8-hydroxy-2′ -deoxyguanosine (8-OHdG): A Critical Biomarker of Oxidative Stress and Carcinogenesis

There is extensive experimental evidence that oxidative damage permanently occurs to lipids of cellular membranes, proteins, and DNA. In nuclear and mitochondrial DNA, 8-hydroxy-2′ -deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2′ -deoxyguanosine (8-oxodG) is one of the predominant forms of free radical-induced oxidative lesions, and has therefore been widely used as a biomarker for oxidative stress and carcinogenesis. Studies showed that urinary 8-OHdG is a good biomarker for risk assessment of various cancers and degenerative diseases. The most widely used method of quantitative analysis is high-performance liquid chromatography (HPLC) with electrochemical detection (EC), gas chromatography-mass spectrometry (GC-MS), and HPLC tandem mass spectrometry. In order to resolve the methodological problems encountered in measuring quantitatively 8-OHdG, the European Standards Committee for Oxidative DNA Damage was set up in 1997 to resolve the artifactual oxidation problems during the procedures of isolation and purification of oxidative DNA products. The biomarker 8-OHdG or 8-oxodG has been a pivotal marker for measuring the effect of endogenous oxidative damage to DNA and as a factor of initiation and promotion of carcinogenesis. The biomarker has been used to estimate the DNA damage in humans after exposure to cancer-causing agents, such as tobacco smoke, asbestos fibers, heavy metals, and polycyclic aromatic hydrocarbons. In recent years, 8-OHdG has been used widely in many studies not only as a biomarker for the measurement of endogenous oxidative DNA damage but also as a risk factor for many diseases including cancer.     

Prognostic Significance of Axillary Lymph Node Micrometastases and Microvessel Count in Breast Cancer

Objective  To investigate the influence of axillary lymph node micrometastases and the microvessel count on the prognosis of patients with breast cancer. Methods  Forty-eight patients with breast cancer, who had no tumor cells in their regional lymph nodes based on conventional histopathologic examination, were re -examined with immunohistochemical LSAB techniques. H&E, anti-EMA, CK 19 and FVIII factor staining was used to identify tumor cells in both lymph nodes and tumor tissues and to count the mtcrovessels. A total of 882 lymph nodes were examined. Results  Immunostaining-positive tumor cells were found in 9.0 %( 79/882) of the dissected lymph nodes. The positive rates were not significantly different between a surviving group and a deceased group (P>0.05). The microvessel count was significantly higher in group that had died (P<0.001). Conclusion  The lymph node micrometastases did not show any correlation with patients’ survival, but the microvessel density had a negative correlation with the survival period in breast cancer patients who had negative axillary lymph nodes.     

Prognostic Value of β-catenin Expression in Breast Cancer Patients: a Meta-analysis

Background: β-catenin plays a crucial role in the progression of breast cancer (BC) and a prognostic role ofin BC patients has been widely reported. However, controversy still remains. Materials and Methods: Identicalsearch strategies were used to search relevant literature in electronic databases updated to July 1, 2014. Individualhazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled HRs with 95%CIs were usedto evaluate the strength of association between positive β-catenin expression in different subcellular locations andsurvival results of BC patients. Subgroup and meta-regression analyses were performed to explore heterogeneity.Funnel plots of Begg’s and Egger’s linear regression test were used to investigate publication bias. Heterogeneityand sensitivity were also assessed. All the work was completed using STATA. Results: A total of 2,204 patientsfrom 12 evaluative studies were finally included. Pooled HRs and 95%CIs suggested that β-catenin expression incytoplasm/nucleus had an unfavorable impact on both overall survival (OS) (HR: 1.93, 95%CI: 1.40-2.65) anddisease free survival (DFS)/ recurrent free survival (RFS) (HR: 1.60, 95%CI: 1.20-2.13) in BC patients. However,here was no significant association between β-catenin expression in the membranes with OS (HR: 0.65, 95%CI:0.42-1.02) or DFS/RFS (HR: 0.66, 95%CI: 0.38-1.13). Publication bias was absent in all of the four outcomes.Sensitivity analysis revealed that the results of this meta-analysis were robust. Conclusions: Positive β-cateninexpression in cytoplasm/nucleus rather than in membrane is a significant prognostic factor in patients with BCwho have been surgically treated.     

