Risk Prognostic Markers Research Articles

Peripheral blood leukocyte telomere length as a possible prognostic marker for the development of atrial fibrillation

Atrial fibrillation is one of the most common heart rhythm disorders. The most prominent risk factor for atrial fibrillation is advanced age. Population ageing contributes to an increase in both the prevalence of this pathology and socio-economic burden of the disease for society in general and the patient in particular. Adequate therapy and prevention of atrial fibrillation requires the search for novel prognostic risk markers for disease development, progression, and patients response to therapy. One of these markers is the length of telomeres structures at the ends of chromosomes that protect them from degradation during cell division. The article provides an overview of world studies, both confirming and disproving the role of leukocyte telomere length in atrial fibrillation development.

Serial circulating tumour DNA analysis for locally advanced rectal cancer treated with preoperative therapy: prediction of pathological response and postoperative recurrence

BackgroundThe “watch-and-wait” approach is a common treatment option amongst patients with locally advanced rectal cancer (LARC). However, the diagnostic sensitivity of clinical modalities, such as colonoscopy and magnetic resonance imaging to determine pathological response, is not high. We analysed the clinical utility of circulating tumour DNA (ctDNA) of patients with LARC to predict response to preoperative therapy and postoperative recurrence.MethodsA serial ctDNA analysis of 222 plasma samples from 85 patients with LARC was performed using amplicon-based deep sequencing on a cell-free DNA panel covering 14 genes with over 240 hotspots.ResultsctDNA was detected in 57.6% and 22.3% of samples at baseline and after preoperative treatment, respectively, which was significantly different (P = 0.0003). Change in ctDNA was an independent predictor of complete response to preoperative therapy (P = 0.0276). In addition, postoperative ctDNA and carcinoembryonic antigen (CEA) were independent prognostic markers for risk of recurrence after surgery (ctDNA, P = 0.0127 and CEA, P = 0.0105), with a combined analysis having cumulative effects on recurrence-free survival (P = 1.0 × 10–16).ConclusionsSerial ctDNA analysis may offer clinically useful predictive and prognostic markers for response to preoperative therapy and postoperative recurrence in patients with LARC.

Changes in High-Density Lipoprotein Cholesterol and Risks of Cardiovascular Events: A Post Hoc Analysis from the PICASSO Trial

Background and purposeWhether pharmacologically altered high-density lipoprotein cholesterol (HDL-C) affects the risk of cardiovascular events is unknown. Recently, we have reported the Prevention of Cardiovascular Events in Asian Patients with Ischaemic Stroke at High Risk of Cerebral Haemorrhage (PICASSO) trial that demonstrated the non-inferiority of cilostazol to aspirin and superiority of probucol to non-probucol for cardiovascular prevention in ischemic stroke patients (clinicaltrials.gov: NCT01013532). We aimed to determine whether on-treatment HDL-C changes by cilostazol and probucol influence the treatment effect of each study medication during the PICASSO study. MethodsOf the 1,534 randomized patients, 1,373 (89.5%) with baseline cholesterol parameters were analyzed. Efficacy endpoint was the composite of stroke, myocardial infarction, and cardiovascular death. Cox proportional hazards regression analysis examined an interaction between the treatment effect and changes in HDL-C levels from randomization to 1 month for each study arm. ResultsOne-month post-randomization mean HDL-C level was significantly higher in the cilostazol group than in the aspirin group (1.08 mmol/L vs. 1.00 mmol/L, P<0.001). The mean HDL-C level was significantly lower in the probucol group than in the non-probucol group (0.86 mmol/L vs. 1.22 mmol/L, P<0.001). These trends persisted throughout the study. In both study arms, no significant interaction was observed between HDL-C changes and the assigned treatment regarding the risk of the efficacy endpoint. ConclusionsDespite significant HDL-C changes, the effects of cilostazol and probucol treatment on the risk of cardiovascular events were insignificant. Pharmacologically altered HDL-C levels may not be reliable prognostic markers for cardiovascular risk.

