Preventable Hazards from in Vitro Fertilization - A Case Series of CF Patients from Bulgaria.

Pre-implantation genetic diagnosis (PGD) is not often performed when donor gametes are used, due to its high cost. This is with the presumption that the donors are healthy. We report on five cases of babies with confirmed cystic fibrosis (CF), being the result from in vitro fertilization (IVF) with donor (4 cases) or own gametes (one case). There has been no family history for CF in any of the families affected. The clinical presentation in the children ranged from meconium ileus to recurrent respiratory infections and severe nasal polyposis. The age of diagnosis also varied from birth until 9 years. Since one of the presented cases was discovered in a very renowned private IVF clinic, the clinic changed their own protocol, and currently they test every donor for CF carriership. The percentage of CF carriers in the donor population is roughly the same as the one predicted in the general population of Bulgaria - 1/33. Although PGD is costly, the costs for proper care for a CF patient are currently much higher. The more economical option would to screen every donor for CF carriership. IVF requires a lot of physical and psychological stamina. The couples that go through this procedure also require a great deal of hope. It is essential to be more preconscious for possible congenital diseases. We advocate every IVF center to test the donors for CF carriership or to provide PGD for their clients.

[BENEFITS AND RISKS AT IMPLEMENTATION OF PROPHILACTIC VACCINES FOR CERVICAL CANCER].

The aim of this review is to present the benefits and risks of the implementation of prophylactic vaccines for cervical cancer. The classical understanding of human papilloma virus (HPV) infection and its role for the cervical oncogenesis, as well as, the place of prophylactic HPV vaccines are discussed. Results concerning the effectiveness of vaccines 10 years after their introduction and data about their safety are presented. Reports of the use in practice of the new 9-valent HPV vaccine and the first results of its implementation are studied.

[Breast cancer developing during pregnancy--clinical cases and review of the literature].

The goal of the present paper is to discuss diagnosis, treatment approaches and histopathologic characteristics of breast cancer developing during pregnancy, based on our results and published literature data. We retrospectively evaluated clinical and pathologic features of tumors, treatment methods, decisions related to pregnancy and final outcome by eight pregnant patients with breast cancer. The patients' age varied from 26 to 36 years. At the last medical examination in October 2013, three among all eight patients were alive, two of them were without local and distant recurrence, and one patient has distant metastases and is carrying out a treatment. The aim of this paper was to discuss the characteristics of breast cancer developing during pregnancy. Retrospectively have been analyzed clinical-pathological characteristics of the tumors in eight pregnant women with breast cancer, the treatment, the management of the pregnancy, and the final outcome. The results are analyzed by comparing with data published in the literature.

[New colposcopic terminology: Rio de Janeiro--2011].

The purpose of this work is to review the new colposcopic classification of the International Federation for Cervical Pathology and Colposcopy (IFCPC) from 2011 and the possibilities for its application in diagnostic and treatment processes and research. It fulfills the necessity for a modern and widely applicable nomenclature of the findings and it is based on the latest knowledge in this area. Colposcopic terminology of the vagina, as part of the pathology of the lower genital tract, is included as well, while the vulva and perineum terminology is not yet finally adopted. Furthermore, the various cervical excisional techniques are evaluated and described. According to experts, the popularity of colposcopy will not diminish and it will continue to be used as a routine technique in daily practice. In a critical sense, despite its descriptive and punctual character, the accepted terminology classification does not give a new interpretation of the severity of changes, and as such, it does not significantly modify the diagnostic and therapeutic approach. The lack of a scoring system that would allow the dynamic comparison of the severity of symptoms and the categories over time is a serious weakness. This limits the new colposcopic classification as no more than a working sheet that descriptively assesses the findings of the lower genital tract.

[Pregnancy and malignant diseases. Part V. Some rare gynecological tumors during pregnancy].

Neoplasia of the vagina, endometrium and fallopian tube have low frequency in pregnant women and in the literature have been reported occasionally. Symptoms of cancer during pregnancy is often ignored by patients and physicians, leading to delayed diagnosis. This publication examines some characteristics of clinical course and management of cases of pregnancy combined with such tumors. Early diagnosis and treatment are essential for the favorable prognosis of the disease as well as of the pregnancy.

[Dysgerminoma of the ovary. Presentation of case report].

