Clinical aspects of decidualization / A decidualizáció klinikai vonatkozásai

An essential component of successful conception and pregnancy is decidualization, which involves structural and functional transformation of the endometrium. The process involves structural changes in the uterine mucosa, transformation of spiral arterioles, numerical and functional adaptation of leukocytes in the endometrium and their subsequent migration, and functional and morphological changes in decidual stromal cells. As part of decidualization, trophoblast cells of embryonic origin perform a physiological invasion of maternal tissue to create the placenta. The success of the process is due to the special antigenicity of the trophoblast cells and the immune communication between the graft (fetus) and the host (mother) through hormones, cytokines and multiple receptorligand connections. Disorders of these processes are the basis of several diseases that threaten conception, implantation, and successful pregnancy, such as recurrent miscarriage, preeclampsia, intrauterine retardation, or preterm birth. In this article, we review the anatomical, immunological, and molecular basis of physiological decidualization to address common disorders in the clinical practice of obstetrics that are related to a dysfunctional decidualization.

The role of natural killer cells in the immune homeostasis of the maternal fetal interface / A természetes ölosejtek szerepe az anyai-magzati immunhomeostasis fenntartásában

Successful conception, implantation and pregnancy require a complex and organized communication between the embryonal (allograft) and the maternal (host) immune system. Different leukocyte subsets have an important role in orchestrating the immune response at the fetal-maternal interface. There are certain similarities between the immune invasion of tumor cells and the physiological invasion of the trophoblastic cells of embryonic origin into the maternal decidua. The decidual natural killer cells are a special subset of natural killer cells and alongside with macrophages and dendritic cells, they are part of the innate immune system therefore they are the first immune cells contacting any intruder whether it is a tumor or embryonic tissue. Interestingly decidual natural killer cells not only do not eliminate invasive trophoblastic cells, but specifically promote their progression. Their angiogenic activity facilitates and coordinates local vascular remodeling of the forming placenta. In this article we review the different nature of trophoblastic cell and decidual natural killer cell interaction, the role of decidual natural killer cells in the vascularization and immune homeostasis of the decidua.

Isolation and culture of decidual natural killer cells from term placenta and complete hydatidiform mole.

Decidual natural killer cells (dNK) have been the focus of many studies because of their unique roles in both the anti-tumor immune response and healthy placental formation. Revealing the immunological mechanisms by which they interact with their target cells may lead to a better understanding of immune evasion of certain tumor cells, including abnormal cells of the different forms of gestational trophoblast disease and miscarriages of immunologic origin. Efforts to perform functional immunological studies on dNK cells have been limited by difficulty obtaining sufficent quantities of cells and sustaining the dNK phenotype. A novel protocol was developed to isolate and culture dNK cells from fresh, term placentas and complete hydatidiform moles.The placental samples were collected from healthy women undergoing scheduled elective cesarean delivery. The molar samples were collected after evacuation and curettage. Tissue samples were made into single cell suspensions using mechanical and enzymatic degradation, followed by fluorescence-activated cell sorting (FACS) using surface markers. The dNK cells were then expanded in cell culture. Their surface markers and cytotoxicity were reassessed by flow cytometry and functional assays. The protocol produces high quantities of enriched dNK cells which can be sustained in cell culture for at least a month, preserving their phenotype and funcionality for a week.

[Distribution of birth weights between 2011 and 2015 and changes in percentile figures between 1996 and 2015. Analyis of the Tauffer database]. / A születési súlyok megoszlása 2011 és 2015 között és a percentilisértékek változása 1996 és 2015 között. A Tauffer-adatbázis feldolgozása.

