Experimental Oncology

NON-STANDARD STRATEGIES IN THE TREATMENT OF ADVANCED CERVICAL CANCER: A CASE SERIES

Background. Cervical cancer (СС) continues to be the leading cancer pathology affecting women of both young and older ages. In the advanced stages of СС, the choice of treatment typically favors chemoradiotherapy. However, in a number of cases, radical surgery may be the only effective treatment. Th s issue requires further analysis. Materials and Methods. Five selected cases of the advanced СС (stages IIa—IVa) that required non-standard treatment are presented. Results. In all presented cases, the radical surgical treatment had an undeniable immediate curative effect. On follow-up, two patients are alive without any evidence of the disease; two patients died from disease progression and one patient is still receiving treatment for bone recurrence. Conclusions. Despite the fact that in most cases of advanced stages of СС, chemoradiotherapy is effectively used, in some selected cases, surgery may be leading and effective if the operation is performed in a radical manner. Important in this regard are the clinical experience, high level of surgical skills, presence of a multidisciplinary team, and the technical equipment of the medical center for performing such operations.

Expression of microRNA in tumor cells of endmetrioid carcinoma of endometrium

Summary. Background: It is known that more than half of the genes encoding human proteins are regulated by various microRNAs (miRNAs, miR), the expression of which may be associated with various pathological conditions. At the same time, the question of assessing the relationship between the expression of particular miRNAs and the aggressive molecular subtype of endometrial cancer remains open. Aim of the study was to determine the relationship between the expression of miR-34a, miR-125b, miR-142 and miR-101 in endometrioid carcinomas of the endometrium (ECE) and the features of the disease course. Materials and Methods: The samples of surgical material of 51 patients with ECE (mean age 59.8 ± 7.1 years), I–III stage were investigated using morphological, immunohistochemical methods, real time polymerase chain reaction (PCR), cytofluorometry. Results: In endometrial tumors with high proliferation index (> Me), the expression of miR-34a, miR-142 and miR-125b significantly decreased (1.8, 2.7 and 1.5 times, respectively) compared with those in ECE with low proliferation index (< Me). The expression of all studied miRNAs was lower in G3 tumors and those that deeply invaded the myometrium compared to G2 carcinomas and tumors with an invasion of < 1/2 myometrium and significantly decreased in tumors of patients with low stage III compared with stage I–II. The high (> Me) microvessel density in ECE was associated with a significant decrease of miR-125b and miR-101 expression, and the presence of signs of epithelial-mesenchymal transition — with a decreased expression of miR-34a and miR-101. Conclusions: The study revealed a significant heterogeneity of expression of miR-34a, miR-125b, miR-142 and miR-101 in ECE, which is associated with changes in morphofunctional characteristics of endometrial carcinoma.

TREATMENT OPTION TO THE FERTILITY-SPARING RADICAL TRACHELECTOMY AFTER NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH CERVICAL CANCER WITH TUMOR SIZE >2CM

Radical trachelectomy combined with pelvic lymphadenectomy (PLND) has been used to treat early stage cervical cancer patients who wish to preserve their fertility. But vaginal, abdominal, laparoscopic, and robotic approaches used for radical trachelectomy with pelvic PLND cause peritoneal damage, which could result in periadnexal adhesion. Here, we propose the neoadjuvant platinum based chemotherapy (NACT) with the vaginal radical trachelectomy with retroperitoneal PLND as a fertility-preserving option for early stage cervical cancer patients. VRT with retroperitoneal PLND was performed in three women with FIGO 2018 stage IB2 and IIA1 cervical cancers. In all three patients, complete response was achieved without causing any intraoperative and severe postoperative complications. NACT for fertility sparing treatment is an innovative approach, which is potentially quite interesting for many young women affected by cervical cancer with the tumor size >2 cm. Vaginal radical trachelectomy with retroperitoneal PLND can be safely performed and peritoneal damage, which can cause periadnexal adhesion, could be avoided. We consider that this surgical approach and NACT may be a good treatment option for women with cervical cancer who wish to preserve their fertility.

Granulosa and theca cell tumor in rat’s ovary after modified Biskind operation

Summary. Background: Earlier, we described morphological changes in rat ovaries in different terms after Biskind’s operation elucidating the factors that affect the precancerous conditions and ovarian neoplasms appearance. The aim of the research was to identify tumor nature on the 120th day after modified Biskind’s operation using immunohistochemical approach. Results: We described morphological changes in rat ovaries on the 120th day after Biskind’s operation, demonstrated development of theca-granulosa cell tumors, and differentiated between Sertoli-Leydig cell tumors and theca-granulosa cell tumors using monoclonal antibodies against Ingibin-alfa, Calretinin, Melan А. Conclusion: Modified Biskind’s model could be used to study sex-cord tumors in rat ovaries.