Controlling Nutritional Status (CONUT) score as immune-nutritional predictor of outcomes in patients undergoing peritoneal dialysis.

The Controlling Nutritional Status (CONUT) score was designed to assess the immune-nutritional status in patients. The aim of this study was to investigate the prognostic value of the CONUT score at the commencement of peritoneal dialysis (PD) for all-cause mortality, cardiovascular disease (CVD), and technique failure. This is a STROBE-compliant, retrospective, observational, single center study. A total of 252 patients with end stage renal disease initially undergoing PD were enrolled in the study. Baseline data were collected from The Third Affiliated Hospital of Soochow University Peritoneal Dialysis database. The primary outcome during follow-up was all-cause mortality. The secondary outcomes were CVD and technique failure. Univariate and multivariate Cox regression analyses were performed to estimate the association between confounding factors and outcomes. The area under the curve represented the test discriminative power of CONUT score and relevant clinical parameters. The Kaplan-Meier curve was used to compare the outcomes of the patients according to the cut-off CONUT score. During a median follow-up period of 1.9 years, 35 patients (13.9%) died, 38 (15.1%) experienced CVD events, 58 (23.0%) experienced technique failure. The high CONUT group (CONUT score>3) had significantly higher all-cause mortality (p=0.02), CVD prevalence (p<0.01), and technique failure rates (p<0.01) than the low CONUT group (CONUT score≤3). The CONUT score was an independent predictor of all-cause mortality (hazard ratio [HR]: 1.565; 95% CI: 1.305-1.876; p<0.001), CVD (HR: 1.346; 95% CI: 1.136-1.594; p=0.001), and technique failure (HR: 1.144; 95% CI: 1.006-1.302; p=0.041). The CONUT score is a straightforward and inexpensive indicator to evaluate the immune-nutritional status; it could be a reliable prognostic marker of all-cause mortality, CVD, and technique failure risk in patients undergoing PD.

Cell cycle progression score and PTEN as prognostic factors for metastasis in intermediate and high-risk prostate cancer.

e16575 Background: To evaluate the cell cycle progression (CCP) score and PTEN as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of NCCN intermediate and high risk prostate cancer. Methods: This IRB-approved case-cohort study included men treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to study outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. Metastasis-free survival (MFS) was analyzed with the Cox proportional hazards model, weighted for case-cohort design. CCP and PTEN were analyzed independently, and adjusted for CAPRA-S. The CCR score, which combines CCP and CAPRA-S, was also analyzed. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: There were 209 patients, of whom 42 were cases (metastasis). Median age was 59 years, 47% had Gleason 4+3 or higher, 48% had non-organ confined tumor, and 18% had seminal vesicle or lymph node involvement. NCCN risk was intermediate in 77% and high in 23%. Median follow-up was 4 years. Both CCP and PTEN, as well as CCR score, were statistically significant in univariate analyses, but only CCP retained statistical significance in a multivariable model of CCP, PTEN, and CAPRA-S (Table). Conclusions: This is the first comparison of the CCP score and PTEN as risk factors for metastasis in a recent RP cohort of patients at NCCN intermediate or high risk. Both CCP score and PTEN were strongly associated with MFS in univariate analyses, but only CCP score retained significance in a multivariable analysis with both biomarkers adjusted for CAPRA-S. [Table: see text]

Evaluation of FTO rs9939609 and MC4R rs17782313 Polymorphisms as Prognostic Biomarkers of Obesity: A Population-based Cross-sectional Study.

