bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracorporeal microchannel device to capture and eliminate circulating tumor cells from cancer patient’s blood.
Authors: Khandare Jayant , D'Souza Alain , Arora Smriti , Singh Balram , Aland Gourishankar , Kale Narendra , Gore Isha , Deshmukh Arnav , Kamble Rick , Jadhav Vikas , Chaturvedi Pankaj ,   Actorius Innovations and Research
Published: June 2022

e14522 Background: Metastatic progression accounts for nearly 90% of cancer-related deaths and has been directly correlated with the presence of circulating tumor cells (CTCs) in numerous carcinomas including breast, lung, ovarian, colorectal, and head and neck cancers. The removal of CTCs from cancer patient’s blood is directly implicated with reduction of extravasation and disease invasiveness to secondary organs. Methods: We designed and printed 3 Dimensional (3D) microchannel devices using biocompatible polymer and packed it with anti-EpCAM (EpCAM) mediated glass-based (G) compositions (G-EpCAM). The computational fluid dynamic (CFD) analysis simulation was explored to optimize the hemodynamic effect of the G-EpCAM device for measuring the pressure and velocity difference for blood along the spiral flow microchannels. Red blood cell (RBC) hemolysis was estimated using G-EpCAM compositions packed in a device to determine optimal biocompatibility. We assessed cancer cell lines (breast cancer MCF7, lung cancer A549) interactions and capture with varying incubation time points, effect of anti-EpCAM concentrations, number of G-EpCAMs, and series of devices. We evaluated G-EpCAM-on-device’s CTC capture capability and biocompatibility using head and neck, colorectal, lung, and ductal breast cancer patient’s blood samples. All G-EpCAM captured CTCs were immuno-stained for cytokeratin 18 (CK18) expression and the optimal fluorescence acquisition intensity was quantified. Results: Extracorporeal G-EpCAM microchannel device was 3D printed and consisted of interlocking top lid and bottom base with inlet and outlet channels. The path length of the spiral device consisted of 20 microchannels with 6.0-feet length. Device accommodated 28 gm of non-hemolytic G-EpCAM compositions. CFD analysis showed 3.8 mm as the ideal channel diameter and 2mm as the superlative G-EpCAM diameter for maximal cells and CTC capture with minimal blood hemolysis (less than 1%) as compared to control. Series 1 and 2 device indicated 90% and 85% cell capture efficiency, respectively using G-EpCAM devices indicating highest interactions and efficiency with cells. Conversely, the first device in series captured the highest cells. In addition, the efficiency improved as the number of G-EpCAM compositions was increased. We accounted device to capture CTCs with specificity having G-EpCAM composition and observed no hemolysis and non-specific interactions with other blood cells like RBCs or leukocytes. Conclusions: Continuous CTC removal from cancer patient’s blood circulation using such device offers promising therapeutic utility in stemming aggressive metastatic invasion and progression for improving the overall survival of epithelial origin cancer patients. Clinical trial information: CTRI U1111/1192-3951.
Immune response during regional chemotherapy.
Authors: Aigner Kornelia , Drothler Stephan , Aigner Karl R. , Aigner Karl R. 
