bluuebunny/crossref_metadata_2025 huggingface dataset:
A protein-based blood panel test for the early detection of colorectal cancer and advanced neoplasia.
Authors: Chavany Christine , Dea Jeffrey , Guevara Monica , Hernandez-Gonzalez Rafael , Valle Rosaura PC , Jendoubi Moncef
Published: January 2025

46

Background:
Early detection of colorectal cancer (CRC) is key to survival. CRC screening compliance is still low because of either the invasive procedure (colonoscopy) or the so-called "ick factor" (stool-based tests). Stool-based tests also lack ability to detect advanced adenoma (CRC precursor). A blood-based test could improve adherence to screening guidelines, but no one has so far been recommended due to a lack of sufficient sensitivity and specificity. Here we report the potential clinical utility of a blood-based biomarker panel providing high sensitivity (SE) and specificity (SP) for CRC and advanced adenomas (AA) as a screening triage option addressing positive patients to colonoscopy.
Methods:
A total of 241 retrospective serum samples (179 CRC, 22 adenoma, 40 healthy controls) were obtained from the Cooperative Human Tissue Network (CHTN) biobank and tested with a proprietary sandwich ELISA that detects dual CRC specific biomarkers (BF7 and CC3). A standard curve was generated and biomarkers concentration in the samples were calculated using a 4-parameter logistic method. The median biomarker concentration values in each patient group were compared to determine whether differences were statistically significant (p< 0.05). Statistical analysis of two-group and multi-group comparisons was carried out using the non-parametric Mann-Whitney U test and the Kruskal-Wallis test, respectively. Receiver operating characteristic (ROC) curves were calculated to evaluate the diagnostic performance, by determining sensitivity (SE), specificity (SP), area under the curve (AUC), and confidence interval (CI). Statistical analysis, ROC curves and scatter plots were performed with GraphPad Prism 7.0.
Results:
Both biomarker's median concentration difference between CRC versus healthy samples groups were found to be statistically significant (p<0.05). Both biomarkers were also elevated in AA as compared to healthy samples, but difference in median concentration was only statistically significant for CC3 (p<0.0001). BF7 serum levels in cancer patients were significantly associated with TMN stage (p=0.019), N stage (p=0.039) and M stage (p=0.0006). No significant associations were found between this biomarker levels and other clinical characteristics of the CRC patients including age. Our test discriminated CRC (all stages) from healthy individuals with a SE of 80% and a SP of 90%. Sensitivity for early (n=95) and late-stage CRC (n=80) was 79% and 84%, respectively. Our test was also able to detect 81% of serum from advanced adenoma patients who are at increased risk of CRC.
Conclusions:
This study illustrates the potential clinical utility of our blood-based assay for the early detection of CRC which has a better sensitivity for advanced adenoma than tests in current clinical use. A large prospective cohort study is planned to further validate the clinical performance of this test.
Phase II study of neoadjuvant FLOT and chemoradiation for trimodality therapy of esophageal/GEJ adenocarcinoma.
Authors: Olsen Jeffrey R. , Leal Alexis Diane , Kim Sunnie S. , Goodman Karyn A. , Binder David , Blum Matthew , Erickson Crystal , Hoyer Robert John , Kemme Douglas Jerome , Lieu Christopher Hanyoung , Liu Arthur , Marsh Megan , Mathew Lynn , McCarter Martin , Messersmith Wells A. , Petit Joshua H. , Shonebarger Daniel , Waxweiler Timothy V
Published: January 2025

466

Background:
Recent data support use of perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) chemotherapy over pre-operative chemoradiation (CRT) for patients with resectable esophageal/GEJ adenocarcinoma with limited studies evaluating combined FLOT/CRT. This prospective phase II study (NCT04028167) evaluated a neoadjuvant approach of FLOT followed by CRT for resectable esophageal/GEJ adenocarcinoma (EAC).
Methods:
Operable patients with cT1-2 N1-2 or cT3-4N any4 Nany non-metastatic EAC were eligible. Neoadjuvant treatment consisted of FLOT x 3 cycles followed by restaging PET and chemoradiation (41.4 Gy / 23 fractions to the primary site and regional lymphatics with weekly carboplatin/paclitaxel). Adjuvant nivolumab for non-pathologic complete response (pCR) was permitted. The primary endpoint was pCR rate among patients receiving the study regimen and undergoing resection, with secondary endpoints including disease free survival (DFS), overall survival (OS), toxicity, and correlative studies. DFS/OS was measured using the Kaplan Meier (KM) method. Interim results are presented after a planned safety analysis.
Results:
Since 4/2020, 23 patients with median age of 62 (range 40-73) have enrolled. cT3-4 and cN+ disease was present in 20/23 (87%) and 16/23 (70%) of patients, respectively. FLOT was completed by 21/23 patients (reasons for discontinuation included allergic reaction and G5 sepsis/endocarditis). All 21 patients initiating chemoradiation completed planned treatment and 17/21 underwent resection (2 refused surgery after achieving cCR, 1 died of cardiac arrest, 1 patient is awaiting surgery). A pCR was observed in 5/17 resected patients (29%), with pCR or near pCR observed in 9/17 (53%). The complete response rate (pCR + cCR for patients refusing surgery) was 7/19 (37%). Adjuvant nivolumab was administered in 9 patients. The median follow-up among all patients was 20 months with 2-year DFS and OS estimates of 61% and 73%. The regimen was tolerated with G3+ hematologic, G3+ gastrointestinal, and G3+ other toxicity observed in 39%, 13%, and 22% of patients, respectively.
Conclusions:
In a locoregionally advanced population, neoadjuvant sequential FLOT followed by CRT was well tolerated with encouraging DFS/OS and a high rate of complete response compared to prior studies. This hybrid platform may enhance both locoregional and distant control and is of interest for expanded evaluation.
Clinical trial information: NCT04028167
.
Identification of candidate biomarkers for gastric cancer by bioinformatics analysis of pooled microarray gene expression datasets in Gene Expression Omnibus.
Authors: Chen Audrey , Wang Fen
Published: January 2025

