Cox Method Research Articles

Estimation of persistent sodium-current density in rat hippocampal mossy fibre boutons: Correction of space-clamp errors.

We used whole-cell patch clamp to estimate the stationary voltage dependence of persistent sodium-current density (iNaP) in rat hippocampal mossy fibre boutons. Cox's method for correcting space-clamp errors was extended to the case of an isopotential compartment with attached neurites. The method was applied to voltage-ramp experiments, in which iNaP is assumed to gate instantaneously. The raw estimates of iNaP led to predicted clamp currents that were at variance with observation, hence an algorithm was devised to improve these estimates. Optionally, the method also allows an estimate of the membrane specific capacitance, although values of the axial resistivity and seal resistance must be provided. Assuming that membrane specific capacitance and axial resistivity were constant, we conclude that seal resistance continued to fall after adding TTX to the bath. This might have been attributable to a further deterioration of the seal after baseline rather than an unlikely effect of TTX. There was an increase in the membrane specific resistance in TTX. The reason for this is unknown, but it meant that iNaP could not be determined by simple subtraction. Attempts to account for iNaP with a Hodgkin-Huxley model of the transient sodium conductance met with mixed results. One thing to emerge was the importance of voltage shifts. Also, a large variability in previously reported values of transient sodium conductance in mossy fibre boutons made comparisons with our results difficult. Various other possible sources of error are discussed. Simulations suggest a role for iNaP in modulating the axonal attenuation of EPSPs. KEY POINTS: We used whole-cell patch clamp to estimate the stationary voltage dependence of persistent sodium-current density (iNaP) in rat hippocampal mossy fibre boutons, using a KCl-based internal (pipette) solution and correcting for the liquid junction potential (2mV). Space-clamp errors and deterioration of the patch-clamp seal during the experiment were corrected for by compartmental modelling. Attempts to account for iNaP in terms of the transient sodium conductance met with mixed results. One possibility is that the transient sodium conductance is higher in mossy fibre boutons than in the axon shaft. The analysis illustrates the need to account for various voltage shifts (Donnan potentials, liquid junction potentials and, possibly, other voltage shifts). Simulations suggest a role for iNaP in modulating the axonal attenuation of excitatory postsynaptic potentials, hence analog signalling by dentate granule cells.

Impacto pronóstico de la enfermedad pulmonar obstructiva crónica y el asma bronquial en pacientes con insuficiencia cardiaca

PurposeTo analyze the impact of chronic obstructive pulmonary disease (COPD) and bronchial asthma on therapeutic management and prognosis of patients with heart failure (HF). MethodsAnalysis of the information collected in a clinical registry of patients referred to a specialized HF unit from January-2010 to June-2012. Clinical profile, treatment and prognosis of patients was evaluated, according to the presence of COPD or asthma. Survival analyses were conducted by means of Kaplan-Meier and Cox's methods. Median follow-up was 1493 days. ResultsWe studied 2577 patients, of which 251 (9.7%) presented COPD and 96 (3.7%) bronchial asthma. Significant differences among study groups were observed regarding to the prescription of beta-blockers (COPD=89.6%; asthma=87.5%; no bronchopathy=94.1%; P=.002) and SGLT2 inhibitors (COPD=35.1%; asthma=50%; no bronchopathy=38.3%; P=.036). Also, patients with bronchial disease received less frequently a defibrillator (COPD=20.3%; asthma=20.8%; no broncopathy=29%; P=.004).COPD was independently associated with increased risk of all-cause mortality (HR=1.64; 95%CI: 1.33-2.02), all-cause death or HF admission (HR=1.47; 95%CI: 1.22-1.76) and cardiovascular death or heart transplantation (HR=1.39; 95%CI: 1.08-1.79) as compared with patients with no bronchopathy. Bronchial asthma was not significantly associated with increased risk of adverse outcomes. ConclusionsCOPD, but not asthma, is an adverse independent prognostic factor in patients with HF.

Risk characteristics with seven epithelial-mesenchymal transition-related genes are used to predict the prognosis of patients with hepatocellular carcinoma.

Epithelial-mesenchymal transition (EMT)-related genes (ERGs) have been shown to play an important role in cancer invasion, tumor resistance, and tumor metastasis of hepatocellular carcinoma. This study sought to examine the prognostic value of ERGs and other pre-hepatoma genes. Relevant data from The Cancer Genome Atlas (TCGA) were analyzed and synthesized. Specifically, 1,014 ERGs were downloaded and subject to a gene set enrichment analysis; 318 different EAG expressions were found, and the possible molecular mechanism of EAG was predicted by GO analysis and KEGG analysis. To determine the prediction of ERGS, a Cox regression model was used to establish a risk hypothesis. Based on risk patterns, patients were divided into high- or low-risk groups. Kaplan-Meier and receiver operating characteristic (ROC) curves confirmed the predictive value of the model. Seven prognostically relevant ERGs (i.e., ECT2, EZH2, MYCN, ROR2, SPP1, SQSTM1, and STC2) were identified. Using Cox's regression analysis method, appropriate cases were selected to establish a new risk prediction model. Under the risk model, the overall survival rate of the low-risk group samples was higher than that of the high-risk group samples (P<0.00001). In short, we developed a risk model for liver cancer based on ERGs terminology. This model improve the postpartum treatment of patients with liver cancer.

