Erik Kudela

Amplification of 3q26 and 5p15 regions in cervical intraepithelial neoplasia

To analyze different amplification patterns of 3q26 and 5p15 regions in low‐grade and high‐grade cervical intraepithelial neoplasia.

mRNA expression in cervical specimens for determination of severe dysplasia or worse in HPV-16/18-positive squamous lesions.

Objectives The objective of current study was to determine the p16INK4a mRNA level in cervical cells by relative quantification (RQ) and to test viral E6 expression in human papillomavirus (HPV) -16 or -18–positive specimens by widely used methods. We targeted the pivotal mRNA level associated with severe dysplasia or worse. Materials and Methods Cervical specimens were taken from 134 women with cervical disease and 132 women with normal cytologic results. The presence of HPV was analyzed by sequencing. The results of p16INK4a and E6 analyses were statistically processed in receiver operating characteristic curve analysis to predict severe dysplasia or worse. Results The HPV DNA was detected in 81.4% (109/134) of women with cervical disease and in 27.3% (36/132) of women with normal cytologic results. HPV-16 or -18 were present in 59.7% (80/134) of abnormal specimens. p16INK4a and E6 mRNA expression was increasing with severity of cervical dysplasia. p16INK4a mRNA expression was found 4.35-fold and 13.15-fold increased in high-grade squamous intraepithelial lesions and squamous cell carcinomas, respectively. E6 mRNA expression was significantly increased (p = .0038) in severe dysplasias or worse. The RQ method achieved better sensitivity (82.6%), and E6 mRNA got better specificity (80.6%) for the prediction of severe dysplasia or worse. Conclusions An increasing level of p16INK4a and E6 mRNA transcripts could mean the potential of cervical dysplasia progression to cancer, but further studies should be done to confirm this proposition. Nevertheless, we consider using both tests to improve the sensitivity and specificity for prediction of severe dysplasia or worse.

Active cigarette smoking and the risk of breast cancer at the level of N-acetyltransferase 2 (NAT2) gene polymorphisms

The aim of our study was to assess the correlation between the tobacco exposure and NAT2 gene (rs1041983 C/T, rs1801280 T/C, rs1799930 G/A) polymorphisms in association with breast cancer development. We wanted to determine the prognostic clinical importance of these polymorphisms in association with smoking and breast cancer. For the detection of possible association between smoking, NAT2 gene polymorphisms, and the risk of breast cancer, we designed a case-controlled study with 198 patients enrolled, 98 breast cancer patients and 100 healthy controls. Ten milliliters of peripheral blood from the cubital vein was withdrawn from every patient. The HRM (high resolution melting) analysis was used for the detection of three abovementioned NAT2 gene polymorphisms. When comparing a group of women smoking more than 5 cigarettes a day with the patients smoking fewer than 5 cigarettes a day, we found out that if women were the carriers of aberrant AA genotype for rs1799930, the first group of women had higher risk of breast carcinoma than the second group. If patients were the carriers of aberrant TT genotype for rs1041983, for rs1801280CC genotype, and rs1799930AA genotype and they smoked more than 5 cigarettes a day, they had higher risk of malignant breast disease than never-smoking women. Our results confirm the hypothesis that NAT2 gene polymorphisms (rs1041983 C/T, rs1801280 T/C, and rs1799930 G/A) in association with long-period active smoking could be the possible individual risk-predicting factors for breast cancer development in the population of Slovak women.

Determination of malignant potential of cervical intraepithelial neoplasia.

Basic diagnostic procedures in cervical cancer screening are able to set the diagnosis but they do not provide any information about the biological nature and behavior of lesions. The causal link of HPV infection and cervical cancer and discoveries of complex interactions between host and HPV genome opened new possibilities in molecular diagnostics. HPV DNA analysis, determination of viral load, detection of E6 and E7 mRNA transcripts, identifying of methylation profiles, genomic changes, miRNAs, and telomerase activity should be the right choice for exact diagnostics and prediction of behavior of premalignant lesions of the cervix. These findings set a completely new light not only in diagnostic but also in management and treatment of cervical dysplasia and cervical cancer.

