Hope for Motherhood: Pregnancy After Allogeneic Hematopoietic Cell Transplantation - a National Multicenter Study.

Improved long-term survival rates after allogeneic hematopoietic cell transplantation (alloHCT) make family planning for young adult cancer survivors an important topic. However, treatment-related infertility risk poses challenges. To assess pregnancy and birth rates in a contemporary cohort, we conducted a national multicenter study using data from the German Transplant Registry, focusing on adult women aged 18-40 who underwent alloHCT between 2003 and 2018. Out of 2,654 transplanted women, 50 women experienced 74 pregnancies, occurring at a median of 4.7 years post-transplant. Fifty-seven of these resulted in live births (77%). The annual first birth rate among HCT recipients was 0.45% (95%CI: 0.31 - 0.59%), which is more than six times lower than in the general population. The probability of a live birth 10 years after HCT was 3.4 % (95%CI: 2.3- 4.5%). Factors associated with an increased likelihood of pregnancy were younger age at alloHCT, non-malignant transplant indications, no total-body-irradiation (TBI) or a cumulative dose of <8 Gray, and non-myeloablative/reduced-intensity conditioning. 72% of pregnancies occurred spontaneously, with assisted reproductive technologies (ART) used in the remaining cases. Preterm delivery and low birth weight were more common than in the general population. This study represents the largest dataset reporting pregnancies in a cohort of adult female alloHCT recipients. Our findings underscore a meaningful chance of pregnancy in alloHCT recipients. ART techniques are important and funding should be made available. However, the potential for spontaneous pregnancies should not be underestimated, and patients should be informed of the possibility of unexpected pregnancy despite reduced fertility. Further research is warranted to understand the impact of conditioning decisions on fertility preservation.

Assisted reproduction after SARS-CoV-2-infection: results of a single-center cohort-study.

PURPOSE: The effects of SARS-CoV-2 infections on the outcome of assisted reproduction techniques (ART) were studied in a retrospective cohort study. METHODS: The outcome of 1581 treatment cycles with embryo transfer at a university fertility center in Germany was compared in years before and during the COVID-19 pandemic. For 335 treatment cycles in 2022 a detailed analysis was carried out depending on infection and immunization status of both partners. RESULTS: ART cycles did not differ in most of the parameters examined between 2018-2022. In spite of comparable clinical pregnancy rates, there was a significantly higher miscarriage rate at 34.6% (27/78) in 2022, compared to 19.7% (29/147) in the pre-pandemic years of 2018-2019 (p = 0.014). In 37.0% of the treatment cycles (124/335) 2022 at least one partner reported a SARS-CoV-2-Infection 6 months before ART, mostly with the virus variant Omicron. Clinical pregnancy rates were lower in cycles without infection. Comparing women with confirmed infection to no infection, a significantly higher risk of miscarriage was seen (62.5% vs. 26.2%, p = 0.009). In treatment cycles of partners with basic immunization against SARS-CoV-2 a statistically significant increase of pregnancy rates was seen comparing to cycles with both unvaccinated partners (p = 0.011). CONCLUSION: The results indicate a negative impact of SARS-CoV-2-infections up to 6 months on ART treatment, in particular an increased risk of miscarriage. Vaccination was associated with a better outcome of ART treatment.

Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients.

OBJECTIVES: Dickkopf-1 (DKK1) is a secreted protein, known for suppressing the differentiation and activity of bone-building osteoblasts by acting as an inhibitor of Wnt-signalling. Soluble DKK1 (sDKK1) has been proposed as prognostic biomarker for a wide range of malignancies, however, clinical relevance of sDKK1 as potential blood-based marker for ovarian cancer is unknown. METHODS: sDKK1 levels were quantified in a cohort of 150 clinically documented ovarian cancer patients by a commercially available DKK1 ELISA (Biomedica, Vienna, Austria). RESULTS: Median sDKK1 level was significantly elevated at primary diagnosis of ovarian cancer compared to healthy controls (estimated difference (ED) of 7.75 ng/mL (95% CI: 3.01-12.30 ng/mL, p=0.001)). Higher levels of sDKK1 at diagnosis indicated an increased volume of intraoperative malignant ascites (ED 7.08 pmol/L, 95% CI: 1.46-13.05, p=0.02) and predicted suboptimal debulking surgery (ED 6.88 pmol/L, 95% CI: 1.73-11.87, p=0.01). sDKK1 did not correlate with CA125 and higher sDKK1 levels predicted a higher risk of recurrence and poor survival (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004; OS: HR=0.561, 95% CI: 0.320-0.986; p=0.044). Prognostic relevance of sDKK1 was partly sustained in wtBRCA patients (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004). CONCLUSIONS: This is the first study demonstrating the prognostic relevance of sDKK1 in ovarian cancer patients, including those with wtBRCA1/2 status. Our data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.