Overexpression of the OCT-1 Gene Is a Biomarker Associated with Poor Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) - Data from a Retrospective Cohort from Latin America: Defining a Very High-Risk Clinical-Molecular Subgroup

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy, representing 30-40% of all non-Hodgkin's lymphomas (NHLs). They comprise a group of aggressive and heterogeneous neoplasms in terms of clinical presentation, response to therapy and prognosis. The OCT-1 gene is a member of the homodomain-POU family of transcriptional regulators of B-lymphoid differentiation. OCT-1 acts by controlling the expression of specific B-cell genes, such as BCL-2, a potent inhibitor of apoptosis that is essential for the differentiation of B-cells in the germinal center. These genes can be expressed in DLBCL, but the role of BCL-2 in its prognosis has been contradictory and the prognostic impact of the OCT-1 gene has not yet been tested in this lymphoma. Methods: In this observational, retrospective, single-center study, we investigated the prognostic impact of BCL-2 and OCT-1 gene expression in Brazilian patients with DLCBL treated with immunopolychemotherapy R-CHOP in a real-world context. The BCL-2 and OCT-1 genes were assessed in 78.5% (77/98) DLBCL patients, and the RNA for quantitative real-time PCR (qRT-PCR) was isolated from formalin-fixed and paraffin-embedded (FFPE) samples. The values obtained for gene expression were transformed into categorical variables according to their medians (6.27 for BCL-2 and 24.5 for OCT-1). The association between clinical and laboratory variables and results of gene expression was verified by the Fischer test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariate analysis was performed using Cox's bivariate regression method and multivariate analysis using Cox multiple regression methodology. Results: The median age of the cohort was 54.5 years (15-84), 50% (49/98) were male, 49.4% (38/77) and 51.4% (40/77) showed expression of OCT-1 and BCL- 2 ≥ median, respectively. The clinical characteristics of the 98 Brazilian patients with DLBCL that comprised our cohort are summarized in Table 1. The overall response rate (ORR) in all patients was 68.4% (67/98), 65.3% (64/98) showed a complete response (CR), and 3.1% (3/98) showed partial response (PR), while 6.1% (6/98) were primary refractory. With a median follow-up of 3.77 years (95% CI: 3.2-4.1), the median overall survival (OS) was 5.43 years (95% CI: 2.2-NR) and the median progression-free survival (PFS) was 5.15 years (95% CI: 2.9-NR). The 5-year OS and PFS was 54.2% (42.2% -64.8%) and 52.0% (40.1-62.6%), respectively. In the univariate analysis OCT-1 ≥ median was associated with shortened OS (HR: 2.45, 95% CI: 1.21-4.96, p = 0.013) and PFS (HR: 2.27, 95% CI: 1.14-4.51, p = 0.019). Overexpression of BCL-2 was associated with worse PFS (HR: 2.00, 95% CI: 1.02-3.95, p = 0.043). Subgroup analysis showed that OCT-1 overexpression predominated in elderly individuals (≥ 60 years) in a statistically significant mode (29/38 cases - 76.3%, p = 0.029). It was also observed that overexpression of OCT-1 was associated with worse OS in the high-risk adjusted International Prognostic Index (aIPI) subgroup (p = 0.048) - Figure 1, and worse PFS in patients ≥ 60 years old (p = 0.025) - Figure 2. In the multivariate analysis, overexpression of OCT-1 was associated with poor PFS (HR: 2.22, 95% CI: 1.06-4.76, p = 0.035). Conclusion: In this study, we demonstrated that overexpression of the OCT-1 gene was an independent prognostic factor associated with adverse outcomes in Brazilian patients with DLCBL. We also show that in patients with unfavorable risk, such as the elderly and those with intermediate-high and high-risk IPI, overexpression of OCT-1 contributed to the identification of a very high-risk clinical-molecular subgroup, where the results with standard R-CHOP therapy are unsatisfactory, and they may benefit from intensified therapeutic strategies. Our results are preliminary and need to be validated in subsequent studies of prospective nature and with an expanded sample. Disclosures No relevant conflicts of interest to declare.

MMP11 expression in intratumoral inflammatory cells in breast cancer.