Introduction and aim: We aimed to provide a current birth weight percentile table for singleton and twin pregnancies stratified by gestational week at delivery and sex using data from all live births in Hungary between 2011 and 2015. In addition, we examined temporal trends in average birth weights in singleton and twin pregnancies by sex in five-year periods between 1996 and 2015. Method: We calculated the 5th, 10th, 25th, 50th, 75th, 90th, and 95th centiles of birth weight for each gestational week by sex for singleton and twin pregnancies using compulsory collected obstetrical data (Tauffer Statistics) in Hungary in 2011-2015. Furthermore, we described changes in birth weights by gestational week between 5-year periods from 1996 to 2015. Results: We present birth weight centiles for live births in both tabular and graphical forms using data from 2011 to 2015. In general, live birth weights in gestational weeks 35-41 were lower in the period of 1996-2005 (the lowest in 1996-2000) and were higher in the period of 2006-2010 compared to the reference period of 2011-2015 (e.g., the average male newborn weighed 3249 g at gestational week 38 in 2011-2015, which is 34.3 [SE at 3.0] g less in 1996-2000, 11.5 [2.9] g less in 2001-2005, and 18.1 [2.9] g more in 2006-2010). Similar trends were not observed in birth weights of twin pregnancies in gestational weeks 35-38. Conclusion: Given the observed substantial change in birth weights during the past 20 years, renewal of the commonly used percentile tables is necessary. Birth weights increased from 1996 to 2010, mainly of mature newborns, followed by a stabilization or slight decrease in the later periods. Orv Hetil. 2019; 160(36): 1426-1436.

The Role of Surgery in the Management of Gestational Trophoblastic Neoplasia The Hungarian Experience.

OBJECTIVE: To review the role of surgery in the management of gestational trophoblastic neoplasia (GTN) over the past 38 years in our national trophoblastic disease center. STUDY DESIGN: Between January 1, 1977, and December 31, 2014, 371 patients with low-risk GTN and 190 patients with high-risk GTN were treated with chemotherapy, surgical interventions, or both. The indications for hysterectomy included excision of large uterine tumor masses, uterine hemorrhage or sepsis, or a drug-resistant uterine focus. Metastases were excised due to the presence of drug-resistant foci or complications of disease such as hemorrhage. RESULTS: Over the period of 1977-2014 74 hysterectomies, 15 resections of vaginal metastases, 3 omentectomies, 13 adnexectomies, 9 lung resections, I nephrectomy, 1 lung resection and nephrectomy, and 2 craniotomies were performed among our patients. While hysterectomy was performed in 51 (26.8%) of 190 high-risk patients, hysterectomy was performed in only 23 (6.2%) of 371 low-risk patients (p < 0.01). From 1977-2006 metastases were resected in 18.3% (26/142) and from 2007-2014 in 16.7% (8/48) of high-risk patients. CONCLUSION: In our center surgery, particularly in the form of hysterectomy, still plays a valuable role in the management of both low- and high-risk GTN.

Changes in the management of high-risk gestational trophoblastic neoplasia in the National Trophoblastic Disease Center of Hungary.

OBJECTIVE: To compare the clinical management of patients with high-risk gestational trophoblastic neoplasia (GTN) among the periods of 1977-1990, 1991-2000, and 2001-2012 at the National Trophoblastic Disease Center of Hungary and to assess the efficacy of the FIGO 2000 staging and risk factor scoring system in comparison to the original WHO prognostic scoring system (1983). STUDY DESIGN: We reviewed the medical records of 185 patients with high-risk GTN. From 1977-2000, patients were classified according to the original WHO prognostic scoring system (1983). From 2001-2012, high-risk patients were categorized by the FIGO 2000 system. We assessed the efficacy of MAC and EMA-CO primary combination chemotherapies. For 1977-2006 and 2007-2012 we assessed the efficacy of MAC and EMA-CO primary combination chemotherapies. RESULTS: From 1977-1990, 63 high-risk patients (average, 4-5 patients/year), from 1991-2000, 50 high-risk patients (average, 5 patients/year), and from 2001-2012, 72 high-risk patients (average, 6 patients/year) were treated primarily with combination chemotherapy (MAC and/or EMA-CO and/or CEB). From 1977-2006, 100 high-risk patients received MAC primary combination chemotherapy and 17 cases received EMA-CO. The ratio of primary MAC primarily with and EMA-CO therapy among our high-risk patients was 5.9 (100/17) over the referred period. From 2007-2012, 21 high-risk patients were treated with primary MAC chemotherapy and 16 patients received EMA-CO. The MAC/EMA-CO ratio over this time interval was 1.3 (21/16). CONCLUSION: We attained complete remission in 95.7% of the high-risk patients. During the last 6 years the use of EMA-CO primary combination chemotherapy increased among our high-risk patients, which has resulted in increased efficacy and fewer side effects.

