Correlation of Microvessel Density with Nuclear Pleomorphism, Mitotic Count and Vascular Invasion in Breast and Prostate Cancers at Preclinical and Clinical Levels

Muhammadnejad, Samad,Muhammadnejad, Ahad,Haddadi, Mahnaz,Oghabian, Mohammad-Ali,Mohagheghi, Mohammad-Ali,Tirgari, Farrokh,Sadeghi-Fazel, Fariba,Amanpour, Saeid Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.1

Background: Tumor angiogenesis correlates with recurrence and appears to be a prognostic factor for both breast and prostate cancers. In the present study, we aimed to investigate the correlation of microvessel density (MVD), a measure of angiogenesis, with nuclear pleomorphism, mitotic count, and vascular invasion in breast and prostate cancers at preclinical and clinical levels. Methods: Samples from xenograft tumors of luminal B breast cancer and prostate adenocarcinoma, established by BT-474 and PC-3 cell lines, respectively, and commensurate human paraffin-embedded blocks were obtained. To determine MVD, specimens were immunostained for CD-34. Nuclear pleomorphism, mitotic count, and vascular invasion were determined using hematoxylin and eosin (H&E)-stained slides. Results: MVD showed significant correlations with nuclear pleomorphism (r=0.68, P=0.03) and vascular invasion (r=0.77, P=0.009) in breast cancer. In prostate cancer, MVD was significantly correlated with nuclear pleomorphism (r=0.75, P=0.013) and mitotic count (r=0.75, P=0.012). In the breast cancer xenograft model, a significant correlation was observed between MVD and vascular invasion (r=0.87, P=0.011). In the prostate cancer xenograft model, MVD was significantly correlated with all three parameters (nuclear pleomorphism, r=0.95, P=0.001; mitotic count, r=0.91, P=0.001; and vascular invasion, r=0.79, P=0.017; respectively). Conclusions: Our results demonstrate that MVD is correlated with nuclear pleomorphism, mitotic count, and vascular invasion at both preclinical and clinical levels. This study therefore supports the predictive value of MVD in breast and prostate cancers.

Overexpression of HER-2/neu in Malignant Mammary Tumors: Translation of Clinicopathological Features from Dog to Human

Muhammadnejad, Ahad,Keyhani, Elahe,Mortazavi, Pejman,Behjati, Farkhondeh,Haghdoost, Iraj Sohrabi Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.12

Background: Canine mammary gland tumors (CMGTs) are the most common tumor found in bitches. Changes in HER-2/neu genes in human breast cancer (HBC) lead to decrease in disease-free survival (DFS) and overall survival rate (OSR). Previous studies have demonstrated that the biological behavior of malignant mammary gland tumors (MMGTs) is similar to that of HBC. The present study aimed at evaluating the relationship between overexpression of HER-2/neu and clinicopathological features in MMGTs to represent a model of prognostic factors for HBC. Materials and Method: The clinicopathological data of 35 MMGTs were obtained. Immunohistochemical staining with HER-2, Ki-67 and CD34 markers was conducted with sections from paraffin-embedded blocks. According to standard protocols, histological type, grade, margin status, lymphovascular invasion (LVI), HER-2/neu score, proliferation rate and microvessel density (MVD) of tumors were determined and the association of HER-2/neu overexpression with these parameters was assessed statistically. Results: The IHC results showed that 12 (34.3%) cases were HER-2/neu positive. Statistical analyses indicated a significant relationship between HER-2 positivity and tumor grade (p=0.043), which also was demonstrated with cancer stage (p=0.035), tumor margin involvement (p=0.016), proliferation index (p=0.001) and MVD (p=0.001); however, there was no statistical relationship between LVI and tumor size. Overexpression of the HER-2/neu gene in MMGTs results in similar biological behavior as that of HBC; as a result, these tumors have can be considered to have important similarities in clinicopathological characteristics. Conclusions: MMGTs can be regarded as an HBC animal model. Further studies in this field would result in new treatments that could be beneficial for both dogs and humans.

