bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated results of the PATH study: Adjuvant therapy with donafenib plus a PD-1 inhibitor for patients with hepatocellular carcinoma at high risk of recurrence after resection.
Authors: Chen Yiwen , Shen Yan , Zhang Min , Wu Jian , Gao Shunliang , Que Risheng , Yu Jun , Tang Xiaofeng , Bai Xueli , Liang Tingbo
Published: January 2025

571

Background:
There is no universally accepted standard treatment option or strategy for post-surgery adjuvant therapy in hepatocellular carcinoma (HCC). Among BCLC A/B patients (pts) with MVI, adjuvant transarterial chemoembolization has been reported to provide a 1-year recurrence-free survival (RFS) rate of around 60-70%. We conducted a pilot study to explore the utility of donafenib combined with a PD-1 inhibitor as adjuvant therapy for pts at high risk of recurrence. Herein, we present the updated results with a median follow-up of 11.6 months.
Methods:
It was planned to enroll 30 HCC pts who had undergone radical surgery and presented with at least one of the following risk factors: a) Presence of microvascular invasion (MVI); b) Presence of satellite nodule(s); c) More than three tumor nodules; d) Portal vein tumor thrombus. Pts with invasion of the main portal venous system were excluded. Donafenib combined with a PD-1 inhibitor (i.e., toripalimab) was initiated at 4 to 8 weeks post-resection and was to be continued for up to six months, unless recurrence occurred or there was an intolerable adverse reaction. No other adjuvant therapies were permitted before enrollment and during the study, except for anti-virus treatment. The primary endpoint was the cumulative 1-year RFS rate. The secondary endpoints included overall survival, quality of life (QoL) measured with the FACT- Hepatobiliary questionnaire, and safety.
Results:
From June 2020 to November 2023, a total of 30 pts were recruited. 27 pts were included in the efficacy analysis. The median time from surgery to enrollment was 1.4 months. MVI was the most common risk factor (n=25, 92.6%). The majority of the pts had only one risk factor (n=23, 85.2%). As of the data cutoff on August 13, 2024, relapse had occurred in four pts and the median RFS was not reached. The 1-year RFS rate was 81.6% (90% CI, 67.8%-95.4%) in all evaluable pts. QoL showed a mild increase from baseline while on adjuvant therapy. No deaths were observed. In the 30 pts who had received at least one dose, the incidence of any grade and grade 3 treatment-related adverse events (TRAEs) were 90.0% (27/30) and 40.0% (12/30), respectively. No grade 4 or 5 TRAEs were reported. The grade 3 TRAEs occurring in at least two pts were palmar-plantar erythrodysesthesia syndrome (13.3%), rash (13.3%), increased alanine aminotransferase (10.0%), and increased aspartate aminotransferase (6.7%).
Conclusions:
The study's duration exceeded expectations due to slow recruitment. Nonetheless, it showed a promising outcome with a regimen of 6 months of adjuvant therapy with donafenib plus toripalimab in BCLC A/B pts at high risk of recurrence. An improvement in QoL was observed among patients during the adjuvant therapy. No new safety issues were identified.
Clinical trial information: NCT04418401
.
Selective internal radiation therapy with yttrium-90 resin microspheres followed by lenvatinib plus PD-1 inhibitor for large or huge advanced-stage hepatocellular carcinoma: A retrospective cohort study from China.
Authors: Huang Jingjun , Huang Wensou , Liang Licong , Guo Yongjian , Cai Mingyue , Lin Liteng , Zhou Jingwen , Zhu Kangshun
Published: January 2025

581

Background:
Yttrium-90 resin microspheres have been introduced into China in recent years, but the efficacy or safety on Chinese patients are rarely reported. This study aimed to evaluate the efficacy and safety of selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres followed by lenvatinib and PD-1 inhibitor in Chinese patients with large (5.1–10.0 cm in diameter) or huge (>10.0 cm) advanced-stage hepatocellular carcinoma (HCC).
Methods:
Data of large or huge Barcelona Clinic Liver Cancer stage C HCC patients treated with SIRT followed by lenvatinib plus PD-1 inhibitor from November 2022 to October 2023 were prospectively collected and retrospectively analyzed. Key endpoints included overall survival (OS), progression-free survival (PFS), complete response rate (CRR), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors, and adverse events (AEs) graded based on Common Terminology Criteria for Adverse Events v5.0. Risk factors affecting PFS were analyzed using univariate and multivariate Cox regression models.
Results:
A total of 30 patients (27 males, 3 females; mean age 54 ± 11 years) were included. The mean longest diameter of the tumor was 9.6 ± 4.2 cm (range: 5.2–17.6 cm). Nineteen (63.3%) patients had more than three intrahepatic lesions, 15 (50.0%) had vascular invasion, and 13 (43.3%) had extrahepatic metastasis. Sixteen (53.3%) patients had undergone prior anticancer therapies. Two patients received two SIRT procedures, and the rest had one. Lenvatinib and PD-1 inhibitor treatment was initiated 3–7 days after the initial SIRT procedure. CRR was 20.0%, ORR was 73.3%, and DCR was 90.0%. Median PFS was 8.0 months (95% CI, 5.6–10.4), and median OS was not reached. OS rates at 6, 12, and 18 months were 93%, 74%, and 74%, respectively. Univariate and multivariate analysis indicated that baseline alpha-fetoprotein levels, baseline eosinophil count, and neutrophil-to-lymphocyte ratio at 1 month after SIRT were independent risk factors for PFS. AEs of any grade occurred in 86.7% of patients, with grade 3 AEs in 23.3%, and no grade 4/5 AEs were recorded.
Conclusions:
SIRT followed by lenvatinib and PD-1 inhibitor demonstrates promising efficacy and a favorable safety profile in Chinese patients with large or huge advanced-stage HCC.
TYRA-430: First reversible FGFR4/3 inhibitor designed to overcome current challenges in FGF19-driven hepatocellular carcinoma treatment.
Authors: Ahmed Mohamed A. , Starrett Jacqueline , Hoffman Isaac , Nelson Kirk , Neal Melissa , Pache Melissandre , Pettitt Emily , Bensen Daniel , Hudkins Robert , Harris Todd , Swanson Ronald
Published: January 2025