467

Background:
Gastric cancer (GC) remains one of the most prevalent malignant diseases worldwide. The high mortality rate is largely due to the limited treatment options and the challenges in diagnosing the cancer at an early stage. Understanding the genetic differences driving the proliferation of GC is crucial for advancing diagnostic methods and developing targeted treatments. This study aims to identify biomarkers involved in the pathogenesis of GC through integrated bioinformatics analysis.
Methods:
Extracted from the Geo Expression Omnibus, three DataSets (GSE118916, GSE79973, and GSE13861) were analyzed for differentially expressed genes (DEGs) using the R statistical language. The three data sets were then compared for common DEGs, which would serve as the focus of this study. These DEGs were functionally analyzed for pathways by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein–protein interaction (PPI) network was constructed to screen out candidate genes.
Results:
The results revealed that 123 DEGs of the three datasets containing 26 upregulated genes and 97 downregulated genes were ascertained in our study. The GO and KEGG enrichment analysis results showed that the functions of DEGs were mainly involved in the retinol metabolic process, xenobiotic metabolic process, collagen type I trimer, potassium: proton exchanging ATPase complex, benzaldehyde dehydrogenase (NAD+) activity, alcohol dehydrogenase (NADP+) activity, Collecting duct acid secretion, and Tyrosine metabolism. Through the PPI analysis network, the core genes with the highest degree of 7 nodes were selected: COL1A1, COL1A2, COL11A1, THBS2, ATP4A, COL10A1, and CXCL8.
Conclusions:
The 7 genes identified in this study may play a vital regulatory role in the occurrence and development of GC and may also be potential therapeutic targets. Further mechanistic studies of the pathogenesis and treatment of GC may be able to identify new targets using these shared pathways. These findings could contribute to a better understanding of the origins of gastric cancer and facilitate the development of early interventions. The bioinformatics analysis conducted in this study offers new insights and directions for further research on gastric cancer.
Histopathological growth patterns of gastric cancer liver metastasis and their association with patient prognosis.
Authors: Sha Dan , Zhuang Qingchun , Wang Liguang , Sinicrope Frank A. , Jing Haiyan , Tian Chunfang , Zhang Shuo , Yang Qian , Sun Jing , Wang Jinshen , Song Wei
Published: January 2025

484

Background:
The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables.
Methods:
Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model.
Results:
Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8
+
T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively.
Conclusions:
Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication.

Univariate and multivariate analysis of prognostic factors for cancer-specific survival.

Characteristics
Univariate analysis
Multivariate rergression analysis

HR (95%CI)
P
HR (95%CI)
P

Gender ( Women vs Men )
1.13(0.61-2.09)
0.71

Age ( >60years vs ≤60years)
1.08(0.60-1.70)
0.98

HGP ( non-desmoplastic HGP vs desmoplastic HGP )
3.63(1.78-7.41)
0.00
3.48(1.37-8.88)
0.01

T stage ( T3-T4 vs T1-T2 )
2.03(1.08-3.80)
0.03
2.29(1.15-4.58)
0.02

N stage ( N1-N3 vs N0 )
3.46(1.66-7.23)
0.00
2.54(1.17-5.56)
0.02

CEA ( >5ng/ml vs ≤5ng/ml )
2.37(1.25-4.48)
0.01
1.56(0.70-3.48)
0.27
Clinical validation of plasma circulating-tumor DNA assay using highly sensitive Safe-SeqS technology for detecting
RAS
and
BRAF
V600E in metastatic colorectal cancer.
Authors: Miyashita Yu , Bando Hideaki , Watanabe Jun , Suwa Yusuke , Kagawa Yoshinori , Kato Takeshi , Hasegawa Hiroko , Komatsu Yoshito , Yuki Satoshi , Asayama Masako , Nishina Tomohiro , Inoue Akira , Oki Eiji , Taniguchi Hiroya , Ohta Takashi , Kotani Daisuke , Nakajima Hiromichi , Yamamoto Koji , Yoshino Takayuki
Published: January 2025

