Browsing by Author "Davidovic, Radoslav (55376761400)"

Rhabdomyosarcoma (RMS) is a highly malignant cancer and is the most common soft tissue sarcoma in children and adolescents, but it is rare in adults (<1% of all adult malignancies). Altered expression and molecular abnormalities of cell-cycle-regulatory proteins are one of the most prominent features in RMS. Therefore, we evaluated the expression of cyclin-dependent kinase inhibitors p57 and p16, as well as p16 methylation status, along with clinicopathological characteristics and overall survival (OS) in RMS patients. This analysis was conducted on 23 pediatric and 44 adult patients. There was a male predominance in both groups and extremities were the most frequent tumor site. In adults, alveolar and pleomorphic types were almost equally represented. The majority of pediatric tumors were low grade, whereas, in adults, only one patient had a low-grade tumor. Seven pediatric (30.43%) and eight adult (18.18%) patients had a low p16 expression. The analysis of methylation status of the p16 promoter showed the presence of methylated allele only in one sample with pleomorphic histology. Six (26.1%) pediatric and 15 (34.1%) adult patients had low p57 expression, while in 17 (73.9%) pediatric and 29 (65.9%) adult patients it was assessed as high. Ninetyone percent of the pediatric patients and 32.6% of adults were alive at the end of the observational period. In adults, significant associations were found between OS and age (P = 0.020), gender (P = 0.027), tumor size (P < 0.001), lymph node status (P < 0.001), presence of metastases (P = 0.015), and p57 expression (P = 0.039). Stratification by histological type showed the correlation of low p57 expression (P = 0.030) and worse OS of patients with alveolar RMS. Univariate analysis identified age > 50 yrs. (HR 2.447), tumors > 5 cm (HR 21.31), involvement of regional lymph nodes (HR 3.96), the presence of metastases (HR 2.53), and low p57 expression (HR 2.11) as predictors of lower OS. Tumor size, regional lymph nodes involvement, and metastases were the independent predictors after multivariate analysis, while p57 did not predict OS in an independent way. In summary, although p57 was not confirmed to be an independent predictor of OS, our results indicate that its low expression may be the marker of aggressive phenotype and poor prognosis in adult RMS patients. Also, our findings suggest that epigenetic inactivation of p16 is not important in the pathogenesis of rhabdomyosarcoma. © 2021

Rhabdomyosarcoma (RMS) is a highly malignant cancer and is the most common soft tissue sarcoma in children and adolescents, but it is rare in adults (<1% of all adult malignancies). Altered expression and molecular abnormalities of cell-cycle-regulatory proteins are one of the most prominent features in RMS. Therefore, we evaluated the expression of cyclin-dependent kinase inhibitors p57 and p16, as well as p16 methylation status, along with clinicopathological characteristics and overall survival (OS) in RMS patients. This analysis was conducted on 23 pediatric and 44 adult patients. There was a male predominance in both groups and extremities were the most frequent tumor site. In adults, alveolar and pleomorphic types were almost equally represented. The majority of pediatric tumors were low grade, whereas, in adults, only one patient had a low-grade tumor. Seven pediatric (30.43%) and eight adult (18.18%) patients had a low p16 expression. The analysis of methylation status of the p16 promoter showed the presence of methylated allele only in one sample with pleomorphic histology. Six (26.1%) pediatric and 15 (34.1%) adult patients had low p57 expression, while in 17 (73.9%) pediatric and 29 (65.9%) adult patients it was assessed as high. Ninetyone percent of the pediatric patients and 32.6% of adults were alive at the end of the observational period. In adults, significant associations were found between OS and age (P = 0.020), gender (P = 0.027), tumor size (P < 0.001), lymph node status (P < 0.001), presence of metastases (P = 0.015), and p57 expression (P = 0.039). Stratification by histological type showed the correlation of low p57 expression (P = 0.030) and worse OS of patients with alveolar RMS. Univariate analysis identified age > 50 yrs. (HR 2.447), tumors > 5 cm (HR 21.31), involvement of regional lymph nodes (HR 3.96), the presence of metastases (HR 2.53), and low p57 expression (HR 2.11) as predictors of lower OS. Tumor size, regional lymph nodes involvement, and metastases were the independent predictors after multivariate analysis, while p57 did not predict OS in an independent way. In summary, although p57 was not confirmed to be an independent predictor of OS, our results indicate that its low expression may be the marker of aggressive phenotype and poor prognosis in adult RMS patients. Also, our findings suggest that epigenetic inactivation of p16 is not important in the pathogenesis of rhabdomyosarcoma. © 2021

