g., CD8+ cells) was examined by flow cytometry (FACS), confocal fluorescent imaging, and western blot techniques (WB). Eventually, the synergistic effect of ICAM1-DXd and PD-1 monoclonal antibody were investigated in an immunocompetent animal model.
Results: ICAM1-DXd potently inhibits cervical tumor growth in preclinical models, and RNA-seq analysis revealed that ICAM1-DXd treatment induces a strong down-regulation of neutrophil activation, especially for Ly6G+/MPO+ TANs, a subtype with pro-tumor function. IHC and FACS results confirmed that pro-tumor TANs were efficiently eliminated in TME by ICAM1-DXd treatment via non-specific phagocytosis in comparison with peripheral blood neutrophils. ICAM1-DXd-phagocytised TANs also elicit a strong bystander killing effect by cleaving the quadra peptide linker of ICAM1-DXD by cathepsin B. This ADC-mediated TAN elimination effectively ameliorates immunosuppressive TME and works in synergy with PD-1 immunotherapy in preclinical models.
Conclusion: In preclinical models of cervical cancer, ICAM1-DXd not only directly ablates cancer cells via antigen recognition but also non-specifically kills tumor-promoting TANs, resulting in an improved tumor immune microenvironment, providing a shred of mechanistic evidence supporting ADC and PD-1 combination therapy.
Citation Format: Shili Yao, Lu Sun, Xiu Zhu, Hanfei Xie, Tong Yang, Peng Guo, Huarong Tang, Tao Zhu. Non-specific elimination of tumor-associated neutrophils by antibody-drug conjugates boosts anti-tumor immunity for PD-1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2611.
Abstract 2620: BCG016, a first-in-class bispecific antibody-drug conjugate targeting 5T4 and MUC1, demonstrates potent preclinical anti-tumor activity
Authors: Han Zhenyan , Shang Chengzhang , Zhang Yifu , An Gao , Guo Chaoshe , An W. Frank , Yang Yi 
Published: March 2024

Abstract
5T4 is a highly expressed tumor-associated antigen associated with adverse clinical outcomes in solid tumors, and is an attractive therapeutic target due to low expression on normal adult tissues. While several therapeutic agents targeting 5T4 antigen are currently being evaluated in human clinical trials, none have yet entered the market. Another target, MUC1, is currently under clinical investigation, with most drugs in clinical trials showing limited efficacy due to shedding of the target antigen MUC1-N. 5T4 and MUC1 are commonly co-expressed in various solid tumors, including lung, breast, colorectal and pancreatic cancers, suggesting that targeting both antigens with a single drug could be a promising therapeutic strategy.
We previously identified and evaluated antibodies targeting human 5T4 and MUC1-C (cleaved MUC1) using RenLite® fully human common light chain mice. Here, selected antibodies were constructed into 5T4 × MUC1 bispecific antibodies (bsAb). The 5T4-MUC1 bsAb demonstrated high avidity in multiple human tumor cell lines by flow cytometry. Notably, the parental 5T4 antibody also binds strongly to many tumor cell lines. Internalization assays demonstrate that the internalization of 5T4-MUC1 bsAb in breast cancer cells was enhanced compared to the parental anti-5T4 and anti-MUC1 monoclonal antibodies, as measured by Incucyte® live cell imaging. Subsequently, the 5T4-MUC1 bsAb was then conjugated with monomethyl auristatin E (MMAE) to generate 5T4 x MUC1 bsADC (BCG016). Cytotoxicity assays indicate that BCG016 improved tumor cell killing in vitro compared to benchmark ADCs, and in vivo efficacy studies showed superior anti-tumor efficacy of BCG016 in patient-derived NSCLC xenografts compared to benchmark ADCs and parental ADC combination therapy.
In summary, we have generated a novel bispecific ADC targeting 5T4 and the cleaved MUC1-C protein, which remains membrane-bound on tumor cells. The 5T4-MUC1 bsADC showed superior anti-tumor efficacy in PDX models and has the potential to be a novel therapeutic for 5T4 and MUC1 co-expressing tumors.
Citation Format: Zhenyan Han, Chengzhang Shang, Yifu Zhang, Gao An, Chaoshe Guo, W. Frank An, Yi Yang. BCG016, a first-in-class bispecific antibody-drug conjugate targeting 5T4 and MUC1, demonstrates potent preclinical anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2620.