Distant Organ Metastasis Research Articles

Abstract 3760: MicroRNA-1 run down the growth and metastasis of small cell lung cancer

Abstract Small cell lung cancer (SCLC) is a highly aggressive and metastatic lung cancer subtype with universal relapse and poor prognosis. The lack of potential drug targets limits targeted therapies for SCLC patients. To track down the potential therapeutic molecules in SCLC, we performed micro-RNA sequencing from the serum samples of SCLC patients and compared with the bulk RNA-sequencing data from SCLC tumor tissues. A consistent downregulation of microRNA-1 (miR-1) was observed in the SCLC patient serum samples, cell lines, and tumor tissues compared to their matched normal control. Overexpression of miR-1 in SCLC cell lines decreased cell growth and oncogenic signaling. Metastatic studies using the intracardiac injection model of SCLC cell lines showed that miR-1 overexpression decreases distant organ metastasis. Interestingly, the loss of function studies using miR-1Zip/sponging showed increased tumorigenesis and metastasis in SCLC subcutaneous and intracardiac xenografts. Mechanistic investigations revealed the CXCR4/FOXM1/RRM2 axis as a unique downstream target of miR-1 in SCLC. We found that FOXM1 transcriptionally regulates the RRM2 expression by directly binding to its promoter site, and miR-1 modulates these interactions through CXCR4. The results of the present study provided a strong preclinical rationale that miR-1 has a high potential for developing innovative SCLC therapies. Citation Format: Parvez Khan, Jawed A. Siddiqui, Shailendra Kumar Maurya, Tamara Mirzapoiazova, Prakash G. Kshirsagar, Ramakanth Chirravuri Venkata, Sanjib Chaudhary, Ranjana Kanchan, Naveenkumar Perumal, Mahek Fatima, Md Arafat Khan, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser. MicroRNA-1 run down the growth and metastasis of small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3760.

Self-assembled multifunctional nanotheranostics against circulating tumor clusters in metastatic breast cancer.

Circulating tumor clusters (CTC) disseminating from the primary tumor are responsible for secondary tumor formation where the conventional treatments such as chemotherapy and radiotherapy does not prevent the metastasis at locally advanced stage of breast cancer. In this study, a smart nanotheranostic system has been developed to track and eliminate the CTCs before it can colonize at a new site, which would reduce metastatic progression and increase the five-year survival rate of the breast cancer patients. Targeted multiresponsive (magnetic hyperthermia and pH) nanomicelles incorporated with NIR fluorescent superparamagnetic iron oxide nanoparticles were developed based on self-assembly for dual modal imaging and dual toxicity for spontaneous killing of CTCs in blood stream. A heterogenous tumor clusters model was developed to mimic the CTCs isolated from breast cancer patients. The nanotheranostic system was further evaluated for the targeting property, drug release kinetics, hyperthermia and cytotoxicity against developed CTC model invitro. Invivo model in BALB/c mice equivalent to stage III and IV human metastatic breast cancer was developed to evaluate the biodistribution and therapeutic efficacy of micellar nanotheranostic system. Reduced CTCs in blood stream and low distant organ metastasis after treatment with the nanotheranostic system demonstrates its potential to capture and kill the CTCs that minimize the secondary tumor formation at distant sites.

Clinical outcomes and risk factors associated with poor prognosis after endoscopic resection of 10-20mm rectal neuroendocrine tumors: a multicenter, retrospective study of 10-year experience.