ObjectivesObesity is a significant risk factor for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity usually results from a combination of causes and contributing factors, including genetics and lifestyle choices. Many studies have shown an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) and the melanocortin-4 receptor (MC4R) genes with body mass index (BMI). Therefore, recognizing the main genes and their relevant genetic variants will aid prediction of obesity risk. The aim of our study was to investigate the frequency of rs9939609 and rs17782313 polymorphisms in FTO and MC4R genes in an Iranian population.MethodsWe enrolled 130 obese patients and 83 healthy weight controls and calculated their BMI. Genomic DNA was extracted from peripheral blood and the frequency of rs9939609 and rs17782313 polymorphisms in FTO and MC4R genes was determined using the tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR).ResultsSignificant associations were found between FTO rs9939609 and BMI. Where homozygous risk allele carriers (A-A) have significant higher odds ratio (OR) of being obese than individuals with normal BMI (OR = 6.927, p < 0.005, 95% confidence interval (CI): 3.48–13.78). No significant correlation between MC4R rs17782313 and obesity were observed when compared to healthy weight individuals. Although subjects with C-C genotype had higher odds of obesity (OR = 1.889, p = 0.077, 95%CI: 0.92–3.84).ConclusionsThis study shows a relationship between FTO polymorphism and increased BMI, therefore, SNP in the FTO gene influence changes in BMI and can be considered a prognostic marker of obesity risk.

Asleep (not night-time) blood pressure as prognostic marker of cardiovascular risk.

Asleep (not night-time) blood pressure as prognostic marker of cardiovascular risk.

Asleep blood pressure: significant prognostic marker of vascular risk and therapeutic target for prevention.

Sleep-time blood pressure (BP) is a stronger risk factor for cardiovascular disease (CVD) events than awake and 24 h BP means, but the potential role of asleep BP as therapeutic target for diminishing CVD risk is uncertain. We investigated whether CVD risk reduction is most associated with progressive decrease of either office or ambulatory awake or asleep BP mean. We prospectively evaluated 18078 individuals with baseline ambulatory BP ranging from normotension to hypertension. At inclusion and at scheduled visits (mainly annually) during follow-up, ambulatory BP was measured for 48 consecutive hours. During the 5.1-year median follow-up, 2311 individuals had events, including 1209 experiencing the primary outcome (composite of CVD death, myocardial infarction, coronary revascularization, heart failure, and stroke). The asleep systolic blood pressure (SBP) mean was the most significant BP-derived risk factor for the primary outcome [hazard ratio 1.29 (95% CI) 1.22-1.35 per SD elevation, P < 0.001], regardless of office [1.03 (0.97-1.09), P = 0.32], and awake SBP [1.02 (0.94-1.10), P = 0.68]. Most important, the progressive attenuation of asleep SBP was the most significant marker of event-free survival [0.75 (95% CI 0.69-0.82) per SD decrease, P < 0.001], regardless of changes in office [1.07 (0.97-1.17), P = 0.18], or awake SBP mean [0.96 (0.85-1.08), P = 0.47] during follow-up. Asleep SBP is the most significant BP-derived risk factor for CVD events. Furthermore, treatment-induced decrease of asleep, but not awake SBP, a novel hypertension therapeutic target requiring periodic patient evaluation by ambulatory monitoring, is associated with significantly lower risk for CVD morbidity and mortality.

Ma et al. reply.

Replying to: H. E. Gee, et al. , 10.1038/nature07362 (2008) Gee et al. contest that microRNA-10b is not a prognostic marker for metastasis risk in breast cancer1. However, their observations do not bear on the pro-metastatic roles of microRNA-10b (miR-10b) as we described them2, nor do they undermine our conclusions1.