Published: June 2022

e14537 Background: Regional chemotherapy is known to yield high drug concentrations in the treated tumor area while keeping systemic drug concentrations low. Regional Chemotherapy can be performed as an intra arterial infusion or isolated perfusion. Known perfusion techniques are isolated limb perfusion, hypoxic pelvic perfusion, hypoxic abdominal perfusion, upper abdominal perfusion, and isolated thoracic perfusion, Only little is known on the effect of chemotherapy on immune cells, especially not if chemotherapy is applied regionally. Since more and more immuno oncologic treatment possibilities arise, that often are combined with chemotherapy, knowledge on the effects on immune cells is crucial. Since systemic chemotherapy often decreases the number of immune cells in general, the more targeted approach of regional chemotherapy is investigated in this study. Methods: In this work, we investigate subpopulations of T-lymphocytes, Natural Killer cells and B-lymphocytes during regional chemotherapy and report on their changes after cycles of intra-arterial chemotherapy infusion followed by chemofiltration. Surface phenotyping of cells from EDTA blood was performed with combinations of monoclonal antibodies (anti- CD3,CD16, CD56, CD45, CD4, CD19, CD8, CD28, HLA-DR, CD39, CD25, CD127, CD45RA, CD45RO) for FACS analysis. 58 Patients with advanced breast cancer, ovarian cancer, head and neck cancer, lung cancer, or bladder cancer received regional chemotherapy as an intra arterial infusion therapy or an isolated perfusion therapy. Results: Contrary to the mild immune cell depletion during the first two cycles a more activated immune status is seen after treatment cycle three. Non-significant increase or stable numbers are observed for T-Lymphocytes and its subsets of CD4+ T-helper cells, CD8+ cytotoxic T-cells, and terminal memory T-cells (CD8+/CD28-/CD57+). Significant increase of cell numbers is observed for B-lymphocytes, regulative CD8+ T-cells (CD8+/CD28-/CD57-), activated HLA-DR+ T cells, and Natural Killer cells while regulative CD4+ T cells are significantly decreased. Conclusions: The data show that regional chemotherapy has controversial effects on the immune cell subpopulations. As every chemotherapy, it does affect immune cells, however to a limited extend, but importantly has an activating potential. Immune activation prevalently takes place after the third cycle of therapy which might be a hint for auto-vaccination caused by phases of repeated tumor necrosis after locally high drug concentrations. Finding the optimal dosage of chemotherapeutics may be crucial to balance direct tumor response, immune toxicity and immune activation.
Analysis of phase I clinical trials (Ph1-CT) new enrollment patterns in the immuno-oncology era.
Authors: Erasun Lecuona Carlos , Soto Juan José , Llop Serna Sandra , Mulet Margalef Nuria , Stradella Agostina , Villanueva Rafael , Calvo Campos Mariona , Jove Casulleras Maria , Cuadra Amor Carmen , Salazar Soler Ramon , Gil-Martin Marta , Oliva Marc , Martin-Liberal Juan 
Published: June 2022

e14549 Background: Immuno-Oncology (IO) has revolutionized anticancer therapeutics and changed the early drug development paradigm. Positive results and limited access to IO drugs in some countries have led to increased enrollment in IO Ph1-CT at an earlier timepoint in patients (pts) disease journey. We evaluated the impact of IO era on enrollment patterns in Ph1-CT. Methods: We retrospectively reviewed pts with recurrent/metastatic solid tumors enrolled in Ph1-CT from January 2018 to June 2021 at the Phase 1 Unit of Catalan Institute of Oncology (ICO), Barcelona, Spain. The primary goal was to assess Ph1-CT enrollment patterns, including use of molecular pre-screening/personalized drug matching, and the availability of alternative standard of care (SOC). Overall response rate (ORR) was assessed according to RECIST 1.1. Clinical benefit rate (CBR) was defined as complete/partial response+stable disease for ≥6 months. Median progression-free survival (mPFS) and overall survival (mOS) using Kaplan-Meier method were provided. Results: A total of 175 pts were enrolled in Ph1-CT. Median age was 54 years (range 43-75), Male:Female = 99:76, 99% had ECOG 0-1. The most prevalent tumors were: 32 (18%) breast, 31 (18%) colorectal, 25 (14%) urogenital and 23 (13%) glioblastoma multiforme. One hundred forty-six (83%) pts were enrolled in Ph1-CT with IO (alone or in combination) and 29 (17%) pts with targeted therapy (TT). Molecular pre-screening tests were required in 24 (14%) pts (22 pts IO vs 2 pts TT trial). Eleven (42%) pts were pre-screening failures. Screening failure (SF) rate was 19%, the main reason being clinical worsening for 7 (4%) pts. Thirty-three (19%) pts had an alternative SOC treatment available at time of enrollment. One hundred two (58%) pts had received ≤1 prior lines and 26 (89%) were IO-naïve. Finally, 129 (74%) out of 175 pts enrolled were treated within Ph1-CT. Out of 129 treated pts, ORR was achieved in 18 (14%) pts (3% complete response) and 44 (34%) had stable disease. CBR was observed in 36 (28%) pts. mPFS was 2.8 months and mOS was 10.9 months. Toxicity grade 3-4 occurred in 25 (19%) of pts and 6 (5%) pts had to interrupt treatment. Seventy-one (55%) pts received subsequent therapies: 22 (17%) in Ph1-CT; 49 (38%) SOC. Eleven (9%) pts received IO as subsequent therapy. Decline in ECOG status (baseline vs end of treatment) occurred in 65 (50%) pts. Conclusions: In our cohort of Ph1CT pts, there has been an increasing number of pts enrolled in IO trials compared to TT. Most pts received treatment within Ph1-CT at an earlier timepoint in the course of their disease (1st or 2nd lines). Our results suggest a clear impact of the IO era on the trends of Ph1-CT availability and enrollment patterns.