Comparison of ultrasound and MRI informativeness for detection and treatment monitoring of cervical cancer metastases in the vagina

Summary. Aim: To assess ultrasound (US) method informativeness in the recurrence detection and treatment monitoring of patients with cervical cancer metastases in the vagina via comparing the US and magnetic resonance imaging (MRI) data. Materials and Methods: 42 patients with recurrence of cervical cancer were examined by transvaginal US and MRI. Data on radiation diagnostics of cervical cancer metastasis in the vagina were compared with pathomorphological data. US and MRI data on the metastatic tumors size were compared. Results: The diagnostic efficiency of US and MRI for recurrence detection was determined. The sensitivity, specificity and accuracy of US were 92.8; 93.3 and 93.3%, respectively, and of MRI — 95.2; 96.6 and 95.8%, respectively. The informativeness of MRI was higher than US in cervical cancer recurrences detection, but the difference was not significant (p > 0.05). US can provide data as informative as MRI for estimation of metastases sizes in the vagina. The mean difference between MRI measurements and US measurements of the metastases volume was 0.79 mm (95% CI 0.62–0.95 cm3). Conclusions: US as a cheaper and simpler method could be an alternative for metastases detecting and treatment monitoring, especially if there are contraindications to MRI.

An uncommon case of vulvar cancer metastatic to breast

Summary. Vulvar carcinoma corresponds to the fourth gynecological malignancy in incidence, with more than forty thousand new cases being estimated worldwide in 2020. It is a disease characterized by locoregional spread presenting high recurrence rates although distant metastases are an uncommon event. The purpose of this work is to describe the diagnosis, treatment, and clinical course of vulvar carcinoma in a patient who presented regional recurrences and late metastasis to the mammary gland. Vulvar cancer is a disease with a well-defined natural history; but with the advancement of therapeutic possibilities in recent years, it has been possible to improve the prognosis, reducing the chance of locoregional recurrence. Thus, the possibility of distance recurrence must be remembered in inpatient follow-up with locally advanced vulvar carcinoma, even if atypically, as in the case reported.

EXPRESSION OF HEPATOCYTE GROWTH FACTOR AND C-MET RECEPTOR IN STROMAL FIBROBLASTS AND TUMOR CELLS OF ENDOMETRIAL CARCINOMA

Background: HGF/c-Met is one of the main signaling pathways that ensure communication between epithelial cells and components of the tumor microenvironment determining the invasive and metastatic potential of many cancers. However, the significance of HGF and c-Met in endometrial carcinoma (ECa) progression remains unclear. Aim: To evaluate copy number variations as well as expression of the c-Met receptor and its ligand HGF in endometrial carcinomas considering the clinical and morphological characteristics of ECa. Materials and Methods: The study was conducted on ECa samples of 57 patients, among which 32 had lymph nodes and/or distant metastasis. The copy number of c-MET gene was estimated by qPCR. The expression of HGF and c-Met in tissue samples was determined by the immunohistochemical method. Results: Amplification of c-MET gene was detected in 10.5% of the ECa cases. In most carcinomas, a combined expression pattern of HGF and c-Met was established, in which co-expression of these markers was observed in tumor cells, and the content of HGF+ fibroblasts increased in the stroma. The expression of HGF in tumor cells was associated with the tumor differentiation grade and was higher in G3 ECa (p = 0.041). The number of HGF+ fibroblasts in the stromal component increased in the ECa cases with metastasis compared to the cases without metastasis (p = 0.032). The content of stromal c-Met+ fibroblasts was higher in deeply invasive carcinomas of patients with metastases than in tumors with invasion of < 1/2 myometrium (p = 0.035). Conclusion: Increased expression of HGF and c-Met in stromal fibroblasts of endometrial carcinomas is associated with metastasis in patients with ECa and deep invasion of the tumor into the myometrium, and can contribute to the aggressive course of the disease.

EXPRESSION OF PROGRAMMED CELL DEATH RECEPTOR IN ENDOMETRIAL CANCER PATIENTS WITH METABOLIC DISORDERS

Aim: To study the expression of the programmed cell death receptor (PD-1) and its ligand (PD-L1) by immunocompetent cells in endometrial cancer patients with metabolic disorders. Materials and Methods: Populations and subpopulations of lymphocytes were analyzed by flow cytometry. Antibodies against CD279 were used to detect PD-1 on the CD4+ and CD8+ T cells. Antibodies against CD14 and CD274 were used to detect PD-L1 on monocytes. Results: In patients with severe metabolic disorders, the expression of PD-1 on CD8+ and CD4+ lymphocytes and the expression of the corresponding PD-L1 on CD14+ cells before treatment and after radiation therapy were higher than in the control group. Conclusion: Theincreased expression of PD-1 and PD-L1 receptors by immunocompetent cells can be considered a new prognostic marker in endometrial cancer patients with morbid obesity.

