[Oncofertility and therapeutic modalities. Survey of literature]. / Onkofertilitás és kezelési lehetoségei. Irodalmi áttekintés.

Surgical and radiological treatment as well as chemotherapy and biological therapy may have harmful effects on young patients' future fertility. Increasingly greater emphasis has been put on ensuring these patients' long-term quality of life, therefore, in addition to survival, preserving their prospective fertility is also among our aims. The term 'oncofertility' has been compounded from two expressions, 'oncology' and attempts to 'fertility preservation'. In gynecology, fertility preservation involves not only special surgical procedures but also interventions intended to preserve gametes, reproductive organs and embryos. Although the term 'oncofertility' was created in the United States of America, it has become an interdisciplinary field of science worldwide. By gaining grounds steadily, it has attracted special attention among experts. In addition to the subdivisions of classical oncology and gynecology, knowledge of oncofertility is broadening so rapidly that one cannot expect experts to be 100% up-to-date in one or another modality. It is special guidance by consultants in oncofertility that can make occasional co-operation among oncologists, radiotherapists, surgeons and infertility specialists really effective. Orv Hetil. 2017; 158(18): 683-691.

Effects of gender roles, child wish motives, subjective well-being, and marital adjustment on infertility-related stress: a preliminary study with a Hungarian sample of involuntary childless men and women.

PURPOSE: The aim of the study is to investigate the infertility-related stress in a Hungarian infertile population and examine the effects of gender roles, child wish motives, subjective well-being, and marital relationship on the experience of infertility according to our self-constructed conceptual framework. METHODS: Validated self-report questionnaires measuring the factors of the conceptual framework were taken in the study carried out in a sample of 53 people attending the fertility unit of a Hungarian clinic. RESULTS: Infertility-related global stress, infertility-related social concerns, and general health problems have more intensive effect on women than on men (all p < 0.05). Women from the infertile group scored higher their femininity (p < 0.001) and lower their general health (p < 0.05) than the reference population. Infertile men believe deeper in meaning of life than women (p < 0.05) or reference population (p < 0.01). Femininity (ß = 0.460, p < 0.05), traditional gender role concepts (ß = -0.248, p < 0.05), general health (ß = -0.474, p < 0.05), and marital relationship (ß = -0.251, p < 0.05) play the strongest role to predict stress caused by infertility. CONCLUSIONS: The current study emphasizes the importance of interrelations of gender role attitudes, gender role identification, general health, and satisfaction in couple relationship with infertility-related stress. In further investigations, both social and personal aspects and their effect on experiencing infertility need to be measured in infertile people, particularly in different cultural settings.

[Citogenetic and molecular genetic studies in infertility in eastern Hungary]. / Infertilitásban végzett citogenetikai és molekuláris genetikai vizsgálatok a kelet-magyarországi régióban.

INTRODUCTION: In developed countries 10-15% of the couples are affected by infertility. In half of them genetic factors can be identified. AIMS: We studied genetic alterations in infertility in Hungarian patients. METHODS: Cyogenetic analyses were performed in 195 females and 305 males. In 17 females FMR1 mutations, in 150 males Y microdeletions, and aneuploidy were studied in the sperm of 28 males. In a carrier male sperm meiotic segregation was studied. RESULTS: The most common aberrations in females were X chromosome aneuploidia and inversion (3.6%), while the same in males Klinefelter-syndrome (3.3%) and autosomal translocations (2%). In two females FMR1 premutation was found. While Y microdeletions were identified only in azoospermic and severe oligozoospermic men, partial microdeletions could also be detected in normozoospermic males. A higher aberration rate was found in cases with abnormality in both the number and motility of sperm. In a male patient with 46,XY,t(3;6)(q21;q23) karyotype, 53.2% of spem carried unbalanced chromosome assortment. CONCLUSIONS: Knowledge of abnormalities may help in genetic counseling and choosing the most effective reproduction technique.

Investigation of the occurrence of torque tenovirus in malignant and potentially malignant disorders associated with human papillomavirus.

