bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor cell proportion scoring (CTPS) based PD-L1 assessment and clinical application of circulating tumor cells (CTCs) on stage IV non-small cell lung cancer (NSCLC) through liquid biopsy.
Authors: Choi Mi Young , Moon Da Hye , Jo Jong-min , Lee Hae Ung , Park Seri , Jeon Byung Hee , Choi Chang Min 
Published: June 2021

e15031 Background: Stage IV lung cancer is the most advanced lung cancer state accompanied by metastasized to the area around the lungs or distant major organs. The most common type of lung cancer is non-small cell lung cancer, which is more aggressive and may spread quickly due to organ-specific complex networks such as lymph and major blood vessels. Thus, only precise diagnostic strategy approaches will determine the effectiveness of the actual and successful clinical treatment. Until a recent date, Immunohistochemistry (IHC) for programmed death-ligand 1(PD-L1) test is the only available biomarker test that purpose diagnostics (CDx) and guide the treatment with immune checkpoint inhibitors in NSCLC. Methods: Given that CDx strategy, tissue biopsy has inevitable limitations, including patient risk, repetitive examination, sample preparation, sensitivity, and accuracy. For this reason, our research team contrived the best strategy for biomarker, PD-L1-specific CTCs in stage IV NSCLC group (N = 30) compared to pulmonary inflammatory patient groups (N = 30) CytoGen Smart biopsy platform. Herein, we removed false-positive cells for the first strategy of distinguishing between lymphoid/myeloid cells and the enriched-CTCs. And the second strategic approach is to calculate the pure CTCs (without false-positive cells) and then CTPS) as measured by the PD-L1 expression among pure-CTCs. That application is the percentage of viable CTCs showing partial or complete stained cells at the deducted cut-off value in each fluorescence, respectively. Results: Consequently, we demonstrated over 80% of the concordance rate between VENTANA PD-L1(SP263) and DAKO PD-L1(SP263) assay tested by the PD-L1 expression on stage IV NSCLC in tissue and pure-CTCs based CTPS from the blood. In contrast, pure-CTCs based CTPS in the pulmonary inflammatory group were all negative (recorded as zero). Conclusions: Conclusively, this study implicates that pure-CTCs based CTPS could be deployed for innovative diagnosis strategies as alternatives for tissue biopsy. Our clinical study's data suggested that the possibility for prompt decision for diagnosis and gain powerful insights to guide the personalized treatment in NSCLCs. Clinical trial information: 2020-0553.
PCSK9 inhibitor evolocumab to increase anticancer activities and reduce cardiotoxicity during doxorubicin and trastuzumab, as sequential treatment, through MyD88/NF-kB/mTORC1 pathways.
Authors: Quagliariello Vincenzo , Buccolo Simona , Iovine Martina , Paccone Andrea , Bonelli Annamaria , Cavalcanti Ernesta , Rea Domenica , De Laurentiis Michelino , Botti Gerardo , Maurea Nicola 
Published: June 2021

e15039 Background: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapy to treat hypercholesterolaemia and related cardiovascular diseases. Evolocumab, a PCSK9 inhibitor, reduced the risk of cardiovascular events in patients with atherosclerotic cardiovascular diseases when added to maximally tolerated statin therapy (± ezetimibe), and recent data from the ODYSSEY OUTCOMES trial indicate that alirocumab added to maximally tolerated statin therapy (± other lipid-lowering drugs) reduces the risk of cardiovascular events in patients with a recent acute coronary syndrome. Methods: Human fetal cardiomyocytes (HFC cell line), human HER2+ breast cancer cells were exposed to subclinical concentration of doxorubicin, trastuzumab, sequential treatment of both (all 100 nM), alone or in combination with evolocumab (50 nM) for 24 and 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Evolocumab co-incubated with doxorubicin alone or in sequence with trastuzumab exerts cardioprotective effects, enhancing cell viability of 35-43% compared to untreated cells (p < 0,05 for all); in cardiomyocytes Evolocumab reduced significantly the cardiotoxicity through MyD88/NF-KB/cytokines axis and mTORC1 Fox01/3α mediated mechanisms. In human HER2+ breast cancer cells, co-exposure of Evolocumab with doxorubicin and trastuzumab increased significantly cell apoptosis and necrosis through the involvement of key cytokines involved in chemoresistence. Conclusions: We demonstrated, for the first time, that the PCSK9 inhibitor evolocumab exerts direct effects in cardiomyocytes and human HER2+ breast cancer cells during doxorubicin and trastuzumab exposure turning on a new light on its possible use in the management of breast cancer therapies.
Discovery of HBW-3-10: A potent, orally active, reversible Bruton’s tyrosine kinase (BTK) inhibitor with antitumor activity in mice.
Authors: Lee Ning , Li Yingfu , Yuan Chester , Liu Guanfeng , Yue Chunchao 
Published: June 2021

