An inverse association between ER and PR with HER-2/
neu has been observed by others [10, 13, 14].
In our study, ER negativity was more strongly associated with HER-2/neu negativity. It was the same with PR negativity. However our study has some limitations. Malaysian population represent a multiracial community with Chinese, Malays and Indians as major racial groups and this biological diversity may be responsible for differences in ER, PR and HER-2/neuexpression. Furthermore our results may have been affected by the use of immuno histochemistry analysis of HER-2/neu. Therefore more studies are needed from Malaysia to verify our findings.
Sarcomatoid variants are a group of biphasic malignant neoplasms exhibiting morphologic evidence of both epithelial and mesenchymal differentiation. More than 100 cases have been reported since the mid 1800s, many originally classified as carcinosarcoma, but in general this is a rare tumour. (69,70) The significance of diagnosing this lesion lies in its association with a poor prognosis. These tumours are typically diagnosed at advanced local stage, and they often exhibit nodal or distant metastases. 70% of patients will die within 2 years of diagnosis.
This is in agreement to the findings of Xiaowei Ye et al, which showed a significant association between HER2/neuexpression and lymph node status but against the findings of En Qi Qiao et al and Linderholm et al, as they have reported no association between the two entities. This study revealed that VEGF expression had no significant association with lymph nodes positivity or negativity as 54.5% of lymph node positive cases and 78.9% of lymph node negative cases exhibited VEGF positivity. This finding was parallel to the findings of En-Qi Qiao et al and Konecny et al. However, Xiaowei Ye et al has documented an association between lymph node positivity and VEGF expression [23,26].
The usage of EHBC-TMA in our study allowed the entire cohort, NNB and EHBC tissues, to be analyzed on one slide, and the benefits of using TMA are well documented. 11 A known Her-2/neu-positive breast carcinoma was used as a positive control. For negative control, the primary antibody was omitted during the incubation step. The EHBC-TMA was incubated for 16 min with a Her-2/neu rabbit monoclonal antibody (clone 4B5, using the Benchmark XT; Ventana Medical Systems) and detected by ultraview universal DAB detection kit (using the Benchmark XT; Ventana Medical Systems, Inc.). Antigen retrieval was performed using the Ventana Cell Conditioner #1 for 32 min. The Her-2/neu protein expression was evaluated using the modified ToGA trial scoring criteria established for gastric and gastroesophageal carcinomas 12–14 as follows: 1) no staining or no membranous staining of tumor cells was scored as “0”; 2) tumor cells with faint membrane staining irrespective of the percentage of tumor cells were scored as “1 + ”; 3) tumor cells with weak to moderate membrane staining irrespective of the percentage of tumor cells were scored as “2 + ”; and 4) tumor cells with strong complete, basolateral, or lateral membrane reactivity irrespective of the percentage of tumor cells were scored as “3 + ”. 14 We used the presence of complete, basolat- eral, or lateral membranous reactivity in ≥ 10% of cells as the cutoff for positivity, as required by the published guidelines. 14 The Her-2/neu IHC score was calculated by two independent pathologists (RS and DC) and a consensus score was reached for each specimen.
The hematoxylin and eosin stained sections which were prepared from formalin fixed paraffin embedded blocks of all the cases of colorectal adenocarcinoma in the department of pathology during the study period were retrieved.
The corresponding formalin fixed paraffin embedded tissues were also obtained which constituted the donor block. Then the hematoxylin and eosin stained slides which contained full sections were examined and the area of interest was marked by using black glass marking pen. The area of interest is nothing but the area of tumor containing well preserved and well stained malignant cells. Then these marked areas on the slides were matched with the donor blocks and the corresponding areas over the donor blocks were also marked with the help of black glass marking pen. This area was used as the site for obtaining cores for the recipient block.
PBC patients had an elevated serum HER-2/neu level. It is possible that PBC patients with elevated serum HER-2/neu levels have more extensive disease than understood.
In 50 publications representing 5,044 patients with MBC, we found (on average) that 48.6% (range 23% to 80%) had elevated serum HER-2/neu levels. In more than 40% of the reports, it was found that 50% or more of the MBC patients had elevated serum HER-2/neu levels . Several recent papers [18,51-53] reported that 50% to 60% of MBC patients had an elevated serum HER-2/neu. This difference may have several explanations, such as differing patient populations or wider use of the standardized FDA cleared serum HER-2/neu test. It also may be that some reports employ hormone receptor-positive patients only whereas others include mixed populations. These data are in sharp contrast to the many publications indicating that only 20% to 30% of patients with PBC have HER-2/neu over-expression by IHC or FISH amplification. It also raises the possibility that HER-2/neu status can change, by whatever mechanism, from PBC to the MBC setting.