50

Background:
We developed a circulating-tumor DNA (ctDNA) test assay for
RAS/BRAF
mutations using next-generation sequencing-based Safe-SeqS technology. The clinical performance of detecting
RAS
and
BRAF
mutations were evaluated versus approved liquid biopsy and tissue testing, respectively.
Methods:
Metastatic colorectal cancer (mCRC) patients (pts) were enrolled. The concordance of the
RAS
mutational status in ctDNA between Safe-SeqS assay and OncoBEAM RAS CRC kit, which is approved as a companion diagnostic in Japan, was evaluated using archival plasma samples. The primary endpoints were positive percent agreement (PPA) and negative percent agreement (NPA). The concordance of the
BRAF
V600E mutational status between plasma-Safe-SeqS assay and tissue-based testing using MEBGEN RASKET-B kit, which is approved as a companion diagnostic in Japan, was prospectively evaluated. The primary endpoints were sensitivity and specificity of Safe-SeqS assay compared to tissue-based testing. Multivariate analysis using LASSO regression model was performed to evaluate the discordance of
BRAF
V600E mutational status between Safe-SeqS assay and tissue-based testing.
Results:
In 125 eligible plasma samples, the PPA and NPA for
RAS
mutational status in ctDNA were 87.1% (95% confidence interval [CI]: 76.1–94.3) and 95.2% (95% CI: 86.7–99.0), respectively. On the other hand, in 103 eligible pts, the sensitivity and specificity of Safe-SeqS assay for
BRAF
V600E mutational status were 69.2% (95% CI: 48.2–85.7) and 98.7% (95% CI: 93.0–100.0), respectively. Multivariate analysis revealed the baseline longest diameter and the number of lesions in pts with peritoneal and/or lung metastasis were factors associated with discordance. The sensitivity for
BRAF
V600E mutations increased to 81.0% (95% CI: 58.1–94.6, fisher’s exact test
p
=0.02) when the 5 pts with lower tumor burden (peritoneal metastasis with the longest diameter <20 mm, and lung metastasis with the longest diameter <20 mm and <10 lesions, according to the previous report [1] ) were excluded.
Conclusions:
The clinical validity of the ctDNA assay for detecting
RAS/BRAF
V600E mutations using Safe-SeqS technology was confirmed in pts with mCRC. Careful attention should be paid for mCRC pts with only peritoneal and/or lung metastases having fewer metastases or smaller diameter lesions. 1. Kagawa Y, et al. Clin Cancer Res 2021.
Impact of inpatient palliative care consultation on end-of-life care among patients with esophageal cancer.
Authors: Baskar Suriya , Schoeneich Robert , Desai Chaula , Grewal Udhayvir Singh
Published: January 2025

502

Background:
Esophageal cancer is an aggressive malignancy with a high global prevalence. Patients often suffer from various debilitating symptoms like dysphagia and cachexia, particularly with more advanced stage disease. Most patients continue to receive aggressive interventions until terminal stages of disease without timely initiation of formal palliative care (PC). We sought to investigate the impact of formal inpatient palliative care consultation on end-of-life (EOL) care among patients with esophageal cancer.
Methods:
The National Inpatient Sample (NIS) was queried to identify all hospitalizations with esophageal cancer utilizing ICD-10 codes C15.x from 2016 to 2020. Hospitalizations with documented inpatient mortality events were extracted and stratified based on reception of PC consultation (ICD-10 code Z51.5). Demographic and clinical data were analyzed using chi-squared tests and independent sample t-tests. A threshold of p-value less than 0.05 was set to determine statistical significance.
Results:
A total of 17,745 patients with esophageal cancer were included, of which 10,370 (58.4%) received PC consultation. Patients that received PC consultation at EOL were more likely to have higher comorbidities per CCI. No significant difference between age and sex was observed between the two cohorts. Patients who received PC consultations at EOL had higher rates of Do Not Resuscitate (DNR) code status (78.1% vs 43.2%, p <0.001) and lower rates of aggressive interventions such as chemotherapy (0.9% vs 1.6%, p<.001), blood transfusions (12.3% vs 18%, p<.001), and mechanical ventilation (28.5% vs 41%, p<0.001). No significant difference was observed in the rates of vasopressor use between the two groups (p=0.83). Hospitalizations with PC consultations were associated with significantly lower total hospitalization cost ($97,879 vs $146,128, p<.001).
Conclusions:
Inpatient PC consultations among patients with esophageal cancer were associated with lower rates of aggressive interventions and higher rates of DNR code status in addition to significantly lower total hospitalization costs. These findings underscore the importance of inpatient PC consultation at the EOL in helping minimize aggressive interpretation and facilitate a greater focus on comfort and quality of life.

No PalliativeN=7375
PalliativeN=10370
p-value

Age (in years)
67.58 ± 10.9
67.58 ± 10.9
.98

CCI
9.1 ± 3.5
9.4 ± 3.3

<.001

Mean length of stay (days)
8.9 ± 14.9
7.5 ± 11.3

<.001

Total Charges
146128 ± 321830
97879 ± 195868

<.001

DNR
3170 (43.2%)
8100 (78.1%)

<.001

Blood transfusion
1320 (18.0%)
1280 (12.3%)

<.001

Mechanical ventilation
3015 (41.0%)
2960 (28.5%)

<.001

Vasopressor
585 (8.0%)
835 (8.1%)
0.83

Chemotherapy
115 (1.6%)
95 (0.9%)

<.001
Racial disparities in secondary metastasis in patients with hepatocellular carcinoma: A 5-year National Inpatient Sample study.
Authors: Saowapa Sakditad , Polpichai Natchaya , Garcia Pleitez Hector J , Bernal Diego Olavarria , Kanitthamniyom Chanakarn , Danpanichkul Pojsakorn , Yanpiset Panat , Tanariyakul Manasawee , Wannaphut Chalothorn , Suenghataiphorn Thanathip , Kulthamrongsri Narathorn , Wattanachayakul Phuuwadith , Siladech Pharit , Das Kanak , Tijani Lukman Aderoju
Published: January 2025

