CLINICAL SIGNIFICANCE OF BRCA1 GENE SEQUENCING AND ITS PROMOTER METHYLATION TESTING IN THE SEARCH STRATEGY FOR THERAPEUTIC TARGETS IN BREAST CANCER TREATMENT.

BACKGROUND: Currently, there is a great interest in the genetic testing of BRCA1 and BRCA2 due to the fact that for patients with breast cancer (BC) with pathogenic variants of these genes, the use of the PARP inhibitors could be also provided in addition to implemented treatment protocols. The aim of this study was to characterize the molecular genetic structure of the BRCA1 gene in BC patients without progenitor germline mutations taking into account the methylation state of the promoter region. MATERIALS AND METHODS: The study involved 210 patients with newly diagnosed BC. The most common germline pathogenic variants of the BRCA1 (185delAG, 5382insC, 4153delA, T300G) and BRCA2 (6174delT) genes were identified in the peripheral blood. A subgroup of 14 patients without progenitor pathological variants of the BRCA1 and BRCA2 genes and with a family history of cancer was randomly selected. For them, BRCA1 gene sequencing by Sanger and hypermethylation of the BRCA1 gene promoter region were analyzed. RESULTS: The following frequencies of BRCA1 mutations were determined in the general group: 5382insC - 8.6%, 4153delA - 0.5%, T300G - 0.5%. The analysis of the BRCA1 gene by Sanger sequencing revealed 11 BRCA1 gene variants in 10 out of 14 BC patients. All of them, according to the currently available data, were defined as "benign" and not clinically relevant. The frequency of the detection of hypermethylation of the BRCA1 gene promoter region in the randomly selected group of patients was 14.3%. CONCLUSIONS: In BC patients, not only common mutations but also the methylation status of the BRCA1 gene promoter region in the peripheral blood should be determined. The whole-genome sequencing of the BRCA1 gene may be the last step in determining the genetic characteristics of BC patients carried out to optimize the treatment and improve survival thanks to the higher prevalence of the progenitor mutations and hypermethylation of the BRCA1 gene promoter.

Systemic chemotherapeutic treatment of patients with breast cancer brain metastases.

Brain metastases of solid tumors are the most common intracranial neoplasms in adults. We provide a short overview of the role of the blood-brain barrier ​​in the pathogenesis of breast cancer brain metastases, and the effectiveness of systemic anticancer therapy in the treatment of such patients.

Prevalence of BRCA1 and BRCA2 genes promoter hypermethylation in breast cancer tissue.

BACKGROUND: Recent advances in the treatment of breast cancer (BC) have been related to the personalization of therapy. The methylation status of the promoter regions of tumor suppressor genes such as BRCA1 and BRCA2 is supposed to be useful as a prognostic factor in BC patients. AIM: To investigate the frequency of hypermethylation in the promoter regions of BRCA1 and BRCA2 genes in tumor tissue of BC patients, and the relation of hypermethylation to the clinical course of the disease. MATERIALS AND METHODS: Molecular genetic studies were performed on 50 BC tissue samples in order to determine the methylation status of the promoter regions of the BRCA1 and BRCA2 genes. RESULTS: Hypermethylation of the BRCA1 promoter region was detected in 34% of BC cases, hypermethylation of the BRCA2 promoter region - in 50% of cases, and hypermethylation of the promoter region of both genes - in 20% of cases. A significant increase in the incidence of hypermethylation of the BRCA2 promoter region was found in the group of patients older than 56 years, mainly in patients with triple-negative breast cancer and without family history of BC. CONCLUSIONS: The high frequency of hypermethylation in the promoter regions of BRCA1 and BRCA2 genes, as well as their co-methylation in tumor tissue of BC patients has been detected.

Bladder sparing surgery in high-grade bladder cancer.

The gold standard for managing muscle-invasive bladder cancer is radical cystectomy (RCE). The RCE is a treatment, which carries high burden of perioperative morbidity and mortality. As biomolecular markers make muscle-invasive high-grade bladder cancer (HGBC) an entity different from non-invasive papillary disease, we tested a hypothesis that alternative bladder preserving surgery (BPS) approaches, such as partial cystectomy and transurethral resection of the bladder would not compromise the oncological results of treating HGBC in selected patients. Aim: To study the cancer specific survival of HGBC patients depending on the mode of surgical treatment - RCE, partial en-block cystectomy, and transurethral resection of the bladder in the practice of the Departments of Urology and Oncology of Bogomolets National Medical University, and to assess the prevalence of bladder sparing surgical management of HGBC in local practice as a part of trimodal treatment approach to bladder preservation. Materials and Methods: Retrospectively we studied the medical records of 3597 urothelial bladder cancer patients, of whom 346 (10%) had high-grade disease and who underwent surgical treatment in 2004-2017. All patients were studied with contact computed tomography of the chest, abdomen, pelvis, and biopsy of the tumor. Based on the results of the diagnostic workup the choice of surgical treatment between RCE, partial cystectomy and transurethral resection was made considering the size of the tumor, location of the tumor in the bladder in relation to the bladder neck, and technical and oncological feasibility of performing the bladder sparing surgery. Kaplan - Meier survival curves were built to compare the results of survival per cancer stage and type of surgical treatment. Survival data of the patients were collected from the cancer registry maintained at the Kyiv Municipal Clinical Oncological Center. Results of data analysis were controlled for confounding parameters, such as adjuvant treatment: perioperative radiotherapy, and chemotherapy. Results: Median follow-up was 93 months (1-226 months). Males were 276 (80%). Average age at diagnosis was 62 ± 4.5 years. By the time of the study 61% of patients have died due to the progression of the disease. All patients with stage I disease (7% or 24 patients) were managed with bladder-sparing surgery. In muscle-invasive disease (309 patients), the RCE was performed in 109 (35.3%) patients, partial cystectomy was performed in 79 (25.6%) patients, and transurethral resection - in 121 (39.1%) patients. The overall 5-year survival of HGBC patients after radical surgical treatment (RCE/BPS) for stage I patients was 0%/83%, for stage II - 43%/58%, for stage III - 37%/42%, and for stage IV - 10%/40%. A total of 44 patients (12.7% of all treated, and 19.6% of treated with bladder sparing) received postoperative radiotherapy after bladder-sparing surgery. A total of 14 patients (4% of all treated) received postoperative chemotherapy. Conclusion: Bladder sparing surgery (partial en-block cystectomy, and transurethral resection of the bladder) in selected patients is not inferior to RCE in terms of cancer-specific survival when treating patients with HGBC of all stages. The bladder sparing surgery was performed in 64.7% of patients with high grade bladder cancer. Utilization of adjuvant treatment is low, 12.7% for postoperative radiotherapy, and 4% for perioperative chemotherapy.

