bluuebunny/crossref_metadata_2025_split huggingface dataset:
FGF19-FGFR4 axis as the inaugural target for determining the efficacy of advanced esophageal cancer treatment.
Authors: Wang Wei , Lin Shuimiao , Zeng Qin , Li Wenjie , Liu Tongxin , Zhou Xiaomei , Wang Rong , Luo Ziyi , Wu Dehua 
Published: June 2024

4035 Background: Advanced esophageal cancer (EC) remains a fatal stage with limited survival benefits from current treatments due to lack of specific targets. Esophageal squamous cell carcinoma (ESCC) is the most common type observed in EC cases. Studies have shown that around 40% of ESCC cases exhibit amplification of chromosome 11q13, which includes genes like FGF19, FGF3, FGF4, and CCND1. Among these, FGF19 and its receptor FGFR4 play crucial roles in cancer progression. Blocking the FGF19-FGFR4 axis could potentially disrupt tumor progression. Anlotinib, a multi-targeting tyrosine kinase inhibitor, targets VEGFR2, PDGFR, and FGFR1-4. In this study, we analyzed the next-generation sequencing (NGS) data from our cohort of advanced EC patients to identify potential therapeutic targets based on their genetic mutations. We also investigated whether FGF19 amplifications could enhance sensitivity to anlotinib-based treatments. Methods: The study was conducted as a retrospective analysis at our institution from October 2017 to August 2021. To be included in the study, patients had to be between 18 and 75 years old, have confirmed metastatic and/or recurrent EC with measurable lesions, and have detailed clinical information without any other primary tumors. We used NGS to analyze the mutation landscape in advanced EC patients. Additionally, we investigated the therapeutic effects of blocking the FGF19-FGFR4 axis by retrospectively analyzing the outcomes of advanced EC patients who received anlotinib-based treatments, which target the FGFR family. We compared overall survival (OS), progression-free survival (PFS), and best response between advanced EC patients with and without FGF19 amplifications who received anlotinib-based treatments. Results: A total of 50 patients with advanced EC (47 with squamous carcinoma and 3 with adenocarcinoma) underwent NGS testing. FGF19 amplifications were the third most common mutation, occurring in 46% of patients, following TP53 (88%) and CCND1 (48%). Among the 26 patients receiving anlotinib-based treatment, 13 (50%) had FGF19 amplifications. Patients with FGF19 amplifications had a 69.2% objective response rate (ORR) and a 100% disease control rate (DCR). None of the 13 patients with FGF19 amplifications developed progressive disease (PD). Patients with FGF19 amplifications showed significant improvements in ORR (69.2% vs. 12.5%, p=0.011) and median PFS (5.3 vs. 2.7 months, HR=0.10, 95%CI: 0.02-0.56, p=0.0015) compared to those without FGF19 amplifications. Improvements in DCR (100% vs. 75%, p=0.06) and median OS (8.7 vs. 7.2 months, HR=0.44, 95CI%: 0.12-1.59, p=0.2) were also observed, albeit not statistically significant. Conclusions: Anlotinib-based therapy showed improved clinical outcomes in patients with FGF19 amplifications. This suggests that targeting FGF19 amplifications could be a promising approach for treating advanced ESCC.
Perioperative chemotherapy for patients with gastric cancer with microsatellite instability or deficient mismatch repair: A systematic review and meta-analysis.
