The Role of Alpha-Fetoprotein (AFP) in Contemporary Oncology: The Path from a Diagnostic Biomarker to an Anticancer Drug.

This article presents contemporary opinion on the role of alpha-fetoprotein in oncologic diagnostics and treatment. This role stretches far beyond the already known one-that of the biomarker of hepatocellular carcinoma. The turn of the 20th and 21st centuries saw a significant increase in knowledge about the fundamental role of AFP in the neoplastic processes, and in the induction of features of malignance and drug resistance of hepatocellular carcinoma. The impact of AFP on the creation of an immunosuppressive environment for the developing tumor was identified, giving rise to attempts at immunotherapy. The paper presents current and prospective therapies using AFP and its derivatives and the gene therapy options. We directed our attention to both the benefits and risks associated with the use of AFP in oncologic therapy.

The role of ABC transporters' gene polymorphism in the etiology of intrahepatic cholestasis of pregnancy.

OBJECTIVES: The etiology of intrahepatic cholestasis of pregnancy (ICP) involves environmental, hormonal and genetic factors. It is thought that ICP may be related to the polymorphic variants of several genes involved in the metabolism and transport of bile acids (BA). The goal of our study was to evaluate the possible role of genetic polymorphic variants of ABC transporters in patients with ICP. MATERIAL AND METHODS: 96 women with ICP (mean age of 30.42 years, mean gestational age of 36.83 gestation weeks) and 211 healthy pregnant women (mean age of 30.68 years, mean gestational age of 39.05 gestation weeks) were enrolled in the study. Genetic analysis was performed using a polymerase chain reaction / restriction fragment length polymorphism (PCR/RFLP) method. The following polymorphisms were analysed: 1331T > C (V444A) ABCB11 and 1954A > G (R652G) ABCB4. RESULTS: Our analysis of frequency of genotypes and alleles of the 1954A > G ABCB4 polymorphism revealed no significant differences between the ICP and control groups. For the 1331T > C polymorphism of the ABCB11 gene the results revealed a higher frequency of 1331CC genotypes in the ICP group (39.58% vs. 29.38%. OR = 1.57, p = 0.05). Also, the frequency of the 1331C allele was higher in the ICP group compared to the control group (64.06% vs. 55.69%, OR = 1.42, p = 0.03). CONCLUSIONS: The overrepresentation of mutated variants of the 1331T > C ABCB11 polymorphism in the ICP group suggests its contribution to the etiology of the intrahepatic cholestasis of pregnancy. Analysis of genotypes' co-existence pointed to the possibility of the mutated variants of polymorphism 1954A > G ABCB4 and 1331T > C ABCB11 having a summation effect on the development of ICP.

Influence of selected factors on serum AFP levels in pregnant women in terms of prenatal screening accuracy - literature review.

Alpha-fetoprotein (AFP) is one of the biochemical components of the triple (T-3) and quadruple (T-4) test used so far in prenatal screening mainly for trisomy 21 (T21) and neural tube defects (NTDs). Based on many years of experience and data collected during these studies, a variety of factors have been identified that can affect a pregnant woman's serum AFP level, and thus the risk assessment of trisomy 21 (T21) and neural tube defects. These include both unaccounted for purely medical data (e.g., from baseline information about the patient, assisted reproduction methods used, comorbidities and emerging pregnancy pathologies) and errors made during statistical analysis. Since the triple or quadruple test is usually performed between 15 and 20 weeks of pregnancy, most scientific studies are based solely on results from this period of pregnancy - limited data are available for the first and third trimesters of pregnancy. In the era of new improved screening tests, AFP has the potential to become an independent marker for pregnancy well-being evaluation.

Alpha-fetoprotein (AFP) - new aspects of a well-known marker in perinatology.

Alpha-fetoprotein (AFP) is a serum protein, which is characteristic of the fetal development period and a well-known oncological marker. The predominance of AFP among serum proteins is common in fetal life, whereas after birthing its functions are gradually taken over by albumins. An understanding of the mechanism of AFP transfer between fetus and mother has led to the development of screening tests for identifying neural tube defects and Down's syndrome. Currently, the knowledge on patophysiology and the possible importance of AFP in perinatology and fetal medicine extends far beyond those 2 disease states. Throughout the 50 years of research on AFP, there has been dynamic progress of diagnostic techniques, from the qualitative ones that are used solely for scientific studies to the widely used radioimmunoassays and immunoenzymatic assays (enzyme-linked immunosorbent assay, chemiluminescence immunoassay, time-resolved fluorescence immunoassay). Some genetic mutations cause complete inhibition of AFP production by the fetus. This affects the results of screening tests during pregnancy, and also leads to constantly high levels of AFP in adults, which are not linked to oncogenesis.

