Indicator Of Shorter Overall Survival Research Articles

High Neutrophil-to-Lymphocyte Ratio Facilitates Cancer Growth-Currently Marketed Drugs Tadalafil, Isotretinoin, Colchicine, and Omega-3 to Reduce It: The TICO Regimen.

Simple SummarySeveral elements that are composed of, or related to, neutrophils, have been shown to inhibit strong immune responses to cancer and promote cancers’ growth. This paper presents the collected data showing these elements and how their coordinated actions as an ensemble facilitate growth in the common cancers. The paper goes on to present a drug regimen, TICO, designed to reduce the cancer growth enhancing effects of the neutrophil related elements. TICO uses four already marketed, readily available generic drugs, repurposed to inhibit neutrophil centered growth facilitation of cancer.This paper presents remarkably uniform data showing that higher NLR is a robust prognostic indicator of shorter overall survival across the common metastatic cancers. Myeloid derived suppressor cells, the NLRP3 inflammasome, neutrophil extracellular traps, and absolute neutrophil count tend to all be directly related to the NLR. They, individually and as an ensemble, contribute to cancer growth and metastasis. The multidrug regimen presented in this paper, TICO, was designed to decrease the NLR with potential to also reduce the other neutrophil related elements favoring malignant growth. TICO is comprised of already marketed generic drugs: the phosphodiesterase 5 inhibitor tadalafil, used to treat inadequate erections; isotretinoin, the retinoid used for acne treatment; colchicine, a standard gout (podagra) treatment; and the common fish oil supplement omega-3 polyunsaturated fatty acids. These individually impose low side effect burdens. The drugs of TICO are old, cheap, well known, and available worldwide. They all have evidence of lowering the NLR or the growth contributing elements related to the NLR when clinically used in general medicine as reviewed in this paper.

Expression of IL4R\u03b1 and IL13R\u03b11 are associated with poor prognosis of soft-tissue sarcoma of the extremities, superficial trunk, and retroperitoneum

BackgroundIL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited.MethodsThis study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test.ResultsIn human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001).ConclusionsThis study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.

BZW2/5MP1 acts as a promising target in hepatocellular carcinoma.

Basic leucine zipper and W2 domain 2 (BZW2), also known as 5MP1, is a protein related to translation regulation. Evidence from previous studies indicates that BZW2 is involved in tumorigenesis in several cancers. However, little is known about the role of BZW2 in hepatocellular carcinoma (HCC). In this study, we first analyzed the gene expression profile of BZW2 in multiple HCC datasets. Next, we explored the biological effects of BZW2 in HCC cell lines. BZW2 was overexpressed in different HCC cohorts. Multivariate analysis confirmed that increased BZW2 expression is an independent prognostic indicator of shorter overall survival. BZW2 coexpressed genes were mainly enriched in the biological processes of ribonucleoprotein complex biogenesis, rRNA metabolism, translational initiation, and negative regulation of metabolic processes. BZW2 depletion reduced proliferation, clonality, and invasion and increased apoptosis in MHCC97-H cells. Furthermore, BZW2 overexpression or knockdown enhanced or impaired c-Myc expression, respectively. Overall, these findings identified BZW2 as a biomarker of HCC and provided novel insight that the effect of BZW2 on the translatome is a potential mechanism that promotes HCC progression via the c-Myc pathway.

The predictive and prognostic significance of cell-free DNA concentration in melanoma.

Melanoma is the leading cause of skin cancer-related deaths worldwide. While there have been significant improvements in the treatment of advanced melanoma in the past decade, biomarker development lagged behind. The majority of liquid biopsy biomarkers rely on the analyses of oncogenic mutations; however, about 20% of melanoma patients are wild type. Therefore, validation of universal predictive and prognostic biomarkers is urgently needed. We analysed plasma samples in a discovery cohort (n=20) and expansion cohort (n=166) of metastatic melanoma patients and healthy donors (n=116). Total plasma circulating cell-free DNA (cfDNA) concentrations were measured on the Qubit® platform using assays for single-(ss) and double (ds)-stranded DNA, DNA spectrophotometry and RNase P qPCR. We explored the diagnostic, predictive and prognostic potential of cfDNA concentration by bio-statistical methods and established a cfDNA threshold for risk stratification. Our selected best method was Qubit® dsDNA assay which quantified higher plasma cfDNA concentrations in melanoma patients than in healthy controls (AUC 72%). Measurement of baseline cfDNA concentration revealed that high cfDNA was associated with presence of metastases and higher AJCC stage (P<0.05). Furthermore, high baseline cfDNA was an indicator of shorter overall survival in patients with oncogenic mutations (HR 2.12, P=0.0008), and in wild-type patients (HR 5.55, P<0.0001). We provide evidence that total cfDNA can be used as a biomarker for melanoma irrespective of the tumour genotype and can provide information on tumour load, risk of progression and risk of death.

