bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering the prognostic value of FGFR2b/2c isoform expression levels in advanced esophagogastric cancer through whole-transcriptome sequencing.
Authors: Hashimoto Tadayoshi , Iida Naoko , Nakamura Yoshiaki , Mishima Saori , Kotani Daisuke , Kawazoe Akihito , Nakayama Izuma , Kuboki Yasutoshi , Shibuki Taro , Imai Mitsuho , Fujisawa Takao , Bando Hideaki , Yoshino Takayuki , Shitara Kohei 
Published: August 2024

53 Background: Fibroblast growth factor receptor (FGFR) isoform switching from FGFR2b to FGFR2c has been implicated in epithelial-to-mesenchymal transition and enhanced invasive potential in various malignancies and potentially be involved in resistance mechanisms to FGFR2b targeted therapy (e.g., bemarituzumab). This study sought to investigate the potential of respective FGFR2 isoform expression evaluation utilizing whole-transcriptome sequencing (WTS) and its correlation with therapeutic efficacy and clinical outcomes in patients with advanced G/GEJ cancer. Methods: Patients with advanced G/GEJ cancer who received systemic therapy at the National Cancer Center Hospital East between May 2021 and September 2023, and were enrolled in the immunological profiling study (UMIN000019129) and MONSTAR-SCREEN-2 (UMIN000043899) were included. FGFR2 protein and RNA expression were assessed via immunohistochemistry (IHC) and WTS with Caris MI Profile, respectively. FGFR2b and FGFR2c isoforms were distinguished by the detection of their respective splice junctions using WTS data. The FGFR2b/(2b+2c) ratio was stratified into FGFR2b-dominat and -containing subtypes using the median value. The log-rank test was used to discern differences in overall survival (OS). Results: Among the 129 patients, 21 (16.3%) exhibited FGFR2-positivity by IHC (staining intensity 2+ or 3+≥1% membranous staining of tumor cells), and a significant correlation was observed between FGFR2 IHC status and RNA expression levels (TPM: transcript per million) in WTS (FGFR2-positive, median TPM=11.1; FGFR2-negative, median TPM=4.7; P=0.002). The distribution of FGFR2b/(2b+2c) ratio (median, 0.89) was: 10.9% (0≤x<0.2), 5.4% (0.2≤x<0.4), 7.0% (0.4≤x<0.6), 12.4% (0.6≤x<0.8), 43.4% (0.8≤x<1.0), and 20.9% (x=1.0). Among 58 patients treated with 1st line therapy, no significant difference in treatment response was observed between the FGFR2b-dominat (67.9%) and FGFR2c-containing subtypes (53.3%) (P=0.259). Overall, the FGFR2c-containing subtype was associated with significantly shorter OS compared to the FGFR2b-dominat subtype (median OS, 10.1 vs. 17.9 months; hazard ratio, 1.72; 95% confidence interval, 1.03-2.86; log-rank P=0.037). Conclusions: Our findings underscore the substantial concordance between IHC and WTS analysis of FGFR2, the feasibility of distinguishing FGFR2 isoforms using WTS, and the prognostic implications of FGFR2c isoform in patients with advanced G/GEJ cancer. Further analysis is warranted in patients receiving FGFR2b targeted treatment.
Effect of deconvoluting single-cell transcriptomics on cellular programs regulated by cell-cell communication in colorectal cancer.