In a previous pilot study, a significantly poorer outcome of laryngeal cancer was found in patients co-infected with human papillomavirus (HPV) and genogroup 1 torque tenovirus (TTV). The present study aimed to collect data on the overall prevalence of TTVs on the prevalence of genogroup 1 TTV in two other malignancies associated with HPV, oral squamous cell cancer and cervical cancer, and in oral and cervical premalignant lesions (oral lichen planus, oral leukoplakia, cervical atypia). Oral samples from all patients were accompanied with a sample from the healthy mucosa. The overall prevalence of TTV was significantly higher both in oral squamous cell cancer and cervical cancer compared with other patient groups or with the respective controls. The prevalence of genogroup 1 TTV was significantly higher in lesions of oral squamous cell cancer and oral lichen planus, but not in lesions of oral leukoplakia (24.6%, 10.1%, and 4.5%, respectively), compared with the prevalence in the oral cavity of controls (1.4%). Co-infection rates with genogroup 1 TTV and HPV were significantly higher in oral squamous cell cancer than in controls, oral lichen planus or oral leukoplakia patients (12.3%, 0.0%, 6.7%, and 4.5%, respectively). The prevalence of genogroup 1 TTV in all cervical samples were comparable. These data suggest that genogroup 1 TTV may be associated specifically with some head and neck mucosal disorders, but disproves a (co)carcinogenic role in oral cancer or cervical cancer as well as an association with HPV or with malignancies associated with HPV.

Comparative analysis of human papillomavirus type 6 complete genomes originated from head and neck and anogenital disorders.

It is increasingly recognized that fundamental differences exist between high-risk and low-risk human papillomavirus (HPV) genotypes regarding interactions with the host. This study aims to join the recently emerging efforts to uncover these differences at the complete genome level and to study how they may influence the disease caused. Sixteen samples of thirteen patients with various HPV6-mediated benign mucosal disorders (nine recurrent respiratory papillomatoses with 2-8 recurrences, one condyloma acuminatum and three premalignant lesions of the genital mucosa) were sampled to determine the complete virus genomes. We collected the 197 HPV6 complete genomes deposited in the GenBank for cluster analysis to determine (sub)lineages. Genome polymorphisms were determined against the reference sequences of the (sub)lineages. Genome polymorphisms of the long control region (LCR) were tested for putative transcription factor binding sites; their functional analysis was performed by transient transfection of cloned whole LCRs into HEp-2 cells using a luciferase reporter system. Genomes from the same patients were always identical. Three, nine and one patients carried HPV6 lineage A, sublineage B1 and B2 variants, respectively. The three lineage A sequences were highly similar to each other, but distinct from the reference genome. A unique non-synonymous single nucleotide polymorphism (SNP) was found in the E5a open reading frame (ORF). Sublineage B1 genomes were more diverse, exhibited unique non-synonymous SNPs in the LCR and the E2/E4, L1, L2 ORFs. LCR activity of lineage A and sublineage B1 differed significantly; activity of one sublineage B1 LCR exhibiting two unique SNPs was significantly higher than that of other B1 LCR variants, close to the mean of LCR activities of lineage A variants. Different HPV6 lineages showed marked differences in variability patterns of the different genome regions. This may be involved in the differences in their distribution in different diseases or patient populations.

Age-specific prevalence of high-risk human papillomavirus infection in a Hungarian female population with positive cytology.

OBJECTIVE: Patients with positive screening results and persistence of high-risk human papillomavirus (HPV) infection represent the population at the highest risk for developing cervical cancer. To describe the epidemiology in this high-risk population, data were collected and analysed at the referral centre for patients with positive cytology. STUDY DESIGN: Between January 1997 and December 2002 the authors performed 3480 virus identifications using the Digene Hybrid Capture system in a female population with positive cytology at cervical cancer screening. Age-specific prevalence data were evaluated and compared between the age groups by running the chi(2) and Pearson chi(2) tests. Subgroup analysis was performed to estimate monthly clearance rates among eligible women with positive HR-HPV results. RESULTS: Low-risk (LR), high-risk (HR) and double infections were detected in 91 cases (2.6%), 1072 cases (30.8%) and 59 cases (1.7%), respectively. A significantly higher incidence of high-, rather than low-risk HPV infections was found in all age groups (p<0.001). Also, in this high-risk population with positive screening a significant decrease was detected in the prevalence of both high- and low-risk infections beyond 35 years of age (p<0.001). However, the decline in the HR-HPV types occurred later than in the case of LR infections, and HR-HPV was of remarkable frequency in the older age groups, which might represent both incidental and prevalent cases. Subgroup analysis for estimating monthly clearance rates revealed no significant differences between the various age groups and between women with various cytology results. CONCLUSIONS: In a population with positive cytology the prevalence of HPV drops with age while the relative frequency of high-risk HPV infection remains at the same level as that of the youngest age group.