ROLE OF STROMAL MICROENVIRONMENT IN THE FORMATION OF INVASIVE, ANGIOGENIC, AND METASTATIC POTENTIAL OF ENDOMETRIOID CARCINOMA OF ENDOMETRIUM

The aim of the study was to determine the association of indicators of the progression of endometrioid carcinoma of the endometrium (ECE) with the type of stromal microenvironment, the counts of CXCL12+ fibroblasts and CD163+ macrophages, and the expression of the chemokine CXCL12 and its receptor CXCR4 in tumor cells. Materials and Methods: Histological preparations of ECE samples (n = 51) were analyzed. Expression of CXCL2 and CXCR4 antigens in tumor cells, the content of CXCL12+ fibroblasts and CD163+ macrophages, and the density of microvessels were determined by the immunohistochemical method. Results: Groups of ECE with desmoplastic and inflammatory stromal reactions were delineated. The majority (80.0%) of tumors with desmoplasia were of low differentiation grade, deeply invading the myometrium; 65.0% of patients with these tumors were at stage III of the disease. In ECE cases of stages I–II, 77.4% of ECE showed an inflammatory type of stroma. The high angiogenic and invasive potential of EC of stages I–II was associated with an inflammatory stromal type, high counts of CD163+ macrophages and CXCL12+ fibroblasts in the tumor microenvironment, high expression of the chemokine receptor CXCR4, and reduced expression of its ligand CXCL12 in tumor cells. In the majority of EC of stage III, the increase in angiogenic, invasive, and metastatic potential was accompanied by the presence of desmoplastic stroma, increased expression of CXCR4 in tumor cells, and a high count of CXCL12+ fibroblasts. Conclusions: The obtained results showed that the morphological architecture of the stromal ECE component is related to the molecular features of its constituents and tumor cells. Their interaction modulates the phenotypic characteristics of ECE associated with the degree of malignancy.

VALIDATION OF A PANEL OF BIOMARKERS ASSOCIATED WITH AGGRESSIVE PHENOTYPE OF ENDOMETRIOID CARCINOMA OF ENDOMETRIUM

Aim: To evaluate the prognostic significance of a panel of biomarkers for the identification of a highly malignant molecular subtype of endometrioid carcinoma of the endometrium (ECE). Materials and Methods: The expression of a number of markers (CD24, CD44, E2F1, FOXP3, Her2/neu, p21WAF1/CIP1, p53, β-catenin, vimentin, Е-cadherin, с-Myc, cyclins D1 and Е1) was determined by the immunohistochemical method in the samples of resected tumors of 127 patients with ECE of I–II stage. The Kullback method and the PanelomiX web tool were used to assess the informativeness and identify the aggressive subtype of ECE. The associative relationships of the studied markers were determined using the STRING v11 database. Results: The study of the prognostic significance of a number of biomarkers in ECE has revealed the informativeness, high specificity and sensitivity (> 95%) of the р53+FOXP3-c-Myc+ phenotype, which is associated with a more aggressive tumor process. Bioinformatics analysis confirmed the correlative relationships between p53, FOXP3 and c-Myc, which are significant prognostic markers associated with cancer progression in ECE patients. Conclusions: The identified molecular phenotype of ECE (р53+FOXP3-c-Myc+) has differential and prognostic significance and objectively reflects a highly malignant subtype of this form of cancer.

Peculiarities of epithelial-mesenchymal transition in endometrial carcinomas

Summary. Epithelial-mesenchymal transition is an important component of tumor progression, due to which the cells of malignant neoplasms acquire invasive and migratory properties. Analysis of the literature and our own data show that the activation of proteins involved in epithelial-mesenchymal transition crucially affects the progression of endometrioid carcinoma of the endometrium and the significant variability of their expression could determine the clinical and morphological heterogeneity of this cancer. The most aggressive endometrioid carcinomas of the endometrium are characterized by a hybrid epithelial-mesenchymal phenotype, which is often associated with a collective type of invasion of endometrial tumor cells into the myometrium.

Molecular phenotype of high-grade endometrioid carcinoma of the endometrium

Summary. Background: Prognosis of the course of tumor progression is one of urgent problems of clinical oncology. A relevant specificity of endometrial cancer is its clinical polymorphism within the same histological type of the disease. The search for molecular-biological features associated with the aggressive phenotype of endometrioid carcinomas is indisputably urgent. Aim: To study molecular-biological features of endometrioid carcinoma of the endometrium (ECE) and to identify the molecular subtype of tumors with high potential of malignancy. Materials and Methods: Surgical specimens of 127 patients with EC, stages I–II, aged 36–72 (the average age — 59.3 ± 3.2) were studied using morphological and immunohistochemical methods. The multivariant analysis with the Kullback’s informative measure and PanelomiX were used to estimate the significance of the expression of specific biomarkers. Results: The expression of a complex of multifunctional markers was evaluated in ECE cells of different malignancy stage: p53, FOXP3, p21WAF1/CIP1, р16INK4a, E2F1, cyclins Е and D1, Her2/neu, с-Myc, Е-cadherin, β-catenin, vimentin, CD44, CD24. A triad of biomarkers with threshold expression levels was determined (р53 > 45%; FOXP3 < 14%; с-Myc > 10%). The high expression of oncogene c-Myc and oncosuppressor p53 along with the low level of FOXP3 in tumor cells of ECE was associated with high proliferative potential, low differentiation grade, and deep invasion of a tumor into the myometrium. Conclusions: The molecular phenotype of ECE, most informative in terms of specificity and sensitivity (95%) — р53highFOXP3lowc-Mychigh, was first characterized, which would help identify a high-grade subtype of this cancer form.