Clinical Significance of HER2-Positive and Triple-Negative Status in Small (≤ 1 cm) Node-Negative Breast Cancer

BackgroundData regarding the clinical significance of HER2⁺ and TN status in patients with small node-negative tumors are limited and conflicting. It remains unclear who, among those with small lesions, might benefit from more aggressive adjuvant therapy.Patients and MethodsWe identified all node-negative breast cancer patients with tumor size ≤ 1 cm diagnosed between January 1, 1995 and December 31, 2008 using our institutional breast service database. Patients were classified according to their receptor status into 3 groups: (1) hormone receptor (HR)-positive (estrogen receptor [ER]- or progesterone receptor [PR]-positive, HER2⁻); (2) HER2⁺ (immunohistochemistry 3⁺ or fluorescence in situ hybridization amplification ≥ 2); and (3) TN (ER⁻, PR⁻, and HER2⁻). RFS was calculated using Kaplan-Meier methods.ResultsAmong 656 patients with tumors ≤ 1 cm, 494 (75%) of the patients were HR⁺, 107 (16%) were HER2⁺, and 55 (9%) were TN. Median age was 59 years (range, 27-92 years). Median follow-up was 3.5 years. The 5-year RFS rates were 98.2%, 97.1%, and 83.5% in patients with HR⁺, HER2⁺, and TN tumors, respectively (P < .001). In multivariate analysis, TN status was associated with worse RFS (hazard ratio, 6.70; 95% confidence interval [CI], 3.02-14.86), and HER2⁺ was not (hazard ratio, 1.64; 95% CI, 0.73-3.69).ConclusionTN, but not HER2⁺ status, was associated with worse RFS in patients with T1abN0 tumors, and adjuvant chemotherapy might be considered in patients with TN breast cancer.     

The Significance of CXCR4 Expression for the Prediction of Lymph Node Metastasis in Breast Cancer Patients

OBJECTIVE The chemokine receptor(CXCR4)CXC chemokine receptor 4)plays an important role in cancer metastasis.We therefore studied differential expression of the CXCR4,as well as that of the biomarker HER2,so as to evaluate whether these biomarkers can be used to predict axillary lymph node metastasis in breast cancer patients. METHODS Immunohistochemistry was used to evaluate the CXCR4 and HER2 expressions and to examine the paraffin sections of the breast cancers at various stages.Positive lymph node expression was found in 80 of the cases,and in 7 there was negative expression. RESULTS Compared to the cases with negative lymph nodes, there was a high expression of CXCR4(26.3% vs.14.3%,P=0.013), and an over-expression of HER2(28.8% vs.14.3%,P=0.011). Moreover,there was a direct correlation between the CXCR4 and HER2 expressions and the tumor staging(P=0.000)and lymph node metastasis(P=0.032).When the two biomarkers,i.e.CXCR4 and HER2,were concurrently labeled,a high expression of one of the biomarkers could be seen in the cases with positive lymph nodes(51.3% vs.28.6%,P<0.003). CONCLUSION The chemokine receptor,CXCR4,is a new-type biomarker in predicting axillary lymph-node metastasis in breast cancers.Compared with the other markers,such as HER2 etc., assessment of CXCR4 can improve the prediction of the presence and extent of lymph node involvement.     