523

Background:
Hepatocellular carcinoma (HCC), a primary liver malignancy, is one of the leading causes of cancer-related mortality worldwide. The incidence and outcomes of HCC vary significantly across racial groups. Secondary metastasis, a key factor in disease progression and prognosis, also appears to differ by race, though these disparities remain poorly understood. This study aims to explore how race influences the metastatic progression of HCC, providing valuable insights into potential racial differences in disease outcomes.
Methods:
A retrospective analysis of National Inpatient Sample (NIS) data from 2016 to 2020 was conducted, identifying adults with HCC using International Classification of Diseases, Tenth Revision (ICD-10) codes, and categorizing them based on the presence of metastasis. The primary outcome was racial differences in organ metastasis. Multivariable logistic regression models were used to adjust for potential confounders and to evaluate the impact of race on all metastatic patterns, with Caucasians as the reference category. Statistical significance was defined as p-values ≤ 0.05.
Results:
The study cohort included 236,985 adult patients with HCC, of whom 34,875 had secondary metastasis. The cohort was predominantly male (77.37%), with 22.63% female. The racial distribution was 52.61% Caucasian, 19.08% African American, 15.04% Hispanic, and 13.27% from other racial groups. After adjusting for confounders, African American patients had significantly higher odds of lung (aOR 1.42, P<0.001), bone (aOR 1.51, P<0.001), and brain metastasis (aOR 1.47, P=0.02), but lower odds of adrenal gland metastasis (aOR 0.74, P=0.003) compared to Caucasians. Asian/Pacific Islander patients demonstrated increased odds of lung (aOR 2.00, P<0.001) and brain metastasis (aOR 1.95, P=0.02). In contrast, Hispanic patients had lower odds of abdominal lymph node (aOR 0.69, P=0.008) and bone metastasis (aOR 0.83, P=0.007).
Conclusions:
This study highlights significant racial disparities in the metastatic patterns of hepatocellular carcinoma, emphasizing the need to consider these differences in clinical management and treatment strategies for HCC patients. Further research is required to investigate the underlying causes of these disparities and their impact on long-term survival.
Development and validation of the SPEAR scoring model and predicting overall survival in unresectable hepatocellular carcinoma patients treated with TACE, molecular targeted therapies, and immune checkpoint inhibitors.
Authors: Li Wenli , Lu Mingjian , Shi Feng , Cheng Xiao , Lu Ruyi , Fan Wenzhe , Zang Mengya , Hu Xiaoyun , Li Qi , Li Rong , Zhu Peilin , Chen Yongru , Su Kaiyan , Cai Qingxian , Yuan Guosheng , Chen Jinzhang
Published: January 2025

533

Background:
To develop and validate a predictive model to identify hepatocellular carcinoma (HCC) patients likely to benefit from combined treatment of transarterial chemoembolization (TACE), molecular targeted therapies (MTTs), and immune checkpoint inhibitors (ICIs).
Methods:
Data from 500 patients with unresectable HCC treated with TACE, MTTs, and ICIs (2019-2023) were analyzed. Patients were divided into a training set (241 from Nanfang Hospital) and a validation set (259 from various hospitals). Key prognostic variables were identified using random forest survival analysis, and the top five were used to construct a Cox proportional hazards model. Model performance was assessed using time-dependent AUC values, calibration curves, clinical decision curves (DCA), and net reclassification improvement (NRI) indices. Risk scores and optimal cut-off values for risk stratification were determined and validated.
Results:
Five key survival variables were identified: serum alpha-fetoprotein (AFP), red cell distribution width coefficient of variation (RDW-CV), aspartate aminotransferase (AST), platelet-to-lymphocyte ratio (PLR), and extrahepatic metastasis (EHM). The Cox model had a C-index of 0.694 in the training and 0.691 in the validation set. The training set's 1-year, 2-year, 2.5-year, and 3-year AUC values were 0.77, 0.73, 0.73, and 0.72, respectively, and 0.74, 0.74, 0.76, and 0.66 in the validation set. The ARAPE model demonstrated a more significant net benefit than existing models. Median overall survival (mOS) was 33.9 months for low-risk, 20.4 months for intermediate-risk, and 14.2 months for high-risk groups in the training set; in the validation set, mOS was 30.8, 18.7, and 10.5 months, respectively.
Conclusions:
The SPEAR model (Serum AFP, PLR, EHM, AST, and RDW-CV) model effectively stratifies risk for HCC patients receiving TACE combined with MTTs and ICIs, aiding in personalized treatment decisions.
Comparison of efficacy and safety of PD-1 and PD-L1 antibodies in combination with hepatic arterial infusion chemotherapy and target therapy for unresectable intrahepatic cholangiocarcinoma: A multicenter retrospective study.
Authors: Xiong Xinhao , Wang Qiaoxuan , Dai Wei , Zhao Rongce , Mei Jie , Zheng Zehao , Gan Junyu , Xu Longzhou , Li Jibin , Zheng Lie , Wei Wei , Zhong Jian-Hong , Guo Rongping , Li Shaohua
Published: January 2025

553

Background:
Immune checkpoint inhibitors (ICIs) in combination with hepatic arterial infusion chemotherapy (HAIC) and target therapy have shown promising antitumor activity in unresectable intrahepatic cholangiocarcinoma (iCCA). The present study aimed to compare the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors in this setting.
Methods:
In this multicenter retrospective study, we included patients with iCCA who received ICIs + HAIC + target therapy from June 2018 to June 2023. Propensity score matching (PSM) was performed to reduce confounding factors. Patients were divided into two groups: those treated with PD-L1 antibody + HAIC + target therapy (Group A) and those treated with PD-1 antibody + HAIC + target therapy (Group B). Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were compared between the two groups. Adverse events were assessed according to CTCAE v5.0.
Results:
A total of 336 patients met the inclusion criteria and were enrolled for analysis. There were no significant differences in OS, PFS, or ORR between the two groups (median OS: 17.7 vs. 25.3 months, P=0.139; median PFS: 8.3 vs. 10.0 months, P=0.534; ORR: 48.4% vs. 31.1%, P=0.051). Following PSM (ratio = 3, caliper = 0.2), 30 patients in Group A and 83 patients in Group B were included. The ORR, according to the modified RECIST criteria, was significantly higher in Group A compared to Group B (50% vs. 28.9%, P=0.037). However, no significant difference in PFS (median 10.0 vs. 9.0 months, P=0.29) or OS (median 17.6 vs. 22.8 months, P=0.293) was observed between the two groups. Adverse events (AEs) occurred in all 113 patients (100%), wherein grade 3–4 AEs were reported for 12 (10.6%) patients in group A and 45 (39.8%) in group B. There was a tendency for Group A to have a lower incidence of grade 3–4 AEs compared to Group B (40.0% vs. 54.2%, P=0.182),although this difference was not statistically significant.
Conclusions:
This study found that in the treatment combining ICIs with HAIC and target therapy for unresectable iCCA, Group A demonstrated a superior tumor response and a more favorable safety profile.
Real-world Child-Pugh scores and outcomes of patients with hepatocellular carcinoma at a high-volume center.
Authors: Tobal Ian , Shuaibi Sameera , Biggs Erin , Mizrahi Jonathan
Published: January 2025

