bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological microenvironment in colon cancer patients with different phenotypes of cancer stem cells.
Authors: Zlatnik Elena Yu , Novikova Inna A. , Ulianova Elena P. , Bondarenko Elena S. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Petrov Dmitriy S. , Kolesnikov Vladimir E. , Savchenko Dmitriy A. , Tolmakh Roman E. , Dashkov Andrey V. , Katelnitskaya Oksana V. , Ilchenko Sergei A. , Dzhenkova Elena A. , Snezhko Aleksandr V. , Kolesnikov Evgeniy N. , Shaposhnikov Aleksandr V. , Kit Oleg I. , Maksimov Aleksey Yu. 
Published: June 2022

e15503 Background: The purpose of this study was to analyze the effect of the CD44+ and CD133+ co-expression in cancer stem cells (CSCs) on lymphocytic microenvironment of colon cancer (CC). Methods: 200 CC patients received surgery as the first stage of treatment. The percentage of CSCs with the expression of CD44+ and/or CD133+ markers was studied in the tumor homogenates by flow cytometry, as well as some indicators of local immunity (CD3+, CD4+, CD8+, T regs (CD4+CD25+CD127dim), CD19+, PD-1, PD-L1, Th0, Tm, CD16/56+ and immunophenotypic characteristics of tumor cells (PD-L1, MHC-ABC). Results: Gradation depending on the absence or presence of co-expression of CSC markers on tumor cells allowed identification of 11 statistically significant differences out of 17 studied parameters of tumor cells and their lymphocytic microenvironment. Co-expression of CSC markers was accompanied by higher percentage of T regs (7.3±0.4 versus 5.3±0.5%), together with lower levels of CD4+ cells. At the same time, a higher content of the total number of T-lymphocytes was noted due to CD8+ with an increase in the percentage of memory T cells and a decline in naive T lymphocytes within this subpopulation. In addition, the co-expression of CSC markers was accompanied by a lower content of PD-L1 (34.3±3.0 vs. 42.9±2.5%) on lymphocytes and its higher content on tumor cells (10.6±1.5 vs. 4.1±0.8%), while the PD-1 expression on lymphocytes was higher (38.4±3.7 versus 22.3±2.9%). The presence of CD44+CD133+ CSCs was also accompanied by lower percentage of tumor cells expressing MHC class I (60.4±4.9 vs. 79.3±7.6%), which characterized the inhibition of recognition processes, and increased levels of CD8+, perhaps, should be considered as compensatory. Conclusions: The lymphocytic microenvironment of CC in the presence of CSCs with the CD44+CD133+ immunophenotype seems to be more immunosuppressive, according to the increase in the local content of T regs and the decrease in MHC-ABC expression. Higher expression of PD-L1 on tumor cells and PD-1 on lymphocytes allows activation of the PD-1/PD-L1 interaction, which enhances the immunosuppressive and growth-stimulating properties of the tumor microenvironment, but at the same time, makes tumor cells adequate targets for immunotherapy with immune checkpoint inhibitors.
A colorectal biomarker think tank collaborative: Devising solutions for patients, caregivers, and cancer care teams.
Authors: Newcomer Kim , Goodman Andrea , Fathi Negeen , Shoeb Abdullah 
Published: June 2022

e15507 Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. With more than a dozen known mutations in colorectal cancer, and growing knowledge about different efficacy of drug options dependent on biomarker status, biomarker testing and results can aid in more effective and lifesaving treatment planning specifically for the unique characteristics of each individual’s tumor. However, biomarker testing in colorectal cancer remains low, and the Colorectal Cancer Alliance aims to increase knowledge and awareness of testing among patients and their care teams. Methods: In 2019, the Alliance distributed an online survey to assess patient, survivor, and caregiver knowledge and understanding of biomarker testing. The results identified patient confusion, suboptimal biomarker testing rates, and critical aspects of patients' medical treatment plan. To further understand identified gaps, the Alliance recruited a diverse set of patients and caregivers at various stages of colorectal cancer for a focus group in 2021 to explore understanding around biomarkers, treatment pathways, biomarker testing decisions, and gaps around current testing and re-testing processes. Working with an expert Advisory Committee, the Alliance utilized findings from the survey and focus group to plan a 2021 Summit focused on identifying solutions for known barriers. Results: Summit participants discussed innovative and evidence-based solutions focused on three audiences: patients, caregivers, and cancer care team members, to close some of the gaps identified previously. Patient solutions focused on cancer field-wide collaborations to create standard language and health literacy standards for biomarkers and testing that allow for clear, transparent notes, patient engagement, and shared decision making. Caregiver solutions focused on elevating the caregiver role as an advocate through updated telehealth infrastructure that allows for caregiver support in the journey. Cancer care team solutions focused on utilizing continuing medical education (CME) courses to create standard health literacy standards, become better advocates for biomarker testing, and create multidisciplinary discussion opportunities between health professionals. Conclusions: Patients and caregivers are overwhelmed by the complexity and variety of treatment options. It is critical that we put swift, collaborative solutions in place with efforts to improve resources, shared language, infrastructure, and advocacy to empower cancer care teams, patients and caregivers alike. We aim to increase knowledge of and access to guideline-concordant biomarker testing, so that patients, caregivers, and cancer care teams can make informed treatment decisions accordingly, and understand the choices and discussions at each step.