It is known that matrix metalloproteinase (MMP)-11 has a role in tumour development and progression, and also that immune cells can influence cancer cells to increase their proliferative and invasive properties. The aim of the present study was to propose the evaluation of MMP11 expression by intratumoral mononuclear inflammatory cells (MICs) as a useful biological marker for breast cancer prognosis. This study comprised 246 women with invasive breast carcinoma, and a long follow-up period. Patients were stratified with regard to nodal status and to the development of metastatic disease. The median follow-up period in patients without metastasis was 146months and in patients with metastatic disease 31months. MMP11 was determined by immunohistochemistry. For relapse-free survival (RFS) and overall survival (OS) analysis we used the Cox's univariate method. Cox's regression model was used to examine the interactions between different prognostic factors in a multivariate analysis. Our results showed that MMP11 expression by stromal cells was significantly associated with prognosis. MMP11 expression by cancer-associated fibroblasts (CAFs) was associated with both shortened RFS and OS, but MMP11 expression by MICs showed a stronger association with both shortened RFS and OS, therefore being the most potent and independent factor to predict RFS and OS.

Renal Disease Is Associated With Poor Outcomes Following Isolated Coronary Artery Bypass Grafting

BackgroundPeople with renal disease have a markedly higher risk of cardiovascular disease as well as morbidity and mortality after cardiac surgery. Little is known regarding the post-operative adverse outcomes following isolated coronary artery bypass graft (CABG) in the Australian population with renal disease. ObjectivesThe aim of this study was to examine the effect of different stages of renal disease on patients' risk of post-operative mortality and complications following isolated CABG in an Australian cohort. MethodsUsing the ANZSCTS (Australian and New Zealand Society of Cardiac and Thoracic Surgeons) registry, data from 44,968 patients who underwent isolated CABG between 2001 and 2014 were used. The effect of renal disease stages on short- and long-term outcomes were examined using multivariable logistic and Cox's regression methods respectively. ResultsThree of 4 Australian patients (74.6%) who underwent isolated CABG had some degree of renal disease: 50.2% mild; 20.9% moderate; 2.1% severe; and 1.6% dialysis-dependent. Adjusted risk of 30-day mortality increased with deteriorating renal disease from mild (1.6-fold) to dialysis-dependent (4.6-fold). Worsening renal disease was also associated with higher risk of post-operative complications. Hazard ratio for long-term survival shows steady increase of mortality risk with worsening renal disease categories from 1.1-fold for mild to 3.9-fold for patients on dialysis. ConclusionsPre-existing renal disease is significantly associated with 30-day and long-term mortality, length of intensive care unit and hospital stay as well as several other post-operative complications.

Prognostic relevance of ATM protein in uveal melanoma and its association with clinicopathological factors.

Uveal melanoma (UM) is an intraocular malignancy commonly arising from choroid which can cause visual loss or metastasis. Ataxia-telangiectasia mutated (ATM) protein is an activator of DNA damage response and its role in uveal melanoma (UM) is still unexplored. Therefore, the study aims to detect the expression and localization of ATM protein and its association with clinicopathological parameters METHODS: Expression of nuclear ATM (nATM) was investigated on 69 formalin fixed paraffin embedded choroidal melanoma samples by immunohistochemistry and validated by western blotting. Results were then correlated with clinical and histopathological parameters. Prognostic significance was determined by the Kaplan-Meier analysis and the multivariate analysis by Cox's hazard proportional method. Loss of nATM was observed in 65% of cases, which was statistically significant with the reduced disease-free survival (p = 0.042). This loss was more frequently found in cases with high-risk histopathological factors like epithelioid cell type, tumor infiltrating lymphocytes and high pigmentation which might help in the progression of melanoma. On multivariate analysis, extraocular spread and loss of nATM were found to be independent prognostic factors (p < 0.05). Our data suggest that loss of nATM protein might serve as a poor prognostic marker in the pathogenesis of uveal melanoma which may lead to increased risk of metastasis.

Mutations in RUNX1 and TP53 Genes Predict Progression in Patients with Lower-Risk Myelodysplastic Syndrome