583

Background:
Hepatocellular carcinoma (HCC) is an aggressive malignancy that accounts for approximately 80-90% of all primary liver cancers and is projected to become the third leading cause of cancer-related mortality by 2030. Previous work demonstrated that human Fibroblast Growth Factor 19 (FGF19) was overexpressed in 20-30% of HCC, thereby exerting an oncogenic effect via signaling through its cognate receptors FGFR4, FGFR3, and the co-receptor Klotho b (KLB). Multiple selective covalent FGFR4 inhibitors have been clinically evaluated in FGF19-overexpressing HCC. However, selective inhibition of FGFR4 alone was insufficient and resulted in low response rates and limited duration, likely due to redundant signaling through FGFR3. Here we describe the first report on the preclinical profile of TYRA-430, a first-in-class reversible FGFR4/3 inhibitor.
Methods:
The preclinical profile of TYRA-430 was assessed
in vitro
in HCC cellular assays and
in vivo
in mouse xenograft models. The
in vitro
potency was assessed by measuring cell viability using Cell Titer-Glo 2.0 Luminescent assay. Percentage of tumor growth inhibition (TGI) was used as a measure to evaluate
in vivo
efficacy of TYRA-430.
Results:
TYRA-430 exhibited potency against Ba/F3 cells dependent on wildtype FGFR3 and FGFR4, as well as the known Cys552 and Val550 gatekeeper (GK) resistance mutations in FGFR4.
In vitro
data showed that TYRA-430 displayed superior potency over the reversible multi-kinase inhibitors sorafenib and lenvatinib, and the covalent FGFR4 inhibitors fisogatinib (BLU-554) and roblitinib (FGF401) in KLB/FGF-19/FGFR3/4 driven models of HCC (Hep3B, HuH-7, and JHH-7 cells). Furthermore, in a human HuH-7 HCC xenograft model in nu/nu mice, TYRA-430 achieved 96% tumor growth inhibition (TGI), compared to 75% TGI for lenvatinib and 86% TGI for FGF401. Additionally, in the GA180 FGF19-driven gastric cancer PDX model, TYRA-430 demonstrated superior efficacy with 93% tumor growth inhibition (TGI), compared to 56% TGI achieved by roblitinib.
Conclusions:
TYRA-430 was active and potent in multiple KLB/FGF-19/FGFR3/4 models of human hepatocellular carcinoma
in vitro
and
in vivo
. Moreover, TYRA-430 displayed potent activity against known FGFR4 resistance mutations compared to covalent FGFR4-specific inhibitors in the clinic. TYRA-430 will be investigated in a Phase 1 clinical trial in hepatocellular carcinoma and other advanced solid tumors.
Analysis of gut and mucosal microbiomes in patients with extrahepatic cholangiocarcinoma.
Authors: Ryu Hyewon
Published: January 2025

620

Background:
Cholangiocarcinoma is an aggressive malignancy with a poor prognosis. While gut microbial dysbiosis is linked to various diseases, including biliary disorders and cancer, its association with cholangiocarcinoma remains unclear.
Methods:
This study compared the mucosal and gut microbiomes of patients with extrahepatic cholangiocarcinoma (n = 21) to those with cholecystitis (n = 21) and healthy individuals (n = 28). Mucosal microbiomes were collected from cancer lesions and gallbladders, with fecal samples obtained from 31 participants. The 16S rRNA gene (V3 and V4 region) was sequenced using the Illumina MiSeq platform and analyzed with QIIME 2.
Results:
16S rRNA sequencing revealed Proteobacteria as the dominant taxon in the cancer cohort, with
Klebsiella, Aeromonas, Staphylococcus, Fusobacterium, and Haemophilus
also enriched. In contrast,
Firmicutes
dominated in the cholecystitis and control cohorts. β-diversity analysis highlighted significant differences between cohorts. Elevated levels of bile acids, particularly chenodeoxycholic acid and ursodeoxycholic acid, were observed in the cancer cohort and positively correlated with
Proteobacteria, Aeromonas, Enterobacter, and Enterococcus.
Conclusions:
These findings suggest that microbiome dysbiosis contributes to cholangiocarcinoma development.
Association of GPR120 and NGF with perineural invasion in cholangiocarcinoma: Clinical and experimental insights.
Authors: He Jun , Qin Lei , Shi Yang , Shen Danyang , Yu Wangjianfei , Zhang Weigang , Yao Jialu , Hu Xiaoyuan
Published: January 2025

