bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative efficacy of systemic sequential regorafenib after TACE combined with first-line targeted drugs (donafenib, sorafenib, or lenvatinib) after treatment failure for advanced hepatocellular carcinoma: A retrospective, single-center, real-world study.
Authors: Wei Ning , Lu Dong , Zhou Chunze , Cheng Delei , Zhang Zhengfeng , Zhang Xingming , Xiao Jingkun , Lv Weifu 
Published: July 2024

e16190 Background: Donafenib is a novel multikinase inhibitor, which is a 1st-line systemic treatment for advanced hepatocellular carcinoma (HCC) in China. Regorafenib is an oral multikinase inhibitor and has been approved as the 2nd-line systemic treatment for advanced HCC based on the RESORCE trial. However, the efficacy of systemic sequential regorafenib after donafenib treatment failure in advanced HCC patients(pts) remains unclear. Methods: A retrospective analysis was conducted on the clinical data of advanced HCC pts treated with donafenib combined with TACE (Dona-TACE), sorafenib combined with TACE (Sora-TACE) or lenvatinib combined with TACE (Lenva-TACE) at The First Affiliated Hospital of USTC from January 2018 to December 2023. A total of 87 of these pts with advanced HCC who received regorafenib as the 2nd-line treatment. The 1st-line targeted drugs, disease control rate (DCR) (defined by the mRECIST), progression-free survival (PFS) and adverse events (AEs) (defined by the CTCAE version 5.0) were recorded and compared. Results: After screening, 27 pts in the Dona-TACE group ,35 pts in the Sora-TACE group and 31 pts in the Lenva-TACE group were included in this study. The baseline characteristics of the three groups were similar. The median treatment duration of regorafenib was 5.2 months in the Dona-TACE group, 4.8 months in the Sora-TACE group and 3.7 months in the Lenva-TACE group. The overall DCRs of sequential regorafenib after donafenib, sorafenib or lenvatinib treatment failed were 79%, 75% and 71%(P>0.05). There was no significant difference in median PFS of regorafenib (4.8, 3.9, 4.1m) in the Dona-TACE, Sora-TACE and Lenva-TACE groups. Compared with other groups, the Dona-TACE group received regorafenib sequentially had a lowest incidence of grade 3-4 AEs (39.1%, P<0.05). All groups had no treatment-related deaths from regorafenib. Multivariate analysis showed that ECOG PS score, up-to-seven criteria, tumor blood supply and Extrahepatic metastasis were independent prognostic factors affecting PFS (HR, 3.220, 3.019, 2.753, 3.142; P < 0.05). No survival differences were observed between the patients who received 1st-line treatment with or without a combination of immune checkpoint inhibitor(ICI) reagents. Conclusions: This retrospective, single-center, real-world study demonstrated that when donafenib failed the regorafenib could still improve the prognosis of advanced HCC pts with fewer AEs. The study will continue to focus on overall survival(OS) and whether combined ICIs or not in the 1st-line/ 2nd-line treatment could have a positive effect on OS.
A machine learning–based radiomics approach to predict MUC4 mutation and response to immunotherapy in cholangiocarcinoma.
Authors: Jia Yunlu , Luo Xiao , Wang Junli , Ruan Jian 
Published: July 2024

e16203 Background: The immunogenicity of MUC4 made it a tumor antigen for immunotherapeutic interventions in cholangiocarcinoma (CCA). Identifying CCA patients with elevated MUC4 expression would be crucial for MUC4-targeted immunotherapies and the prediction response to immunotherapy. Methods: In this retrospective study, 55 CCA patients who received first-line treatment with pembrolizumab in combination with gemcitabine plus cisplatin (GP) chemotherapy were enrolled. Enrolled patients underwent surgery before, and their postoperative specimens were subjected to whole exome sequencing and proteomic sequencing, and matched magnetic resonance imaging (MRI) data were collected. We employed a random forest classifier based on radiomic features to predict the status of key genes mutation including MUC4 and tested it on an internal and an external validation CCA cohort. Odds ratio of MUC4 expression for objective response to pembrolizumab plus GP was tested with logistic regression analysis. Association of MUC4 expression with progression-free survival (PFS) and overall survival (OS) was analyzed with a Cox proportional hazard regression. Results: A radiomics nomogram that incorporates radiomics signature and MUC4 mutation showed good calibration and discrimination in the training cohort (AUC = 0.762), internal validation cohort (AUC = 0.812) and external validation cohort (AUC = 0.801). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival. High expression of MUC4 portended significantly lower overall and recurrence-free survival than decreased MUC4 expression levels (P < 0.001). Findings from cell experiments revealed targeting MUC4 with bosutinib showed inhibitory effects on cell proliferation and promoted apoptosis. Additionally, the combination of bosutinib with a PD-1 inhibitor increased the inhibitory effect. Investigating the feasibility of translating these findings into clinical trials for patients with CCA is an important next step. Conclusions: The integration of MUC4-based immunotherapy and incorporating radiomics-based biomarkers could significantly advance personalized medicine and contribute to more effective treatment strategies for CCA patients.
