tbuckley/cabot-search 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: Ning Wei, Dong Lu, Chunze Zhou, Delei Cheng, Zhengfeng Zhang, Xingming Zhang, Jingkun Xiao, Weifu Lv
Journal: Journal of Clinical Oncology (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&gt;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&lt;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 &lt; 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.
Efficacy and safety of regorafenib combined with PD-1 inhibitors in patients with advanced hepatocellular beyond atezolizumab plus bevacizumab: A retrospective analysis of real-world evidence.
Authors: Xinfeng Zhang, Jiamin Cheng, Bowen Chen, Tianlan Zhang, Yinyin Li, Linzhi Zhang, Jinghui Dong, Yinying Lu
Journal: Journal of Clinical Oncology (2024)

e16172 Background: In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapy scheme is debatable and the efficacy of regorafenib combined with PD-1 inhibitors is still unclear. Methods: In this retrospective study, advanced HCC patients who received regorafenib combined with PD-1 inhibitors progressing after atezolizumab plus bevacizumab were consecutively enrolled from February 2022 to January 2024. Main efficacy endpoint was overall survival (OS), following progression free survival (PFS), evaluated in accordance with RECIST v1.1. Adverse events (AEs) were recorded according to CTCAE v5.0. Results: A total of 11 eligible patients were enrolled, with 8 in Child-Pugh A and 3 in Child-Pugh B7. All patients had hepatitis B infection by with tumor embolus. All patients were classified as Barcelona Clinic Liver Cancer stage C. The AFP level is above 400ng/ml in all patients. At data cut-off at February 2024, the median OS was 16.9 months and the median PFS was 3.7 months. The 3-month and 6-month PFS rates were 70% and 35% , respectively. The 12-month OS rate was 71.4%. Grade≥3 TRAEs occurred in 9.1% (1/11) of the patients. Conclusions: Though application of regorafenib combined with PD-1 inhibitors progressing after atezolizumab plus bevacizumab present safe and effective in our cohort, these data need to be confirmed in prospective comparative studies. [Table: see text]
Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution
Authors: Irene Casanova-Salas, Daniel Aguilar, Sarai Cordoba-Terreros, Laura Agundez, Julian Brandariz, Nicolas Herranz, Alba Mas, Macarena Gonzalez, Rafael Morales-Barrera, Alexandre Sierra, Mario Soriano-Navarro, Pablo Cresta, Gisela Mir, Sara Simonetti, Gonçalo Rodrigues, Sara Arce-Gallego, Luisa Delgado-Serrano, Irene Agustí, Elena Castellano-Sanz, Richard Mast, Matias de Albert, Ana Celma, Anna Santamaria, Lucila Gonzalez, Natalia Castro, Maria del Mar Suanes, Javier Hernández-Losa, Lara Nonell, Hector Peinado, Joan Carles, Joaquin Mateo
Journal: Cancer Cell (2024)

Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from in vitro and in vivo models of metastatic prostate cancer (mPC) reveal a high contribution of tumor material to EV-loaded DNA/RNA, validating the findings in two cohorts of longitudinal plasma samples collected from patients during androgen receptor signaling inhibitor (ARSI) or taxane-based therapy. EV-DNA genomic features recapitulate matched-patient biopsies and circulating tumor DNA (ctDNA) and associate with clinical progression. We develop a novel approach to enable transcriptomic profiling of EV-RNA (RExCuE). We report how the transcriptome of circulating EVs is enriched for tumor-associated transcripts, captures certain patient and tumor features, and reflects on-therapy tumor adaptation changes. Altogether, we show that EV profiling enables longitudinal transcriptomic and genomic profiling of mPC in liquid biopsy.
TACE-HAIC combined with donafenib and immunotherapy for hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT): A retrospective analysis.
Authors: Linan Yin, Ruibao Liu, Xunbo Hou, Junrong Lu
Journal: Journal of Clinical Oncology (2024)