569

Background:
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and most often occurs in the setting of cirrhosis. Patients (pts) with advanced HCC are not eligible for curative intent therapies such as ablation, surgical resection, or liver transplantation. For the past five years, immune checkpoint inhibitor (ICI)-based systemic therapy regimens have been the mainstay of first-line treatment for pts with advanced HCC. Most trials assessing ICI-containing regimens, including IMBRAVE150 and HIMALAYA, excluded pts with Child-Pugh (CP) scores worse than A. Unfortunately, fewer than half of pts maintain a CP A score at the time of HCC diagnosis and referral to medical oncology. Real-world data on CP scores of patients undergoing ICI-based therapy for advanced HCC at the time of medical oncology referral and treatment start are lacking.
Methods:
Pts who initiated treatment with either atezolizumab plus bevacizumab (A+B) or durvalumab plus tremelimumab (D+T) in the Ochsner Health system between 1/1/20 and 12/31/23 were included in this analysis. CP scores were calculated at the time of their initial medical oncology visit and again at the time of their first systemic therapy cycle. Pt demographics and clinical outcomes were analyzed.
Results:
200 pts were identified in this study, 159 of whom (79.5%) were male. Median age at treatment start was 66.8 years. 117 pts (58.5%) were Caucasian and 63 pts (31.5%) were African American (AA). 152 and 48 pts received A+B and D+T, respectively. At the time of first medical oncology visit, 58 pts (29%) were classified as CP B (n=51) or C (n=7). At the treatment start date, 82 pts (41%) were classified as CP B (n=73) or C (n=9). The median survival across all groups was 10.5 m. Median survival CP A, B, and C pts were 15.4, 7.6, and 1.6 months (m), respectively. 6-month survival rates for CP A, B, and C pts were 75.7%, 52.2%, and 0%, respectively. 12-month survival rates for CP A, B, and C pts were 58.2%, 35.1%, and 0%, respectively. There was no statistically significant difference in CP score at either time point between Caucasian and AA pts.
Conclusions:
Although pts with CP scores worse than A were not included in the pivotal studies that have established recent standard of care therapies for pts with advanced HCC, a significant proportion of pts being treated with ICI-based regimens have at least CP B liver disease, with a poorer prognosis in that subset of pts. Extremely poor survival rates for those with CP C scores argue against use of ICI-based treatment for these pts. In this analysis, no significant difference was observed in CP scores between Caucasian and AA pts.
Adjuvant chemoradiation combined with immunotherapy for patients with high-risk resectable extrahepatic cholangiocarcinoma and gallbladder cancer: A phase II, multicenter, randomized controlled trial (ACCORD trial).
Authors: Kuang Ming , Peng Zhenwei , Shen Shun-Li , Chen Shuling , Xiao Han
Published: January 2025

570

Background:
Extrahepatic cholangiocarcinoma (ECC) and gallbladder cancer (GBC), as the majority of biliary tract cancer (BTC), has a markedly high risk of recurrence after surgery. However, adjuvant treatments specifically for resectable ECC and GBC patients are scare and adjuvant chemotherapy alone delivers limited efficacy. Immunotherapy and radiotherapy are potential effective treatments and both of them may synergize with chemotherapy.
Methods:
ACCORD was a multicenter, phase 2, randomized controlled trial to assess the efficacy and safety of chemoradiation with immunotherapy as an adjuvant treatment in resectable ECC/GBC, compared to observation. The primary endpoint was overall survival (OS) and the secondary endpoints included recurrence-free survival (RFS) and safety. Patients in the chemoradiation-anti-PD-1 group received Camrelizumab intravenously every 3 weeks after surgery. Camrelizumab therapy was not terminated until disease progression, unacceptable toxic effects occurred or informed consent withdrawal. After 2 courses of Camrelizumab treatment, chemoradiation was carried out simultaneously. Patients in the observation group received no anticancer treatment unless relapse was detected.
Results:
From March 2020 to June 2022, a total of 93 ECC/GBC patients after curative resection were randomized 1:1 into chemoradiation-anti-PD-1 group (
n
=46, Camrelizumab + concurrent Capecitabine and radiotherapy) and observation group (
n
=47). The 1-year, 2-year and 3-year OS rate were 95.7%, 71.4%, and 58.2% in the chemoradiation-anti-PD-1 group, and 80.9%, 52.9%, 30.5% in the observation group (Hazard ratio (HR) 0.43, 95% confidence interval 0.24-0.79;
P
=0.004). The 1-year, 2-year and 3-year RFS rate were 78.3%, 54.0%, and 40.3% in the chemoradiation-anti-PD-1 group, and 55.3%, 27.0%, 17.2% in the observation group, with a hazard ratio of 0.46 (95% CI, 0.28 to 0.76;
P
< 0.001). In the chemoradiation-anti-PD-1 group, the main adverse effect ≥ grade 3 were anemia (7 [15.2%]), dermatitis radiation (5 [10.9%]), and nausea (5 [10.9%]); and 100% of patients completed the whole treatment.
Conclusions:
Chemoradiation combined with immunotherapy as an adjuvant therapy demonstrated superior survival outcomes over observation in resectable ECC/GBC patients with a well-tolerable safety profile, supporting the potential of this combination treatment as effective adjuvant therapy for these high-risk patients.
Clinical trial information: NCT04333927
.
Current status of physicians’ perception of HCC conversion/downstaging therapy: A nationwide survey in China.
Authors: Bi Xinyu , Liang Xiao , Tan Guang , Zhao Hai-Tao , Huang Tao , Zhao Ming , Chen Jinzhang , Zhu Xiao-Dong , Xue Jianfeng , Sun Hui-Chuan , Cai Jianqiang ,   China Liver Cancer Study Group Young Investigators (CLEAP)
Published: January 2025