Expression of chemokine receptor CXCR4 in tumor cells and content of CXCL12+-fibroblasts in endometrioid carcinoma of endometrium

Summary. Background: The expression of the CXCL12 chemokine and its receptor CXCR4 in the stromal component of the tumor plays an important role in tumor cell migration, proliferation, inhibition of apoptosis and determination of invasive and metastatic potential of malignant neoplasms of various genesis. The significance of CXCL12 and CXCR4 expression in endometrial tumor cells for cancer progression is not fully understood. Aim: To evaluate the content of CXCL12+-fibroblasts and expression of CXCL12 and CXCR4 in endometrial cancer cells, depending on the tumor stage. Materials and Methods: Surgical material of 45 patients with endometrioid carcinoma of the endometrium (ECE) of the stages I–II and III was studied using morphological and immunohistochemical methods. Results: In ECE of stage I–II CXCR4 expression was lower (43.3 ± 4.2%) while CXCL12 expression was higher (33.6 ± 2.4%) compared with the corresponding indices​​ in ECE of stage III (63.6 ± 3.5%, 24.5 ± 1.9%, respectively, p < 0.05). In ECE of stage III, high expression of CXCR4 (> Me) and low CXCL12 (< Me) was observed in 80% of samples; these tumors invaded more than 1/2 of the myometrium. There was a positive correlation between the depth of tumor invasion in the myometrium and the presence of metastases and CXCR4 expression in tumor cells (R = 0.5 and R = 0.4, respectively, p < 0.05) and the negative correlation with the expression of CXCL12 (R = –0.6 and R = –0.3, respectively, p < 0.05). In tumors that deeply invaded the myometrium, a high number of the CXCL12+-fibroblasts (> Me) (14.9 ± 1.3%) was detected. Conclusion: The obtained data reflect the communication of the immunosuppressive factor of the tumor microenvironment, i.e. CXCL12+-fibroblasts and CXCR4 expressing tumor cells. We suggest that the aggressiveness of ECE is determined by the combined effect of these two factors.

ANALYSIS OF FACTORS INFLUENCING TREATMENT OUTCOMES OF UTERINE SARCOMAS

Background. Uterine sarcoma (US) is a rare type of tumor characterized by aggressive clinical behavior and high recurrence rate. Its histopathological heterogeneity has led to a lack of consensus regarding risk factors that could guide the selection of optimal treatment strategies for this pathology. Aim. To investigate the factors influencing treatment outcomes of US. Materials and Methods. We conducted a retrospective analysis of the treatment outcomes of 107 women diagnosed with stage I—II US from 2010 to 2023. The follow-up period ranged from 1.0 to 156.0 months. Kaplan — Meier survival curves were used for the analysis of overall survival (OS) and recurrence-free survival (RFS) rates. The correlation between the studied parameters was analyzed including relative risk (odds ratio, OR) and correlation coefficient. Results. The assessment of OR allowed us to identify the following prognostic factors with a negative impact on the 5-year OS and RFS of patients with US: differentiation grade G3, necrotic areas in tumor tissue, lymphovascular invasion, high mitotic activity (11 or more mitoses per 10 HPF), nuclear atypia 4+, negative ER and PR statuses, and high Ki-67 expression. Conclusions. Survival of patients with US depends on tumor grade, necrosis, and lymphovascular invasion of tumor tissue; mitotic activity and nuclear atypia; ER and PR statuses; and the level of Ki67 expression.

INTERPLAY OF EPIGENETIC REGULATION OF KI-67 AND P53 BY MIR-21 AND MIR-34A IN CERVICAL INTRAEPITHELIAL NEOPLASIA

Background. Cervical cancer (CC), primarily linked to persistent HPV infection, arises from complex genetic and epigenetic alterations. The early detection of cervical intraepithelial neoplasia (CIN) allows for CC prevention. Recent data highlights the importance of epigenetic biomarkers, including non-coding RNAs such as miR-21 and miR-34a. Our aim was to investigate the interplay between Ki-67 and p53 expression and their epigenetic regulation by miR-21 and miR-34a to better predict the course of CIN. Materials and Methods. Tumor biopsies from 50 patients with CIN 1–3/HSIL were analyzed. We performed immunohistochemical analysis of Ki-67 and p53 expression and qRT-PCR for the analysis of miRNA expression. Results. The average miR-21 and miR-34a levels were 5.8 ± 2.8 and 1.42 ± 0.85 (a.u.), respectively, while Ki-67 and p53 averaged 136.9 ± 79.9 and 93.15 ± 49.5 H-score points. Positive correlations were found between miR-21 and Ki-67 (r = 0.76) and miR-34a and p53 expressions (r = 0.65). Tumors with low Ki-67 showed 2.48-fold lower miR-21 levels, and low p53 tumors showed 4.2-fold lower miR-34a levels. While no correlation with age or menstrual status was found, miR-21 (r = 0.78), Ki-67 (r = 0.68), and miR-34a (r = –0.59) correlated with CIN grading (p < 0.05). The miR-21 and Ki-67 levels increased in CIN 2 and CIN 3 compared to CIN 1 in both HPV-positive and HPV-negative samples. The miR-34a levels were the lowest in CIN 3 HPV-negative samples and significantly decreased with CIN progression in HPV-positive samples. The p53 levels were significantly higher in CIN 3 cases of both the HPV-positive and HPV-negative groups. Conclusion. Our study demonstrates that the miR‑21, miR-34a, Ki-67, and p53 expression levels are significantly correlated with each other and are distinctly associated with the progression of CIN grades and HPV status, highlighting their potential as crucial CC biomarkers.