A phase 1 study of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, in patients with advanced solid tumors.
Authors: Ho Ching-Liang , Chao Tsu-Yi , Chang Chia lun , Lin Hsuan-Yu , Yang Futang , Wang Qingyu , Zhu Jun 
Published: June 2022

e14560 Background: Serplulimab, a novel humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T cells and showed anti-tumor activity in several xenograft models. This phase 1 study was designed to assess the safety and tolerability of serplulimab in patients with metastatic or recurrent solid tumors. Methods: This prospective, open-label, two-cohort (dose-finding cohort [up to 30 patients]; dose expansion cohort [up to 27 patients]) phase 1 study was conducted in patients with metastatic or recurrent solid tumors who had failed standard therapy. In the dose-finding cohort, Bayesian optimal interval (BOIN) design was adopted to explore the MTD of serplulimab. Patients were administered serplulimab (Q2W) at doses of 0.3, 1, 3, or 10 mg/kg via intravenous infusion until disease progression, the maximum of 1 year, withdrawal from the study, or death, whichever occurred first. In the dose expansion cohort, nine eligible patients were enrolled in each dose group to receive fixed doses of serplulimab at 200 (Q2W), 300 (Q3W) or 400 mg (Q4W). The primary objective of this study was to identify the safety profile and the MTD of serplulimab. The PK profile and the preliminary efficacy were also examined as secondary objectives. Results: Here we only report the results from the dose-finding cohort. As of July 27, 2020, 29 patients were enrolled and treated with at least one dose of serplulimab (0.3 mg/kg group, n = 3; 1 mg/kg group, n = 4; 3 mg/kg group, n = 6; 10 mg/kg group, n = 16). At baseline, the mean age of enrolled patients was 60.0 years, with a mean BMI of 24.7 kg/m2, a mean BSA of 1.7 m2, and a mean LVEF of 67.1%. All patients presented with stage IV tumors at baseline, among whom 79.3% were diagnosed with metastatic disease. Only one patient in the 3 mg/kg dose group experienced DLTs, which was reported during the first cycle. The MTD was not determined yet. Overall, 28 (96.6%) patients experienced at least one TEAE during the study, mostly of grade 1 or 2. No notable differences were observed among the dose groups with regard to the incidence of TEAEs. The most frequently reported TEAEs was decreased appetite (41.4%), fatigue (31.0%), nausea (27.6%), pyrexia (27.6%), and pleural effusion (27.6%). Minimal accumulation of serplulimab was observed following multiple dose administrations. The preliminary anti-tumor efficacy of serplulimab was demonstrated by a DCR of 60.0%, an ORR of 8.0%, and a median PFS of 107.0 days. Conclusions: In summary, serplulimab up to 10 mg/kg was well tolerated and showed promising anti-tumor activity in patients with metastatic or recurrent solid tumors. Serplulimab is currently being investigated in phase 3 studies among patients with NSCLC, SCLC, esophageal cancer, mCRC, etc. Clinical trial information: NCT03468751.
Solid tumor patients with G12V and G13D KRAS aberrations have poor survival following ICI treatment.
