STop OVarian CAncer (STOPOVCA) young: Protocol for a multicenter follow-up study to determine the long-term effects of opportunistic salpingectomy on age at menopause.

BACKGROUND: Opportunistic salpingectomy comprises additional bilateral salpingectomy during abdominal surgery as a prophylactic method to reduce the risk of ovarian cancer. However, opportunistic salpingectomy may potentially damage (micro)blood circulation to the ovaries, resulting in earlier onset of menopause. PRIMARY OBJECTIVE: To evaluate the long-term effects of opportunistic salpingectomy on the onset of menopause in women who underwent sterilization through salpingectomy compared with a control group who underwent sterilization by tubal ligation or no surgery at all. STUDY HYPOTHESIS: Opportunistic salpingectomy does not lower the mean age at onset of menopause. TRIAL DESIGN: In a multicenter observational noninferiority study, we will prospectively compare the age at menopause of women initially aged 35-45 who underwent sterilization through opportunistic salpingectomy with a similarly aged control group who underwent sterilization by tubal ligation or no sterilization. Participants will be asked to complete an annual questionnaire on onset of menopause to eventually determine whether there is more than a one-year decrease in mean age at onset of menopause in the opportunistic salpingectomy group. Follow-up will last until determination of menopause, with a maximum of 15 years. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria: pre-menopausal; age between 35 and 45; intact ovaries. EXCLUSION CRITERIA: post-menopausal; previous bilateral salpingectomy or oophorectomy; previous hysterectomy; abnormal karyotype; previous or current chemotherapy or pelvic radiation. PRIMARY ENDPOINT(S): Determination of age of menopause measured by annual questionnaire. SAMPLE SIZE: 1200 (400 intervention group; 800 control group). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: It is estimated that recruitment will be completed by 2023 and results will be published by 2039. GOV IDENTIFIER: NCT04757922 PROTOCOL VERSION: : Version 1, February 2021.

EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer.

Ovarian cancer is the most lethal gynecological malignancy due to late detection associated with dissemination throughout the abdominal cavity. Targeted photodynamic therapy (tPDT) aimed at epithelial cell adhesion molecule (EpCAM), overexpressed in over 90% of ovarian cancer metastatic lesions, is a promising novel therapeutic modality. Here, we tested the specificity and activity of conjugates of EpCAM-directed designed ankyrin repeat proteins (DARPins) with the photosensitizer IRDye 700DX in in vitro and in vivo ovarian cancer models. EpCAM-binding DARPins (Ec1: Kd = 68 pM; Ac2: Kd = 130 nM) and a control DARPin were site-specifically functionalized with fluorophores or IRDye 700DX. Conjugation of anti-EpCAM DARPins with fluorophores maintained EpCAM-specific binding in cell lines and patient-derived ovarian cancer explants. Penetration of DARPin Ec1 into tumor spheroids was slower than that of Ac2, indicative of a binding site barrier effect for Ec1. DARPin-IRDye 700DX conjugates killed EpCAM-expressing cells in a highly specific and illumination-dependent fashion in 2D and 3D cultures. Furthermore, they effectively homed to EpCAM-expressing subcutaneous OV90 xenografts in mice. In conclusion, the high activity and specificity observed in preclinical ovarian cancer models, combined with a high specificity in patient material, warrant a further investigation of EpCAM-targeted PDT for ovarian cancer.

Peptide-mediated delivery of therapeutic mRNA in ovarian cancer.

Ovarian cancer is the most lethal gynecological malignancy in the developed world. In spite of intensive research, the mortality has hardly decreased over the past twenty years. This necessitates the exploration of novel therapeutic modalities. Transient protein expression through delivery of mRNA is emerging as a highly promising option. In contrast to gene therapy there is no risk of integration into the genome. Here, we explore the expression of mRNA in models of ovarian cancer of increasing complexity. The cell-penetrating peptide (CPP) PepFect 14 (PF14) was used to formulate CPP-mRNA nanoparticles. Efficient expression of a reporter protein was achieved in two-dimensional tissue cultures and in three-dimensional cancer cell spheroids. PF14 nanoparticles greatly outperformed a lipid-based transfection agent in vivo, leading to expression in various cell types of tumor associated tissue. Protein expression was restricted to the peritoneal cavity. Messenger RNA expression across different cell types was confirmed in primary ovarian cancer explants. As ovarian cancer is confined to the peritoneal cavity in most cases, the results create the basis for applications in which the tumor microenvironment is transiently modified through protein expression.

A Patient With a Low-grade Mucinous Neoplasm Involving the Ovary and Pseudomyxoma Peritonei Originating in an Isolated Intestinal Duplication.

A considerable number of mucinous ovarian tumors are metastatic from other primary tumors, mainly from the gastrointestinal tract, and primary malignant mucinous ovarian tumors are considered rare. Mucinous ovarian tumors occurring within the clinical syndrome of pseudomyxoma peritonei are assumed to almost always originate from the appendix. We describe a patient with a low-grade mucinous tumor involving the ovary in coexistence with pseudomyxoma peritonei, who underwent appendectomy 25 yr earlier. The tumor originated from a rare cystic gastrointestinal duplication found in the mesenteric fat showing adenomatous changes. This illustrates that even in absence of the appendix, mucinous ovarian tumors occurring with pseudomyoma peritonei rarely arise from the ovary.