Application of Next-Generation Sequencing to Realize Principles of Precision Therapy in Management of Cancer Patients

All cancers are diseases of the genome, since the cancer cell genome typically consists of 10,000s of passenger alterations, 5—10 biologically relevant alterations, and 1—2 “actionable” alterations. Therefore, somatic mutations in cancer cells can have diagnostic, prognostic, and predictive value. Traditional methods are widely used for testing, such as immunohistochemistry, Sanger sequencing, and allele-specific PCR. However, due to the low throughput, these methods are focused exclusively on testing the most common mutations in target genes. The modern next generation sequencing (NGS) is a technology that enables precision oncology in its current form. ESCAT and ESMO Guidelines defined NGS for routine use in patients with advanced cancers such as non-squamous non-small cell lung cancer, prostate cancer, ovarian cancer, and cholangiocarcinoma. The high sensitivity of the NGS method allows it to be used to search for specific mutations in circulating tumor DNA in blood plasma and other body fluids. NGS testing has evolved from hotspot panels, actionable gene panels, and disease-specific panels to more comprehensive panels. The exome and whole genome sequencing approaches are just beginning to emerge, that is why panel-based testing remains most optimal in oncology practice. NGS is also widely used to identify new and rare mutations in cancer genes and detect inherited cancer mutations.

Features of recurrence of endometrioid type endometrial cancer of I stage

Summary. The aim of this study was to determine the rates of recurrences of stage I endometrial cancer (EC) and features of their localization depending on the clinical and pathological characteristics of the tumor and methods of patients’ treatment. Patients and Methods: The study included 968 patients with stage I endometrioid EC, who underwent surgical treatment in the Department of Oncogynecology of the National Cancer Institute in 2015–2019. Surveillance of patients lasted from January 2015 to December 2020, with a minimum follow-up period of 1 year from the date of surgery. Adjuvant radiation or chemotherapy was performed depending on the clinical and pathological characteristics of the EC case. Results: During the follow-up period, recurrences were observed in 7.0% of cases and were most often found in stage IC of low differentiation grade. It was found that during surgical treatment without adjuvant therapy relapses occurred in 12–36 months after the start of treatment, with adjuvant radiation therapy — in 6–18 months, and with adjuvant chemotherapy — in 32–60 months. Recurrences most often occurred in patients with EC who underwent surgical treatment in combination with chemotherapy (p < 0.05). The lowest number of recurrences was recorded among patients who underwent surgery as an only treatment. The best 5-year survival rate was observed in the group of patients with surgical treatment (93%), and the worst — in the patients treated with combination of surgery and chemotherapy (57%). In patients without recurrences, the survival rate after treatment was 97%, while in patients diagnosed with relapses, the survival rate was 65%. Conclusion: Despite the predominantly favorable course of EC stage I, some patients develop relapses. The rate and localization of recurrences depend on the histological structure of the tumor and treatment regimens of the EC patients.

Expression of miRNAs in the Presence of HPV Infection in Cervical Dysplasia Samples: A Pilot Study

Background. Cervical cancer is a major health concern, with human papillomaviruses (HPV) infection being a key risk factor. However, not all HPV-infected individuals develop cancer, suggesting the additional factors may be involved. This study aims to evaluate the differences in the miR-155 and -205 expression in cervical tissue with dysplasia depending on the presence of HPV and confirmed cancer diagnosis. Materials and Methods. The expression of miR-155 and -205 in 30 formalin-fixed paraffin-embedded primary cervical tissue biopsy samples was evaluated using RT-PCR. Results. The expression levels of miRNA-155 and -205 in cervical dysplasia samples without malignant transformation was lower than these in carcinoma in situ tissues (0.74 ± 0.21 and 1.65 ± 0.42 vs. 1.37 ± 0.18 and 2.35 ± 0.32, respectively). In carcinoma in situ cases, we found higher levels of miRNA-155 and -205 (1.6 and 1.38 times, respectively) in CIN-3/ HSIL samples compared to CIN-2/HSIL samples. The expression of both miRNAs tended to increase in HPV-positive cases and in the presence of malignant transformation compared to HPV-negative dysplasia and dysplasia without signs of malignant transformation, respectively. Conclusions. The obtained data indicate a potential relationship between the presence of HPV infection and the expression profile of miRNA-155 and -205.