622

Background:
Cholangiocarcinoma (CCA) is a highly malignant biliary tumor characterized by frequent perineural invasion (PNI), which is associated with a poor prognosis; however, the underlying mechanisms remain unclear. G-protein-coupled receptor 120 (GPR120) has been implicated in the development of various tumors, while nerve growth factor (NGF) has a strong correlation with PNI. This study aims to elucidate the role of GPR120 in the production of NGF and to investigate the mechanisms by which PNI is induced in CCA.
Methods:
We conducted a retrospective review of medical records for 386 patients with cholangiocarcinoma (CCA), including both extrahepatic (ECC) and intrahepatic (ICC) types, who underwent curative resection at the Department of General Surgery, First Affiliated Hospital of Soochow University, between January 2015 and December 2021. NGF and GPR120 expression were assessed in 60 paraffin-embedded archived CCA tissue samples via immunohistochemical staining (IHC), with an additional 60 normal bile duct samples serving as controls. All tissues were sourced from the aforementioned 386 patients, none of whom received preoperative treatment. Tumors were staged according to AJCC classification. Western blot analysis was employed to evaluate NGF and GPR120 expression in CCA cell lines (QBC 939, RBE, HUCCT-1, and HCCC-9810). To assess the invasion and migration capabilities of CCA cell lines, QBC 939 and HCCC-9810 were treated with TUG-891 (a GPR120 agonist) and AH7614 (a GPR120 inhibitor).
Results:
Both GPR120 and NGF were found to be upregulated in CCA tissues, correlating with aggressive clinicopathological features. IHC staining revealed cytoplasmic localization of GPR120 and NGF, with significantly higher expression in cancerous tissues compared to adjacent noncancerous samples. Among the 386 patients, PNI was observed in 339 (87.8%). PNI correlated with tumor diameter, CA 19-9 levels, TNM stage, preoperative bilirubin levels, tumor differentiation, and preoperative drainage. Notably, GPR120 expression increased in poorly differentiated tumors and advanced clinical stages, indicating a clinical association with CCA progression. In vitro studies demonstrated that GPR120 promoted invasion and migration in the QBC 939 and HCCC-9810 cell lines. Western blot analysis confirmed elevated GPR120 levels in these lines, which also exhibited higher NGF expression. The GPR120 inhibitor AH7614 significantly reduced invasion in QBC 939 and HCCC-9810 cells, while the GPR120 agonist TUG-891 showed no effect on any of the CCA cell lines tested.
Conclusions:
GPR120 and NGF are implicated in perineural invasion (PNI) in CCA, with a notable correlation between GPR120 and NGF in the context of PNI occurrence.
Exclusive liver invasion as prognostic indicator in T3 gallbladder cancer.
Authors: Lee Woohyung , Shin Arum , Song Ki Byung , Lee Jae Hoon , Hwang Dae Wook , Kim Song Cheol
Published: January 2025

631

Background:
T3 gallbladder cancer (GBC) contains a diverse range of invasive tumors. However, distinct prognostic outcomes may be observed among T3GBC confined to localized range despite sharing the same T3GBC. There is uncertainty regarding whether there are noticeable prognostic variances between tumors that invade the liver, or serosa only and those that extend to adjacent organs. This study aims to investigate prognostic differences according to the extent of invasion in patient with T3GBC.
Methods:
The patients with T3GBC who underwent curative intent surgery from February 2002 to December 2021 were analyzed. The patients were divided into those who had tumor invaded liver only, serosa only, or extended beyond. Their clinicopathologic characteristics, perioperative details and prognostic data were compared. Survival analyses were carried out using the log-rand test including subgroups considering nodal metastasis, and other T stages. Cox-proportional hazard model including other factors were used to identify the independent risk factors for survival.
Results:
We identified 194 patients with T3GBC. The patients with tumor invaded liver only, serosa only, and adjacent organs were 86, 33, and 35, respectively. The median survival was 23 months. The patients with invasion limited to the liver showed better survival than those who involve adjacent structures (26 months vs 9 months, p < 0.001). In multivariate analysis, it was demonstrated that the concomitant presence of invasion in structures other than the liver serves as independent prognostic factors for survival. (hazard ratio [HR], 6.8, 95% confidence interval [CI] 1.746 – 26.803, p = 0.006) as well as lymphovascular invasion (HR 2.5, 95% CI 1.093 – 4.193, p= 0.026 ).
Conclusions:
In the T3 gallbladder cancer, exclusive liver invasion is a better prognostic indicator compared to concurrent invasion around adjacent structure. It is crucial to recognize that the extent of invasion in T3GBC patients before surgery. Multicenter studies are needed for the definite results.
Tumor vascularity as a predictor of FGFR inhibitor response in FGFR2-fused intrahepatic cholangiocarcinoma.
Authors: Meza Kelly , Villegas De Leon Sergio , Pant Shubham , Tang Tin-Yun , Meric-Bernstam Funda , Hu Zishuo Ian , Javle Milind M. , Lee Sunyoung S.
Published: January 2025

