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Ku70/80 protein inhibitors reduce the repair of DNA double-strand breaks via the Ku70/80 pathway, so they can be used to treat cancers with Ku70/80 overexpression. Since the association of Ku70/80 with germline CHEK2 mutations in breast cancer is unknown, in this study we evaluated the expression of Ku70/80 in breast cancers with germline CHEK2 mutations. Immunohistochemistry with a Ku70/80 antibody on tissue microarrays from 225 CHEK2-associated breast cancers was used and automatically assessed with computerized image analysis. We report that the vast majority of breast cancers expressed high level of nuclear Ku70/80 and a small percentage of tumors (3.5%) were negative for Ku70/80 expression. There was a significant difference between the nuclear Ku70/80 expression in CHEK2-associated vs. CHEK2-non-associated breast cancers in all tumors (p = 0.009), and in the estrogen receptor (ER) positive subgroup of breast cancers (p = 0.03). This study is the first reporting an association of Ku70/80 expression with CHEK2 germline mutations in breast cancer. The results suggest that evaluation of Ku70/80 expression in breast cancer may improve the selection of breast cancer patients for Ku70/80 inhibitor therapy, and point to CHEK2-associated breast cancer and a subset of ER-positive breast cancer as potential suitable targets for such therapy.

Abstract The NOD2 gene has been associated with susceptibility to Crohn's disease and individuals with Crohn's disease are at increased risk for cancer at a number of organ sites. We studied the association between the 3020insC allele of the NOD2 gene and cancer among 2604 cancer patients and 1910 controls from Poland. Patients were diagnosed with one of twelve types of cancer in the Szczecin region between 1994 and 2004. Significant associations were found for colon cancer (OR = 1.8; 95% CI 1.2 to 2.6), for lung cancer (OR = 1.7; 95% CI = 1.1 to 2.5) and for ovarian cancer (OR = 1.6; 95% CI 1.1 to 2.3). In addition, a significant association was found for early-onset laryngeal cancer (OR = 2.9; 95% CI 1.4 to 6.2) and for breast cancer in the presence of DCIS (OR = 2.1 95% CI = 1.2 to 3.6). The NOD2 3020insC allele is relatively common (in Poland 7.3% of individuals) and may be responsible for an important fraction of cancer cases. We estimate that the lifetime cancer risk among carriers of this allele is 30% higher than that of individuals with two wild-type alleles.

Oestrogen receptor α (ERα) is responsible for activation of gene transcription, while oestrogen receptor β (ERβ) serves as a negative regulator of ERα function. Since ER status is a prognostic and predictive factor in some cancers, we analysed the immunohistochemical expression of ERα and ERβ in Reed-Sternberg (RS) cells in paraffin-embedded lymph node specimens from 27 children with classical Hodgkin lymphoma (HL) in relation to histological type, clinical stage, age, and gender. Percentage of RS cells with positive nuclear reaction for the presence of ERα and/or ERβ was assessed. ERα positive RS cells were present in 11% (3/27) of lymph nodes (range 1-8%, mean 0.4%) whereas ERβ positive RS cells were detected in 96% (26/27) of lymph nodes (range 1-97.5%, mean 61.8%). The highest percentage of ERβ positive RS cells was observed in patients with the most advanced (IVB) disease as compared to patients with lower stages (90.3% vs. 56.9% respectively, p = 0.004). To the best of our knowledge this is the first report on the expression of ERβ in RS cells in children. We conclude that RS cells in classical HL in children seem to be mainly ERβ positive and ERα negative.

Nuclear factor ĸB (NF-ĸB) is a transcription regulator of proliferation and cell death. Increased activation of NF-ĸB may be responsible for treatment failure in children with acute lymphoblastic leukaemia (ALL). This study aimed to assess changes in NF-ĸB activation in peripheral blood mononuclear cells prior to and after 6 and 12 h of prednisone administration in relation to age, initial WBC count at diagnosis and early treatment response in childhood ALL. The study comprised 55 children with de novo ALL. Cells were stained with mouse anti-NF-ĸB (p65) antibody followed by goat anti-mouse antibody conjugated with FITC and measured by laser scanning cytometer. The nuclear/cytoplasmic (N/C) ratio of NF-ĸB reflecting activation of NF-ĸB was decreased 12 h after treatment in the standard risk group patients, whereas it remained statistically unchanged in the non-standard risk group patients. Changes in the N/C ratio of NF-ĸB were not associated with age and early treatment response; however, in children with an initial WBC count higher than 20 000/μl at diagnosis, this ratio was increased after 6 and 12 h from prednisone administration. The association of higher activation of NF-ĸB with an elevated initial WBC count suggests that activation of NF-ĸB may be responsible for treatment failure in children with ALL.