Germ-cell tumors account for about 20% of all ovarian tumors and the dysgerminoma is the most common in this group. The treatment is surgical, followed by chemotherapy and radiotherapy in greater stage than IA. The aim of this article is to present a case report of 18-years-old patient with a left ovary dysgerminoma who had undergone a surgery--left-side ovariectomy. One year later when the patient was pregnant in 6 m.l., retroperitoneal recurrence was diagnosed by ultrasound examination. The patient has completed her pregnancy and delivered by caesarean section. Retroperitoneal recurrence of the same tumor, inoperable at this stage was histologically confirmed during the operation. The treatment continued with two courses of neoadjuvant chemotherapy followed by radical surgery with removal of the whole left kidney and the tumor. After that 2 courses of adjuvant chemotherapy were conducted, followed by prophylactic external beam radiotherapy for retroperitoneal lymph nodes. No data for local recurrences and distant metastases were found during the regular examinations, performed 2 years later. The treatment of dysgerminoma is discussed. This treatment must be complex one and should include radical surgery, chemotherapy and radiotherapy.

[Rare clinical case of inflammatory macromastia in childhood].

AThe present and rare case is of a patient who developed macromastia in childhood. Usually, gigantomastia can occur as a complication due to pregnancy or it may occur in puberty, which is known as virginal breast hypertrophy, the second of which is more frequent. In our case, during the first decade of life, her breasts rapidly increased and reached gigantic sizes over a short period of time. The breasts were handing below the inguinal ligament and required a sling to support them. A phlegmon in the right axilla with a septic condition were the complications of this pathologic entity. The surgical intervention with postponed reconstruction was performed.

[Pregnancy and malignant diseases. Part III--. Vulvar cancer].

Vulvar cancer is among the rarest gynecological tumors. It is extremely rare in pregnant women. In the scientific literature, data has been recorded for no more than 50 cases of vulvar cancer during pregnancy. The etiological and pathogeneteic role of the HPV infection is discussed. The early histological diagnosis and treatment of every vulvar neoplasia during pregnancy are preconditions for a favorable prognosis for the disease and the pregnancy likewise. The management for women with vulvar cancer and pregnancy needs to be determined by a multidisciplinary staff with obstetrician-gynecologists, oncologists and neonatologists, while the point of view of the patient also has to be taken into account.

[Pregnancy and malignant diseases. Part III--Ovarian cancer].

The frequency of ovarian tumors during pregnancy is from 1:81 to 1:328 and most of them are functional cysts. Ovarian cancer varies from 1:10 000 to 1:25 000 pregnancies. It presents 2-5% of all ovarian tumors in pregnant women. If ovarian cancer is detected it should be managed according to the stage of the disease, nevertheless of pregnancy. Chemotherapy during pregnancy is under discussion, due to the lack of randomized trials. All chemotherapeutic agents are potentially teratogenic, especially in the first trimester. Retrospective investigations of the implementation of chemotherapy in the second and third trimester did not show congenital anomalies, but in some cases there is a fetal retardation. If diagnosed early, ovarian cancer may have good outcome for mother and newborn.

[Application of the RNA-based HPV test in the diagnostics of cervical epithelial changes].

UNLABELLED: Our purpose was to investigate the diagnostic value of the RNA-based HPV test (NucliSENS EasyQtm HPV) which utilizes NASBA technology for determination of the expression of E6/E7 of five high-risk HPV types (16, 18, 31, 33 u 45). METHODS: Two hundred women aged 16 to 61 (mean 34.44) were prospectively studied. All of the women were subject to colposcopy, cytology and target biopsy. PCR DNA typing for 12 high-risk HPVs and RNA typing for E6/E7 oncogenes of five high-risk HPV were performed in parallel with a diagnostic kit NucliSens HPV v1.0 (bioMerieux). RESULTS: The colposcopy showed 119 normal and 81 abnormal findings (mild in 70 and heavy in 11). Cytological results were normal and non-neoplastic in 167, low-grade in 30 and high-grade in 3 women. The histological examination showed normal and inflammatory changes in 50, HPV findings in 94, low grade CIN in 35 and high grade CIN in 21 patients. DNA tests were positive in 148 (74.37%) women, 60 (40.54%) with one and the rest with 2 and more genotypes. A positive RNA-NASBA test with one genotype was found in 23 women. The comparison of the two typing tests established a full correlation between the detected by the PCR high-risk type HPV and the presence of E6/ E7 mRNA transcripts from the same HPV genotype. CONCLUSION: Our results confirmed the high diagnostic possibilities of NASBA technology. This gave women with precancerous lesions of the cervix an opportunity to receive more precise diagnostics.

[Pregnancy and malignant diseases. Part II--cervical cancer].