Main Effects and Interactions of Carbonic Anhydrase IX, Hypoxia-inducible Factor-1α, Ezrin and Glucose Transporter-1 in Multivariate Analysis for Disease Outcome in Rectal Cancer

Strong expression of carbonic anhydrase IX (CA IX), hypoxia-inducible factor-1α (HIF-1α), ezrin and glucose transporter-1 (GLUT-1) were previously shown to be interrelated and to affect clinicopathological prognostic factors. In the current study, operative samples from 178 rectal cancer patients, 77 treated with short-course, 47 with long-course preoperative radiotherapy (RT), and 54 with no preoperative treatment, as well as 80 preoperative biopsies from the RT group were analysed using multivariate modelling in order to assess the role of these markers as predictors of disease outcome. Multivariate survival analysis revealed several sets of panels with the potential ability to identify patients at increased or decreased risk of dying from their disease or disease recurrence. The most remarkable panel, consisting of moderate/strong expression of CA IX, positive HIF-1α expression and negative/weak GLUT-1 expression in operative samples and negative/weak ezrin expression in preoperative biopsies was associated with 47.5-fold risk of death from this disease. These results should, however, be interpreted with caution due to the heterogeneity of the patient population in this retrospective study.     

Thirty-Year Trends of Survival and Time-Varying Effects of Prognostic Factors in Patients With Metastatic Breast Cancer—A Single Institution Experience

Background

Metastatic breast cancer is generally considered an incurable disease. In our study we aimed to detect a time trend of survival over the past 30 years and account for time-varying effects of the prognostic factors.

Expression and Prognostic Significance of Multidrug Resistance Associated Protein (MRP) Gene in Non-small Cell Lung Cancer by in Site Hybridization

It has been a hot spot in molecular biology to research the mechanism of multi-drug resistance and its reverse.[1] In the present study, we had examined MRP gene mRNA overexpression on the paraffin-embedded tissues that suffering from NSCLC using in situ hybridization labeled with digoxigenin probes combined with immunohistochemistry. All the patients were retrospectively followed-up. To research the relationship between MRP gene overexpression on NSCLC and the histology, tumor size, n…     

Preliminary Study on the Expression and the Significance of S-Phase Kinase Associated Protein 2 in Atypical Ductal Hyperplasia and Breast Cancer

In 1995 Skp2 was cloned by Zhang et al.[1]from human fibroblasts and it was shown that Skp2 interacts by combining with cyclin de- pendent kinase 2 (cyclin-CDK2). Skp2 is a member of the F-box fam- ily of substrate-recognition subunits of Skp2-Cullin-F-bo…     

The Effect of P-Glycoprotein (P-gp), Nuclear Factor-Kappa B (Nf-κb), and Aldehyde Dehydrogenase-1 (ALDH-1) Expression on Metastases,Recurrence and Survival in Advanced Breast Cancer Patients

Objective: To investigate the level of three drug resistance proteins; P-glycoprotein 1 (P-gp), nuclear factorkappa-light-chain-enhancer of activated B cells (NF-κB) and aldehyde dehydrogenase isoform 1 (ALDH1) expressionand their relationship to metastasis, recurrence and survival in advanced breast cancer patients that received neoadjuvantchemotherapy. Methods: This study is a combination of prospective and retrospective cohort study involving onehundred and thirty one cases of advanced stage invasive breast cancer that have received neoadjuvant chemotherapy.Initial biopsy specimens (incisional biopsy or core biopsy) were taken from paraffin blocks. Immunohistochemistry(IHC) was used to detect P-gp, NF-κB, and ALDH1 expression. Prospectively analysed patients were followed for fiveyears and evaluated for recurrence and death. Results: The expression of P-gp has no significant statistical correlationto metastases (p = 0.659), recurrence (p = 0.862) and survival (p = 0.835) in advanced stage breast cancer patientswho received neoadjuvant chemotherapy. Similarly, ALDH1 was not correlated to metastases (p=0.120), recurrence(p = 0.186) and survival (p = 0.254) statistically. We found that NF-κB expression showed a significant correlation tometastases (p=0.004), recurrence (p = 0.016) and overall survival (p = 0.041) in advanced stage breast cancer patientsafter neoadjuvant chemotherapy. Conclusion: NF-κB expression is a potential marker that can be used to assess orto predict increasing risk of metastases, recurrence and survival in advanced stage breast cancer patients who receiveneoadjuvant chemotherapy.     