Clinical epidemiology and management of gestational trophoblastic neoplasia in Hungary in the past 34 years.

OBJECTIVE: To review our clinical experience in the treatment of patients with gestational trophoblastic neoplasia (GTN) over the past 34 years in our national trophoblastic disease center. STUDY DESIGN: Between January 1, 1977, and December 31, 2010, 331 patients with low-risk GTN and 174 patients with high-risk GTN (altogether 505) were treated. The patients were directed to the national trophoblastic disease center from all parts of Hungary. The patients were between 14 and 54 years of age, with an average age of 28.7 years. Primary chemotherapy was selected based upon the patient's stage and prognostic score of GTN. RESULTS: Among 237 low-risk patients, 228 (96.2%) achieved remission as a result of primary methotrexate (MTX) therapy. Out of 94 low-risk patients 90 (95.7%) achieved remission as a result of primary actinomycin-D (Act-D) therapy. MTX, Act-D and cyclophosphamide (MAC) as a primary therapy was used in 118 high-risk cases, and 110 (93.2%) patients achieved complete remission. A total of 32 high-risk patients were treated with the etoposide, high-dose MTX/folinic acid, Act-D, cyclophosphamide and vincristine (EMA-CO) regimen, and of 26 primary therapies complete remission was achieved in 21 (80.8%) cases. Primary cisplatin, etoposide and bleomycin (CEB) therapy was successful in 16 of 17 high-risk cases (94.1%). Metastases were found in 47.3% (239/505) of the patients. Hysterectomy was performed in 68 of 505 (13.5%) cases. Chemotherapy, surgical intervention or other supplementary treatments resulted in 100% remission in cases of nonmetastatic and metastatic low-risk disease. Comparison of mean prognostic scores resulted in significant differences between CEB and MAC, CEB and EMA-CO, and MAC and EMA-CO. CONCLUSION: Our data indicate that MTX/folinic acid or Act-D should be the primary treatment in patients with nonmetastatic or metastatic low-risk GTN. Patients with high-risk metastatic GTN should be treated primarily with combination chemotherapy. Our data support the effectiveness of MAC, EMA-CO and CEB regimens. Results also show that patient care under the direction of experienced clinicians serves to optimize the opportunity for cure and minimize morbidity.

30 years' experience in the treatment of low-risk gestational trophoblastic neoplasia in Hungary.

OBJECTIVE: To review the clinical experience in the treatment of patients with low-risk gestational trophoblastic neoplasia (GTN) over the past 30 years in a national trophoblastic disease center. STUDY DESIGN: Between January 1, 1977, and December 31, 2007, 302 patients with low-risk GTN were treated. The patients were directed to our institution from all parts of Hungary. The patients were 14 to 53 years of age with an average age of 28.3 years. Methotrexate (MTX)/folinic acid or actinomycin-D (Act-D) primary chemotherapy was selected based upon the patient's stage and prognostic score of GTN. RESULTS: Among 218 low-risk patients, 210 (96.3%) achieved remission as a result of MTX therapy. In 8 patients (3.7%), MTX-Act-D-cyclophosphamide (MAC) combination chemotherapy was needed to achieve complete remission, in some cases assisted by operation. Among 84 patients, 81 (96.4%) achieved remission as a result of Act-D therapy. In 3 cases (3.6%) complete remission was achieved by MAC combination chemotherapy. We detected metastases in 22.8% (69/302) of our low-risk patients. Chemotherapy, surgical intervention or other supplementary treatments resulted in 100% remission in cases of low-risk nonmetastatic and metastatic disease. CONCLUSION: Our data indicate that MTX/folinic acid or Act-D should be the primary treatment in patients with nonmetastatic or metastatic low-risk GTN. Importantly, patients with resistance to single-agent chemotherapy regularly achieve complete remission with MAC combination chemotherapy. Results show that patient care under the direction of experienced clinicians serves to optimize the opportunity for cure and minimize morbidity.