[Prenatal care]. / Schwangerenvorsorge.

Through rational antenatal care, it is possible to identify maternal and fetal risks at an early stage of pregnancy. These risks, which are detected by medical history and examinations, serve as the basis for further medical care and interventions in pregnancy and during birth. Studies show that maternal and fetal mortality and morbidity can be reduced by applying structured and comprehensive national prenatal care concepts. The World Health Organization (WHO) recommends at least eight antenatal controls. According to WHO guidelines, clinical documentation in the form of women-held case notes should be used to ensure good traceability of the medical examinations and findings in the individual pregnancy. For more than 50 years, antenatal care in Germany has been provided in a standardized and clearly structured manner and implemented nationwide. The established maternity document ("Mutterpass") and regular adaptations to the maternity guidelines form the foundation for this. This CME article presents international recommendations and publications focusing on the prenatal care, current developments in Germany, and controversies regarding antenatal care.

Motherhood after cancer: fertility and utilisation of fertility-preservation methods.

PURPOSE: Due to modern and individualised treatments, women at reproductive age have a high survival rate after cancer therapy. What are pregnancy and birth rates of women after cancer and how often do they use cryopreserved ovarian tissue or gametes? METHODS: From 2007 to 2015, 162 women aged 26.7 ± 6.9 years were counselled for fertility preservation at a single University Fertility Centre. A questionnaire study was performed in average 3 and 6 years after the diagnosis of cancer. The women were asked about their fertility, partnership, family planning, and pregnancy history. 72 women (51%) answered a written questionnaire in 2016. 59 women were reached again by phone in 2019 (82%). RESULTS: The preferred method of fertility preservation was ovarian tissue cryopreservation (n = 36, 50%); none of the women had ovarian hyperstimulation in order to cryopreserve oocytes. About 3 years after treatment, 37 women of 72 women (51%) of the women with a mean age of 29.9 years had a strong wish to conceive. 21/72 (29%) had actively tried to conceive after successful cancer treatment; eight women (11%) were already pregnant or had children. Six years after cancer diagnosis 16/59 (27%) women had ongoing anticancer treatment. 12/59 (20%) were pregnant or had children, while 39% (23/59) had no menstrual cycle. Only one woman used her cryopreserved ovarian tissue, but did not become pregnant. CONCLUSION: After cancer and gonadotoxic treatment, women's desire to have a child is substantial. In this study, the rate of spontaneous pregnancies and births was 20% 6 years after gonadotoxic therapies. Not every woman, however, has the opportunity to conceive: factors impairing fertility include ongoing cancer treatment or persistent disease, no partner, no menstrual cycle, as well as other reasons for infertility.

Endometrial human chorionic gonadotropin (hCG) expression is a marker for adequate secretory transformation of the endometrium.