Authors: Chen Lujia , Zhang Han , Lu Binfeng , Cooper Gregory F. , Saeed Anwaar , Lu Xinghua 
Published: August 2024

59 Background: Colorectal cancer (CRC) is the 3rd most common cancer. The consensus molecular subtypes among CRC tumors reflects the heterogeneity of composition and functional states of cells in the tumor microenvironments (TME), which in turn may underlie diverse behaviors of disease progression and responses to anticancer treatments. Cells within a TME communicate through intricate cell-cell communication (CCC) networks. The altered state of one cell can influence the states of other cells through ligand-receptor-mediated signal transduction. Gaining insight into the cellular states of cells and understanding their complex communications in a TME is vital for uncovering the heterogeneous mechanisms governing tumor growth, immune evasion, and therapy resistance. Methods: In this meta-analysis of eight single-cell cohorts encompassing 153 patients and 279 samples with more than 600,000 cells, we advance the understanding of CCC networks in CRC through a novel analytical framework. Employing hierarchical language modeling, we identify gene expression modules (GEMs) that mirror single-cell signaling states, crucial for deciphering the complexity of intercellular interactions. By applying causal discovery methods, we systematically uncover GEMs likely regulated by ligand-receptor signaling and cross-cell-type communication. We further validate the discovered CCC using spatial transcriptomic data by testing the spatial co-localization. Results: This analysis reveals nine cross-cell-type CCC programs, marked by highly correlated GEMs across various cell types, shedding light on the intricate CCC networks within the TME. The discovered CCC programs include malignant program, proliferation program, stromal interactions, stromal-myeloid interactions, innate immunity interactions, regulatory interactions, epithelial-lymphocyte interactions and exhaustion program. Each program is composed of GEMs from various cell types. Spatial transcriptomics further validate these findings by demonstrating the co-localization of GEMs within CCC programs in distinct spatial domains, emphasizing the spatial dynamics of tumor intercellular communication. We successfully construct the CCC subnetworks connected by ligand-receptor signaling. Our interactive website and analytical framework equip researchers with powerful tools to explore complex mechanisms, potentially uncovering novel drug targets and refining strategies for precision immunotherapies. Conclusions: This study provides an in-depth analysis of colorectal cancer by: 1) Cataloging GEMs that precisely depict the transcriptomic processes unique to individual cell clusters or shared among multiple cell clusters. 2) Presenting the CCC networks driven by ligand-receptor interactions within the TME supported by both single-cell RNA-seq data and spatial transcriptomic data.
Predicting chemotherapy response in patients with advanced or metastatic pancreatic cancer using machine learning.
Authors: Kim Moonho , Choi Gyucheol , Koo Jamin 
Published: August 2024

60 Background: When determining the initial chemotherapy regimen for advanced or metastatic pancreatic cancer, various factors must be evaluated. The decision between FOLFIRINOX and Gemcitabine/Nab-paclitaxel (GnP) is challenging, as patient survival hinges on the efficacy and toxicity profiles of these treatments, alongside individual patient characteristics and vulnerabilities.This study aims to guide the selection of an appropriate first-line chemotherapy regimen for advanced or metastatic pancreatic cancer by leveraging machine learning (ML) methods to predict survival outcomes. Methods: We conducted a retrospective analysis involving a cohort of 151 patients who underwent systemic chemotherapy for advanced or metastatic pancreatic cancer at Gangneung Asan Hospital in South Korea between 2019 and 2023. The initial data consisted of 17 types of demographic and clinical characteristics, as well as time-course of response and survival outcomes. The ML models predicting overall survival (OS) were developed using the XGBoost method. The minimal set of covariates resulting in the highest predictive performance during 5-fold cross validation were chosen as inputs to each model. Results: The median age of the patients was 66 years, with 62.3% being male. The ML models achieved the ROC-AUC of 0.81 when predicting OS after 12 months following the initial administration of FOLFIRINOX (n=61) or GnP (n=47). Five (peritoneal metastases, other metastases, bilirubin level, white blood cell counts, and retroperitoneal lymph node metastases) or four (age, tumor location, sex, and metastatic status) covariates were used to achieve the predictive accuracy for the two regimens, respectively. The median OS of the high versus low risk groups of FOLFIRINOX predicted by the ML models were significantly different (7 vs 18 months, P < 0.01), recording the hazard ratio (HR) of 2.79 (95% CI, 1.47-5.26). Similarly, the median OS of the high and low risk groups of GnP were significantly different (8 vs 16 months, P < 0.001, HR 3.50, 95% CI, 1.60-7.66). Conclusions: We developed the ML models that can compute the probability of OS based on the routinely collected data from patients with advanced or metastatic pancreatic cancer. To the best of our knowledge, this is the first ML solution aimed at aiding clinicians in the selection of the first-line chemotherapy regimen for pancreatic cancer.
The dynamic changes of circulating myeloid-derived suppressor cells (MDSCs) subsets in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy.