Authors: Jung Jaeyun , Park Sehhoon , Lee Jeeyun , Kim Seung 
Published: June 2022

e14567 Background: KRAS gene has been well known as a dominant oncogene which activates downstream signaling for tumor growth. The new therapeutic drug targeting specific KRAS mutation (G12C) has been developed and several clinical trials are testing KRAS inhibitors in solid tumor patients. In line with this, we have surveyed the prevalence and clinical features of solid tumor patients with KRAS aberration in 1,744 oncology patients who received next generation sequencing (NGS) in a clinical practice. Methods: Between 2019 amd 2021, 1,744 oncology patients have received NGS (TruSight Oncology 500 panel; 523 genes) at Samsung Medical Center. . Matched clinical and histology outcomes including programmed cell death-ligand 1 (PD-L1) 22C3 expression (n = 798) and immunotherapy treatment outcomes (n = 409) were analyzed based on genomic alteration. Results: Among the thirty-three different cancer types, the most common cancer types were colorectal cancer (CRC) (N = 547, 31.4%), followed by gastric cancer (GC) (N = 381, 21.8%), and sarcoma (N = 155, 8.9%). Of 1,744 patients, any KRAS aberrations (CNVs, SNVs) were detected in 487 (27.9%) patients (CNV: Copy Number Variation, SNV: Small Nucleotide Variation). Of the 51 (2.9%) patients with KRAS amplification, 18 (35.3%) patients were CRC followed by GC (N = 9, 17.6%). Each 4 cases were found in Cholangiocarcinoma (CCC), sarcoma, melanoma and pancreatic cancer (8%, respectively). Copy number of KRAS were distributed from 4 to over 50, while bladder cancer had the highest median value of copy number(median: 148), followed by CCC(median: 16.2). Of 454 SNV cases, the most frequent cancer type was CRC (N = 259, 57.0%) and pancreatic cancer (N = 89, 19.6%). Except 4 cases, all SNV mutation type was missense mutation. G12D amino acid change was the most frequent(N = 182), followed by G12V(N = 100), G13D(N = 48), and G12C(N = 20). However, only the patients with G12V and G13D mutation had significantly shorter OS and PFS in ICI treatment. Conclusions: Based on our comprehensive survey of next generation sequencing focused on KRAS aberration, we identified approximately 2.9% KRAS amplification and 26.0% KRAS SNV in patients with metastatic solid tumors. It was demonstrated that G12V, G13D were important mutations which were related to the response to ICI treatment in real-world data.[Table: see text]
Slit mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Bao Aihua , Zhao Lele , Chen Dong-sheng , Li Si , Yu Yangyang , Xiao Mingzhe , Qi Chuang 
Published: June 2022

e14572 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlyingpredictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Slits (Slit1, 2 and 3) are highly conserved secreted glycoproteins that play important roles in tumorigenesis, including cancer cell proliferation, motility and angiogenesis. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between SLIT and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between SLIT gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with SLIT mutation were significantly associated with better PFS (HR = 0.27; 95% CI, 0.14-0.52; P < 0.001), objective response rate (ORR, 63.3% vs 25.2%; P < 0.001) and durable clinical benefit (DCB, 86.7% vs 63.0%; P = 0.048) after ICIs therapy, compared with those with wide-type SLIT. SLIT mutation were associated with increased TMB ( P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between SLIT mutation and PFS remained significant (HR = 0.38; 95% CI, 0.19-0.77; P = 0.007). In contrast, no association between SLIT mutation and OS (LUAD: P = 0.57 ; LUSC: P= 0.1) or PFS (LUAD: P = 0.71; LUSC: P = 0.55) was observed in TCGA datasets, suggesting that SLIT mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, SLIT mutation was significantly associated with higher naive B cell, plasma B cell, activated memory CD4+ T cell, CD8+ T cell, as well as lower M2 macrophage and Treg cell. Moreover, SLIT mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. In addition, GSEA analysis revealed that SLIT mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway and activation of NF-κB in B-cell. Conclusions: Our results demonstrated that SLIT mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of SLIT in immunotherapy is needed to be further studied.
The utilization of artificial intelligence to produce clinically relevant scores on PD-L1 immunostained non-small cell lung cancer biopsies.