Authors: Liu Baike , Cai Zhaolun , Yin Yuan , Wang Jingjing , Shen Chaoyong , Yin Xiaonan , Jiang Tianxiang , Han Yihui , Zhang Bo 
Published: June 2024

4039 Background: Currently, the efficacy of perioperative chemotherapy for gastric cancer (GC) patients with deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) remains controversial. It is still inconclusive whether chemotherapy can be spared for dMMR/MSI-H GC patients. Meanwhile, in the different therapeutic settings (e.g. neoadjuvant, adjuvant, or both), the efficacy of chemotherapy remains to be clarified. Therefore, a systematic review and meta-analysis in this regard was conducted. Methods: Studies comparing perioperative chemotherapy with surgery alone in resectable dMMR/MSI-H GCs (up to December 1, 2023) were included. The hazard ratio (HR) and its 95% confidence interval (CI) of survival outcomes were extracted from the original research or recalculated using Kaplan-Meier curves if the number of patients at risk was provided. In the pooled analysis, a random-effects model was employed. Subgroup analyses (perioperative chemotherapy in stage II and stage III diseases) and sensitivity analysis including studies reporting the results from multivariable analyses were conducted. This study was previously registered on PROSPERO platform (CRD42023494276). Results: Nineteen studies, encompassing over 1500 dMMR/MSI-H GC patients, were included in this study. The results revealed that perioperative chemotherapy (including neoadjuvant and adjuvant chemotherapy) did not significantly improve the overall survival (OS) (HR 0.86, 95% CI 0.57–1.31) and disease-free survival (DFS) (HR 0.70, 95% CI 0.46–1.05) in dMMR/MSI-H GCs. Furthermore, adjuvant chemotherapy did not confer a significant survival advantage for dMMR/MSI-H GCs (OS, HR 0.83, 95% CI 0.50–1.37) and (DFS, HR 0.67, 95% CI 0.41–1.07). Similar results were observed for neoadjuvant chemotherapy (OS, HR 1.09, 95% CI 0.55–2.15). In addition, stage stratification analysis demonstrated no significant survival benefit of adjuvant chemotherapy for stage II (OS, HR 0.77, 95% CI 0.31–1.90) or stage III (OS, HR 0.72, 95% CI 0.36–1.46) dMMR/MSI-H GCs. In the sensitivity analysis, the results remained consistent. Conclusions: Perioperative (including adjuvant and/or neoadjuvant) chemotherapy does not significantly improve survival in resectable dMMR/MSI-H GC patients. Immunotherapy may be better suitable for these patients in the future.
Effect of phosphoproteomic subtyping of gastric cancer on chemotherapy and guidance of targeted cancer therapy.
Authors: Shoji Hirokazu , Hirano Hidekazu , Nojima Yosui , Gunji Daigo , Shinkura Akina , Muraoka Satoshi , Abe Yuichi , Narumi Ryohei , Nagao Chioko , Aoki Masahiko , Obama Kazutaka , Honda Kazufumi , Mizuguchi Kenji , Tomonaga Takeshi , Yoshikawa Takaki , Kato Ken , Boku Narikazu , Adachi JUN 
Published: June 2024

4050 Background: Gastric cancer is the fifth most common malignancy and the fourth leading cause of death from malignant neoplasms worldwide, and advanced unresectable or recurrent advanced gastric cancer (AGC) has a poor prognosis, so further therapeutic development is needed. However, only a few molecular targeted agents are effective for AGC, and precision medicine using genomic profiling has limited scalability due to the low rate of alterations matched to single pharmacotherapy and complex networks of signal transduction activated by multiple oncogenic proteins. Thus, it is imperative to establish a new concept of precision medicine adapt to the dynamic changes in cancer. Methods: We collected endoscopic biopsy specimens from 84 chemo-naïve gastric cancer patients. We also serially collected endoscopic biopsy specimens from 9 AGC patients receiving 2nd line therapy (pre-treatment: 9 patients, post-treatment [2 months later]: 6 patients, and end of treatment: 2 patients). Each specimen was immediately snap frozen in liquid nitrogen within 20 s after collection. Ultra deep proteome and phosphoproteome analysis were performed by multiplex analysis using TMT reagent. Genomic analysis was performed by using a targeted high-multiplex PCR-based NGS panel. Results: Ultrasensitive mass spectrometry-based proteomics using 84 chemo-naïve gastric cancer specimens quantified an average of 21000 phosphorylation sites and clearly divided gastric cancer into subtype 1 (proliferative type, 35%), subtype 2 (EMT type, 15%), and subtype 3. (OxPhos type, 50%). The association between these subtypes with TCGA subtypes was low. Subsequent analysis using serially collected gastric cancer specimens from 9 patients unveiled the dynamic transitions within cancer tissues, along with the concomitant rewiring of the kinome network, ultimately resulting in the acquisition of the EMT subtype throughout the course of treatment. We investigated elaborate intracellular signaling related to EMT in gastric cancer and validate therapeutic approaches targeting AXL in vitro and in vivo. Conclusions: Our proof-of-concept of phosphoproteome analysis of fresh-frozen endoscopic biopsy specimens is capable of not only defining cancer subtyping but also capturing dynamic cancer signaling changes in response to therapy. In particular, serial biopsy analysis can track the cancer evolution which is expected to provide resources for the development of new treatments and biomarkers for AGC adaptively in the future.