SEVERE DISEASE PROGRESSION OF POSTMOLAR GESTATIONAL NEOPLASM IN A VIETNAMESE YOUNG FEMALE PATIENT AFTER TREATMENT REFUSAL: INSIGHTS FROM A CASE REPORT AND LITERATURE REVIEW

Choriocarcinoma is characterized as the most aggressive malignant alternation of gestational trophoblastic neoplasm; however, this illness is a curable malignancy. Although a rarity, this disease affects a female patient’s life and causes a fatal condition. Choriocarcinoma is a life-threatening disease since it is initially insidious and can rapidly lead to masive hemorrhage, even death. Choriocarcinoma should be suspected in childbearing-age women with the high-risk scores according to FIGO. The study aims to report a severe case of widespread metastatic choriocarcinoma to optimize the treatment with multiagent chemotherapy and a multidisciplinary cooperation at our center. A G1P0 20-year-old woman was referred to the hospital for suspicion of metastatic choriocarcinoma after self-stopping chemotherapy because of the COVID-19 pandemic. During hospitalization, the tumor metastasized and presented profuse intraabdominal hemorrhage. The patient underwent immediate surgical intervention to control bleeding, and a definitive diagnosis was accurately established by the histopathological examination. After surgery, the EMA/CO regimen was administered as the first line of treatment, despite the patient being in a coma and requiring a ventilator machine. After 6 cycles of the EMA/CO regimen, her serum β-hCG level decreased to 8 mUI/mL, however, her β-hCG concentration was not down to a negative value. Thus, the patient received paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE regimen) for complete remission following 2 cycles. The delays in choriocarcinoma treatment are prognostic factors for worse outcomes, whereas chemotherapy may be considered a suitable treatment even in a patient’s coma, thus improving a prognosis substantially.

PRIMARY OVARIAN SYNOVIAL SARCOMA — A CASE REPORT

Synovial sarcoma is an aggressive soft tissue sarcoma, which most often occurs in the limbs near the joints. It accounts for 5–10% of all soft tissue sarcomas. It extremely rarely affects the pelvis. So far, only 4 cases of primary involvement of the adnexa have been described. We present a case of a 77-year-old female patient diagnosed with a rapidly growing pelvic formation, subsequently diagnosed as monophasic synovial sarcoma of the ovary. Synovial sarcoma derived from the adnexa is a rare disease that is virtually unknown. The diagnosis is complex, and there is a poor prognosis.

Incidence and long-term effects of treatment of malignant germ cell neoplasms in Ukraine

Summary. Aim: To describe incidence of malignant germ cell neoplasms (GCNs) in Ukraine and assess the medical care to patients with GCNs and its efficacy. Materials and Methods: Records on 6495 males and 1038 females with malignant GCNs diagnosed in 2000–2013 extracted from the database of National Cancer Registry of Ukraine have been analyzed using methods of descriptive epidemiology and survival evaluation. Results: In Ukraine, GCNs covered 79.1% of testicular cancers and 48.9% of ovarian cancers in patients aged 0–19 years, while their proportions in total cancer incidence did not exceed 0.7% in males and 0.1% in females. Most of GCNs in males (75.9%) were diagnosed at the reproductive age (20–49) and in females 72.2% of GCNs were diagnosed at the age of 0–44 years. Female gonadal GCNs were divided by germinomatous and nongerminomatous as 49.3% vs 50.7% while in males this proportion was 65.3% vs 34.7%. Age-specific incidence of genital GCNs in Ukraine reached peak values in males aged 25–39 years and in females aged 10–24 years. Nonseminomatous testicular GCN cases were more common than seminomatous cases in males until the age of 30 years with an incidence of seminomas peaked 10 years later than non-seminomas. Ovarian germinomas were more common than non-germinomas in females aged 15–29. Total GCN incidence rate in 2013 was 1.99 ± 0.090/0000 in males and 0.32 ± 0.040/0000 in females, being closer to that in the countries of Eastern Europe and Asia. In Ukraine, 5-year survival of patients with testicular GCN of stage I who received surgery combined with chemotherapy or radiotherapy was lower than that reported for Europe and USA, and substantially lower in patients with stages II–IV. Five-year survival of patients with ovarian GCN treated with surgery plus chemotherapy was close to that reported in a study for populations of European countries. Conclusion: The trends and patterns of GCN incidence in Ukraine are similar to those in other European countries, while patterns of treatment and survival in Ukraine are closer to that in countries in transition. Further research and analysis are impossible without due registration of both the diagnosis and the treatment undertaken as well as close follow-up of patients’ life status.