e15062 Background: The first generation irreversible BTK inhibitor ibrutinib has been approved for the treatment of B cell-related diseases, including chronic lymphocytic leukemia (CLL), for several years. However, CLL patients who used ibrutinib may develop drug resistance due to acquired mutations, in particular BTK C481S that directly impacts the binding of ibrutinib. In recent years, efforts have been made to develop the second generation reversible BTK inhibitors that are effective against both wild-type and C481S mutated B-cell malignancies. LOXO-305 and ARQ-531 are two examples of the second generation reversible BTK inhibitors in advanced clinical trials for ibrutinib-resistant CLL. Methods: New reversible BTK inhibitors were designed, synthesized and tested for enzymatic activities against wild-type and C481S-mutated BTK. Highly active compounds were confirmed for growth effects in diffuse large B-cell lymphoma derived TMD8 cells. Their microsomal stability and ADME properties were also assessed. Potent and bioavailable compounds were further evaluated in vivo efficacy using a TMD8 xenograft tumor model in mice. A 14-day toxicity study in rats was performed correspondingly. Results: As shown in the table, HBW-3-10 has greater potency and pharmacokinetic profile (rats, 10mg/kg PO) than ARQ-531. In a TMD8 mouse xenograft study, HBW-3-10, ARQ-531 and ibrutinib were compared directly, all dosed at 10mg/kg QD, and the resulting tumor growth inhibition rates (TGI) are 38.3%, 9.3% and 22.5%, respectively. Based on our data, HBW-3-10 is more efficacious than ARQ-531 and ibrutinib. In a 14-day preliminary toxicity experiment in rats, both HBW-3-10 and ARQ-531 were dosed 100mg/kg QD. Animals in ARQ531 group started showing signs of sickness on day 3, and all died on day 6 due toxicity; in contrast, no animal in HBW-3-10 group showed any sign of sickness or died during the entire course of study. Conclusions: We have discovered a novel second generation reversible BTK inhibitors HBW-3-10, that has a superior preclinical profile, efficacy and safety than other known ones. HBW-3-10 provides a valuable clinical candidate for treating Ibrutinib resistant CLL and beyond![Table: see text]
Deep learning to identify a gene signature associated with molecular subtypes that predicts prognosis in colorectal cancer.
Authors: Cai Du , Wang Wei , Zhong Min-Er , Fan Dejun , Liu Xuanhui , Li Cheng-Hang , Huang Ze-Ping , Zhu Qiqi , Lv Min-Yi , Hu Chuling , Duan Xin , Wu Xiaojian , Gao Feng 
Published: June 2021

e15520 Background: Identifying robust prognostic risk groups of colorectal cancer (CRC) will significantly improve patients’ outcomes. However, CRC has been demonstrated to be molecularly heterogeneous which affected clinical decision-making. Recently, a comprehensive study proposed four consensus molecular subtypes (CMSs) of CRC with a comprehensive biological and clinical characterization, but a cost-effective clinical assay for prognosis is lacking. To fill this gap, we present a supervised framework using deep learning to identify CMS associated gene signature for prognosis. Methods: A total of 1,729 CRC patients with complete follow-up data were included in this study. We first applied a supervised deep learning-based framework in the training cohort ( n = 624) to extract the CMS-associated deep features and then identified a gene panel highly correlated to these deep features. Subsequently, the prognostic power of this gene signature was evaluated on 6 independent CRC datasets. Results: We identified a 21-gene signature associated CMS subtypes and a trained risk model significantly predicted patients’ disease-free survival (DFS) on six independent CRC datasets ( n = 1,729): Training cohort ( n = 624, HR = 2.53, 95% CI: 1.53-4.18, P < 0.001), Validation 1 cohort ( n = 557, HR = 1.77, 95%CI: 1.27 – 2.47, P < 0.001) and Validation 2 cohort merged by other four datasets ( n = 548, HR = 2.10, 95%CI: 1.50 – 2.93, P < 0.001). Especially, this 21-gene signature can also stratify stage 2 and 3 patients into distinct survival groups: Training cohort ( n = 338, HR = 2.14, 95%CI: 1.18-3.85, P < 0.01), Validation 1 cohort ( n = 457, HR = 1.63, 95%CI: 1.12 – 2.37, P < 0.01) and Validation 2 cohort ( n = 437, HR = 1.73, 95%CI: 1.37 – 2.82, P < 0.001), outperformed Oncotype DX on the same cohorts. Conclusions: To summarize, using our DL-based framework, we successfully developed a CMS-associated gene signature for robust prognostic prediction in CRC. Compared with genome-wide expression profile-based CMS classification system, the 21-gene panel can be easily deployed in clinical practice to facilitate decision making.
Landscape of homologous recombination-related (HRR) genes mutations in colon cancer.
Authors: Zhao Tuanjie , Ren Chuncheng , Zhang Zhiliang , Liu Huanhuan , Wang Huina , Zhang Yanrui , Zhang Yun , Liang Xiayuan , Lou Feng , Cao Shanbo , Zhang Yuru 
Published: June 2021