Prevalence of HER-2-Positive Invasive Breast Cancer: A Systematic Review from Iran

Keyhani, Elahe,Muhammadnejad, Ahad,Karimlou, Masoud Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.11

Background: The HER-2/neu gene is altered in 15-20% of breast cancer patients. Immunohistochemistry (IHC) is considered to be the most cost-effective method for HER-2 detection in many countries. Approximately 8,000 new cases of breast cancer are observed annually in Iran. The aims of this study were to conduct a systematic review of the literature on the rate of HER-2-positive breast cancer diagnosed by IHC in Iran. Methods: A systematic search of the medical literature using the Medline/PubMed, ISI and SID databases revealed articles published in the English and Persian languages evaluating HER-2-positive breast cancer in Iran. Results: From 22 studies, 3,033 patients were evaluated, of whom 1,350 were diagnosed as HER-2-positive by IHC HER-2 testing. The mean percentage of HER-2-positive patients was 44.5%, which is higher than that recorded in international statistics. Results of this meta-analysis showed a significant heterogeneity between ratios. There was a statistically significant difference between the results of pre- and post implementation of 2007 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline. IHC HER-2 testing has been performed in Iran for over 10 years. Similar to many other countries, before establishment of an infrastructure for IHC diagnostic tests, HER-2 testing was routinely performed in Iran. Our study showed that the statistics reported from Iran varied widely; for instance, the rate of HER-2-positive cases varied from 23.3% to 81.0%. Conclusions: Our results demonstrate that the lack of standardization and harmonization of this test have led to marked variations in breast cancer diagnosis in Iran.

Angiogenesis Markers in Breast Cancer - Potentially Useful Tools for Priority Setting of Anti-Angiogenic Agents

Keyhani, Elahe,Muhammadnejad, Ahad,Behjati, Farkhondeh,Sirati, Fereidoon,Khodadadi, Faranak,Karimlou, Masoud,Moghaddam, Fatemeh A.,Pazhoomand, Reza Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.12

Background: Breast cancer is the most common malignancy among women in both developed and developing countries. The burden is increasing in low-income and middle-income countries (LMCs) and threatens the public health of such societies. Introduction of expensive monoclonal antibodies to cancer treatment regimens poses a real challenge in the health systems of LMCs. Despite controversy of cost-effectiveness of bevacizumab in breast cancer, some studies indicate gain of patients from this drug. The present study aimed to propose a priority setting model for administration of anti-angiogenic agents in breast cancer via assessment of tumor angiogenesis by the microvessel density (MVD) method and associations with clinicopathological characteristics (including simultaneous mutations of TP53 and HER-2 genes). Materials and Methods: Age, axillary lymph nodes status, tumor size, stage and grade, estrogen and progesterone receptors status, HER-2/neu status (by immunohistochemistry and FISH test), TP53 mutation, Ki-67 (for proliferation assay) and CD34 (for angiogenesis assay) were assessed in 111 breast cancer patients. The molecular subtype of each tumor was also determined and correlations of simultaneous mutations of HER-2 and p53 genes with angiogenesis and other clinicopathological characteristics were evaluated. Results: There were significant associations between simultaneous mutations of HER-2 and p53 genes and all other parameters except tumor size. The degree of angiogenesis in the ERBB2 subtype was greater than the others. Younger patients showed a higher angiogenesis rate rather those older than 50 years. Conclusions: Our results demonstrated that patients with simultaneous mutations of HER-2 and p53 genes, those with ERBB2 molecular subtype and also younger women (often triple negative) seem more eligible for obtaining anti-angiogenic agents. These results suggest a model for priority setting of patients with breast cancer for treatment with anti-angiogenic drugs in LMCs.

Systematic Review of Available Guidelines on Fertility Preservation of Young Patients with Breast Cancer

Haddadi, Mahnaz,Muhammadnejad, Samad,Sadeghi-Fazel, Fariba,Zandieh, Zahra,Rahimi, Gohar,Sadighi, Sanambar,Akbari, Parya,Mohagheghi, Mohammad-Ali,Mosavi-Jarrahi, Alireza,Amanpour, Saeid Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.3

Background: Since the survival rate of breast cancer patients has improved, harmful effects of new treatment modalities on fertility of the young breast cancer patients has become a focus of attention. This study aimed to systematically review and critically appraise all available guidelines for fertility preservation in young breast cancer patients. Materials and Methods: Major citation databases were searched for treatment guidelines. Experts from relevant disciplines appraised the available guidelines. The AGREE II Instrument that includes 23 criteria in seven domains (scope and purpose of the guidelines, stakeholder involvement, rigor of development, clarity, applicability, editorial independence, and overall quality) was used to apprise and score the guidelines. Results: The search strategy retrieved 2,606 citations; 72 were considered for full-text screening and seven guidelines were included in the study. There was variability in the scores assigned to different domains among the guidelines. ASCO (2013), with an overall score of 68.0%, had the highest score, and St Gallen, with an overall score of 24.7%, had the lowest scores among the guidelines. Conclusions: With the promising survival rate among breast cancer patients, more attention should be given to include specific fertility preservation recommendations for young breast cancer patients.