Purpose: To determine various clinical, radiographic, and pathological parameters which may indicate an increased risk of Giant cell tumour of bone (GCTB) recurrence after surgical therapy. Methods: The study included a total of 164 GCTB samples; 118 (72 %) primary tumours, and 46 (28 %) recurrences; which were analyzed on immunohistochemistry for expression of Ki67, p53, cyclin D1, and β-catenin. Results: Among 13 analyzed clinical, radiological, and histological variables, which presented possible predictive factors for the incidence of GCTB relapse, univariate logistic regression (ULR) extract three highly statistically significant parameters: 1) lesion localization, 2) nuclear p53 expression in mononuclear cells, and 3) nuclear cyclin D1 expression in giant multinuclear cells. The multivariate logistic regression (MLR), revealing that p53 expression in mononuclear cells was the most significant predictive factor (HR = 6,181 p < 0,001), the positivity of which indicated six times higher probability for recurrence in GCTB. The expression of cyclin D1 in giant cells, containing less than 15 nuclei, was also statistically significant (HR = 8,398, p = 0,038) for predicting the recurrence, and demonstrated eight times more frequent recurrence in positive tumours. Conclusions: This study confirmed independent predicting factors for GCTB reccurence: p53 expression in mononuclear tumour cells and cyclin D1 expression in giant multinuclear cells. Results are new addition to generally known parameters, such as: localization of lesion, number of surgical interventions, clear destruction of cortex with the presence of extracompartmental lesion, and histological criteria for malignancy and can help in further research and treatment of GCTB. © 2016, SICOT aisbl.

Aim of the study is to determine the possible roles of p53, cyclin D1, B-catenin and Ki-67 in the increase in risk of fractures in patients with giant cell tumor of bone. The study included a total of 164 patients with giant cell tumor of bone (GCTB), 21 (12.8%) with and 143 (87.2%) without fracture. The samples were analyzed immunohistochemically for expression of Ki-67, p53, cyclin D1 and β-catenin. According to the immunohistochemical expression of p53 and Ki-67 in mononuclear stromal cells, as well as of cyclin D1 in multinuclear giant cells, there was no significant association with immunopositivity and risk of fractures. However, our research revealed that patients with cytoplasmic expression of b-catenin in stromal cells had three times more frequent occurrence of pathological fractures, which was highly statistically significant (χ2 = 7.065; p = 0.008). Moreover, a highly statistically significant correlation between the nuclear expression of β-catenin in giant cells and the incidence of pathological fractures was also found (χ2 = 8.824; p = 0.003). The study showed that β-catenin expression highly correlates with the incidence of pathological fractures in patients with GCTB. Taking into account that β-catenin is closely linked to activation of the Wnt signaling pathway in GCTB pathogenesis, one could postulate that activation of the Wnt pathway is one of the contributing factors to locally destructive behavior of this tumor, as well as to the incidence of pathological fractures. © 2016, Versalius University Medical Publisher. All rights reserved.

X-chromosome instability has been a long established feature in Alzheimer's disease (AD). Premature centromere division and aneuploidy of the X-chromosome has been found in peripheral blood lymphocytes and neuronal tissue in female AD patients. Interestingly, only one chromosome of the X pair has been affected. These results raised a question, 'Is the X-chromosome inactivation pattern altered in peripheral blood lymphocytes of women affected by AD?' To address this question, we analyzed the methylation status of androgen receptor promoter which may show us any deviation from the 50 : 50% X inactivation status in peripheral blood lymphocytes of women with AD. Our results showed skewed inactivation patterns (>90%). These findings suggest that an epigenetic alteration on the inactivation centers of the X-chromosome (or skewing) relates not only to aging, by might be a novel property that could account for the higher incidence of AD in women. © 2015 - IOS Press and the authors.