A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastric cancer: Efficacy and safety analysis (BOLD-100-001).
Authors: Spratlin Jennifer , Rha Sun Young , O'Kane Grainne M. , Oh Do-Youn , Elimova Elena , Goodwin Rachel Anne , Kim Seung Tae , Koo Dong-Hoe , McAllister E. Russell , Jones Michelle , Snow Malcolm , Lemmerick Yasmin , Spera Gonzalo , Pankovich Jim 
Published: June 2024

4059 Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. BOLD-100 demonstrated synergy in established preclinical models in combination with various anticancer therapies, particularly in treatment resistant cell lines. Methods: This is a prospective, Phase 2 study. Advanced gastric cancer (GC) patients received BOLD-100 (625 mg/m2) with FOLFOX on day 1 of each 14-day cycle until progressive disease or unacceptable toxicity. The primary objective was to evaluate progression free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR) of BOLD-100+FOLFOX. Bayesian modelling was used to continually reassess these endpoints, the posterior probability of superiority to an historical landmark for each endpoint. Results: As of 31 Dec 2023, 21 pts with advanced gastric cancer, median age 61 years [range 35, 84] were treated. All patients had stage IV disease and ECOG ≤ 1. Patients had a median of 4 prior systemic therapies [0, 7], 1 with no prior therapy, 2 had 2 prior therapies, 5 with 3 prior therapies, and 13 patients with 4 or more prior therapies. 20/21 patients received prior platinum with 18/21 receiving prior FOLFOX/CAPOX. While on study, pts received a median of 6 cycles BOLD-100 + FOLFOX [range 1-27]. Median PFS and OS was 4.3 [95% credible interval (CI) 2.8, 7.1] months and 7.9 [CI 4.8, 15] months, respectively. ORR was 11% [CI 2, 31] and DCR was 72% [49, 89] in the 18 evaluable patients. Two pts achieved a partial response, 4 pts had target tumor reductions, and 11 pts had stable disease. Treatment was well tolerated. 19 pts had ≥1 treatment-related adverse events (AEs), most commonly neutrophil count decreased (n = 7, 33%), nausea (n = 6, 29%), and peripheral sensory neuropathy (n = 4, 19%). Most AEs were grade (G) 1-2. 7 patients (33%) had G3/4 neutrophil count decreased. Conclusions: BOLD-100 plus FOLFOX is an active, well-tolerated treatment regimen in the heavily pre-treated advanced GC. The reported mPFS, mOS, ORR and DCR data in this analysis shows promising clinical activity. The combination of BOLD-100 with FOLFOX is worthy of further study. Clinical trial information: NCT04421820 .
Conversion surgery for tislelizumab combined chemotherapy for T4a/N3 esophageal squamous cell carcinoma (ESCC): A prospective, single-arm, phase II study.
Authors: Zhang Chen , Shang Xiaobin , Yue Jie , Chen Chuangui , Duan Xiaofeng , Ma Zhao , Chen Zuoyu , Wang Shangren , Zhao Gang , Liu Liang , Zhang Weihong , Li Runmei , Xiong Yanjuan , Yang Fan , Xiao Jianyu , Cao Fuliang , Guo Feng , Zhou Dejun , Ren Xiubao , Jiang Hongjing 
Published: June 2024

4069 Background: T4a/N3 ESCC is treated with neoadjuvant concurrent chemoradiotherapy plus surgery or radical chemoradiotherapy according to NCCN guidelines. This study aimed to evaluate the safety and efficacy of conversion therapy of Tislelizumab combined with chemotherapy in patients with T4a/N3 ESCC. Methods: This is a prospective, single-arm, single-center clinical trial. A total of 40 patients with newly diagnosed ESCC (cT4a/N3) received 2-4 cycles of paclitaxel (135 mg/m2) on day 1, and cisplatin (80 mg/m2) on day 1, Tislelizumab (200 mg) on day 2, every 3 weeks. After an efficacy evaluation, the patients will undergo radical esophagectomy resection within 4-6 weeks after conversion therapy. The primary endpoints are the safety and the R0 resection rate. The secondary endpoints include the objective response rate (ORR), a postoperative pathological complete response (pCR), major pathological response (MPR), overall survival (OS), disease-free survival (DFS). Exploratory endpoint is to examine immune biomarker of the efficacy of conversion therapy for ESCC. Results: 40 patients were enrolled, the ORR was 95%(38/40), and 60% (24/40) patients who completed conversion treatment underwent esophagectomy. R0 resection rate was 100% (24/24) with no reoperations or perioperative deaths. 70% (28/40) patients experienced at least one treatment-related adverse event (TRAE) and 12.5% (5/40) patients reported grade 3 and above TRAEs. For these surgical patients, the MPR and pCR rates were 33% (8/24) and 20.8% (5/24) respectively. Flow cytometry showed that the percentage of CD3+CD4+CD8-T cells was significantly increased in peripheral blood after conversion therapy (p-value 0.02). Conclusions: Tislelizumab combined with chemotherapy, followed by radical esophagectomy resection has promising efficacy and good safety for T4a/N3 ESCC. Clinical trial information: NCT05449483 .