Arteriovenous malformation of vein of Galen as a rare non-hypoxic cause of changes in fetal heart rate pattern during labor

The aim of this case report is to describe a rare non‐hypoxic cause of pathological changes in fetal heart rate pattern during labor, and to determine management, including a description of important prenatal aspects when pathologic cardiotocographic recording is performed during labor. A fetus with rare arteriovenous malformation of the vein of Galen, which represents less than 1% of all intracranial arteriovenous malformations, was monitored by intrapartum external cardiotocography in the 37 + 5 gestational week. The baby was born by cesarean section because of signs of imminent intrauterine hypoxia on cardiotocography. However, metabolic acidosis was not confirmed in umbilical cord blood sampling. Despite intensive neonatal care management, the newborn died 31 h after delivery because of progressive cardiac decompensation, hypotension and multi‐organ failure. Precise diagnosis of the abovementioned pathology, a pre‐labor plan for delivery and postnatal prognosis assessment can significantly contribute to the avoidance of a misdiagnosis of fetal hypoxia and unnecessary operative delivery with marked medico‐legal consequences.

Bilateral ovarian angiosarcoma arising from the mature cystic teratomas – A case report and review of the literature

Highlights • We present the first case of bilateral ovarian angiosarcoma arising from the mature teratomas.• Due to widespread disease, we performed limited surgical procedure consisting of bilateral adnexectomy and omentectomy.• This work summarizes the current knowledge in the diagnosis and treatment of angiosarcomas arising in the mature teratomas.• Promising results are expected from the trials devoted to antiangiogenic strategies in treatment of aggressive sarcomas.

Perivascular epithelioid cell tumors of the uterine cervix.

The World Health Organization (WHO) defines PEComas as mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular cells. Uterus is the most common site of a subgroup of PEComas not otherwise specified(NOS). PEComas of the uterine cervix are extremely rare, and only thirteen cases have been described in the English literature to date. In this review, we summarize the available data concerning diagnostics, immunohistochemical analysis, genetics and treatment of cervical PEComas. Radical hysterectomy with bilateral salpingooophorectomy is the best surgical approach available. Adjuvant therapy in its present form is not efficient. Therefore, further studies are needed to evaluate the newest treatment strategies.

The examination of superior mesenteric artery circulation in fetus during pregnancy

Abstract Objective: The aim of the study was a comprehensive examination of the circulation of superior mesenteric artery in different weeks of pregnancy using Doppler ultrasound examination. Methods: The study was conducted at the Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University, Slovakia between the years 2008 and 2012. Dynamics and changes in superior mesenteric artery circulation were studied in 856 women. Results of Doppler examination were processed and subsequently evaluated for each gestational week separately. Results: We found that changes in resistance index of superior mesenteric artery are slower and have a tendency to decrease as a consequence of a gradual decrease in vascular resistance. The changes in pulsatility index are different in nature; there is a tendency for there are to be repeating periods of higher and then lower values, which are subject to a more pronounced dependence on flow rate, especially end diastolic velocity, and Vmean. Conclusions: This article and its results bring a new, comprehensive view not only of physiological changes in the splanchnic circulation, but also of changes that may be subject to a certain extent, not only to the sex, but primarily to the weight of the fetus, which, of course, indirectly reflects its metabolic and respiratory demands.

