bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly accurate detection of early-stage colorectal cancer using tumor and immune extracellular vesicles biomarkers.
Authors: Hembrough Todd A. , Mudgal Poorva , Opheim Zachary , Bandoski Cheryl , Isaac Issa , Mehnert Martin , Anschau Valesca , Ezrin Alan
Published: January 2025

262

Background:
Colorectal cancer (CRC) is one of the most common cancers worldwide, and early detection is critical for successful treatment and improved survival rates. However, precancerous and early-stage CRC present significant diagnostic challenges due to the small size of lesions and the very low expression of tumor-specific biomarkers in the bloodstream. Current genomics-based diagnostic methods struggle to detect these early-stage and precancerous lesions, making it imperative to develop more sensitive and specific approaches. Circulating extracellular vesicles (EVs) are emerging as a promising solution for early-stage CRC detection. Since EVs are produced by tumor cells as well as tumor microenvironment and host immune response cells, EVs offer the means to detect and monitor small early-stage tumors through both direct detection of tumor-associated biomarkers as well as tumor specific host response and tumor microenvironment biomarkers.
Methods:
To identify novel early-stage CRC specific biomarkers, we performed proteomics analysis on EVs purified from patient plasma using size exclusion chromatography and a proprietary buffer system that enhances EV and corona protein recovery. TrueDiscovery Data-independent acquisition (DIA) mass spectrometry (MS) analysis was conducted on 24 pre-cancer/stage 0 and 25 stage 1 CRC patients and 75 normal patient plasma samples. An in-house developed machine learning pipeline was used to identify differentially expressed proteins and model candidate multiplexes to identify those with extremely high diagnostic accuracy (> 0.99).
Results:
An average of ~2,500 proteins were identified per sample and included in bioinformatics analysis. Comparative analysis between control patient EVs and either pre-cancerous/Stage 0, or Stage 1 colon cancer EVs using an in-house Machine Learning pipeline identified 336 and 493 differentially expressed proteins for each group (FDR adjusted p-value < 0.001). Of these, the best 17 pre/stage 0 proteins and 53 stage 1 proteins were trained and tested using Support Vector Machine to assess all potential 3-plexes in order to identify those with mean diagnostic accuracy > 99%. This yielded 5 3-plexes in precancer/stage 0 and 34 3-plexes in stage 1 with near perfect diagnostic accuracy. These plexes are currently being assessed in single analyte and multiplex immunoassays with the goal of translating candidate 3-plexes to the clinical.
Conclusions:
Key biomarkers from CRC patient EVs indicate the potential to detect and diagnose early-stage and low tumor burden cancers using our methods. Interestingly, the most accurate 3-plexes consist of proteins from immune, inflammatory and metabolic processes, suggesting that for the detection of early stage cancer it may be critical to include both tumor and host specific biomarkers.
A retrospective study of colorectal cancer CT imaging features involving microsatellite instability.
Authors: McLaughlin Scott , Stearns Jack , Chiu Albert , Hutzley Samantha , Kuckelman Tristan , Kloft Luke , Bay Curt , Kundranda Madappa N. , Chang John
Published: January 2025

265

Background:
This study aimed to identify correlations between CT imaging characteristics accessible to the radiologist with microsatellite instability (MSI) status among colorectal cancer. Noninvasive identification of MSI status can decrease time to treatment if pathology can be bypassed.
Methods:
109 colorectal cancer patients were identified retrospectively from 2011 to 2018 with an average age of 61 years (58 male, 51 female) and had MSI pathological assessment. These subjects all had CT abdomen and pelvis obtained at the time of initial diagnosis. Imaging features of both the primary and metastatic lesions were assessed. Primary lesion features included: location, size, stage, attenuation compared to the liver, growth pattern, tumor margin, primary mass area, and the presence/absence of mesenteric infiltration. Metastatic lesion features included: size, attenuation relative to liver, and enhancement pattern. Patient age, sex, and tumor staging were obtained from patient medical records. Statistical analysis was performed using various methods, including chi-square, Mann-Whitney and Kruskal-Wallis tests.
Results:
5 tumor characteristics displayed a statistically significant relationship with MSI status. MSI-H lesions were more likely to be clinical Stage 2, and MSI-L lesions were more likely to be Clinical Stage 3 (p=0.012). Tumors with distant metastasis were more likely MSI-L versus regional metastasis were more likely MSI-H (p<0.001). Primary mass area was larger in the MSI-H than MSI-L group (p<0.001). Tumors in the left colon are more likely to be MSI-L versus CRC tumors in the right colon are more likely to be MSI-H (p<0.001). MSI-H tumors had a lower primary tumor Hounsfield Unit standard deviation (SD) than MSI-L tumors (p=0.002). The remaining features were not statistically significant. For primary lesion, these include mesenteric infiltration (p=0.189), tumor margin (p=1.000), enhancement pattern (p=0.498), growth pattern (p=0.127), tumor CT density (p=0.162), and liver density (p=0.105). Enhancement of metastasis also had no difference (p=0.376).
Conclusions:
Multiple CT imaging characteristics were predictive of MSI classification in CRC tumors, holding potential clinical relevance that can help guide individualized therapy. While these results were statistically significant, more research must be done to validate these findings and to derive useful nomograms.
Development of a methylation-based, tissue-agnostic test for the detection of molecular residual disease by circulating tumor DNA.
Authors: Shen John Paul Y.C. , Reiter Johannes , Babiarz Joshua , Srinivasan Preethi , Lu Fei , Haghshenas Ehsan , Chen Tzu-Chun , Liang Nathan , Joshi Jayashree , Huang Hsiao-Yun , Cerna Liliana , Alexander Spenser , Gutman Boris , Kushwaha Garima , Aushev Vasily N. , Cruz-Correa Marcia , Rabinowitz Matthew , Kawli Trupti , Aleshin Alexey , Cohen Stacey A.
Published: January 2025