Background and AimsA part of lower-risk myelodysplastic (LR-MDS) patients progress to higher-risk MDS or acute myeloid leukemia. These patients have more aggressive type of disease than is expected based on their classification according to the International Prognostic Scoring System. Alongside, recent advances in DNA sequencing have enabled the identification of a large number of mutated genes in more than 80% of MDS patients. We focused on the identification of mutational profile that would be predictive of disease progression in LR-MDS patients.MethodsWe examined samples from 73 LR-MDS patients by TruSight Myeloid Sequencing Panel containing 54 genes (Illumina) to determinate the mutational profile. In 32 (44%) patients, paired samples processed at the time of diagnosis and during progression were analyzed. The median age of patients was 64.5 years (range, 29-83 years). The median observation period was 33.4 months (range, 4.5-195.9 months) from diagnosis, 36 (49%) patients remained alive including 8 who underwent HSCT. The FASTQ files were analyzed by NextGENe V2.4.2.2 (SoftGenetics). The survival distributions were estimated using the Kaplan-Meier method and prognostic factor analysis was performed with Cox's multivariate regression method. The Mann-Whitney test was used to determine the group independence.ResultsIn total, 70% of patients had a recurrent mutation in at least one gene of the panel (87.5% of patients with progression and 56% without progression). The patients, who progressed, carried on average of 2.4 mutations and unprogressed patients 1.9 mutations. Most of the mutations detected in LR-MDS were in SF3B1 (30.1% of patients) and DNMT3A (24.7% of patients) genes but had no effect on overall survival (OS). Multivariate analysis demonstrated that RUNX1 and TP53 mutations were the strongest independent prognostic factors for OS (HR: 14.9; p=0.0001/HR:6.3; p=0.0007) at the time of diagnosis and also for progression-free survival (PFS) (HR: 3.6; p=0.05/HR:3.3; p=0.05). Moreover, mutations in these genes were detectable in 59.4% of patients with disease progression and only in 4.8% of patients without progression, who however were followed shortly (4.7 months). The median OS was 27.9 and 39.6 months in the patients with mutations of RUNX1 and TP53 genes compared to 84.2 months (p <0.0001) in patients without these mutations. The new mutations acquired during progression were present most in NRAS and PTPN11 genes. The variant allele frequency (VAF) of other mutations detected at the time of diagnosis increased during disease progression. Presence of mutations in TP53 gene (p=0.0006), RUNX1 gene (p=0.003), IPSS-R score (p=0.01) and hemoglobin level (p=0.05) were independent variables between patients with and without progression.ConclusionsThe goal of the study was to detect mutations in relevant genes that might predict disease progression up to 6 years from the time of diagnosis in LR-MDS patients and comparison of mutant allele frequencies in selected cases between the time of diagnosis and disease progression. We found that 60% of patients who progressed, carried mutations in RUNX1 and TP53 genes at the time of diagnosis. On the contrary, other mutations detectable at the time of diagnosis had no effect on OS and PFS. The VAF of mutations detected at the diagnosis increased at the time of progression. The NRAS and PTPN11 genes contained most of the new mutations acquired during progression. In conclusion, the results indicate that routine monitoring for mutations in LR-MDS should be performed to refine the risk prediction of disease progression.Supported by AZV grants (16-33485A, 16-31689A, 17-31398A and NV18-03-00227), RVO-VFN64165 and the project for conceptual development of research organization (00023736) from the Ministry of Health of the Czech Republic. DisclosuresNo relevant conflicts of interest to declare.

Significance of preoperative ischemia- modified albumin in operable and advanced gastric cancer.

Oxidative stress plays an important role in promoting proliferation and metastases of cancer, which can be represented by ischemia-modified albumin (IMA). The purpose of this study was to evaluate serum IMA level in patients with operable advanced gastric cancer and analyze its prognostic significance. A total of 274 patients with primary stage III gastric cancer underwent curative operation were enrolled in this study. Serum IMA level was measured within 24 hours before surgery, comparing with 112 healthy donors. The correlation between serum IMA level and survival outcome was analyzed by the Kaplan-Meier with Log-Rank test and Cox's regression methods, respectively. Serum IMA level from gastric cancer was higher than healthy control (0.41 ± 0.12 VS 0.23 ± 0.08; P< 0.001). Finally, 173 and 181 patients out of all 274 patients studied had died and recurrent, respectively. All patients were stratified into two groups using the optimal cutoff value (0.45) of IMA level using a sensitivity of 92.5% and a specificity of 65.2% as optimal conditions from receiver operating curve analysis. Patients with a IMA ⩾ 0.45 had poorer mean overall survival (44.68 months VS 30.94 months, P= 0.010) and mean recurrence free survival (42.36 months VS 28.82 months, p= 0.01) than patients with a IMA < 0.45 in univariate analysis and IMA also been confirmed as independent predictor for survival for GC patients in multivariate analysis (OR, 0.731; 95% CI: 0.329-1.282; p= 0.023). Serum IMA level can be considered as an independent prognostic factor for operable and advanced gastric cancer.