PURPOSE: Successful embryo implantation into the endometrium depends on embryonic characteristics and proper endometrial development. Reproductive medicine often focuses on embryo quality, whereas reliable diagnostic tests for endometrial receptivity are still needed. We previously found that human chorionic gonadotropin (hCG), one of the earliest proteins secreted by the embryo, was also expressed by the luteal phase endometrium around the implantation window. Here, we tested our hypothesis of endometrial hCG as an implantation marker. METHODS: Endometrial biopsies and serum samples were taken from patients undergoing routine infertility diagnostics. Correlations of immunohistochemically detected endometrial hCG expression with adequate endometrial secretory transformation, the infiltration of CD45-positive leukocytes, clinical diagnostic parameters, and endometrial thickness were analyzed. RESULTS: A highly significant correlation between the endometrial score, as a measurement for regular secretory transformation, and the intensity of hCG staining was found. The invasion of CD45-positive leukocytes increased with progressing endometrial secretory transformation and rising endometrial hCG expression. In addition, serum progesterone concentrations correlated with hCG expression by the endometrial glands. CONCLUSIONS: Our results suggest endometrial hCG as a possible diagnostic parameter characterizing the endometrial secretory transformation and, thus, possibly also its implantation capability.

Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2).

PURPOSE: The antimalarial drug artesunate (ART) is a promising candidate for cancer treatment as it displays anticancer effects in various models. While in short-term treatment of malaria, an excellent safety profile has been found for ART, the potential long-term treatment of cancer patients demands a phase I dose-finding clinical trial determining the daily ART dose which would be well tolerated as add-on therapy. METHODS: Patients with metastatic breast cancer were to receive either 100 or 150 or 200 mg oral ART daily as add-on to their guideline-based oncological therapy for a study period of four weeks with frequent clinical and laboratory monitoring until 4-8 weeks thereafter. According to the statistical design, recruitment was scheduled in groups of three patients in order not to miss a more than 33% frequency of dose-limiting adverse events (DL-AE) prior to dose escalation. RESULTS: Twenty-three patients were recruited, and all planned dose levels were applied. During the actual trial period of 4 ± 1 weeks, three patients experienced six DL-AEs altogether (leucopenia, neutropenia, asthenia, anemia) possibly related to ART (not exceeding 33% in any dose level). CONCLUSIONS: Up to 200 mg/d (2.2-3.9 mg/kg/d) oral ART were safe and well tolerated; therefore, 200 mg/d are recommended for phase II/III trials. Safety monitoring should include reticulocytes, NTproBNP, as well as audiological and neurological exploration.

Medical microrobots in reproductive medicine from the bench to the clinic.

Medical microrobotics is an emerging field that aims at non-invasive diagnosis and therapy inside the human body through miniaturized sensors and actuators. Such microrobots can be tethered (e.g., smart microcatheters, microendoscopes) or untethered (e.g., cell-based drug delivery systems). Active motion and multiple functionalities, distinguishing microrobots from mere passive carriers and conventional nanomedicines, can be achieved through external control with physical fields such as magnetism or ultrasound. Here we give an overview of the key challenges in the field of assisted reproduction and how these new technologies could, in the future, enable assisted fertilization in vivo and enhance embryo implantation. As a case study, we describe a potential intervention in the case of recurrent embryo implantation failure, which involves the non-invasive delivery of an early embryo back to the fertilization site using magnetically-controlled microrobots. As the embryo will be in contact with the secretory oviduct fluid, it can develop under natural conditions and in synchrony with the endometrium preparation. We discuss the potential microrobot designs, including a proper selection of materials and processes, envisioning their translation from bench to animal studies and human medicine. Finally, we highlight regulatory and ethical considerations for bringing this technology to the clinic.

Correction: Diagnostic Benefit of the Detection of Mitotic Figures in Endometriotic Lesions.

[This corrects the article DOI: 10.1055/a-1580-0601.].

Life-time experience of violence as a risk factor for symptomatic endometriosis.

The aim of this questionnaire study is to investigate the impact of life-time experiences of violence on the course and severity of endometriosis at a University Endometriosis Center. It also explores women's attitudes toward medical screening for violence. The questionnaire covered demographic data, medical data, information involving possible experiences of psychological, physical, sexual, and intimate partner violence as well as violence screening in medical care. Questionnaires of 118 participants were analyzed. 41/118 women reported some form of violence (34.8%). These women had a significantly higher risk for severe dysmenorrhea, use of analgesics, and comorbidities in comparison to women without life-time experiences of violence. Statistically significant differences were also found for employment status and impaired working ability. More than 60% of women considered the aspect of violence as important for health. However, only 17.1% of women with experiences of violence recalled being asked about violence by a medical professional. The study results suggest that experiences of violence have a significant impact on the course and severity of endometriosis. The findings highlight the importance of healthcare providers to be aware of the potential impact of violence on women's health, and routine screening for violence in medical care, especially in women with endometriosis.