266

Background:
Clinical validation studies support tumor-informed molecular residual disease (MRD) as a prognostic biomarker for disease recurrence across multiple solid tumor types. However, these tests are not always feasible due to the occasional lack of tumor tissue. Here, we discuss the design of a test for tissue-agnostic MRD detection and its application to a cohort of patients with colorectal cancer (CRC).
Methods:
A targeted panel composed of differentially methylated regions was developed. A machine-learning model was trained on differential methylation patterns in order to classify plasma samples as MRD-positive or MRD-negative. Performance of the independently trained classifier was assessed in a cohort of 247 patients enrolled in the Bespoke CRC trial (NCT04264702). These patients had MRD results available using a tumor-informed circulating tumor DNA (ctDNA) assay (Signatera), of whom 163 were persistently MRD-negative without clinical progression and 84 had MRD-positive results. Tissue-agnostic MRD results were compared to the tumor-informed results by calculating the percent positive agreement (PPA). Additionally, the differentially methylated allele fraction (DMAF) from the tissue-agnostic test was compared with variant allele frequencies (VAFs) from the tumor-informed test.
Results:
In the Bespoke CRC clinical cohort (72% non-Hispanic White, 54% male, mean age 61.4±12.3 years), 71 (28%) patients had stage II CRC, and 147 (60%) had stage III CRC. Overall, PPA was 86% (95% CI: 70-100%) and specificity was 97% (95% CI: 93-100%). When categorizing based on tumor-informed MRD VAF levels, PPA was 97% for VAF >0.2%, 100% for VAF 0.1-0.2%, 89% for VAF 0.04-0.1%, and 68% for VAF <0.04%. The DMAFs strongly correlated with the VAFs from the tumor-informed test and the correlation was independent of disease stage, histology, age, and sex.
Conclusions:
This is the first study of its kind demonstrating high concordance between a tissue-agnostic MRD test and a clinically validated tumor-informed ctDNA assay. These findings demonstrate that in cases where tissue is not available or of inadequate quality, a methylation-based tissue-agnostic assay may serve as a potential alternative for MRD detection.
Comparative analysis of demographics and outcomes in hospitalized patients with young- versus average-onset colorectal cancer in New York state (2017-2022).
Authors: Ramesh Mrinalini , Fakhari-Tehrani Yasmin , Deenadayalan Vaishali , Yuan Guangwei , Yu Han , Vadehra Deepak , Mukherjee Sarbajit
Published: January 2025

27

Background:
Recent studies have shown an increasing incidence of colorectal cancer (CRC) among young patients. This study investigates clinical outcomes and healthcare utilization among young (<50) versus average onset (≥50) CRC patients admitted to hospitals in New York State (NYS).
Methods:
We performed a retrospective analysis using the Statewide Planning and Research Cooperative System (SPARCS) database from 2017 to 2022. Patients were divided into two groups: young-onset colorectal cancer patients (YOCRC, <50 years) and average onset colorectal cancer patients (AOCRC, ≥50 years). The study population was further stratified by demographic and clinical characteristics. All associations were compared using the Kruskal-Wallis test, along with multivariate linear and logistic regression in RStudio version 4.4.1, at a significance level of ≤0.05. Clinical characteristics, including severity of illness and risk of mortality, were defined using the All Patient Refined (APR) grading system.
Results:
A total of 9,904 patients were identified (948 YOCRC and 8,956 AOCRC) with a primary admitting diagnosis of CRC from 2017 to 2022. In comparing the two age groups, AOCRC patients had a higher proportion of White, and female patients, whereas the YOCRC group included a higher proportion of Black and male patients (p<0.001). The median length of stay was greater for AOCRC patients (5 days) compared to YOCRC patients (4 days), p<0.001. Both age groups showed an upward trend in total cost of stay in the recent years. AOCRC patients were more likely to have increased severity of illness graded as major-extreme (60% vs 48%), while a higher proportion of YOCRC patients were classified as minor-moderate disease (51% vs 40%), p<0.001. Similarly, AOCRC patients experienced a higher risk of mortality compared to YOCRC patients (p<0.001). Regarding procedures, AOCRC patients needed more transfusions (13%) than YOCRC patients (9.3%), p<0.001. YOCRC patients were also more likely to be discharged home (71% vs 46%), while AOCRC patients often required home health services or skilled nursing (p<0.001). Notably, while the risk of mortality was higher for AOCRC patients, it has been decreasing overall from 2017 to 2022 [OR 0.92 (95% CI: 0.84-0.99), p=0.039].
Conclusions:
AOCRC patients experienced greater severity of disease, higher mortality risk, and required more assistive care at discharge compared to YOCRC patients. The total cost of hospital stays has been rising for both groups. Policies focused on earlier outpatient interventions may help reduce the burden of inpatient care and rising costs.
Comprehensive landscape of FGFR variations and prognosis revelance in colorectal cancer from circulating tumor DNA and tissue gene analyses in 2083 patients.
Authors: Lyu Xiaoshuang , Cai Runkai , Han Bohan , Deng Yanhong
Published: January 2025