585

Background:
Conversion or downstaging therapy for intermediate and advanced unresectable hepatocellular carcinoma (HCC) has emerged as a significant exploring area of clinical practice and research in recent years. Nonetheless, there exists considerable variability in both the selection criteria for patients undergoing conversion therapy and the regimens selected for conversion across different regions and medical institutions. The present study aims to elucidate the current clinical application of conversion therapy in China, as well as to identify the considerations that physicians take into account when selecting eligible patients for conversion therapy and determining the appropriate conversion modality.
Methods:
Physicians meeting predefined inclusion criteria were invited to complete an online questionnaire from January to July, 2024. The collected data were subsequently pooled and analyzed descriptively.
Results:
A total of 120 valid questionnaires were retrieved, mainly form surgical (69.2%, n=83) and interventional (30.8%, n=37) departments. Generally, the study showed that approximately 51% of stage Ib-IIIa patients will be selected for the treatment goal of conversion or downstaging, and the overall successful rate as meeting criteria for surgical resection after treatment was 36%. Three primary factors were prioritized by physicians for determination of conversion therapy: the type of portal vein tumor thrombus (PVTT) (97%, 116/120), the future liver volume (90%, 108/120), and Child-Pugh classification (90%,108/120). In the specific physician group who selected the following attributes, patients classified as Child-Pugh A (82%, 89/108) or Child-Pugh B7 (66%, 71/108), those with tumor diameter exceeding 5 cm (92%, 98/106) and Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 (89%, 76/85) were most frequently selected for conversion therapy. Additionally, study showed that patients presenting with Vp1-2 (72%, 83/116) and Vp3 (71%, 82/116) could also be considered for conversion therapy. Currently, the prevalent treatment approach of conversion therapy involves a combination of local and systemic therapies, which is utilized in approximately 73% of cases. Among systemic treatment methodologies, the combination of Lenvatinib and immunotherapy is the most widely adopted by physicians. Besides, higher ORR was the foremost consideration for 83% (99/120) of physicians, followed by rapid response (68%, 82/120), adherence to guidelines and consensus (63%, 76/120), and lower tumor progression rate (58%, 70/120).
Conclusions:
This study elucidates the current status of conversion therapy for HCC in China. The findings underscore the necessity for optimizing conversion modalities and advancing standardized practices in the application of conversion therapy.
Durvalumab (DUR) effectiveness in advanced biliary tract cancer (aBTC) patients based on real-world data evidence.
Authors: Rodriguez-Pascual Jesus , Hernández Gema , Ugidos Lisardo , Parralejo Alejandro , Rodriguez-Castaño Juan Diego , Serrano Juan Jose , Ayuso Angel
Published: January 2025

598

Background:
Based on TOPAZ-1 trial, Durvalumab (DUR) plus gemcitabine and cisplatin significantly improved overall survival (OS) in advanced biliary tract cancer (aBTC) patients. Real-World data evidence can evaluate the benefit of this combination outside controlled studies comparing patients treated with standard chemotherapy with or without DUR.
Methods:
Using the TriNetX Global Collaborative Network, a platform that operates globally based on anonymized and aggregated clinical data, a sample of aBTC patients from 128 healthcare organizations (HCOs) who met the initial criteria was selected. 5-year overall survival (OS) was analyzed between these cohorts using a Kaplan-Meier analysis. Hazard Ratio (HR) and its 95% confidence interval (95%CI) were calculated to evaluate the difference between cohorts. Propensity Score Matching (PSM) was used to balance the cohorts based on age, gender, and race mitigating possible cofounding variables. All statistical analyses were conducted utilizing the TriNetX Analytics function in the online research.
Results:
A total of 1099 patients met the study criteria and were included in our study. 399 received DUR plus chemotherapy and 700 received only chemotherapy. Patients treated with DUR showed a significant better OS compared to patients treated with only chemotherapy, both previous to PSM and before PSM (post-PMS median OS 418 days vs 359 days, HR 0.862, 95%CI 0.759-0.979, p=0.022).
Conclusions:
This is the largest World-Real Data study exploring the effectiveness of Durvalumab in aBTC patients outside clinical trials, confirming a similar benefit than TOPAZ-1 study.
The Oncopig hepatocellular carcinoma model: An innovative large animal platform for evaluating treatment effects.
Authors: Chau Ian , Elkhadragy Lobna , Gaba Ron C. , Schook Lawrence B , Schachtschneider Kyle
Published: January 2025

619

Background:
Hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis and limited treatment options. Systemic therapies for advanced HCC include sorafenib, lenvatinib, and atezolizumab plus bevacizumab. However, given the limited efficacy of systemic treatment options, novel treatment approaches including combination of systemic and locoregional therapies (LRTs) is required to improve patient outcomes. These approaches require advanced large animal models to prove effectiveness. Pigs represent an ideal platform that provide both regulatory acceptable and clinically relevant large animal cancer models due to their similar physiology, size, genetics, immunity, and metabolism in relation to humans. The Oncopig HCC model is an ideal tool for testing LRT and other oncolytic based treatments.
Methods:
The Oncopig cancer model develops tumors following induced expression of