Utility of an amplicon-based ctDNA platform for advanced cholangiocarcinomas (CCA) in Asia.
Authors: Kwok Gin Wai , Poh Jonathan , Cher Chae Yin , Pinweha Pannapa 
Published: July 2024

e16206 Background: Cholangiocarcinoma represents a major cause of cancer mortality in Asia. While clinical outcomes have improved with the addition of anti-PD1/PDL1 agents to standard-of-care chemotherapy for advanced disease, recent data suggests that novel agents against IDH1 mutations, FGFR2 and NTRK rearrangements, BRAF V600E mutations, and microsatellite instability (MSI) are effective. Tumor-based next generation sequencing (NGS) is routinely recommended by guidelines but is limited by tissue availability and quality in patients with unresectable disease. A comprehensive circulating tumor DNA-based (ctDNA) NGS platform offers an acceptable alternative, but its clinical utility and pickup rate for oncogenic drivers remain unknown. Methods: In our multi-national cohort of advanced CCA across 5 countries, we explored the utility of Lucence LiquidHALLMARK (LHM), a Medicare-reimbursed, amplicon-based NGS ctDNA platform targeting 80 cancer related genes, 10 fusions, and MSI. Performance of LHM has been previously reported. Data was retrieved in-house by a de-identified centralized database and pooled for analysis. Here, we report the demographic and genomic findings of our cohort and highlight the impact of testing on actionable molecular alteration discovery. Results: Between Jan 2020 and Dec 2023, 60 samples from 56 patients (62.5% male) with advanced CCA in Hong Kong SAR (50.0%), Singapore (41.1%), Thailand (3.6%), Philippines (3.6%), and Malaysia (1.8%) underwent LHM testing. Metastatic disease accounted for 83.9% and 8.9% had locally advanced disease. Median age was 67 years (range 33-88), with 34% and 30% of tests obtained during first-line therapy and at diagnosis respectively. Only 6 cases had available tissue NGS results. Analysis on 56 baseline samples showed an 80.4% discovery rate (45/56 patients) for ≥1 molecular alterations. A median of 2 variants (mean 3.27) was detected per sample, with variant allele fraction ranging from 0.05% to 66.5%. Importantly, 8.9% (5/56) of patients harbored ≥1 actionable variants, including 3 with FGFR2 rearrangements ( FGFR2- WAC, FGFR2- ACTR1A, FGFR2- CAMK2D) and 2 with BRAF V600E drivers. A further 3 patients had potentially druggable variants in IDH2 and FGFR3 and 12 harbored BRCA1/2 variants, of which 4 were deleterious. None of the samples had MSI. Top 10 mutated genes were TP53 (48%), KRAS (21%), BRCA2 (18%), PIK3CA (11%), TERT (9%), CDKN2A (9%), SMAD4 (9%), FGFR2 (7%), BRAF (7%), and CDK6 (5%). Limited histopathological and treatment outcomes are available in the current dataset. Conclusions: Our advanced cholangiocarcinoma cohort of 56 patients from 5 Asian countries showed that an amplicon based ctDNA liquid biopsy platform overcomes the tissue-related challenges of genomic profiling specific to unresectable biliary tumors. We showed an 80.4% discovery rate for any molecular alterations and a 8.9% pickup rate for variants with strong actionability.
Phase I study of ProAgio, an αvβ3 integrin cytotoxin, in patients with previously treated advanced pancreatic cancer and other solid tumors.