Duration of HPV-associated risk for high-grade cervical intraepithelial neoplasia.

OBJECTIVE: To evaluate the duration of high-risk HPV-associated cancer risk. STUDY DESIGN: Patients who had had a routine diagnostic Hybrid Capture Tube Test (HCT) due to squamous cell abnormalities of the uterine cervix were followed-up until the endpoint of histologically diagnosed cervical intraepithelial neoplasia (CIN). RESULTS: Six hundred and thirty-eight women were followed during a cumulative follow-up of 16,423 patient months. The adjusted relative risk associated with the positive HR-HCT test for high-grade CIN/52.0 (20.9-19.2)/ proved to be higher than that of the cytological atypia/5.44 (2.52-11.77)/. At the end of the 30 months of follow-up the crude and adjusted risks for CIN2+ were 214.3 (28.4-1615.7) and 196.7 (25.4-1525.2), respectively in the HPV 16/18 group, and after 30 months, the crude and adjusted RR decreased to 57.6 (10.4-318.9) and 29.2 (5.02-170.0). In the groups of other high-risk types and possibly high-risk types the general tendency was the same. However, new CIN2+ cases were not detected after the 30th month of follow-up in these later groups. CONCLUSIONS: HPV16/18 associated relative risk is nearly 200 times higher than that of the HPV negative population and an outstanding risk persists with duration of about 30 months. The risk is manifested in progression to high-grade CIN lesions mainly within a 2 years interval after the first detection of HPV 16/18 infection.

Role of human papillomavirus (HPV) testing in the follow-up of patients after treatment for cervical precancerous lesions.

OBJECTIVE: To evaluate the role of human papillomavirus (HPV) testing in post-treatment follow-up of patients after therapeutic excision of the cervix due to positive screening tests. STUDY DESIGN: A hospital-based retrospective analysis was performed with prospective collection of patient data of women screened for cervical cancer at a Gynecologic Outpatient Clinic. Patients after therapeutic excision due to positive screening results were identified and followed up with HPV testing and serial cytology. RESULTS: After 61 treatment for cervicalis intraepithelialis neoplasia (CIN), high-risk HPV infection was detected during the post-treatment follow-up at 18 cases (29.5%), 10 of them had persisting cytological atypia (positive predictive value (PPV): 56%), 5 developed CIN (PPV: 28%). When the HPV test was negative (43 patients) in the post-treatment period, neither CIN nor persisting cytological atypia developed (negative predictive value (NPV): 100%) during 1201 patient months (median 26 months). CONCLUSIONS: A negative HPV test eliminates the risk of recurrent disease after treatment for CIN.

The prevalence of the HPV 16 genome, integrated viral status and p53 genotype in cervical cancer population of north-eastern Hungary, the correlation with the established markers of tumour progression.

OBJECTIVES: To evaluate the prevalence of the HPV 16 integrated status and the p53 genotype in cervical cancer in north-eastern Hungary and their correlation with the established prognostic factors. STUDY DESIGN: Parallel with the routine histological examination, Southern blot hybridisation and multiplex PCRs were used to detect type/physical state of HPV DNA in primary tumours and in regional lymph nodes combined with p53 genotyping of 83 patients. RESULTS: 46.9% (39/83) prevalence rate of HPV 16 genome was found. The frequency of viral integration (76.9% in primary tumours and 95.2% in regional lymph nodes) and that of the p53Arg homozygous genotype (64.1%) proved to be higher than reported from other parts of the world. The HPV 16 integration and the p53 genotype, failed to correlate with the FIGO stage and lymphatic spread. CONCLUSION: The prevalence of the integrated status of the HPV 16 genome combined with homozygous p53Arg genotype is relatively high in Hungary. These factors however failed to show a strong correlation with the established markers of tumour progression.

