Biomarker For Prognosis In Patients Research Articles

Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma.

We investigated whether elevated neutrophil-to-lymphocyte ratio (NLR) was associated with poor anti-tumor immunity and prognosis in patients with intrahepatic cholangiocarcinoma (ICC). Clinicopathologic data of 102 patients with ICC who underwent hepatectomy was retrospectively analyzed. The Kaplan-Meier method and Cox regression model were used to analyze the survival and prognosis. The percentage of overall lymphocytes, T cells and CD8+ T cells in the high NLR group was lower than that in the low NLR group. The percentage of PD-1+CD4+ and PD-1+CD8+ T cells was higher and the percentage of IFN-γ+CD4+ and IFN-γ+CD8+ T cells was lower in the high NLR group than that in the low NLR group (p = 0.045, p = 0.008; p = 0.012, p = 0.006). Density of tumor-infiltrating CD3+ T cells in the high NLR group was lower than that in the low NLR group (p < 0.001). Elevated NLR was an independent predictor for poor overall survival (OS; p = 0.035) and recurrence-free survival (RFS; p = 0.008). These results indicate that elevated NLR is associated with poor anti-tumor immunity and could be a poor biomarker for prognosis in patients with ICC.

Upregulation of miRNA-130a Represents Good Prognosis in Patients With HBV-Related Acute-on-Chronic Liver Failure: A Prospective Study.

Prompt and accurate prediction of the outcome is the key to make correct medical decision and to reduce the mortality in patients with HBV-related acute-on-chronic liver failure (ACLF). Increasing evidence have certified that small, noncoding microRNAs (miRNAs) play critically regulatory roles in the pathogenesis of liver diseases. However, it remains unclear whether and how miRNAs involve in the prognosis of ACLF.Microarray analysis was performed to characterize the miRNA expression profiles in liver tissues from 1 HBV-related ACLF patient and 1 matched healthy control. Nine miRNAs with at least 5 folds difference between these 2 persons were picked out. The present prospective study involving 39 HBV-related ACLF patients including 20 recovered and 19 nonrecovered patients, which include death (n = 9) and liver transplantation (n = 10). The serum expression of these miRNAs detected by quantitative real-time Polymerase Chain Reaction (qRT-RCR) was then compared between the 2 groups. Moreover, the correlation between the serum miRNAs and the prognostic indexes for ACLF was analyzed.The result of microarray analysis showed 9 miRNAs had different expression in liver tissues of ACLF patient compared with healthy control (upregulated: miRNA-130a, -21, -143, and -200a; downregulated: miRNA-486-5p, -192, -148a, -122, and -194). Unlike the expression profiles in liver tissue, 8 serum miRNAs except miRNA-194 were markedly upregulated in ACLF patients (P < 0.05). Remarkably, the serum expression of miRNA-130a and miRNA-486-5p was higher in recovered than nonrecovered ACLF patients (P < 0.05). Especially, the serum miRNA-130a was negatively correlated with international normalized ratio, prothrombin time, Model for End-Stage Liver Disease score, and positively correlated with prothrombin time activity. The AUC for recovered versus nonrecovered patients of miRNA-130a was 0.741 (P = 0.02).miRNA-130a might be a useful prognosis biomarker in patients with HBV-related ACLF.

Low expression of fibulin-1 correlates with unfavorable prognosis in gastric cancer.

The tumor-suppressing role of fibulin-1 has been described in several types of cancers. However, the expression and role of fibulin-1 in the development and progression of gastric cancer (GC) remain largely unknown. In this study, RT-PCR and immunochemistry were used to detect the fibulin-1 expression in GC samples. We have found that the fibulin-1 protein and mRNA levels were downregulated in GC. When investigating the correlation between fibulin-1 expression and clinicopathological characteristics, we have found that low fibulin-1 protein expression was associated with poor tumor differentiation and advanced N stage. Low fibulin-1 protein expression was also an independent prognostic factor for patient survival. To clarify the reason of fibulin-1 downregulation in GC, the mRNA expression and methylation status of fibulin-1 were examined in GC fresh tissue samples (n = 36). We found that the transcriptional expression of fibulin-1 was negatively associated with fibulin-1 promoter hypermethylation, and fibulin-1 hypermethylation was associated with Helicobacter pylori infection. Finally, the effects of fibulin-1 overexpression on cell proliferation and apoptosis were examined. We have found that fibulin-1 overexpression suppressed the growth of GC both in vitro and in vivo and induced apoptosis by increasing cleaved caspase-3 expression. In conclusion, fibulin-1 acts as a tumor suppressor gene, is frequently hypermethylated in GC, and can potentially serve as a useful biomarker for patient prognosis.