Authors: Skorupan Nebojsa , Schmidt Keith Thomas , Koehler Eve , Lee Min-Jung , Steinberg Seth M. , Figg William Douglas , Liu Zhi-Ren , Alewine Christine 
Published: July 2024

e16336 Background: The limited clinical benefit of combination chemotherapy in patients with advanced pancreatic cancer is in part attributed to the tumor’s dense, hypoxic stroma that is largely composed of extracellular matrix, cancer-associated fibroblasts (CAFs), and myeloid cells. ProAgio is a pegylated peptide drug that targets and kills cells expressing integrin αvβ3, such as CAFs and endothelial cells. Preclinical activity of ProAgio was demonstrated in murine pancreatic cancer models. Here we describe the dose escalation arm of the first-in-human Phase 1 trial of ProAgio in patients with advanced solid malignancies, including pancreatic cancer. Methods: The dose escalation arm of this single institution study of ProAgio monotherapy enrolled adults with previously treated, histologically confirmed advanced solid tumors for which no curative therapy exists. Participants were required to have evaluable disease. The primary objective was to determine the recommended Phase 2 dose (RP2D) of ProAgio. Secondary objectives assessed the safety (CTCAE v. 4.03), pharmacokinetics, and objective response rate. ProAgio was administered as an intravenous infusion every 1-2 weeks depending on the dose level. Response was determined by serial imaging (CT or MRI) or serum tumor marker assessment. Results: Twenty-eight participants (26 with pancreatic adenocarcinoma and 2 with other gastrointestinal malignancies) were treated as of January 30, 2024, completing enrollment to all 6 planned dose levels. ProAgio has been remarkably well tolerated with only transient grade 1 or 2 treatment-related adverse events observed in most participants. Two participants had grade 2 infusion related reaction but were able to continue treatment with increased dose of diphenhydramine pre-medication. Isolated serious adverse events of hyperglycemia, acute kidney injury, or anemia (all grade 3) considered at least possibly related to ProAgio were observed in 3 separate participants. Five participants with pancreatic cancer receiving weekly dosing of ProAgio had stable disease, 2 of which had interval stabilization in CA 19-9 tumor markers. RP2D determination is pending completion of pharmacokinetic analyses. Conclusions: ProAgio is safe and well-tolerated at all dose levels. A dose expansion phase of 15 participants will begin enrolling once RP2D is determined. Clinical trial information: NCT05085548 .
Clinical characteristics and treatment outcomes of advanced penile squamous cell carcinoma: Real-world evidence from a tertiary cancer center in Brazil.
Authors: Parrela Vinicius Cruz , Polho Gabriel Berlingieri , Andrade Matheus de Oliveira , Almeida Moreno Santos Rogerio , Alves Gustavo Luis , Arneiro Matheus Henrique Juliani , Felix Vitor Hugo , Hidalgo Filho Cassio Murilo , Cazellato Pacheco de Mello Murilo , Mota Jose Mauricio 
Published: July 2024

e17025 Background: Penile cancer is a rare disease worldwide. However, Brazil has an annual incidence of 1.5 cases per 100,000 inhabitants, representing 2% of male cancers. This study aims to evaluate clinical characteristics and treatment outcomes of patients (pts) with advanced penile squamous cell carcinoma (SCC) in a large tertiary cancer center in Brazil. Methods: We performed a retrospective database analysis of pts with advanced penile squamous cell carcinoma (SCC) treated at Instituto do Cancer do Estado de Sao Paulo between January 2008 and October 2023. Medical records were reviewed for demographic, clinicopathological features and treatment outcomes data. Cumulative survival probabilities were computed using the Kaplan-Meier method. Prognostic factors associated with survival were evaluated through univariate analyses, using the Cox regression model. Results: We identified 91 pts with advanced penile SCC eligible for analysis. Median age was 62 years (IQR 44.5-64.5), most were married (53.8%), diagnosed with stage T3/T4 (60.4%), and N2/N3 (64.9%) SCC. At diagnosis, 65% were classified as stage IV (T4, N3, or M1 disease). De novo metastasis occurred in 35% pts. Neoadjuvant chemotherapy was given to 30.8%, mainly ITP regimen containing paclitaxel, ifosfamide, and cisplatin (46.4%). First-line palliative chemotherapy was given to 50.5%, being carboplatin and paclitaxel the predominant choice (47.8%). Disease progression occurred in 54% pts, after a median follow-up of 21.8 months. At the last follow-up, 61.5% had nodal disease. Most common sites of metastasis were lung (50.5%) and liver (19.8%). Overall survival (OS) was 12.9 months (95% CI 9.8 - 18.3). Prognostic factors significantly correlated with OS were ECOG 0-1 (HR 0.40, 95% CI 0.21 - 0.74, p=0.003) and complete response post-chemotherapy (HR 0.14; 95% CI 0.02 - 0.80, p=0.02). No association with survival was found for region/state of origin, distance from patient’s home to the hospital, marital status, education level, and age. Conclusions: Advanced penile squamous cell carcinoma (SCC) presents significant challenges in Brazil, with high rates of advanced disease at diagnosis. OS correlated with complete response to chemotherapy and performance status.