The efficacy of endoscopic resection for of 10-20mm rectal neuroendocrine tumor (NET) remains controversial. We aimed to evaluate the clinical outcomes and risk factors associated with poor prognosis after endoscopic resection of 10-20mm rectal NET and to determine the optimal treatment. Patients who underwent endoscopic resection for rectal NET in four tertiary hospitals were enrolled, and data on with the clinical outcomes and risk factors related to poor prognosis were retrospectively analyzed. A total of 105 patients who underwent endoscopic submucosal resection (ESD; n = 65, 61.9%), modified endoscopic mucosal resection (mEMR; n = 31, 29.5%), and conventional EMR (cEMR; n = 9, 8.6%) were enrolled. The mean follow-up period was 41.2 ± 21.9months. In the morphologic findings, the mean diameter was 11.6mm (range 10-19); the shape was sessile (50.5%) and mixed type (49.5%), and surface depression was observed in 41.9% of patients. In the histologic findings, 87.6% of patients had G1 and 12.4% G2 tumor grade, and 3.8% of patients had lymphovascular invasion. The overall en bloc and histologically complete (R0) resections were 99.1% and 76.2%, respectively. cEMR was a less-frequently developed R0 resection. In the univariate and multivariate analyses for R0 resection, only surface depression was significantly associated. Regional or distant organs metastasis during follow-up developed in three patients (2.9%) and was significantly associated with female sex, redness, G2 tumor grade, and non-ESD methods. Patients who underwent endoscopic resection of 10-20mm rectal NET had good prognosis; therefore, endoscopic resection can be considered as the first-line treatment, particularly for 10-14mm rectal NET. However, the risk factors, such as female sex, redness, G2 tumor grade and non-ESD methods, were associated with regional or distant metastases during follow-up. Therefore, patients with these risk factors should be carefully monitored.

Can neutrophil-lymphocyte ratio and mean platelet volume be used to predict metastasis in individuals with lung cancer?

Chronic inflammation plays an important role in the etiopathogenesis of many life-threatening chronic diseases, including cancer. Currently, the relationship between inflammation, native immunity and cancer is widely accepted; however, many of the mechanisms mediating this relationship remain undetermined and the clinical significance of these markers is unclear. The purpose of this study was to investigate the potential of neutrophil-lymphocyte ratio (NLR) and mean platelet volume (MPV) to indicate the existence of metastasis in lung cancer. This retrospective cross-sectional study evaluated patients with lung cancer of any pathological type who was admitted to the Palliative Care Unit of the referral hospital in the region between January 2019 and February 2020. Patient characteristics, distant organ metastasis, treatments, NLR and MPV values were noted. Patients were grouped as with or without metastasis. Characters, NLR, MPV values were compared. One hundred twenty-six patients were included. The mean age of the patients was 61.17 ± 9.4 years and 7.9% (n = 10) were female. The patients with a history of chemotherapy were 47% (n = 60) and distant organ metastases were present in 38.9% (n = 49) of the patients. The mean MPV value of 49 patients with distant metastasis was 8.34 ± 0.8 fL. MPV values of those with metastasis were found to be significantly higher than those without (P = .010). There was no significant difference in NLR values between groups (P = .920). Lung cancer patients with metastasis were found with higher MPV values. MPV can be effective and most accessible test in prediction of metastasis in lung cancer patients regardless of the pathological type.

Incidence, prognostic factors and a nomogram of cervical cancer with distant organ metastasis: a SEER-based study

This study was to investigate the incidence, survival and prognostic factors of cervical cancer with distant organ metastasis, and to develop a nomogram to predict the prognosis of cervical cancer. We used the Surveillance, Epidemiology and End Results (SEER) database to screen patients diagnosed with cervical cancer from 2010 to 2014. The chi-squared test was used to analyse the differences in clinical characteristics, and we used Kaplan–Meier methods to perform survival analysis. Univariate and multivariate Cox proportional hazard regression models were used to estimate prognostic factors, and we developed a visual nomogram to judge the prognosis. We found that lung metastasis was the most common in cervical cancer patients with distant organ metastasis. Age, race, characteristics of the tumour, and therapy should be considered when analysing the prognosis of cervical cancer patients. The findings of this study may help clinicians to formulate individualised treatment strategies. Impact Statement What is already known on this subject? Distant organ metastasis of cervical cancer mainly involves lung, bone, liver and brain. Once it occurs, the survival and prognosis will be threatened seriously. What the results of this study add? 4176 patients were included, and lung metastasis was the most common in cervical cancer with distant organ metastasis (3.5%). Additionally, age, race, tumour grade, histological type, T-stage, N-stage, lung, liver and bone metastasis and the treatment mode are significantly related to the outcomes of cervical cancer patients. Furthermore, we developed a nomogram that could predict the probability of three-year and five-year OS. What the implications are of these findings for clinical practice and/or further research? The findings of this study may drive more and more studies focussing on the comprehensive prognostic assessment, diagnosis, and treatment of distant metastasis of cervical cancer. Besides, clinicians can utilise these findings to formulate individualised treatment strategies.