Serum Procalcitonin and Procalcitonin Clearance as a Prognostic Biomarker in Patients with Severe Sepsis and Septic Shock.

We evaluated the tendency of the plasma concentration and procalcitonin (PCT) clearance (PCTc) to act as biomarkers of prognosis in patients with severe sepsis and septic shock. From 2011 to 2013, we prospectively analyzed patients with sepsis admitted to the intensive care unit (ICU). The serum PCT was evaluated at the time of sepsis diagnosis and again after 48 h (day 3) and 96 h (day 5). PCTc after 48 h (PCTc-day 3) and 96 h (PCTc-day 5) was also calculated to evaluate the prognostic value for survival in patients with sepsis. A total of 48 patients were included. Overall mortality was 16.7% (8 patients). PCTc was higher in survivors than in nonsurvivors, with significant differences on day 3 and day 5 (p = 0.033; p = 0.002, resp.); however, serum PCT levels on day 1, day 3, and day 5 were not significant prognostic factors for survival. The prognosis of patients with severe sepsis and septic shock may be associated with PCTc. Dynamic changes of PCT reflected as PCTc at 48 h (day 3) and 96 h (day 5) after admission to the ICU may serve as a predictor of survival in critically ill patients with severe sepsis.

Loss of Tricho-Rhino-Phalangeal Syndrome-1 (TRPS1) expression as a Biomarker of Poor Prognosis in Patients with Gastric Cancer

Loss of Tricho-Rhino-Phalangeal Syndrome-1 (TRPS1) expression as a Biomarker of Poor Prognosis in Patients with Gastric Cancer

Noncoding RNAs and their functional involvement in regulation of chronic myeloid leukemia.

Noncoding RNAs (ncRNAs) comprise multiple classes of transcripts that have no protein-coding ability but play critical roles as RNA regulators in various cellular processes. To date, the well-studied ncRNAs are microRNAs (miRs) that generally act as regulators of gene expression through binding to target mRNAs. Recent advances in high-throughput sequencing technologies have led to the discovery of thousands of unannotated noncoding transcripts, especially long noncoding RNAs (lncRNAs). These lncRNAs are being increasingly recognized as key regulators in diverse biological processes via a variety of mechanisms. Aberrant expression of miRs and lncRNAs has been shown to be associated with many human diseases and cancers. Increasing ncRNAs have been identified as biomarkers for patient prognosis and potential therapeutic agents for cancers. Furthermore, it is worth noting that progresses have been made in understanding the functional involvement of ncRNAs in Bcr-Abl-induced chronic myeloid leukemia (CML). Here, we highlight the pathogenesis of CML, functional significance of miRs and lncRNAs in regulation of CML development and involved mechanisms underlying their action.

Elevated serum creatinine and low albumin are associated with poor outcomes in patients with liposarcoma.

Low serum albumin levels and impaired kidney function have been associated with decreased survival in patients with a variety of cancer types. In a retrospective cohort study, we analyzed 84 patients with liposarcoma treated at from May 1994 to October 2011. Uni- and multivariable Cox proportional hazard models and competing risk analyses were performed to evaluate the association between putative biomarkers with disease-specific and overall survival. The median age of the study population was 51.7 (range 19.6-83.8) years. In multivariable analysis adjusted for AJCC tumor stage, serum creatinine was highly associated with disease-specific survival (Subdistribution Hazard ratio (SHR) per 1 mg/dl increase = 2.94; 95%CI 1.39-6.23; p = 0.005). High albumin was associated with improved overall and disease-specific survival (Hazard Ratio (HR) per 10 units increase = 0.50; 95%CI 0.26-0.95; p = 0.033 and SHR = 0.64; 95%CI 0.42-1.00; p = 0.049). The serum albumin-creatinine-ratio emerged to be associated with both overall and disease-specific survival after adjusting for AJCC tumor stage (HR = 0.95; 95%CI 0.92-0.99; p = 0.011 and SHR = 0.96; 95%CI 0.93-0.99; p = 0.08). Our study provides evidence for a tumor-stage-independent association between higher creatinine and lower albumin with worse disease-specific survival. Low albumin and a high albumin-creatinine-ratio independently predict poor overall survival. Our work identified novel prognostic biomarkers for prognosis of patients with liposarcoma.