Ultra-deep sequencing with unique molecular identifier(UMI) for detection of ctDNA by fragment profiling using machine learning.
Authors: Yukai Hu , Nan Hu , Rui Liao , Bing Wang , Xiaohong Duan , Chunyan Yang , Lifen Wang , Wan Qianhui , Pei Zhihua , Qiming Zhou , Wang Dongliang 
Published: June 2022

e15508 Background: Liquid biopsy has been well known for its potential in cancer detection, non-invasive tumor genotyping and disease surveillance. However, ctDNA levels are low in the early stages of monitoring and postoperative progression of most tumors, which makes detection and analysis of ctDNA quite complicated. Methods: In our study, fixed-sequence UMI double-ended sequencing with a 1123-gene panel was used both on blood samples from 200 healthy donors and tissue-plasma samples from 1000 colorectal cancer (CRC) patients. First, GATK mutation detection was performed on tissue and plasma samples from 700 CRC patients to obtain trustable positive mutation sites in DBSNP138 database, meanwhile Samtools MPileUP analysis was performed on 200 healthy samples to obtain negative sites at low frequencies below 1%. Then, six features were extracted from the supporting variation sequences for the two above types of loci: IS (insert size), VBQ (variation base quality), MRBQ (mean read base quality), PIR (position in read), MQ (mapping quality) and R1&R2 (read 1 and read 2 of the paired-end sequencing). All the above data were used to establish the training set model; after that, SNV background noise was modeled by SVM and optimized through five-fold cross-validation. Last, plasma samples from 300 CRC patients were used as a validation set to verify the accuracy of the model. Results: The test set of 300 CRC patients was used to verify the accuracy of the model, in which， the effectiveness of VAF mutation frequency above 0.2% was 95%, and above 0.02% was 80% in plasma. Conclusions: We established a specific method based on UMI two-terminal capture with machine learning modeling, which was significantly superior to any available method in eliminating noise background errors and filtering false-positive low-frequency mutation.
Prediction value of TRIM29 on immunotherapy in colorectal cancer.