Current approaches in the clinical management of pregnancy-associated breast cancer—pros and cons

Malignancies are one of the leading causes of mortality in women during their reproductive life. Treatment of gynecological malignant tumors during pregnancy is possible but not simple, since it creates a conflict between care of the mother and the fetus. BC is the most prevalent malignancy diagnosed in pregnancy, ranking up to 21% of all pregnancy-related malignancies. Due to its stets increasing prevalence, aggressive cancer subtype, and severe ethical and psychological aspects linked to the disease, experts raise an alarm for an acute necessity to improve the overall management of the PABC—the issue which has strongly motivated our current paper. Comprehensive research data and clinical experience accumulated in recent years have advanced our understanding of the disease complexity. PABC treatment must be individualized with an emphasis on optimal care of the mother, while observing standard treatment protocols with regard to safety of the fetus. Treatment protocols should be elaborated based on the individualized patient profile, bearing in mind the acute danger to the mother, maximizing the therapy efficacy and minimizing harmful effects to the fetus. Complex consulting on treatment options, their impacts on pregnancy and potential teratogenic effects requires tight “doctor-patient” collaboration. Complications that may arise due to the treatment of breast cancer in pregnancy require a multiprofessional expertise including oncologists, neonatologists, perinatologists, obstetricians, teratologists, and toxicologists, and an extensive psychological support throughout the pregnancy and after giving birth. Thereby, specifically psychological aspects of PABC diagnosis and follow-up are frequently neglected, being not yet adequately explored in the entire disease management approach. Herewith, we update the status quo regarding the currently available diagnostic modalities, complex treatment algorithms, and novel clinical approaches which altogether argue for an urgent necessity of a paradigm shift moving away from reactive to predictive, preventive, and personalized medical approach in the overall management of PABC meeting the needs of young populations, persons at high risk, affected patients, and families as the society at large.

Methylation of CADM1 and MAL together with HPV status in cytological cervical specimens serves an important role in the progression of cervical intraepithelial neoplasia

Cervical cancer (CC) is the second most common type of cancer affecting the female population. The development of CC takes several years, and involves a precancerous stage known as cervical intraepithelial neoplasia (CIN). A key factor in the development of disease is the human papillomavirus (HPV) infection, which initiates carcinogenesis. Furthermore, CC is also impacted by epigenetic changes such as DNA methylation, which causes activation or exclusion of certain genes, and the hypermethylation of cytosines in promoters, thereby switching off previously active genes. The majority of DNA methylation events occur at cytosine-guanine nucleotides, which in the human genome are known as CpG islands. The aim of the present study was to investigate the methylation levels in intronic sequences of the two tumor suppressor genes cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation associated protein (MAL) using cytological samples and to identify potential biomarkers involved in CIN by pyrosequencing. DNA was isolated from cervical smears from patients with CINs, with healthy patients serving as a control group. Samples were converted by treatment with sodium bisulfite and subsequent pyrosequencing to detect the methylation status of the selected genes. The presence of HPV DNA infection analyzed by the polymerase chain reaction, was detected in each sample. Of the total number of samples (n=91), the present study confirmed the presence of one or two high-risk subtypes of HPV in 39 cases (42.85%) and HPV infection was significantly associated with CIN2+ lesions. For the two genes (MAL and CADM1) the present study confirmed that the median methylation was significantly higher in HPV positive patients [P=0.0097, 95% confidence interval (CI): (−0.030, −0.003)/P=0.0024, 95% CI: (−0.06, −0.01)] when compared with patients negative for HPV DNA infection, and the average methylation was demonstrated to be increased with the degree of cervical lesion. The present study used logistical regression to model the dependence between the case/control statuses (control group vs. Dg. 1–4). The area under the curve values for MAL were: 84% for cervical inflammation, 71% for CIN1, 73.4% for CIN2+ and 77% for squamous cell carcinoma (SCC); and for CADM1 were: 88.6% for cervical inflammation, 68% for CIN1, 80% for CIN2+ and 89% for SCC. The present study confirmed that there were statistically significant differences between the methylation levels of individual CpGs and significantly higher median methylation in patients positive for HPV16/18. CADM1 exhibited higher levels of methylation in almost every study group when compared with MAL during the transition of CIN and appeared to be a promising biomarker for future study.