BLZF1 expression is of prognostic significance in hepatocellular carcinoma

BLZF1, a member of b-ZIP family, has been implicated in epigenetic regulation and Wnt/β-catenin signaling. Its expression and clinical significance in human cancers remain largely unknown. In this study, we showed that BLZF1 expression was reduced in hepatocellular carcinoma (HCC) tissues, compared to the paracarcinoma tissues, at both mRNA and protein levels. Results of immunohistochemistry revealed that BLZF1 was presented in both nuclear and cytoplasm. Decreased expression of nuclear and cytosolic BLZF1 in HCC was depicted in 68.2% and 79.2% of the 634 cases. Nuclear BLZF1 expression was significantly associated with tumor multiplicity (P = 0.048) and tumor capsule (P = 0.028), while cytosolic BLZF1 expression was correlated with serum AFP level (P = 0.017), tumor differentiation (P = 0.001) and tumor capsule (P = 0.003). Kaplan–Meier analysis indicated both nuclear and cytosolic BLZF1 expression was associated with poor overall survival. Low nuclear BLZF1 also indicated unfavorable disease-free survival and high tendency of tumor recurrence. Furthermore, multiple Cox regression analysis revealed nuclear BLZF1 as an independent factor for overall survival (Hazard Ratio (HR) = 0.827, 95% confident interval (95%CI): 0.697–0.980, P = 0.029). The prognostic value of BLZF1 was further confirmed by stratified analyses. Collectively, our data suggest BLZF1 is a novel unfavorable biomarker for prognosis of patients with HCC.

Abstract 3612: Study of the functional importance of PPARγ in honokiol-induced apoptosis of hepatoma cells

Abstract Hepatocellular carcinoma (HCC) is the leading cause of death in male cancer patients in Asia. PPARγ exhibited an inhibitory role in hepatocarcinogenesis in vitro and in vivo. Recently, it was found that honokiol functions not only as a RXR agonist but also a PPARγ agonist, and is capable of potentiating the activation of PPARγ in the presence of PPARγ agonist rosiglitazone in HLE human hepatoma cells. It also has been reported that honokiol exerts inhibitory effects on the growth and migration in hepatoma cells. However, whether PPARγ overexpression modulates the honokiol-induced growth inhibition in hepatoma cells is not known. Firstly, we examined the expression of PPARγ in tumor samples from 83 HCC patients by immunohistochemical staining. Our results showed that 53 samples had no PPARγ and the clinical parameters including tumor number, stages, and macroscopic vascular invasion (MVI) showed significant negative correlation with PPARγ expression. However, the expression of PPARγ was not associated with disease free survival or overall survival of patients with HCC. Using PPARγ overexpressed SK-Hep1 cells (SK-Hep1-PPARγ) for in vitro analyses, we found that 40 μM honokiol treatment of SK-Hep1-PPARγ cells induced a 20% increase of growth inhibition at 48 hour as compared to vector control cells by MTT assay. This corresponded well with the 15% increase in G0/G1 phase after honokiol treatment at 24 hour compared to vector control cells. In addition, honokiol treatment resulted in decreased cyclin D1, increased p21 and KLF4 expressions in SK-Hep1-PPARγ cells. Moreover, miRNA array analyses showed that increased expression of miR-222, let-7i, miR-628-3p and miR-664 as well as decreased miR-1291, miR184 and miR1249 were observed in SK-Hep1-PPARγ cells. In conclusion, PPARγ is not only a biomarker for prognosis of patients with HCC but also play an important role in the honokiol-induced growth inhibition of hepatoma cells. The functional importance of PPARγ regulated miRNA is currently under further investigation. Citation Format: Chin-Wen Chi, Hui-Tzu Hsu, Jia-Dong Hou, Chih-Chun Lee, Ying-Ju Kuo, Hsin-Chen Lee, Cheng-Yuan Hsia. Study of the functional importance of PPARγ in honokiol-induced apoptosis of hepatoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3612. doi:10.1158/1538-7445.AM2015-3612