Association of Apathy With Risk of Incident Dementia

Fear of dementia is pervasive in older people with cognitive concerns. Much research is devoted to finding prognostic markers for dementia risk. Studies suggest apathy in older people may be prodromal to dementia and could be a relevant, easily measurable predictor of increased dementia risk. However, evidence is fragmented and methods vary greatly between studies. To systematically review and quantitatively synthesize the evidence for an association between apathy in dementia-free older individuals and incident dementia. Two reviewers conducted a systematic search of Medline, Embase, and PsychINFO databases. Inclusion criteria were (1) prospective cohort studies, (2) in general populations or memory clinic patients without dementia, (3) with clear definitions of apathy and dementia, and (4) reporting on the association between apathy and incident dementia. PRISMA and MOOSE guidelines were followed. Data were extracted by 1 reviewer and checked by a second. Main outcomes were pooled crude risk ratios, maximally adjusted reported hazard ratios (HR), and odds ratios (OR) using DerSimonian-Laird random effects models. The mean age of the study populations ranged from 69.2 to 81.9 years (median, 71.6 years) and the percentage of women ranged from 35% to 70% (median, 53%). After screening 2031 titles and abstracts, 16 studies comprising 7365 participants were included. Apathy status was available for 7299 participants. Studies included populations with subjective cognitive concerns (n = 2), mild cognitive impairment (n = 11), cognitive impairment no dementia (n = 1), or mixed cognitive and no cognitive impairment (n = 2). Apathy was present in 1470 of 7299 participants (20.1%). Follow-up ranged from 1.2 to 5.4 years. In studies using validated apathy definitions (n = 12), the combined risk ratio of dementia for patients with apathy was 1.81 (95% CI, 1.32-2.50; I2 = 76%; n = 12), the hazard ratio was 2.39 (95% CI, 1.27-4.51; I2 = 90%; n = 7), and the odds ratio was 17.14 (95% CI, 1.91-154.0; I2 = 60%; n = 2). Subgroup analyses, meta-regression, and individual study results suggested the association between apathy and dementia weakened with increasing follow-up time, age, and cognitive impairment. Meta-regression adjusting for apathy definition and follow-up time explained 95% of heterogeneity in mild cognitive impairment. Apathy was associated with an approximately 2-fold increased risk of dementia in memory clinic patients. Moderate publication bias may have inflated some of these estimates. Apathy deserves more attention as a relevant, cheap, noninvasive, and easily measureable marker of increased risk of incident dementia with high clinical relevance, particularly because these vulnerable patients may forgo health care.

Abstract 4233: Racial differences in patterns of cytogenetic abnormalities in multiple myeloma

Abstract Introduction: African American (AA) patients with Multiple Myeloma (MM) are diagnosed at younger ages and show an age-adjusted incidence twice as high as that seen in European Americans (EA); however, a study by Waxman et al found higher disease specific survival in AA. A recent study showed differences in chromosomal aberrations between AA and EA, but further work is needed to understand racial differences in cytogenetics through Fluorescent In Situ Hybridization (FISH) using an extensive array of probes. Methods: We identified 470 consecutive patients with MM from the University of Chicago Cancer Cytogenetics Laboratory from October 2003-January 2017. Of those, 127 (22%) patients had abnormal karyotypes and 343 were evaluated by FISH using a panel of 18 probes. Twenty-two patients who self-identified as Hispanic, Multiracial, Asian, or Indian were dropped from the analysis due to low numbers. For the remaining 311 patients, we obtained data on IGH translocations (partner genes included IGH/FGFR3 fusion [t(4;14)(p16.3;q32)]; IGH/CCND1 fusion [t(11;14)(q13;q32)]; IGH/MAF fusion [t(14;16)(q32;q23)]); TP53 loss [17p13.1]; CDKN2C loss [1p32.3]; CKS1B gain [1q21]; ATM losss [(11)(q22.3)11(q22.3)]; trisomy of chromosomes 3, 7, 9, 12, and 15; and chromosome 13 loss or interstitial deletion of 13q. We grouped the FISH results as high (loss of TP53, loss of CDKN2C; CKS1B gain, IGH/MAF fusion), intermediate (IGH/FGFR3 fusion), or standard (Trisomies 3, 7, 9, 15; Gain of TP53, Gain of ATM, chromosome 13 loss) prognostic risk markers. Results: Of 311 patients, 172 (55.3%) are self-reported EA, 130 (41.8%) are AA. Compared with EA, AA patients were more likely to be females (44.8% vs. 59.2%, respectively) and older than 65 years at diagnosis (47.7% vs. 56.2% respectively). Overall, 6.3% of patients were younger than 45 years at diagnosis, but there was no racial difference in the proportion of young patients. Compared with EA, AA patients assessed with standard risk probes were less likely to have standard risk cytogenetic features (48% vs. 66%; p-value=0.02). AA patients showed a lower percentage of hyperdiploidy, 36.5% of AA patients assessed were positive for hyperdiploidy compared with 57.1% of assessed EA (p=0.02). Despite the lower proportion of AA with cytogenetic markers associated with favorable prognosis, there was no significant difference between EA and AA patients in the prevalence of adverse prognostic markers, such as TP53 deletion, IGH/MAF fusions, or CKS1B gain. However, we did observe that AA patients were more likely to have loss of CDKN2C (16.7% vs 3.6%, p=0.02). Conclusions: We found that compared with EA, AA patients are less likely to have cytogenetic features associated with favorable prognosis (i.e. hyperdiploidy), yet AA do not have a higher prevalence of high risk cytogenetics. These findings suggest that cytogenetics alone may not fully explain racial/ethnic differences in MM mortality. [Meytal Chernoff and Madina Sukhanova are co-first authors of this abstract.] Citation Format: Meytal B. Chernoff, Madina Sukhanova, Liz Stepniak, Wei Zhang, Brian C. Chiu. Racial differences in patterns of cytogenetic abnormalities in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4233.

