The Role of Glutathione Transferase Omega-Class Variant Alleles in Individual Susceptibility to Ovarian Cancer.

The tumor microenvironment is affected by reactive oxygen species and has been suggested to have an important role in ovarian cancer (OC) tumorigenesis. The role of glutathione transferases (GSTs) in the maintenance of redox balance is considered as an important contributing factor in cancer, including OC. Furthermore, GSTs are mostly encoded by highly polymorphic genes, which further highlights their potential role in OC, known to originate from accumulated genetic changes. Since the potential relevance of genetic variations in omega-class GSTs (GSTO1 and GSTO2), with somewhat different activities such as thioltransferase and dehydroascorbate reductase activity, has not been clarified as yet in terms of susceptibility to OC, we aimed to investigate whether the presence of different GSTO1 and GSTO2 genetic variants, individually or combined, might represent determinants of risk for OC development. Genotyping was performed in 110 OC patients and 129 matched controls using a PCR-based assay for genotyping single nucleotide polymorphisms. The results of our study show that homozygous carriers of the GSTO2 variant G allele are at an increased risk of OC development in comparison to the carriers of the referent genotype (OR1 = 2.16, 95% CI: 0.88-5.26, p = 0.08; OR2 = 2.49, 95% CI: 0.93-6.61, p = 0.06). Furthermore, individuals with GST omega haplotype H2, meaning the concomitant presence of the GSTO1*A and GSTO2*G alleles, are more susceptible to OC development, while carriers of the H4 (*A*A) haplotype exhibited lower risk of OC when crude and adjusted haplotype analysis was performed (OR1 = 0.29; 95% CI: 0.12-0.70; p = 0.007 and OR2 = 0.27; 95% CI: 0.11-0.67; p = 0.0054). Overall, our results suggest that GSTO locus variants may confer OC risk.

Glutathione Transferase P1: Potential Therapeutic Target in Ovarian Cancer.

Chemotherapy resistance of ovarian cancer, regarded as the most lethal malignant gynecological disease, can be explained by several mechanisms, including increased activity of efflux transporters leading to decreased intracellular drug accumulation, increased efflux of the therapeutic agents from the cell by multidrug-resistance-associated protein (MRP1), enhanced DNA repair, altered apoptotic pathways, silencing of a number of genes, as well as drug inactivation, especially by glutathione transferase P1 (GSTP1). Indeed, GSTP1 has been recognized as the major enzyme responsible for the conversion of drugs most commonly used to treat metastatic ovarian cancer into less effective forms. Furthermore, GSTP1 may even be responsible for chemoresistance of non-GST substrate drugs by mechanisms such as interaction with efflux transporters or different signaling molecules involved in regulation of apoptosis. Recently, microRNAs (miRNAs) have been identified as important gene regulators in ovarian cancer, which are able to target GST-mediated drug metabolism in order to regulate drug resistance. So far, miR-186 and miR-133b have been associated with reduced ovarian cancer drug resistance by silencing the expression of the drug-resistance-related proteins, GSTP1 and MDR1. Unfortunately, sometimes miRNAs might even enhance the drug resistance in ovarian cancer, as shown for miR-130b. Therefore, chemoresistance in ovarian cancer treatment represents a very complex process, but strategies that influence GSTP1 expression in ovarian cancer as a therapeutic target, as well as miRNAs affecting GSTP1 expression, seem to represent promising predictors of chemotherapeutic response in ovarian cancer, while at the same time represent potential targets to overcome chemoresistance in the future.

Massive fetomaternal hemorrhage as a cause of severe fetal anemia.

Introduction: Fetomaternal hemorrhage (FMH) is a transfu-sion of fetal blood into the maternal circulation. A volume of transfused fetal blood required to cause severe, life-threatening fetal anemia, is not clearly defined. Some authors suggest vol-umes of 80 mL and 150 mL as a threshold which defines mas-sive FMH. Therefore, a rate of massive FMH is 1 : 1,000 and 1 : 5,000 births, respectively. Fetal and neonatal anemia is one of the most serious complications of the FMH. Clinical manifesta-tions of FMH are nonspecific, and mostly it presented as re-duced fetal movements and changes in cardiotocography (CTG). The standard for diagnosing FMH is Kleihaurer-Betke test. Case report: A 34-year-old gravida (G) 1, para (P) 1 was hospitalized due to uterine contractions at 39 weeks of gesta-tion. CTG monitoring revealed sinusoidal fetal heart rate and clinical examination showed complete cervical dilatation. Im-mediately after admission, the women delivered vaginally. Ap-gar scores were 1 and 2 at the first and fifth minute, respec-tively. Immediately baby was intubated and mechanical ventila-tion started. Initial analysis revealed pronounced acidosis and severe anemia. The patient received intravenous fluid therapy with sodium-bicarbonate as well as red cell transfusion. With all measures, the condition of the baby improved with normaliza-tion of hemoglobin level and blood pH. Kleihaurer-Betke test revealed the presence of fetal red cells in maternal circulation, equivalent to 531 mL blood loss. The level of maternal fetal hemoglobin (HbF) and elevated alpha fetoprotein also con-firmed the diagnosis of massive FMH. Conclusion: For the successful diagnosis and management of FMH direct commu-nication between the obstetrician and the pediatrician is neces-sary as presented in this report.