X-chromosome instability has been a long established feature in Alzheimer's disease (AD). Premature centromere division and aneuploidy of the X-chromosome has been found in peripheral blood lymphocytes and neuronal tissue in female AD patients. Interestingly, only one chromosome of the X pair has been affected. These results raised a question, 'Is the X-chromosome inactivation pattern altered in peripheral blood lymphocytes of women affected by AD?' To address this question, we analyzed the methylation status of androgen receptor promoter which may show us any deviation from the 50 : 50% X inactivation status in peripheral blood lymphocytes of women with AD. Our results showed skewed inactivation patterns (>90%). These findings suggest that an epigenetic alteration on the inactivation centers of the X-chromosome (or skewing) relates not only to aging, by might be a novel property that could account for the higher incidence of AD in women. © 2015 - IOS Press and the authors.

Tamoxifen is a standard therapeutical treatment in patients with estrogen receptor positive breast carcinoma. However, less than 50% of estrogen receptor positive breast cancers do not respond to tamoxifen treatment whereas 40% of tumors that initially respond to treatment develop resistance over time. The underlying mechanisms for tamoxifen resistance are probably multifactorial but remain largely unknown. The primary aim of this study was to investigate the impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen by analyzing loss of heterozygosity (LOH) and immunohystochemical expression of PTEN in 49 primary breast carcinomas of patients treated with tamoxifen as the only adjuvant therapy. The effect of PTEN inactivation on breast cancer progression and disease outcome was also analyzed. Reduced or completely lost PTEN expression was observed in 55.1% of samples, while 63.3% of samples displayed LOH of PTEN gene. Inactivation of PTEN immunoexpression significantly correlated with the PTEN loss of heterozygosity, suggesting LOH as the most important genetic mechanism for the reduction or complete loss of PTEN expression in primary breast carcinoma. Most importantly, LOH of PTEN and consequential reduction of its immunoexpression showed significant correlation with the recurrence of the disease. Besides, our study revealed that LOH of PTEN tumor suppressor was significantly associated with shorter disease free survival, breast cancer specific survival and overall survival. In summary, our results imply that LOH of PTEN could be used as a good prognostic characteristic for the outcome of breast cancer patients treated with tamoxifen. © 2012 Landes Bioscience.

Tamoxifen is a standard therapeutical treatment in patients with estrogen receptor positive breast carcinoma. However, less than 50% of estrogen receptor positive breast cancers do not respond to tamoxifen treatment whereas 40% of tumors that initially respond to treatment develop resistance over time. The underlying mechanisms for tamoxifen resistance are probably multifactorial but remain largely unknown. The primary aim of this study was to investigate the impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen by analyzing loss of heterozygosity (LOH) and immunohystochemical expression of PTEN in 49 primary breast carcinomas of patients treated with tamoxifen as the only adjuvant therapy. The effect of PTEN inactivation on breast cancer progression and disease outcome was also analyzed. Reduced or completely lost PTEN expression was observed in 55.1% of samples, while 63.3% of samples displayed LOH of PTEN gene. Inactivation of PTEN immunoexpression significantly correlated with the PTEN loss of heterozygosity, suggesting LOH as the most important genetic mechanism for the reduction or complete loss of PTEN expression in primary breast carcinoma. Most importantly, LOH of PTEN and consequential reduction of its immunoexpression showed significant correlation with the recurrence of the disease. Besides, our study revealed that LOH of PTEN tumor suppressor was significantly associated with shorter disease free survival, breast cancer specific survival and overall survival. In summary, our results imply that LOH of PTEN could be used as a good prognostic characteristic for the outcome of breast cancer patients treated with tamoxifen. © 2012 Landes Bioscience.