Authors: Fauza Dilafitria , Manuel RALPH G , Sudoyo Aru Wisaksono , Steven Ricci , Gultom Fajar Lamhot , Basir Ibrahim , Kurniawan Dicky , Budiyati Akterono Dwi 
Published: August 2024

62 Background: Increased level of circulating myeloid-derived suppressor cells (MDSCs) have been associated with higher tumor stage, poorer survival, and poorer response to therapeutic agents in colorectal cancer (CRC). It has been reported that the common first-line chemotherapy involving combination with oxaliplatin mediated MDSCs depletion via induction of cell death. However, this phenomenon is yet to be further investigated since it only occurred in polymophonuclear MDSC (PMN-MDSC) subset, not in monocytic MDSC (M-MDSC). The present study aims to learn deeper on the dynamic changes of circulating MDSCs in response to oxaliplatin-based treatment in CRC patients. Methods: This was a prospective study that recruited 30 treatment-naïve patients with varying stage of CRC who were scheduled to receive oxaliplatin-based chemotherapy. Blood sampling was conducted prior and at several time points during and after chemotherapy. Multicolor flow cytometry assay was used to analyze the proportion of HLA-DR-, CD33+, and CD15+ (PMN-MDSC) and CD14+ (M-MDSC) cells within peripheral blood mononuclear cells (PBMCs). Other essential tumor biomarkers such as carcinoembryonic antigen (CEA) and tumor infiltrating lymphocytes (TILs) were assessed as well. As control, 14 healthy subjects were recruited. Results: Our result showed that circulating PMN-MDSCs was significantly higher in CRC patients compared to healthy subjects (p=0.003), whilst insignificant result was shown by M-MDSCs (p=0.890). Following chemotherapy, MDSCs level showed dynamic changes. Interestingly, a subgroup of CRC patients with decreased in both PMN- and M-MDSCs levels on D-14 chemotherapy were consistently showed a significant decreased of MDSCs level during and after therapy completion compared to baseline (p=0.0078). Conclusions: Circulating MDSCs level, particularly PMN-MDSCs in CRC patients was significantly higher compared to healthy subjects. Changes in both circulating PMN- and M-MDSCs levels at D-14 chemotherapy might have prognostic value in oxaliplatin-based chemotherapy.
i-Biomarker CaDx: A circulating miRNA-based multi-cancer detection test with generative and explainable AI for colorectal cancer.
Authors: Floares Alexandru , Sarghie Larisa , Zety Adrian Vasile , Androutsos Lampros , Oliveira Rafael , Calin George , Floares Carmen , Manolache Florin 
Published: August 2024

64 Background: Colorectal cancer (CRC), the second most deadly cancer, underscores the critical need for early detection to significantly improve treatment outcomes and survival rates. Colonoscopy, flexible sigmoidoscopy, and the fecal immunochemical tests (FIT), often fail to capture early disease, significantly decreasing the survival chance. Circulating miRNA is a promising non-invasive biomarker for various cancers, including CRC. The i-Biomarker CaDx (patent pending) is an innovative multi-cancer early detection and diagnosis platform, covering 32 cancer types with an impressive accuracy rate of 99-100%. This study focuses on the effectiveness of i-Biomarker CaDx for CRC, employing significant data collection and leveraging insights from Generative AI (GenAI) and Explainable Artificial Intelligence (XAI). Methods: We collected various available datasets (e.g. GSE106817, etc.) encompassing 305 colorectal cancer patients and a matching number of healthy controls. Microarray was employed to profile circulating miRNAs. We used various classification paradigms, e.g., decision trees, neural networks, etc. Hyperparameter optimization was conducted, and the best-performing classifiers were amalgamated in the final model, weighted by their respective efficacies. We assessed i-Biomarker CaDx's performance through cross-validation and independent test sets. The XAI provided detailed insights into miRNA variations associated with personalized diagnostic. GenAI integrated the test into the screening and early detection best practice workflows and performs Functional Analysis. Results: i-Biomarker CaDx shows exceptional diagnostic accuracy of 99-100%, surpassing conventional colorectal cancer diagnostic methods like colonoscopy, flexible sigmoidoscopy, and FIT. It can also be used for personalized treatment response monitoring. I-Biomarker effectively deciphers intricate miRNA relationships relevant to colorectal cancer using XAI. Thus, our analyses shed light on miRNA patterns and their associations with colorectal cancer, enhancing the understanding of the underlying molecular complexities of the disease. It goes further by explaining the personalized cellular and molecular mechanisms involved, and it will be integrated into the corresponding medical workflows. Conclusions: Our AI-powered multi-cancer early diagnostic platform demonstrates outstanding performance in detecting CRC, surpassing traditional diagnostic methods like colonoscopy, flexible sigmoidoscopy, and FIT. XAI allows for in-depth exploration of miRNA alterations and their impact on CRC, enriching our interpretations at both the population and individual levels. These findings underscore the substantial potential of i-Biomarker CaDx as a transformative, non-invasive diagnostic tool for CRC.