e15525 Background: Homologous recombination deficiency (HRD) might serve as a biomarker of immunotherapy and chemotherapy response. In addtion, HRD is associated with sensitivity to PARP inhibitor (PARPi) therapy. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. Here, we focused on mutational landscape of HRR genes and the relationship between HRR-related genes and clinical outcomes in colon cancer. Methods: We prospectively sequenced 784 Chinese patients with colon cancer using next-generation sequencing techniques with 808 cancer-related genes. 290 patients with somatic mutation from the TCGA project were included. The 15 HRR genes were selected on clinical evidence of sensitivity to PARP inhibitors and immunotherapy. TCGA datasets were performed to identify the correlations between HRR gene mutations and clinical outcomes. Results: In the Chinese cohort, 11.5% (90/784) patients exhibited deleterious somatic mutation in HRR genes, including ATM (3.3%), BRCA2 (2.4%), CDK12 (2.4%), BRCA1 (1.0%), BRIP1 (1.0%), CHEK2 (0.5%), BARD1 (0.4%), RAD54L (0.4%), PALB2 (0.3%), and RAD51B (0.3%). In TCGA cohort, 28.6% (83/290) patients had at least one deleterious somatic mutation in HRR genes, including ATM (14.8%), BRCA2 (9.0%), CDK12 (7.9%), BRIP1 (3.8%), BRCA1 (3.4%), FANCL (3.1%), CHEK2 (2.4%), PALB2 (2.1%), PPP2R2A (2.1%), RAD54L (2.1%), CHEK1 (1.7%), BARD1 (1.4%), RAD51C (1.4%), RAD51B (1.0%), and RAD51D (0.3%). Overall, the mutational frequency of HRR genes in the Chinese cohort was lower than that in the TCGA cohort (p < 0.001). In the TCGA cohort, colon patients with HRR-mut had significantly higher tumor mutational burden and incidence of microsatellite instability high and enhanced immune activity than patients with HRR-wt. Furthermore, In the MSK-IMPACT cohort treated by immune checkpoint inhibitor, patients with HRR-mut had significantly better OS (p = 0.009) and increased immune activities, such as infiltration of cytotoxic cells (p < 0.05) and exhausted CD8+ T cells (p < 0.01), and increased the IFN-γ scores (p < 0.05) than patients with HRR-wt. Conclusions: Our data suggest that detection of somatic mutations in HRR genes might contribute to identify patients who might benefit from immune checkpoint blockade therapy and PARP inhibitors. In addition, the molecular features of HRR provide new opportunities to predict the tumor response to multiple treatments. Exploring other biomarkers of HRD to predict the response to PARPi and immunotherapeutic in colon cancer is necessary.
Prognostic role of apolipoprotein and lactate dehydrogenase levels in resectable colorectal cancer.
Authors: Ma Yifei , Lu Ping , Liang Xinjun , Wei Shaozhong 
Published: June 2021