Treatment patterns, health care utilization, and costs of ovarian cancer in Central and Eastern Europe using a Delphi panel based on a retrospective chart review.

OBJECTIVE: Despite the considerable disease burden of ovarian cancer, there were no cost studies in Central and Eastern Europe. This study aimed to describe treatment patterns, health care utilization, and costs associated with treating ovarian cancer in Hungary, Poland, Serbia, and Slovakia. METHOD: Overall clinical practice for management of epithelial ovarian cancer was investigated through a 3-round Delphi panel. Experts completed a survey based on the chart review (n = 1542). The survey was developed based on clinical guidelines and the International Federation of Gynecology and Obstetrics Annual Report. Means, ranges, and outlier values were discussed with the experts during a telephone interview. Finally, consensus estimates were obtained in face-to-face workshops. Based on these results, overall cost of ovarian cancer was estimated using a Markov model. RESULTS: The patients included in the chart review were followed up from presurgical diagnosis and in each phase of treatment, that is, surgical staging and primary surgery, chemotherapy and chemotherapy monitoring, follow-up, and palliative care. The 5-year overall cost per patient was €14,100 to €16,300 in Hungary, €14,600 to €15,800 in Poland, €7600 to €8100 in Serbia, and €12,400 to €14,500 in Slovakia. The main components were chemotherapy-associated costs (68%-74% of the total cost), followed by cost of primary treatment with surgery (15%-21%) and palliative care (3%-10%). CONCLUSIONS: Patients with ovarian cancer consume considerable health care resources and incur substantial costs in Central and Eastern Europe. These findings may prove useful for clinicians and decision makers in understanding the economic implications of managing ovarian cancer in Central and Eastern Europe and the need for innovative therapies.

Early dumping syndrome and reflux esophagitis prevention with pouch reconstruction.

BACKGROUND: Total gastrectomy causes numerous disorders, such as reflux esophagitis, dumping syndrome, malabsorption, and malnutrition. To minimize the consequences, different variants of reconstruction are performed. The aim of our study is the comparison of two reconstructive methods: the standard Roux-en-Y and a new modality of pouch interposition, preduodenal-pouch interposition. This study aims to investigate the advantage of bile reflux prevention and to reduce symptoms of dumping syndrome after 3- and 6-mo follow-up. MATERIALS AND METHODS: A total of 60 patients were divided in two groups: (A) 30 patients with Roux-en-Y reconstruction, and (B) 30 patients with the preduodenal-pouch (PDP) type of reconstruction. Endoscopic examination and endoluminal jejunal limb pressure measurements were performed. Scintigraphic measurements of half-emptying time were performed to evaluate meal elimination in the context of reflux esophagitis and early dumping syndrome. The Japan Society of Gastrointestinal Surgery has provided guidelines with which to classify the symptoms of early dumping syndrome. Patients were followed up for periods of 3 and 6 mo after the surgery. RESULTS: Our study groups did not differ with regard to the level of reflux esophagitis (P = 0.688). Average values of pressure at 10 and 15 cm below the esophago-jejunal junction were significantly lower in the PDP group (P < 0.001). Elimination of the test meal between two groups was not significant (P = 0.222). Evaluation of early dumping syndrome symptoms revealed a significant reduction among PDP patients after 3 and 6 mo. CONCLUSION: Our study showed significant superiority of the new pouch reconstruction over the standard Roux-en-Y approach in the treatment of early dumping syndrome.

[Multifoetal pregnancies complicated by reversed arterial perfusion: report of four cases].

INTRODUCTION: Twin reversed arterial perfusion syndrome (TRAP) or acardiac anomaly presents a rare and severe complication affecting monochorionic multiple pregnancies occurring in 1 per 35,000 pregnancies or 1 per 100 of monozygotic twins. We report four cases of multiple pregnancies with TRAP diagnosed over the last 2 years, which were under check-up and treatment during the entire pregnancy course finalized by delivery. OUTLINE OF CASES: In two cases pregnancies were trigeminal, and other two geminal, with acardia of one foetus, by anceps type in three and acephalus in one. Expectant management was initially done in all cases. The relation of acardiac and donor abdominal circumference was below 50% and negative signs of the donor's cardiac failure were detected in two cases, so that expectative management was continued until delivery. Due to obstetric indications, a cesarean section was performed on the 33rd and 34th gestational week, and healthy newborns were delivered. Another two acardiac twins had abdominal circumference ratio between the acardiac fetus and the donor of over 50%, and signs of congestive heart failure in the donor, which indicated invasive therapeutic procedure with absolute alcohol chemisclerosis; it was done by alcohol injection into the acardiac abdominal aorta which interrupted the retrograde blood-flow into the acardiac umbilicus. In the first case a successful intervention was performed at 29th gestational week, but after 12 hours distress signs were registered. The delivery was finalized by a cesarean section, and a live donor was delivered. In the second case the intervention was successfully done at the 20th gestational week, and after 96 hours from the intervention lethal ending of the donor was registered. CONCLUSION: Bearing in mind that the occurrence of TRAP is rare, it is necessary to sum-up experiences from a larger number of centres to determine efficient therapeutic procedure.