Study of neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) as a predictor inflammatory marker for diabetic nephropathy in type 2 diabetic patients

Background: Diabetes mellitus (DM) is a systemic disease having serious microvascular and macrovascular complications. DN in T2DM has an inflammatory pathology. Many inflammatory markers have been found to be related to DN, such as interleukin1 (IL1), IL6, IL8, transforming growth factor beta 1(TGF-β1) and tumor necrosis factor alpha (TNF α). However, their measurement is not used routinely as it is not easy to do it, in this respect. Search for inflammatory markers for the disease is a continuous process to enhance the diagnostic and treatment process. Aim of the Work: To assess neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) as a predictor inflammatory markers for diabetic nephropathy in type 2 diabetic patients. Patients and Methods: This study is a prospective one that was carried out on one hundred (100) type 2 Diabetes mellitus (T2DM) patients attending to internal medicine outpatient clinic and inpatient department of internal medicine at Al-Azhar university hospital, Damietta and twenty five (25) apparently healthy volunteers as a control. The populations of the study were classified into three groups according to their level of albuminuria. All were subjected tofull history and Clinical examination, Laboratory tests include Fasting mid-stream urine samples were obtained and examined for complete urine analysis and albumin/creatinine ratio (UACR),Complete blood count (CBC), HbA1c,Fasting blood sugar, Renal Function Tests,eGFR and Abdominal ultrasonography, Fundus examination and ECG and Assessment of NLR &PLR. Results: Our study showed that there was high statistically significant increased NLR, PLR and UACR in group IB when compared to group IA, II and III. Also there was statistically significant increased NLR,PLR and UACR in group IA in comparison to group II and also there was statistically significant increased NLR,PLR and UACR in group II in comparison to group III. Conclusion: Neutrophil lymphocyte ratio (NLR) & Platelet lymphocyte ratio (PLR) was significantly associated with diabetic nephropathy (DN) and high Neutrophil lymphocyte ratio (NLR) & Platelet lymphocyte ratio (PLR) values may be considered as a predictor and a prognostic risk markers of diabetic nephropathy (DN).

Integrated bioinformatics analysis reveals that the expression of cathepsinS is associated with lymph node metastasis and poor prognosis in papillary thyroid cancer.

