Melanie Henes

Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T-cell responses

Immune tolerance toward the semiallogeneic fetus plays a crucial role in the maintenance of pregnancy. Myeloid‐derived suppressor cells (MDSCs) are innate immune cells characterized by their ability to modulate T‐cell responses. Recently, we showed that MDSCs accumulate in cord blood of healthy newborns, yet their role in materno–fetal tolerance remained elusive. In the present study, we demonstrate that MDSCs with a granulocytic phenotype (GR‐MDSCs) are highly increased in the peripheral blood of healthy pregnant women during all stages of pregnancy compared with nonpregnant controls, whereas numbers of monocytic MDSCs were unchanged. GR‐MDSCs expressed the effector enzymes arginase‐I and iNOS, produced high amounts of ROS and efficiently suppressed T‐cell proliferation. After parturition, GR‐MDSCs decreased within a few days. In combination, our results show that GR‐MDSCs expand in normal human pregnancy and may indicate a role for MDSCs in materno–fetal tolerance.

Head-to-Head Comparison of the RNA-Based Aptima Human Papillomavirus (HPV) Assay and the DNA-Based Hybrid Capture 2 HPV Test in a Routine Screening Population of Women Aged 30 to 60 Years in Germany

ABSTRACT Testing for E6/E7 mRNA in cells infected with high-risk (HR) human papillomavirus (HPV) might improve the specificity of HPV testing for the identification of cervical precancerous lesions. Here we compared the RNA-based Aptima HPV (AHPV) assay (Hologic) and the DNA-based Hybrid Capture 2 (HC2) HPV test (Qiagen) to liquid-based cytology (LBC) for women undergoing routine cervical screening. A total of 10,040 women, 30 to 60 years of age, were invited to participate in the study, 9,451 of whom were included in the analysis. Specimens were tested centrally by LBC, the AHPV test, and the HC2 test, and women who tested positive on any test were referred for colposcopy. Genotyping was performed on all HR-HPV-positive samples. Test characteristics were calculated based on histological review. As a result, we identified 90 women with cervical intraepithelial neoplasia grade 2+ (CIN2+), including 43 women with CIN3+. Sensitivity differences between the AHPV test and the HC2 test in detecting CIN2+ (P = 0.180) or CIN3+ (P = 0.0625) lesions were statistically nonsignificant. Of three CIN3 cases that were missed with the AHPV test, two cases presented lesion-free cones and one had a non-HR HPV67 infection. The specificity (<CIN2) and positive predictive value (CIN2+) of the AHPV test were significantly higher (both P < 0.001) than those of the HC2 test. The overall agreement between the tests was substantial (κ = 0.77). Finally, we present results for several possible triage strategies, based on the primary screening test being either the AHPV test or the HC2 test. In summary, the AHPV assay is both specific and sensitive for the detection of high-grade precancerous lesions and may be used in primary cervical cancer screening for women ≥30 years of age.

Fertility preservation methods in young women with systemic lupus erythematosus prior to cytotoxic therapy: experiences from the FertiProtekt network

Objectives: Despite new treatment options, some patients with systemic lupus erythematosus (SLE) need to be treated with the cytotoxic agent cyclophosphamide (CYC). Unlike malignant disease, there are no recommendations for ovarian protection in SLE. The clinical experience of the FertiPROTEKT network as well as recommendations after literature review will be presented in this paper. Methods: Retrospective analyses of counselling and treatment data from the FertiPROTEKT register with special respect to SLE patients under 40 years prior to planned CYC treatment. Results: A total of 2836 patients were advised prior to cytotoxic treatment in one of the FertiPROTEKT centres during January 2007 to November 2011. Of those, 68 patients (mean age 25 +/− 6.07years) were counselled for severe SLE. Only five women did not make use of a fertility preservation method. Sixty-three patients (92.6%) decided in favour of a fertility preservation method. The largest proportion (91.2%) opted for treatment with a GnRH analogue. Ovarian tissue removal for cryoconservation was performed in 16 patients (25%). Stimulation therapy for cryoconservation of fertilized egg cells was performed in three patients (4.4%). Conclusions: When counselling patients with SLE for fertility preservation one has to be aware of the disease-specific risks. According to the literature, a safe and effective option in SLE up to now has been the use of a GnRH analogue. Cryoconservation of ovarian tissue must still be seen as an experimental treatment, but as data on removal, cryoconservation, retransplantation and pregnancies are steadily rising, this presents a promising option for young SLE patients. Cryoconservation of oocytes must be very critically evaluated due to the need for a stimulation therapy and should only be performed after particular consideration of the individual risks.