e16174 Background: The probability of Chinese hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) is relatively large and the long-term survival of this part of patients is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. We want to explore the efficacy and safety of TACE plus hepatic arterial infusion chemotherapy combined with Donafenib, anti-PD-1 antibody in uHCC patients with PVTT. Methods: We retrospectively analyzed the patients who were diagnosed as uHCC with PVTT and received the treatment of TACE plus HAIC combined with Donafenib, anti-PD-1 antibody as first-line therapy from Dec 2021 to Jun 2023 in Harbin Medical University Cancer Hospital. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progress free survival (PFS), overall survival (OS) and safety. Results: Of 106 patients included in the analysis, all of them received first-line treatment of TACE (embolization of pirarubicin hydrochloride 40mg, iodized oil 10-20ml with or without gelatin sponge) plus HAIC (oxaliplatin 85 mg/m 2 2h, leucovorin 400 mg/m 2 1h, fluorouracil bolus 400 mg/m 2 in the first 10 minutes, and fluorouracil infusion 2400 mg/m 2 for 46h) combined with donafenib 200mg bid, anti-PD-1 antibody Q3W. The median age was 58 years (IQR, 52-64). The study population was predominantly male (79.2%), and 79.2% were HBV-positive. All HCC patients are accompanied by PVTT, most of which are VP3(72.6%).The rate of patients with extrahepatic metastasis were 16.0%. All patients were classified as BCLC stage C and 84.0% were classified as CNLC stage IIIa. As of December 2023, 106 patients had received at least one imaging evaluation, 11 (10.4%), 60 (56.6%) and 28 (26.4%) of them achieved complete response, partial response and stable disease, and the overall objective response rate and disease control rate was 67.0% and 93.4% per modified RECIST criteria respectively. With 16.3 months of median follow-up time, the 12-month PFS rate was 81.3% and the 12-month OS rate was 90.1%. The median PFS and OS were not reached. 103 of all patients had at least one treatment-related AE (TRAE), and treatment-related deaths did not occur in this study. Grade 3 TRAEs occurred in 33 (31.1%) patients, and no grades 4 or 5 were reported. The most common Grade 3 TRAEs included aspartate transaminase increased (18.9%), platelet count decreased (14.2%) and blood bilirubin increased (8.5%). Conclusions: TACE-HAIC combined with Donafenib and immunotherapy are effective and tolerable for uHCC patients with PVTT.
Combination of compound screening with an animal model identifies pentamidine to prevent Chlamydia trachomatis infection
Authors: Katja Knapp, Romana Klasinc, Anna Koren, Magdalena Siller, Ruth Dingelmaier-Hovorka, Mathias Drach, Juan Sanchez, David Chromy, Marlene Kranawetter, Christoph Grimm, Andreas Bergthaler, Stefan Kubicek, Hannes Stockinger, Georg Stary
Journal: Cell Reports Medicine (2024)

Chlamydia trachomatis (Ct) is the most common cause for bacterial sexually transmitted infections (STIs) worldwide with a tremendous impact on public health. With the aim to unravel novel targets of the chlamydia life cycle, we screen a compound library and identify 28 agents to significantly reduce Ct growth. The known anti-infective agent pentamidine-one of the top candidates of the screen-shows anti-chlamydia activity in low concentrations by changing the metabolism of host cells impairing chlamydia growth. Furthermore, it effectively decreases the Ct burden upon local or systemic application in mice. Pentamidine also inhibits the growth of Neisseria gonorrhea (Ng), which is a common co-infection of Ct. The conducted compound screen is powerful in exploring antimicrobial compounds against Ct in a medium-throughput format. Following thorough in vitro and in vivo assessments, pentamidine emerges as a promising agent for topical prophylaxis or treatment against Ct and possibly other bacterial STIs.
A retrospective analysis of efficacy and safety of lenvatinib combined with PD-1 inhibitor and chemotherapy in advanced biliary tract cancer (BTC).
Authors: Hu Li, Lingzhan Meng, Peng Yu, Li Cao, Zizheng Wang, Jin Yan, Yanling Shao, Bin Shi, Zhenyu Zhu
Journal: Journal of Clinical Oncology (2024)