Prevalence of human herpesvirus 6A and 6B during pregnancy.

The aim of the present study was to assess the frequency of human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B) infection during pregnancy. 100-100 blood samples were collected from pregnant and non-pregnant women, then nucleic acid was isolated from both plasma and leukocytes fraction. Nested and real-time PCR were used to detect and differentiate HHV-6A and HHV-6B DNA and to determine viral loads. Reverse transcription PCR (RT-PCR) for HHV-6 U79/80 mRNA was performed in order to reveal active HHV-6 replication.HHV-6A and HHV-6B active infections were not detected in blood samples neither from pregnant nor from non-pregnant women. Frequency of HHV-6B and HHV-6A latency did not show difference between the studied groups (15% vs. 16%). HHV-6B latency was dominant in both studied groups (14/15 and 15/16). Beside these results, in leukocyte samples of one pregnant and three non-pregnant women high HHV-6A viral loads (1.28 × 105 - 5.07 × 105 GEq / 1.5 × 106 leukocytes) were detected, and viral DNA was also found in plasma samples. Although RT-PCR did not confirm virus replication, but chromosomal integration was also not proved unequivocally, the number of 0.08-0.33 HHV-6 copy / 1 leukocyte refers more to postnatal infection.

Novel human polyomaviruses in pregnancy: higher prevalence of BKPyV, but no WUPyV, KIPyV and HPyV9.

BACKGROUND: Immunosuppression due to pregnancy may lead to higher susceptibility to infections and reactivation of latent infections, such as BK polyomavirus (BKPyV). There is lack of information about the prevalence of novel human polyomavirus 9 (HPyV9), WU (WUPyV) and KI (KIPyV) during pregnancy. OBJECTIVES: To study whether pregnancy results in higher prevalence of HPyV9, WUPyV, KIPyV and their correlation with BKPyV. STUDY DESIGN: Plasma, urine and throat swab samples from 100 pregnant and 100 non pregnant women were screened for the presence of WUPyV, KIPyV, HPyV9 and BKPyV by PCR. RESULTS: No WUPyV DNA was detected in plasma, urine and respiratory samples from pregnant and non pregnant women. KIPyV DNA was found in two plasma samples from non pregnant women (2%) and not detected in other samples from neither pregnant nor non pregnant women. HPyV9 DNA was determined in all sample types of pregnant and non pregnant women, respectively. There were no significant differences between pregnant and non pregnant women in HPyV9 DNA frequencies for plasma (2% vs. 6%), urine (3% vs. 2%) and respiratory samples (2% vs. 2%). Prevalence of BKPyV in urine samples was significantly higher (p=0.039) in pregnant women (13%) then in non pregnant women (4%); co infection with KIPyV and/or HPyV9 was not detected. CONCLUSIONS: In contrast with BKPyV, infection with WUPyV, KIPyV and HPyV9 was not detected more frequently during pregnancy. To the best of our knowledge HPyV9 was detected first in respiratory samples in our study.

Meiotic segregation study of a novel t(3;6)(q21;q23) in an infertile man using fluorescence in situ hybridization (FISH).

Male carriers with balanced reciprocal translocations can produce a variable proportion of unbalanced gametes resulting in reproductive failures. The presence of a structural rearrangement may induce an interchromosomal effect. This is characterized by abnormal bivalents not involved in the reorganization thereby yielding non-disjunction, which would present as aneuploid spermatozoa for these chromosomes. In the present case report segregation analysis of the sperm and investigation of interchromosomal effect were carried out using cytogenetic and fluorescence in situ hybridization (FISH) analysis on blood lymphocytes. The karyotype of the patient was 46,XY,t(3;6)(q21;q23). During sperm segregation analysis a total of 2,002 sperms were evaluated, of which 46.8% showed normal/balanced (alternate segregation mode) and 53.2% of sperm showed an abnormal signal pattern. A significant difference in the frequency of the estimated number of chromosome anomalies was observed in the translocation carrier when compared to the normozoospermic group (P<0.0001) and the oligozoospermic group (P<0.0001). Meiotic segregation analysis of sperm together with aneuploidy assessment for X, Y, and 17 chromosomes using FISH allows for the determination of a reproductive prognosis in male balanced translocation carriers and can be used for appropriate genetic counseling.