Perioperative FLOT + immunotherapy for resectable gastric and gastroesophageal junction cancer: A systematic review and meta-analysis.
Authors: Revillas Lorenz Fort Estrada , Lalusis John Kelvin , Dy Carlos 
Published: August 2024

66 Background: The current standard of care for resectable gastric and GEJ cancers is perioperative chemotherapy with FLOT.Although its benefits in improving rates of pathologic complete response, increasing prospects of R0 resection, and improving survival have been proven, efforts to find novel strategies which can improve on its gains continue.The addition of an immune checkpoint inhibitor to FLOT has been a focal point of research in this field. This meta-analysis evaluated high-quality data from clinical trials to determine the efficacy of this chemoimmunotherapy combination. Methods: A systematic search of English-language articles on PubMed, Cochrane and Google scholar was done to identify randomized trials investigating the use of perioperative FLOT and immune checkpoint inhibitors in the treatment of resectable gastric and GEJ cancer. Quality of studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials. Inverse variance was the statistical method used with random effects as the analysis model in the production of the Forest plot and calculation of odds ratio at 95% CI. Results: Three RCTs (N = 1446), each with two arms, were included in the meta-analysis. The Phase II Dante Trial (N= 295)compared perioperative FLOT alone with perioperative atezolizumab + FLOT. The Phase III Keynote 585 trial(N=203) and the phase III Matterhorn trial (N=948) compared perioperative placebo + FLOT with perioperative pembrolizumab + FLOT, and perioperative Durvalumab + FLOT, respectively. Risk of bias and heterogeneity were low. Pooled results showed that in patients given perioperative FLOT + immunotherapy, there is statistically significant improvement in the rate of pathologic complete response (OR 2.60 95% CI 1.88-3.61, p <0.0001). In terms of rate of R0 resection, there was no statistically significant difference between the two groups (OR 1.02 95% CI 0.75-1.38,p= 0.92). Conclusions: This analysis shows that adding immunotherapy to FLOT improves the rate of pathologic complete response, and maintains the high rate of R0 resection, in resectable gastric and GEJ cancers. Favorable results of pending survival outcomes from these trials may help re-shape the current standard of care in this field.
Multimodal analysis of methylation and fragmentomic profiles in plasma cell free DNA for differentiation of benign and malignant breast tumors.