278

Background:
FGFR genomic alterations have been identified, and several FGFR inhibitors are approved for various malignancies, including bladder and cholangiocarcinoma. However, limited studies have shown FGFR alterations and their prognostic impact in colorectal cancer (CRC).
Methods:
This retrospective analysis involved tissue and blood samples from a single-institute cohort (The Sixth Affiliated Hospital of Sun Yat-sen University) of stage I-IV CRC patients from 2014 to 2024. FGFR genomic alterations were analyzed using tissue NGS and plasma ctDNA. Disease-free survival (DFS) for stages I-III and progression-free survival (PFS) for stage IV were compared between FGFR-altered and negative CRC patients, matched in a 1:2 ratio. Validation of genomic alterations and their prognostic impact was conducted using cBioPortal and TCGA data.
Results:
FGFR alterations were found in 7.89% of 608 tissue samples and 10.95% of 2083 ctDNA samples. The most frequent alteration was FGFR1 amplification in all cohorts, along with FGFR2 p.R165W and FGFR3 p.A634T mutations in ctDNA. FGFR alterations correlated with younger age, left-sided colon tumors, adenocarcinomas, poor differentiation, advanced TNM staging, and multi-organ metastasis. Prognostic analysis showed a higher proportion of FGFR alterations in stage IV patients (66.23% vs. 59.14%), lower rates of no evidence of disease (NED) (6.62% vs. 17.68%), and significantly shorter PFS (median 17 vs. 20 months, HR 2.184, p=0.007). In stages I-III, FGFR-altered patients also had a lower NED rate (79.22% vs. 82.19%) and significantly shorter DFS (median 13 vs. 29 months, HR 2.833, p=0.002). Among frequent alterations, FGFR1 amplification was significantly associated with poor prognosis (PFS 17 vs. 20 months, HR 2.221, p=0.014; DFS 13 vs. 29 months, HR 2.964, p=0.002), while others showed no significant correlation. In stage IV patients receiving bevacizumab, FGFR1 alteration was linked to significantly shorter PFS (p=0.0021). KEGG analysis indicated FGFR1 was associated with angiogenesis pathways. FGFR alteration profiles and prognostic outcomes were consistent across tissue samples, ctDNA analyses, and databases.
Conclusions:
Our study outlines the genomic landscape and prognostic significance of FGFR in CRC, highlighting FGFR1 amplification as the dominant alteration. FGFR alterations were associated with poorer outcomes, as reflected in lower NED rates and shorter DFS and PFS. FGFR1 amplification was notably linked to reduced DFS and PFS, and it correlated with shorter PFS in patients receiving bevacizumab, indicating a potential link to resistance against bevacizumab.

ctDNA n=2083
Tissue genen=608
cBioPortal Databasen=6998

FGFR Total
228/10.95%
48/7.89%
528/8.0%

FGFR1
76/3.65%
29/4.77%
264/4.0%

FGFR2
78/3.74%
10/1.64%
125/1.9%

FGFR3
104/4.99%
10/1.64%
139/2.1%
Safety and biomarker assessment of ST316, a novel peptide antagonist of ß-catenin, in patients with advanced solid tumors.
Authors: El-Khoueiry Anthony B. , Lakhani Nehal J. , Henry Jason Timothy , Powell Steven Francis , Mettu Niharika B. , Gakuria Joyce , Abbate Franco , Nuciforo Paolo , Rotolo Jim , Vainstein Haras Abi
Published: January 2025

286

Background:
Constitutive activation of ß-catenin, resulting in its nuclear accumulation and deregulated transcriptional activity, is a key event in colorectal cancer (CRC). Additionally, pathway mutations correlate with immune exclusion in CRC and across different tumor types. Disruption of the interaction of ß-catenin and its co-activator BCL9 is sufficient to suppress oncogenic ß-catenin transcriptional activity, without impacting its homeostatic functions in normal tissue. ST316 is a first-in-class, cell-penetrating peptide antagonist of the ß-catenin and BCL9 interaction. Preclinical evaluation revealed significant bioavailability and potent activity in CRC models with no impact on ß-catenin homeostatic functions such as intestinal stem cell survival or bone morphology.
Methods:
A phase 1-2 (P1-2) escalation-expansion study has enrolled patients (pts) with advanced solid tumors likely to harbor abnormalities in the Wnt/ß-catenin pathway, to assess the safety, pharmacokinetics (PK), biomarker and preliminary activity of ST316, and to recommend a P2 dose (RP2D). Paired biopsies were collected when feasible and assessed for drug penetration and pharmacodynamic biomarkers. Peripheral blood (PB) collected pre- and post-treatment was assessed by flow cytometry for polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs).
Results:
As of Sep.24,

2024; 23 pts with CRC (N=14), NSCLC (N=4), PDAC (N=2), or Breast and Ovarian cancer (N=1, each), were treated in 6 cohorts (0.5-12mg/kg) with IV ST316, once weekly. Treatment related AEs were observed in 17/23 pts and were mostly low grade, except for 2 G3 AEs that resolved: Fatigue (1) and ALT/AST elevation (1). No dose-limiting toxicities (DLTs) were observed. Single agent ST316 showed disease stabilization in 4 pts. PK analysis showed dose-proportional increases in Cmax and AUC for doses up to 8 mg/kg. IHC analysis showed substantial tumor penetration of ST316 in all analyzed samples and evidence of a treatment-induced redistribution of β-catenin in a subset of pts. PB analysis indicated high baseline levels of the ß-catenin-driven immunosuppressive PMN-MDSCs , followed by a significant decrease after ST316 exposure (p<0.005). The RP2D selected for combination cohorts in CRC is 8mg/kg; additional PD assessments are ongoing.
Conclusions:
Monotherapy ST316 was well-tolerated with dose-proportional PK and substantial tumor uptake. Pharmacodynamic analyses demonstrate mechanistic evidence of antagonism of ß-catenin signaling, including redistribution of ß-catenin subcellular localization and significant depletion of the ß-catenin-driven immunosuppressive PMN-MDSC population. Based on these data, ST316 advanced into P2 in CRC pts in combination with SoC in 2
nd
and 3
rd
line.
Clinical trial information: NCT05848739
.
A multimodal deep learning approach for the prognostic stratification of patients with colorectal cancer (CRC).
Authors: Shaker Nuha , Shaker Noor , Singhi Aatur D.
Published: January 2025