Lack of Metformin Effects on Different Molecular Subtypes of Breast Cancer under Normoglycemic Conditions: An in vitro Study

Sadighi, Sanambar,Amanpour, Saeid,Behrouzi, Bita,Khorgami, Zhinoos,Muhammadnejad, Samad Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.5

Background: In the past few years, a considerable number of preclinical studies have been proposed metformin as a potential anticancer agent, but some of these studies suffer from a number of methodological limitations such as assessment of cytotoxicity in the presence of supraphysiological glucose concentrations or applying suprapharmacological levels of the drug. These objections have limited the translation of published preclinical data to the clinical setting. The present study aimed to investigate direct anticancer effects of metformin on different molecular subtypes of breast cancer with pharmacological concentrations and under normoglycemic conditions in vitro. Materials and Methods: Breast cancer cell lines from luminal A, luminal B, ErbB2 and triple-negative molecular subtypes were treated with a pharmacological concentration of metformin (2mM) at a glucose concentration of 5.5mM. Time-dependant cell viability was assessed by dye exclusion assay. MTTbased cytotoxicity assays were also performed with metformin alone or in combination with paclitaxel. Results: Metformin did not show any growth inhibitory effects or time-dependant cytotoxicity on breast cancer cell lines in the presence of normal glucose concentrations at the therapeutic plasma level. No augmentation of the antineoplastic properties of paclitaxel was apparent under the tested conditions. Conclusions: Metformin is probably unable to exert cytotoxic or cytostatic effects on breast cancer subtypes at pharmacological concentrations and normal plasma glucose levels. These results highlight the importance of establishing a higher steady-state plasma concentration of metformin in the clinical setting for assessment of anticancer effects in normoglycemic patients.

in vitro Assessment of Antineoplastic Effects of Deuterium Depleted Water

Soleyman-Jahi, Saeed,Zendehdel, Kazem,Akbarzadeh, Kambiz,Haddadi, Mahnaz,Amanpour, Saeid,Muhammadnejad, Samad Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.5

Background: In vitro, in vivo and clinical studies have demonstrated anti-cancer effects of deuterium depleted water (DDW). The nature of this agents action, cytotoxic or cytostatic, remains to be elucidated. We here aimed to address the point by examining effects on different cell lines. Materials and Methods: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) -based cytotoxicity analysis was conducted for human breast, stomach, colon, prostate cancer and glioblastoma multiforme cell lines as well as human dermal fibroblasts. The cell lines were treated with decreasing deuterium concentrations of DDW alone, paclitaxel alone and both. One way analysis of variance (ANOVA) was used for statistical analysis. Results: Treatment with different deuterium concentrations of DDW alone did not impose any significant inhibitory effects on growth of cell lines. Paclitaxel significantly decreased the survival fractions of all cell lines. DDW augmented paclitaxel inhibitory effects on breast, prostate, stomach cancer and glioblastoma cell lines, with influence being more pronounced in breast and prostate cases. Conclusions: DDW per se does not appear to have inhibitory effects on the assessed tumor cell lines as well as normal fibroblasts. As an adjuvant, however, DDW augmented inhibitory effects of paclitaxel and thus it could be considered as an adjuvant to conventional anticancer agents in future trials.

Development of Gold-Coated Magnetic Nanoparticles as a Potential MRI Contrast Agent

Ali Reza Montazerabadi,Mohammad Ali Oghabian,Rasoul Irajirad,Samad Muhammadnejad,Davoud Ahmadvand,Hamid Delavari H,Seyed Rabie Mahdavi 성균관대학교(자연과학캠퍼스) 성균나노과학기술원 2015 NANO Vol.10 No.4

Gold-coated superparamagnetic iron oxide nanoparticles (SPIONs) coated with methylpolyethylene glycol (mPEG) are synthesized and investigated as a magnetic resonance (MR) imaging contrast agent. The synthesized mPEG-core@shells are characterized by UV-visible spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), vibrating sample magnetometry (VSM), zeta-potential analysis and X-ray diffraction (XRD). In addition, the transverse relaxivity of the mPEG-core@shells is measured using a 3 T MRI scanner. The cytotoxicity of the mPEG-core@shells is tested in the LNCaP cell line using an 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results show that the mPEG-core@shell particles are semispherical with hydrodynamic size of ~65 nm and a transverse relaxivity of 162.3 mM-1 S-1. The mPEG-core@shell particles demonstrate good stability in biological media without any significant in vitro cytotoxicity under high cellular uptake conditions. Finally, in vivo imaging shows that mPEG-core@shells are a potential contrast agent for use in early-stage detection.