bluuebunny/crossref_metadata_2025_split huggingface dataset:
FG-M108 plus nab-paclitaxel and gemcitabine (AG) as first-line (1L) treatment for patients with Claudin-18.2 (CLDN18.2) positive locally advanced unresectable or metastatic pancreatic cancer (PC): Preliminary results from the phase 1b study.
Authors: Jin Zhaoyu , Zhang Yanqiao , Liu Funan , Zhang Shu , Gong Jifang , Zhang Miao , Liang Xinjun , Wang Junye , Li Yun , Yang Xiaochun , Yang Yaping , Shen Lin 
Published: June 2024

4142 Background: PC is one of the most lethal cancers with limited treatment options and poor outcomes. The CLDN18.2 antigen is frequently expressed in malignant gastrointestinal cancers including pancreatic cancer. FG-M108 is a human monoclonal antibody specifically targeting CLDN18.2 with optimal affinity and enhanced antibody-dependent cellular cytotoxicity. Methods: A multi-center phase 1b study of FG-M108 (NCT04894825) is ongoing, with one cohort evaluating the safety, tolerability, preliminary efficacy, pharmacokinetics, and immunogenicity of FG-M108 plus AG in patients with locally advanced unresectable or metastatic PC. Only patients with positive CLDN18.2 expression (IHC 1+/2+/3+≥10%) were eligible. This cohort of patients received FG-M108 (intravenous, 300 mg/m2 day 1) plus gemcitabine (intravenous, 1000 mg/m2, days 1 and 8) and nab-paclitaxel (intravenous, 125 mg/m2, days 1 and8) every 3 weeks until disease progression, unacceptable toxicity, or discontinuation. The primary safety endpoint was the incidence of adverse events (AEs) and the secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS). Responses were assessed by RECIST 1.1 every 6 weeks. AEs were graded using CTCAE v5.0. Results: As of January 15, 2024, 31 patients received 300 mg/m2 FG-M108 plus chemotherapy. The most common FG-M108 related AEs were nausea (43.5%), emesis (30.4%), neutropenia (21.7%), and anemia (21.7%). The most common grade ≥3 AEs of any cause were neutropenia (26.1%). FG-M108–related serious AEs occurred in 29.0% of patients. No FG-M108–related grade 4 or 5 AEs and no treatment-related deaths were reported. Median PFS and median OS have not been reached yet. Of the 14 patients who received tumor evaluation at least once, ORR was 50.0% (7/14) and DCR was 100% (14/14). Conclusions: FG-M108 plus AG showed excellent safety profile and promising clinical efficacy as 1L treatment for patients with CLDN18.2+ locally advanced unresectable or metastatic PC. The safety and efficacy, especially PFS and OS, of FG-M108 plus AG treatment will be further evaluated. Clinical trial information: NCT04894825 .
Association of gut microbe and stress-related cancer metastasis and oleic acid degradation.
Authors: He Zhen , Liu Chen , Lan Ping 
Published: June 2024

e15517 Background: Cancer patients often face psychological distress. Cancer metastasis is critical for prognosis. Recent research highlights the link between chronic stress and metastasis. However, the underlying mechanisms is far from known. Methods: Animal models of cancer metastasis were used to explore the effect of chronic stress in promoting tumor metastasis. A combination of antibiotic cocktail treatment, fecal microbiota transplantation and germ-free mice were carried out to confirm whether the pro-metastatic ability of chronic stress was dependent on gut microbiota. 16S rDNA sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Additionally, we assessed hormone changes post-stress and demonstrated the correlation between glucocorticoid elevation and gut microbiota through in vivo and in vitro experiments. Finally, we validated our hypothesis using a prospective colorectal cancer cohort. Results: Mice undergone chronic stress had significantly increased cancer metastasis compared with stress-free control mice. Gut microbial dysbiosis was observed in mice undergone chronic stress, with Bifidobacterium being significantly depleted. Stress hormone, corticosterone could alter intestinal epithelium metabolism, and thus inhibit the growth of Bifidobacterium. Metabolomic analysis showed increased Oleic Acid (OA) in the colonic contents from chronic stress-treated mice, and the pro-metastatic role of OA were examined in vitro and in vivo experiments. Supplement of Bifidobacterium animalis (isolated from feces of the stress-free control mice) could decrease the level of OA and inhibit pro-metastasis effect of stress in mice. OhyA which encoded oleate hydratase was identified in Bifidobacterium animalis by whole genome sequencing. Heterogeneous expression of OhyA in Escherichia coli BL21 showed that supplement of OhyA could decrease the level of OA and abrogate the pro-metastatic effect of chronic stress. We found that glucocorticoid secretion increases during chronic stress, promoting the nuclear translocation of glucocorticoid receptors in epithelial cells and activating the transcription of downstream target genes. Through integrated metabolomic analysis, we demonstrated that glucocorticoids degrade guanine, reducing its concentration in the intestine and thereby inhibiting the growth of Bifidobacterium. Furthermore, our investigation into clinical cohorts revealed that patients with higher stress scores are more prone to tumor metastasis, accompanied by a decrease in the abundance of Bifidobacterium in the gut and an increase in serum and fecal oleic acid levels. Conclusions: Chronic phycological stress promotes cancer metastasis by inhibiting the growth of probiotic microbe Bifidobacterium through modulating epithelium purine metabolism and increasing the level of OA.
Rising trend of early-onset colorectal cancer in the US: Incidence and projections to 2030.
Authors: Pan Chun-Wei , Villaroman Adrian , Cuartas Maria Cristina , Gupta Shweta 
Published: June 2024