287

Background:
Traditional prognostic systems like the AJCC TNM staging for colorectal cancer (CRC) often fall short in predicting long-term patient outcomes. These systems often rely on limited pathologic features, leading to generalized approaches to treatment despite diverse tumor heterogeneity, such as the complex interaction between the tumor-host microenvironment. There is therefore a pressing need for more accurate, scalable tools to enhance decision-making and predict outcomes for patients with CRC.
Methods:
Tumor sections from 191 CRC patients were comprehensively stained for CD8 to examine CD8-positive tumor-infiltrating lymphocytes (TILs). To account for tumor heterogeneity, multiple areas of the tumor were evaluated to include intertumoral and peritumoral areas. Slides were digitized and quantitatively analyzed using a cloud-based platform (SpatialX Diagnostics, Inc. USA). Additionally, clinicopathologic features including patient demographics, 8th edition AJCC staging, lymphovascular invasion (LVI), perineural invasion (PNI), mismatch repair (MMR) protein status, tumor location, presence/development of distant metastases, and patient follow-up were collected. Merging CD8 AI findings with clinicopathologic features, a complete data set was available for 175 patients. Cases were randomly assigned into 70% training and 30% validation. In the training set, unsupervised artificial intelligence (AI) models integrated clinicopathologic data and CD8-positive TIL counts using vision transformer models. The final model combined spatially resolved pathologic features with clinical variables to statistically predict overall survival (OS) and distant metastasis risk (DMR).
Results:
In the validation cohort, the model stratified patients into two groups based on a deep learning-derived risk score, with statistically significant differences between low-risk and high-risk groups for OS (p<0.02) and DMR prediction (p<0.0001), For OS prediction, the model selected tumor site, PNI, MMR status, epithelial and stromal CD8-positive TILs, and 5 deep vision features as the top 10 clinically significant features. For DMR prediction, the age, T- and N-stage, PNI, and 6 deep vision-derived features as key predictors.
Conclusions:
As captured by vision transformers, the distribution and spatial arrangement of CD8-positive TILs are critical factors in patient stratification for OS and DMR. AI-driven models like the one herein offer the potential for more personalized management strategies, advancing CRC management and improving patient outcomes beyond traditional prognostic staging systems and parameters.
The role and molecular mechanism of GDF5 in regulating cell migration and angiogenesis via the Hippo-YAP signaling pathway in colorectal cancer.
Authors: Lei Peijie , Jiang Tao
Published: January 2025

292

Background:
Distant metastasis is a leading cause of poor prognosis and mortality in colorectal cancer (CRC) patients, with angiogenesis playing a crucial role in tumor progression. The TGF-β superfamily has been shown to significantly influence tumor angiogenesis, yet the biological function and molecular mechanism of Growth Differentiation Factor 5 (GDF5), a member of this superfamily, remain unexplored in CRC. Given that the efficacy of current anti-angiogenic therapies is limited to a subset of patients, identifying new therapeutic targets involved in tumor angiogenesis is of great clinical importance. GDF5, with its potential role in angiogenesis regulation, presents a promising candidate to bridge this therapeutic gap.
Methods:
In this study, we analyzed GDF5 expression in CRC tissue samples using both the TCGA dataset and samples from our center, revealing significantly lower GDF5 expression in tumors compared to adjacent normal tissues. Moreover, GDF5 downregulation correlated with lymph node metastasis and disease recurrence. Functional assays in vitro demonstrated that GDF5 overexpression reduced tumor cell migration and invasion, while its knockdown produced the opposite effect. Co-culture assays showed that GDF5 knockdown significantly enhanced endothelial cell migration and angiogenesis, whereas overexpression diminished these effects. Additionally, F-actin cytoskeletal staining indicated that GDF5 overexpression led to cytoskeletal remodeling in endothelial cells. Mechanistically, we found that GDF5 overexpression in tumor cells downregulated the epithelial-mesenchymal transition (EMT) marker Slug and upregulated E-cadherin, while downregulating N-cadherin. In endothelial cells, GDF5 inhibited the Hippo-YAP signaling pathway, increasing YAP phosphorylation and reducing nuclear YAP levels. Conversely, GDF5 knockdown suppressed YAP phosphorylation and promoted its nuclear translocation.
Results:
Our findings demonstrate that GDF5 functions as a tumor suppressor in CRC by regulating cell migration and angiogenesis. This study reveals that GDF5 exerts its anti-cancer effects by modulating both EMT in tumor cells and cytoskeletal changes in endothelial cells, leading to the inhibition of the Hippo-YAP signaling pathway and reduced angiogenic potential. These results identify GDF5 as a promising new target for anti-angiogenic therapy in CRC, offering potential avenues for improving treatment strategies in patients resistant to current therapies.
Conclusions:
GDF5 acts as a tumor suppressor in colorectal cancer by inhibiting cell migration and angiogenesis through modulation of the Hippo-YAP signaling pathway, making it a promising therapeutic target for anti-angiogenic treatment in patients resistant to current therapies.
Retrospective study of fluoropyrimidine chemotherapy dosing and toxicity in patients with screen-detected deleterious
DPYD
gene variants.
Authors: Leatheng Chanbormey , Ephraim Adam , Brooks Gabriel A.
Published: January 2025