Abstract 594: AGT mutations as a prognosis factor in patients with astrocytoma

Abstract Background: Astrocytomas are the most common and lethal brain tumors. The median survival of patients is 15 months. The study of genetic alterations may help to understand the mechanisms of development and behavior of the disease and thus understand the risk factors and prognostic factors. AGT gene and its peptide derivatives, are involved in cell proliferation and neoangiogenesis and resistance to apoptosis, hence the pathogenesis of astrocytomas. Objective: To identify somatic and germinal AGT gene variations in from patients with astrocytoma. Material and methods: 155 randomly selected files from patients diagnosed with astrocytoma between 2008-2014 were revised to determined clinical prognosis factor in Mexican population. In 25 patients, the molecular analysis of the whole codification region, 5´UTR and 3´UTR of the gene AGT was done in tumors biopsy and blood. Each amplified region had a depth of minimum 1500x. IonReporter software was utilize to analyze the genetic variants and using Integrative Genomic Viewer we confirmed that each variant had a Phred higher than 25. Genotypic frequencies were compared with HapMapMex. Results The clinical variants associated with prognosis were age (OR 0.01 IC 95% 1.02-1.07, p = 0.000), Grade IV (OR 17.11, IC 95% 1.89-132.13 p = 0.011), location of tumor (OR 1.17, IC 1.2-6.3, p = 0.016), total resection (OR = .186, IC 95% .098-.622, p = 0.003, Karnofsky (OR = .05, IC 95% 0.024-0.24, p = 0.003), motor deficiency (OR = 3.5, IC = 1.1-10.5, p = 0.025). In blood were found 11 genetic variants. rs4049, rs2148582, rs699, rs4762 and rs1926723 were associated with risk of tumor in the codominant model. rs5050 (- A20C) was statistically associated with the prognosis (OR 10.8, IC 1.16-100.51 p = 0.036). These variant it is part of a haplotype related to low expression of angiotensinogen. In biopsies of 2 patients missense mutations were found p.Arg477His in one patient and Gly226Ala -Pro165Ser in another one. Conclusion: In 8% of the tumors samples new somatic mutations were found. The genetic variant rs5050 of AGT is a prognosis biomarker in patients with astrocytoma. Citation Format: Talia Wegman-Ostrosky, Ernesto Soto-Reyes, Silvia Vidal-Millan, Sonia Mejia, José Sánchez-Corona, Luis A. Herrera. AGT mutations as a prognosis factor in patients with astrocytoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 594. doi:10.1158/1538-7445.AM2015-594

Abstract 1208: Glutamine modulates cellular NAD+/NADH homeostasis thereby regulating cancer metastasis, drug sensitivity in cancer cells

Abstract Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine-addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Recently, we uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low-invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high-invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the cellular NAD+/NADH homeostasis, which mediates cancer metastasis and progression. On the other hand, the overexpression of NAD+ biosynthesis pathway enhances glutamine's entry into TCA cycle for cancer metastasis, as well as chemo-drug resistance. Our findings suggest that a combined approach of targeting high-invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting NAD+ biosynthesis pathway may lead to potential therapeutic approaches for treating OVCAs. Our insights will present a unique opportunity for overcoming the drug resistance limitation in clinical trials in ovarian cancers. Citation Format: Lifeng Yang, Abhinav Achreja, Tyler Moss, Joelle Baddour, Katherine Stilles, Lisa Chiba, Sun Hye Kim, Josh Morse, Juan Marini, Anil K. Sood, Prahlad T. Ram, Deepak Nagrath. Glutamine modulates cellular NAD+/NADH homeostasis thereby regulating cancer metastasis, drug sensitivity in cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1208. doi:10.1158/1538-7445.AM2015-1208

MYC Expression Is Prognostic in Therapy Related Acute Myeloid Leukemia (AML) and AML with Myelodysplastic Syndrome (MDS)-Related Changes