Western blotting for HER-2/neu, COX-2, and P450arom Cells collected from non-transfected, pcDNA3.1-transfec- ted, and pcDNA3.1-HER2-transfected groups were lysed with 250 μl protein extracting fluid (RIPA lysis buffer: 50 mM Tris [pH 7.4], 150 mM NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS), homogenized for 10 min, incubated in an ice-bath for 1 h, and centrifuged at 12,000 × g for 30 min at 4°C. Supernatants were col- lected, and protein concentrations were determined using the BCA protein assay system (Pierce, USA). Proteins were separated by 12% SDS-PAGE and were transferred to PVDF membranes. After blocking overnight at 4°C in 1 × PBS, 0.1% Tween 20, and 5% non-fat milk, membranes were incubated with anti-HER-2/neu (1:800), COX-2 (1:400), P450arom (1:400) and β-actin (1:800) polyclonal antibodies (Santa Cruz Biotechnology, USA) for 3 h at room temperature. Membranes were washed twice and in- cubated with horseradish peroxidase-conjugated goat anti- rabbit secondary antibody (ZhongShan, China, 1:1,500) for 2 h at room temperature. Immunodetection was performed by chemiluminescence (ECL reagent, Beyotime, China) and membranes were exposed to film. Images were captured using a transmission scanner. For quantification, target pro- teins were normalized to β-actin (the internal standard) by comparing the gray-scale values of proteins to correspond- ing β-actin values. Quantification was performed using UVP Gelworks ID Advanced v2.5 software (Bio-Rad, USA).
2. Microsatellite instability pathway in which there is defects in DNA mismatch repair.
CLASSIC ADENOMA –CARCINOMA SEQUENCE
This accounts for 80% of sporadic colon tumours. Mutation of APC gene which is a tumour suppressor gene occurs early in the neoplastic process. Tumour occurs when both the copies are functionally inactivated. APC is a negative regulator of beta catenin which is a component of WNT signaling pathway. Beta catenin accumulates when there is loss of APC function and this translocates to nucleus and activates transcription of MYC and Cycle D1 genes which promote proliferation of cells.
The E-cadherin mediated cell adhesion sys- tem acts as an invasive suppressor system, and tumors with reduced E-cadherin expression have a higher frequency of lymph node in- volvement and distant metastasis. This abnor- mal E-cadherin expression seems to be an early event in tumorigenesis. 42 Abnormal expression of E-cadherin occurs in a considerable propor- tion of gastric carcinomas and correlates with loss of differentiation. 16 In our study we found that only 2 out of 20 LD cases lacked E-cad- herin expression whereas all HD showed nor- mal expression. GD is usually from type 1 GD which is the precursor of intestinal type gastric cancer. Alterations in E-cadherin expression are mainly limited to approximately half of the diffuse type of gastric cancer. Thus it may be plausible that we can not see this abnormal expression in the majority of dysplasia cases.
Background: Bladder cancer is one of the commonest malignancies with high morbidity and mortality rates. Human Epidermal Growth Factor Receptor -2 (Her-2/Neu) seems to play role in the pathogenesis and prognosis of bladder carcinomas; However it is expression and prognostic significance were variable between different studies.
Association of HER-2/neu and VEGF with different histological parameters: Before analyzing the possible association between HER-2/neu and VEGF we tried to find out any association of these two markers with different histological characteristics. HER-2/neu overexpression was associated with histologic grade but not with tumor size and lymph node involvement, while VEGF expression was not associated with any of the parameters (Table-2). HER-2/neu overexpression was observed in 50%, 75.80% and 20.70% cases among histologic grades I, II and III respectively. This indicated higher expression of HER-2/neu in grade II followed by grade I and least in grade III. This finding of lower HER-2/neu positivity in the worst histologic grade is unusual.
Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China Received May 16, 2015; Accepted June 26, 2015; Epub July 1, 2015; Published July 15, 2015
Abstract: Purpose: To investigate the association between hormone receptors and HER-2/neu in different age groups of women with breast cancers. Methods: A total of 1036 women with breast cancers were recruited. All the patients were divided into nine groups. The expression of hormone receptors and HER-2/neu was studied by IHC, while FISH test was used to determine HER-2/neu status in cases scored IHC 2+. The association between hormone receptors and HER-2/neu in different age groups was evaluated using the χ 2 test. Multivariate analysis was used to find out the independent factors predicting HER-2/neu amplification. Significant findings: The expression of ER and PR was inversely correlated with HER-2/neu status in women aged >40 years. By multivariate analysis, as far as the overall groups were concerned, PR, lymph node status and tumor grade were independently associated with HER-2/
Gastric carcinoma is one among the top five causes of cancer in both males and females. It is also listed among the top cancer related mortalities. Despite the advancements in the treatment of gastric cancer, none has shown to improve the survival significantly. There was no additional improvement in overall survival with addition of Epirubicin or Docetaxol to Cisplatin and 5FU combinations although the response rate was better. The role of targeted therapy has recently come into play after the establishment of the role of HER-2/neu over-expression in gastric malignancies. Trastuzumab ,an anti HER-2/neu antibody ,in combination with Cisplatin and 5FU in advanced gastric carcinoma patients has shown to improve overall survival in TOGA trial This study was undertaken to find out the prevalence and the clinicopathological correlation in HER-2/neu over –expression in gastric carcinoma patients.
indicate poor prognosis and poor response to chemotherapy in HER2/NEU over expressed cases of gastric cancer, but as on now, no study is clear in India.