Expression of Lymphoma-2 Gene and NF-κB in Human Adenoid Cystic Carcinoma Tissue and Its Relation with Disease Prognosis

Background: Adenoid cystic carcinoma (ACC) is a common tumor of the head and neck. It is characterized by slow growth, strong invasiveness, easy recurrence and distant organ metastasis. Bcl-2 and NF-κB are indicated to relate to tumor growth, proliferation and apoptosis. This study aims to analyze the relationship between Bcl-2, NF-κB and ACC. Methods: With ELISA method to detect Bcl-2 and NF-κB expression in the blood of patients with ACC, patients with benign adenoma and healthy controls, and the expression of Bcl-2 and NF-κB in tissues was detected by immunohistochemistry, and their relationship with ACC was analyzed. relevance. Relationships between clinicopathological features. Results: The levels of Bcl-2 (4.16±1.34 ng/ml) and NF-κB (4.47 ± 1.37 ng/ml) as well as positive rates of Bcl-2 and NF-κB (87.5% and 85%) were significantly elevated in the ACC group (P <0.05). Bcl-2 was positively correlated with NF-κB (P <0.05). Of note, Bcl-2 and NF-κB expressions were correlated with the incidence frequency, histological type, clinical stage, lymph node metastasis and distant metastasis of ACC patients (P < 0.05) as the distant metastasis is an independent risk factor. Conclusion: In summary, Bcl-2 and NF-κB expression in ACC patients is associated with the clinicopathological features of ACC.

Association between small nucleolar RNA host gene expression and survival outcome of colorectal cancer patients: A meta-analysis based on PRISMA and bioinformatics analysis.

Growing evidence shows that long non-coding RNA small nucleolar RNA host genes (lncRNA SNHGs) enact an pivotal regulatory roles in the shorter survival outcome of colorectal cancer (CRC). However, no research has systematically evaluated the correlation among lncRNA SNHGs expression and survival outcome of CRC. This research indented to screen whether exist potential prognostic effect of lncRNA SNHGs in CRC patientss using comprehensive review and meta-analysis. Systematic searches were performed from the six relevant databases from inception to October 20, 2022. The quality of published papers was evaluated in details. We pooled the hazard ratios (HR) with 95% confidence interval (CI) through direct or indirect collection of effect sizes, and odds ratios (OR) with 95% CI by collecting effect sizes within articles. Detailed downstream signaling pathways of lncRNA SNHGs were summarized in detail. 25 eligible publications including 2,342 patients were finally included to appraise the association of lncRNA SNHGs with prognosis of CRC. Elevated lncRNA SNHGs expression was revealed in colorectal tumor tissues. High lncSNHG expression means bad survival prognosis in CRC patients (HR=1.635, 95% CI: 1.405-1.864, P<0.001). Additionally, high lncRNA SNHGs expression was inclined to later TNM stage (OR=1.635, 95% CI: 1.405-1.864, P<0.001), distant lymph node invasion, distant organ metastasis, larger tumor diameter and poor pathological grade. Begg's funnel plot test using the Stata 12.0 software suggested that no significant heterogeneity was found. Elevated lncRNA SNHGs expression was revealed to be positively correlated to discontented CRC clinical outcome and lncRNA SNHG may act as a potential clinical prognostic index for CRC patients.