e15523 Background: Colorectal cancer (CRC) remains a critical health issue in the United States, particularly notable for its rising incidence in individuals under 55 years. Factors such as lifestyle habits, and genetic predispositions may contribute to pathogenesis while inadequate screening protocols may lead to delayed diagnoses in this younger demographic. Currently, the initial CRC screening guidelines recommend lowering the start age to 45. We seek to provide current data on the US CRC incidence and estimate the burden by 2030. Methods: Using the CDC National Center of Health Statistics database, we queried the incidence rates of CRC from 1999 to 2020. These are reported in Crude rate and age-adjusted rates to standard year 2000 populations per 100,000 person-years. The Autoregressive Integrated Moving Average model was used to predict the projected incidence rate by 2030. R software version 2023.09 was used for analysis. Results: The study identified 3,201,843 CRC cases from 1999-2020, with a notable increase in incidence rates, especially in younger demographics. The largest increase was in the 30-34 age group, with an AAPC of 2.76, followed by the 25-29 and 35-39 age groups, with AAPCs of 2.57 and 2.24, respectively. In contrast, older age groups showed a decline, with the 75-79 age group decreasing from 9.20 to 3.76, and an AAPC of -4.05%. By 2030, early-onset colorectal cancer is expected to rise, particularly in the 40-44 age group (AAPC of 3.26%) and the 35-39 age group (AAPC of 2.92%). The increase is projected mainly in the 25-54 age groups. Conversely, older populations, particularly the 75-79 age group, are projected to see a decrease in incidence rates, from 3.76 to 1.17 per 100,000 by 2030. Conclusions: Our study highlights a significant rise in early-onset CRC, especially in the 25-54 age group, with an increasing projection by 2030 while older age groups are expected to experience a decrease in incidence rates. Consideration should be given to expanding CRC screening in patients younger than 45. [Table: see text]
Impact of delirium on outcomes among hospitalized patients with colorectal cancer: A United States population-based cohort study.
Authors: Arya Yajur , Syal Arshi , Casipit Carlo , Casipit Bruce Adrian , Ratnani Akshay , Leighton John Charles , Dourado Claudia M. 
Published: June 2024

e15524 Background: Delirium is commonly encountered among hospitalized patients. It leads to cognitive and functional decline, resulting in longer recovery time. Patients with cancer, especially those undergoing surgery, are at higher risk for delirium and its adverse effects. Our study aims to explore the impact of delirium on hospitalized patients with colorectal cancer. Methods: We utilized the 2020 National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified patients with colorectal cancer and delirium using appropriate ICD-10 diagnostic codes. We stratified patients with colorectal cancer based on the presence or absence of delirium. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of < 0.05 was considered statistically significant. The aim of this study was to investigate the impact of delirium on in-hospital mortality, hospital length of stay (LOS), and total hospitalization charge among hospitalized patients with colorectal cancer. Results: We identified a total of 77130 hospitalized patients with colorectal cancer, of which 1.91% (1475/77130) had concomitant delirium. The overall in-hospital mortality among patients with colorectal cancer was 2.74% (2115/77130). Among those with concomitant delirium, the mortality rate was significantly higher at 10.51% (155/1475, p < 0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, delirium was found to be an independent predictor of increased in-hospital mortality (adjusted OR 3.34; 95% (confidence interval [CI], 2.05-5.42; p < 0.001), longer LOS (coefficient 4.72; CI 3.26-6.18; p < 0.001), and higher total hospitalization charge (coefficient $36247; CI $22123- $50371; p < 0.001). Conclusions: Our analysis showed that delirium significantly worsens outcomes, including increased in-hospital mortality, LOS, and cost of healthcare utilization among hospitalized patients with colorectal cancer. Efforts should be made to prevent and proactively manage delirium in the inpatient setting, particularly with non-pharmacological techniques. Further prospective studies are needed to better describe these associations.
Efficacy and safety of fruquintinib across different subgroups of patients with previously treated metastatic colorectal cancer: A meta-analysis.
Authors: Leite da Silva Luis Felipe , Peixoto Renata D'Alpino , Zheng-Lin Binbin , de Menezes Junior Alonso , Batalini Felipe 
Published: June 2024