Subjective Birth Experience Predicts Mother-Infant Bonding Difficulties in Women With Mental Disorders.

Background: The subjective experience of giving birth to a child varies considerably depending on psychological, medical, situational, relational, and other individual characteristics. In turn, it may have an impact on postpartum maternal mental health and family relationships, such as mother-infant bonding. The objective of the study was to evaluate the relevance of the subjective birth experience (SBE) for mother-infant bonding difficulties (BD) in women with mental disorders. Methods: This study used data from N = 141 mothers who were treated for postpartum mental disorders in the mother-baby day unit of the Psychosomatic University Clinic in Dresden, Germany. Patients' mental status at admission and discharge was routinely examined using a diagnostic interview (SCID I) and standard psychometric questionnaires (e.g., EPDS, BSI, PBQ). Both, the SBE (assessed by Salmon's Item List, SIL) as well as medical complications (MC) were assessed retrospectively by self-report. The predictive value of SBE, MC, as well as psychopathological symptoms for mother-infant BD were evaluated using logistic regression analyses. Results: About half of this clinical sample (47.2%) reported a negative SBE; 56.8% of all mothers presented with severe mother-infant BD toward the baby. Mothers with BD showed not only significantly more depressiveness (EPDS: M = 16.6 ± 5.6 vs. 14.4 ± 6.2*), anxiety (STAI: M = 57.2 ± 10.6 vs. 51.4 ± 10.6***), and general psychopathology (BSI-GSI: M = 1.4 ± 0.7 vs. 1.1 ± 0.6**) compared to women without BD, but also a significantly more negative SBE (SIL: M = 79.3 ± 16.2 vs. 61.3 ± 22.9***). Moreover, the SBE was the most powerful predictor for BD in univariate and multiple logistic regression analyses [OR = 0.96*** (95% CI 0.94-0.98) vs. OR = 0.96** (95% CI 0.93-0.98)], even when univariate significant predictors (e.g., current psychopathology and MC during birth) were controlled. Conclusions: A negative SBE is strongly associated with mother-infant bonding in patients with postpartum mental disorders. It needs to get targeted within postpartum treatment, preferably in settings including both mother and child, to improve distorted mother-infant bonding processes and prevent long-term risks for the newborn. Furthermore, the results highlight the importance of focusing on the specific needs of vulnerable women prior to and during birth (e.g., emotional safety, good communication, and support) as well as individual factors that might be predictive for a negative SBE.

Diagnostic Benefit of the Detection of Mitotic Figures in Endometriotic Lesions.

Objectives Endometriosis is a chronic disease which is diagnosed by surgical intervention combined with a histological work-up. Current international and national recommendations do not require the histological determination of the proliferation rate. The diagnostic and clinical importance of the mitotic rate in endometriotic lesions still remains to be elucidated. Methods In this retrospective study, the mitotic rates and clinical data of 542 patients with histologically diagnosed endometriosis were analyzed. The mean patient age was 33.5 ± 8.0 (17 - 72) years, and the mean reproductive lifespan was 21.2 ± 7.8 (4 - 41) years. Patients were divided into two groups and patients' reproductive history and clinical endometriosis characteristics were compared between groups. The study group consisted of women with confirmed mitotic figures (n = 140, 25.83%) and the control group comprised women without proliferative activity according to their mitotic rates (n = 402, 74.27%). Results Women with endometriotic lesions and histologically confirmed mitotic figures were significantly more likely to have a higher endometriosis stage (p = 0.001), deep infiltrating endometriosis (p < 0.001), ovarian endometrioma (p = 0.012), and infertility (p = 0.049). A mitotic rate > 0 was seen significantly less often in cases with incidental findings of endometriosis (p = 0.031). The presence of symptoms and basic characteristics such as age, age at onset of menarche, reproductive lifespan and parity did not differ between the group with and the group without mitotic figures. Conclusion This study shows that a simple histological assessment of the mitotic rate offers additional diagnostic value for the detection of advanced stages of endometriosis. The possible role as a predictive marker for the recurrence of endometriosis or the development of endometriosis-associated cancer will require future study.