638

Background:
Fibroblast growth factor receptor 2 (FGFR2) fusion is a well-established mutation in intrahepatic cholangiocarcinoma (iCCA), accounting for approximately 10% of cases. Current treatments, including pemigatinib, infigratinib, and futibatinib, have shown promising results with response rates of less than 40%. Most patients experience progression within 6-8 months, and reliable biomarkers to predict treatment response are still lacking. This study aimed to assess the clinical outcomes of FGFR inhibitors in patients (pts) with FGFR2-fused iCCA, while investigating tumor vascularity as a potential predictor of treatment efficacy.
Methods:
We retrospectively analyzed data from 134 pts treated at MD Anderson Cancer Center between 2009 and 2024, focusing on 73 pts with comprehensive clinical data. The cohort included pts treated with futibatinib (n=16), infigratinib (n=16), pemigatinib (n=36), and derazantinib (n=5). Tumor vascularity was assessed via Hounsfield units (HU) from CT images, including a mathematical parameter to calculate a ratio of hypervascular tumor rim thickness to tumor diameter. Transcriptomic analysis of 11 pts was performed to explore mRNA expression related to tumor vasculature. Kaplan-Meier analysis for progression-free survival (PFS) and ANOVA for statistical comparisons were applied.
Results:
The median age was 60 years, and 41 pts were female. For FGFR2-fused iCCA, median PFS for first-line gemcitabine-based chemotherapy with or without immunotherapy was 4.07 months [3.0-5.1]. Among FGFR inhibitors, mPFS was 7.07 months [95% CI: 5.10-8.16], with no significant difference in outcomes between FGFR inhibitors. 59 pts had comparable CT images and were grouped into 3 groups based on K-means clustering: Group 1 (n=30) had mPFS of 3.07 months [2.03-4.10]; Group 2 (n=22), mPFS of 9.10 months [8.2-11.2]; Group 3 (n=7), mPFS of 34.03 months [18.2-37.6]. Group 1 had the most hypovascular tumors (the lowest HU in the periphery of tumors), while Group 3 had the most hypervascular tumors (p=0.017). The HU ratio of the hypervascular tumor rim thickness to tumor diameter showed a trend, with the highest ratio in Group 3 and the lowest in Group 1 (p=0.09). Transcriptomic analysis revealed a trend toward higher VEGF/VEGFR gene expression in hypervascular tumors. Eight pts received second-line FGFR inhibitors, with mPFS of 5.0 months [2.1-8.3].
Conclusions:
Pts with FGFR2-fused iCCA have a shorter PFS on first-line chemotherapy, and PFS outcomes for FGFR inhibitors were consistent with existing data. Tumor vascularity, as assessed by CT imaging, may be a valuable predictor of response to FGFR inhibitors. This study suggests that hypervascular tumors may have better outcomes, warranting further investigation in a larger cohort to confirm these findings and establish tumor vascularity as a predictive biomarker for FGFR inhibitor therapy.
A phase III study of combination therapy with everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumor (JCOG1901, STARTER-NET).
Authors: Hijioka Susumu , Honma Yoshitaka , Machida Nozomu , Mizuno Nobumasa , Hamaguchi Tetsuya , Boku Narikazu , Sadachi Ryo , Hiraoka Nobuyoshi , Okusaka Takuji , Hirano Hidekazu , Boku Shogen , Ikeda Masafumi , Takeuchi Satoshi , Fukushima Noriyoshi , Kojima Motohiro , Mitome Noriko , Sano Yusuke , Yoshikawa Takaki , Kanemitsu Yukihide , Ueno Makoto ,   Japan Clinical Oncology Group
Published: January 2025

652

Background:
There is limited evidence regarding the benefit of adding somatostatin analogs to molecular targeted agents for well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This phase III trial was conducted to compare everolimus plus lanreotide (EVE/LAN) with everolimus monotherapy (EVE) in patients with unresectable or recurrent GEP-NETs in the first-line setting.
Methods:
Patients with grade 1 or grade 2, nonfunctioning GEP-NETs with poor prognostic factors (Ki-67 labeling index (LI) 5-20% or diffuse liver metastases) were randomly assigned (1:1) to EVE (10 mg/day) or EVE/LAN (EVE + LAN 120 mg every 28 days). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS), and other secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. The study was based on the hypothesis of an assumed median PFS of 11.0 months for EVE, expecting a 4-month improvement by EVE/LAN (HR: 0.73). The planned sample size was 250, requiring 195 events overall with a one-sided alpha level of 5%, a power of 70%, an accrual period of 5 years, and a follow-up period of 1.5 years.
Results:
Between April 2020 and June 2024, a total of 178 patients were enrolled, and the planned interim analysis was conducted in 145 patients (72 in the EVE and 73 in the EVE/LAN) in June 2024 with a data cut-off date of Nov 2023. The median PFS was 11.5 months in the EVE arm and 29.7 months in the EVE/LAN arm (HR 0.38 [99.91% CI 0.15–0.96], P = 0.00017 < the prespecified significance level of 0.00046, by the stratified log-rank test). The HR for OS was 0.97 (95% CI: 0.24-3.90). The ORR and DCR were 8.7% (6/69) and 87.0% (60/69) in the EVE arm and 26.8% (19/71) and 91.5% (65/71) in the EVE/LAN arm, respectively. Both hematologic and non-hematologic toxicities tended to be more frequent in the EVE/LAN arm than in the EVE arm. No treatment-related deaths were observed in either arm. Based on the efficacy results, the Data and Safety Monitoring Committee recommended early termination of the study.
Conclusions:
The EVE/LAN provides statistically significant prolongation of PFS compared with EVE monotherapy, and the safety profile of EVE/LAN was manageable. The EVE/LAN might be a new standard treatment in the first-line setting for well-differentiated grade 1/2 GEP-NETs with poor prognostic factors. Clinical trial information: jRCT1031200023.
Comparative outcomes of neuroendocrine tumors in the historically underserved population of Bronx, NY: Montefiore Einstein Comprehensive Cancer Center.
Authors: Takchi Andrew , Bhatt Ahan , Bernabe Carolina , Mundi Prabhjot Singh , Kuang Chaoyuan , Bteich Fernand , Saenger Yvonne M. , Kaubisch Andreas , Laderian Bahar
Published: January 2025