Authors: Van Thi Tuong Vi , Nguyen Hanh Thi-Hue , Nguyen Thien-Chi Van Van , Vo Dac Ho , Tran Trung Hieu , Nguyen Trong Hieu , Doan Nhu Nhat Tan , Huynh Le Anh Khoa , Nguyen Xuan Vinh , Giang Hoa , Phan Minh-Duy , Nguyen Hoai Nghia , Tran Le Son 
Published: August 2024

7 Background: Breast cancer ranks as the second leading cause of cancer-related mortality among women globally. Early detection of breast cancer is crucial for improving patient outcomes and reducing mortality rates. Liquid biopsy, which relies on circulating tumor DNA (ctDNA) shed by breast tumors into the bloodstream, presents a promising non-invasive approach for early breast cancer detection. However, accurately distinguishing between benign breast abnormalities and malignant tumors remains a significant clinical challenge, as misdiagnosis can lead to unnecessary invasive procedures. Methods: Herein, we employed a multimodal analysis approach, namely SPOT-MAS (Screen for the Presence of Tumor by DNA Methylation and Size), to profile alterations in methylation and fragment length patterns of cell-free DNA (cfDNA) from 169 breast cancer-confirmed patients and 99 patients diagnosed with benign breast lumps including cysts, fibroadenomas, and fibrocystic changes. A robust machine learning model was constructed using these signatures to differentiate between breast cancer patients and individuals with benign lesions. Results: Our genome-wide analyses identified distinct profiles of methylation changes, copy number alterations, and end motifs in cfDNA, enabling discrimination between breast cancer patients and individuals with benign conditions. Notably, we observed a significant enrichment of Thymine and Adenine at cfDNA cleavage sites in breast cancer patients. Moreover, our target sequencing analyses uncovered distinct methylation patterns in the regulatory regions of multiple genes, including hypermethylation in GPR126 or hypomethylation in TOP1 or MAFB in breast cancer cfDNA. Our multi-featured model achieved an AUC of 0.92 (95% CI: 0.88–0.97), a specificity of 97.44% and sensitivities of 57.14% and 61.70% for stage I and stage II–III patients, respectively. Furthermore, our multimodal assay effectively differentiated multiple molecular subtypes of breast tumors from benign lesions, achieving the highest sensitivity of 71.43% with Luminal A, followed by Luminal B, Triple Negative Breast Cancer (TNBC), Luminal B-HER2, and HER2 with sensitivities of 66.67%, 60%, 58.33% and 55.56%, respectively. Conclusions: Our findings demonstrate the potential of cancer-specific methylation and fragmentomic patterns in plasma cfDNA as novel biomarkers for accurately discriminating between breast cancer and benign lesions. This capability reduces the false-positive rate and helps avoid unnecessary biopsies in current clinical practice.
Clinical characteristics and outcomes in patients with early-onset locally advanced rectal cancer.
Authors: Pretta Andrea , Ziranu Pina , Giampieri Riccardo , Donisi Clelia , Randon Giovanni , Moledda Giusy , Morano Federica , Spanu Dario , Cadoni Andrea , Cimbro Erika , Dell'Utri Veronica , Rizzo Daiana , Codipietro Claudia , Semonella Francesca , Puzzoni Marco , Pusceddu Valeria , Zorcolo Luigi , Berardi Rossana , Pietrantonio Filippo , Scartozzi Mario 
Published: August 2024

70 Background: Despite a reduction in both the incidence and mortality of CRC in the elderly population, recent studies have highlighted an increase in the incidence of early-onset CRC (EO-CRC). Clinical and prognostic data in this context are limited and conflicting. The aim of our study was to evaluate the clinical differences and outcomes of patients with early onset locally advanced rectal cancer. Methods: We retrospectively collected data from 305 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was overall survival (OS) while while secondary objectives were overall response rate (ORR) and major TRG. Results: Twenty five (8,2%) pts were EO-RC and 280 (91,8%) were LO-RC. In EO-RC the locations were distributed as follows: 9 (36%) lower rectum, 13 (52%) medium rectum, and 3 (12%) upper rectum. Pathologic responses were as follows: 3 (12%) TRG-0, 6 (24%) TRG-1, 10 (40%) TRG-2, and 6 (24%) TRG-3. While the radiological responses were as follows: 2 (8%) CR, 15 (60%) PR, 7 (28%) SD, and 1 (4%) PD. In LO-RC the locations were: 78 (27,8%) lower rectum, 153 (54,6%) medium rectum, and 49 (17,6%) upper rectum. Pathologic responses were as follows: 29 (10,4%) TRG-0, 60 (21,4%) TRG-1, 159 (56,8%) TRG-2, and 32 (11,4%) TRG-3. Radiological responses were as follows: 25 (8,9%) CR, 155 (61,4%) PR, 64 (22,9%) SD, and 19 (6,8%) PD. The 10 year overall survival was significantly higher in LO-RC patients compared to EO-CRC patients: 92.54% versus 70.83% (p = 0.0005). Conclusions: Compared to LO-RCs, EO-RC patients had more frequent low rectal tumors and higher rates of major pathological responses. Despite this, 10-year OS was found to be inferior in EO-RC. Further studies and insights will be necessary to better understand the biological and clinical characteristics of early-onset tumors.