The prognosis of the majority of patients with papillary thyroid cancer (PTC) is excellent, although there are patients who experience disease recurrence and progression. The aim of the present study was to identify potential prognostic risk markers in PTC. Differentially expressed genes (DEGs), identified from four Genome Expression Omnibus cohorts were subjected to functional enrichment analyses with Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genome pathways. Hub genes, filtered from cytoHubba, were validated using the The Cancer Genome Atlas (TCGA) cohort, and their associations with clinicopathological features and prognosis were analyzed. A total of 277 DEGs were identified following data preprocessing. DEGs were primarily enriched in ‘small cell lung cancer’, ‘ECM-receptor interaction’, ‘pathways in cancer’ and ‘tyrosine metabolism’. Hub genes [APOE, cathepsin S (CTSS), insulin receptor substrate 1 (IRS1), KIT, LGALS3, RUNX2 and TGFBR1] were extracted from cytoHubba. Their expression in the TCGA cohort was consistent with that in the GEO cohorts. CTSS (P=0.006) and IRS1 (P=0.005) were associated with disease-free survival, as determined using the Kaplan-Meier analysis. CTSS was an independent risk factor for poor disease-free survival (HR, 2.649; 95% CI, 1.095–6.409; P=0.031). Patients with high expression of CTSS exhibited different histological types (increased tall-cell subtype and reduced follicular subtype; P<0.001), more frequent lymph node metastasis (P<0.001) and advanced tumor-node-metastasis stages (P=0.049) compared with the low-expression group. High expression of CTSS was independently associated with lymph node metastasis (OR, 2.015; 95% CI, 1.225–3.315; P=0.006). Therefore, CTSS may serve as a predictive risk marker for the progression and prognosis of PTC.

Systemic redox biomarkers and their relationship to prognostic risk markers in autosomal dominant polycystic kidney disease and IgA nephropathy

BackgroundOxidative stress is evident from an early stage in chronic kidney disease (CKD). Therefore, we investigated redox biomarkers in polycystic kidney disease (ADPKD) and IgA nephropathy (IGAN). MethodsThis is a case-control study with three groups: ADPKD (n = 54), IGAN (n = 58) and healthy controls (n = 86). The major plasma aminothiols with their redox species were examined: homocysteine (Hcy), cysteinglycine (CG), cysteine (Cys) and glutathione (GSH). The redox ratio was the ratio of reduced free and oxidized aminothiols in plasma. We investigated malonedialdehyde (MDA) and advanced oxidation protein products (AOPP), and ten single nucleotide polymorphisms of antioxidant enzymes. ResultsPatients had elevated oxidized free Hcy and Cys with associated low redox ratios – most pronounced in IGAN. Patients with IGAN had elevated AOPP and possibly MDA. Oxidized free Hcy and Cys with redox ratios were correlated to AOPP, MDA and proteinuria. Furthermore, there was an independent relationship to parathyroid hormone (PTH). IGAN had an elevated frequency of Val16Ala SNP rs4880, which influence the function of mitochondrial superoxide dismutase 2 (p = 0.03). ConclusionsPatients with ADPKD and IGAN have evidence of oxidative stress from stage 1 to 4 – most pronounced in IGAN. In patients, aminothiol redox biomarkers were correlated to AOPP, proteinuria and PTH, which are known prognostic markers in CKD. It may be possible that oxidative stress influences PTH dysregulation in CKD.The association between IGAN and the redox related variant allele rs4880(C) might indicate a new susceptibility locus for IGAN, but this needs verification.

Evolving Role of Natriuretic Peptides from Diagnostic Tool to Therapeutic Modality.

Natriuretic peptides (NP) are widely recognized as key regulators of blood pressure, water and salt homeostasis. In addition, they play a critical role in physiological cardiac growth and mediate a variety of biological effects including antiproliferative and anti-inflammatory effects in other organs and tissues. The cardiac release of NPs ANP and BNP represents an important compensatory mechanism during acute and chronic cardiac overload and during the pathogenesis of heart failure where their actions counteract the sustained activation of renin-angiotensin-aldosterone and other neurohormonal systems. Elevated circulating plasma NP levels correlate with the severity of heart failure and particularly BNP and the pro-peptide, NT-proBNP have been established as biomarkers for the diagnosis of heart failure as well as prognostic markers for cardiovascular risk. Despite activation of the NP system in heart failure it is inadequate to prevent progressive fluid and sodium retention and cardiac remodeling. Therapeutic approaches included administration of synthetic peptide analogs and the inhibition of NP-degrading enzyme neutral endopeptidase (NEP). Of all strategies only the combined NEP/ARB inhibition with sacubitril/valsartan had shown clinical success in reducing cardiovascular mortality and morbidity in patients with heart failure.