The malignancies of the uterine cervix are the most common neoplasia during pregnancy. Cancer in situ varies from 0, 11 to 0, 55% and invasive cervical cancer is found in around 0, 03% of pregnant women. The summarized data by different authors shows that the cervical cancer can be found in the wide range between 1:250 to 1:13000 pregnancies (mean 1:2000 to 1:3000). The specific characteristics of the clinical course, diagnostics and treatment approaches in cases with cervical cancer during pregnancy are presented. The way of delivery, the outcome for the fetus and the results of the treatment in these cases are discussed.

Is cervical cancer screening necessary or the "Paradox" example of Bulgaria.

PURPOSE: The present study aimed at analyzing the results of cervical screening carried out in Bulgaria, its effect on basic epidemiological indices, age-related incidence of cervical cancer and their dynamics. It also highlighted the way in which the suspension of organized screening has influenced the epidemiological data for cervical cancer. METHODS: Analyses were carried out, based on data from the National Cancer Register, the Central Institute of Statistics and the Oncological Dispensaries. Simple mathematical methods were used to analyze the attendance rate, the rate of inadequate smears and share of biopsies in women with abnormal cytology. Cohort analysis was utilized in determining age-specific incidence. RESULTS: Incidence and mortality were stable during the first 15 years of screening activities, followed by a constant increase which became most obvious after the final interruption of organized screening. The ratio between invasive cancer and carcinoma in situ ranged from 2:1 in 1982 to over 5:1 in 2002 and was due to the faster increasing rates of invasive cancer. Age groups' and birth-cohort analysis for 3 time points (1975, 1990, and 2005) with different screening characteristics showed highest incidence in middle-aged women and a higher risk of cervical cancer for every subsequent generation. CONCLUSION: Bulgaria gives yet another, though "paradoxical", example in support of the importance of organized cervical screening. This conclusion has been reinforced by a distinct deterioration of epidemiological characteristics of cervical cancer in our country as a result of absence of an organized screening. This serious situation lends valid reasons to recommend that the relevant health authorities take a political decision to launch a programme in compliance with the European standards.

[Clinical study on the effect of vaginal administration of micronized progesterone at dysfunctional uterine bleeding in premenopause].

The aim of the present study was to establish the effectiveness of vaginal administration of micronized progesterone at 37 premenopausal women aged between 40-49 years (mean 44.5) with dysfunctional uterine bleeding. All women were subject of classical dilatation and curettage and after that micronized progesterone (Utrogestan) was applied vaginally 3 tablets 2 times per day, starting at 14 day of the menstrual cycle for 12 days. The control examination has been performed after finishing of 6 months therapy. The main criteria for the assessment of the therapeutic effect was the comparison of the character of genital bleeding, vegetative symptoms before and after the administration of the gestagene, as well as the examination of the level of hemoglobin, the thickness of the endometrium and at 12 women the histological findings from the control curettage. The results of our study show the presence of statistically significant difference for the effectiveness of micronized progesterone at dysfunctional uterine bleeding according to the intensity (p = 0.0068), duration of the bleeding (p = 0.00), decreasing of the endometrial thickness (p = 0.00), as well as lack of such difference when follow the level of hemoglobin (p = 0.4663) and vegetative symptoms (p = 0.9555). On the basis of conducted clinical study the authors confirm the preventive effect of the micronized progesterone, as an effective and safe alternative in treating of premenopausal women with dysfunctional uterine bleeding.

[Prophylaxis and screening of precancer and cancer of the uterine cervix in the XXI century].

At the beginning of the XXI century a tendency of promotion of new methods aimed at modernization and optimization of cervical cancer screening is outlined. In the present review the diagnostic confidence of the cytological method as well as the new technologies (thin prep technique, automated screening, HPV typization, genetic markers and other modern digital visualization methods) is discussed. Each of these methods has its own priorities and disadvantages and the aim of future investigations should be to choose the most appropriate screening scheme, in order to improve the control of this disease.

[Therapeutic results in patients with endometrial cancer].

The aim of the present study is to analyze the patients with endometrial cancer, treated at Gynecology Clinic of the National Oncology Hospital, Sofia according to the stage of the disease, histological type, differentiation, the peculiarities of the spreading and metastases, the therapeutic methods applied and the obtained results. For the period 2002-2004, 152 women with endometrial cancer were treated at the clinic. Predominate the patients with first stage cancer 117 (77%) and with endometroid adenocarcinoma/adenoacantoma 116 (76.3%), as well as these who were treated with surgery 134 (88.2%), followed by radio, hormonotherapy. Among the surgical procedures the simple total hysterectomy with bilateral salpingoophorectomy was the most frequent applied method - 119 (79.2%) patients, followed by radical hysterectomy with bilateral salpingoophorectomy and lymph node dissection 25 (16.7%). At the end of the 3 years study period 118 (77.6%) women are alive and 34 (22.4%) are dead. For 28 (18.5%) patients the reason for the death was the oncological disease and for 6 (3.9%)--other type of disease. Our results demonstrate once again, that therapeutic success of patients with endometrial cancer depends directly of the exact determination of the prognostic factors and administration of complex approach in the treatment of every patient.