Background: MYC mRNA overexpression has been described in acute myeloid leukemia (AML), but no studies have assessed MYC protein expression in AML where its clinical significance is unknown. In this study our aim is to assess MYC protein expression across all AML subtypes and explore its prognostic value in in a subset of patients (pts) with particularly poor prognosis, namely those with AML with myelodysplastic syndrome (MDS)-related changes (AML-MRC) and therapy-related AML (t-AML). Characterized by unfavorable cytogenetics, the prognosis of patients with AML-MRC and t-AML is often dismal, even in patients who undergo allogeneic stem cell transplant. There is a need for further molecular characterization of AML-MRC and t-AML to identify prognostic markers to optimally risk-stratify to better guide treatment decisions in these pts.Objectives: In the current study we sought to: (1) assess MYC protein expression by immunohistochemistry (IHC) performed on bone marrow (BM) specimens of pts with all types of AML, including acute promyelocytic leukemia (APL), and myelodysplastic syndromes (MDS), and (2) explore the prognostic significance of MYC protein expression in AML-MRC and t-AML (2008 WHO criteria).Methods: MYC protein expression was assessed by IHC on BM obtained from pts with AML, APL, and MDS, and from patients without hematologic neoplasms (normal controls). MYC expression was considered positive if > 5% blasts in BM showed nuclear reactivity. For cases classified as t-AML and AML-MRC by WHO 2008, MYC expression was correlated with molecular, cytogenetic, and clinical outcome data. X-tile software was used to identify the optimal cutoff point to dichotomize pts by MYC protein expression.Results: We evaluated BM MYC expression in 306 pts during 2006-2013 with newly diagnosed AML (n=246) or APL (n=11), previously treated AML (induction failure or relapse) (n=30), MDS (n=19), AML-MRC (n=68), t-AML (n=10), and normal BM (n=11). The median age was 61 yrs (13-88) with 54% men. Normal BM showed negligible MYC expression, ≤2% positive nuclei. The median MYC expression varied across diseases: newly diagnosed AML 25% (range 0-38%), APL 50% (range 19-75%), previously treated AML 20% (range 0-80), MDS 5% (range 0-30%) (differences between groups, p=0.0001).High MYC expression correlated with high LDH (rs = 0.285, p<0.0001), WBC (rs = 0.225, p<0.0001) and BM blasts (rs 0.417, p<0.0001). Among newly diagnosed AML pts 20 had normal MYC expression ≤ 2%. MYC rearrangement by FISH was not detected in tested normal karyotype AML cases with variable MYC expression levels. MYC rearrangement by FISH was not detected in tested normal karyotype AML cases with variable MYC expression levels.The clinical significance of MYC expression was examined in 78 pts with previously untreated AML-MRC and t-AML (59% men, median age 64 years). Pts with MYC expression above a determined cutoff of 21% had a significantly worse median overall survival (OS) of 8 months compared to 17 months in those with MYC ≤ 21% (p=0.035).Disease free survival (DFS) was also inferior in pts with higher MYC expression. Median DFS was 3 months in pts with MYC >21% and 8 months for pts with MYC ≤ 21% (p=0.064). The rate of CR was 63% in pts with MYC≤ 21% and 37% in those >21%, however this difference was not statistically significant.In pts with newly diagnosed AML-MRC and t-AML, high MYC expression did not correlate with markers of proliferation (high LDH, WBC and BM blasts). Furthermore, MYC levels were similar across karyotypes: trisomy 8 (where MYC resides), complex, and core binding factors.Conclusion: MYC protein expression is a strong predictor of survival and an important biomarker of prognosis in patients with t-AML and AML-MRC. On BM IHC, pts with >21% MYC-positive blasts have an inferior OS, DFS, and remission rate than pts with ≤ 21% MYC-positive blasts. Increased MYC protein expression is independent of rearrangement status by FISH. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 3754: Hippo pathway effector Yes-associated protein and cisplatin resistance in transitional cell carcinoma of the bladder