671

Background:
Neuroendocrine tumors (NETs) pose different clinical implications based upon age at diagnosis, with regards to early-onset (EO<50yrs) versus late-onset (LO>=50yrs) disease. While primary-tumor resection is crucial for localized NETs, its benefit in metastatic cases without metastasectomy remains uncertain. This study examines variables associated with survival in EO versus LO cases, including primary tumor resection.
Methods:
A retrospective cohort of 91 patients with gastrointestinal(GI)-NETs were identified as part of an IRB-approved project. Disease-stage (local vs. metastatic), tumor grade (G1-3), 5-year-survival, primary-tumor removal, and race/ethnicity were included in this analysis.
Results:
Among all patients, 31.9% identified as Hispanic, 33% as non-Hispanic Black, 22% as non-Hispanic White, and 13.1% as other. Among all patients, 79 were classified as G1/G2. Among LO patients, 87.5% (n=63) were G1/G2, among which 46% (n=29) were metastatic. Among EO patients, 84% (n=16) were G1/G2, among which 68.8% (n=11) were metastatic. In the LO group with G1/G2 tumors, 5-year survival rate was 48.3% for metastatic disease and 58.8% for localized disease. For EO with G1/G2 tumors, the 5-year survival rate was 72.7% for metastatic disease and 80% for localized disease. In the EO G1/G2 group, 5 of the 11 patients with metastatic disease had primary tumor removal without metastasectomy with 100% 5-year survival rate. In the LO G1/G2 group, 7 of 29 metastatic patients had primary tumor removal without metastasectomy, with 86% 5-year survival rate. Resection of primary tumor (without metastasectomy) in patients with metastatic G1/G2 NETs was associated with improved 5-year survival, independent of age at diagnosis (
p-value
=0.008), as shown in the table.
Conclusions:
This study helps to emphasize the importance of primary tumor removal in improving survival outcomes for patients with metastatic low-grade GI-NETs, regardless of age. Further investigation is warranted to study the role of certain imperative variables such as site of metastases, number of metastases, and patient co-morbidities.

Survival outcomes based on primary tumor removal in metastatic low-grade GI-NETs.

No 5-year survival
5-year survival

Primary tumor removal without metastasectomy
1
11

No surgery
12
8
Vascular endothelial growth factor receptor (VEGFR) -tyrosine kinase inhibitors combined with programmed death receptor-1 (PD-1) inhibitors as third- or later-line treatment in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): A retrospective study.
Authors: Li Xiaoqian , Liu Fang , Liu Bo , Yang Jing , Han Shumei
Published: January 2025

68

Background:
Microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) shows a low response to programmed death receptor-1 (PD-1) inhibitors. Recent studies suggest that combining vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs) with PD-1 inhibitors may enhance the anti-cancer activity for mCRC patients. Multiple antiangiogenic drugs have been approved by the FDA and NMPA for the treatment of later-line mCRC. Nevertheless, the effects of various anti-angiogenic drugs when used in combination with immunotherapy for mCRC treatment is not yet fully established.
Methods:
We conducted a non-interventional, retrospective study. Data were compiled from patients with mCRC at Shandong Cancer Hospital. Eligible patients must have received a combination of anti-angiogenic drugs and PD-1 inhibitors following at least two lines of standard treatment. The treatment period spanned from August 2019 to April 2024. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS).
Results:
At the cut-off date (April 29th, 2024), 79 eligible patients were available for analysis. Of these, 49 patients received fruquintinib in combination with PD-1 inhibitors (F group), 30 patients received investigator-selected other anti-angiogenic agents in combination with PD-1 inhibitors (NF group). The baseline characteristics of the two groups were well balanced. The median overall survival (OS) was significantly longer in the F group compared to the NF group (hazard ratio [HR]: 0.36, 95% CI 0.14-0.96, P=0.042). The median OS was not reached (95% CI 21.1-NA) in the F group, whereas it was 19.1 months (95% CI 12.6-NA) in the NF group. Subgroup analyses of OS were generally consistent with benefit in the whole population across nearly all subgroups. In contrast to NF group, individuals in F group demonstrated a significant enhancement in overall survival (OS) when patients had received prior bevacizumab (HR: 0.26, 95% CI 0.07-0.75, P=0.015), had no prior treatment with cetuximab (HR: 0.23, 95% CI 0.26-0.97, P=0.045), or had experienced surgical resection at baseline (HR: 0.34, 95% CI 0.12-0.95, P=0.041). The median PFS between two groups showed no statistically significant difference (HR: 0.65, 95% CI 0.38-1.13, P=0.127), F group 6.1 months (95% CI 4.6-10.3) versus NF group 4.4 months (95% CI, 3.0-7.5).
Conclusions:
Fruquintinib demonstrated improved OS over other anti-angiogenic agents when combined with immunotherapy for third or later-line MSS mCRC treatment.
Evaluation of the impact of lymph node ratio on survival in patients with pancreatic cancer undergoing neoadjuvant therapy.
Authors: Thomas Maren , Huston Jamie , Shridhar Ravi , Meredith Kenneth Lee
Published: January 2025