Prognostic CT features in patients with untreated thymic epithelial tumors

To determine the prognostic CT features in patients with untreated thymic epithelial tumors (TETs). Clinical data and CT imaging features of 194 patients with pathologically confirmed TETs were retrospectively reviewed. The subjects included 113 male and 81 female patients between 15 and 78 years of age, with a mean age of 53.8 years. Clinical outcomes were categorized according to whether relapse, metastasis or death occurred within 3 years after the first diagnosis. Associations between clinical outcomes and CT imaging features were determined using univariate and multivariate logistic regression analyses, while the survival status was analyzed by Cox regression. In this study, we analyzed 110 thymic carcinomas, 52 high-risk thymomas and 32 low-risk thymomas. Percentages of poor outcome and patient death in thymic carcinomas were much higher than those in patients with high-risk and low-risk thymomas. In the thymic carcinomas groups, 46 patients (41.8%) experienced tumor progression, local relapse or metastasis and were categorized as having poor outcomes; vessel invasion and pericardial mass were confirmed to be independent predictors by logistic regression analysis (p < 0.01). In the high-risk thymoma group, 11 patients (21.2%) were categorized as having poor outcomes, and the CT feature pericardial mass was confirmed to be an independent predictor (p < 0.01). In survival analysis, Cox regression showed that CT features of lung invasion, great vessel invasion, lung metastasis and distant organ metastasis were independent predictors for worse survival in the thymic carcinoma group (p < 0.01), while lung invasion and pericardial mass were independent predictors for worse survival in high-risk thymoma group. No CT features were related to poor outcome and worse survival in the low-risk thymoma group. Patients with thymic carcinoma had poorer prognosis and worse survival than those with high-risk or low-risk thymoma. CT can serve as an important tool for predicting the prognosis and survival of patients with TETs. In this cohort, CT features of vessel invasion and pericardial mass were related to poorer outcomes in those with thymic carcinoma and pericardial mass in those with high-risk thymoma. Features including lung invasion, great vessel invasion, lung metastasis and distant organ metastasis indicate worse survival in thymic carcinoma, whereas lung invasion and pericardial mass indicate worse survival in high-risk thymoma.

The roles of 68 Ga-PSMA PET/CT and 18 F-FDG PET/CT imaging in patients with triple-negative breast cancer and the association of tissue PSMA and claudin 1, 4, and 7 levels with PET findings.

Aim of study is to compare the results of Gallium-68-prostate-specific membrane antigen ( 68 Ga-PSMA) and 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography(PET)/computed tomography (CT), to evaluate the correlation between PET findings and the level of PSMA, Claudin (Clau) 1, 4, and 7 receptors obtained by immunohistochemical (IHC) analysis, and to determine potential predictive and prognostic values in TNBC. Forty-seven lesions of 42 subjects diagnosed TNBC both underwent PET/CT scan for preoperative staging/restaging were prospectively included study. PSMA, Clau 1, 4, and 7 expressions were IHC evaluated from the biopsy samples of the primary tumor (PT). Maximum standardized uptake value(SUV max) of the PT, lymph node, and distant organ metastases (DOMs) on 18 F-FDG and 68 Ga-PSMA PET/CT were compared with PSMA, Clau 1, 4, and 7 receptor expressions. IHC analyses on 29 BC lesions to demonstrate Clau expression showed 86% (25/29) Clau 1, 86% (25/29) Clau 4, 45% (13/29) Clau 7, and 48% (14/29) PSMA-positive. The mean DOM (SUVmax) was 15.5 ± 11.6 for 18 F-FDG and 6.0 ± 2.9 for 68 Ga-PSMA. Axial diameter of BC PT had a significant positive correlation with 18 F-FDG SUVmax, 68 Ga-PSMA SUVmax, and PSMA scores. BC lesions 68 Ga-PSMA SUVmax had a significant negative correlation with the Ki-67 index. Axial diameter of the primary tumor had significant negative correlation with Clau 7 scores ( r = -0.409, P = 0.034). Absence of Clau 1 expression found to significantly increase the rate of DOM (100% vs. 28%) ( P = 0.014). All patients with axillary lymph node (ALN) metastases ( n = 17, 100%) exhibited Clau 4 positivity ( P = 0.021). The presence of PSMA expression observed to significantly increase the rate of ALN metastases (64.7% vs. 25%) ( P = 0.035). Confirming PSMA expression with PET imaging would be significant as PSMA, a theranostic agent, may be a considerable potential agent for radionuclide treatment strategies, in addition to its additional diagnostic contribution to FDG, especially in patients with metastatic TNBC, which is an aggressive, heterogeneous disease.