e15589 Background: Most patients with mCRC eventually develop disease progression or intolerance to first- and second-line therapy. Fruquintinib, a selective oral tyrosine kinase inhibitor of VEGFRs 1, 2, and 3, has emerged as a novel treatment option for refractory mCRC. We conducted a meta-analysis to assess the safety and efficacy of Fruquintinib for the treatment of refractory mCRC compared to placebo in specific patient subgroups of interest. Methods: We systematically searched PubMed, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) reporting Fruquintinib efficacy. The data extraction followed PRISMA guidelines and our protocol was registered in PROSPERO (CRD42023477783). Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. The likelihood of Fruquintinib being associated with adverse events (AEs) was expressed by odds ratios (ORs). Results: Of the 1138 studies yielded by the search, three were included, totaling 1178 patients, of whom 786 (67%) received Fruquintinib. This meta-analysis of three randomized trials assessed the clinical outcomes of Fruquintinib in the intervention group compared with placebo in refractory mCRC. Pooled results from all three studies suggested the superiority of Fruquintinib in PFS (HR: 0.29 [0.25, 0.34], 95% CI, I² = 10%, p < 0.01) and OS (HR: 0.66 [0.57, 0.76], 95% CI, p < 0.01). Notably, subgroup analysis showed that Fruquintinib was associated with improved PFS in patients with prior use of VEGF inhibitors (HR: 0.32 [0.27, 0.38], 95% CI, p < 0.01) and those with more than three prior lines of treatment (HR: 0.37 [0.25, 0.53], 95% CI, p < 0.01), RAS wild-type status (HR: 0.25 [0.13, 0.35], 95% CI, p < 0.01), or RAS mutated (HR: 0.33 [0.28, 0.40], 95% CI, p < 0.01). In the safety analysis, fruquintinib and placebo showed no significant differences in serious AEs; nonetheless, the VEGFR inhibitor was associated with more frequent grade ≥ 3 AEs (OR: 3.13 [1.15, 8.53], 95% CI, p = 0.03). Conclusions: This meta-analysis supports the efficacy of Fruquintinib for refractory mCRC regardless of previous use of VEGF inhibitors, the number of previous treatment lines, and gene RAS mutational status, without a significant increase in serious adverse events. [Table: see text]
The utility of multiple clinical variables in predicting survival outcome for patients with rectal cancer: An integrated regression and retrospective cohort analysis.
Authors: Zhong Jiasheng , Lei Fuming , Gao Qingkun , Shi Jingyi , Sun Zhuang , Huang Wensheng , Zhai Zhichao , Ding Changming , An Ke , Wang Shufang , Zhang Jialin 
Published: June 2024

