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Background: About 3885 women are diagnosed with breast cancer and 1285 die from the disease each year in Bulgaria. However no genetic testing to identify the mutations in high-risk families has been provided so far., Methods: We evaluated 200 Bulgarian women with primary invasive breast cancer and with personal/ family history of breast cancer for the presence of unequivocally damaging germline mutations in BRCA1/2 using Sanger sequencing., Results: Of the 200 patients, 39 (19.5 %) carried a disease predisposing mutation, including 28 (14 %) with a BRCA1 mutation and 11 (5.5 %) with a BRCA2 mutation. At BRCA1, 6 different mutations were identified, including 2 frameshifts, 1 nonsense and 1 missense that had been previously reported (c.5030_5033delCTAA, c.5263_5264insC, c.4603G > T, c.181 T > G), and 2 frameshifts, which were novel to this study (c.464delA, c.5397_5403delCCCTTGG). At BRCA2, 7 different frameshift mutations were identified, including 5 previously reported (5851_5854delAGTT, c.5946delT, c.5718_5719delCT, c.7910_7914delCCTTT,c.9098_9099insA) and 2 novel (c.8532_8533delAA, c.9682delA). A BRCA1 mutation was found in 18.4 % of women diagnosed with breast cancer at/or under the age of 40 compared to 11.2 % of women diagnosed at a later age; a BRCA2 mutation was found in 4 % of women diagnosed at/or under the age of 40 compared to 6.5 % of women diagnosed at a later age. A mutation was present in 26.8 % patients with a positive family history and in 14.4 % of women with a negative family history. The most prevalent mutation observed in 22 patients (11 %) was BRCA1 c.5263_5264insC, a known Slavic mutation with founder effect in Eastern European and AJ communities. Other recurrent mutations were BRCA2 c.9098-9099insA (2 %), BRCA1 c.181T > G (1 %) and BRCA2 c.5851_5854delAGTT (1 %). Notably, BRCA1 c.5263_5264insC represented 56 % of all mutations identified in this series. Of the 22 patients with BRCA1 c.5263_5264insC, 9 were diagnosed with early onset breast cancer, 11 with TNBCs, 4 with bilateral breast cancer, and 6 with both breast and ovarian cancer., Conclusions: This is the first comprehensive study of the BRCA1/2 mutation spectrum in Bulgaria and will assist the establishment of efficient protocols for genetic testing and individualized risk assessment for Bulgarian breast/ovarian cancer patients and healthy individuals at a high-risk.

Purpose: To evaluate the clinical application of (99m) Tc-methoxyisobutylisonitrile (MIBI) scintigraphy as a functional method for assessment of multidrug resistance (MDR) in breast cancer patients and the correlation of these results with P-glycoprotein (P-gp) overexpression and objective response to chemotherapy., Patients and Methods: 22 women, 35-68 years old with breast cancer, suitable for neoadjuvant chemotherapy were included onto this study. Two or three cycles of neoadjuvant chemotherapy were administered (FEC in 15 and CMF in 7 patients). Planar and SPECT (99m) Tc-MIBI scintigraphy was carried out before and after neoadjuvant chemotherapy. Focal (99m) Tc-MIBI uptake in breast cancer lesions was used as a scintigraphic criterion of abnormality. Tumor/background uptake (T/B Index) was calculated. Immunohistochemistry was carried out after surgery for P-gp detection in all cases. The degree of expression was evaluated according to semiquantitative score analysis from 0 to 4., Results: Planar imaging was true positive in 20 patients, false positive in 1 (with breast cancer and mastopathy), and false negative in 1 (with wide tumor necrosis and deep location in the breast). SPECT imaging was true positive in 21 patients and false positive in 1. In 3 patients with multifocal disease additional tumour masses were visualized using SPECT. Sensitivity was 95% (21/22) and 100% (22/22), respectively, for planar and SPECT detection of breast cancer. P-gp expression was positive in 40.8% of the patients and negative in 59.2%. Intense (99m) Tc-MIBI uptake was shown on the planar images in 21 patients independently of the P-gp expression. There was no significant relationship between T/B Index and P-gp detection. Objective response included 2 clinical complete remissions, partial response in 1 patient, minimal response in 12, and no change in 7. Some clinical results corresponded to (99m) Tc-MIBI scintigraphic data: after neoadjuvant chemotherapy T/B Index was reduced > or = 20% in 9 patients with objective response., Conclusion: SPECT is an important diagnostic approach for identification of breast cancer with deep location and satellite tumour spots in multifocal disease. T/B Index did not correlate with P-gp overexpression on baseline (99m) Tc-MIBI scan. Objective clinical results after neoadjuvant chemotherapy corresponded to scintigraphic results in 75% of the patients with minimal response.

On tumor NKLy/LL the author have studied the efficiency of cloning, the fraction of proliferating and resting cells and the rate of DNA synthesis in peripheral and central tumor sites. It was shown that the more far from the periphery the less fraction of labelled cells and the rate of DNA synthesis but the greater are differences in the content of proliferating cells in some sites. The efficiency of cloning in peripheral and central tumor sites does not differ, the fraction of clonogenic cells being larger than that of proliferating ones. Following persistent administration of 3H-thymidine in animals, it was found that the number of colonies produced by proliferating cells is considerably less than the general efficiency of cloning. It is concluded that resting cells can divide infinitely and are clonogenic ones.