293

Background:
Fluoropyrimidine chemotherapy agents are commonly used to treat solid tumors. Fluoropyrimidines are degraded by the enzyme dihydropyridine dehydrogenase (DPD), encoded by the
DPYD
gene. Deleterious variants in
DPYD
leads to functional DPD deficiency and increased toxicity risk.
Methods:
We conducted a retrospective study of patients with screen-detected deleterious
DPYD
variants who were treated with fluoropyrimidine chemotherapy between 01/01/15-04/15/23. Outcomes of interest were initial fluoropyrimidine dosing, dose adjustments (cycles 2-6), and early toxicities.
Results:
We identified 12 patients with heterozygous
DPYD
variants, including *2A (n=5), c.2846A>T (3), c.1129-5923C>G (2) and *13 (2). Initial chemotherapy regimens included FOLFOX (7), mFOLFIRINOX (3) and CAPEOX (1). Of 11 patients receiving FOLFOX/mFOLFIRINOX, nine began treatment with a 50-60% reduction of the 5-FU infusion dose, one received a 25% reduction, and one received a standard dose (due to treatment initiation prior to return of the genotype result). Seven patients tolerated the initial 5-FU infusion dose without further dose reductions, including three who tolerated limited dose-escalation. Four patients required further dose reduction from the cycle 1 dose, due to toxicity. The patient who received a standard 5-FU infusion dose in cycle 1 experienced grade 3 toxicity, but tolerated subsequent treatment after 50% dose reduction. The patient treated with CAPEOX tolerated 4 planned cycles with a 50% capecitabine dose reduction.
Conclusions:
Most patients who screened positive for deleterious
DPYD
gene variants tolerated fluoropyrimidine chemotherapy with a 50% dose reduction. However, 3 of 12 patients experienced toxicity requiring treatment discontinuation or dose reduction to less than 50% of the standard 5-FU dose.
Effect of changes in body composition and sociodemographic factors on colon cancer survival.
Authors: Catala Vilaplana Ignacio , Smith Gillian V.H. , Schulte Hannah K. , Lim Howard J , Hanley Gillian E , Campbell Kristin L.
Published: January 2025

296

Background:
Muscle mass, muscle quality, and adipose tissue volumes have been shown to affect colon cancer survival. Further research is required to understand how change in body composition during treatment impacts colon cancer outcomes, and how covariables such mental health and socioeconomic status affect this relationship. The aim of this project was to examine how changes in body composition during chemotherapy for colon cancer impact the duration of disease-free survival (DFS) and how sociodemographic covariables (age, sex, social isolation, depression, anxiety, income, community size) influence this relationship.
Methods:
Computed tomography (CT) scans from the time of diagnosis and the end of chemotherapy were obtained from individuals treated for stage III colon cancer with oxaliplatin at BC Cancer between 2012 and 2016. Whole body tissue volumes were estimated based on CT images at the level of the third lumbar vertebra, analysed using
DAFS Express
(Voronoi Health Analytics Inc., Vancouver BC). Muscle quantity was measured as skeletal muscle index (SMI), and muscle quality was measured as skeletal muscle density (SMD) and skeletal muscle gauge (SMG). Quantity of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and total adipose tissue (TAT) were also measured. Social isolation, anxiety, and depression symptoms were measured using the validated Psychosocial Screen for Cancer–Revised. Neighbourhood income and community population were estimated using postal codes. Cox proportional hazard models were calculated for the effect of body composition variables on DFS, and interactions with sociodemographic variables.
Results:
Significant reductions in SMI, SMD, SMG, VAT, IMAT and TAT were observed between diagnosis and post-chemotherapy (n=282). Improved survival was associated with higher SMD and lower IMAT at diagnosis and post-chemotherapy, lower VAT at diagnosis, and an increase in VAT or TAT during chemotherapy. Body composition had a more significant effect on survival in individuals who were older, female, or lived in smaller communities.
Conclusions:
Significant reductions in SMI, SMD, SMG, VAT, IMAT and TAT were observed between diagnosis and post-chemotherapy (n=282). Improved survival was associated with higher SMD and lower IMAT at diagnosis and post-chemotherapy, lower VAT at diagnosis, and an increase in VAT or TAT during chemotherapy. Body composition had a more significant effect on survival in individuals who were older, female, or lived in smaller communities.
Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC).
Authors: Shitara Kohei , Wainberg Zev A. , Tabernero Josep , Van Cutsem Eric , Coutzac Clélia , De La Fouchardiere Christelle , Lee Jeeyun , Rha Sun Young , Kang Yoon-Koo , Fanning Philip , An Grace , Jin Feng , Forgie Alison J , Pons Jaume , Tsiatis Athanasios , Randolph Sophia , Lee Keun-Wook
Published: January 2025