Metabolic parameters of [18F]FDG PET-CT before and after radiotherapy may predict survival and recurrence in cervical cancer

Background Cervical cancer is the fourth most common female malignancy. [18F]-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT) is routinely performed in patients with locally advanced cervical cancer for staging and treatment response evaluation. With this retrospective, observational cohort study, we wanted to investigate the prognostic value of the maximum standardised uptake value (SUVmax) and the volumetric parameters of metabolic tumour volume (MTV) and total lesion glycolysis (TLG) before and after treatment in women with cervical cancer, with overall survival (OS) and recurrence as outcome measures. Methods Women with cervical cancer referred for curative radiotherapy and who underwent two PET-CT scans (before treatment and approximately 7 months post-treatment) were included. SUVmax, MTV and TLG were measured at baseline and post-treatment on the primary tumour, pelvic and distant lymph node metastases, distant organ metastases, and on total tumour burden. The PET parameters were associated with OS by Cox regression and recurrence by multivariable logistic regression. Kaplan-Meier curves and C-index were used to visualise the prognostic potential of the different measures. Results A total of 133 patients were included. At the primary tumour level and on total tumour burden, age- and clinical-stage adjusted analyses showed a significant association between PET parameters and OS and recurrence when measured post-treatment. At baseline (pre-treatment), MTV and TLG were associated with OS and recurrence, whereas SUVmax was not. C-index from adjusted Cox models on total tumour burden showed higher values for the post-treatment PET compared to baseline. Kaplan-Meier curves demonstrated a greater prognostic potential for MTV and TLG compared to SUVmax, both at baseline and post-treatment. Conclusions The FDG PET-CT-derived parameters SUVmax, MTV, and TLG measured post-treatment can predict OS and recurrence in cervical cancer. Parameters measured before treatment had overall lower prognostic potential, and only MTV and TLG showed significant association to OS and recurrence.

Identification of immunocell infiltrates and effective diagnostic biomarkers in laryngeal carcinoma.

Laryngeal cancer (LC) is a malignant tumor that occurs in the head and neck. Laryngeal cancer is one of the most common cancers of the neck and head, and its prognosis has always been poor. The incidence of LC increased gradually and showed an early rising trend. Laryngeal cancer is rarely studied in relation to immunity, Malignant tumors will change the state of the human body in various ways to adapt to their own survival and avoid the immune system. This study aims to explore the immune molecular mechanism of laryngeal cancer through bioinformatics analysis. The gene expression data was downloaded for 3 microarray datasets: GSE27020, GSE59102, and GSE51985. CIBERSORT algorithm was performed to evaluate immune cell infiltration in tissues between LC and healthy control (HC). Differentially expressed genes (DEGs) were screened. Functional correlation of DEGs were analyzed by Gene Ontology, Gene Set Enrichment Analysis and Kyoto encyclopedia of genes and genomes. Candidate biomarkers were identified by cytoHubba of Cytoscape. Spearman correlations between the above biomarkers and infiltrating immune cells were explored using R software analysis. The immune cell types of LC and HC were significantly different. Twenty-one DEGs were obtained by cross-screening. The function of DEGs is closely related to the number of immune cells. Five central genes (TNNT3, TNNI2, Desmin, matrix metallopeptidase 9 and cytotoxic T lymphocyte antigen 4) were screened. The HUB gene was demonstrated to have the ability to diagnose LC and HC with good specificity and sensitivity. The correlation between immune cells and biomarkers showed that hub gene was positively correlated with macrophages and dendritic cells, and negatively correlated with CD4 + T cell. TNNT3, TNNI2, Desmin, matrix metallopeptidase 9 and cytotoxic T lymphocyte antigen 4 can be used as diagnostic biomarker for LC. Macrophages, dendritic cells and CD4 + T cell may participate in the occurrence and development of LC.

Stromal POSTN Enhances Motility of Both Cancer and Stromal Cells and Predicts Poor Survival in Colorectal Cancer.

Evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) has rapidly been accumulating. To uncover clinicopathological importance of periostin (POSTN) expression in colorectal cancer (CRC), the present study immunohistochemically examined its expression status. Furthermore, to reveal its mechanisms involved, molecular experiments were performed. In CRC tissues, 44% of the cases (119/269) exhibited POSTN expression in the CAFs. In contrast, CRC cells expressed POSTN at almost undetectable levels. Survival analyses identified that patients with POSTN-positive CRC had a significantly worse 5-year survival rate (63.2% vs. 81.2%; p = 0.011). Univariate analyses revealed that POSTN positivity was associated with peritoneal (p = 0.0031) and distant organ metastasis (p < 0.001). Furthermore, immunohistochemical analyses identified a significant association between POSTN and p53 complete loss status in CRC cells. Decorin and fibroblast activation protein expression in CAFs was also associated with POSTN. POSTN significantly enhanced the migration of both CRC cells and fibroblasts with FAK and AKT or STAT3 activation, and co-culture assays demonstrated the communication between CRC cells and fibroblasts, which enhanced STAT3 activation in fibroblasts. On the basis of our results, we speculated that stromal POSTN accelerated metastasis via stromal remodeling capacity and activated the migration of both tumor and stromal cells.

Abstract PR013: Lymph node colonization promotes distant tumor metastasis through the induction of tumor-specific immune tolerance

Abstract The majority of cancer-associated deaths result from distant organ metastasis, yet the mechanisms that enable this process remain poorly understood. For most solid tumors, colonization of regional or distant lymph nodes (LNs) typically precedes the formation of distant organ metastases, yet it remains unclear whether LN metastasis plays a functional role in disease progression. LNs are major sites of anti-tumor lymphocyte education, including in the context of immunotherapy, yet LN metastasis frequently correlates with further disease progression. Here, we find that LN metastasis represents a critical step in tumor progression through the capacity of such metastases to induce tumor-specific immune tolerance in a manner that promotes further dissemination of tumors to distant organs. Using an in vivo passaging approach of a non-metastatic syngeneic melanoma, we generated 300 unique cell lines exhibiting varying degrees of LN metastatic capacity. We show that the presence of these LN metastases enables distant organ seeding of metastases in a manner that the parental tumor cannot, and this effect is eliminated in mice lacking an adaptive immune response. Furthermore, this promotion of distant seeding by LN metastases is tumor specific. Using flow cytometry and single-cell sequencing to perform comprehensive immune profiling, we identify multiple cellular mediators of tolerance. In particular, we find that LN metastases have the capacity to both resist NK cell cytotoxicity and induce regulatory T cells (Tregs). Furthermore, depletion of NK cells in vivo enables non-metastatic tumors to disseminate to LNs, and ablation of Tregs using FoxP3-DTR mice eliminates the occurrence of lymphatic metastases. Adoptive transfer of Tregs from the LNs of mice bearing LN metastasis to naïve mice facilitates metastasis in a manner that Tregs from mice without LN metastases cannot, and we find that these Tregs are induced in an antigen-specific manner. Whole exome sequencing revealed that neither the metastatic proclivity nor immunosuppression evolve through the acquisition of driver mutations, loss of neoantigens, loss of MHC class I presentation, or decreases in melanoma antigen expression. Rather, by RNA-seq and ATAC-seq, we show that a conserved interferon signaling axis is upregulated in LN metastases and is rendered stable through epigenetic reprogramming of chromatin accessibility resulting from chronic exposure to interferons in vivo. Furthermore, using CRISPR/Cas9, we find that these pathways are required for LN metastatic seeding, and validate their conserved significance in additional mouse models of pancreatic ductal adenocarcinoma and head and neck squamous cell carcinoma and humans with LN metastatic disease. Together, these findings demonstrate a critical role for LN metastasis in promoting tumor-specific immunosuppression. Citation Format: Nathan E. Reticker-Flynn, Weiruo Zhang, Julia A. Belk, Pamela A. Basto, Andrew J. Gentles, John B. Sunwoo, Ansuman K. Satpathy, Sylvia K. Plevritis, Edgar G. Engleman. Lymph node colonization promotes distant tumor metastasis through the induction of tumor-specific immune tolerance [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR013.

MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis

BackgroundSmall cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood.MethodsTo identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions.ResultsA consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC.ConclusionsOur findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies.Graphical MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.

Cell-free SLC30A10 messenger ribonucleic acid (mRNA) expression and their association with vitamin-D level among non-small cell lung cancer (NSCLC) patients.

