scholarly journals EVALUATING MMP-2 AND TGFß-RI EXPRESSION IN CIRCULATING TUMOR CELLS OF PANCREATIC CANCER PATIENTS AND THEIR CORRELATION WITH CLINICAL EVOLUTION

2019 ◽  
Vol 32 (2) ◽  
Author(s):  
José Luiz GASPARINI-JUNIOR ◽  
Marcello Ferretti FANELLI ◽  
Emne Ali ABDALLAH ◽  
Ludmilla Thomé Domingos CHINEN
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Peripheral Blood ◽  
Clinical Characteristics ◽  
Epithelial Mesenchymal Transition ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Clinical Findings ◽  
Mesenchymal Transition

ABSTRACT Background: Metastasis is common in the diagnosis of pancreatic cancer, and the presence of epithelial-mesenchymal transition markers in circulating tumor cells may suggest worse prognosis. Aim: To correlate the number of circulating tumor cells (CTCs) in the peripheral blood of patients with a locally advanced or metastatic pancreatic tumor and the protein expression involved in epithelial-mesenchymal transition (EMT) in CTCs with clinical characteristics, progression-free survival (PFS) and overall survival (OS). Method: This was a prospective study conducted using peripheral blood samples collected at three different times. CTCs were quantified by the ISET test and analyzed by immunocytochemistry. Proteins involved in EMT (vimentin, TGFß-RI and MMP2) were analyzed in all CTCs. Results: Twenty-one patients were included. Median CTCs detected were 22, 20 and 8 CTCs/8 ml blood at baseline, first and second follow-up, respectively. No statistically significant correlation was found in correlating the number of CTCs and the evaluated clinical characteristics, PFS, or OS. There was no difference in PFS and OS among the EMT markers in the groups with and without markers. Conclusion: CTC analysis was not relevant in this sample for comparing clinical findings, PFS and OS in patients with pancreatic cancer. However, marker analysis in CTCs could be useful for the MMP-2 and/or TGFß-RI expression, as observed by the separate PFS curve.

scholarly journals Circulating Tumor Cells Expressing Krüppel-Like Factor 8 and Vimentin as Predictors of Poor Prognosis in Pancreatic Cancer Patients

2021 ◽  
Vol 28 ◽  
pp. 107327482110271
Author(s):  
Peng Zhu ◽  
Hui-Ying Liu ◽  
Fu-Chen Liu ◽  
Fang-Ming Gu ◽  
Sheng-Xian Yuan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Peripheral Blood ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Prognostic Significance ◽  
Immunomagnetic Separation ◽  
Mesenchymal Transition

Background: Circulating tumor cells (CTCs) with an epithelial-mesenchymal transition phenotype in peripheral blood may be a useful marker of carcinomas with poor prognosis. The aim of this study was to determine the prognostic significance of CTCs expressing Krüppel-like factor 8 (KLF8) and vimentin in pancreatic cancer (PC). Methods: CTCs were isolated by immunomagnetic separation from the peripheral blood of 40 PC patients before undergoing surgical resection. Immunocytochemistry was performed to identify KLF8+ and vimentin+ CTCs. The associations between CTCs and time to recurrence (TTR), clinicopathologic factors, and survival were assessed. Univariate and multivariate analyzes were performed to identify risk factors. Results: Patients with CTCs ( n = 30) had a higher relapse rate compared to those without ( n = 10) (70.0% vs 20.0%; P < 0.01). The proportion of KLF8+/vimentin+ CTCs to total CTCs was inversely related to TTR ( r = −0.646; P < 0.01); TTR was reduced in patients with > 50% of CTCs identified as KLF8+/vimentin+ ( P < 0.01). Independent risk factors for recurrence were perineural invasion and > 50% KLF8+/vimentin+ CTCs (both P < 0.05). Conclusion: Poor prognosis can be predicted in PC patients when > 50% of CTCs are positive for KLF8 and vimentin.