e16173 Background: Lenvatinib combined with PD-1 inhibitor and chemotherapy has showed a relatively high antitumor activity for ICC in phase 2 clinical trials. This study retrospectively analyzes the efficacy and safety of real-world lenvatinib combined with PD-1 inhibitor and chemotherapy in BTC. Methods: Patients with advanced BTC who received lenvatinib combined with PD-1 inhibitor plus oxaliplatin and gemcitabine (Gemox) chemotherapy were retrospectively screened. The overall survival, progression-free survival, objective response rate, disease control rate and safety were evaluated. Results: From Jan 2021 to Apr 2023, 27 pathologically-confirmed advanced BTC pts were enrolled. The median age is 61 (range, 39-74) years, 18 (66.7%) were male. Fourteen patients had TNM stage Ⅳdisease, and 7 patients had stage III. Twenty-six (96.3%) patients had an ECOG performance status of 1. All patients were child-pugh A. Fourteen patients had metastasis, 8 patients with lymph node metastasis, 4 with bone metastasis. 11 (40.7%) had positive PD-L1 expression. At baseline, 18 (66.7%) patients had a CA19-9 level &gt; 200 U/mL. The median CEA level was 3.56 ng/mL; 48.1% of the patients had a level &gt; 5 ng/mL. At the date cut off (Dec 15, 2023), the median follow-up time was 10.4 months (range: 4.8-25.7). ORR was 70.4% (19/27), and disease control rate (DCR) was 85.2% (23/27). Three pts with locally advanced disease were down-staged and then underwent resection. They remained disease-free survival at the end of last follow-up. The median PFS was 9.0 months (95% CI: 4.0-14.0) and median duration of response (DOR) was 9.8 months. The median OS was 20.4 months (95% CI: 13.6-27.2). 12-months OS rate was 73.3% (95% CI: 57.5%-89.2%).20/27 pts experienced treatment-related adverse events (AE). No grade 5 AE was observed. The most common AE was fatigue 66.7% (18/27), headache 7.4% (2/27). Grade 3 fatigue and grade 3 kidney injury occurred in 1 patient separately. Conclusions: Lenvatinib combined with PD-1 inhibitor and Gemox chemotherapy provided remarkable efficacy with reasonable tolerability in advanced BTC patients.
Combining immune checkpoint inhibitors and molecular-targeted agents with hepatic arterial infusion chemotherapy for hepatocellular carcinoma with inferior vena cava and/or right atrium tumor thrombus.
Authors: Suixing Zhong, Ning Lyu, Ming Zhao
Journal: Journal of Clinical Oncology (2024)