Primary pulmonary choriocarcinoma: a case report.

BACKGROUND: Primary pulmonary choriocarcinoma (PPC) is an extremely rare clinical entity. In contrast with gestational trophoblastic tumors that show an extreme sensitivity for chemotherapy, extragonadal choriocarcinomas are mostly unresponsive to surgical and chemotherapeutic treatment and are associated with poor prognosis. The reason non-gestational choriocarcinomas behave so differently from gestational tumors is unknown. CASE: In the present case we report a 30-year-old female patient with primary choriocarcinoma of lung localization who was successfully treated with surgical resection and multiple cycles of combination chemotherapy. During her recovery she was followed up by human chorionic gonadotropin (hCG) titer measurement, and after 1 year of close surveillance of beta-hCG levels her disease achieved complete remission. CONCLUSION: Because of the extreme rarity of this malignancy, there are no standardized therapeutic guidelines for treatment. The first choice in treatment of PPC is surgical resection. Postoperatively chemotherapy is indicated immediately, because definitive histologic diagnosis is not essential before chemotherapy since beta-hCG is a reliable tumor marker for choriocarcinoma.

25 years' experience in the treatment of gestational trophoblastic neoplasia in Hungary.

OBJECTIVE: To review our clinical experience in the treatment of gestational trophoblastic neoplasia (GTN) over the past 25 years in our national trophoblastic disease center. STUDY DESIGN: Between January 1, 1977, and December 31, 2001, we treated 355 patients with GTN. The patients were between 14 and 53 years of age, with an average of 28.3. Primary chemotherapy was selected based on the patient's stage of gestational trophoblastic tumor (GTT) and prognostic score. RESULTS: We found metastases in 49.3% (175 of 355) of our patients. Of 173 patients, 162 (93.2%) achieved remission as a result of methotrexate therapy. In 11 patients (6.8%) complete remission was achieved by combination chemotherapy, in some cases assisted by operation. Of 68 patients, 63 (92.6%) achieved remission as a result of actinomycin D therapy, and 5 (7.4%) achieved complete remission by combination chemotherapy. Chemotherapy, surgical intervention or other supplementary treatments resulted in 100% successful therapy in cases of nonmetastatic and low-risk metastatic disease. CONCLUSION: According to our experience, methotrexate/folinic acid or actinomycin D should be the primary treatment in patients with nonmetastatic or low-risk metastatic GTN. Patients with resistance to single-agent chemotherapy regularly achieve remission with combination chemotherapy.

How long should patients be followed after molar pregnancy? Analysis of serum hCG follow-up data.

OBJECTIVE: We analyzed human chorionic gonadotropin (hCG) follow-up data of patients with molar pregnancy. Women often do not complete recommended post-disease screening. Our purpose was to determine if continuing follow up of uncomplicated molar cases beyond attaining undetectable hCG levels is necessary for detecting relapse of gestational trophoblastic disease. STUDY DESIGN: One hundred fifty patients treated at Hungarian National Health Center were analyzed. Those who developed persistent disease before hCG had become undetectable were excluded from further analysis (n=24; 16%). RESULTS: Among 126 uncomplicated cases, 72 patients (57%) completed follow up, and 54 (43%) discontinued their protocol before it had been completed. Of 120 patients who achieved at least one undetectable hCG level, none had any evidence of relapse. CONCLUSION: In uncomplicated hydatidiform mole, our analysis indicates that once undetectable serum hCG levels are attained, relapse is unlikely. Although further monthly checks are advisable, the likelihood of recurrence appears very low.