Authors: Mehra Navi , Patel Bhavika , Allen Stephanie , Talwalkar Sameer S. , Thagaard Jeppe , Ramsing Thomas W. , Overgaard Agnete , Caldara Jeni 
Published: June 2022

e14576 Background: Immunotherapies targeting complex programmed death-ligand 1 (PD-L1) interactions have been groundbreaking in the treatment of non-small cell lung cancer (NSCLC), offering new strategies for patients who are likely to respond. PD-L1 binds to the checkpoint PD-1 to regulate T cells, which has an important role in boosting the immune response. Identifying patients who may benefit from PD-L1 focused care is dependent on the interpretation of the drug’s associated companion diagnostic (CDx) immunohistochemistry (IHC) assay. PD-L1 IHC assays stratify NSCLC patients using a Tumor Proportion Score (TPS), a manual scoring paradigm which must be applied by a clinical pathologist. Application of the score is complex as it requires the reader to visually exclude stromal and tumor-infiltrating immune cells across a full sample, retaining PD-L1 expression information for true tumor cells only. Methods: In this study, we utilized the PD-L1 [28-8] immunohistochemistry (IHC) assay to stain 10 NCSLC specimens. Stained slides were then imaged using the AT2 scanner (Leica Biosystems, Buffalo Grove, IL) scanner and analyzed using the Visiopharm Image Analysis platform. Results: The intricacy of TPS application is time consuming for the pathologist and introduces opportunity for inter- and intra-reader variability. Our novel image analysis approach utilizes artificial intelligence (AI) to automatically denote tumor nests and exclude tumor-infiltrating immune cells. The remaining true tumor cells may then be quantified for PD-L1 expression across the full biopsy, producing a TPS for each sample. Conclusions: This method allows for great accuracy and time-efficiency in providing a TPS than traditional methods, which may result in improved patient care.
Comprehensive characterization and functional implications of mesenchymal stem cell-related genes in pancancer: A new horizon for immunotherapy.
Authors: Tang Chaozhi , Ma Jiakang , Wang Xueting , Lei Fang , Lu Kaining , Zhang Wentao , Zhu Yuyan , Yao Xudong , Yang Bin 
Published: June 2022

e14577 Background: Accumulated evidence demonstrates that mesenchymal stem cells (MSCs) contribute to tissue regeneration, tumor progression, chemotherapy resistance, and mediate tumor immune escape by modulating the stroma and immunity of the tumor microenvironment. However, little is known about the role of MSCs in cancer patients receiving immunotherapy. Therefore, we investigated the comprehensive characterization of MSC-related genes and their functional implications in pan-cancer immunotherapy. Methods: We performed a pan-cancer analysis of 59 MSC-related genes, which was used to calculate an MSC score with single sample gene set enrichment analysis. Multivariate Cox regression analysis was performed to identify a potential independent prognostic marker for cancer. TIDE algorithm and neural network were utilized to assess the predictive accuracy of MSC-related genes for immunotherapy. Results: MSC-related gene expression showed significant differences inconsistently between normal and tumor samples across the 33 cancer types (p < 0.05). Cox regression analysis suggested that the MSC score is an independent prognostic marker for papillary renal cell carcinoma (TCGA; OS, RFS and DSS, all p < 0.05), mesothelioma (TCGA and GSE29354, OS, all p < 0.05), glioma (TCGA and GSE107850, OS, all p < 0.05), and stomach adenocarcinoma (TCGA, GSE84437, GSE15459, GSE13861 and GSE62254, OS; GSE13861 and GSE62254, RFS; all p < 0.05). The abundance of fibroblasts was also more representative of the MSC score compared to the stromal score. Samples with a high MSC score were predicted to have low responsiveness to immunotherapy, which was validated across seven immune checkpoint therapy datasets (IMvigor210, 27.52% (low) vs 18.12% (high); GSE78220, 64.28% (low) vs 42.86% (high); GSE135222, 30.77% (low) vs 28.57% (high); GSE165252, 36.11% (low) vs 28.57% (high); GSE79671; 38.89% (low) vs 33.33% (high); PRJEB25780, 45.45% (low) vs 8.70% (high); GSE176307, 22.22% (low) vs 13.64% (high)). TIDE algorithm and Neural network demonstrated a good predictive accuracy of MSC-related genes for immunotherapy (CESC, COAD, DLBC, GBM, KIRC, LAML, LIHC, LUAD, LUSC, MESO, OV, PCPG, PRAD, SARC, SKCM, THCA, UCEC, and UCS; all ROC ≥0.9). Conclusions: We characterized the MSC-related genes across multiple cancer types and highlighted their potential as a predictive biomarker for immunotherapy response and prognosis. A prospective clinical trial is warranted to confirm these findings.