Low cytokeratin- and low EpCAM-expressing circulating tumor cells in pancreatic cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11046-11046 ◽  
Author(s):  
Daniel Adams ◽  
Susan Tsai ◽  
Olga V. Makarova ◽  
Peixuan Zhu ◽  
Shuhong Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Nuclear Structure ◽  
Circulating Tumor Cells ◽  
Peripheral Blood ◽  
Epithelial Mesenchymal Transition ◽  
Size Exclusion ◽  
Mesenchymal Transition ◽  
Cytokeratin Expression ◽  
Capture Techniques

11046 Background: To date, detecting circulating tumor cells (CTCs) in the peripheral blood of pancreatic patients using standard immuno-capture techniques has met with limited success. As pancreatic cancer is prone to metastasize at distant sites, and therefore should have high numbers of CTCs, it is possible that immuno-capture methods are not suitable for this disease. Using a microfiltration approach, we show that CTCs are present in the peripheral blood in over 75% of pancreatic cancer patients, and that two distinct subtypes can be identified. Methods: Pancreatic patient samples were provided by Medical College of Wisconsin, Milwaukee, WI. CellSieve microfilters, with precision 7 micron diameter pores distributed in uniform arrays were employed. 7.5 mL of whole blood was diluted in pre-fixation solution and filtered through CellSieve microfilters. CTCs collected by this size exclusion technique were fixed, permeabilized, and stained with DAPI, an antibody cocktail against cytokeratin 8, 18 and 19 (FITC), EpCAM (PE), and CD45 (Cy5). CTCs, defined as cytokeratin positive and CD45 negative, were found in two distinct subtypes. One subtype had the “classic” characteristics of a CTC, with high EpCAM and cytokeratin expression, identifiable cytokeratin filamentation, and a cancer-like nuclear structure. The second subtype is indicative of a CTC undergoing epithelial-mesenchymal transition (EMT), with low or no EpCAM, weak cytokeratin expression, and a smooth oval nuclear structure. Results: The “classic” CTCs were found in ~20% (n=40) of patient samples. The EMT-like CTCs were found in ~75% of the same patient cohort. Neither cell was present in any healthy subjects (n=30). EMT-like CTCs consistently lacked EpCAM expression and commonly presented as multi-cell clusters, or microemboli, in ~40% of the cases. Conclusions: We show that two distinct CTC subtypes circulate in the blood of most pancreatic patients. The low expression of cytokeratin and EpCAM of the EMT-like subtype implies that immuno-capture based CTC isolation methods have limited utility for pancreatic cancer. Further, this subtype provides a useful strategy for tracking pancreatic CTCs over the course of treatment.

Phase Ib clinical study of CBP501, cisplatin, and nivolumab administered every three weeks in patients with advanced refractory tumors: Efficacy in dose-escalation and expansion cohorts.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3059-3059
Author(s):  
Marc Ryan Matrana ◽  
Frank Tsai ◽  
James M. Cleary ◽  
Suma Satti ◽  
Erkut Borazanci ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Dose Escalation ◽  
Epithelial Mesenchymal Transition ◽  
Single Agent ◽  
Locally Advanced ◽  
Mesenchymal Transition ◽  
Phase Ib ◽  
Expansion Cohort