Immunohistochemical Detection of Phospho-Akt,Phospho-BAD,HER2 and Oestrogen Receptors α and β in Malaysian Breast Cancer Patients

Activation of Akt signaling pathway has been documented in various human malignancies, including breast carcinoma. The objective of this study is to determine the incidence of Akt phosphorylation in breast tumours and its relationship with expression of ER-α, ER-β, HER2, Ki-67 and phosphorylated Bcl-2 associated death domain (p-BAD). Immunohistochemical staining was performed to detect these molecules on 43 paraffin-embedded breast tumour tissues with commercially available antibodies. Eighteen (41.9%), 3 (7.0%), 23 (53.5%), 35 (81.4%), 21 (48.8%), 29 (67.4%), and 34 (81.0%) of breast tumours were positive for nuclear ER-α, nuclear ER-β, membranous HER2, cytonuclear p-Akt (Thr308), p-Akt (Ser473), p-BAD and Ki-67, respectively. ER-α expression was inversely correlated with HER2 and Ki-67 (P = 0.041 and P = 0.040, respectively). The p-Akt (Ser473) was correlated with increased level of p-BAD (Ser136) (P = 0.012). No relationship of Akt phosphorylation with HER2, ER-α or ER-β was found. The p-Akt (Ser473) immunoreactivity was significantly higher in stage IV than in stage I or II (P = 0.036 or P = 0.009). The higher Ki-67 and lower ER-α expression showed an association with patient age of <50 years (P = 0.004) and with positive nodal status (P = 0.033), respectively. Our data suggest that the Akt phosphorylation and inactivation of its downstream target, BAD may play a role in survival of breast cancer cell. This study does not support the simple model of linear HER2/PI3K/Akt pathway in breast cancer.     

Patient Involvement in Care and Breast Cancer Patients’ Quality of Life - a Structural Equation Modeling (SEM) Approach

In cancer patients, improving the quality of life is a basic goal of treatment, with the patient – physician relationship as a major factor. Therefore the aim of this structural equation modeling study was to analyze the influence of patient involvement in care on quality of life in 411 breast cancer patients undergoing outpatient chemotherapy and radiotherapy. Two questionnaires were used: 1-patient-physician questionnaire, 2-EORTC QLQC-30 (to measure QOL). The structural equation model exhibited an excellent data fit (Chi-Square= 31.04 / RMSEA= 0.042), T-values for all paths with the exception of that between patient satisfaction and emotional- cognitive function, were significant. According to the findings, various aspects of the physician-patient relationship are significantly and positively associated with quality of life and increasing patient involvement in care by increasing trust and satisfaction, was associated with marked improvement. The findings of this study emphasized the importance of an effective relationship between doctor and patient as a contributing factor for improving the quality of life. Therefore it is suggested that policymakers and decision-makers active in strategic planning for the health system and physicians responsible for treatment pay more attention to developing and improving relationships with patients as an approach to improving patient outcomes, particularly with reference to quality of life.     

Prognostic Implications of Tumoral Expression of Insulin Like Growth Factors 1 and 2 in Patients With Non–Small-Cell Lung Cancer

IntroductionThe currently available systemic therapies for non–small-cell lung cancer (NSCLC) have limited efficacy. Previous studies indicated an association of elevated insulinlike growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor expression levels with poor survival in patients with NSCLC. To better understand the molecular biomarkers involved in the IGF signaling pathway in NSCLC, the expression levels of IGF-1 and IGF-2 are characterized and evaluated for their association with IGF-1R and phosphorylated IGF-1R (pIGF-1R) expression in NSCLC.Materials and MethodsA total of 352 patients who underwent NSCLC resection with curative intent were studied. The expression patterns of the IGF-1, IGF-2, IGF-1R, and pIGF-1R proteins were assessed immunohistochemically using tissue microarrays.ResultsThe IGF-1 expression was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC), whereas the IGF-2 score was higher in patients with SCC than those with ADC. Likewise, the IGF-1 score was higher in patients with mutated epidermal growth factor receptor (mtEGFR) than in those with wild type EGFR (wtEGFR), whereas the IGF-2 score was higher in patients with wtEGFR than in those with mtEGFR. Patients with low levels of IGF-1 expression had longer overall survival (OS) than those with high IGF-1 expression, and subgroup analyses found a significant difference in OS only in patients with ADC.ConclusionThe overexpression of IGF-1 predicts poor survival among patients with NSCLC, especially those with ADC. These results might serve as a future guide for clinical trials involving IGF-1R-targeting agents.     