Abstract P3-08-05: Validation of a nomogram for predicting recurrence among women with ductal carcinoma in situ and breast conserving surgery in an integrated health care system

Abstract Current management of ductal carcinoma in situ (DCIS) most often entails removing the lesion by breast-conserving surgery. Quantifying the risk of a patient's ipsilateral breast event (IBE) recurrence, either invasive cancer or DCIS, after breast conserving surgery remains a clinical concern. The aim of this study was to validate the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram to predict IBE recurrence in patients from our institution. Patients and Methods We retrospectively identified 608 patients in the Kaiser Permanente Northwest integrated healthcare system with a diagnosis of DCIS who had undergone local excision from 1990 through 2007. We assessed the performance of the MSKCC nomogram for predicting IBE recurrence using measures of discrimination (how well risk scores separate those with and without the event) and calibration (agreement between predicted and observed risk). We calculated Harrell's C and R2D to provide estimates of discrimination. We calculated the calibration slope by performing a Cox regression using the prognostic index (PI; predicted log relative hazard based on the original Cox coefficients), with a slope not significantly different from 1 indicating no difference in discrimination from the development sample. We also examined discrimination by comparing the KM curves of 4 risk groups and in a Cox regression as a predictor, which were created using Cox's method (4 groups using the 16th, 50th, &amp; 84th percentiles), as no risk groups were defined in the MSKCC development study. We examined whether there was model misfit by testing each predictor in a Cox regression with an offset of the PI. Finally, we assessed calibration by plotting the observed rates and associated 95% CIs against the predicted probabilities for groups based on 4 risk groups and octiles. Results The median follow-up time for the KPNW cohort was 125 months. The 10-year IBE recurrence rate was 9.5%, 95% CI [7.0%, 13.0%). Harrell's C was .70, which is comparable to what has been found in other validation studies. The PI accounted for 22% of variation in time (R2D =.22, 95% CI [.08, .38]). The test of the calibration slope provided no support that discrimination in this sample differs from the development study (LR χ2(1)=0.21, p=.65). An examination of the Kaplan-Meier curves among the risk groups showed good separation of the high risk group compared to the others, but little separation between the lowest two risk groups. None of the predictors demonstrated evidence for differential weighting from the MSKCC coefficients (p values ranged from .08 to .97). Calibration was good for the lowest, low, and moderate risk groups, but there was underprediction in the high risk group. When examining calibration using octiles, we found a similar pattern to that of other validation studies in which the highest octile had the furthest departure from perfect agreement. Conclusion The MSKCC nomogram for predicting IBE recurrence in patients with DCIS who were treated with local excision have some utility, and our results are consistent with other validation efforts. However, there is much potential to further increase the prediction of recurrence beyond what is possible with the MSKCC nomogram. Citation Format: Leo MC, Francisco M, Jenkins C, Weinmann S. Validation of a nomogram for predicting recurrence among women with ductal carcinoma in situ and breast conserving surgery in an integrated health care system [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-05.

Prognostic value of SUVmax measured by pretreatment 18F-FDG PET/CT in patients with primary gastric lymphoma.

The aim of this retrospective study was to determine whether glucose metabolism assessed by fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) provides prognostic information independent of established prognostic factors in patients with gastric lymphoma. We reviewed the medical records of 86 patients retrospectively (men, 42; women, 44; mean age 58±13 years) with pathologically proven gastric lymphoma (34 mucosa-associated lymphoid tissue and 52 aggressive non-Hodgkin's lymphoma). They underwent F-FDG PET/CT as part of a pretreatment work-up from February 2004 to July 2012. For the analysis, patients were classified by age, sex, Musshoff stage, serum lactate dehydrogenase, International Prognostic Index score, extragastric spread, and visual intensity [visual assessment and maximum standardized uptake value (SUVmax), respectively]. The relationship between F-FDG uptake and survival was analyzed using the Kaplan-Meier method with a log-rank test and Cox's proportional-hazard regression method. The median survival of all 86 study participants was 1117 days and the median SUV measured by PET/CT was 6.1 (range, 1.9-32.7). Patients with an SUVmax less than or equal to 5.2 survived significantly longer than patients with an SUVmax more than 5.2 (median, 1163 vs. 1004 days; P=0.003). Survival was also found to be significantly related to age (P=0.0005), histological type (P=0.004), extragastric spread (P=0.0004), International Prognostic Index score (P<0.0001), serum lactate dehydrogenase (P=0.02), stage (P<0.0001), and visual intensity (P=0.041). A multivariate analysis showed that patients with a higher SUVmax [P=0.021; 95% confidence interval (CI), 1.52-8.14; hazard ratio (HR)=6.29], older age (P=0.001; 95% CI, 4.64-219.96; HR=18.8), more aggressive histologic type (P=0.006; 95% CI, 2.20-70.63; HR=12.76), and higher stage (P=0.0006; 95% CI, 5.81-206.43; HR=17.48) showed worse survival. A higher SUVmax on pretreatment F-FDG PET/CT can predict poorer survival in patients with gastric lymphoma.