Abstract IA05: Immunoprevention of oral cancers

Abstract Oral pre-malignant lesions (OPLs) are usually clinically characterized as leukoplakia or erythhroplakia, and confer an increased risk of oral cancer. Despite decades of clinical investigations with candidate chemopreventive agents such as 13-cis-retinoic acid, beta-carotene, fenretinide, green-tea extract, celecoxib, erlotinib, among others, a standard-of-care chemoprevention strategy for oral cancers has not yet been developed. Importantly, OPLs and oral cavity cancers are not related to HPV, thus HPV vaccines are not expected to be effective in this setting. One of the greatest challenges in managing patients with OPLs is determining risk for malignant transformation and need for intervention. To that end, retrospective and prospective studies have been completed by our group and others and demonstrate that LOH profiles (primarily at 13p14 and/or 9p21) in OPLs are associated with higher incidence of oral cancers. LOH is now considered the most robust prognostic marker of cancer risk in this setting, and these data now set the stage for development of clinical trials focused on molecularly-defined high risk groups of OPLs. Immune checkpoint blockade with antibodies directed at programmed cell death protein 1 (PD-1) has recently been successfully developed for the management of advanced head and neck squamous cell carcinomas, validating the importance of immune modulation in the progression of these invasive tumors. Given the favorable toxicity profile, there is interest in studying these agents for prevention of oral cancers in patients with high risk OPLs. In this presentation, we will review the data that support a role for immune surveillance and immune editing in the development of oral cancers, and describe the rationale and clinical trial design of the Immunoprevention of Oral Cancer (IPOC) study, the first randomized trial to evaluate the PD-1 inhibitor pembrolizumab for oral cancer prevention in patients with molecularly-defined high-risk OPLs. Citation Format: William N. William, Jr. Immunoprevention of oral cancers [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA05.

Serum uric acid as a potential marker for heart failure risk in men on antihypertensive treatment: The British Regional Heart Study

The role of serum uric acid (SUA) as a prognostic marker for incident heart failure (HF) in hypertensive subjects is uncertain. We have prospectively examined the relationship between SUA and incident HF in 3440 men aged 60–79years separately in those on and not on antihypertensive treatment who were followed up for a mean period of 15years. Men on SUA lowering drugs and those with history of HF or myocardial infarction were excluded. There were 260 incident HF cases. The men were divided into three groups of SUA concentrations/levels (<350, 350–410 and >410μmol/L). Raised SUA was associated with significantly increased risk of HF in men on antihypertensive treatment (N=949) but not in those without (N=2491) (p=0.003 for interaction). In men on antihypertensive treatment those with hyperuricemia (>410μmol/L) had the most adverse biological risk profile for HF including the highest rates of atrial fibrillation and renal dysfunction and the highest mean level of BMI, c-reactive protein and cardiac function (cardiac troponin T). Treated hypertensive men with SUA levels>410μmol/L showed an increase in risk of HF of more than twofold compared to those on treatment with levels <350μmol/L even after adjustment for lifestyle characteristics and biological risk factors [adjusted hazard ratio 2.26 (1.23,4.15)]. SUA improved prediction of HF beyond routine conventional risk factors (p=0.02 for improvement in c-statistics). SUA as a marker of increased xanthine oxidase activity may be a useful prognostic marker for HF risk in older men on antihypertensive treatment.

Identification and functional analysis of risk-related microRNAs for the prognosis of patients with bladder urothelial carcinoma.