[A case of 11 operation because of genitourilal abnormalites and cervical carcinoma].

A case of young woman with 11 operation because of genitourinal abnormalities and cancer of the uterine cervix. The patient was with bladder exstrophy and 2nd stage cervical cancer, treated operatively and with chemotherapy. Because local recurrence she was operated 3 times. The patient died 3 years after initial treatment of the cervical cancer.

Characterization of clonogenic stromal cells isolated from human endometrium.

Human endometrium is an object of extensive restructuring and remodeling during the female reproductive life and it is quite tempting to assume that these periodic changes happen with the participation of cells that should have the basic characteristics of multipotent cells. The aim of this study was to search for the presence of cells with plastic adherence, clonogenicity, and differentiation in human endometrium. To this end, human endometrial stromal cells were cultured in vitro for more than 15 passages. Flow cytometry analysis of the cultured cells showed that they were positive for CD29, CD73 and CD90, which are considered to be the markers of cells with mesenchymal origin. The cells were negative for the hematopoietic cell markers (CD45, CD34, CD14, CD3, CD19, CD16/56, and HLA-DR). Further, it was shown that the cultured cells had 15% clonogenic efficiency and could be induced to differentiate into adipogenic cells containing typical lipid-rich vacuoles. These results demonstrate that the human endometrium contains a low number of cells with the characteristics of endometrial stromal stem/progenitor cells, which seem to belong to the family of the mesenchymal stem cells. It can be speculated that these cells are engaged into the monthly restructuring and remodeling of human endometrium.

Five-year overall survival and prognostic factors in patients with cervical cancer in Bulgaria.

PURPOSE: To perform a population-based analysis on the 5-year survival rate and to analyse the significance of various prognostic factors for survival in patients with cervical cancer in Bulgaria for the period 1993-2002. PATIENTS AND METHODS: A total of 9,457 women were analyzed using the data of the National Cancer Registry. Their mean age was 51.41 years. Survival analysis was performed using the life table method. Analysis of factors affecting survival was performed by the Cox proportional hazards regression model. The statistical processing was carried out with the SPSS program/PC+v.11.01 for Windows. RESULTS: The overall cumulative 5-year survival was 47.12%. According to age, higher survival was observed in women younger than 35 years. Women in towns had better survival than those in villages. Significant difference was observed between squamous cell carcinoma and adenocarcinoma and some rare histological types. According to stage, survival was higher for stages I and II and was decreasing with advancing disease stage. Better survival was achieved with surgical treatment. In the Cox regression analysis, the highest relative risk was associated with advanced clinical stage, with symptomatic therapy only, with rare histological types, age over 65 years, and village residents. CONCLUSION: According to these results, Bulgaria is among the countries with low 5-year cervical cancer survival. Survival at the population level depends on several factors. The most important among them could be attributed to the absence of organized cervical screening.

Flexible hysteroscopy in irregular uterine bleeding.

PURPOSE: The objective of our study was to analyze the possibilities of diagnostic flexible hysteroscopy in women with irregular uterine bleeding. PATIENTS AND METHODS: The study involved 661 women aged 26-72 years (mean 46.23) with mild to moderate irregular uterine bleeding who agreed to have invasive investigations. Diagnostic hysteroscopy by panoramic fibrohysteroscope Pentax LH-150 II (5 mm in diameter) was performed initially to all patients, followed by classical dilatation and curettage (D & C). RESULTS: Different types of normal endometrium were found in 248 (37.52%) women, hyperplasia and polyposis in 300 (45.39%), suspected changes for atypia and neoplasia in 82 (12.40%) and other different findings in 31 (4.69%). Subsequent D & C showed lack of adequate material from the uterine cavity in 26 (3.93%) women, in 538 (81.39%) the morphological findings were due to hormonal and dyshormonal reasons, 66 (9.98%) were with different precancer and cancer lesions and in 31 (4.69%) cases, clinically and morphologically, bleeding was due to the presence of submucosal myomas, intrauterine devices, residua and pathology of the chorion. CONCLUSION: The comparison of the hysteroscopy results with clinical and histological findings from D & C showed good diagnostic possibilities of the flexible hysteroscopy for evaluation of women with irregular bleeding (sensitivity 74.07% and specificity 90.61%). This examination is relatively simple, safe and requires simultaneous performance of a direct biopsy, in order to improve the accuracy of the results.