702

Background:
Pancreatic cancer continues to have a dismal prognosis despite improvements in surgical care. Resection status and lymph node status continues to be key factors impacting prognosis. There remains significant debate on the utility of increasing nodal harvest in patients undergoing surgery, while others report an improvement in survival. We sought to evaluate the impact of lymph node positivity to lymph nodes resected in patients with pancreatic cancer undergoing resection.
Methods:
Utilizing the National Cancer Database, we identified patients diagnosed with pancreatic cancer who underwent neoadjuvant chemotherapy (NCT) or neoadjuvant chemoradiation (NCR) followed by resection. We then stratified by nodal status and calculated a LN+/LNR (lymph node resected) ratio. Pearson’s Chi-square test was used to compare categorical variables. Survival analysis was estimated by the Kaplan-Meier method and associated log-rank test. Propensity score matching (PSM) was completed for variables of age, sex, tumor size, LN removed, LN positive, pathogenic T- stage and N-stage, grade, 30- and 90-day mortality, R0 resection, facility volume, response, adjuvant therapy, and LNR. Significance was considered at p-value ≤0.05.
Results:
We identified 4117 patients with a median age of 65 (25-90). There were 2323 patients who underwent NCT and 1794 who underwent NCR. The median LN resected in the NCT was 18 vs 15 in the NCR, p<0.001. However, there were more LN+ in the NCT vs NCR, 2.1 vs 0.9, p<0.001. The R0 resection rates were lower in the NCT vs NCR 81% vs 86%, p<0.001. Additionally, complete response rates were higher amongst the NCR, 9.2% vs 4.7%, p<0.001. Lymph node ratios were consistently higher in the NCT cohorts among all ratio strata, p<0.001. Patients with pN+ disease had a median and 5-year survival of 26.4mo and 17% compared to their pN- counterparts at 38.8mo and 36%, p<0.001. Patients treated with NCT demonstrating a LNR of 0.01-0.1 had median and 5-year survival of 32.8 and 27%, LNR 0.11-0.4 (25.5mo and 12%), and LNR>0.4 (19.1mo and 10%), p<0.001. Patients treated with NCR demonstrating a LNR of 0.01-0.1 had median and 5-year survival of 29.1 and 21%, LNR 0.11-0.4 (25.8mo and 17%), and LNR>0.4 (21.3mo and 5%), p<0.001. PSM confirmed a higher LNR in the NCT cohort compared to NCR, p<0.001, however survival was also longer in these patients among the LNR 0.01-0.1, and 0.11-0.4, p<0.001.
Conclusions:
Lymph node status in patients with pancreatic cancer continues to be a significant prognostic indicator of survival. Moreover, lymph node ratio may be a more accurate predicter of survival in patients undergoing neoadjuvant chemotherapy and neoadjuvant chemoradiation.
Aflibercept (AFL) vs. ramucirumab (RAM) -based therapy in patients with advanced colorectal cancer: Efficacy comparison using real-world data evidence from TriNetX platform.
Authors: Rodriguez-Pascual Jesus , Hernández Gema , Ugidos Lisardo , Parralejo Alejandro , Rodriguez-Castaño Juan Diego , Serrano Juan Jose , Ayuso Angel
Published: January 2025

71

Background:
FOLFIRI in combination with Aflibercept (AFL) or Ramucirumab (RAM) prolongs overall survival compared with FOLFIRI alone in patients with advanced colorectal cancer (aCCR) as second-line therapy, however, there are no comparative studies between them.
Methods:
Utilizing the TriNetX Global Collaborative Network, a platform that operates globally based on anonymized and aggregated clinical data, a sample of aCCR 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 platform.
Results:
A total of 1046 patients met the study criteria and were included in our study. 523 received AFL and 523r received RAM-based therapy. Patients treated with AFL showed a significant better OS compared to patients treated with RAM, both previous to PSM and before PSM (post-PMS median OS 430 days vs 317 days, HR 0.797, 95%CI 0.683-0.930).
Conclusions:
In this study, based on Real World data, Aflibercept showed superior results to Ramucirumab in advanced colorectal cancer patients treatment. To date this is the largest study comparison between this two therapeutic options.
A novel 2-2 5-5 model for stratifying liver metastasis burden in patients with pancreatic cancer.
Authors: Kim HyeonKi , Lee Wooyeon , Kim Junsoo , Shin Dong Woo , Choi Young Hoon , Seo Wootaek , Lim Hee-Eon , Jung Kwangrok , Kim Jaihwan , Hwang Jin-Hyeok , Lee Jong-chan
Published: January 2025

711

Background:
In metastatic pancreatic cancer (MPC), hepatic metastasis is uniformly counted as just ‘one organ metastasis’ regardless of its metastatic tumor burden. This study aims to develop a novel stratification system for liver metastasis based on tumor burden, and to evaluate its prognostic significance in MPC patients.
Methods:
Patients with MPC treated at Seoul National University Bundang Hospital from 2011 to 2021 were included as the training cohort. Patients with liver-only metastasis were selected for analysis. Liver metastasis burden was categorized by the number and maximum diameter of metastases as measured from diagnostic CT images. Optimal cutoffs for metastasis number and size were determined using Cox proportional hazards regression, adjusted for chemotherapy regimen. An independent cohort from Seoul St. Mary’s Hospital and Hallym University Sacred Heart Hospital served as the validation group. The ‘H category classification’ suggested by the Japanese Society for Cancer of the Colon and Rectum (JSCCR) was also referenced.
Results:

A total of 1,257 patients were included, with 1,084 in the training cohort and 173 in the validation cohort. In the training cohort, data from 311 patients with liver-only metastasis were analyzed to derive the Two-two five-five (‘2-2 5-5’) criteria, classifying metastasis into Oligo-metastasis (≤2 metastases and ≤2 cm), Meso-metastasis (non-oligo and non-mega), and Mega-metastasis (≥5 metastases or ≥5 cm). Median overall survival (OS) significantly differed between the groups: Oligo (11.4 months), Meso (9.2 months, HR 1.66, 95% CI 1.14–2.43), Mega (5.6 months, HR 2.63, 95% CI 1.94–3.58) in the training cohort; Oligo (5.8 months) vs Mega (1.81 months, HR 1.94, 95% CI 1.16–3.22) in the validation cohort.
Conclusions:
This 2-2 5-5 model effectively stratifies MPC patients with hepatic metastasis into three prognostic groups, demonstrating significant survival differences in both training and validation cohorts. This could rationalize the independent therapeutic strategies by extent of hepatic metastasis.

Demographic characteristics of patients classified according to “two-two five-five” criteria.