3059 Background: CBP501 is a 12-amino acid G2 checkpoint abrogator and calmodulin-modulating peptide that increases platinum influx into tumor cells and induces tumor immunogenic cell death. CBP501 also suppresses platinum-induced release of cytokines by macrophages, lowers cancer stem cell populations, and reduces migration, invasion, and epithelial-mesenchymal transition of tumor cells. We report safety and efficacy outcomes from dose-escalation and expansion cohorts of a Phase Ib study of CBP501 combined with cisplatin and nivolumab (NCT03113188). Methods: An open-label Phase I trial was conducted using a 3+3 design: CBP501 and cisplatin were dosed simultaneously by 1h infusion Q3W at 4 different combined dose levels (CBP501: 16 or 25 mg/m2; cisplatin: 60 or 75 mg/m2) in the dose-escalation cohort. Nivolumab (240 mg) was dosed on the same day as a 1h infusion following CBP501/cisplatin. CBP501 and cisplatin were fixed at 25 and 60 mg/m2, respectively, in the expansion cohort. Eligible patients had pathologically confirmed, locally advanced or metastatic solid tumors, age ≥18 years, ECOG PS 0-1, life expectancy > 3 months. The dose-expansion cohort had pretreated metastatic exocrine pancreatic cancer or microsatellite stable colorectal cancer (CRC). Scans were performed every 6 weeks while on study, then every 3 months. Results: The most common related adverse events (AEs) were infusion-related reaction (rash, itching, hives; n = 32/37 [Gr 1, n = 4; Gr 2, n = 28]; 86%) and anemia (n = 19/37 [Gr 1/2, n = 10; Gr 3, n = 9]; 51%). There were no additional safety signals other than those known for each agent. At January 9, 2020 (interim analysis), efficacy was evaluable in 17/19 patients in the dose-escalation cohort. Unconfirmed partial response was seen in 18% (3/17; 1 pancreatic, 1 colorectal, 1 cholangiocarcinoma), with > 3 months stable disease (SD) in 41% (7/17), disease control in 41% (7/17), and > 8 months overall survival (OS) in 53% (9/17). In the expansion cohort, efficacy was evaluable in 8/13 patients with pancreatic cancer: > 4 months SD was 50% (4/8), median progression-free survival 4.2 months, and median OS 5.9 months (6/8 ≥3rd line). The CRC cohort median OS for all CRC patients (n = 10) including the dose-escalation cohort (n = 5) was 17.5 months (10/10 ≥3rd line). Conclusions: The triple-drug combination is reasonably tolerable with preliminary signs of efficacy in refractory solid tumors, including those in which cisplatin and nivolumab have limited single-agent activity. Clinical trial information: NCT03113188 .

Relationship between circulating tumor cells and ZEB1 expression in tumor cells in colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15509-e15509
Author(s):  
Inna A. Novikova ◽  
Oleg I. Kit ◽  
Elena Yu. Zlatnik ◽  
Elena P. Ulianova ◽  
Aleksandr B. Sagakyants ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Peripheral Blood ◽  
Epithelial Mesenchymal Transition ◽  
Detection System ◽  
Morphological Characteristics ◽  
Cellsearch System ◽  
Mesenchymal Transition ◽  
Zeb1 Expression

e15509 Background: Intravasation and circulation of tumor cells involves active invasion of cells with an enhanced migration potential as a result of the epithelial-mesenchymal transition (EMT). The ZEB1 protein is one of the key regulators of this process. Our purpose was to evaluate the association between the amount of circulating tumor cells (CTCs) in the peripheral blood of patients with different stages of colorectal cancer and the expression of ZEB1 by tumor cells. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. The numbers of CTCs were measured in the peripheral blood before surgery using the Veridex CellSearch system (Janssen). CTCs were registered taking into account morphological characteristics and expression of epithelial cell adhesion markers EpCAM, CD45, cytokeratins 8,18,19. The blood sample was evaluated according to the following criteria: 0 CTCs, 1-3 CTCs, and more than 3 CTCs. Tissues of surgically removed tumors were studied with IHC analysis using rabbit polyclonal anti-ZEB1 antibodies (Biorbyt Ltd.) diluted 1:200 and the Reveal Polyvalent HRP-DAB Detection System. The percentage and the intensity of staining were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. ZEB1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: From 1 to 402 CTCs were determined in 62.9% cases (in 188 of 299 patients); CTCs were not registered in 37.1% cases (111 of 299). Positive ZEB1 expression was observed in 80.6% (241 of 299 patients), while the negative one was much more rare – 19.4% (58 of 299 patients). The rates of CTC detection significantly increased with the positive ZEB1+ expression, compared to the negative expression (75.1% vs. 12.1%). CTCs >3 were detected in the blood in 39.0% in ZEB1+ tumors, but not in ZEB1- tumors. 1-3 CTCs were observed 3 times more often in ZEB1+ tumors (36.1% vs. 12.1; p≤0.05). Conclusions: Statistically significant association was revealed between the epithelial-mesenchymal transition marker ZEB1 expression by tumor cells and the amount of CTCs in the peripheral blood (p < 0.001).

scholarly journals Prognostic and Therapeutic Significance of Circulating Tumor Cell Phenotype Detection Based on Epithelial-Mesenchymal Transition Markers in Early and Midstage Colorectal Cancer First-Line Chemotherapy