Abstract Background: Transitional cell carcinoma of the bladder (TCC) arises from the cells lining the bladder and accounts for 90% of bladder cancers. Current standard of care for muscle-invasive TCC is surgery with perioperative cisplatin-based chemotherapy regimens. Some tumors are quite sensitive to cisplatin but others either acquire resistance or are refractory. A reduced drug availability, an increased efficacy of the DNA damage repair machinery or defects in the apoptotic process are the main mechanisms involved in cisplatin resistance. The Hippo tumor suppressor pathway controls multiple cellular functions that are important for tumorigenesis and drug-resistance, including proliferation, apoptosis and oxidative stress regulation. Specifically, the overexpression of Yes-associated protein (YAP), one of the two repressed-targets of this pathway, prevents tumor necrosis factor-induced apoptosis in mouse liver and protects cancer cells from chemotherapy-induced apoptosis. Intriguingly, this transcriptional co-activator has been shown to be involved in bladder cancer progression and to be a biomarker for poor prognosis of patients with TCC. Furthermore, in ovarian cancer, YAP has been shown to confer resistance to cisplatin. Thus, we hypothesized that YAP may be involved in cisplatin resistance in bladder cancer and could predict drug response in TCC patients. Methods: Cisplatin activity and YAP protein expression and localization were analyzed in different in vitro and in vivo models of TCC: 1) Collection of bladder cancer cell lines, genetically manipulated by knocking-down or overexpressing YAP; 2) Cell line models of cisplatin resistance, obtained by long term continuous in vitro exposure to increasing drug concentrations; 3) Two TCC patient derived xenograft (PDX) models and derived primary cells (RP-B-01 and RP-B-02) with different intrinsic sensitivity to cisplatin. Furthermore, by continuous in vivo cisplatin treatment (2.5 to 5 mg/Kg, 1x/week, i.p.), we are currently establishing a cisplatin resistant RP-B-02 model. In vitro cisplatin effect was evaluated in apoptosis, proliferation and colony formation assays. Results: YAP expression and nuclear localization was inversely correlated with cisplatin sensitivity in TCC cell lines. Cisplatin-resistant TCC cell lines expressed higher YAP than parental counterparts. Cisplatin-induced apoptosis was significantly increased by YAP knockdown in T24 cell line. In vivo cisplatin treatment showed a greater anti-tumor effect in the low YAP-expressing RP-B-02 model as compared to the high YAP-expressing RP-B-01 tumors. Expression of YAP in human TCC specimens will be also presented. Summary: Overall, these data suggest that YAP has a role in bladder cancer response to cisplatin and highlights the potential therapeutic application of YAP as a biomarker of cisplatin sensitivity in TCC patients. Citation Format: Eric Stefano Ciamporcero, He Shen, Sreenivasulu Chintala, Swathi Ramakrishnan, Sheng Yu Ku, Kiersten M. Miles, Stefania Pizzimenti, Candace Johnson, Jianmin Zhang, Giuseppina Barrera, Roberto Pili. Hippo pathway effector Yes-associated protein and cisplatin resistance in transitional cell carcinoma of the bladder. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3754. doi:10.1158/1538-7445.AM2014-3754

Letter regarding Chen et al. entitled "a systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma".

Letter regarding Chen et al. entitled "a systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma".

High-risk human papillomavirus infection associated with telomere elongation in patients with esophageal squamous cell carcinoma with poor prognosis.

Telomere maintenance is crucial in carcinogenesis and tumor progression. The results of a previous study from the authors indicated that infection with high-risk human papillomavirus (HR-HPV) types 16, 18, and 58 was a risk factor for esophageal squamous cell carcinoma (ESCC) in the Shantou region of China. In the current study, the authors explored the association between HR-HPV infection, telomere length (TL), and DNA methylation and their significance in the prognosis of patients with ESCC. TL and DNA methylation were analyzed by real-time polymerase chain reaction and methylation-specific polymerase chain reaction in 70 cases of ESCC tumor (T) and paired nontumor (NT) tissues and 50 cases of normal esophagus (NE). The prognostic value of TL and DNA methylation in ESCC was analyzed. TL gradually decreased from NE to NT to T tissue. TL in tumor tissue (T-TL) was found to be longer in tissue that was positive for HR-HPV compared with negative tissue and was found to be positively associated with viral load (Spearman correlation, 0.410; P = .037) and integration (represented by the ratio of HR-HPV E2 to E6/E7 genes; P = .01). The DNA methylation ratio of human telomerase reverse transcriptase was more prevalent with long (≥ 0.7) compared with short (< 0.7) T-TL and was positively correlated with T-TL (Spearman correlation, 0.318; P = .007) and HR-HPV integration (P = .036). Furthermore, Cox proportional hazards modeling revealed a high ratio of T-TL to NT-TL (≥ 0.80) as a factor of poor prognosis, independent of other clinicopathologic variables. HR-HPV infection and integration related to telomere elongation and DNA methylation of human telomerase reverse transcriptase may be a potential biomarker of prognosis in patients with ESCC.