Lung cancer has been major cause of cancer related death and day by day Non-small cell lung cancer (NSCLC) cases are increasing globally. Present study explored the link between SLC30A10 mRNA expression with vitamin-D level among the NSCLC patients. Present study included newly diagnosed 100 NSCLC patients and 100 healthy controls. Quantitative real time PCR was performed to check the SLC30A10 mRNA expression after cDNA synthesis from extracted total RNA from serum sample. Vitamin-D level was also analyzed in all the NSCLC patients by electrochemiluminscence based immunoassay method. Present research work observed decreased SLC30A10 mRNA expression (0.16 fold) among the NSCLC patients, decreased SLC30A10 mRNA expression was linked with advanced stage (0.15 fold, P < 00001) of disease and distant organ metastases (0.11 fold, P < 00001) compared to its contrast. Decreased level of vitamin-D was also observed with advanced stage (17.98 ng/ml, P < 00001) of disease and distant organ metastases (16.23 ng/ml, P < 00001) compared to its contrast. Positive correlation was observed between SLC30A10 mRNA expression with vitamin-D level among the NSCLC patients suggesting decrease or increase in SLC30A10 mRNA expression mau decreases or increase the vitamin-D level. NSCLC patients with vitamin-D deficiency had 0.14 reduced SCL30A10 mRNA expression while insufficient (P = 0 .06) and sufficient (P = 0.03) showed comparatively high SCL30A10 mRNA expression. Study concluded that down regulation of SLC30A10 mRNA and vitamin-D deficiency may involve in advancement of disease and distant organ metastases. It was also suggested that the decrease of increase in SLC30A10 expression may cause the decrease of increase in vitamin-D level among the NSCLC patients may be involved in disease severity and worseness of NSCLC disease.

Comparison of metastatic versus non-metastatic breast cancer at the time of diagnosis and risk factors for primary metastatic breast cancer

Objective: The most common type of cancer in women is breast cancer. Despite an increase in the rate of early detection, distant organ metastasis is still seen at the time of diagnosis. The purpose of this study was to identify the predictive risk factors for breast cancer patients with distant organ metastases and to compare them to those without distant organ metastases. Materials and Methods: The study included data from patients who applied to our clinic for follow-up or treatment between January 2020 and July 2020. After meeting the exclusion criteria, the remaining 115 patients were included in the study. Study participants were divided into two groups: metastatic (group I) and non-metastatic (group II). Logistic regression analysis is used to assess the predictive risk factors. Results: There is a significant difference between groups in terms of the breast side, T-stage, N-stage, CA 15-3, and albumin levels (p&lt; 0.05). In univariate analyses, T-stage, CA 15-3, estimates glomerular filtration rate (eGFR), alkaline phosphatase, and albumin levels were statistically found to be significant (p&lt;0.05). In multivariate analysis, CA 15-3 (OR: 1.017; 95% CI: 1.005-1.030, p = 0.006), eGFR (OR: 0.944; 95% CI: 0.894-0.996, p = 0.034), and albumin (OR: 0.087; 95% CI: 0.011-0.676, p = 0.020) were found to be predictive risk factors for metastatic breast cancer. Conclusion: High T-stage, N positivity, high CA15-3 levels, and low albumin levels were observed in the metastatic breast cancer group. CA 15-3, eGFR, and albumin levels were found to be predictive factors for metastatic breast cancer at the initial diagnosis. New studies are needed to validate these findings.

Quantification of Invadopodia Formation and Matrix Degradation Activity.

Cancer cells possess a remarkable capacity to dissociate from a primary tumor, invade the surrounding tissues and vasculature, and eventually form metastases in distant organs. This complex and multistep process remains one of the major causes of mortality in cancer patients worldwide. Multiple studies have highlighted the role of actin-rich structures called invadopodia ("invasive feet"), which adhere to the matrix, contain and secrete matrix-degrading proteinases, and apply protrusive forces generated by the actin cytoskeleton, which drive the invasive process. Here, we describe a fluorescent microscopy-based protocol for imaging and quantifying both invadopodia formation and matrix degradation.