332

Background:
Evorpacept (Evo) is a high affinity, CD47-blocker with an inactive Fc region designed to safely magnify anticancer antibody dependent cellular phagocytosis. Evorpacept is being evaluated across cancers, in combination with anticancer antibodies and checkpoint inhibitors.
Methods:
The ASPEN-06 randomized phase 2 trial evaluates Evo in combination with standard trastuzumab (T), ramucirumab (R) and paclitaxel (P) for the treatment of patients with HER2+ GC. Patients with 2
nd
or 3
rd
line HER2+ advanced or metastatic GC that has progressed on or after prior anti-HER2 therapy were randomized to Evo (30 mg/kg Q2W) plus TRP or TRP. HER2 status was determined in the most recent GC tissue sample. Primary study objectives were to compare confirmed ORR of Evo-TRP to an assumed ORR of RP (=30%) with one-sided alpha error of 0.025 and to identify a clinically meaningful contribution of Evo to TRP in ORR (delta>10%).
Results:
Among the entire randomized population (N=127) the ORR was 40.3% (Evo-TRP) and 26.6% (TRP), respectively. The difference between Evo-TRP's ORR compared to historical RP's ORR was not statistically significant (p=0.095), but Evo-TRP's ORR demonstrated a meaningful delta of 13.7% over TRP's ORR (p=0.028 in an exploratory analysis). Median DOR for Evo-TRP and TRP was 15.7 and 7.6 months, respectively. In a prespecified population with HER2+ disease in fresh tumor tissues after prior anti-HER2 treatment (N=48), Evo-TRP's ORR (54.8%) compared favorably to historical RP's ORR (p=0.030) with a delta of 31.7% over TRP's ORR of 23.1% (p=0.004 in an exploratory analysis). Evo-TRP was well tolerated with a safety profile consistent with prior experience. Updated results including PFS will be presented at the meeting.
Conclusions:
The addition of Evo to TRP showed promising activities in HER2+ GC. The magnitude of response was greatest in tumors identified as HER2+ using fresh biopsies emphasizing the importance of biopsies post anti HER2 therapy. Consistent with Evo’s mechanism of enhancing antibody dependent phagocytosis, these data support its ongoing investigation as an adjunct to anti-HER2 gastric cancer therapy.
Clinical trial information: NCT05002127
.
The influence of depression on esophageal cancer outcomes: Using the National Inpatient Sample (NIS) 2021.
Authors: Babu Kalaivani , Rajarajan Srinishant , Bhanushali Charmi , Ramanan Sruthi , Chattaraj Asmi , Ramachandran Sai Prasad , Ramesh Nithya , Khataniar Himshikar , Correa Amit
Published: January 2025

338

Background:
Esophageal cancer (EC) remains a challenging malignancy with high morbidity and mortality rates. Depression is prevalent among cancer patients and has been shown to affect various clinical outcomes. This study aims to evaluate the impact of depression on mortality, length of stay (LOS), and hospitalization charges in patients with esophageal cancer using data from the NIS.
Methods:
We conducted a retrospective, population-based study using the NIS data to analyze patients diagnosed with esophageal cancer. Depression was the primary exposure variable using the appropriate ICD-10 code. We applied survey-weighted descriptive statistics, logistic regression, and linear regression models to assess outcomes, adjusting for demographic and clinical factors, including age, sex, race, comorbidities (Charlson Comorbidity Index), hospital teaching status, and regional characteristics.
Results:
A total of 40,855 patients with esophageal cancer were included, with 11.4% (n = 4,855) having a concurrent diagnosis of depression. The unadjusted mortality rate for the cohort was 9.18%, with depressed patients showing a lower mortality rate (6.45% vs. 9.53%, p = 0.0018). After adjusting for covariates, depression was associated with significantly lower in-hospital mortality (adjusted OR 0.63, 95% CI 0.48–0.83, p = 0.001). While the unadjusted mean length of stay (LOS) was slightly higher in depressed patients (7.66 vs. 7.25 days, p = 0.132), adjusted models showed no significant difference (β = 0.42 days, p = 0.132). Depression was associated with lower unadjusted total hospitalization charges ($92,321 vs. $104,156, p = 0.023), and in adjusted analyses, depressed patients incurred significantly lower costs (β = -$10,327, 95% CI -$19,233 to -$1,421, p = 0.023). Significant predictors of increased hospitalization charges included teaching hospital status (β = $34,029, p < 0.0001) and large hospital size (β = $38,481, p < 0.0001).
Conclusions:
Depression, while common among patients with esophageal cancer, was unexpectedly associated with lower in-hospital mortality, despite a longer length of stay and higher comorbidity burden. This suggests that depressed patients may receive more comprehensive or prolonged care, which could contribute to their reduced mortality risk. Additionally, despite extended hospital stays, these patients incurred significantly lower hospitalization costs, indicating possible differences in resource utilization or treatment intensity. These findings highlight the complex relationship between mental health and cancer outcomes, emphasizing the need for further research to explore the mechanisms behind these associations and to better tailor care for esophageal cancer patients with depression.
Retreatment with immune checkpoint inhibitors (ICIs) for patients with advanced gastric cancer: A retrospective, real-world study.
Authors: Jia Yong-Xu , Liu Yihan , Han Hui-Qiong , Gao Ya-Ping , Qin Yanru
Published: January 2025