Genetic variants of progesterone receptor in etiology of preterm delivery.

OBJECTIVES: Preterm delivery (PTD) accounts for around 11% of pregnancies worldwide. Unfortunately, no diagnostic indicator, specific mechanism or genetic predisposition has yet been identified. One of the hypotheses suggest local or functional progesterone decrease as a potential reason for preterm uterine contractions leading to preterm delivery. It is believed that any change in progesterone receptor DNA may be crucial for higher risk of preterm delivery due to abnormal response to prostaglandins, normally inhibited by properly built progesterone. The aim of this study was to determine whether there is an association between progesterone gene polymorphisms (PROGINS and +331G/A) and preterm birth. MATERIAL AND METHODS: A total of 230 women were enrolled, including 115 cases of preterm deliveries (between 22 and 36 weeks of gestation) and 115 healthy mothers of full-term infants. Genomic DNA was isolated from the blood sample. Polymerase chain reaction (PCR) amplification was carried out in a final volume of 25 µL. Genotyping was assayed by PCR. Statistical analysis of the results was conducted with p < 0.05 accepted as statistically significant. RESULTS: For both PROGINS (Alu ins/del) and +331G/A (rs10895068) polymorphisms were equally frequent in case and control group. The prevalence of PGR alleles in both groups was also comparable. CONCLUSIONS: The results of our study showed no association between progesterone gene polymorphisms (PROGINS and +331G/A) and risk of preterm delivery. Identifying mechanisms to prolong the length of gestation, particularly in women at risk for preterm delivery, will improve both maternal and fetal outcomes.

FokI vitamin D receptor polymorphism as a protective factor in intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis in pregnancy (ICP) is a pregnancy-specific liver disorder. Its etiology is not fully understood. Increasing evidence indicates the important role of vitamin D and the vitamin D receptor (VDR) in this disorder. The presence of polymorphic variants in the VDR gene could influence its activity and susceptibility to ICP development. The goal of the study was to investigate the role of four genetic polymorphisms of the VDR gene - Fok (rs731236), Bsm (rs1544410), Apa (rs7975232), and Taq (rs731236) - in the etiology of ICP in Polish women. MATERIAL AND METHODS: Ninety-eight women with confirmed ICP and 215 healthy pregnant women as a control group were recruited to the study. We examined four SNPs of the VDR gene: BsmI (rs7975232), TaqI (rs1544410), ApaI (rs228570), FokI (rs731236). Genotyping was performed using the PCR/RFLP method. RESULTS: We observed higher frequency (borderline significant) of the Ff-ff genotypes containing at least one mutated allele of the VDR FokI polymorphism in the control group compared to the ICP group (p = 0.045, OR = 1.71, 95% CI 1.01-2.88). The frequency of the mutated f allele was slightly higher in controls (49.1%) than in the ICP group (43.4%) (OR = 1.26, 95% CI 0.90-1.77), but the difference was not statistically significant (p = 0.196). CONCLUSIONS: Our results showed that the maternal VDR FokI polymorphism could play a protective role in ICP development and probably modulate the risk of ICP occurrence in pregnant women in the Polish population. In the future, to confirm these observations, research in larger, ethnically stratified and clinically analyzed groups is necessary.

The relevance of IL-1ß and IL-1RN gene polymorphisms in the etiology of preterm delivery in the population of Polish women.