Clinical impact of soluble Neuropilin-1 in ovarian cancer patients and its association with its circulating ligands of the HGF/c-MET axis.

Background: Neuropilin (NRP) is a transmembrane protein, which has been shown to be a pro-angiogenic mediator and implicated as a potential driver of cancer progression. NRP-1 up-regulation in ovarian cancer tissue predicts poor prognosis. However, the clinical relevance of the soluble form of NRP-1 (sNRP-1) as a circulating biomarker in ovarian cancer patients is unknown. Methods/patients cohort: sNRP-1 levels were quantified in a cohort of 88 clinically documented ovarian cancer patients by a commercially available sNRP-1 enzyme-linked immunosorbent assay (ELISA) kit (Biomedica, Vienna, Austria). Patients (81.8% with FIGOIII/IV) received primary cytoreductive surgery with the aim of macroscopic complete resection (achieved in 55.7% of patients) and the recommendation of adjuvant chemotherapy in line with national guidelines. Results: Higher levels of sNRP-1 reflected more advanced disease (FIGO III/IV) and indicated a trend towards suboptimal surgical outcome, i.e. any residual tumor. sNRP-1 was neither related to the patients' age nor the BRCA1/2 mutational status. Patients with higher sNRP-1 levels at primary diagnosis had a significantly reduced progression-free survival (PFS) (HR = 0.541, 95%CI: 0.304 - 0.963; p = 0.037) and overall survival (OS) (HR = 0.459, 95%CI: 0.225 - 0.936; p = 0.032). Principal component analysis showed that sNRP-1 levels were unrelated to the circulating hepatocyte growth factor (HGF) and the soluble ectodomain of its receptor the tyrosine kinase mesenchymal-epithelial transition (c-MET), suggesting that there is no proportional serological concentration gradient of soluble components of the NRP-1/HGF/c-MET signaling axis. Conclusions: In line with the previously shown tissue-based prognostic role, we demonstrated for the first time that sNRP-1 can also act as a readily accessible, prognostic biomarker in the circulation of patients with ovarian cancer at primary diagnosis. Given its known role in angiogenesis and conferring resistance to the poly ADP-ribose polymerase (PARP) inhibitor olaparib in vitro, our results encourage more detailed investigation into sNRP-1 as a potential predictive biomarker for bevacizumab and/or PARP-inhibitor treatment.

Are two children at once better than one? Risk analysis of twin pregnancies and births after assisted reproduction.

OBJECTIVES: Pregnancies and births following assisted reproductive treatment (ART) are related to an increased risk for adverse perinatal outcomes. The aim of this retrospective cohort study at a University Hospital with a tertiary perinatal center was the combined risk analysis of singleton and twin pregnancies after ART in comparison to spontaneously conceived pregnancies. STUDY DESIGN: Maternal and fetal risks were analyzed in subgroups after spontaneous conception (N = 14,233) and ART (N = 785) during the 6-year study period from 2014 to 2019. Odds ratios for perinatal risks between the groups were calculated and adjusted for maternal age and gestational week at birth using a matched control analysis. Subgroups of preterm delivery were compared. RESULTS: The overall maternofetal risks after ART are higher than after spontaneous conception. Maternal risks after ART are mainly related to higher maternal age (p < 0.001). Preterm delivery and neonatal complications are more frequent in twins than in singletons (p < 0.001), but no statistically significant differences were seen in comparison in the subgroup of twins due to conception. Higher maternal age and body mass index did not increase the risk of preterm birth in twin pregnancies. CONCLUSIONS: Maternal risks in pregnancies after ART are mainly influenced by maternal age. The strongest risk factor in ART pregnancies is a multiple pregnancy. Every 5th pregnancy after ART was a twin pregnancy with higher risks for preterm delivery, maternal hospitalization and adverse neonatal outcome (p < 0.001). Advanced maternal age in ART cannot be altered, but twin pregnancies can be actively avoided using the single embryo transfer strategy.