Trastuzumab is a monoclonal antibody which specifically targets HER2 protein by directly binding to extracellular domain of receptor and successfully used for breast cancer patients ,but not yet been tried in India for gastric cancer patients. This study may pave way for the introduction of trastuzumab in treating patients with advanced gastric malignancies and thereby enhance survival rates and improve the quality of life of those patients justifying the cost benefits.
.The protein encoded by this gene is suggested to be a growth factor receptor involved in the growth and progression of malignant cells (10) .
Despite many studies that have been conducted in gastric carcinoma worldwide for the expression of E Cadherin, EGFR, p53 and HER-2/Neu and for their prognostic importance, the results are still contradictory. Some found a statistically significant association of these markers with prognosis and survival, while others found no such association. In a related development, targeted therapy against EGFR and HER-2/Neu has attracted much attention recently. Hence accurate evaluation of expression of EGFR and HER-2/Neu proteins might help to identify eligible candidates for new targeted therapy.
HER-2/neu positivity may activate ER expression through signaling kinases, and the combined target of mi- togenic estrogen plus the monoclonal antibody therapy against HER-2/neu—over expressing tumors expand chances of survival for many patients. Being a developing country, with lack of specialized and optimally equipped health organizations, lack of health awareness and the cost for these tests were noted as limiting factors for access to basic health care service and resulted in advanced tumor grade at time of patient presentation .
Further in vivo studies are required to establish the signifi- cance of phosphorylated Akt in relation to HER-2 and sub- cellular localisation of p21 WAF1/CIP1 , with future possibilities that immunodetection of phosphorylated p21 WAF1/CIP1 may imply activation of this pathway. Clinical relevance of HER-2-expressing tumours with cytoplasmic p21 WAF1/CIP1 is emphasised by the independent prognos- tic significance of both parameters. Prognostic signifi- cance of cytoplasmic p21 WAF1/CIP1 at 5 years retains its predictive potential for OS and RFS at 9 years. The com- bined evaluation of cytoplasmic p21 WAF1/CIP1 and HER-2 positively did not increase prognostic significance in this study, due to limited patient numbers in the respective subsets. As previously reported, nuclear p21 WAF1/CIP1 expression was generally low and provided no prognostic information [17,33,35]. Future studies will be required to address what are the best markers.
Her2neu expression correlated with tumor grade and progression. Evaluation expression was more accurate in predicting the clinical outcome and had
ribution License, which permits unrestricted use,
. Deletion or inactivation of specific genes leads to changes in fundamental role of such genes like loss of cell division regulation, programmed death (apoptosis), and correction or guard against the propagation of genetic 2003; Ichabod Jung and Edward . Ki67 is a cell cycle-related nuclear protein expressed by proliferating cells. Immunohistochemically it can be observed in proliferating cells. Nuclear antigen expression is a measure of cell growth fraction and hence biological aggressiveness of a malignancy (Antonio Lopez . HER2 is normally responsible for regulating cell proliferation and survival. Overexpression of Her2neu is seen in high grade and stage of urothelial tumors 2012; Ghada et al., 2014). Aside from its prognostic significance determination of Her2neu status in patient with urothelial tumors may have therapeutic INTERNATIONAL JOURNAL OF CURRENT RESEARCH
In this work, regarding previous published studies (19, 30-32), we considered HER- 2/neu over expression as a prognostic factor, depicting a poor prognosis. On the other hand, surgical stage is by itself another proven prognostic factor. Our aim was to establish a correlation between HER-2/neuexpression status and stage. The absence of this relation in our results might be due to the fact that HER-2/neu positive tumors have a more aggressive pathologic behavior, which is reflected in more common micrometastatic disease at presentation and more distant failures later after treatment. Additionally, it should be noted that there are inconsistencies in the literature regarding the clinical significance of HER-2 over expression which may be due to problems of selecting the best methodology, standardizing the methods, and determining the correct cut off points.
Colon cancer is the third prevalent cancer in men and women and it accounts for nearly 15% of all the diagnosed cancers.
The worldwide incidence rates of colon cancer are increasing to approximately 2%, annually . Immunohistochemistry refers to the process of localizing proteins in the cells of a tissue section, thus exploiting the principle of antibodies binding specifically to antigens in biological tissues. Immunohistochemistry is relatively inexpensive, widely available, easy to preserve and less time con- suming and it requires a routine microscope.