Survival outcomes with adjuvant immunotherapy after hepatic resection in patients with intermediate/advanced (BCLC stage B/C) hepatocellular carcinoma: Insights from a propensity-matched multicenter study.
Authors: Yang Tian , Wang Ming-Da , Xu Xiao , Xu Jia-Hao , Fan Zhong-Qi , Diao Yong-Kang , Chen Zhong , Jia Hang-Dong , Liu Fu-Bao , Zeng Yong-Yi , Wang Xian-Ming , Li Chao , Pawlik Timothy M. , Lau Wan Yee , Shen Feng , Lv Guo-Yue 
Published: June 2024

4096 Background: With the growing interest in adjuvant immunotherapy for reducing recurrence and improving prognosis after hepatic resection in hepatocellular carcinoma (HCC), particularly in high-risk patients, this study aims to evaluate the impact of adjuvant immunotherapy on long-term recurrence and survival in patients with intermediate/advanced HCC. Methods: A prospective multicenter database was utilized to identify patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Propensity score matching (PSM) was employed to equate recurrence-free survival (RFS) and overall survival (OS) between patients receiving adjuvant immune checkpoint inhibitors (ICIs) and those who did not. Multivariate Cox-regression analysis was used to identify independent predictors of RFS and OS. Results: Out of 627 patients, 109 (23.3%) received adjuvant immunotherapy, with most ICI-related adverse reactions being grade I-II. The ICI agents used among these 109 patients were tislelizumab (51.4%, n=56), sintilimab (29.3%, n=32), camrelizumab (9.2%, n=10), pembrolizumab (6.4%, n=7), and toripalimab (3.7%, n=4). All patients receiving adjuvant immunotherapy completed at least 3 months of ICI treatment, with no patients discontinuing the treatment due to irAEs. PSM resulted in 99 matched pairs with comparable baseline characteristics. In this cohort, patients receiving adjuvant immunotherapy showed significantly improved median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) compared to those who did not. Multivariable analyses confirmed adjuvant immunotherapy as an independent factor for better RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyses suggested prognostic benefits of adjuvant immunotherapy in both intermediate and advanced-stage HCC. Conclusions: This real-world observational study indicates that adjuvant immunotherapy is associated with improved RFS and OS in patients undergoing curative-intent resection for intermediate/advanced HCC. These findings support the need for future randomized controlled trials to establish definitive evidence for this high-risk population.
Predictors of short-term death and long-term survival in advanced hepatocellular carcinoma (HCC) treated with contemporary tyrosine kinase inhibitors (TKI) or immunotherapy: A multicenter analysis from the HCC-CHORD consortium.
Authors: Dibajnia Pooya , Freeman Mark , Krishnan Tharani , LEE Cha Len , Ramjeesingh Ravi , Solar Vasconcelos Joao Paulo , Lyubetska Hanna , Provost Esther , Li Jessica , Ding Philip Q. , Lim Howard J , Knox Jennifer J. , Gordon Vallerie Lynn , Cheung Winson Y. , Tam Vincent C. , Meyers Brandon M. 