The levels of soluble cMET ectodomain in the blood of patients with ovarian cancer are an independent prognostic biomarker.

The tyrosine kinase mesenchymal-epithelial transition (cMET) is typically overexpressed in up to 75% of patients with ovarian cancer, and cMET overexpression has been associated with poor prognosis. The proteolytic release of the soluble cMET (sMET) ectodomain by metalloproteases, a process called ectodomain shedding, reflects the malignant potential of tumour cells. sMET can be detected in the human circulation and has been proposed as biomarker in several cancers. However, the clinical relevance of sMET in ovarian cancer as blood-based biomarker is unknown and was therefore investigated in this study. sMET levels were determined by enzyme-linked immunosorbent assay in a set of 432 serum samples from 85 healthy controls and 86 patients with ovarian cancer (87% FIGO III/IV). Samples were collected at primary diagnosis, at four longitudinal follow-up time points during the course of treatment and at disease recurrence. Although there was no significant difference between median sMET levels at primary diagnosis of ovarian cancer vs. healthy controls, increased sMET levels at primary diagnosis were an independent predictor of shorter PFS (HR = 0.354, 95% CI: 0.130-0.968, P = 0.043) and shorter OS (HR = 0.217, 95% CI: 0.064-0.734, P = 0.014). In the follow-up samples, sMET levels were prognostically most informative after the first three cycles of chemotherapy, with high sMET levels being an independent predictor of shorter PFS (HR = 0.245, 95% CI: 0.100-0.602, P = 0.002). This is the first study to suggest that sMET levels in the blood can be used as an independent prognostic biomarker for ovarian cancer. Patients at high risk of recurrence and with poor prognosis, as identified based on sMET levels in the blood, could potentially benefit from cMET-directed therapies or other targeted regimes, such as PARP inhibitors or immunotherapy.

Psychosomatically Oriented Diagnostics and Therapy for Fertility Disorders. Guideline of the DGPFG (S2k-Level, AWMF Registry Number 016/003, December 2019).

Aim The purpose of this official guideline published and coordinated by the German Society for Psychosomatic Gynecology and Obstetrics [Deutsche Gesellschaft für Psychosomatische Frauenheilkunde und Geburtshilfe (DGPFG)] is to provide a consensus-based overview of psychosomatically oriented diagnostic procedures and treatments for fertility disorders by evaluating the relevant literature. Method This S2k guideline was developed using a structured consensus process which included representative members of various professions; the guideline was commissioned by the DGPFG and is based on the 2014 version of the guideline. Recommendations The guideline provides recommendations on psychosomatically oriented diagnostic procedures and treatments for fertility disorders.

Continuous Body Temperature Monitoring to Improve the Diagnosis of Female Infertility.

Introduction Ovulatory dysfunction is a major cause of female infertility. We evaluated the use of continuous body temperature monitoring with a vaginal biosensor to improve standard diagnostic procedures for determining ovulatory dysfunction. Material and Methods This prospective interventional study was performed in a reproductive medicine department of a university hospital. The menstrual cycles of 51 women with infertility were monitored and analysed using three different strategies: sonographic and hormonal assessment (standard approach), continuous core body temperature measurement and analysis using the algorithm of OvulaRing, and lowest daily body temperature measurement monitored with a vaginal biosensor and analysed based on the body temperature curves used in natural family planning. Results Statistically significant differences were found in the temperature curves of women with luteal phase deficiency and polycystic ovary syndrome compared to women with normal menstrual cycles. The analysis of individual cyclofertilograms can be used to detect cycle phases and estimate the date of ovulation. Conclusions Continuous body temperature monitoring with a vaginal biosensor can improve the standard diagnostic procedures used to determine ovulatory dysfunction, especially if dysfunction is due to luteal phase deficiency and polycystic ovary syndrome. Analysis of the lowest daily body temperature combined with the basal body temperature measurements used in fertility awareness methods may be equieffective to continuous body temperature measurements with OvulaRing. The results of this study show that a revised diagnostic approach using fewer hormonal assessments combined with continuous body temperature monitoring can reduce the number of appointments in an infertility clinic as well as the costs.