Relationship between Clinicopathological Profile and Tumor Budding Status in Colorectal Adenocarcinoma at Dr. Cipto Mangunkusumo General National Hospital: A Retrospective Study

Background: Colorectal adenocarcinoma (CA) is one of the most common malignancies. Tumor budding (TB) status is associated with poor prognosis in patients. Prognosis is influenced by the clinicopathological profile. This study aims to determine the relationship between the clinicopathological profile with TB status in CA at Dr. Cipto Mangunkusumo General National Hospital.Method: A cross-sectional retrospective analytic study using secondary data in the form of cases in large bowel malignancy resection preparations at the Department of Anatomical Pathology in 2019-2021. A total of 213 samples were taken from all cases according to the inclusion and exclusion criteria. Chi square statistical analysis was performed to see the clinicopathological relationship with TB status.Results: Most common TB status were low grade with 92 cases. Most cases were ≥ 50 years old (64.3%), male (50.7%), located in the left colon (77.5%), histopathological degree low grade (85.9%), depth of invasion on pT3 (61.5%), lymphovascular invasion (LVI) (50.2%), lymph node metastasis (52.6%), stage 3 American Joint Committee on Cancer (AJCC (42.3%), without perineural invasion (PNI) (79.3%) and without distant metastases (82.6%). Statistical analysis test showed that there was a significant relationship between the degree of histopathology, depth of invasion, LVI, lymph node metastasis, and AJCC stage (p 0.001) and tumor location (p = 0.036).Conclusion: TB status was significantly related histopathological degree, LVI, lymph node metastasis, depth of invasion, AJCC stage, and tumor location. TB status was not associated with PNI and distant organ metastases.

Impact of the COVID-19 Pandemic on Diagnosis of Lung Cancer.

Non-COVID hospital admissions decreased during the COVID-19 pandemic and follow-up of people in the lung cancer risk group was delayed. There are not enough studies on the effects of the pandemic period on the diagnosis of lung cancer. In this study, it was aimed to determine the characteristics of patients diagnosed with lung cancer in the pre-pandemic and pandemic period and to investigate the effects of the pandemic on the diagnosis of lung cancer. Patients with newly diagnosed lung cancer 16months before and after the detection of the first COVID-19 case were retrospectively analyzed for their characteristics at the time of diagnosis. Age, gender, pathological diagnosis, distant organ metastasis status, and also pathological stages at the time of diagnosis of the patients were analyzed. Two hundred forty-six patients were included in the study. One hundred forty-five of the patients were diagnosed in the pre-pandemic period and 101 during the pandemic period. Mean age of patients was 64.24years and 91.87% were male. Pathological diagnosis distributions were similar in the pre-pandemic group and the pandemic period group. Distant organ metastases were present in 59.31% of the pre-pandemic group and 65.35% of the pandemic group. There was no significant difference in terms of the stages of the patients at the time of diagnosis. Number of patients diagnosed with lung cancer during the pandemic period was lower. The characteristics of the patients were similar. These results may have resulted from the decrease in applications to health institutions due to social isolation and fear of COVID-19 infection, and limitations in accessing health services.

Dual NGS Comparative Analysis of Liquid Biopsy (LB) and Formalin-Fixed Paraffin-Embedded (FFPE) Samples of Non-Small Cell Lung Carcinoma (NSCLC).

Lung cancer ranks second worldwide after breast cancer and third in Europe after breast and colorectal cancers when both sexes and all ages are considered. In this context, the aim of this study was to emphasize the power of dual analysis of the molecular profile both in tumor tissue and plasma by NGS assay as a liquid biopsy approach with impact on prognosis and therapy modulation in NSCLC patients. NGS analysis was performed both from tissue biopsies and from cfNAs isolated from peripheral blood samples. Out of all 29 different mutations detectable by both NGS panels (plasma and tumor tissue), seven different variants (24.13%; EGFR L858R in two patients, KRAS G13D and Q61H and TP53 G244D, V197M, R213P, and R273H) were detected only in plasma and not in the tumor itself. These mutations were detected in seven different patients, two of them having known distant organ metastasis. Our data show that NGS analysis of cfDNA could identify actionable mutations in advanced NSCLC and, therefore, this analysis could be used to monitor the disease progression and the treatment response and even to modulate the therapy in real time.