The prognostic significance of HPV-16 genome status of the lymph nodes, the integration status and p53 genotype in HPV-16 positive cervical cancer: a long term follow up.

OBJECTIVE: Prognostic evaluation of HPV-16 genome status of the pelvic lymph nodes, the integration status of HPV-16 and p53 codon 72 polymorphism in cervical cancer. DESIGN: Prospective cohort study. SETTING: Department of Gynaecological Oncology, University of Debrecen, Hungary. SAMPLE: Thirty-nine patients with HPV-16 positive cervical cancer. METHODS: Primary tumour specimens of 39 cervical cancer patients with HPV-16 positive primary tumour were subjected to multiplex polymerase chain reaction using HPV-16 E1/E2, E7 and p53 codon 72 allele-specific primers. Pelvic lymph nodes of the same patients were also tested for the presence of HPV-16 DNA and for its integration status using HPV-16 E7 and E1/E2 ORF specific primers, respectively. MAIN OUTCOME MEASURES: Progression-free survival. RESULTS: Metastatic lymph nodes carried HPV-16 DNA more frequently than nodes with no evidence of disease (100.0% vs 35.7%, P = 0.001). Cases with HPV-16 positive nodes had higher recurrence rate than those with HPV-16 negative nodes (42.9% vs 11.1%, P = 0.009). There was no difference between cases with and without histologically proven nodal disease with regard to integration status of HPV-16 DNA in the primary tumour (integrated 90.9% vs 71.4%, episomal 9.1% vs 21.4%, mixed 0% vs 7.1%) and p53 codon 72 polymorphism (Arg/Arg 54.5% vs 67.9%, Pro/Pro 0 vs 7.1%, Arg/Pro 45.5% vs 21.4%). CONCLUSIONS: Regardless of the presence of nodal metastasis, HPV-16 status of the nodes is a significant predictor of recurrent disease. HPV-16 integration status and p53 codon 72 genotype do not seem to have a bearing on disease outcome in cervical cancer with HPV-16 positive primary.

Moderate variation of the oncogenic potential among high-risk human papillomavirus types in gynecologic patients with cervical abnormalities.

The oncogenic potential of human papillomavirus (HPV) infection was assessed by following the disease course in 455 patients who had had a routine diagnostic Hybrid Capture HPV test due to squamous cell abnormalities of the uterine cervix as detected by cytology and/or colposcopy. At entry, 308 patients had cytologic atypia classified as P3 by the Papanicolau classification, 168 had a positive high-risk HPV test, and 23 were infected only with low-risk HPV. The patients were followed-up using the patient registry until the endpoint of histologically diagnosed cervical intraepithelial neoplasia (CIN). High-grade CIN was diagnosed in 75 surgical biopsies. High-risk HPV infection (relative risk: 76.8 CI(95): 23.7-249.5), cytologic atypia (RR: 16.2 CI(95): 3.9-66.6), and age above 35 (RR: 1.99 CI(95): 1.26-3.16) were independent risk factors for high-grade CIN, while the viral load did not predict oncogenic progression (P = 0.47). After PCR-RFLP typing, the high-risk types were classified into groups as follows: (1) types 16 and 18, (2) types 45, 52, and 56, (3) types 31, 33, 35, 51, and 58. The relative risks of high-grade CIN were 119.1 (CI(95): 36.2-390.9) for group 1, 44.4 (CI(95): 9.8-201) for group 2, and 39.7 (CI(95): 10.9-144.8) for group 3, respectively. The risk ratios between the groups of high-risk types were found to differ at most by a factor of 2.98 (corrected P value: 0.007) indicating that the oncogenic potential varies moderately within the high-risk group of HPVs.