Expression and Effects of High-Mobility Group Box 1 in Cervical Cancer

We investigated the significance of high- mobility group box1 (HMGB1) and T-cell-mediated immunity and prognostic value in cervical cancer. HMGB1, forkhead/winged helix transcription factor p3 (Foxp3), IL-2, and IL-10 protein expression was analyzed in 100 cervical tissue samples including cervical cancer, cervical intraepithelial neoplasia (CIN), and healthy control samples using immunohistochemistry. Serum squamous cell carcinoma antigen (SCC-Ag) was immunoradiometrically measured in 32 serum samples from 37 cases of squamous cervical cancer. HMGB1 and SCC-Ag were then correlated to clinicopathological characteristics. HMGB1 expression tends to increase as cervical cancer progresses and it was found to be significantly correlated to FIGO stage and lymph node metastasis. These findings suggest that HMGB1 may be a useful prognostic indicator of cervical carcinoma. In addition, there were significant positive relationships between HMGB1 and FOXP3 or IL-10 expression (both p < 0.05). In contrast, HMGB1 and IL-2 expression was negatively correlated (p < 0.05). HMGB1 expression may activate Tregs or facilitate Th2 polarization to promote immune evasion of cervical cancer. Elevated HMGB1 protein in cervical carcinoma samples was associated with a high recurrence of HPV infection in univariate analysis (p < 0.05). HMGB1 expression and levels of SCC-Ag were directly correlated in SCC (p < 0.05). Thus, HMGB1 may be a useful biomarker for patient prognosis and cervical cancer prediction and treatment.

Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer.

Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine-addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low-invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high-invasive OVCA cells are markedly glutamine dependent.Consistent with our findings, OVCA patients' microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high-invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low-invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.

PT041 Applicability of BNP as a Biomarker of Prognosis in Long-Term Mortality in a Cohort of Elderly Patients in South Brazil

Introduction: The BNP is used as a biomarker of prognosis, in the short term, in patients with heart failure (HF). The prognostic role of the long-term mortality is not enough studied. Objectives: To validate the BNP test as a biomarker of long-term prognosis in patients with suspected HF. Methods: Three hundred eighteen patients, who presented at the emergency room, from March 2003 through September 2009, with suspected HF, took part of this study. The accuracy of BNP to identify patients with heart failure and the search from the association with the level of BNP (POCT Biosite) and with the long-term prognosis were evaluated. The cause of death was identified through the search of death certificates in registries, informed by the Brazilian Information Service of Mortality. Results: Most of the patients were white (93.1%), female (63.8%), and aged 77.3 8.6 years. HF was diagnosed based in a new gold standard that considered the Framingham and Boston criteria plus echocardiography and ECG. HF was present in 170 pt (53.5%). Most of these 108 pt (63.5%) had HF with Preserved Ejection Fraction (HFPEF). The functional class III and IV NYHA was present in 87%. The BNP presented AUC 0.93 (CI 95%, 0.88 to 0.97). The best cutoff of BNP was 180 pg/ml with S 0.83 (CI 95%, 66.7 to 80.4) and Sp 0.90 (CI 95%, 76.7 to 95.4). LR + 6.7 (95 %, 3.1 to 14.3), accuracy of 77.7. In the bivariate analysis BNP> 180pg/ml was associated with a higher risk of mortality. In multivariate analysis HR BNP> 180pg/ml remained associated with increased risk of mortality HR 3.4 (HF 1.2 to 9.6 p 50% and mortality of 26%. The comparison HFS group and NHF showed RRR 0,21 (CI 95% 0,05 – 0,38) p<0,001. Betwin HFPEF group and N-HF group RRR 0,12 (CI 95% -0,02 0,27). HFS and HFPEF the RRR 0,089 (CI 95% -0,67 – 0,24). Ninety nine 99 deaths were recorded in the total group. Conclusion: The level of the BNP showed association with mortality index. The BNP is an independent prognostic biomarker of long-term mortality in patients with HF. Disclosure of Interest: None Declared

PT043 Diagnostic and prognostic value of the B-type natriuretic peptide in elderly patients, in south Brazil, with suspected heart failure in the emergency room