Robert W. Cox's Method of Historical Structures Redux

This article argues that Cox's Method of Historical Structures (MHS), although a highly useful tool for understanding the world, should be adapted to make it more effective as a framework for understanding world order in the twenty-first century. The advent of the method helped rejuvenate critical scholarship in international relations and international political economy during the 1980s. It offered a way out of the excessively structural approaches that had dominated critical thinking in the 1960s and 1970s. Cox's method enabled the unpacking of a structure, so that the components that made up any particular configuration could be considered analytically. Providing guidance on how to look at an historical order, and how to consider the component features of that structure, proved to be a revelation for many critical scholars of international relations. Surprisingly, given Cox's highlighting of the distinction between critical and problem-solving theory introduced in the same Millennium article, what really distinguishes Cox's approach, and why it has had the impact it has, is the pragmatism of the method. The MHS offers the possibility of a more closely reasoned analysis of world order than was previously available. It was the practical and somewhat systematic quality of the MHS that made it influential because it offered to facilitate empirical research by critical scholars. Thirty-five years on, the Method looks less satisfactory and this article offers some suggestions for its development.

Clinical Significance of Preoperative CD8+ Central Memory T Cells for Operable Pancreatic Adenocarcinoma

Background: CD8+ central memory T cells (CD8+ Tcm) have superior roles in antitumor immunity. The purpose of this study was to detect CD8+ Tcm in the peripheral blood of patients with pancreatic adenocarcinoma and to analyze its clinic significance. Methods: Seventy two patients with primary pancreatic adenocarcinoma who underwent curative operation were enrolled. The percentage and absolute count of CD8+ Tcm in the peripheral blood of patients were analyzed through flow cytometry and the multiplatform predicate method, respectively, and these values were compared to those of the healthy control. The correlation between CD8+ Tcm and survival was analyzed by the Kaplan-Meier with log-rank test and Cox's regression methods, respectively. Results: The percentage of CD8+ Tcm from pancreatic adenocarcinoma was higher than the healthy control (16.79 ± 9.43% vs. 11.41 ± 4.67%, p = 0.028), which also had a relationship with the lymph node status. Patients with high-level CD8+ Tcm had a significantly higher median survival than those with low CD8+ Tcm (18 vs. 12 months, p = 0.004); a similar result was obtained in absolute CD8+ Tcm count. It was revealed in multivariate analysis that both percentage and absolute count of CD8+ Tcm was an independent prognostic factor for overall survival. Conclusions: CD8+ Tcm can be considered an independent prognostic factor for operable pancreatic adenocarcinoma, which was also associated with the lymph nodes metastasis.

Survival for ten years and prognostic factors for women with breast cancer in Joinville in the State of Santa Catarina, Brazil

Breast cancer has the highest incidence among women, and reduces survival among female sufferers. This article aims to evaluate the survival and its prognostic factors in women with breast cancer, treated by public sector, in Joinville, Santa Catarina, Brazil. Retrospective cohort study nested in a case-control. The data has been obtained by a questionnaire, by the review of records and death certifications. In the analysis of survival it has been applied the Kaplan-Meier's statistical method and the Cox's method. 170 women have been evaluated. The survival in ten years was 83.1% (95% CI 74.1 to 89.3%), and 21 (12.4%) deaths were identified at the time period. The probability of being alive was smaller for those in advanced stages of cancer; the risk of death was higher among those who had another kinds of cancer associated, and among those unsatisfied with life. The death's ratio was 17.1 times bigger among women diagnosed in advanced stages. The variable staging presented higher association with the survival in evaluated women. Detecting the disease early minimizes the mortality by breast cancer.

Statistical Analysis of Biological Survival Data

The objective of this study is to throw the light on applications of survival analysis in veterinary and biological sciences. In veterinary sciences especially in dairy farms, there are important factors in dairy herds which have a great role in their effects on another important factor which is called days open. There are many statistical methods used to model and analyse the data under these circumstances, but here some methods of survival analysis will be used because there are two types of data in the study (complete data and incomplete or censored data). The common statistical methods cannot be used to analyse the censored data. Some methods such as Kaplan- Meier method, Log-rank method and the Cox's proportional hazard model method will be used in this study. The data were obtained from different lactation records, covering the period between 2004 and 2007. These milk records are of U.S. Holstein cows belonging to Dina farms. The result showed that based on the K-M survivorship percentiles, overall median days open of dairy cattle was at (134 days). There were a non-significant difference between seasons, and a highly significant difference between years and lactation order. The result from Cox's proportional hazard model showed that lactation order increased the chance of pregnancy. Age at calving, days in milk, and season and year of calving decreased it. The result of testing Cox's model assumptions using a Schoenfeld residuals showed no correlation between partial residuals of the variables under study and rank of days open, so the proportional hazard assumption is satisfied.