Oligo-metastasis(n = 88)
Meso-metastasis(n = 59)
Mega-metastasis(n = 164)
Total(n = 311)
P-value*

Age, median (range)
66.0 (33.2-91.0)
67.1(37.2-86.9)
68.7 (40.1-94.6)
67.9 (33.2-94.6)
0.587

Male, n (%)
43 (48)
36 (61)
91 (55)
170 (54)
0.330

Tumor location(Head), n(%)
47 (53)
27 (45)
60 (36)
134 (43)
<0.05

Number of liver metastasis, median (range)
1 (1-2)
3 (1-4)
12 (2-14)
5 (1-14)
<0.05

Maximal size of liver metastasis, cm (IQR)Average size of liver metastasis, cm (IQR)
10.6 (8.1-13.1)10.3 (8.0-12.1)
15.9 (10.1-24.2)13.5 (7.8-19.1)
21.6 (16.8-33.7)13.2 (10.5-19.2)
17.2 (10.9-25.2)11.9 (9.2-17.1)
<0.05<0.05

CA19-9 (U/mL)
462 (103-1,334)
560 (89-1,480)
1,170 (100-9,500)
745 (100-3,700)
<0.05
Real-world survival comparison of second-line treatment strategies for patients with RAS/RAF wild-type, right-sided metastatic colorectal cancer.
Authors: Swami Nishwant , Hwang Wei-Ting , Mamtani Ronac , O'Hara Mark H. , Chapin William Joseph
Published: January 2025

73

Background:
For patients with RAS/RAF wild type metastatic colorectal cancer (mCRC), systemic therapy usually includes fluoropyrimidine-based chemo + anti-VEGF or anti-EGFR targeted therapy. The PARADIGM trial established tumor sidedness as an important predictive biomarker for patients with RAS/RAF wild-type disease; in right-sided tumors, there was no survival difference between first-line chemo + anti-EGFR vs. chemo + anti-VEGF. However, there is no comparative data to guide second-line treatment decisions in this population. We aim to compare the effectiveness of second-line chemo + anti-EGFR versus chemo + anti-VEGF therapy for patients with RAS/RAF wild-type, right-sided mCRC who received first-line chemo + anti-VEGF.
Methods:
We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data obtained from ~280 cancer clinics and curated via technology-enabled abstraction. Patients ≥18 years old with RAS/RAF wild-type, right-sided mCRC who received first-line therapy consisting of chemotherapy ((FOLFIRI or FOLFOX or CAPEOX) + anti-VEGF and initiated second-line chemotherapy with either anti-EGFR or anti-VEGF targeted therapy between January 2013-May 2024 were included. Multiple imputation with chained equations imputed missing values for sidedness, RAS/RAF status, and propensity score covariates (age, gender, year of diagnosis, synchronous/metachronous disease, MMR/MSI status, ECOG score, CEA level, and first-line therapy duration). Cox proportional hazards modeling with stabilized inverse probability of treatment weighting (IPTW) assessed the association of anti-EGFR vs anti-VEGF treatment with overall survival.
Results:
4,444 patients received appropriate first-line treatment and received chemo + anti-EGFR or chemo + anti-VEGF in the second line. Across 25 imputations, an average of 444 patients met inclusion criteria: 175 patients received chemo + anti-EGFR and 269 patients received chemo + anti-VEGF. Following IPTW, baseline characteristics were balanced between treatment groups. Patients who received chemotherapy + anti-EGFR had a 24% increased hazard of death when compared with patients who received chemotherapy + anti-VEGF, though this was not statistically significant (HR 1.24, 95% CI 0.96 – 1.61, p=0.097).
Conclusions:
Among patients with RAS/RAF wild-type, right-sided mCRC who received first-line chemotherapy + anti-VEGF, there is some evidence to support continuing anti-VEGF therapy vs. switching to anti-EGFR therapy in the second line, though the result was not statistically significant. Future studies should explore predictive biomarkers for EGFR vs VEGF-directed treatment for this population to determine the patients most likely to benefit from anti-EGFR therapy during their disease course.
The effect of renin-angiotensin system inhibitors on patients with pancreatic cancer receiving systemic treatment: A retrospective cohort study from TriNetX US collaborative networks.
Authors: Chou Cheng-Wei , Lin Jun-Fu , Lin Ching-Heng
Published: January 2025

734

Background:
This study aimed to assess the impact of renin-angiotensin system inhibitors, including angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), on patients with pancreatic cancer undergoing systemic chemotherapy.
Methods:
We conducted a global, retrospective collaborative network analysis using TriNetX data from January 1, 2014, to December 31, 2023, to explore this question. The study captured data on pancreatic cancer diagnoses, comorbidities, medications, and survival outcomes. Propensity score matching (PSM) was used to create 1:1 matched groups. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated to assess survival outcomes, while the Kaplan–Meier method was employed to evaluate survival probabilities. Subgroup analyses were performed based on sex, age, surgery, race, and comorbidities.
Results:
The study included 1,861 patients who were on ARBs/ACEIs and 4,875 patients who were not on these medications at baseline. After 1:1 propensity score matching, both groups were well-balanced with 1,627 patients each. Compared to the non-ARBs/ACEIs group, patients receiving ARBs/ACEIs demonstrated significantly better overall survival (HR: 0.846, 95% CI: 0.753–0.949). Subgroup analyses revealed significantly improved survival outcomes in patients on ARBs/ACEIs, including those without surgery (HR: 0.846, 95% CI: 0.749–0.956), males (HR: 0.762, 95% CI: 0.640–0.908), patients aged 65 years and older (HR: 0.801, 95% CI: 0.709–0.906), and White patients (HR: 0.806, 95% CI: 0.704–0.924). Notably, similar survival benefits were observed in patients with comorbidities such as diabetes, ischemic heart disease, dyslipidemia, and hypertension.
Conclusions:
In the largest TriNetX matched cohort study on pancreatic cancer, the use of ARBs/ACEIs was associated with a reduced risk of overall mortality. However, prospective studies are needed to further evaluate the effects of concomitant ARB/ACEI use in patients with pancreatic cancer undergoing systemic treatment.
Physical activity and sedentary behavior patterns after early-onset colorectal cancer diagnosis.
Authors: Holowatyj Andreana Natalie , Keller Samantha R , Rosen Allison , Babyak Rebecca , Hunzinger Katherine J
Published: January 2025