Authors: Han Jing , Zhang Xue , Fan Zhisong , Wang Long , Feng Li , Li Dan , Zuo Jing , Wang Yudong , Zhou Xinliang , Liu Jiayin 
Published: June 2022

e15533 Background: Our previous study have found that TRIM29 expressed higher in right colon cancer than left colon cancer and rectal cancer.But the main functions of TRIM29 was not fully clarified.Bioinformatics can be used for exploring the biological function of a gene.So we further explored the molecular mechanism by using bioinformatics analysis.The results showed that TRIM29 correlated to immune dysfunction.Mismatch repair deficient(dMMR) is closely related to the efficacy of immunotherapy in colorectal cancer.We also used GEO data to explore the relationship between TRIM29 and dMMR.At last, clinical pathological data were used to explore the relationship between TRIM29 and tumor lymphocyte infiltration. Methods: At first, bioinformatics analysis was used to further explore the molecular mechanism of TRIM29.Hub genes correlated with TRIM29 and Reactome/KEGG Pathway of the hub genes were identified and performed using String database(http://string.embl.de/).TISIDB(http://cis.hku.hk/TISIDB/) was utilized to analyse the correlations between TRIM29 expression and tumor infiltrating lymphocytes, immunomodulator and chemokine.Then GEO public data including 583 sample size was download and used to confirm the correlation ship between TRIM29 expressed and pMMR/dMMR status.At last, HE sections of the 227 CRC patients were collected to explore the connection between TRIM29 and tumor infiltrating lymphocytes. Results: Functional annotations and immune activity analysis showed TRIM29 is related to tumor infiltrating lymphocytes and due to immune dysfunction in colorectal patients.For tumor infiltrating lymphocytes analyzing, elevated TRIM29 was significantly associated with Act_DC, iDC,monocyte, NK,NKT, pDC, Tcm_CD4, Tcm_CD8, Tem_CD8 and Th1 cell infltration in colorectal ( P< 0.05), leading to a general increase in immune infiltration.For chemokines analyzing,elevated TRIM29 was significantly associated with high expression of CXCR1,CXCR2 and CXCR4( P< 0.05).For immunostimulators analyzing,TRIM29 over-expression was significantly associated with C10orf54, CD70, CD276, HHLA2 and ICOSLG, causing immune imbalance( P< 0.05).For immunoinhibitors analyzing, elevated TRIM29 expression was significantly associated with PD-L1, LGALS9, PD-1, PVRL2,TGFBR1,TIGIT and VTCN1( P< 0.05).The HE results revealed that high TRIM29 protein expression was correlated with high tumor-infiltrating lymphocytes ( P= 0.0053).GSE39582 data analyzing results showed that dMMR patients expressed higher TRIM29 level than dMMR patients( P= 0.0014). Conclusions: High TRIM29 expression is related to tumor infiltrating lymphocytes and due to immune dysfunction in colorectal patients.Elevated TRIM29 expression up regulating immune checkpoint molecules after immune stimulation to avoid immune damage.TRIM29 may serve as a new biomarker for immunotherapy.
An Immune-metabolic signature (IMMETCOLS) identifies three clusters in mCRC with different immune-phenotype distribution and potential clinical implications.
Authors: Archilla Ivan , Pedrosa Leire , Garcia de Herreros Marta , Fernandez-Mañas Laia , Esposito Francis , Jares Pedro , Figueras Carolina , López Sandra , Oliveres Helena , Foguet Carles , Cascante Marta , Maurel Joan , Cuatrecasas Miriam 
Published: June 2022

e15534 Background: The overall response rate following immune check-point blockade (ICB) is < 5% in microsatellite stable (MSS) advanced colorectal cancer (mCRC), and between 30-35% in MSI mCRC. We here evaluate the relationship between our immune-metabolic signature (IMMETCOLS) distribution (cluster (IMC) 1; mesenchymal glycolytic, IMC 2; epithelial-non glycolytic and IMC 3; epithelial mitochondrial oxidative) with immune phenotypes (inflamed (IF), immune-excluded (IE) and immune-desert (ID)) in MSS and MSI mCRC patients (pts). Methods: We have analyzed IMMETCOLS in a retrospective cohort of 128 mCRC pts enriched with MSI-H and BRAF genotype using the nCounter platform (Nanostring Technologies, US). Immune phenotypes were evaluated by immunohistochemistry using 7 immune markers (CD68, CD163, CD8, CD3, FOXP3, PD-L1 and PD1) in a subset of 47 mCRC pts (27 MSS and 20 MSI), in TMAs containing 4 cores from the center of the tumor (CT) and invasive front (IF). The number of stained immune cells was counted using a computerized image analysis system, and PD-L1 was evaluated using CPS score (< 1 vs > 1). Patients having a CD3 cell count below 572 cells/mm2 and a CD8 density below 175 cells/mm2 in IF or CT were considered as ID. (Halama Nils, 2011). CD3 density was also semi-quantitatively estimated in peritumoral stroma and intra-tumoral (range 1-4), defining as IE those cases with a difference > 1 between the two regions in both IF and CT (Brooks JM, 2019). Results: Cluster distribution was similar between MSI (IMC1-40%, IMC2-20% and IMC-40%) and MSS (IMC1-34%, IMC2-24%, IMC3-43%) pts. Patients with high LDH levels (> 1.5ULN) were enriched with IMC3 phenotype (p < 0.0001). MSI have increased CD3 (p = 0.002), CD68 (p = 0.002) and CD163 (p = 0.001) in CT than MSS patients. IMC1 pts had increased CD163/CD68 ratio in CT (p = 0.004). 75% of MSI pts were IE and 25% IF. 55% of MSS pts were IE, 38% ID and 7% IF. IMMETCOLS/ immune-phenotype distribution was: IMC1 (16% ID/ 84% IE), IMC2 (12% ID/ 63% IE/ 25% IF) and IMC3 (35%ID/ 47% IE/ 18% IF). PD1 immuno-expression > 1% (IF and CT) and PD-L1 positivity was observed in 38%, 30% and 28% of pts respectively. There were no differences in PD-L1 (CPS) and PD1 expression between MSS and MSI tumors. Inflamed tumors show higher PD-L1 expression compared with IE and ID immune-phenotypes (p = 0.014). PD1 > 1% expression at IF was significatively lower in IMC1 vs IMC2 and IMC3 tumors (p = 0.032). Conclusions: IMC1 subtype is associated with low PD1 expression, high CD163/CD68 ratio and IE phenotype even in MSI-H mCRC patients. Therefore, IMMETCOLS testing would be of value to identify MSI mCRC pts that do not benefit to ICB therapy.