Anemia and Left Ventricular Hypertrophy With Renal Function Decline and Cardiovascular Events in Chronic Kidney Disease

BackgroundAnemia is a common complication in patients with chronic kidney disease (CKD), which may initiate or accelerate left ventricular hypertrophy (LVH). This study is designed to assess whether the coexistence of anemia and LvH is independently associated with the rate of renal function decline and increased cardiovascular events in patients with CKD stages 3 to 5. MethodsThis longitudinal study enrolled 415 patients, who were classified into 4 groups according to sex-specific median values of hemoglobin and with/without LVH. The change in renal function was measured by estimated glomerular filtration rate slope. Cardiovascular events were defined as cardiovascular death, hospitalization for unstable angina, nonfatal myocardial infarction, sustained ventricular arrhythmia, hospitalization for congestive heart failure, transient ischemia attack, and stroke. The relative risk of cardiovascular events was analyzed by Cox's regression method. ResultsThe estimated glomerular filtration rate slope was significantly lower in the group with lower hemoglobin and LVH than in the other groups (P = 0.031). In addition, patients with lower hemoglobin and LVH were independently associated with increased cardiovascular events (hazard ratio, 4.269; 95% confidence interval, 1.402–13.000; P = 0.011). ConclusionsOur findings showed that the coexistence of anemia and LVH was independently associated with faster renal function decline and poor cardiovascular outcomes in patients with CKD. Assessments of serum hemoglobin level and LVH by echocardiography may help identify a high-risk group of poor renal and cardiovascular prognosis in patients with CKD stages 3 to 5.

Improved Prognostic Assessment Of Patients With MDS By IPSS-R and MDS-CI

PurposeMyelodysplastic syndrome (MDS) is a broad spectrum of bone marrow failure syndromes characterized by diversity concerning clinical behavior, influence on patient's outcome and risk for leukemic evolution. For more accurate prognostic assessment, the International Prognostic Scoring System (IPSS) has been recently revised. The purpose of this single-center study was to validate the r-IPSS and to compare this model with the MD Anderson Risk Model Score (MDAS), the IPSS and the (revised) WHO classification-based Prognostic Scoring System (WPSS(-R)). Furthermore, the predictive value of the MDS-Specific Co-morbidity Index (MDS-CI) as several other prognostic factors were analyzed. MethodsData were retrospectively collected from 222 MDS patients diagnosed at the VUmc between January 2000 and 2013. Selection was based on informative cytogenetics and the availability of peripheral blood and bone marrow counts. The MDAS, (r-)IPSS, (r-)WPSS and MDS-CI were applied and the impact of individual prognostic factors on patients' outcome was investigated. Kaplan-Meier method was used for estimating survival and the value of prognostic models was determined by Cox's multivariate regression method. ResultsOf our study population, 25 (11%), 83 (38%), 51 (23%), 37 (17%) and 25 (11%) patients were classified according to the IPSS-R as very low, low, intermediate, high and very high risk with, respectively, median overall survival (OS) of 129 (95%CI 96-161), 89 (95%CI 73-105), 43 (95%CI 30-57-61), 31 (95%CI 20-42) and 19 (95%CI 7-31) months (P < 0.000). Compared to the MDAS, IPSS, WPSS(-R) and MDAS, the IPSS-R had a higher predictive power for OS. The MDS-CI was of significant predictive value additional to IPSS-R (P < 0.003). Low risk MDS-CI patients who underwent stem cell transplantation (SCT) had a significantly higher mean overall survival (OS), respectively 104 versus 43 months (P < 0.038). However, mean OS of intermediate and high risk MDS patients who received SCT was not better. ConclusionOur data confirm the predictive value of the IPSS-R and show the additional value of the MDS-CI. Combined application of these models refines the prognostic assessment and identifies co-morbidity among MDS patients, which may assist and influence clinical decision making. Disclosures:No relevant conflicts of interest to declare.

심리음향 분석을 이용한 MP3 저작권 보안을 위한 적응적 워터마킹

본 논문에서는 오디오 컨텐츠 저작권 보안을 위하여 MP3 공격에 강인한 워터마킹 방법을 제안한다. 일반적인 주파수 도메인에서의 워터마킹 방법인 Cox의 스프레드 스펙트럼 방법에서는 DCT후 값이 큰 저주파수의 계수에 순차적으로 워터마크를 삽입하였다. 임의의 주파수 계수에 삽입하는 방법은 효과적이지 못하므로, 본 논문에서는 심리음향 모델을 분석하여 MP3 공격시 손실이 적은 주파수 계수에 적응적인 함수를 적용하여 가중치를 부여한 후 계수에 워터마크를 삽입하는 방법을 제안한다. 다양한 음원에 대하여 실험한 결과, 제안한 방법은 기존의 방법들에 비해 워터마크의 보존하고 원본 음원의 왜곡을 줄이는 두 가지 측면 모두 좋은 결과를 나타내었다. In this paper, we suggest a new audio watermarking method for audio contents copyrights that can efficiently provide protection from MP3 compression attacks. Watermarks were inserted at the coefficients repeatedly from low frequencies to high frequencies after DCT transform in commonly used Cox's spread spectrum method. Because the methods using arbitrary coefficients are not effective, we use the new weight functions that make small losses for the watermark coefficients during attacks, using psychological acoustics. In the results of various sound clips, the suggested method had overall better outcomes than the Cox's method by preserving watermarks and reducing distortions of the original sounds.