OBJECTIVES: Preterm delivery (PTD) is one of the important challenges for perinatal medicine due to prematurity and associated complications. The mechanisms leading to the PTD occurrence are not fully clarified and it is assumed that PTD is a complex phenomenon caused by many different pathophysiological factors. Nowadays, an important role is attributed to genetic determinants of PTD, pointing to possible relevance of polymorphic variants of candidate genes to participate in the etiology of PTD. The aim of the study was to assess the relevance of +3953C > T IL-1ß and 86 bp VNTR IL-1RN gene polymorphisms in the etiology of PTD in Polish women. MATERIAL AND METHODS: Study group consisted of 150 women (mean age 29.2 ± 5.6 years, mean weeks of gestational age 33.7 ± 2.8 gw.) with preterm delivery (22 + 0 - 36 + 6 gw.). To the control group 150 healthy pregnant women (mean age 29.0 ± 3.7 years, mean weeks of gestational age 39.3 ± 1.2 gw.) who delivered > 37 gw. were enrolled. All investigated polymorphisms were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The interesting observation was the notice of overrepresentation of 2/2 genotype of IL-1RN gene in the control group (8.0 vs. 3.3%, p = 0.06) and 2 allele in the control group (25.0 vs. 20.0%, p = 0.07). CONCLUSIONS: The +3953C > T polymorphism of IL-1ß gene probably is not connected with the risk of preterm delivery. The study results points to the possible modulating effect of mutated IL-1RN* 2 allele (86 bp VNTR polymorphism) of IL-1RN gene in decreased risk of preterm delivery.

MTHFR genetic polymorphism and the risk of intrauterine fetal death in Polish women.

OBJECTIVES: To evaluate the role of MTHFR genetic variants in the etiology of intrauterine fetal death in the second part of pregnancy at women from Polish population. MATERIAL AND METHODS: A case-control study was performed on a 76 women with a positive history of at least one in- trauterine fetal death after 22 gestational week and 400 healthy controls. The MTHFR genotyping for polymorphic sites 667C > T, 1298A > C, 1793G > A was determined by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) method. RESULTS: For 1298A > C polymorphism, no statistically significant higher frequency of AA vs. AC+CC genotype was observed in the IUFD group 67.1 % vs. 55.2% in the control group (OR = 0.61, p = 0.05, pcorr = 0.15). We observed overrepresentation of three-locus haplotype CCG (p = 0.20; pcorr = 0.56) and two-locus haplotype CC (p = 0.17; pcorr = 0.48) in the IUFD group compared to controls. CONCLUSIONS: There was no observed relationships in genotype frequency of MTHFR 677C > T and 1793G > A variants, however 1298A > C showed a slightly higher but statistically insignificant prevalence in IUFD compared to the controls in Polish population. Further studies on a larger population are needed.

[Correlation of birthweight and the prediction of fetal and neonatal status]. / Relacja masy ciala odnoszonej do wieku oraz stanu plodu i noworodka.

OBJECTIVE: Quantitative evaluation of direct neonatal risk for small-for-gestational-age (SGA) fetuses. DESIGN: Retrospective analysis of perinatal data base. MATERIALS AND METHODS: Six thousand one hundred twenty four pregnant women undergoing labor at term were enrolled to a study. Standard deviation scores (Z) of birthweight adjusted to the age were calculated. Receiver-operator characteristic were constructed for Z scores in prediction of obstetrical outcome. RESULTS: Birthweight Z score < -1.2 was statistically related to higher occurrence of neonatal depression. Incidence of significant neonatal arterial acidemia (pH < 7.10) was dependent on birthweight Z score in wide range, even among appropriate-for-gestational-age (AGA) ones. Adjusted birthweight had the high predictive value for extremely deep neonatal disturbances. CONCLUSIONS: Classic criterion of SGA fetal weight (10%), as an index of increased perinatal risk, is statistically and biologically proper. Some cases of intrauterine growth restriction, related to insufficient feto-maternal exchange, probably does not lead to SGA birthweight presence. Adjusted birthweight is clinically usefull for limited number of patients.

[Fetal abdominal area growth velocity in prediction of fetal and neonatal well-being]. / Relacja szybkosci wzrastania pola powierzchni przekroju brzucha plodu oraz stanu plodu i noworodka.

OBJECTIVE: Evaluation of new methodology of fetal growth assessment. DESIGN: Retrospective analysis of prospectively collected data. MATERIALS AND METHODS: One hundred ninety five pregnant women undergoing labor at term were enrolled to the study. Standard deviation scores (Z) of fetal abdominal area (FAA) growth velocity in about one month period in the third trimester and adjusted to the age birthweight Z scores were calculated. Receiver-operator characteristic (ROC) were constructed for both Z scores in prediction of obstetric outcome. RESULTS: Areas under the ROC curve for FAA were statistically significantly bigger in prediction of fetal distress (p < 10(-3)) or neonatal acidemia (p < 10(-6)) or depression (p < 0.005). CONCLUSIONS: Fetal abdominal area growth velocity measurement is superior to a fetal weight in fetal well-being assessment and may be a simple method of intrauterine growth restriction diagnosis and even definition.