e15541 Background: Apolipoprotein b (apob), apolipoprotein a1 (apoa1), and lactate dehydrogenase (LDH) levels are circulating biomarkers that relate to tumor inflammation. This study aimed to evaluate the prognostic role of apob/apoa1 and LDH in resectable colorectal cancer (CRC). Methods: 513 patients of colorectal cancer (CRC) from Hubei cancer hospital were included finally, and we collected the pre-operative laboratory results within a week before surgery. We combined the two indicators and divided them into three groups (group 1: apob/apoa1-LDH low; group 2: apob/apoa1 or LDH high; group 3: apob/apoa1-LDH high). Kaplan-Meier survival analysis, univariate COX regression and multivariate COX regression were used to assess the prognoses of colorectal cancer patients. Results: The median follow-up was 35 months. Our study found that the prognosis of group 1 was better than group 2 in both overall survival (88.2% vs. 75.4% vs. 61.9%) (P≤0.001) and diseases-free survival (77.4% vs. 64.7% vs. 42.8%) (P≤0.001), and group 3 was the worst. By multivariate analysis, the new predictive marker obtained by combining apob/apoa1 and LDH could independently predict outcomes in CRC [overall survival: (HR: 1.487; 95% CI, 1.074-2.061); diseases-free survival (HR: 1.381; 95% CI, 1.045-1.827)]. Conclusions: New marker based on apob/apoa1 and LDH is useful for predicting the prognosis of patients with CRC. However, more research is needed in the future.
Functional precision medicine in colorectal cancer based on patient-derived tumoroids and in-vitro sensitivity drug testing.
Authors: Jensen Lars Henrik , Jakobsen Anders Kristian Moeller , Havelund Birgitte Mayland , Abildgaard Cecilie , Vagn-Hansen Chris , Dam Claus , Lindebjerg Jan , Canto Luisa M , Rogatto Silvia Regina , Rafaelsen Soeren Rafael , Hansen Torben 
Published: June 2021

e15567 Background: Precision oncology based on in-vitro, functional assays has potential advantages compared to the much more common molecular approach, but the clinical benefit is unknown. We here report the results from the largest prospective interventional clinical trial testing the clinical outcome in colorectal cancer patients treated with drugs showing cytotoxic effect in matched patient-derived tumoroids. Methods: This single-center, phase II trial included patients with metastatic colorectal cancer previously exposed to all standard therapies. Specimens from one to three 18-16 G core needle biopsies were manually dissected, enzymatically treated, cultivated, and incubated to form 3D spherical microtumors, i.e. tumoroids. In the assay for in-vitro sensitivity testing, the tumoroids were challenged with single drugs and combinations thereof to determine patient-specific responses. Using tumoroid screening technology (IndiTreat, 2cureX, Copenhagen, Denmark), results were generated by comparing the sensitivity of the individual patient’s tumoroids with a reference panel from other patients. The testing included standard cytostatics and drugs with proven effect in previous early-phase clinical trials, a total of 15 drugs. The primary endpoint was the fraction of patients with progression-free survival (PFS) at two months. Based on placebo arms in randomized last-line trials, a minimal relevant difference of 20% (20% to 40%) was stated. Using Simon's two-stage design, a sample size of 45 patients was calculated with at least 14 PFS at two months (significance 5%, power 90%). Results: Ninety patients were enrolled from 9/2017 to 9/2020. Biopsies from 82 patients were obtained and sent for tumoroid formation of which 44 (54%, 95% CI 42-65) were successful and at least one treatment was suggested. Thirty-four patients initiated treatment according to the response obtained in the drug assays within a median of 51 days from inclusion (IQR 39-63). The primary endpoint, PFS at two months, was met in 17 of 34 patients (50%, 95%CI 32-68). There were no radiological responses. Median PFS was 81 days (95% CI 51-112) and median OS was 189 days (95% CI 103-277). Conclusions: Precision oncology using a functional approach with patient-derived tumoroids and in-vitro drug sensitivity testing seems feasible. The approach is limited by the fraction of patients with successful tumoroid development. The primary endpoint was met, as half of the patients were without progression at two months. Further clinical studies are justified. Clinical trial information: NCT03251612.
Impact of RAS status and prior targeted therapy on the activity of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in daily practice. Final results of the QoLiTrap prospective non-interventional study.
Authors: Hofheinz Ralf Dieter , Kröning Hendrik , Zahn Mark-Oliver , Scholten Felicitas , Derigs Hans-Günter , Pederiva Stefanie , Anchisi Sandro , Bohanes Pierre Oliver , Gruenberger Birgit , Windemuth-Kieselbach Christine , Piringer Gudrun , Thaler Josef , Moos Roger von 
Published: June 2021