[Fetal cerebral-umbilical Doppler ratio in prediction of fetal distress in patients with preeclampsia].

BACKGROUND/AIM: The use of color Doppler ultrasonography provides noninvasive observation, confirmation and quantification of pathophysiological processes in fetoplacental circulation in pregnant patients. By blood vessel mapping and the obtained waves spectral analysis it is posible to evaluate vascular resistency of the fetus blood vessels. The aim of the study was to evaluate cerebral-umbilical pulsatility index ratio in fetal circulation in prediction of fetal distress in patients with preeclampsia. METHODS: By measurement of pulsatility indices in medial cerebral and umbilical arteries in 400 patients with uncomplicated pregnancy, normal values were calculated for fetuses from 15-40 weeks. In our study group 70 patients with preeclampsia were included. Cerebral-umbilical (C/U) ratio was calculated after pulsatility indices in medial cerebral artery and umbilical artery determining by the spectral Doppler analysis of flow velocity waveforms in these vessels. Fetal outcome was analyzed by measurement of the Apgar score at the 5th minute and fetal pH at birth. RESULTS: The mean C/U ratio values in the third trimester of normal pregnancy were between 1.8 and 1.9. The mean C/U ratio values in the patients complicated with preeclampsia were significantly lower comparing to normal pregnancies (ANOVA, p < 0.05). The mean 5th minute Apgar score in the study group was 6.35 +/- 1.58, and the mean fetal pH at birth was 7.16 +/- 0.15. Linear regression test showed a highly significant correlation between low C/U ratio and fetal pH at birth in patients with preeclampsia (r = 0.49, p < 0.01). CONCLUSION: The C/U ratio values obtained from spectral Doppler analysis in fetal vessels showed a highly significant correlation with fetal pH at birth in the patients with preeclampsia. The results of our study confirmed the reliability of C/U ratio in estimation of fetal condition in preeclamptic patients. Very low C/U ratio values in patients with preeclampsia indicate that in these fetuses fetal acidosis and fetal distress may be expected.

The value of sentinel lymphadenectomy in radical operative treatment of cervical cancer.

BACKGROUND/AIM: Therapy of the early stages of cervical carcinoma is surgical or radiation therapy, and for advanced stages chemoradiotherapy. Pelvic and paraaortic lymphadenectomy in early stages offers the most important prognostic factor for survival. To evaluate the method and possible influence on surgical and therapy of the disease, we performed sentinel node (SN) identification and excision during open radical hysterectomy and lymphadenectomy in stage Ib-IIa cervical carcinoma. METHODS: Fifty patients initially diagnosed with invasive squamous-cell cervical cancer stage Ib-IIa were included in the study. Only blue dye was used for sentinel node mapping. During the surgery sentinel nodes were identified and sent to histopathology separately from the other lymph nodes. After lymphadenectomy, radical hysterectomy was performed. RESULTS: The mean age of our fifty patients was 49.10 years (SD = 5.92), and the mean number of extracted lymph nodes per patient was 25.78 (SD = 5.58). The number of sentinel nodes identified per patient was between 0 and 5, mean 2.60 (SD = 1.54). There were no inframesenteric paraaortic sentinel nodes found among the patients. The dominant tumor grades were 1 and 2, 40% and 50% respectively, and 37 out of 50 patients (74%) had tumor diameter less than 2 cm. In four patients (8%) SN were not identified. In the rest of 46 patients the presence of SN was bilateral (19 patients, 38%) or unilateral (27 patients, 54%). Positive SN were found in 17 patients (34%), and negative in 29 patients (58%). Out of the whole group of patients (50), 21 of them (42%) had positive lymph nodes (LN). In the crosstab statistics, no differences were noticed in the group without SN found, in comparison with tumor grade and diameter. Finally, our test showed sensitivity of 85% (SE = 8%), specificity 100%, positive predictive value of 100%, negative predictive value of 89.6% (SE = 5.60%), and effectiveness of 93% (SE = 3.6%) regarding sentinel lymphadenectomy. CONCLUSION: This method of sentinel lymph node identification is simple, but not reliable enough to support further laparoscopic SN excision in order to make the final decision about the treatment of cervical cancer.

Pregnancy using gonadotropins and performing intrauterine insemination in a woman with hypogonadotropic hypogonadism.

Hypogonadotropic hypogonadism is one of the causes of infertility. In women with hypogonadotropic hypogonadism both follicle-stimulating hormone and luteinizing hormone are required to induce optimal follicular growth and steroidogenesis. We described a case of singleton pregnancy in a 38-year-old patient, presenting with primary hypogonadotropic amenorrhea and empty sella syndrome, treated with human menopausal gonadotropins and performing intrauterine insemination in first attempt. This therapy led to maturation of two follicles and one of them was fertilized. A singleton pregnancy ensued and a normal infant was delivered by cesarean section.