343

Background:
Immunotherapy combined with chemotherapy has become the standard first-line treatment for advanced gastric cancer and is recommended by multiple guidelines and consensuses. After the first line immunotherapy, there is still controversy over whether immune inhibitors can continue to be used across lines after progression.
Methods:
This is a single-center, retrospective, observational, real-world study. We collected clinical information of patients with advanced gastric cancer hospitalized at the First Affiliated Hospital of Zhengzhou University from January 2018 to July 2024. All patients received combination therapy with ICIs inhibitors for at least 2 cycles in the first-line and at least 2 cycles of ICI inhibitor-based therapy in the second-line after first-line progression. The efficacy and safety of treatment were evaluated, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), the progression pattern of retreatment with immune checkpoint inhibitor, grade 3-5 treatment-related adverse events (TRAEs), and immune-related adverse events (irAEs). Cox regression model was used to investigate the influence of multiple factors on survival.
Results:
We included 217 patients with a median age of 59.0 (18-84) years, of which 70.0% were male. The median OS and PFS were 9.8 (95% CI 8.8-10.8) months and 4.6 (95% CI 4.0-5.3) months. The ORR and DCR were 22.7% (95% CI 17.1-29.0) and 56.2% (95% CI 49.0-63.1). For the second-line treatment regimens, there were 87 (40.1%) patients and 130 (59.9%) patients received immunotherapy combined with chemotherapy (I+C) and immunotherapy combined with chemotherapy and anti-angiogenic drugs(I+C+A) respectively. The median OS was 9.3 (95% CI 8.5-10.1) months and 11.5 (95% CI 9.3-13.7) months, p=0.032. The median PFS was 4.2 (95% CI 3.1-5.3) months and 5.2 (95% CI 4.3-6.1) months, p=0.082. Cox regression model analysis showed that ECOG 0-1, PFS≥6 months in the first-line treatment, second-line regimen (I+C+A), and second-line medication > 3 cycles were independent prognostic factors for OS in the second-line treatment. The incidence of grade ≥3 TRAEs was 20.7%, and the incidence of irAEs was 6.5%. No treatment-related deaths occurred.
Conclusions:
This real-world study results showed that retreatment with immune checkpoint inhibitors had promising clinical benefit for patients with advanced gastric cancer and manageable safety.

Efficacy of different groups.

　
n
mOS（m）
mPFS（m）
ORR（%）
DCR（%）

ITT
217
9.8
4.6
22.7
56.2

ECOG

0-1

180
9.8
4.7
19.5
56.8

2

37
8.6
4.0
38.2
52.9

1-Line PFS

＜3m

61
5.5
2.2
1.7
17.2

≥3m

156
11.7
6.0
31.0
71.7

＜6m

136
7.4
3.2
2.4
38.7

≥6m

81
15.1
8.0
54.4
83.5

Second-line treatment

I+C

87
9.3
4.2
16.9
54.2

I+C+A

130
11.5
5.2
26.7
57.5

Second-line treatment cycle

≤3

97
7.4
2.9
4.8
31.0

　

＞3

120
13.1
6.2
35.3
73.9
Real-world biomarker testing and first-line treatment patterns among locally advanced, unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma patients in the US.
Authors: Tzala Lia , Wellen Maria , Luu Tony , Gleason Michelle Kathleen , Majer Istvan Matyas , Reading Stephanie Rummans
Published: January 2025

348

Background:
Advanced-stage gastric cancer and gastroesophageal junction adenocarcinoma (advG/GEJC) are leading causes of cancer-related morbidity and mortality. Chemotherapy is the traditional first-line (1L) therapy for patients in the advanced setting, with targeted and immunotherapy considered based on biomarker expression. This study aimed to describe real-world HER2 and PD-L1 testing practices and 1L treatment patterns among advG/GEJC patients.
Methods:
A retrospective cohort study was conducted among adult patients diagnosed with advG/GEJC between 01 Jan 2017 and 30 Jun 2023 usingthe US-based Flatiron Health electronic health record-derived de-identified database. HER2 and PD-L1 testing practices were evaluated prior to and up to 1-month post-1L treatment initiation or 6 months post-advG/GEJC diagnosis date in untreated patients. 1L treatment regimens were described overall and stratified by HER2 and PD-L1 expression.
Results:
Among 4,256 advG/GEJC patients, the average age was 67 years with the majority male (68%), non-Hispanic white (44%), and with metastatic disease (64%). Nearly three quarters (72%) of patients included received a HER2 test and 55% had a HER2 test with a valid result within the timeframe mentioned above. More than a quarter of patients (27%) received a PD-L1 test and 25% had a PD-L1 test with a valid result. PD-L1 testing before the approval of nivolumab in 1L (i.e. before 2021) showed testing at 19% (490/2,629; 17% with a valid result) and from 2021 onward at 40% (643/1,627; 37% with a valid result). Across the full cohort, half of the patients received chemotherapy alone (52%) and one quarter received no treatment (25%). Similar treatment patterns were observed in the subset of 1,117 patients who did not receive a HER2 or PD-L1 test; 54% received chemotherapy alone and 36% no treatment. Of the 340 patients who were tested for HER2 and were HER2 positive, half (52%) received trastuzumab combination therapy, 23% received chemotherapy alone, and 18% had no treatment. Of the 301 patients who received a PD-L1 test with a combined positive score (CPS) ≥5 from 2021 onward, 41% received immunotherapy, 34% received chemotherapy alone and 18% had no treatment. Prior to 2021, most patients with a PD-L1 test and CPS >5 used chemotherapy alone (57%; 132/233), 13% (31/233) received PD-L1 targeted therapies and 19% (43/233) received no treatment.
Conclusions:
This study describes a potential subset of US advG/GEJC patients who do not receive a HER2 or PD-L1 test and/or do not receive eligible targeted or immunotherapy as part of routine clinical practice. As precision medicine options continue to evolve, these data suggest an opportunity to further understand the drivers for biomarker testing as well as the factors impacting the use of biomarker-informed treatment options.
Prognostic impact of postoperative complications after neoadjuvant therapy followed by esophagectomy for esophageal cancer: An exploratory analysis of phase III trial JCOG1109.
Authors: Booka Eisuke , Kato Ken , Ito Yoshinori , Daiko Hiroyuki , Koyanagi Kazuo , Yamamoto Miho , Ogata Takashi , Fukuda Takashi , Fujita Takeo , Abe Tetsuya , Takahashi Masanobu , Watanabe Masayuki , Ichikawa Hiroshi , Hihara Jun , Kanda Mitsuro , Hamai Yoichi , Tsushima Takahiro , Machida Ryunosuke , Sasaki Keita , Takeuchi Hiroya
Published: January 2025