Prognostic Significance of Inflammatory Markers in Patients with Oral Cavity Tumors

Introduction: In the present study, we aimed to evaluate the relationship between neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and systemic immune inflammation index (SII) values and overall survival (OS) and disease-free survival (DFS) in patients undergoing radiotherapy with a diagnosis of oral cavity cancer (OCC).Methods: 58 patients were included who were treated with a diagnosis of OCC who applied to Cumhuriyet University Faculty of Medicine Radiation Oncology Clinic between January 2009 and December 2018. Kaplan-Meier analysis was used to determine OS and DFS. Multivariate Cox regression analysis was also performed to detect independent prognostic factors.Results: All patients had a squamous cell carcinoma (SCC) of the oral cavity composed of 50 tongue SCC and 8 buccal SCC. Cut-off values in ROC analysis: 954 [Area=0.665 (0.511-0.800), p=0.06] for SII, 174 [Area=0.659 (0.608-0.795), p<.001] for PLR and 3.2 [Area=0.699 (0.556-0.841), p=0.016] for NLR. Prognostic factors affecting OS were SII, PLR, NLR and age. SII, NLR, PLR and grade were statistically significant prognostic factors for DFS. However, SII was an independent prognostic factor.Conclusion: In this study, high SII value was found to be an indicator of shorter OS and DFS in patients with OCC.

High KCNQ1OT1 expression might independently predict shorter survival of colon adenocarcinoma.

To explore the expression profile of KCNQ1OT1 and its prognostic value in colon and rectal adenocarcinoma (COAD and READ) separately. clinicopathological, genomic and survival data from The Cancer Genome Atlas and GSE39582 were obtained for a secondary analysis. KCNQ1OT1 was significantly up-regulated in both COAD and READ compared with adjacent normal tissues. However, its up-regulation was only independently associated with shorter overall survival (hazard ratio: 2.02; 95% CI: 1.18-3.46; p =0.01) and recurrence-free survival (hazard ratio: 2.79, 95% CI: 1.54-5.07; p < 0.01) in COAD, but not in READ. KCNQ1OT1 up-regulation might serve as a valuable independent prognostic indicator of shorter overall survival and recurrence-free survival of COAD, but not READ.

Long Noncoding RNA PTTG3P Expression Is an Unfavorable Prognostic Marker for Patients With Hepatocellular Carcinoma.

Objective: PTTG3P, which maps to chromosome 8q13.1, is a novel long noncoding RNA with oncogenic properties in cancers. In this study, we aimed to investigate the prognostic value of PTTG3P in terms of overall survival and recurrence-free survival and its potential regulatory network and transcription pattern in patients with hepatocellular carcinoma.Patients and Methods:An in silico analysis was performed using data from the Cancer Genome Atlas-Liver Hepatocellular Carcinoma.Results:Results showed that the high PTTG3P expression group was consistently associated with shorter overall survival and recurrence-free survival, regardless of pathological stages or tumor grade. High PTTG3P expression was an independent indicator of shorter overall survival (hazard ratio: 2.177, 95% confidence interval: 1.519-3.121, P < .001) and recurrence-free survival (hazard ratio: 2.222, 95% confidence interval: 1.503-3.283, P < .001). The genes strongly coexpressed with PTTG3P are enriched in several KEGG pathways that are closely associated with carcinogenesis and malignant transformation of hepatocellular carcinoma.Conclusion:Based on the findings, we infer that PTTG3P expression might serve as an independent prognostic biomarker in primary hepatocellular carcinoma.

Angiogenin Upregulation Independently Predicts Unfavorable Overall Survival in Proneural Subtype of Glioblastoma.