e16177 Background: Patients with hepatocellular carcinoma and inferior vena cava and/or right atrium tumor thrombus (HCC-IVC/RATT) have a poor prognosis and lack evidence for standard first-line systemic treatment due to its low incidence. This study aims to evaluate the effectiveness and safety of three treatments in HCC-IVC/RATT patients: immune checkpoint inhibitors plus molecular-targeted agents (ICI-MTA), hepatic arterial infusion chemotherapy (HAIC), and their combination (ICI-MTA-HAIC). Methods: This multicenter retrospective cohort study included consecutive HCC-IVC/RATT patients who received ICI-MTA, HAIC, or ICI-MTA-HAIC from June 1, 2014, to December 31, 2022. The propensity score matching (PSM) was used to balance baseline characteristics. Survival analysis was conducted using Kaplan-Meier curves and compared using the log-rank test. Results: A total of 243 HCC-IVC/RATT patients were included, with 144 receiving ICI-MTA-HAIC, 29 receiving ICI-MTA, and 70 receiving HAIC. Before PSM, the ICI-MTA-HAIC group had significantly superior median overall survival (OS) of 16.5 months, progression-free survival (PFS) of 8.0 months, and objective response rate (ORR) of 47.9%, in comparison to both the ICI-MTA (OS: 7.7 months, P &lt; 0.001; PFS: 3.5 months, P = 0.001; ORR: 24.1%, P = 0.019) and HAIC groups (OS: 9.1 months, P = 0.003; PFS: 4.9 months, P = 0.007; ORR: 25.7%, P = 0.002) among HCC-IVC/RATT patients based on RECIST v1.1 criteria. The ICI-MTA and HAIC groups didn’t exhibit significant differences in OS, PFS, or ORR ( P = 0.061, 0.043, 0.869, respectively). After PSM, similar results were obtained across the three groups. All adverse reactions were manageable, and no unexpected adverse reactions or treatment-related deaths were observed among the three groups. Conclusions: ICI-MTA-HAIC was a safe and effective therapy that prolonged the survival of HCC-IVC/RATT patients compared to ICI-MTA or HAIC.
Multi-scale signaling and tumor evolution in high-grade gliomas
Authors: Jingxian Liu, Song Cao, Kathleen J. Imbach, Marina A. Gritsenko, Tung-Shing M. Lih, Jennifer E. Kyle, Tomer M. Yaron-Barir, Zev A. Binder, Yize Li, Ilya Strunilin, Yi-Ting Wang, Chia-Feng Tsai, Weiping Ma, Lijun Chen, Natalie M. Clark, Andrew Shinkle, Nataly Naser Al Deen, Wagma Caravan, Andrew Houston, Faria Anjum Simin, Matthew A. Wyczalkowski, Liang-Bo Wang, Erik Storrs, Siqi Chen, Ritvik Illindala, Yuping D. Li, Reyka G. Jayasinghe, Dmitry Rykunov, Sandra L. Cottingham, Rosalie K. Chu, Karl K. Weitz, Ronald J. Moore, Tyler Sagendorf, Vladislav A. Petyuk, Michael Nestor, Lisa M. Bramer, Kelly G. Stratton, Athena A. Schepmoes, Sneha P. Couvillion, Josie Eder, Young-Mo Kim, Yuqian Gao, Thomas L. Fillmore, Rui Zhao, Matthew E. Monroe, Austin N. Southard-Smith, Yang E. Li, Rita Jui-Hsien Lu, Jared L. Johnson, Maciej Wiznerowicz, Galen Hostetter, Chelsea J. Newton, Karen A. Ketchum, Ratna R. Thangudu, Jill S. Barnholtz-Sloan, Pei Wang, David Fenyö, Eunkyung An, Mathangi Thiagarajan, Ana I. Robles, D.R. Mani, Richard D. Smith, Eduard Porta-Pardo, Lewis C. Cantley, Antonio Iavarone, Feng Chen, Mehdi Mesri, MacLean P. Nasrallah, Hui Zhang, Adam C. Resnick, Milan G. Chheda, Karin D. Rodland, Tao Liu, Li Ding
Journal: Cancer Cell (2024)

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.
Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity
Authors: Patricia J. Rodriguez, Brianna M. Goodwin Cartwright, Samuel Gratzl, Rajdeep Brar, Charlotte Baker, Ty J. Gluckman, Nicholas L. Stucky
Journal: JAMA Internal Medicine (2024)