PREDICTIVE POWER OF OXIDATIVE STRESS BIOMARKERS IN RECURRENCE AND SURVIVAL IN ADVANCED CERVICAL CANCER

The aim of our study was to measure the levels of 8-hydroxy-2-deoxyguanosine, malondialdehyde, and antioxidant enzymes in patients with locally advanced cervical cancer prior to treatment to determine how these evaluated biomarkers are associated with cervical cancer recurrence and to estimate their potential in further research and clinical use. Materials and Methods. The study included 45 female patients with newly diagnosed advanced cervical cancer who underwent concomitant chemoradiotherapy. The blood and urine samples were collected prior to treatment, between December 2013 and April 2016, and subsequent laboratory analysis was performed. After the medium follow-up of 29 months, the patients were divided into 3 groups according to the time of disease recurrence. A statistical analysis was performed in order to evaluate the relationship between the previously measured biomarkers and recurrence. Results. Taken individually, the parameters of oxidative stress did not reveal significant differences between the three groups in our study. Nevertheless, the catalase and glutathione S-transferase activities were the best predictors of the recurrence. Based on the activities of these two oxidative enzymes, it was possible to separate the group of patients without recurrence after follow-up from the other two groups of patients with recurrent disease. Conclusions. The parameters of oxidative stress have a certain predictive value on the outcome of patients with advanced cervical cancer after concomitant chemo-radiotherapy.

Experience with the use of HIPEC in advanced serous ovarian cancer after complete and optimal cytoreduction

Background: Ovarian cancer (OC) is one of the most demanding unresolved issues in oncogynecology. In Ukraine, there are over 3000 new cases of the disease annually. 24.6% of patients die within the first year after diagnosis. It indicates the relevance of developing new and optimizing existing OC treatment programs. Aim: To analyze the short-term results of hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with primary (non-recurrent) advanced serous OC, in comparison with the group of patients after standard cytoreductive surgery (CRS) of high and medium complexity, according to the following indicators: the effect on metabolism, postoperative complications, length of stay in intensive care unit and hospital, timing of adjuvant chemotherapy initiation. Materials and Methods: Cases of 35 patients with advanced serous OC who underwent the treatment at the Oncogynecology Department of the National Cancer Institute from December 2018 to April 2020 were analyzed. For the assessment of surgical procedures volumes, a surgical complexity scoring system was used. HIPEC was performed in 20 patients (57.1%), while 15 patients (42.9%) underwent standard CRS. Results: At the beginning and end of the HIPEC procedure, a shift in acid-base state and the development of hyperthermia were evident. At the end of the 1st day of the postoperative period, statistically significant changes (p < 0.05) were revealed in pH, base excess, body temperature, alanine transaminase and aspartate transaminase levels in patients from HIPEC group indicating the development of metabolic acidosis and toxic liver damage. The negative effects of HIPEC developed at the end of the procedure may persist at the end of the first postoperative day. While metabolic acidosis diminishes, the signs of hepatotoxicity persist. Toxic liver damage is the most frequent complication of the postoperative period detected more often (p < 0.05) after HIPEC in comparison with standard CRS. Standard adjuvant chemotherapy began on average in 31.9 ± 4.4 days in HIPEC group and 18.6 ± 1.6 days in CRS group (p < 0.05). Conclusions: The data obtained indicate that HIPEC negatively affects metabolism and aggravates the severity of disorders that develop during the CRS phase. The use of HIPEC postpones the initiation of adjuvant chemotherapy, which is probably associated with a longer period of restoration of the functions of organs and systems of patients (in particular, liver function). The feasibility of HIPEC in advanced serous OC treatment requires further research.

FEATURES OF OXIDATIVE METABOLISM AND GENETIC DISORDERS IN PERIPHERAL BLOOD LYMPHOCYTES OF PATIENTS WITH PRIMARY CERVICAL CANCER

Background: The combination of chemo- and radiotherapy used as main treatment of locally advanced cervical cancer (CC) may lead to side effects in healthy cells, which undermine the effectiveness of treatment and quality of life. The assessment of damage level in healthy radiosensitive cells from the tumor environment before the treatment is important in order to predict and prevent remote side effects of radiation. Aim: To study the oxidative metabolism and genetic disorders in peripheral blood lymphocytes (PBL) of primary CC patients in order to evaluate the possibilities of predicting radiation complications based on the molecular and biological properties of PBL. Materials and Methods: Peripheral blood samples were collected from 13 primary CC patients T1–4N0–1M0–1, and PBL were routinely isolated. The oxidative metabolism (mitochondrial trans-membrane potential, superoxide anion radical (О2•) generation, reactive oxygen species (ROS) production in PBL as well as the level of SH-groups in plasma and pro/antioxidant ratio in hemolysates were examined. The development of genetic instability was determined by estimation of DNA double-strand breaks (DNA-DSB), frequency and spectrum of chromosome aberrations and apoptosis. Results: The marked increase in the intensity of О2• generation in PBL (1.5-fold), depletion of SH-groups content (1.6-fold) and a shift in the pro-antioxidant balance (1.4-fold) towards its prooxidant component were observed in the blood of primary CC patients as compared to healthy individuals. These oxidative stress related events were accompanied by an increase in the level of DNA-DSB (2.1-fold), apoptosis (3.5-fold) and frequency of cells with chromosome aberrations (3.9-fold). On the contrary, significant decrease in mitochondrial trans-membrane potential (2.0-fold) and ROS generation in PBL (4.0-fold) were detected. Conclusion: Preliminary data indicate a violation of redox processes regulation, a shift in the pro-antioxidant balance towards its pro-oxidant component, accompanied by an increase in the level of DNA damage, development of genetic instability and apoptotic death of blood lymphocytes in primary CC patients.