KRAS
G12D

and

TP53
R167H

driver mutations utilizing an adenoviral vector encoding Cre recombinase (AdCre). Oncopig HCC cell lines were developed by isolating hepatocytes from Oncopig liver biopsies and transformed in vitro via exposure to AdCre. Transgene expression and hepatocyte cell origin were validated by RT-PCR and arginase-1 staining, respectively. Comparison of in vitro Oncopig, human, and murine HCC cell line phenotypes (proliferation, migration, and chemotherapeutic response) was performed. Oncopig HCC tumor formation was performed via autologous intrahepatic injection of Oncopig HCC cells. Tumor formation was evaluated using ultrasound and CT imaging.
Results:
Oncopig and human HCC cell lines displayed similar cell cycle lengths and migration rates. Oncopig HCC cells were consistently more predictive of human HCC responses than murine cells when treated with standard chemotherapeutic agents (doxorubicin, cisplatin, mitomycin C, and sorafenib). Importantly, consistent with human HCC, Oncopig HCC cells were non-responsive to 5-fluorouracil, while murine HCC cells were responsive. Intrahepatic injection of Oncopig HCC cells resulted in tumors visible on ultrasound and CT scan within 2-4 weeks. Resulting tumors were consistent with human tumors on imaging. Histological analysis of tumor biopsies confirmed the identity of the resulting masses as HCC tumors based on positive arginase-1 and KRAS
G12D
staining.
Conclusions:
The Oncopig HCC model may be more predictive of human HCC chemotherapeutic responses than currently employed murine models. Tumors develop rapidly (within 2-4 weeks) and are readily identified on ultrasound and CT imaging, making this an ideal model for evaluation of novel therapeutic approaches. Further exploration and development of additional tumor models including further translational characterization will be important for broader utility.
Influence of MRP4 levels on clinical outcomes in biliary tract cancer.
Authors: Arroyo Gerardo F. , Sahores Ana , Ituarte Ana Carolina , Inklemona Cristina , Rojo Sandra , Kowalyszyn Ruben Dario , Davio Carlos , May Maria
Published: January 2025

624

Background:
Biliary tract cancer (BTC) are rare tumors with a poor prognosis.Multidrug resistance protein 4 (MRP4) is a transmembrane efflux transporter that influences on cellular growth and differentiation. Recent studies have linked high MRP4 levels to increased aggressiveness in pancreatic cancer and other tumor types. This study aimed to evaluate the role of MRP4 in BTC and its association with clinical outcomes in a real-world cohort from endemic areas in Argentina.
Methods:
We conducted a retrospective analysis of clinical outcomes and MRP4 expression in paraffin-embedded tissue samples from 78 patients with BTC. Immunohistochemistry staining was performed, and MRP4 expression was scored based on staining intensity and the percentage of positive cells. A score exceeding 100 was classified as high MRP4 levels. Statistical analyses included Chi-square, Kaplan-Meier survival curves, and log-rank tests, with significance set as
p
<0.05 (two-tailed).
Results:
High MRP4 levels were observed in 46 out of the 78 samples (59%). Patients with gallbladder cancer (n=64) and elevated MRP4 levels had significantly poorer overall survival (OS) compared to those with low MRP4 levels (median 11.3 and 14.5 months, high and low,
p
=0.038). In the broader BTC cohort evaluable for survival (n=73; 64 gallbladder, 7 cholangiocarcinoma, 1 ampulla of Vater, and 1 biliary undefined) patients with elevated MRP4 levels had non-significant shorter OS (median 12.4 and 13.5 months, high and low,
p
=0.17). Poorly differentiated tumors were more likely to express high MRP4 levels (
p
=0.06). High MRP4 expression was found in 59% of localized stages (0-II) and in 57% of advanced stages (III, IV and relapsed).
Conclusions:
High MRP4 expression is common in BTC, particularly gallbladder cancer, and could be a marker of poor prognosis. MRP4 levels appear more elevated in poorly differentiated tumors, and are similar in both, early and advanced stages, suggesting its involvement in early tumor progression. Further prospective studies are needed to confirm MRP4 as a biomarker. If MRP4 is a driver gene, targeting with inhibitors could represent a promising therapeutic strategy for these challenging tumors.
A real-world study of treatment patterns among patients (pts) with metastatic colorectal cancer (mCRC) receiving third-line (3L) or fourth-line (4L) treatment in the US.
Authors: Li Huichu , Kopetz Scott , Yin Yu , Peng Jianling , Keenan Hillary
Published: January 2025