The impact of locoregional treatment on survival of patients with primary metastatic breast cancer.

The aim of the study was to investigate the impact of primary tumor locoregional treatment (surgery or/and radiotherapy) on overall survival in patients with primary metastatic breast cancer (PMBC). MATERIALS AND METHODS: This retrospective study included 295 wo-men aged from 23 to 76 years with PMBC. Among the 295 patients, the effect of locoregional treatment of primary tumor on survival outcomes was evaluated in 177 women with distant metastases at diagnosis of breast cancer. 35 patient received breast surgery (group 1), 95 patients with PMBC - radiotherapy (group 2) and 47 patients - combination of breast surgery and radiation (group 3). The remaining 118 patients didn't receive surgery or/and radiotherapy (group 4). All patients received systemic cytotoxic chemotherapy. RESULTS: The groups of patients with PMBC did not differ significantly by age, menstrual function, ER status, Her2 receptor status, site of metastasis and number of metastatic lesions. 2- and 5-year overall survival in patients of group 1 was 54 and 32%, group 2 - 47 and 8%, group 3 - 73 and 18%, whereas in patients from group 4 - 26 and 9%, respectively. The median survival of patients who underwent surgery was 36 months, patients with PMBC who received radiotherapy - 24 months, patients who obtained combination of breast surgery and radiation - 30 months vs 18 months in patients who did not undergo primary tumor locoregional treatment. CONCLUSIONS: The results of this study showed a favourable effect of locoregional treatment in patients with PMBC.

Risk Factors of the Invasive Breast Cancer Locoregional Recurrence.

BACKGROUND: The aim of the research was to estimate the frequency of the locoregional breast cancer recurrence appearance, the recurrence-free period continuance, and the 3- and 5-year survival depending on the scope of the surgical intervention, menstrual profile, and histological and molecular-biologic characteristics of the primary tumor. PATIENTS AND METHODS: Among 218 patients with a breast cancer, 99 patients had breast-conserving surgery (BCS) and 119 underwent radical mastectomy (RME); all patients had regional lymphatic nodes dissection. The size and the primary tumor differentiation degree, metastasis presence in the regional lymph nodes, ER expression, PR, and Her/2neu were assessed as the prognostics factors. RESULTS: It was defined that the locoregional recurrence appearance frequency in patients with BCS turned out to be 13%, and in patients after RME it turned out to be 9%; the recurrence-free period continuance was 53 ± 8 months and 56 ± 10 months, respectively. CONCLUSIONS: The locoregional cancer recurrence frequency is higher in women with the menstrual function being preserved at the moment of the primary tumor detection than in postmenopausal patients and also in patients having the hyperexpression of the Her/2neu. The ipsilateral cancer recurrence decreases the 3-year survival by 7,1% and the 5-year one by 20,3%, respectively.

[The variations of transplant anastomosis to the pharynx or esophagus during partial or total esophagoplasty].

Different modifications of colic and gastric transplants connection to the gullet or esophagus in the neck have been described. The most functional and cosmetic types of anastomoses have been specified. The utility of single-stage subtotal or total esophagoplasty with the use of colon segment regardless of the transplant length has been proved. The short- and long-term follow up of different modifications of anastomoses has been given.

[Application of total and subtotal esophagoplasty in the treatment of cicatricial esophageal stenosis].

The most safe variants of subtotal (in 58 patients) and total (in 20) esophagoplasty performance, using colonic segment (y 76) and stomach (in 2) for cicatricial esophageal stenosis with cervical anastomosis formation with pharynx (in 20) and esophagus (in 58) were used. Main stages of the patients preoperative preparation were determined, securing achievement of best immediate and late results after artificial esophagus formation. The expediency of a one-staged subtotal and total esophagoplasty performance was proved, using colonic segment, independent of the transplant length. The immediate and late results were analyzed.

[Prevention and treatment of complications after reconstructive surgery on the trachea]. / Profilaktika i lechenie oslozhnenii posle vypolneniia rekonstruktivnykh operatsii na trakhee.

The results of treatment of 590 patients are analyzed, to whom the operations on trachea were conducted. In 91 patient 99 complications have occurred, 35 (6.4%) patients died. But due to the operation method refinement, new approaches elaboration, improvement of the measures of tracheoplasty complications prophylaxis and treatment, 2 (1.4%) patients died of 142 operated on during last years.