Ovarian Epithelioid Hemangioendothelioma. Case Report

Epithelioid hemangioendothelioma is a rare vascular sarcoma commonly occurring in the liver, soft tissues, and organs of the chest cavity. This study provides a detailed description of the clinical presentation, diagnosis, and treatment of epithelioid hemangioendothelioma of the ovary in a 71-year-old patient. According to the pathohistological examination, a mesenchymal tumor of the ovary with epithelioid cells was diagnosed. The immunohistochemical tests confirmed the diagnosis of epithelioid hemangioendothelioma. This clinical case is of interest for clinical practitioners due to the rare location of the tumor in female reproductive organs, which has not been previously documented in the medical literature.

APPENDICULAR MUCINOUS CYSTADENOMA AND CYSTOADENOSARCOMA IN GYNECOLOGICAL PRACTICE. CLINICAL CASES AND LITERATURE REVIEW

Tumors of the right uterine appendages cannot always be distinguished from mucous neoplasms of the appendix (MA) at the preoperative stage. According to the literature, MA is traditionally considered more common in women than in men at the age of 50 years, with a ratio of 4:1. We have identified 2 cases of surgical treatment of MA in gynecological practice, one of mucinous cystadenoma and the other of mucinous cystadenocarcinoma. We present the visual intraoperative assessment of the appendix condition in cystadenoma and cystadenocarcinoma, clinical manifestations, diagnostic discrepancies, and operative tactics. The literature on the detection of appendicular mucocele that mimics ovarian tumor formations in women has been reviewed. The features of diagnostics and possible diagnostic errors were summarized. Diagnostic laparoscopy, visual and operative clinical experience of the surgeon, and cytological and histological examinations of intra- and postoperative results allow for an adequate treatment. It is advisable that the stages and course of appendectomy be reviewed by operating gynecologists and, if necessary, general surgeons.

SIGNIFICANCE OF miRNA-185-5P AND miRNA-424-5P AS PROGNOSTIC MARKERS IN PROGRESSION OF EARLY-STAGE ENDOMETRIAL CANCER

Aim. To compare the expression of miRNA-185-5p and miRNA-424-5p in tumor cells and peripheral blood serum (PBS) of patients with endometrioid carcinoma of the endometrium (ECE) and to evaluate the significance of these biomarkers in cancer progression. Materials and Methods. The study was conducted on the samples of peripheral blood serum (PBS) and tumor tissue of 58 patients with stage I ECE using clinical and morphological methods and real-time polymerase chain reaction. Results. A significant increase in the levels of circulating and tumor-associated miRNA-424-5p was established in ECE patients with a history of recurrences compared to patients without recurrences. To the contrary, the expression level of miRNA-185-5p increased in the PBS and decreased in the tumor tissue of ECE patients with recurrences compared to the patients without recurrence. In addition, we revealed that the expression levels of the studied miRNAs were associated with the differentiation grade and degree of tumor invasion. We established that miRNA-424-5p levels in PBS could serve as the most significant indicator for predicting the occurrence of recurrence in patients with ECE (AUC = 0.991; Sp 94.0%; Se 99.9%). Conclusions. The expression features of miRNA-185-5p and miRNA-424-5p in the PBS and tumor tissue of patients with ECE are associated with the aggressiveness of cancer course and the risk of recurrence.

A RARE UTERINE TUMOR: DISSEMINATED PERITONEAL LEIOMYOMATOSIS. CLINICAL OBSERVATIONS

Background. Disseminated peritoneal leiomyomatosis (DPL) is an extremely rare benign disease characterized by widespread lesions of the abdominal cavity, pelvis, and retroperitoneal space with tumor nodules of varying size and number, which are benign neoplasms consisting of smooth muscle fibers in their histological structure. Aim. To analyze clinical cases of DPL with a concise review of the current state of the DPL diagnosis and treatment. Materials and Methods. We analyzed 5 clinical cases of DPL of female patients aged 39—50 years (mean age 46.2 years) who underwent surgical treatment at the National Cancer Institute from 2010 to 2021. In all 5 patients, the diagnosis of DPL (8898/1) was verified according to pathological (using routine hematoxylin/eosin staining) and immunohistochemical (IHC) studies. Results. All patients underwent surgical treatment with a laparotomy approach, the extent and radicality of which depended on the location and number of tumor lesions. At the time of follow-up, all 5 patients were alive and did not receive any special oncological treatment. Conclusions. DPL is characterized by a variety of clinical manifestations from polyserositis to acute abdomen, depending on the location and size of the main tumor focus. IHC analysis is the criterion for the final diagnosis, and radical removal of all tumor foci provides the best therapeutic prognosis. The treatment should be carried out in highly specialized cancer centers where surgeons have gained sufficient experience in performing cytoreductive surgery.