64

Background:
There are limited real-world data describing 3L and 4L treatments for pts with mCRC. However, the landscape is evolving with new options becoming available, including fruquintinib, a highly selective oral inhibitor of all 3 VEGF receptors, approved by the US FDA in November 2023. This study aimed to understand pt characteristics and real-world treatment patterns in 3L and 4L to characterize the standard of care, adherence to guidelines, and identify unmet needs among pts with mCRC in the US, prior to recent changes in the landscape.
Methods:
A retrospective study of adults with mCRC who had received ≥3L of therapy between 1/1/2018 and 3/31/2023 in the US-based Flatiron electronic health records database. In two cohorts, defined by initiating 3L and 4L systemic treatment, pt demographics, clinical characteristics, and treatment by line of therapy were summarized.
Results:
Overall, 5401 pts were included in the 3L cohort and 2868 pts in the 4L cohort: median age at baseline was 63 and 62 years (yrs), 56% and 56% were male, 43% and 43% had a
KRAS
variant, and 46% and 49% had liver metastasis, respectively. 96% of pts in the 3L cohort received standard chemotherapy (CT) +/- targeted therapy as 1L treatment (55% CT + anti-vascular endothelial growth factor [VEGF] therapy; 34% CT only; 7% CT + anti-epidermal growth factor receptor [EGFR] therapy). In 2L, 87% of pts had standard CT-containing regimens (53% CT + anti-VEGF therapy; 19% CT alone; 15% CT + anti-EGFR therapy). A similar treatment history was observed for the 4L cohort. Commonly used 3L regimens in the 3L cohort were trifluridine/tipiracil (TAS-102; 11%), regorafenib (rego; 10%), and standard CT-containing regimens (54%; including: 12% FOLFIRI + bevacizumab [bev], 7% FOLFOX + bev, 4% FOLFIRI, 3% FOLFOX, and 15% standard CT + anti-EGFR therapy). Approximately 47% (n=2513) of pts did not receive subsequent treatments after 3L. In the 4L cohort, use of TAS-102 (16%) and rego (15%) increased slightly in 4L, accompanied with a moderate decrease in CT-containing regimens (42%; including 6% FOLFOX + bev, 5% FOLFIRI + bev, 3% FOLFOX, 3% FOLFIRI, and 12% standard CT + anti-EGFR therapy). Approximately 4% of pts in the 3L and 4L cohorts received TAS-102 + bev in 3L and 4L, respectively. Pts receiving standard CT-containing regimens were slightly younger (<65 yrs: 3L 57%, 4L 58%) and had better Eastern Cooperative Oncology Group performance status (ECOG PS; 0-1: 3L 77%, 4L 77%) vs pts receiving TAS-102 (<65 yrs: 3L 54%, 4L 58%; ECOG PS 0-1: 3L 70%, 4L 68%) or rego (<65 yrs: 3L 50%, 4L 53%; ECOG PS 0-1: 3L 68%, 4L 70%).
Conclusions:
Characterization of treatment patterns in US pts from 1/2018 to 3/2023 showed that standard CT +/- targeted therapy was used frequently in 3L and 4L, demonstrating an unmet need for additional therapies. Approval of novel treatments, such as fruquintinib, may help to address this need.
Patient-centered adverse event reporting in clinical trials: A novel approach using ECOG-ACRIN E2211.
Authors: Tan Wan Ying , Cramer Laura D. , Graham Noah , Vijayvergia Namrata , Lustberg Maryam B. , Benson Al B. , Kunz Pamela L.
Published: January 2025

658

Background:
The Common Terminology Criteria for Adverse Events (CTCAE) classifies adverse events (AEs) in clinical trials but traditionally limits the analysis to a single occurrence per patient and grade 3-4 AEs, overlooking frequent and lower grade AEs. We propose a new approach of AE reporting that captures both the safety profile and patient experience.
Methods:
We analyzed related AEs collected in the ECOG-ACRIN E2211 [Phase II capecitabine + temozolomide (Arm A) vs. temozolomide (Arm B) in advanced pancreatic neuroendocrine neoplasms] by CTCAE v4.0 and limited to hematologic and gastrointestinal (GI) categories for this exploratory analysis. We calculated AE burden, defined as the average occurrence of AE per patient experiencing the AE, measured by total occurrence of AEs, and divided by number of patients who developed the AE. We then compared burden of grade 3-4 AEs vs. grades 1-4 AEs. Sex differences were evaluated using t-tests.
Results:
For hematologic AEs, 72 patients reported 426 occurrences across grades 1-4 and 24 patients reported 39 occurrences for grades 3-4, resulting in AE burdens of 5.9 (grades 1-4) versus 1.6 (grades 3-4). For GI AEs, 108 patients reported 997 grade 1-4 events, and 13 patients reported 22 grade 3-4 events, resulting in AE burdens of 9.23 versus 1.69, respectively. Sex differences in AE burden are tabulated below (Table). For example, in Arm B, anemia burden was 4.8 (males) vs 2.7 (females) [p=0.068] for grades 1-4 and 0 (males) vs 1 (females) for grades 3 and 4.
Conclusions:
This AE reporting approach, accounting for the burden across grade 1-4, offers a different and more patient-centered assessment of AEs in clinical trials and may help better identify sex-based differences.

Burden of AEs by treatment arm and sex distribution.

Burden of Related AEs

Categories of AEs

Arm A (N=65)

Arm B (N=68)

Grade 1-Grade 4

Grade 3-Grade 4

Grade 1-Grade 4

Grade 3-Grade 4

Male

Female

p-value

Male

Female

p-value

Male

Female

p-value

Male

Female

p-value

Hematologic

Anemia
2.9
3
0.937
0
0

4.8
2.7
0.068
0
1*

Neutropenia
1.7
2.2
0.686
1
1*

1.2
2.3
0.064
1
1.1
0.356

Thrombocytopenia
4.3
2.6
0.241
1*
1.2

3.6
3.3
0.781
1
1
**

Gastrointestinal

Abdominal pain
2.5
2.2
0.835
0
0

3.1
3
0.955
0
1*

Constipation
4.1
3.2
0.515
1*
0

4.9
3.3
0.169
0
0

Diarrhea
1.8
3.6
0.158
0
0

2.6
2.5
0.940
1.25
1
0.390

Nausea
4.2
4.9
0.619
0
0

4.4
4.2
0.893
1
1**
**

Vomiting
2.2
1.9
0.703
0
0

1.8
2.8
0.241
1
1
**

*Only 1 patient in each group **No variance within each group.