Faculty of Medicine

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Axillary lymph node metastases in early (pT1) breast carcinomas: Most of the common prognostic factors lack predictive value.
(University of Ioannina, 2003-09)
Yashar, Genghis
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Ivkovski, Ljube
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Zografski, George
Introduction: Axillary lymph node status is an important prognostic feature for patients with breast cancer, but the diagnostic and therapeutic value of axillary lymph node dissection in early breast carcinomas has been questioned. Aim: The purpose of this retrospective study was to determine whether routine biological tumor markers, in addition to conventional clinical and histopathological features can predict axillary lymph node metastases in early breast carcinomas (pT1). Material and methods: Data from 90 patients with pT1 breast cancer who underwent radical mastectomy or lumpectomy with axillary lymph node dissection between January 2000 and April 2003 were investigated. The association between axillary lymph node status and several clinicopathological factors (age, size, tumor grade, histological type), as well as immunohistochemical expression of estrogen and progesterone receptors (ER/PgR), Ki-67 and p53, were analyzed. Hormone receptor status, Ki-67 and p53 expression were assessed by immunohistochemistry and the results were evaluated by performing the standardized scoring system. Results: From the total of 90 patients, 35 (396) were with axillary lymph node metastases. Among the factors studied only the tumor size appeared to correlate with the incidence of lymph node involvement, but this was not statistically significant (p=0.07). Axillary lymph node involvement was present in 4 (286) of the 19 patients with primary tumors <1cm (pT1a+pT1b), compared with 31 (44%) of the 71 with tumors >1cm (pT1c). Hormone receptor status, proliferative activity (Ki-67), and p53 expression were not predictors of nodal involvement in early breast carcinomas. Conclusion: Therefore, biological tumor markers as well as most of the common prognostic clinicopathological factors are not reliable predictors of lymph node metastasis in early breast carcinomas.
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HER2/neu expression in correlation with p53 and Ki-67 immunoreactivity and clinicopathological parameters in breast cancer patients.
(Blackwell Publishing, 2002-10)
Yashar, Genghis
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Ivkovski, Ljube
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Kraleva, Slavica
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Prodanova, Irina
Introduction: Although the role of HER2/neu status is still unsettled, its determination is valuable in selecting breast carcinoma patients for adequate Herceptin therapy. Aims: The purpose of this study was to evaluate the association among HER2/neu, p53 and Ki-67 immunoreactivity, as well as clinicopathological parameters (tumour size, histopathologic grade, nuclear grade, tumour type. lymph-node status and age) in breast cancer patients. Materials and methods: HER2/neu, p53 and Ki-67 expression was determined in 169 post-operative stage I-III (UICC. 1997) breast cancer patients using the standardized DAKO HercepsTest and by immunoperoxidase technique. respectively. The results were evaluated by performing the standardized scoring system. Discussion and conclusion: HER2/neu expression was positive in 66 patients (37%). There was no association between HER2/neu expression and p53 or Ki-67 immunoreactivity as well as any clinicopathological parameter, while the values of Ki-67 and p53 were strongly interrelated (P < 0.001). Ki-67 was also in significant correlation to tumour size, lymph-node involvement and tumour type (P<0.001), while p53 was only related to patients' age (P <0.01). These results indicate that HER2/neu is an independent prognostic marker in differentiating a subgroup of high-risk breast cancer patients. Additional studies are required to adjust HER2/neu testing results to clinical outcome.
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Association between Her2/neu expression and hormon receptor status in breast cancer patients.
(2002-06)
Yashar, Genghis
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Kraleva, Slavica
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Vasev, Nikola
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Ivkovski, Ljube
Determination of HER2/neu expression by immunohistochemistry is mandatory for application of Herceptin® therapy in breast cancer patients. The purpose of this study was to investigate the association between HER2/neu expression and hormone receptor status, as well as with other clinicopathological parameters in breast cancer patients. HER2/neu, p53 and Ki-67 expression was determined in 169 postoperative stage I-III (UICC, 1997) breast cancer patients using the standardized DAKO HercepsTest® and immunoperoxidase technique, respectively. The results of HER2/neu immunoreactivity were evaluated by performing the standardized scoring system (0 = negative, 1+ = weakly positive, 2+ = positive, 3+ = strongly positive staining), while ER and PgR were scored in a semiquantitative fashion (ER-ICA and PR-ICA). The results from HER2/neu expression were correlated to hormonal receptor status and clinicopathological parameters (tumor size, histopathologic grade, nuclear grade, histologic type of the tumor, lymph node status and patient age). Statistical significance was determined with χ2 and Fisher’s exact test. HER2/neu expression was positive in 66 patients (37%). There was no significant association between the values of HER2/neu and ER/PgR status, or with any other clinicopathological parameter. ER status significantly correlated with PgR status (p<0.01), tumor size (p<0.01), lymph-node involvement (p<0.01) and tumor type (p<0.01). PgR status was related to the histopathologic grade (p<0.01), lymph-node status (p<0.01), tumor type (p<0.01) and patient age (p<0.01). HER2/neu is a relatively new promising marker in predicting the response to target specific therapy. However, its predictive value remains a complex and inconclusive subject. According to our results, the prognostic potential of HER2/neu seems to be independent from hormone receptor status and any other clinicopathological parameter in breast cancer patients.
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Expression of p53 and Ki-67 immunoreactivity in breast cancer patients.