Utidelone for heavily pretreated metastatic castration-resistant prostate cancer after failing docetaxel treatment: An open-label, single-arm, phase II trial.
Authors: Chen Meiting , An Xin , Xue Cong , Li Haifeng , Yang Wei , Huang Riqing , Peng Jing , Tang Li , Wang Jun , Li Yonghong , Shi Yanxia 
Published: July 2024

e17036 Background: The appropriate chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) that progressed after docetaxel treatment remains unmet medical needs. Utidelone (UTD1) is a genetically engineered epothilone analog with antitumor activity in taxane-resistant cancers. UTD1 was approved for advanced breast cancer in 2021. This study was designed to evaluate the safety and efficacy of UTD1 in mCRPC. Methods: In this perspective, phase II clinical trial, men with progressive mCRPC after docetaxel and abiraterone, and/or enzalutamide, and/or apalutamide received UTD1 monotherapy treatment at a total dose of 150 mg/m2 for five days intravenous, every three weeks until disease progression, or intolerable toxicity, or death. We reported the preliminary results for potential benefits in this new treatment. The primary endpoint was prostate specific antigen (PSA) response rate, defined as a 50% or greater reduction in serum PSA. The secondary endpoint included investigators-assessed objective response rate (ORR) and disease control rate (DCR) according to RECIST v1.1, radiographic progression-free survival (rPFS) according to PCWG3 criteria, overall survival (OS), and safety. The trial was registered at Chinese Clinical Trial Registry (No. ChiCTR2200061635). Results: By January 31st, 2024, twenty-five mCRPC patients with a median age of 67 years were enrolled in this study at Sun Yat-sen University Cancer Center since March 23rd, 2022. Patients received an average of 4.2 lines of prior anticancer treatments: 100% of them received docetaxel, 96.0% of them received abiraterone, and 80.0% progressed after enzalutamide, and/or apalutamide. 28.0% of patients had visceral metastases, and 88.0% patients had bone metastases. At of the cut-off date, the PSA response rate was 16.0%. The median rPFS and OS were 4.9 months and 7.1 months, respectively. One patient had a durable response for 19.2 months and had been remaining on study treatment to date. One PR and four SD were observed in ten patients with measurable lesions, resulting in an overall ORR and DCR of 10.0% and 50.0%, respectively. The most common treatment-related adverse events (TRAEs) including peripheral sensory neuropathy (76.0%), dyspepsia (72.0%), anemia (64.0%), constipation (60.0%), fatigue (64.0%), nausea (36.0%), leukocytopenia (32.0%), arthralgia (32.0%), dizziness (32.0%), vomiting (20.0%), and diarrhea (20.0%) were manageable. The 3/4 grade TRAEs included anemia (16.0%), and diarrhea (4%). No treatment-related death occurred. Conclusions: UTD1 has demonstrated promising efficacy and favorable tolerance in heavily pretreated mCRPC patients after progression on docetaxel in the preliminary analyses. Additional randomized trials are warranted for this new regimen. Clinical trial information: ChiCTR2200061635.
Effect of ionizing radiation on JAK/STAT pathway and immune microenvironment in cervical cancer.