[Order of twins--random choice of natural selection?]. / Kolejnosc rodzenia sie blizniat--wybór losowy czy dobór naturalny?

OBJECTIVE: Testing of hypothesis that the order of twins is random. DESIGN: Confrontation of birthweight and incidence of stillbirth between twins. MATERIALS AND METHODS: The group of 829 twin deliveries was investigated. Probability of distribution was assessed according to Bernoullie's trials schema. RESULTS: The first twin was usually heavier then the second one (p = 0.05), especially at term. Order of twin delivery was influenced by a birthweight difference > 250 g. In cases of single twin intrauterine death, the alive, term baby was delivered as the first one statistically more common (p = 0.029), despite of smaller number of cases. Discussion suggests that differences between twins are rather reasons of observed order than results. CONCLUSION: Hypothesis of natural selection of stronger baby for the first delivery was presented.

[The incidence of uterine leiomyomas in pregnancy and their influence upon its course]. / Czestosc wystepowania miesniaków macicy oraz ich wplyw na przebieg ciazy.

OBJECTIVES: Uterine myomas are observed in pregnancy more frequently now than in the past. With the increasing age of the obstetric population and the widespread use of sonography, uterine myomas are more frequently detected during pregnancy. The objective of the study was to assess the incidence of the uterine myomas during pregnancy and their influence upon the pregnancy. METHODS AND RESULTS: Among 670 women who delivered by cesarean section 162 had uterine myomas. The incidence of the uterine myomas was statistically significant in women who where older than 25 (p. < 2 x 10(-4)). A statistically significant increased incidence of threatened preterm delivery was observed in patients with uterine myomas larger than 600 cm3 (p < 0.05). In this population uterine myomas did not significantly alter the incidence of intrauterine growth retardation. CONCLUSIONS: Uterine myomas were observed in 24% of pregnant women. The presence of uterine myomas larger than 600 cm3 increases the incidence of the threatened preterm delivery.

[Course of pregnancy, delivery and puerperium in women with Marfan syndrome]. / Przebieg ciazy, porodu i pologu u ciezarnej z zespolem Marfana.

Obstetric course and neonatal outcome in women with Marfan syndrome is the aim of numerous analyses. It is well known that pregnancies complicated by Marfan syndrome increase the risk of maternal morbidity and premature mortality. The main cause of this is cardiovascular abnormalities (aortic root dilatation, aortic dissection, rupture of the aorta, other cardiac abnormalities). We have presented a case history of a pregnant woman with a Marfan syndrome and the review of the literature.

[The incidence of ovarian tumors in the third trimester of pregnancy]. / Wystepowanie guzów jajnika w trzecim trymestrze ciazy.

METHOD AND RESULTS: Between 1993 and 2000, 7529 patients underwent cesarean section (24.3% of 31,798 delivering women) at University Hospital in Poznan. There were 52 cases of simultaneous adnexal surgery among them because of ovarian tumors (1 case/144 abdominal deliveries; 1 case/612 pregnancies). In 43 cases tumor was accidentally diagnosed at time of operative delivery (1/174 abdominal deliveries). The average age of all delivering women was 27 +/- 7 yrs, among abdominally delivering 28 +/- 7 yrs. The respective value for patients with ovarian tumor was significantly higher--30 +/- 7 yrs. The mean diameter of the tumor was 4.8 +/- 4.7 cm, but the largest 30 cm. In 9 cases adnexectomy was performed, remaining patients were treated conservatively. Benign cyst teratoma was diagnosed in 26.9%, cystis simplex in 21.2%, fibroma in 15.4%, endometriosis and luteal cyst every in 9.6%. There were two cases of malignant tumors, both diagnosed earlier: dysgerminoma and adenocarcinoma. CONCLUSIONS: 1. incidence of ovarian tumors of pregnant women was previously probably underestimated, 2. the risk of malignant ovarian tumor is relatively low.