The aim of the present study was to investigate risk-related microRNAs (miRs) for bladder urothelial carcinoma (BUC) prognosis. Clinical and microRNA expression data downloaded from the Cancer Genome Atlas were utilized for survival analysis. Risk factor estimation was performed using Cox's proportional regression analysis. A microRNA-regulated target gene network was constructed and presented using Cytoscape. In addition, the Database for Annotation, Visualization and Integrated Discovery was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, followed by protein-protein interaction (PPI) network analysis. Finally, the K-clique method was applied to analyze sub-pathways. A total of 16 significant microRNAs, including hsa-miR-3622a and hsa-miR-29a, were identified (P<0.05). Following Cox's proportional regression analysis, hsa-miR-29a was screened as a prognostic marker of BUC risk (P=0.0449). A regulation network of hsa-miR-29a comprising 417 target genes was constructed. These target genes were primarily enriched in GO terms, including collagen fibril organization, extracellular matrix (ECM) organization and pathways, such as focal adhesion (P<0.05). A PPI network including 197 genes and 510 interactions, was constructed. The top 21 genes in the network module were enriched in GO terms, including collagen fibril organization and pathways, such as ECM receptor interaction (P<0.05). Finally, 4 sub-pathways of cysteine and methionine metabolism, including paths 00270_4, 00270_1, 00270_2 and 00270_5, were obtained (P<0.01) and identified to be enriched through DNA (cytosine-5)-methyltransferase (DNMT)3A, DNMT3B, methionine adenosyltransferase 2α (MAT2A) and spermine synthase (SMS). The identified microRNAs, particularly hsa-miR-29a and its 4 associated target genes DNMT3A, DNMT3B, MAT2A and SMS, may participate in the prognostic risk mechanism of BUC.

CARRIAGE OF THYROID ANTIBODIES AS A RISK FACTOR IN THE DEVELOPMENT AND PROGRESSION OF ENDOCRINE OPHTHALMOPATHY

The influence of the carrier of thyroid autoantibodies (to thyroid-stimulating hormone receptor, to thyroglobulin, to thyroid peroxidase) on the clinical course of endocrine ophthalmopathy (EOP), developed on the background of diffuse toxic goiter (139 patients). We studied the role of carrier of monoantibodies and their combinations. It has been proven a direct link between the presence of the analyzed thyroid autoantibodies and the clinical course of EOP. It is shown that the presence of antibodies to thyroid peroxidase and anti-thyroglobulin antibodies is not a lesser important risk factor for the development of EOP in patients with diffuse toxic goiter than the presence of antibodies to the receptor for thyroid-stimulating hormone, and the multiple carriers is associated with more frequent development of active forms of EOP and higher amplitude of inflammation of the orbit. Thus, serological indices and spectrum of thyroid antibodies revealed the depth of systemic disorders of autoimmunity, associated with an increased risk of the development of local autoimmune inflammation in the orbit and can serve as prognostic risk markers of development of highly active and severe forms of EOP.

CSPG4: A Target for Selective Delivery of Human Cytolytic Fusion Proteins and TRAIL.

Chondroitin-sulfate proteoglycan 4 (CSPG4) is a transmembrane glycoprotein overexpressed on malignant cells in several cancer types with only limited expression on normal cells. CSPG4 is implicated in several signaling pathways believed to drive cancer progression, particularly proliferation, motility and metastatic spread. Expression may serve as a prognostic marker for survival and risk of relapse in treatment-resistant malignancies including melanoma, triple negative breast cancer, rhabdomyosarcoma and acute lymphoblastic leukemia. This tumor-associated overexpression of CSPG4 points towards a highly promising therapeutic target for antibody-guided cancer therapy. Monoclonal αCSPG4 antibodies have been shown to inhibit cancer progression by blocking ligand access to the CSPG4 extracellular binding sites. Moreover, CSPG4-directed antibody conjugates have been shown to be selectively internalized by CSPG4-expressing cancer cells via endocytosis. CSPG4-directed immunotherapy may be approached in several ways, including: (1) antibody-based fusion proteins for the selective delivery of a pro-apoptotic factors such as tumor necrosis factor-related apoptosis-inducing ligand to agonistic death receptors 4 and 5 on the cell surface; and (2) CSPG4-specific immunotoxins which bind selectively to diseased cells expressing CSPG4, are internalized by them and induce arrest of biosynthesis, closely followed by initiation of apoptotic signaling. Here we review various methods of exploiting tumor-associated CSPG4 expression to improve targeted cancer therapy.