Ineffective apoptosis is one of main causes of a treatment failure in childhood acute lymphoblastic leukemia (ALL). p53 plays a crucial role in triggering apoptosis of ALL in response to prednisone treatment. MDM2 is the endogenous inhibitor of apoptosis that downregulates the functional activity of p53 protein. This study is aimed to evaluate changes in MDM2 and p53 expression in peripheral blood mononuclear cells collected from children with ALL prior to and after 6 and 12 h of prednisone administration in relation to early treatment response. The study comprised 35 children with newly diagnosed ALL, subdivided into good (n = 24) and poor (n = 11) early treatment responders. MDM2 - associated APC fluorescence and p53 - associated FITC fluorescence were measured by the laser scanning cytometer. In the group of poor responders, p53 and MDM2 fluorescence were significantly higher than in the group of good responders. In the group of good early treatment responders, a statistically significant rise of p53 fluorescence measured in the nucleus and in the cytoplasm 12 h after prednisone administration as well as increase in MDM2 fluorescence measured in the cytoplasm 6 and 12 h after prednisone administration were seen. These data suggest that pretreatment overexpression of MDM2 protein may contribute to poor early treatment response.

Background: Bax activation and intracellular redistribution as well as its prognostic significance during steroid-induced apoptosis of leukemic cells in childhood acute lymphoblastic leukemia (ALL) remain a matter of controversy. The purpose of this study was to assess time-resolved changes in Bax activation and its intracellular distribution as well as the percentage of apoptotic cells evaluated by PARP cleavage in response to prednisone treatment in childhood ALL., Material/methods: The study comprised 43 children with de novo ALL. Bax activation and PARP cleavage were measured by laser scanning cytometry in peripheral blood mononuclear cells collected prior to and 6 and 12 hours after prednisone administration., Results: The mean pretreatment proportion of p89 PARP-positive cells was 3.5%. Six and twelf hours after prednisone administration it increased significantly (p<0.01) only in the group of good treatment responders. A significant rise (p<0.05) in cytoplasmic Bax expression was seen in the good responders as early as 6 hours after prednisone administration followed by a significant rise in Bax nuclear expression after 12 hours. At the same time points the mean percentage of apoptotic cells as well as Bax expression in the cytoplasm and nucleus remained unchanged in the group of poor responders., Conclusions: Increased Bax nuclear accumulation (and possibly also aggregation) together with increased PARP cleavage observed within 12 hours after prednisone oral administration were associated with and may predict good outcome in children with newly diagnosed ALL.

The aim of this study was to evaluate associations between seven morphometric parameters of the nucleoli and nuclei of methyl green and pyronin Y (MG-PY) stained tumour cells of invasive ductal breast carcinoma with relapse-free survival (RFS) and overall survival (OS) time. Histological sections from 150 invasive ductal breast cancers were stained with MG-PY and the following parameters were evaluated by computer image analysis: the nucleolar area, long to short nucleolar axis ratio, nucleolar shape parameter assessing the degree of nucleolar roundness, long to short nuclear axis ratio, number of nucleoli in the nucleus and the percentage of the nuclear cross-section surface area occupied by the nucleoli. A statistically significant association between a nucleolar shape polymorphism and the number of nucleoli in the nuclei of tumour cells and the RFS but not OS was found in the entire group of patients as well as patients with axillary lymph node metastases. A higher polymorphism of nucleolar shape and a higher number of nucleoli in the nuclei of breast cancer cells were associated with decreased relapse-free survival (p < 0.05). The remaining morphometric parameters showed no statistically significant association with RFS or OS. The results indicate that morphometry of nucleoli in MG-PY stained histological sections can be useful in the analysis of associations between nucleolar parameters and prognosis of patients with invasive breast cancer.