(Institute of Oncology, Sremska Kamenica, Yugoslavia, 2001-03)
Yashar, Genghis
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Kubelka, Katerina
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Zografski, George
The aim of this study is to investigate the association between p53, Ki-67 expression and hormone receptor status as well as clinicopathological parameters in breast cancer patients. The study group consists of 146 breast cancer patients (stage I to stage III, according to the postoperative TNM classification of UICC, 1997 guideline system) who underwent radical mastectomy with axillary lymphadenectomy between January 1998 and March 2000. The expression of p53, Ki-67, estrogen receptor (ER) and progesterone receptor (PgR) has been evaluated by using standard immunoperoxidase technique. The scoring system has been performed for determination the results of p53 and Ki-67 immunoreactivity. The semiquantitative ER-ICA and PR-ICA scoring system has been used for assessment of staining for ER and PgR. The results from p53 and Ki-67 expression were correlated to hormon receptor status, and to clinicopathological parameters. Statistical significance was determined with x2 test. Strong correlation was found between the values of p53 and Ki-67 (p<0.00001), p53 and ER (p=0.0004), Ki-67 and ER (p=0.0006) as well as ER and PgR (p<0.0001). p53 and Ki-67 expressed additional correlation to the age of the patients (p=0.01). No correlation was found between p53, Ki-67, ER as well as PgR and lymph node involvement or the stage of the disease. The preliminary results of our study suggest that determination of p53 and Ki-67 expression associated to hormone receptor status and some clinicopathological parameters could be helpful in standardizing the protocols for further treatment of breast cancer patients. However, additional investigations with long term follow-up of the patients are needed to clarify the prognostic significance of p53 and Ki-67 immunoreactivity
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Potential prognostic significance of apoptosis related oncogenes: p53, bcl-2 and mdm-2 in early stage cervical carcinoma
(2003-09)
Prodanova, Irina
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Yashar, Genghis
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Kubelka-Sabit, Katerina
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Zografski, George
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Introduction: Evaluations of expression of apoptosis related oncogenes are being increasingly called upon in an attempt to better understand the carcinogenesis of cervical carcinoma and to provide possible prognostic information. The aim of this study was to analyze the expression of bcl-2, p53 and mdm-2 oncoproteins and cellular proliferative marker Ki-67 in early stage cervical carcinoma, with an emphasis on their association with human papillomavirus (HPV) infection, recurrence rate and lymph node status. Material and methods: Using immunohistochemistry, 69 radical hysterectomy specimens with cervical carcinoma (pT1b1/pT1b2) were studied. Evaluation of expression of p53, bcl-2, mdm-2 and Ki-67 was performed in surface area, center and invasion front of the neoplasms. The HPV presence was determined by CARD in situ hybridization. Results and conclusion: In the invasion front bcl-2 was expressed in 31 (45%), p53 in 37 (53%) and mdm-2 in 33 (47%) cases. HPV infection was detected in 40 (58%) cases. Carcinomas with a higher Ki-67 labeling index were more frequently HPV positive than HPV negative (82.5% vs 17.5%, p<0.01). No association was found between p53, mdm-2 or Ki-67 and either lymph node status or recurrence rate. Negative staining for bcl-2 was associated only with the presence of lymph node metastasis (74% vs 26%, p=0.05), and not with the recurrence rate. Significant correlation among expression of bcl-2, p53, mdm-2 oncoprotein and Ki-67 values was also observed. These results suggest that further study of a larger series is needed to confirm whether bcl-2, either alone or in combined evaluation with other markers, could be a useful marker to identify more aggressive behavior in early stage cervical carcinoma.
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Immunohistochemical expression and prognostic significance of DCC (deleted in colon cancer), p53 protein and proliferative marker Ki-67 in colorectal colon cancer.
(Springer, 2005-05)
Yashar, Genghis
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Prodanova, Irina
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Kubelka-Sabit, Katerina
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Objectives: The objective of this study was to evaluate the immunohistochemical expression of Deleted in colon cancer (DCC), p53 protein and proliferating index Ki-67 in correlation with various clinico-pathological (age, sex, tumor status, lymph node involvement, localization, tumor diameter, grade of differentiation, histological type) and biomolecular parameters (loss of heterozygosity of the long arm of chromosome 18 and microsatellite instability) in colorectal cancer patients. In addition, the prognostic significance of their influence on overall survival (OS) was also estimated. Methods: A retrospective analysis of 100 patients with colorectal cancer who underwent large bowel resection with regional lymphadenectomy was conducted in the period between 1995 and 2000. All the patients were in stage II and stage III of the disease according to the postoperative TNM classification of UICC (1997) guidelines. The immunohistochemical expression of protein products of the DCC, p53 tumor suppressor genes and Ki-67 proliferating index were semi-quantitatively evaluated. Biomolecular analyses for the loss of heterozygosity of the chromosome 18q and microsatellite instability were performed with the Polymerase chain reaction (PCR) technique. Results: In our case series, 57 (57%) patients were in stage II, and the remaining 43 (43%) patients in stage III of the disease. During the follow-up period (mean 53, range 5-97 months), 41(41%) patients died of the disease. The expected 5-year OS rate was 58.6%. In the univariate analysis, tumor status, lymph node involvement, sex, age, tumor grade, p53 protein expression and Ki-67 proliferating index were parameters with prognostic significance related to OS (p<0.05). Among these variables, in the multivariate analysis the tumor status and Ki-67 proliferating index were selected as independent and significant prognostic factors related to OS (p=0.0019). According to the value of the prognostic index (PI) defined by Cox regression model, the patients were categorized in two distinct risk groups. The 5-year OS rate of the low- and high-risk group patients was 65.0% vs. 29.4% (p=0.001). The 5-year OS for stage II was 71.1% vs. 40.0% (p=0.05) and for stage III of the disease it was 54.8% vs. 25.0% (p=0.03), respectively. Conclusions: These data indicate that defining prognostic groups in each stage of the disease allow an exact and objective selection of colorectal cancer patients with different death risk. Therefore, the prognostic index (PI) as an indicator of the patient’s place in the prognostic spectrum could be a sound basis for an appropriate planning.

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