74

Background:
Sedentary lifestyle and physical inactivity are established risk factors for colorectal cancer diagnosed among adults younger than age 50 years (early-onset CRC). However, patterns of physical activity (PA) and sedentary behavior (SB) in patients after an early-onset CRC diagnosis are less understood.
Methods:
The Reproductive Health After Cancer Diagnosis and Treatment (REACT) Study is a patient-partnered, cross-sectional study in cooperation with 23 community partners and patient advocates that recruited adults with a first primary cancer (diagnosis age: 18-49 years) over an 8-week period (October to December 2021). Patient-reported sociodemographic, cancer and cancer impact, PA and SB questions were prospectively collected via questionnaire. Frequency, duration and intensity of leisure-time, work-related and transportation-related PA were summed as minutes per week (min/wk). Time spent on SB was calculated by hours spent sitting on a typical day. Diagnosis age- and year-adjusted Spearman correlation coefficients were calculated between PA and SB by cancer treatment status.
Results:
A total of 131 patients were diagnosed with a first primary early-onset CRC between 2016 and 2021 (median [IQR] age, 40.0 [35-45] years; 82.4% female) in REACT. One hundred thirteen patients (86.3%) were concerned about their physical fitness or getting enough exercise after cancer diagnosis—of whom 62.8% (n=71 of 113) were somewhat or very concerned about their physical fitness/exercise. Among 80 patients with early-onset CRC and complete PA/SB data (86.3% female), 28.8% were not adherent to PA guidelines for aerobic activity (≥150 min/wk) and 56.3% reported long sedentary time (>6 hr/day). The proportion of patients across PA/SB groups also statistically significantly differed by treatment status among those diagnosed between 2019 and 2021 (p=0.049), but not between 2016 and 2018 (p=0.25). While PA was not significantly correlated with SB for early-onset CRC patients who were not actively undergoing treatment (r=-0.16,
p
=0.32), there was a statistically significant moderate inverse correlation between PA with SB among early-onset CRC patients under active cancer treatment (r=-0.58,
p
=0.004).
Conclusions:
One in every 2 early-onset CRC patients reported long sedentary time and one in every 4 early-onset CRC patients in this study did not meet the Physical Activity Guidelines for Americans. With over 80% of patients expressing concern about their physical activity and exercise after an early-onset CRC diagnosis, and differences in PA/SB patterns observed by treatment status, these findings warrant prospective, longitudinal studies of objectively-measured PA and SB among young patients in order to support tailored strategies (e.g., exercise prescriptions) that improve patient health and outcomes across the CRC continuum.
Preclinical development of the lipid nanoparticle–based mRNA vaccine with multiple natural T cell epitopes for pancreatic cancer.
Authors: Chang Josephine , Zheng Kevin , Li Yiming , Shan Wanting , Zheng Lei , Mao Hai-Quan , Fu Juan , Zhou Jiawei
Published: January 2025

752

Background:
Immunotherapy has recently emerged as a promising avenue in cancer treatment; however, its effectiveness on pancreatic ductal adenocarcinoma (PDAC) is hindered by the lack of effector T cells in the tumor microenvironment. One of the strategies to overcome the resistance of PDAC to immunotherapy involves identifying immunogenic tumor-associated and specific antigens for the development of personalized cancer vaccines. The mRNA platform has become an attractive platform for antigen presentation. The delivery of mRNA cancer vaccines via lipid nanoparticles (LNPs) enables intracellular delivery and controlled release of the payload, offering improved vaccine efficacy. However, mRNA vaccines presenting human T cell epitopes often lack a preclinical model for antitumor immune efficacy testing.
Methods:
A syngeneic mouse model of PDACs was established by implanting KPC tumor cells into the livers by hemispleen surgery. mRNA vaccine expressing five 25-mer peptide regions were synthesized. Two mouse CD8+ T cell epitopes were predicted. Their MHC binding was tested by the T2 binding assay. CD8+ T cells specific for these two epitopes were examined by ELISpot assays and were quantified by ImmunoSpot ELISpot Reader to identify changes in IFN-g secretion.
Results:
Using mass spectrometry analysis, we successfully identified natural HLA class I and class II-binding epitopes in the neoplastic tissues of human PDACs. For the design of mRNA vaccine, we chose five 25-mer peptide regions that each contains both class I and class II epitopes punctuated by AAY and GPGPG linkers and followed by an MITD sequence, which all aim to improve the efficiency of antigen presentation to dendritic cells. Using NetMHC, we predicted H2Kb or H2Db-binding epitopes LYPFPLAL and SMVQMTFL, within these five human peptide regions. The T2 binding assay showed a lack of evident binding of both peptides to the T2-Kb or T2-Db cells. However, the ELISpot assay showed that LYPFPLAL, but not SMVQMTFL, can induce the IFN-g expression from CD8+ T cells derived from splenocytes of the KPC tumor mice vaccinated by a peptide vaccine containing both peptides. Therefore, this result confirmed that LYPFPLAL is a mouse CD8+ T cell epitope and can be used to monitor antigen-specific CD8+ T cell response in response to the mRNA vaccine treatment in the syngeneic mouse model of PDACs.
Conclusions:
Antitumor efficacy of our above-designed mRNA vaccine can be tested in the syngeneic mouse hemispleen model of KPC tumors. Mouse LYPFPLAL epitope-specific CD8+ T cell response can serve as a surrogate marker for the antitumor efficacy of this mRNA vaccine in mouse models for PDAC.