The Prognostic Significance of a Combined Determination of Cathepsin D and Estrogen Receptors in Breast Carcinomas with Positive Axillary Lymph Nodes

It has been reported that cathepsin-D (Cath-D), which is a pro- teinase, may enhance the growth of the tumor cells by degrading the basement membranes and extracellalar matrix. This action allows the cancer cells to easily invade the regional tissues and …     

Analysis of the indicence and Survival of Female Breast Cancer Patients in Beijing Over a 20-Year Period

A bout 30-years of information concerning cancer morbidity and mortality has been collected by the Cancer Registration Office of Beijing since its establishment in 1976. The information suggested that lung cancer and female breast cancer (FBC) are relativ…     

Clinicopathologic Features and Molecular Subtypes of Breast Cancer in Young Women (Age ≤35)

Introduction: Breast cancer in young women is a relatively rare disease; however it tends to be more aggressive and is the leading cause of cancer death in this population. The aim of this study is to investigate the clinical and biological features of breast cancer arising in young Turkish breast cancer patients. Materials and Methods: Patients with breast cancer aged 35 or less (≤35 years) were selected for the study. In total 211 cases were included. Pathologic features; histologic subtypes, grade, lymphovascular invasion, axillary involvement, and stage were recorded for each. Results: The most common subtype was luminal B (36.5%), followed by luminal A (30.8%), triple negative (23.2%) and HER2+(9.5%) subtypes. Twelve percent of the patients had stage 4, 32.7% had stage 3, 46.4% had stage 2, and 6.2% had stage 1 disease at the time of diagnosis. Mean tumour diameter was 3.87 cm (range 0.3-13 cm). The axillary lymph nodes were positive in 74.4% of the patients, while lympho-vascular invasion was seen in 56.4%. Some 9.5% of patients had grade 1, 51.2% had grade 2, and 31.8% had grade 3tumors. Conclusions: Young women with breast cancer in Turkey are more likely to present with luminal B subtype. Tumors in young women are more likely to present with advanced disease, to be high grade and and to have more lymphovascular invasion. Further research should focus on whether we need new treatment strategies for young patients with breast carcinoma.     

The Prognostic Significance of Maximum Standardized Uptake Value of Primary Tumor in Surgically Treated Non–Small-Cell Lung Cancer Patients: Analysis of 413 Cases

BackgroundIntegrated PET/CT is widely used in the preoperative staging and prognostic assessment of non–small-cell lung cancer (NSCLC) patients. The aims of this study were to evaluate the prognostic significance of SUV_max of primary tumor in patients undergoing surgical treatment and, in order to minimize technical interferences, to verify whether SUV_max standardized by SUV_max liver or SUV_max blood pool provided additional prognostic information.Patients and MethodsA retrospective study of 413 consecutive NSCLC patients undergoing potentially curative surgical resection after PET/CT obtained in the same PET center over a 6-year period. The SUV_max was calculated drawing region of interest around the primitive tumor, the liver, and the aortic arch in PET images. The same procedure was performed for 2 adjacent planes and the average of these measures was considered.ResultsNine patients were considered 30-day postoperative deaths and were excluded from the analysis. At the end of the study, 312 (77.2%) of the 404 patients were alive (median follow-up, 26 months) and 92 had died (median survival, 17 months). At multivariate analysis tumor-node-metastasis stage, primary tumor grading and primary tumor SUV_max (T-SUV_max) were found to be independent prognostic factors, while T-SUV_max/SUV_max blood pool ratio, and T-SUV_max/SUV_max liver ratio were not.ConclusionsT-SUV_max is an independent predictor for survival in NSCLC patients undergoing surgery and might be helpful in guiding adjuvant treatment strategies. SUV_max of primary tumor normalized by SUV blood pool or SUV liver does not provide additional prognostic information.