e15610 Background: Prior studies have investigated clinical factors impacting the survival rates of rectal cancer patients. However, a robust and precise model for discerning these risks, which can be identified by integrated regressions analysis has yet to be established. The aim of this study is to develop and evaluate the diagnostic value of the constructed prediction model based on selected clinical variables. Methods: Patients diagnosed with stage II-III rectal cancer (April 2015-June 2021) were retrospectively enrolled as the primary cohort. Individual variables were extracted and then subjected to a K-adaptive partitioning algorithm for cut-off point determination and grouping. The Cox and least absolute shrinkage and selection operator regression (LASSO) regression were applied for independent predictors selection over significant overall survival (OS), and a nomogram was subsequently constructed. The performance of the constructed model was evaluated using the receiver operating characteristics (ROC) curves, calibration curves, and decision curve analysis (DCA), and stepwise compared with data cohorts derived from TCGA and SEER databases. Results: The Cox-LASSO analysis results considered the four independent variables as significant predictors, yielding the risk score equation: 1.086(for CEA level≥7.5 ng/ml) -1.7756(if gender is male) +1.829*(pT stages) +0.582*(pN stages). Notably, the distal resection margin (DRM) was excluded from the final model following the analysis (p = 0.060, 95%CI: -0.04-2.17). The constructed model (C-index:0.790, 95%CI: 0.673-0.743, AUC:0.873) outperformed the conventional TNM staging models (C-index:0.539, 95%CI:0.121-0.957, AUC:0.735). It stratified patients into low- or high-risk groups with significant OS differences (93% vs. 37%, p≤0.0001, respectively). The calibration curves for OS probability showed strong homogeneities between predictions and actual observations. DCA revealed positive net benefits at evaluated first, third, and fifth years. Moreover, the external validations confirmed the accurate prediction following the constructed model, with AUC of 0.745 and 0.705 for the TCGA and SEER datasets, respectively. Conclusions: This study resulted in a novel and effective prediction model for rectal cancer patients based on conventional clinical characteristics. It demonstrated solid performance and can serve as a convenient tool for OS prediction, aiding in rectal cancer patients' risk scoring and clinical decision-making.
A multi-center, open-label phase 1/1b dose finding, safety, and pharmacokinetic study of MBRC-101, an Anth-EphA5 monomethyl auristatin (MMAE) antibody drug conjugate, in advanced refractory solid tumors.
Authors: Sen Shiraj , Salkeni Mohamad Adham , Albany Costantine , Gandhi Neel Jitendra , Edenfield William Jeffery , Parsons Kellogg , Chen Isan , Powderly John D. 
Published: June 2024

TPS3161 Background: EphA5 receptor is a member of the Ephrin receptor tyrosine kinase family. Several lines of compelling nonclinical evidence indicate EphA5 is a novel and selective target for solid tumor-directed therapy. Expressed only minimally in normal tissues, it is highly expressed in non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma (HNSCC), and breast, colorectal, pancreatic, gastric, and hepatic malignancies. MBRC-101 is a novel antibody drug conjugate (ADC) composed of an anti-EphA5 antibody conjugated to an MMAE payload (drug-to-antibody ratio of 4) through a valine citrulline cleavable linker. In pre-clinical toxicology studies and testing against a variety of cell-derived (CDX) and patient-derived (PDX) xenograft solid tumor models expressing EphA5--including NSCLC, triple negative breast cancer (TNBC), and HNSCC--MBRC-101 demonstrated favorable safety profiles and robust anti-tumor activity. Methods: This first-in-human, Phase 1/1b, multicenter, open-label study is examining the safety and efficacy of MBRC-101 in patients with advanced metastatic solid tumors refractory to standard treatment. Phase 1 will identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101 at one or more dosing regimens. Phase 1b will evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs. Phase 1 will enroll patients (n ≈ 30) with advanced or metastatic solid tumors. EphA5 expression will not be required for enrollment into Phase 1 but will be assessed retrospectively. A modified toxicity probability interval (mTPI-2) method will guide dose escalation using a pre-specified decision matrix. The primary endpoints are MTD, dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), and clinical laboratory tests. Phase 1b (n ≈ 60 patients) will include 3 expansion cohorts (n ≈ 20 patients per cohort): Cohort A, NSCLC; Cohort B, triple negative or HR+/HER2- breast cancer; and Cohort C, solid tumors irrespective of histologic tissue type (i.e., tumor agnostic) excluding NSCLC and breast cancer. Expression of EphA5 in primary or metastatic tumor tissue will not be required for enrollment into cohorts A and B but will be required for Cohort C. The primary endpoints are TEAEs, clinical laboratory tests, and investigator-assessed objective response rate (ORR) by RECIST v1.1 and clinical evaluation. Secondary endpoints for Ph1 and 1b include PK analytes and EphA5 expression as determined by immunohistochemistry (IHC). A Safety Review Committee will monitor safety at each dose escalation in Phase 1 and at regular intervals throughout Phase 1b. Clinical trial information: NCT06014658 .
A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1.
Authors: Yamamoto Noboru , Doi Toshihiko , Patel Manish R. , Garrido-Laguna Ignacio , Wu Sutan , Nishioka Satoshi , Nakajima Keiko , Carneiro Benedito A. 
Published: June 2024

TPS3165 Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (DXd). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors. Methods: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll up to 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid TA-MUC1-expressing tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS-3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a. Clinical trial information: NCT05875168 .