Objective:Angiogenin is a small protein that exerts potent stimulating effects on angiogenesis. In this study, we aimed to examine the expression of angiogenin in different subtypes of glioblastoma and estimated its independent prognostic value.Methods:The genomic and survival data from The Cancer Genome Atlas-glioblastoma were extracted for a secondary study. Results The expression of angiogenin was upregulated in glioblastoma tissues and varied significantly in different subtypes. Although the proneural subtype had the lowest angiogenin expression, high angiogenin expression was associated with significantly worse overall survival. However, this association was not observed in other subtypes. By performing univariate and multivariate analysis using Cox regression model, we observed that high angiogenin expression was an independent indicator of shorter overall survival in proneural glioblastoma (hazard ratio: 1.669, 95% confidence interval: 1.033-2.696, P = .036), after adjustment of age, gender, isocitrate dehydrogenase 1 mutation, temozolomide chemotherapy and radiation therapy. In addition, we also observed a correlation between elevated angiogenin expression and the hypomethylated status of its DNA. The hypermethylation group had significantly better overall survival.Conclusions:Angiogenin upregulation might serve as a biomarker for unfavorable overall survival in the proneural subtype of glioblastoma.

SYCP2 expression is a novel prognostic biomarker in luminal A/B breast cancer.

To explore the prognostic value of synaptonemal complex protein-2 (SYCP2) in different subtypes of breast cancer. Patients & materials: In silico bioinformatic analysis was conducted using large databases. SYCP2 was only significantly upregulated in luminal B tumors compared with the adjacent normal tissues. SYCP2 expression was an independent indicator of shorter overall survival in luminal A patients (hazard ratio: 2.269; 95% CI: 1.059-4.862; p=0.035) and luminal B patients (hazard ratio: 2.546; 95% CI: 1.020-6.355; p=0.045). Its expression was negatively correlated with the methylation status of multiple CpG sites (cg22214414, cg23241473 and cg07347645) in both luminal A and luminal B tumors. Increased SYCP2 expression might be an independent indicator of shorter overall survival in both luminal A and luminal B patients.

SIRT6 Is Involved in the Progression of Ovarian Carcinomas via β-Catenin-Mediated Epithelial to Mesenchymal Transition.

SIRT6 is involved in various cellular signaling pathways including those involved in tumorigenesis in association with β-catenin. However, the role of SIRT6 in tumorigenesis has been controversially reported and the studies on the role of SIRT6 in ovarian cancers is limited. In this study, we evaluated the expression and roles of SIRT6 in conjunction with the expression of active β-catenin in 104 human ovarian carcinomas and ovarian cancer cells. In human ovarian carcinomas, the expressions of SIRT6 and active β-catenin were associated with higher tumor stage, higher histologic grade, and platinum-resistance. Moreover, nuclear expression of SIRT6 (104 ovarian carcinomas; P = 0.010, 63 high-grade serous carcinomas; P = 0.040), and activated β-catenin (104 ovarian carcinomas; P = 0.013, 63 high-grade serous carcinomas; P = 0.005) were independent indicators of shorter overall survival of ovarian carcinoma patients in multivariate analysis. In OVCAR3 and OVCAR5 ovarian cancer cells, knock-down of SIRT6 significantly inhibited the migration and invasion of cells, but did not inhibit the proliferation of cells. SIRT6-mediated invasiveness of ovarian cancer cells was associated with the expression of epithelial-to-mesenchymal transition-related signaling molecules such as snail, vimentin, N-cadherin, E-cadherin, and activated β-catenin. Especially, SIRT6-mediated increase of invasiveness and activation of epithelial-to-mesenchymal transition signaling was attenuated by knock-down of β-catenin. In conclusion, this study suggests that SIRT6-β-catenin signaling is involved in the epithelial-to-mesenchymal transition of ovarian cancer cells, and the expression of SIRT6 and active β-catenin might be used as indicators of poor prognosis of ovarian carcinoma patients. In addition, our results suggest that SIRT6-β-catenin signaling might be a new therapeutic target of ovarian carcinomas.

UCK2 upregulation might serve as an indicator of unfavorable prognosis of hepatocellular carcinoma.