Abstract P2-05-14: Clinical significance of Lysil oxidase-like 2 (LOXL 2) in breast cancer

Abstract Introduction: Several preclinical studies provided relevant evidences that lysine oxidase-like 2 (LOXL2) is associated with invasiveness and metastasis in breast cancer. To investigate the clinical significance of LOXL2, we performed survival analysis with LOXL-2 in breast cancer patients. Method: A cohort treated at Gangnam Severance hospital, Seoul, Korea between January 1996 and December 2004 was studied. The immunohistochemical analyses with LOXL-2 antibody were performed in the 309 patients. The patients was stratified into two groups based on the expression level of LOXL-2. Kaplan-Meier and Cox's methods were used to define prognostic factors associated with breast cancer survival. Results: LOXL-2 positive group was 50 patients (16.2%) and 259 patients (83.8%) are LOXL-2 negative group. The proportion of estrogen receptor-negative patients was significantly higher in LOXL-2 positive group (54.0 vs. 37.0 %, P = 0.040). The Kaplan-Meier overall survival estimate at 5 year for the breast cancer patients with negative LOXL-2 was higher than that for the patients with positive LOXL-2 (88.0 vs. 71.8 %, P = 0.008). In the multivariate analysis for overall survival, lymph node metastasis (Hazard Ratio (HR) 0.32, 95% confidence interval (CI) 0.17–0.61) and positive LOXL-2 (HR 0.53, 95% CI 0.29–0.97) were significantly associated. In the multivariate analysis for distant metastasis-free survival, age younger than 35 years (HR 0.52, 95% CI 0.30–0.91), lymph node metastasis (HR 0.29, 95% CI 0.16–0.54), high histologic grade (HR 0.54, 95% CI 0.32–0.89) and positive LOXL-2 (HR 0.55, 95% CI 0.31–0.97) were demonstrated as significant prognostic factors. Conclusion: In breast cancer patients, overexpression of LOXL-2 is a poor prognostic factor for overall survival and distant metastasis-free survival. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-14.

Prognostic value of SUVmax measured by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography in Patients with Pancreatic Cancer.

Recent studies have been conducted on the relationship between fluorodeoxyglucose (FDG) uptake in F-18 FDG PET/CT and prognosis in patients with pancreatic cancer, but these studies have been carried out in small numbers of patients. The aim of this retrospective study was to determine in a large number of patients whether glucose metabolism as assessed by F-18 FDG PET/CT provides prognostic information independent of established prognostic factors in patients with pancreatic cancer. We reviewed retrospectively the medical records of 165 patients (men 105, women 60, mean age 67 ± 10years) with a diagnosis of pancreatic cancer that had undergone F-18 FDG PET/CT as part of a pretreatment workup from January 2004 to December 2009. Subsequently, all patients underwent surgery, cyberknife, radiotherapy, and/or chemotherapy. For the analysis, patients were classified by age, demographic data, maximum standardized uptake value (SUVmax), size, location, serum level of CA19-9, type of treatment, and AJCC stage. The relationship between FDG uptake and survival was analyzed using the Kaplan-Meier with log-Rank test and Cox's proportional-hazard regression methods. Median survival for all 165 study subjects was 290days and median SUV by PET/CT was 5.8 (range: 0-25.1). Patients were allocated to high (> 4.1) and low (≤4.1) SUV groups, and median survivals of these patients were 229days and 610days, respectively, which were significantly different (p < 0.0001). Furthermore, SUVmax was found to be significantly related to survival in each stage, i.e., there were 1267days in stage I, 440days in stage II, 299days in stage III, and 143days in stage IV (p < 0.0001). The median survival was also found to be significantly related to tumor size (p = 0.001), site (p = 0.0298), serum level of CA19-9 (p = 0.0017), distant metastasis (p < 0.0001), and type of treatment (p < 0.0001). Multivariate analysis study revealed that the patients with a low SUV (p = 0.0298), a lower serum level of CA19-9 (p = 0.0071), a lower stage (p = 0.0017), and no distant metastasis (p < 0.0001) had longer survivals. In addition, SUVmax values were found to have a similar hazard ratio of distant metastasis; it was well known predictor. Furthermore, SUVmax values showed a higher hazard ratio than that of other clinicopathologic predictors. The present study shows that SUVmax on F-18 FDG PET/CT can provide a prognostic information in patients with pancreatic cancer.