Introduction: Little is known regarding the behaviour of serum anti-p53 antibodies (p53 Ab) in postoperative follow-up of patients with colorectal carcinoma and whether it can be used as an additional marker. The aim of this study was to evaluate usefulness of p53 Ab and CEA level for postoperative monitoring of recurrence or metastasis in patients after surgery due to colorectal cancer with normal pre-operative CEA levels and anti-p53 anitbodies., Material and Methods: The research group consisted of 124 patients with colorectal cancer diagnosed on the basis of histopathological or cytological examination. Colonoscopy, abdominal ultrasound, serum CEA and anti-p53 antibody tests were done at the time of diagnosis and every 6-month from surgery., Results: The occurrence of recurrence or metastasis was preceded by the appearance of anti-p53 antibodies 6 months earlier on average, in 5 patients, and the increased CEA level was preceded 9 months earlier on average, in 7 patients. The relationship between the increased CEA level and the occurrence of recurrence or metastasis was statistically significant (p < 0.0001); however statistically significant relationship was not found in the case of anti-p53 antibodies assessment. Performing these two tests simultaneously, at the same time with the same patients caused the increase of accuracy of recurrence or metastasis from 0.45 to 0.68., Conclusion: Multiple assessments of both serum p53 Ab and CEA during postoperative monitoring increase the probability of early detection of recurrence or metastasis in patients with colorectal cancer and normal CEA level before surgery.

Objective: In vitro assessment of ICAM-1, VCAM-1 and P-selectin expression on endothelial cells cocultured with c-erbB2-positive (SK-BR-3) and c-erbB2-negative (MCF-7) breast carcinoma cell lines., Material and Methods: The expression of adhesion molecules was determined by immunofluorescence, and measured by a laser scanning cytometer., Results: Endothelial cells cocultured with c-erbB2-negative breast carcinoma cell line--as compared to endothelial cells cultured without carcinoma cells--demonstrated an increase in the expression of VCAM-1 and P-selectin, a decrease in the expression of ICAM-1, and an increase of the maximal pixel intensity of ICAM-1, VCAM-1 and P-selectin orange fluorescence. A higher increase of the expression and maximal pixel intensity of ICAM-1, VCAM-1 and P-selectin was observed in endothelial cells cocultured with c-erbB2-positive breast carcinoma cells as compared to endothelial cells cocultured with c-erbB2-negative cell line., Conclusions: An increase in the expression of adhesion molecules on endothelial cells cocultured with c-erbB2-positive breast carcinoma cells may be responsible for the increased adhesion of tumor cells to endothelium and the increased invasiveness of c-erbB2-positive breast carcinomas.

Several predispositions to colorectal cancer have been identified, but little is known about genetic susceptibilities to disease in older persons. Colorectal cancer is a risk in Crohn's disease and is believed to be associated with an inappropriate inflammatory response. Recently, the NOD2 gene has been associated with Crohn's disease, which further strengthens the notion that the inflammatory response plays a crucial role in this disease. Several mutations have been identified in the NOD2 gene, which appear with significantly higher frequency in patients with the disease. One such mutation (3020insC) is believed to be clearly causative because it results in a prematurely truncated protein with a predicted reduction in functional efficiency. In this report, we have examined the frequency of the 3020insC mutation in a series of 856 individuals including 556 patients with colorectal cancer. The frequency of the 3020insC mutation in a consecutive series of 250 non-hereditary nonpolyposis colorectal cancer patients >50 years of age was significantly elevated compared with the control population (odds ratio, 2.23; P = 0.0046). The results indicate that NOD2 may be a predisposing factor to colorectal cancer characterized by an older average age of disease onset in persons who do not harbor any other genetic predisposition to disease.

Aim: The expression of p53 protein was compared in primary gastric carcinomas and coexisting regional and distant metastases. The purpose of the study was to evaluate whether p53 staining in regional lymph-node metastases might improve the value of p53 as a prognostic marker and determine the behaviour of its protein during gastric cancer progression., Material and Methods: 60 gastric cancer patients were included into the study. In all patients the expression of p53 was assessed in primary tumours and in regional lymph-node metastases. Additionally in 12 patients the p53 expression was determinated in distant metastases. The number of all secondary tumours studied was 153. Formalin fixed, paraffin embedded material and three-stage immunohistochemical methods were used., Results: p53 accumulation was detected in 24 (40%) of primary gastric carcinomas. In each patient p53 expression in primary regional and distant metastatic tumours was identical., Conclusions: Our results show that assessment of p53 in lymphnode metastases does not improve prognostic value of p53 in gastric carcinoma and support the view that p53 alterations occur before and maintain during metastatic spread.