Importance Although tirzepatide and semaglutide were shown to reduce weight in randomized clinical trials, data from head-to-head comparisons in populations with overweight or obesity are not yet available. Objective To compare on-treatment weight loss and rates of gastrointestinal adverse events (AEs) among adults with overweight or obesity receiving tirzepatide or semaglutide labeled for type 2 diabetes (T2D) in a clinical setting. Design, Setting, and Participants In this cohort study, adults with overweight or obesity receiving semaglutide or tirzepatide between May 2022 and September 2023 were identified using electronic health record (EHR) data linked to dispensing information from a collective of US health care systems. On-treatment weight outcomes through November 3, 2023, were assessed. Adults with overweight or obesity and regular care in the year before initiation, no prior glucagon-like peptide 1 receptor agonist receptor agonist use, a prescription within 60 days prior to initiation, and an available baseline weight were identified. The analysis was completed on April 3, 2024. Exposures Tirzepatide or semaglutide in formulations labeled for T2D, on or off label. Main Outcomes and Measures On-treatment weight change in a propensity score–matched population, assessed as hazard of achieving 5% or greater, 10% or greater, and 15% or greater weight loss, and percentage change in weight at 3, 6, and 12 months. Hazards of gastrointestinal AEs were compared. Results Among 41 222 adults meeting the study criteria (semaglutide, 32 029; tirzepatide, 9193), 18 386 remained after propensity score matching. The mean (SD) age was 52.0 (12.9) years, 12 970 were female (70.5%), 14 182 were white (77.1%), 2171 Black (11.8%), 354 Asian (1.9%), 1679 were of other or unknown race, and 9563 (52.0%) had T2D. The mean (SD) baseline weight was 110 (25.8) kg. Follow-up was ended by discontinuation for 5140 patients (55.9%) receiving tirzepatide and 4823 (52.5%) receiving semaglutide. Patients receiving tirzepatide were significantly more likely to achieve weight loss (≥5%; hazard ratio [HR], 1.76, 95% CI, 1.68, 1.84; ≥10%; HR, 2.54; 95% CI, 2.37, 2.73; and ≥15%; HR, 3.24; 95% CI, 2.91, 3.61). On-treatment changes in weight were larger for patients receiving tirzepatide at 3 months (difference, −2.4%; 95% CI −2.5% to −2.2%), 6 months (difference, −4.3%; 95% CI, −4.7% to −4.0%), and 12 months (difference, −6.9%; 95% CI, −7.9% to −5.8%). Rates of gastrointestinal AEs were similar between groups. Conclusions and Relevance In this population of adults with overweight or obesity, use of tirzepatide was associated with significantly greater weight loss than semaglutide. Future study is needed to understand differences in other important outcomes.
A retrospective study on the efficacy and safety of donafenib combined with transarterial chemoembolization (TACE) and with/without immunotherapy in intermediate-advanced hepatocellular carcinoma (HCC).
Authors: Cong Chen, Shouzhong Fu, Suming Zhao, Hongxin Yuan, Feng Dai, Weiwei Gu, Zhuxin Gu, Rongfeng Shi, Xiaohu Yang, Xiaohua Lu, Pengfei Jia, Luyi Si, Hui Zhao
Journal: Journal of Clinical Oncology (2024)

e16171 Background: Recent phase III clinical trial ZGDH3 and several real-world studies have demonstrated the potential of Donafenib in improving overall survival (OS) in advanced HCC. This study aims to evaluate the efficacy and safety of Donafenib combined with TACE and with/without immunotherapy as first-line treatment in intermediate-advanced HCC. By retrospectively analyzing data from previous clinical trials, we will further explore the potential of Donafenib in enhancing the survival rate of patients with intermediate-advanced HCC and its safety profile. Methods: Thirty-eight patients diagnosed with intermediate-advanced HCC through pathology or clinical assessment were included in the study. We conducted a retrospective analysis of the efficacy and safety of patients treated with at least one cycle of Donafenib between September 2021 and December 2023, at the Affiliated Hospital of Nantong University and the Third People's Hospital of Nantong City. The primary endpoints were Objective Response Rate (ORR) and Progression-Free Survival (PFS). Secondary endpoints included Disease Control Rate (DCR), overall survival (OS) and safety. Safety and efficacy were assessed according to CTCAE v5.0 and mRECIST, respectively. Survival data were calculated using the Kaplan-Meier method. Results: The median age was 67 years old, and 76.3% were male. 39.5% of patients had Child-Pugh score A, 39.5% had BCLC stage B, and 60.5% had stage C. 17 patients (44.7%) received Donafenib combined with TACE treatment, while the remaining patients (55.3%) received Donafenib combined with TACE and immunotherapy. The median duration of therapy (mDOT) was 7.18 months (range, 2.14 -21.75). The ORR and DCR were 57.89% (22/38) and 89.47% (34/38), respectively. The median follow-up time was 9.17 months (range, 2.99-27.93), and the 6-month PFS rate was 81.1% (95% CI: 67.1%-98.0%). The 12-month PFS rate was 73.7% (95% CI: 56.5%-96.2%). The 6-month OS rate was 94.0% (95% CI: 86.2%-100.0%), and the 12-month OS rate was 88.1% (95% CI: 75.6%-100.0%), with the median PFS and OS not reached yet. Most patients took Donafenib 200mg twice a day. A total of 6 patients (15.79%) experienced grade 3 adverse events (AEs). The common grade 3 AEs included hand-foot syndrome (7.89%), diarrhea (2.63%), rash (2.63%), and hypertension fatigue (2.63%). No grade 4 or 5 AEs or new safety signals were found. Conclusions: Donafenib combined with TACE and with/without immunotherapy showed manageable safety and promising efficacy in intermediate-advanced HCC patients.