e15570 Background: The anti-angiogenic fusion protein aflibercept targets VEGF-A, VEGF-B and PIGF. It is approved in combination with FOLFIRI for treatment of mCRC previously treated with an oxaliplatin-containing regimen. We evaluated the influence of RAS status and prior targeted therapy on the efficacy and safety of aflibercept plus FOLFIRI in daily practice. Methods: QoLiTrap is a large international (Germany, Austria, Switzerland), non-interventional study evaluating the quality of life (QoL), efficacy and safety of aflibercept plus FOLFIRI in daily clinical practice. The primary endpoint was QoL assessed by EORTC QLQ-C30 questionnaire. Secondary endpoints included overall survival (OS), progression-free survival (PFS), tumor response and safety. Patients were evaluable for primary and secondary endpoint analysis if they had a QoL questionnaire at baseline and at least 2 post baseline. Safety was analyzed in all patients exposed to at least one dose of study drug. We report here the results by RAS status and prior targeted therapy received. Results: 1277 patients with mCRC were treated (median age 66 years, males 64.8%, right colon tumor 27.6%, liver metastases 53.2% , ECOG 0-1 84.7%) mainly in second-line (50.3%) but also in third-line (23.1%) and fourth-line (11.9%) setting. Median duration of treatment was 12 weeks. Overall, 872 patients were evaluable for the efficacy analysis. At baseline, the global health (mean) score was 58.7 and the mean change from baseline over 12 weeks was -4.6%. A clinically meaningful decline of -10 points was not reached, regardless of RAS status and prior targeted therapy. Secondary endpoints are provided in the Table below. Most common all grade adverse events were diarrhea (34.2%), nausea (17.9%), fatigue (17.2%), stomatitis (17.2%) and hypertension (11.6%). Conclusions: Aflibercept plus FOLFIRI administered in daily practice shows no deleterious effect on QoL and retains its activity irrespective of RAS status and prior targeted therapy. The safety profile was manageable. Clinical trial information: AIO-LQ-0113. [Table: see text]
The importance of maintenance chemotherapy in the first and second lines of treatment of metastatic colorectal cancer.
Authors: Gridnev Danila , Popov Anatoly , Islamova Dina , Makarov Vladislav , Vozny Edouard , Kudryavtseva Anna 
Published: June 2021

e15583 Background: The first and second lines of CT is decisive in the treatment of colorectal cancer. Choosing the right one allows you to increase PFS and improve long-term results. Surgical treatment and maintenance chemotherapy (MT) increase PFS and OS, as they can be prescribed at any stage of treatment. Methods: The analysis included 192 patients diagnosed with metastatic colorectal cancer (mCRC) who received treatment between 2014 and 2019. The average age of the patients was 62 years. At the beginning of treatment, the overall condition of all patients was ECOG1. Primary mCRC had 129 (67%) patients. In 63 (33%) patients, locally advanced disease was first diagnosed, which were included in the study after progression. PFS and OS for all patients were calculated from the start of the 1st line. Localization of the primary tumor in 42 (22%) patients was on the right side of the colon and on the left side in 149 (78%) and 1 patient did not show primary tumor. Among the patients with primary metastatic disease, 100 (52%) had isolated metastases, while the remaining 92 (48%) had 2 or more localizations. Different types of surgical treatment of metastases in the liver occurred in 41 (21%) patients. 119 patients never received MT (with any number of lines) and made a comparison group(A). 73 patients received MT in at least one of the CT lines (B). 12 patients received MT in the 1st and 2nd CT (C). These groups were homogeneous in terms of gender, age, ECOG, accessibility of surgical treatment of distant metastasis, mutational status of the tumor, and accessibility of biotherapy. Evaluation of the effect was performed using RECIST criteria, at intervals of 3 months or the appearance of clinical symptoms of progression. The treatment was carried out before the progression. At the time of analysis, 94 patients are alive and continue to receive treatment. Results: We compared in all three groups: In group A: OS - 12.9 months, PFS 1-line CT - 9.5 months, PFS 2-line CT - 4.5 months In group B: OS - 27.6 months, PFS 1-line CT - 13.6 months, PFS 2-line CT - 9.1 months In group C: OS - 38.3 months, PFS 1-line CT - 14.2 months, PFS 2-line CT - 9.1 months. “Five-year” survival (In those patients who were observed from the start of the study for all 5 years) in group A was 5,8 %, in group B 15 %, and in group C 16 %. Conclusions: Increase of PFS and OS in patients who received MT at least at one of the stages of treatment, and continues to increase in patients receiving MT in the first two lines CT. Thus, MT is a necessary component of the treatment of mCRC.