Typical and Atypical Associated Findings in a Group of 346 Patients with Mayer-Rokitansky-Kuester-Hauser Syndrome

STUDY OBJECTIVE The Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome is characterized by vaginal and uterine aplasia in a 46,XX individual. Multiple abnormalities may be associated with MRKH syndrome, and it appears to overlap other syndromes. The aim of this study was to describe the spectrum of associated malformations and syndromes as well as abnormal karyotypic findings in a large cohort of 346 patients. DESIGN, SETTING, AND PARTICIPANTS The study is a retrospective analysis of 346 MRKH patients treated in the University Hospital in Tuebingen between 1998 and 2013. MAIN OUTCOME MEASURES The dataset was screened for typical associated malformations as well as atypical malformations and abnormal karyotypes. A complete review of the literature was included. RESULTS Among our cohort of 346 patients, we found that 53.2% had MRKH type 1, 41.3% had MRKH type 2, and 5.5% had MURCS syndrome. The group with associated malformations included 57.6% renal, 44.4% skeletal, and 30.8% other malformations. Additionally, we found 2 cases of absent radius syndrome, 3 cases of anal atresia, and 1 patient with oculodentodigital dysplasia, and other atypical malformations. Abnormal karyotypes were found in 5 cases, and 39 siblings and 11 parents had known malformations. CONCLUSIONS This study supports the hypothesis that the syndrome has a multifactorial pathogenesis. With the high numbers of associated malformations reported in this study, patients with MRKH syndrome should be regarded as having a complex syndrome. Molecular-genetic analyses in larger numbers of children after surrogacy, twin pregnancies, and familial cases may make it possible to obtain further information about the etiology of the syndrome.

Ovarian reserve alterations in premenopausal women with chronic inflammatory rheumatic diseases: impact of rheumatoid arthritis, Behçet’s disease and spondyloarthritis on anti-Müllerian hormone levels

OBJECTIVE Recent publications have shown a negative influence of SLE on female ovarian reserve. Other authors have not found a significant impact of Crohns disease or early RA on anti-Müllerian hormone (AMH) levels. This study aimed to investigate the potential effect of Behçets disease (BD), RA and SpA on ovarian reserve as reflected by serum AMH levels. METHODS Serum samples from 33 RA, 32 SpA and 30 BD patients without previous cytotoxic treatment were analysed and compared with age-matched, healthy controls. AMH was quantified using a standard ELISA with a standard value of 1-8 ng/ml; values <1 ng/ml defined a reduced ovarian reserve. RESULTS Median age was 26, 28.5 and 33 years and median disease duration was 6, 5.9 and 7 years for RA, SpA and BD patients, respectively. Compared with healthy controls, patients had significantly reduced AMH levels, with a median value for RA of 1.8 ng/ml (control 2.4 ng/ml; P = 0.009), for SpA of 1.5 ng/ml (control 2.3 ng/ml; P = 0.013) and for BD of 1.1 ng/ml (control 1.9 ng/ml; P = 0.007). HLA-B27 had a negative influence on ovarian reserve in SpA patients, whereas other serological parameters did not in the other diseases. CONCLUSION This is the first study to show a reduced ovarian reserve in patients with RA, SpA or BD. Together with our findings in SLE, we conclude a negative influence of chronic rheumatic diseases on ovarian reserve.

Fertility Preservation in Prepubertal Girls Prior to Chemotherapy and Radiotherapy—Review of the Literature

Significant improvement in the survival rates of children with pediatric cancers has been achieved over the last 25 years, so the number of long-term survivors is increasing and their subsequent quality of life is of increasing importance. One of the most serious side effects of chemotherapy or radiotherapy is damage to the ovarian function, which can lead to loss of fertility. The degree of this damage depends on the substances used, the dose of radiotherapy reaching the ovaries, and the age of the girl at the time of treatment. Up to now, the only established method of fertility preservation has been cryoconservation of fertilized egg cells or embryos, but this is not possible in prepubertal girls because of their sexual immaturity. Removal of ovarian tissue and subsequent cryoconservation with the option of later orthotopic retransplantation is therefore an option to these girls. This method can lead to pregnancy and birth in adult women. Up to now there are no studies about the retransplantation of ovarian tissue which was removed before puberty. Displacement of the ovaries away from the radiation field before radiation to the pelvic area can be considered; however, the data is controversial. One problem in the use of fertility preservation methods in these very young patients is that they undergo procedures which, because of their age, they mostly do not understand and the parents must make a decision based on the assumed later wishes of their daughter.

Pregnancy after Successful Cancer Treatment: What Needs to Be Considered?