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Guang Lu ◽  
Zhiwen Lu ◽  
Caixia Li ◽  
Xianping Huang ◽  
Qiang Luo
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Progression Free Survival ◽  
Cell Phenotype ◽  
Survival Prognosis ◽  
Free Survival ◽  
Mesenchymal Transition

Purpose. Epithelial-mesenchymal transition (EMT) is related to the process of metastasis and challenges the detection of circulating tumor cells (CTCs) based on epithelial cell adhesion molecules. Circulating tumor cells (CTCs) have been proven to be a prognostic indicator of colorectal cancer (CRC). Although there is evidence that CTC heterogeneity based on EMT markers is associated with disease progression, no standard recommendations have been established for clinical practice. This study is aimed at evaluating the prognostic significance of dynamic CTC detection based on EMT for early and midstage colorectal cancer patients. Methods. 101 patients with early to midterm CRC were admitted from January 2016 to September 2018. All patients underwent CRC radical surgery and standard chemotherapy. Patients in the postchemotherapy were able to epithelial mesenchymal transformed (EMT) CTC testing in peripheral blood using the CanPatrol™ system. Multiple CTC tests were performed according to patient’s own condition and different follow-up time points. Based on patient’s basic information and follow-up data, the Kaplan-Meier method was utilized to establish the progression-free survival model, and the log-rank test was utilized to compare the survival rates between the two groups. Result. Total CTC change of the patient is the best method to predict whether progression-free survival progresses in tumor patients ( Area = 0.857 ). The second detection of total number of CTCs ( P < 0.01 ) detected after chemotherapy, epithelial CTCs ( P = 0.032 ), the increased total number of CTCs ( P < 0.01 ), and the increased number of mesenchymal CTCs ( P = 0.015 ) are significantly related with patient’s poor progression-free survival. Conclusion. Analysis of the second CTC count and classification after follow-up are more related to the survival prognosis of the tumor. The joint analysis of CTC dynamic monitoring data is a good tool to judge patient’s survival prognosis.

scholarly journals Development and Validation for Prognostic Nomogram of Epithelial Ovarian Cancer Recurrence based on Circulating Tumor Cells and Epithelial–Mesenchymal Transition

2020 ◽  
Author(s):  
Jiani Yang ◽  
Jun Ma ◽  
Yue Jin ◽  
Shanshan Cheng ◽  
Shan Huang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Risk Stratification ◽  
Epithelial Ovarian Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Ca 125 ◽  
Mesenchymal Transition ◽  
Cox Regression Analysis ◽  
Significant Difference

Abstract We aimed to determine prognosis value of circulating tumor cells(CTCs) undergoing epithelial–mesenchymal transition(EMT) in epithelial ovarian cancer(EOC) recurrence. We used CanPatrol CTC-enrichment technique to detect CTCs from blood samples and classify subpopulations into epithelial, mesenchymal and hybrids. To construct nomogram, prognostic factors were selected by Cox regression analysis. Risk stratification was performed through Kaplan–Meier analysis among training group(n=114) and validation group(n=38). By regression screening, both CTC counts(HR 1.187; 95%CI 1.098-1.752; p=0.012) and M-CTC(HR 1.098; 95%CI 1.047-1.320; p=0.009) were demonstrated as independent factors for recurrence. Other variables including pathological grade, FIGO stage, lymph node metastasis, ascites and CA-125 were also collected(p < 0.005) to construct nomogram. The C-index of internal and external validation for nomogram was 0.913 and 0.874. We found significant predictive value for nomogram with/without CTCs (AUC 0.8705 and 0.8097). Taking CTC counts and M-CTC into separation, the values were 0.8075 and 0.8262. Finally, survival curves of risk stratification based on CTC counts(p=0.0241), M-CTC(p=0.0107) and the nomogram(p=0.0021) were drawn with significant difference. In conclusion, CTCs could serve as a novel factor for EOC prognosis. Nomogram model constructed by CTCs and other clinical parameters could predict EOC recurrence and perform risk stratification for clinical decision-making.Trial registration: Chinese Clinical Trial Registry, ChiCTR-DDD-16009601, October 25, 2016

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