Study of the effectiveness of chemotherapy in patients with colorectal cancer depending on the location of the metastatic lesion.
Authors: Kamishov Sergey Viktorovich , Niyozova Shakhnoza Khamoidinovna 
Published: June 2022

e15540 Background: The reason for the increased interest in the chemotherapeutic treatment of metastatic colorectal cancer (CRC) is the steady increase in the incidence of this oncological pathology, as well as the high incidence of neglect of the tumor process in a significant proportion of patients in the absence of improvement in long-term treatment results. Methods: In 84 patients with metastatic CRC (mCRC), the clinical effect and toxicity of the FOLFOX4 and CAPOX regimens were studied. In 51 (60.7%) patients, multiple metastases in various organs were most common, in 18 (21.4%) - solitary, and only in 15 (17.9%) patients - solitary. Among the examined patients, men accounted for 46 (54.7%), women - 38 (45.2%). The average age of men was 57.2+0.2 years, women 65.4+0.4 years. Patients underwent 2-4 courses of treatment, after which the effect of PCT was evaluated according to the REGIST scale (2009). Results: Out of 84 patients with mCRC who received 2-4 courses of palliative chemotherapy according to the FOLFOX4 and CAPOX regimens, complete regression of the process was observed in 14 (16.7%) patients, partial regression in 34 (40.5%) patients, stabilization of the process in 19 (22.6%) and in 17 (20.2%) progression of the disease was revealed. At the same time, the highest objective response rate (PR + FR) was with metastases in the liver - 16 (76.1%) and lungs - 12 (63.1%). Of the 3 patients with brain metastases, stabilization was noted in 2 cases and progression of the process in 1 case. With combined distant metastases (lungs + liver and lungs + bones), there were 2-3 times more patients who were not sensitive to therapy than those who were sensitive. With combined distant metastases (lungs + liver and lungs + bones), there were 2-3 times more patients who did not respond to therapy than those who were sensitive to treatment. The “treatment sensitive” group included 48 (57.1%) patients with complete and partial regression. The “treatment-resistant” group consisted of 36 (42.9%) patients with progression and stabilization of the disease. Conclusions: The highest objective response rate (PR+FR) in patients with mCRC was with metastases in the liver - 16 (76.1%) and lungs - 12 (63.1%). The comparatively better results in metastatic lesions of the liver and lungs are obviously associated with a more developed blood supply to these organs, which leads to a better supply of chemotherapy drugs and the effectiveness of treatment. At the same time, the combination of localization of CRC metastatic lesions in various organs significantly worsens the results of treatment.
Clinical and molecular characterization of fusion genes in colorectal cancer.