Uridine-cytidine kinases (encoded by UCK1, UCKL1, and UCK2) catalyze the phosphorylation of uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP). In this study, using data from the Cancer Genome Atlas (TCGA), we analyzed the expression profile of uridine-cytidine kinase genes in hepatocellular carcinoma (HCC), their prognostic value, and the epigenetic alterations associated with their dysregulation. Results showed that UCKL1 and UCK2, but not UCK1 were significantly upregulated in HCC tissues than in adjacent normal tissues. Only UCK2 was significantly upregulated in the deceased group and the recurrence group, compared to the control groups. Multivariate analysis confirmed that increased UCK2 expression was an independent prognostic indicator of shorter overall survival (OS) (HR: 1.760, 95% CI: 1.398-2.216, P < 0.001) and recurrence-free survival (RFS) (HR: 1.543, 95% CI: 1.232-1.933, P < 0.001). Two CpG sites (cg09277749 and cg21143899) were significantly hypomethylated in HCC tissues than in adjacent normal tissues and were negatively correlated with UCK2 expression. However, survival analysis showed that only high methylation of cg0927774 was associated with better OS and RFS of HCC patients. Based on the findings above, we infer that UCK2 upregulation might be a valuable prognostic marker in HCC. The methylation of status cg0927774 might play a critical role in its expression. © 2018 IUBMB Life, 71(1):105-112, 2019.

Clinically significant association of elevated expression of nuclear factor E2-related factor 2 expression with higher glucose uptake and progression of upper urinary tract cancer

BackgroundThere is growing evidence that the transcription factor nuclear factor E2-related factor 2 (Nrf2) is the major participant in regulating antioxidants and pathways for detoxifying reactive oxygen species (ROS), as well as having a vital role in tumor proliferation, invasion, and chemoresistance. It was also recently reported that Nrf2 supports cell proliferation by promoting metabolic activity. Thus, Nrf2 is involved in progression of cancer. Upper urinary tract urothelial carcinoma (UTUC) is a biologically aggressive tumor with high rates of recurrence and progression, resulting in a poor prognosis. However, the role of Nrf2 in UTUC is largely unknown.MethodsIn order to study the role of Nrf2 in UTUC from the metabolic perspective, we retrospectively assessed Nrf2 expression in the surgical specimen and the preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy-glucose positron emission tomography (18F-FDG-PET) of 107 patients with UTUC who underwent radical nephroureterectomy.ResultsIncreased expression of Nrf2 in the primary lesion was correlated with less differentiated histology, local invasion, and lymph node metastasis, and was also an independent indicator of shorter overall survival according to multivariate analysis. Furthermore, increased expression of Nrf2 was associated with higher preoperative SUVmax by the primary tumor on 18F-FDG-PET, while Nrf2 expression and SUVmax were also significantly correlated in the metastatic lymph nodes. Among the 18 patients with lymph node metastasis at nephroureterectomy who underwent retroperitoneal lymph node dissection and received adjuvant chemotherapy, the patients with higher Nrf2 expression in the primary tumor had worse recurrence-free survival.ConclusionsThese results suggest that constitutive activation of Nrf2 might be linked with tumor aerobic glycolysis and progression of UTUC, indicating that Nrf2 signaling in the tumor microenvironment promotes progression of UTUC.

Prognostic Significance of Bcl-2, Tumor-Associated Macrophages, and Total Neoplastic and Inflammatory Lymph Node Involvement in Advanced Stage Classical Hodgkin’s Lymphoma

Background: Although Hodgkin’s lymphoma (HL) is a curable cancer, current treatment strategies based on risk stratification and response modulation are not precise enough. The predictive power of biological and morphological parameters is controversial, with prognostic models not reaching wide acceptance. Patients and Methods: We analyzed the prognostic relevance of 8 parameters in 85 advancedstage classical HL patients, in order to determine whether tissue-based variables could add prognostic value to standard clinical parameters, thus contributing to better risk stratification at presentation. Results: Univariate analysis confirmed 5 indicators of shorter overall survival (OS): Bcl-2 overexpression; increased CD68+ tumor-associated macrophages (TAM); international prognostic score (IPS) > 2; bulky disease; and total lymph node involvement (TLNI) with regard to neoplastic and inflammatory cells. Apart from TLNI, these parameters influenced lower event-free survival (EFS). Multivariate analysis identified 5 independent factors for OS: Bcl-2 overexpression; increased CD68+ TAM; TLNI; IPS > 2; and bulky disease. Increased CD68+ TAM, IPS > 2, and bulky disease affected the EFS. Utilizing the cumulative score of unfavorable prognostic factors for OS, we designed a prognostic model stratifying patients into 4 risk groups (with 0–1, 2, 3, or 4–5 factors), each with progressively reduced OS (p < 0.001). Conclusion: Our findings support the combination of tissue-based variables with clinical parameters at diagnosis, identifying patients who are at higher risk of poor outcome.