The purpose of this study was to define the value of angiogenesis as a prognostic factor indicating early relapse. We assessed the relationship between parameters of angiogenesis (microvessel count--MVC, microvessel area--MVA and microvessel perimeter--MVP) and relapse-free survival at 50 months in 226 women with invasive ductal breast carcinoma. Anti CD31 antibody was used as a marker of endothelial cells. Microvessel density was measured according to Weidner et al. using a computerised image analysis. The mean parameters of angiogenesis were significantly higher in women with relapse than in those without recurrence within 50 months after surgery. In node negative patients relapse did not occur if MVC was below 38.7. In node-negative subgroup with grade II carcinomas parameters of angiogenesis in the primary tumour differed significantly depending on the presence or absence of relapse. Univariate and multivariate analysis showed the prognostic value of angiogenesis parameters in all study groups with respect to 50-month relapse-free survival. In node negative subgroup only 62.5% of women with tumors with high MVC and as much as 94.9% with low MVC survived 50 months without recurrence. In the Cox analysis of node-negative subgroup only MVC, MVP and MVA were the independent prognostic factors. In women with node-negative disease the evaluation of angiogenesis can identify a subgroup of patients with high risk of relapse, hence it may help in decisions concerning adjuvant therapy. Computerised image analysis is a good and objective technique for evaluating the intensity of angiogenesis in breast cancer.

Histomorphologic evaluation of the pharyngoesophageal sphincter (pes) in the decreased persons aged 11-82 was done. These persons, in the lifetime, never suffered from: a) neurologic diseases (among others-myasthenia, progressive muscle atrophy), b) neoplasm of the esophagus, c) dysphagia. The aim of the report was the explanation whether the degenerative changes in pes, seen in the course of ageing, should be included into the risk factors of the high pressure occuring in its area after total laryngectomy. The analysis of the histopathological specimens revealed that after 40 years of age connective tissue in the pes is spreading and the number of muscular fibers is decreasing. Till 60 years of age the degenerative process in pes is very differentiated. Some histopathological specimens, in persons of this age section, didn't differ much from those seen in young cases. In the following decades o life degenerative process intensifies successively. In the histopathological specimens intensive proliferation of the fibrotic and fat tissue was found and considerable decrease of muscular fiber number. The investigations on risk factors of high pressure in the area of pes (results made know in paper given for print) revealed that in elder patients after total laryngectomy, its values are higher than in young ones. In patients till 55 years of age, in 72.29% (n = 26/36) of examined cases, the pressure in the pes area didn't exceed 3.99 kPa (30 mmHg). In the age of 55 years and above such a pressure was observed only 39.1% (n = 18/46) of examined. Degenerative changes in pes, depending on age, can be in part of patients (particularly in elder ones) one of the risk factors of the high pressure in the pes area, which should be taken in account in prognosis of esophageal speech mastering by the patient.

The purpose of the study was to correlate angiogenesis parameters (microvessel count, area and perimeter) with some clinical and morphological factors in 251 invasive ductal breast carcinomas in women. Endothelium was stained with antiCD31 antibody, and measurements were made using a computerised image analysis in the whole study population and separately for two subgroups with and without metastases to axillary lymph nodes. High angiogenesis parameters in primary tumours were associated with older age, large tumour diameter, high grade and the associations were statistically significant. Furthermore the microvessel density was significantly higher in tumours metastasising to lymph nodes as compared with tumours without metastases. Microvessel perimeter was found to be the most useful of vessel parameters analysed. The correlation between angiogenesis and some clinical and morphological parameters, especially lymph node status may indicate the prognostic value of angiogenesis in invasive ductal breast carcinomas.

Nephrogenic adenoma is a rare benign lesion of the urinary tract involving mainly the urinary bladder. The clinical manifestations, endoscopic signs and histopathological pattern of NA should be differentiated from a cancer, which may be a source of misinterpretation. Here we report a case of a 70-year-old man previously treated for papillary urothelial carcinoma. Six months later he developed a tumour, giving rise to a suspicion of recurrence. Histopathologically the tumour was diagnosed as nephrogenic adenoma. It is the first case of nephrogenic adenoma in Polish literature.