Authors: Zhang Yongchun , Jiang Yuqi , Wu Yaping , Zhang Lei , Chen Zhiying , Qi Yingxue , Yin Xiangyu 
Published: July 2024

e17516 Background: STAT proteins play an important role in the development and progression of cervical cancer, and inhibition of the JAK/STAT pathway may be critical for enhancing tumor cell death. Delivering a certain dose of ionizing radiation (IR) directly to the lesion is one of the conventional treatments for cervical cancer. Whether IR will trigger changes in the JAK/STAT pathway and tumor immune microenvironment (TIME) is unknown and continues to be explored. Methods: We collected 30 patients received IR therapy with locally advanced cervical cancer (LACC) at the Affiliated Hospital of Qingdao University. Matched pre-IR and post-IR tumor tissue samples were collected from all patients, and the samples underwent RNA sequencing based on the nCounter platform (NanoString Technologies, Seattle, USA) and protein testing based on immunohistochemistry (IHC) staining. All tumor TIME cell infiltration scores were calculated as arithmetic mean of the constituent genes. P-values were calculated via the T Test. Results: RNA sequencing of tumor tissue from LACC patients before and after IR showed 35 differential genes. The results of GSEA pathway enrichment analysis of differential genes showed that compared with before IR, the IFN-α response pathway, IFN-γ response pathway and epithelial mesenchymal transition pathway were significantly up-regulated and enriched after IR. These three pathways collectively affect changes in the downstream JAK/STAT pathway. Moreover, compared with before IR, the cell infiltration abundance of overall macrophages (P=0.0087) and M2 macrophages (P=0.0043) increased significantly after IR. M1 macrophages also showed an increasing trend, but there was no statistically significant difference. In addition, further verification of changes in several proteins on the JAK/STAT pathway by IHC. The results showed that overall macrophages (P=0.0087) and M1 macrophages (P=0.026), PD-L1 (p=0.003), JAK1 (p=0.021) and STAT3 (p=0.018) were significantly increased after IR compared with before IR. M2 macrophages and STAT1 (p=0.734) also showed an increasing trend, but there was no statistically significant difference. It is worth noting that Kendall's tau-b correlation analysis was used to study the correlation of protein changes. The results found that the changes in PD-L1 expression before and after radiotherapy were related to STAT3 (Kendall's tau-b=0.487, P=0.02), JAK1 (Kendall's tau-b=0.513, P=0.015), there is a strong positive correlation. Conclusions: This study found that IR affects changes in cervical cancer TIME and these changes may promote the transition to an immunosuppressive phenotype. In addition, IR may affect changes in PD-L1 levels through the JAK1/STAT3 pathway. This needs to be further verified by designing large prospective clinical trials in the future.
Safety and clinical activity of cadonilimab, an anti PD-1/CTLA-4 bispecific antibody, for patients with persistent, recurrent, or metastatic cervical cancer (R/M CC): A retrospective, real-world study.
Authors: Fan Shi , Wang Tao , Zhang Qiying , Wang Juan , Su Jin , Liu Zi 
Published: July 2024

e17522 Background: Recurrent, metastatic or persistent cervical cancer (R/M cc) patients have limited treatment options. Immune chechpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies, cadonilimab monotherapy has shown promising efficacy and tolerable toxicity in pre-treated R/M CC (NCT04380805).We aimed to assess the safety and clinical activity of Cadonilimab combination therapy(including chemotherapy, radiotherapy, targeted therapy, or immunotherapy) in patients with advanced r/m CC. Methods: Pts (FIGO stage IIIc2r-IVb CC) previously treated with or not candidates for standard therapy, aged ≥ 18 years, with ECOG PS ≤ 2, and measurable (RECIST 1.1) or evaluable disease, were enrolled.All patients received at least one dose of Cadonilimab (10mg/kg, Q3W or 6mg/kg Q2W), 32 patients received concurrent radiotherapy, 66 patients received concurrent chemotherapy, 57patients received targeted therapy, and 4 patients received local injections of oncolytic virus.Immune-related adverse events (irAEs), objective response rate (ORR) and disease control rate (DCR) were evaluated. Results: 82 pts were enrolled from Jul 13, 2022, to Dec 20, 2023. As of Jan 10, 2024, we assessed safety in all pts and efficacy in pts with at least one tumor assessment result. IrAEs of any grade occurred in 46 (56.1%) pts. Grade ≥ 3 irAE occurred in 15 (18.3%) pts. The most frequent were irAEs hypothyroidism (28,34%), Rash (5,6%), infusion reaction (3,3.7%), hepatitis (2,2.4%), there were no toxic deaths reported. The ORR was 70.4% (57/81,95% CI:60.2%-80.5%) with 23 (28.4%) CR,34 PR, 5 SD, and the DCR was 76.5% (62/81,95% CI:67.1%-86.0%). Especially, 6 Pts had previously received immunotherapy, and 2 of them achieved PR. mPFS and mOS data are not mature by cut-off date. Conclusions: Cadonilimab combined with standard therapy (including radiotherapy, chemotherapy and targeted therapy) was well tolerated, with encouraging antitumor activity in pts with R/M CC. Pts who had failed checkpoint inhibitor therapy may still benefit from cardonilimab. Meanwhile, long-term safety and activity evaluation still needs following up.