Published: June 2024

4098 Background: Advances in systemic therapy for HCC have increased treatment options, including TKIs and immunotherapy combinations. Variables that predict patient outcomes may be helpful in personalizing treatment decisions. The aim of this study was to identify predictors of short-term death (STD) and long-term survival (LTS) for HCC patients. Methods: Retrospective review of patients with advanced HCC who received a TKI or immunotherapy combinations was conducted between Aug 2018 to Aug 2022 in the Canadian provinces of British Columbia, Alberta, Nova Scotia, Manitoba, as well as from select institutions in Ontario (n = 2). Prior locoregional therapies were permitted. Variables examined were: Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh class, albumin-bilirubin (ALBI) grade, alpha fetoprotein (AFP) level, microvascular invasion (MVI), and distant metastases. Multivariate logistic regression was used to determine independent predictors of STD (patient survival < 6 months vs others) and LTS (patient survival > 18 months vs others). Results: 520 patients with the following baseline characteristics were included: median age 66, 84.6% male, 87.4% ECOG performance status 0-1, 69.7% BCLC stage C, and 88.7% Child-Pugh A. First-line treatments were primarily: lenvatinib 57.3%, sorafenib 8.1%, and atezolizumab/bevacizumab 31.7%. Median progression-free survival was 7.4 months (95% CI: 6.2 to 8.4), and overall survival was 17.1 months (95% CI:, 15.1 to 18.8). Independent predictors of STD were (odds ratio): ALBI grade (2.26), MVI (2.13), and distant metastases (2.14). These three factors were also predictive for LTS: ALBI grade (0.45), MVI (0.49), and distant metastases (0.36). Child-Pugh class, AFP, and BCLC stage were not predictive of STD nor LTS (Table). Conclusions: This study supports higher ALBI grade, MVI and distant metastases as predictors of STD, while lower ALBI grade, absence of MVI and lack of distant metastases were predictive of LTS in HCC patients treated with contemporary TKIs or immunotherapy combination regimens. These predictors may help guide treatment decisions in patient populations underrepresented in clinical trials, including patients with Child-Pugh B7 score who are often excluded. [Table: see text]
OPTIMIZE-1 primary analysis: Safety, efficacy and biomarker results of a phase 1b/2 study combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Van Laethem Jean-Luc , Borbath Ivan , Geboes Karen Paula , Cassier Philippe Alexandre , Lambert Aurélien , Mitry Emmanuel , Prenen Hans , Pilla Lorenzo , Blanc Jean-Frédéric , Gallego Jiménez Inmaculada , Pazo Cid Roberto A. , Rodríguez Garrote Mercedes , Feliú Jaime , Nordbladh Karin , Enell Smith Karin , Gomez Jimenez David , Ellmark Peter , Pico de Coaña Yago , Ambarkhane Sumeet Vijay , Macarulla Teresa 
Published: June 2024

4133 Background: With a 5 year overall survival (OS) rate <5%, PDAC is a leading cause of cancer related mortality. Currently available systemic therapies are not curative and new therapeutic options are needed. Mitazalimab is a human CD40 agonistic IgG1antibody that reduces immune suppression, sensitizes the tumor to chemotherapy, and induces long lasting anti-tumor T cell responses. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study assessing mitazalimab's safety and efficacy combined with mFOLFIRINOX (mFFX) in chemotherapy naïve mPDAC patients (pts). Methods: In the first 21 day cycle, mitazalimab was administered on day 1 and 10 and mFFX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle with mitazalimab given 2 days after mFFX. The primary endpoint is objective response rate (ORR) compared to 30% ORR for FFX (Conroy, 2011) (80% power; α (1-sided) =0.10). Secondary and exploratory endpoints include Duration of Response (DoR), progression free survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Seventy pts with mPDAC were treated with mFFX + mitazalimab (safety set: 5 at 450 µg/kg and 65 at 900 µg/kg). 57 patients at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. The most common grade ≥3 AEs were neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%) and thrombocytopenia (11.4%), consistent with FFX safety profile. Two pts discontinued treatment due to AEs. Confirmed ORs were observed in 23 pts (40.4%), including 1 complete responder (CR). Median OS, PFS and duration of Response (DoR) were 14.3 months (mo), 7.4 mo and 12.5 mo respectively, with a median follow up of 12.7 mo. 29 pts (51%) remain in the study (32% on treatment, 19% in survival follow up). Efficacy results including correlation with detected KRAS G12 mutations are summarized (Table). Conclusions: Mitazalimab in combination with mFFX is a feasible regimen with a manageable safety profile. The primary endpoint was met; KRAS G12 V and R mutations were associated with better efficacy. Given the promising DoR linked with survival benefit in previously untreated mPDAC, these results merit continued development of mitazalimab in a confirmatory phase 3 study. Clinical trial information: NCT04888312 . [Table: see text]