Introduction: The BNP is used as a biomarker of prognosis, in the short term, in patients with heart failure (HF). The prognostic role of the long-term mortality is not enough studied. Objectives: To validate the BNP test as a biomarker of long-term prognosis in patients with suspected HF. Methods: Three hundred eighteen patients, who presented at the emergency room, from March 2003 through September 2009, with suspected HF, took part of this study. The accuracy of BNP to identify patients with heart failure and the search from the association with the level of BNP (POCT Biosite) and with the long-term prognosis were evaluated. The cause of death was identified through the search of death certificates in registries, informed by the Brazilian Information Service of Mortality. Results: Most of the patients were white (93.1%), female (63.8%), and aged 77.3 8.6 years. HF was diagnosed based in a new gold standard that considered the Framingham and Boston criteria plus echocardiography and ECG. HF was present in 170 pt (53.5%). Most of these 108 pt (63.5%) had HF with Preserved Ejection Fraction (HFPEF). The functional class III and IV NYHA was present in 87%. The BNP presented AUC 0.93 (CI 95%, 0.88 to 0.97). The best cutoff of BNP was 180 pg/ml with S 0.83 (CI 95%, 66.7 to 80.4) and Sp 0.90 (CI 95%, 76.7 to 95.4). LR + 6.7 (95 %, 3.1 to 14.3), accuracy of 77.7. In the bivariate analysis BNP> 180pg/ml was associated with a higher risk of mortality. In multivariate analysis HR BNP> 180pg/ml remained associated with increased risk of mortality HR 3.4 (HF 1.2 to 9.6 p 50% and mortality of 26%. The comparison HFS group and NHF showed RRR 0,21 (CI 95% 0,05 – 0,38) p<0,001. Betwin HFPEF group and N-HF group RRR 0,12 (CI 95% -0,02 0,27). HFS and HFPEF the RRR 0,089 (CI 95% -0,67 – 0,24). Ninety nine 99 deaths were recorded in the total group. Conclusion: The level of the BNP showed association with mortality index. The BNP is an independent prognostic biomarker of long-term mortality in patients with HF. Disclosure of Interest: None Declared

PT042 Impact of the extracardiac variables on BNP cut-offs within a cohort of patients with suspected heart failure in a tertiary referral hospital

Introduction: The BNP is used as a biomarker of prognosis, in the short term, in patients with heart failure (HF). The prognostic role of the long-term mortality is not enough studied. Objectives: To validate the BNP test as a biomarker of long-term prognosis in patients with suspected HF. Methods: Three hundred eighteen patients, who presented at the emergency room, from March 2003 through September 2009, with suspected HF, took part of this study. The accuracy of BNP to identify patients with heart failure and the search from the association with the level of BNP (POCT Biosite) and with the long-term prognosis were evaluated. The cause of death was identified through the search of death certificates in registries, informed by the Brazilian Information Service of Mortality. Results: Most of the patients were white (93.1%), female (63.8%), and aged 77.3 8.6 years. HF was diagnosed based in a new gold standard that considered the Framingham and Boston criteria plus echocardiography and ECG. HF was present in 170 pt (53.5%). Most of these 108 pt (63.5%) had HF with Preserved Ejection Fraction (HFPEF). The functional class III and IV NYHA was present in 87%. The BNP presented AUC 0.93 (CI 95%, 0.88 to 0.97). The best cutoff of BNP was 180 pg/ml with S 0.83 (CI 95%, 66.7 to 80.4) and Sp 0.90 (CI 95%, 76.7 to 95.4). LR + 6.7 (95 %, 3.1 to 14.3), accuracy of 77.7. In the bivariate analysis BNP> 180pg/ml was associated with a higher risk of mortality. In multivariate analysis HR BNP> 180pg/ml remained associated with increased risk of mortality HR 3.4 (HF 1.2 to 9.6 p 50% and mortality of 26%. The comparison HFS group and NHF showed RRR 0,21 (CI 95% 0,05 – 0,38) p<0,001. Betwin HFPEF group and N-HF group RRR 0,12 (CI 95% -0,02 0,27). HFS and HFPEF the RRR 0,089 (CI 95% -0,67 – 0,24). Ninety nine 99 deaths were recorded in the total group. Conclusion: The level of the BNP showed association with mortality index. The BNP is an independent prognostic biomarker of long-term mortality in patients with HF. Disclosure of Interest: None Declared