Correction: Continuous Body Temperature Monitoring to Improve the Diagnosis of Female Infertility.

[This corrects the article DOI: 10.1055/a-1191-7888.].

The role of stress and self-efficacy in somatic and psychological symptoms during the climacteric period - Is there a specific association?

OBJECTIVES: To investigate the influence and specificity of sociodemographic and psychological factors on the perception of symptoms associated with menopause. STUDY DESIGN: Data are based on a nationwide cross-sectional survey study in Germany. A representative sample of 1350 females aged 14-95 years was examined. Sociodemographic factors, perceived stress, and self-efficacy were assessed. Women were divided into three age groups (young women ≤ 44 years; perimenopausal women 45-60 years; older women ≥ 61 years), and the Menopause Rating Scale (MRS) was used over the entire life span. MAIN OUTCOME MEASURES: Total score on the Menopause Rating Scale (MRS) and hot flushes/sweating assessed via the MRS. RESULTS: The MRS total score increased with age. Both MRS total score and hot flushes were positively associated with perceived stress in all three age groups. The MRS total score was negatively associated with self-efficacy; for hot flushes, this association could be shown for perimenopausal women only. Furthermore, interaction effects between perceived stress and self-efficacy were found: in perimenopausal and older women, the association between perceived stress and the MRS total score was stronger the lower self-efficacy was. This interaction effect was not observed in younger women. No interaction effect was found in any age group for hot flushes. CONCLUSIONS: Our data indicate that self-efficacy influences the severity of symptoms measured with the MRS. Interventions aimed to reduce stress and strengthen self-efficacy could lead to a lower symptom burden in perimenopausal women.

Long-term add-on therapy (compassionate use) with oral artesunate in patients with metastatic breast cancer after participating in a phase I study (ARTIC M33/2).

BACKGROUND: The antimalarial artesunate (ART), a semisynthetic derivative of artemisinin from the Chinese herb artemisia annua has remarkable anticancer properties in vitro and in vivo. Its excellent safety profile known from short-term therapy in malaria was confirmed in an open phase I trial (ARTIC M33/2) for dose-finding as add-on therapy for four weeks. PURPOSE: Patients with metastatic breast cancer, who had not experienced any clinically relevant adverse events (AE) during participation in ARTIC M33/2, were offered to continue ART as compassionate use (CU). Regular monitoring was continued in order to ensure adequate individual safety and tolerability and to collect information about long-term treatment with ART. Clinically relevant AEs or second progression of disease during ART were reasons for discontinuation of the add-on therapy. STUDY DESIGN: Compassionate use was offered open-label to participants of ARTIC M33/2. METHODS: Patients continued to take 100, 150 or 200 mg oral ART daily as add-on therapy to their guideline-based oncological therapy. Clinical and laboratory monitoring included audiological and neurological examination, ECG, NTproBNP and reticulocyte determination. Cumulative treatment days and cumulative ART doses encompass both the phase I study as well as the continued add-on treatment period (CU). RESULTS: Following the 4 ±â€¯1 weeks of the phase I trial, thirteen patients continued the add-on therapy as CU, resulting in a total of 3825 treatment days. In individual patients up to 1115 cumulative treatment days (37 months) and cumulative ART doses up to 167.3 g were reached. A total of 25 AEs grade ≥ 2 at least possibly related to ART long-term add-on therapy were documented, two, six and 17 in dose groups 100, 150 and 200 mg/d ART respectively. Six of these AEs were classified as grade 3, two in patients taking 150 and four in patients on 200 mg/d, none of them being probably or certainly related to ART. CONCLUSIONS: In thirteen patients with metastatic breast cancer up to 200 mg/d long-term oral ART (2.3-4.1 mg/kg BW/d) in up to 1115 cumulative treatment days (37 months) did not result in any major safety concerns.