356

Background:
We previously reported that postoperative complications after esophagectomy were significantly associated with poor long-term prognosis in the prospective randomized trial JCOG9907 (Ann Surg, 2017). JCOG1109 evaluated the efficacy and safety of neoadjuvant docetaxel plus cisplatin plus 5-FU (DCF), radiation with cisplatin plus 5-fluorouracil (CF-RT) compared with cisplatin plus 5-fluorouracil (CF) for locally advanced esophageal squamous cell carcinoma, and demonstrated the superiority of DCF compared with CF in improving overall survival (OS). In this exploratory analysis, we investigated the association between postoperative complications and prognosis in JCOG1109, where more intensive preoperative therapies and thoracoscopic esophagectomy (TE) were introduced.
Methods:
Patients with potentially resectable advanced thoracic esophageal cancer were randomly assigned to CF, DCF, or CF-RT therapies and followed by open esophagectomy (OE) or TE with regional lymphadenectomy in JCOG1109. The impacts of postoperative complications (≥ Grade 2) on long-term prognosis including OS and progression-free survival (PFS) were investigated in each of the three preoperative therapies.
Results:
Between December 2012 and July 2018, 601 patients were randomized (CF/DCF/CF-RT; 199/202/200). Of 589 eligible patients, 541 patients underwent esophagectomy (183/181/177). Any postoperative complications, pneumonia, anastomotic leakage, recurrent laryngeal nerve paralysis, or infectious complications had no significant impact on OS in each of the three arms. When divided into OE or TE, the impact of any postoperative complications on OS was attenuated by introducing TE in each of three arms; from neoadjuvant CF followed by OE group [hazard ratio (HR) 1.557, 95% confidence interval (CI) 0.881-2.752] to TE group [HR 0.802, 95% CI 0.424-1.515], from neoadjuvant DCF followed by OE group [HR 1.151, 95% CI 0.575-2.306] to TE group [HR 0.703, 95% CI 0.3363-1.471], and from neoadjuvant CF-RT followed by OE group [HR 1.548, 95% CI 0.840-2.852] to TE group [HR 1.186, 95% CI 0.627-2.245].
Conclusions:
JCOG1109 showed no association between postoperative complications and long-term prognosis. The prognostic impact of postoperative complications might be attenuated by the introduction of minimally invasive esophagectomy (open to thoracoscopy) even after more intensified preoperative therapy (CF to DCF or CF to CF-RT). Clinical trial information: CRB3180009.
Association of early tumor shrinkage with survival in patients with HER2-positive advanced gastric cancer treated with trastuzumab deruxtecan.
Authors: Fukuda Koshiro , Ooki Akira , Osumi Hiroki , Fukuoka Shota , Yoshino Koichiro , Tamba Mikako , Udagawa Shohei , Shimozaki Keitaro , Ogura Mariko , Wakatsuki Takeru , Chin Keisho , Fujishiro Mitsuhiro , Shinozaki Eiji , Yamaguchi Kensei
Published: January 2025

360

Background:
Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody and a cytotoxic topoisomerase I inhibitor, has been approved as third or later-line treatment for unresectable HER2-positive advanced gastric cancer (AGC) based on the results of phase II DESTINY-Gastric 01 trial. However, there are few studies on real-world clinical outcomes and clinicopathological factors associated with efficacy of T-DXd in patients with HER2-positive AGC.
Methods:
This single-center retrospective study enrolled patients with AGC treated with T-DXd as third- or later-line chemotherapy between March 2018 and December 2023. Early tumor shrinkage (ETS) was defined as the relative change in the sum of longest diameters of RECIST target lesions at 8 ± 2 weeks compared with baseline. Prognostic outcomes were assessed using the log-rank test and Cox proportional hazards regression model.
Results:
A total of 57 patients were enrolled. The median age was 66 years (range, 31–82); 68% were male; 79% had HER2 3+; 23% had pulmonary metastasis; 67% were treated with T-DXd in the third-line setting. At a median follow-up of 27.6 months, the median progression-free survival (PFS) was 4.5 months (95% confidence interval [CI], 3.8–5.5), and the median overall survival (OS) was 7.3 months (95% CI, 4.9–9.4). Among 40 patients with target lesions, the overall response rate was 35.0% and the disease control rate was 90.0%. Patients with ETS had notably longer PFS (median PFS (months) 8.6 vs 4.1,
P
< 0.01) and OS (median OS (months) 9.1 vs 6.1,
P
< 0.01) than those without ETS. In multivariate analysis, ETS was associated with significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.08–0.63;
P
= 0.004) and OS (HR, 0.27; 95% CI, 0.12–0.65;
P
= 0.004), whereas pulmonary metastasis was associated with significantly shorter OS (HR 2.46, 95% CI, 1.07–5.65;
P
= 0.03).
Conclusions:
This study showed that achieving an ETS was significantly associated with a favorable prognosis in patients with HER2-positive AGC treated with T-DXd.