Over the last decade, advances in oncology led to improved treatment results and increasing numbers of long-term cancer survivors. Fulfilling the desire to have children is important for many patients after cancer treatment. Consequently, oncologists, gynecologists and obstetricians are seeing more patients who wish to conceive after treatment. The necessary prerequisites that should be considered when supporting a planned pregnancy after cancer treatment are discussed in this article. The possible consequences of chemotherapy and radiotherapy on the course of pregnancy and the health of the offspring, as well as the interactions between cancer and pregnancy, are reviewed with the focus on childhood cancer, malignant lymphomas, and breast cancer. Despite chemo- or radiotherapy, neither the teratogenic risk nor the risk of adventitious cancers appears to be increased for the offspring of cancer survivors. However, there is a slightly higher risk of miscarriage after chemotherapy. In case of radiation to the uterus, there is a higher risk of premature birth, intrauterine growth retardation, and increased perinatal mortality. The effect is more pronounced after prepubertal radiation than for postpubertal radiation. The former cancer patient’s desire to conceive can nevertheless be supported, given that pregnancy and birth are closely monitored.

Fertility protection: complications of surgery and results of removal and transplantation of ovarian tissue

Fertility-preserving measures are becoming important for patients receiving oncological treatment. One method involves cryopreservation of ovarian tissue and transplanting it when treatment is completed. We report complications resulting from surgical and fertility medicine, and the results of procedures for the removal and transplantation of ovarian tissue carried out within the FertiProtekt network. A survey using a structured questionnaire was conducted among the FertiProtekt network centres between November 2015 and June 2016. The analysis included surgical techniques used to remove and transplant ovarian tissue, surgical complications and results. Laparoscopic removal and transplantation of ovarian tissue have a low risk of complications. Surgical complications occurred in three of the networks 1373 ovarian tissue removals (n = 1302) and transplantations (n = 71); two complications (0.2%) occurred during removal and one during transplantation. Menstruation resumed in 47 out of 58 women (81%) who underwent ovarian tissue transplantation. Hormonal activity occurred in 63.2% of transplantations with a follow-up of 6 months or over. Sixteen pregnancies occurred in 14 patients, with nine births. The risks and complications of removal and transplantation of ovarian tissue are similar to those of standard laparoscopy. These procedures are becoming standard for fertility protection in cancer patients.

Fertility preservation in young female lymphoma patients: review of available options and initial experiences with their implementation in clinical routine.

Background: High cure rates in women suffering from Hodgkin’s disease or aggressive non-Hodgkin’s lymphoma are often achieved at the cost of impaired ovarian function or infertility. Different strategies can be offered to protect fertility. Early experiences with the implementation of a specialised fertility preservation clinic are analysed with the aim to assess the need for and acceptance of the clinic, as well as the delay of treatment caused by the different approaches. Available options are reviewed. Patients and Methods: Data on underlying malignancy and fertility preservation measures in women of childbearing age treated for aggressive lymphoma and Hodgkin’s disease with curative intent between November 2006 and January 2010 were retrospectively analysed. Results: Among 111 female lymphoma patients, 30 were eligible for counselling. Nineteen accepted the offer. The main reason for declining was completed family planning. Eight further patients were referred from elsewhere. Of the counselled patients, 96% decided to pursue at least 1 protective strategy, 39% chose an invasive procedure (cryopreservation of ovarian tissue or oocyte aspiration following hormonal stimulation). These procedures deferred the start of systemic treatment within the expected range, no undue delays were observed. Conclusions: Female lymphoma patients have a large demand for counselling about measures to protect fertility. In a proper setting, counselling and intervention can be offered without undue delays menacing the chance for cure.

Characteristics and attitudes of women in relation to chosen fertility preservation techniques: a prospective, multicenter questionnaire-based study with 144 participants

OBJECTIVE What are the patients attitudes about their fertility and about the counselling process at the time when fertility preservation counselling is performed? STUDY DESIGN A survey regarding fertility concerns and counselling performance in relation to the chosen fertility preservation procedure such as no treatment, GnRH agonists, and freezing of ovarian tissue or oocytes/zygotes was prospectively conducted in four university centres and one private centre, all belonging to the network FertiPROTEKT in Germany and Switzerland. RESULTS All women (n=145) received a questionnaire at the first counselling appointment. The mean age of the patients was 30 years (±5.8, range 17-43 years). 91% were referred by their treating oncologists. Single patients preferred invasive strategies, such as freezing of oocytes/zygotes (44.3%) or freezing of ovarian tissue (36%), whereas only 19.7% opted for no treatment/GnRH agonists. In married couples, the proportions were 28.9%, 31.1% and 40.0% respectively. Women without children also opted more frequently for invasive strategies, such as freezing of oocytes/zygotes (84.5%) or freezing of ovarian tissue (74.1%), and less frequently for no treatment/GnRH agonists (63.3%). Physical and psychological status, current and future fertility concerns and satisfaction with the counselling process were equal in all treatment groups. CONCLUSION As fertility concerns and attitudes about the counselling process were independent from the fertility preservation procedure chosen, the preferred treatment can hardly be predicted and therefore all women should be counselled about all possible fertility preservation techniques.