Authors: Karan Canan , Tan Elaine , Sarfraz Humaira , Walko Christine Marie , Kim Richard D. , Knepper Todd C , Sahin Ibrahim Halil 
Published: June 2022

e15568 Background: Next-generation sequencing (NGS) based molecular profiling technologies have revealed several oncogenic fusion genes that are actionable with small molecule inhibitors leading to practice change, particularly in lung cancer. The molecular and clinical characteristics of these gene fusions are not well defined in colorectal cancer patients (CRC). In this study, we aimed to define clinical and molecular characteristics of fusion genes in patients with CRC who underwent molecular profiling. Methods: Molecular characteristics of tissue confirmed 917 CRC patients were retrieved from the Moffit Cancer Center Clinical Genomics Action Committee database. Patients’ demographic and clinicopathological features and treatment history were collected from the database. All fusion genes were shown by hybridization-based NGS computational algorithms that determined cancer‐related genes, including single‐nucleotide variations, indels, microsatellite instability (MSI) status. Results: Among a total of 917 patients, 24 patients with CRC (2.6%) were found to have at least one fusion gene with a total number of 26 pathogenic fusions. The gene fusions are shown in Table. The most common, potentially targetable, fusion genes in our cohort were (1) RET fusions 0.5% (5/917), (2) ALK fusions 0.4% (4/917), (3) ROS1 fusions 0.2% (2/917), (4) NTRK1 fusion 0.1% (1/917), (5) NRG1 fusion 0.1% (1/917). Fusion genes were more common in MSI-H CRC (N = 27), and 3 (11.1%) patients with MSI-H CRC were found to have fusion genes [(RET (2) and NTRK(1)]. Fusion genes were present in both RAS wild-type (54%; 13/24) and RAS mutant (46%; 11/24) tumors. Most patients were older than 50 years (75%, 18/24) and had left-sided tumor (61.1%) tumor. Conclusions: Fusion genes are rare events in CRC. While fusion genes seem to be more prevalent in MSI-H CRC, RAS status does not correlate with the frequency of fusion genes. Actionable RET and ALK/ROS gene fusion are more common than NTRK fusion genes in this cohort of CRC patients.[Table: see text]
Characterization of NTRK alterations in metastatic colorectal cancer.
Authors: Karan Canan , Tan Elaine , Sarfraz Humaira , Walko Christine Marie , Kim Richard D. , Knepper Todd C , Sahin Ibrahim Halil 
Published: June 2022

e15569 Background: Increased molecular profiling ability has resulted in the recognition of important actionable genes that can be used to direct targeted therapies in colorectal cancers (CRC). Neurotrophin receptor tyrosine kinase (NTRK) gene fusions are one of these molecular alterations that are potentially actionable with novel targeted therapeutics. However, other biologically pathogenic NTRK alterations, including point mutations, are not yet actionable in CRC. This study aimed to characterize NTRK alterations, including fusions in metastatic CRC patients. Methods: Molecular characteristics of 917 patients with CRC were collected from the Moffitt Cancer Center Clinical Genomics Action Committee database. Demographic, clinicopathological, and molecular data and treatment history were abstracted from electronic medical records. Mutations with potential oncogenic activity are considered “potentially pathogenic”, while alterations with proven oncogenic activity such as fusions are considered “pathogenic”. Results: There were 917 patients with CRC from November 2013 to December 2021, and 77 of them had NTRK alterations excluding synonymous mutations (8.3%, 77/917). Six patients had potentially pathogenic NTRK alterations, including one NTRK rearrangement (0.6%, 7/917); however, only 1 patient had an actionable pathogenic NTRK1 fusion (0.1%, 1/917), while the others (70) were a variant of unknown significance (VUS). The majority of NTRK alterations were missense mutations (92%; 71/77). The NTRK1 fusion partner was LMNA and occurred in the setting of an MSI-H tumor (3.7%; 1/27). Among patients with pathogenic and potentially pathogenic alterations (N = 7), there was only 1(14%) patient who had low tumor mutation burden (TMB) (< 10 mut/MB). Most patients were older than 50 years (70.1%, 54/77) and male (58.4%, 45/77). Thirty-six patients (46..7%) had right-sided tumor, while 41 patients (53.2%) left-sided. Across all NTRK alterations cohort, MSI-H was found in 10.3% (7/77), and POLE/POLD1 pathogenic mutations were seen in 6.4% (5/77) patients. Conclusions: NTRK gene fusion is a relatively rare event (< 1%) in CRC, including the MSI-H subtype. The majority of NTRK alterations in CRC are VUS, and they are not actionable, and they tend to be seen in the tumors with high TMB (TMB > 10). Hypermutator tumors cause frequent VUS alterations in the NTRK gene with unknown clinical relevance.