[Recurrent miscarriage turns out to be lung cancer]. / Herhaalde miskraam blijkt longkanker.

BACKGROUND: If a positive pregnancy test is followed by profuse vaginal bleeding, the diagnosis of miscarriage can generally be made. Sometimes, however, elevated hCG levels may be associated with a phantom pregnancy, which may be a paraneoplastic symptom. CASE DESCRIPTION: A 27-year-old woman was referred for a diagnosis after having experienced 3 consecutive miscarriages. The diagnostic workup could not identify an underlying cause. After 3 more biochemical miscarriages, the original diagnosis was called into question and extensive testing for ectopic hCG production was performed. It appeared that the false pregnancies were paraneoplastic symptoms of an hCG-producing non-small cell lung cancer. After a lobectomy, the hCG levels returned to normal and a spontaneous pregnancy and uncomplicated delivery followed. CONCLUSION: Phantom pregnancy as a paraneoplastic symptom is extremely rare, but should be considered in patients presenting with recurrent, non-objectifiable miscarriages. Careful documentation of the menstrual cycle is necessary for early detection of the condition. The fact is that vaginal bleeding after a positive pregnancy test can still be a normal menstruation.

Review of the role of the plasminogen activator system and vascular endothelial growth factor in subfertility.

OBJECTIVE: To assess the importance of the plasminogen activator (PA) system and vascular endothelial growth factor (VEGF) in subfertility. DESIGN: Review. SETTING: Two university IVF centers. INTERVENTION(S): Systematic literature search (MEDLINE, Science Direct, and bibliographies of published works). RESULT(S): The PA system in the male is involved in the passage of spermatozoa precursor cells over the blood-testis barrier, the epididymal maturation of spermatozoa, the modifications of the sperm surface for capacitation, the acrosome reaction and zona pellucida attachment, and finally the facilitation of spermatozoa to move into the fallopian tubes. In the female, the PA system plays a role during ovulation in the release of the oocyte from the follicle, the facilitation of oocyte movement into the fallopian tubes, and the extracellular matrix degradation important for angiogenesis in the ovary. The function of VEGF during fertilization is largely unknown. It has been suggested that VEGF is important for the fluid and proteins in semen and fluid secretion in the female genital tract, thereby influencing sperm motility and survival. The latter could be due to an effect of VEGF on testicular microvasculature, through which an adequate microenvironment for spermatogenesis is provided. In the female, VEGF is involved in the regulation of the cyclic ovarian angiogenesis, the development and/or selection of follicles, the accumulation of follicular fluid, and corpus luteum angiogenesis. CONCLUSION(S): The role of the PA system and VEGF in reproduction most likely is of great interest. However, much of the data are derived from experimental animal studies. So far, information on the importance of these systems in humans is scarcely investigated. Therefore, further research is required to elucidate the role of the PA system and VEGF in the pathogenesis and prevention of male and female subfertility. Eventually, this will contribute to the improvement of the diagnosis of subfertility and may possibly lead to targeted therapeutic management of subfertility.

Influence of pesticides on male fertility.

Several studies have shown a decline in human semen quality and increased risks of male subfertility. This paper provides an overview of the mechanisms of pesticide-induced reproductive toxicity and the effects on male fertility since exposure to pesticides may be one of the causes of these disorders. Pesticides may directly damage spermatozoa, alter Sertoli cell or Leydig cell function, or disrupt the endocrine function in any stage of hormonal regulation (hormone synthesis, release, storage, transport, and clearance; receptor recognition and binding; thyroid function; and the central nervous system). These mechanisms are described with respect to the effects of pesticide exposure in vitro and in vivo. In epidemiologic studies, effects on sperm quality and time to pregnancy are reviewed. Clear effects on male fertility have been demonstrated for some pesticides [eg, dibromochloropropane, ethylene dibromide]. But results from more recent studies are inconsistent, and no uniform conclusion can be drawn about the effects of pesticides on male reproduction.

Possible role of the plasminogen activation system in human subfertility.

OBJECTIVE: To correlate components of the plasminogen activator (PA) system with fertility outcome parameters in participants in an IVF/intracytoplasmic sperm injection (ICSI) procedure. DESIGN: Case-control study. SETTING: Outpatient clinic for IVF/ICSI treatment at the Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. PATIENT(S): One hundred and fifty-six couples undergoing an IVF/ICSI procedure. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), and t-PA-PAI-1 complex concentrations in the ejaculate, spermatozoa, and follicular fluid (FF). RESULT(S): Concentrations of t-PA were higher in spermatozoa of the male factor subfertility group (geometrical mean, 77.1 pg/million spermatozoa; 25th-75th percentiles, 31.8-211.2), compared to fertile men (geometrical mean, 1.91; 25th-75th percentiles, 0.74-5.79) and idiopathic subfertile men (geometrical mean, 3.14; 25th-75th percentiles, 0.97-9.97). Furthermore, the concentration of t-PA in spermatozoa was significantly associated with pregnancy (odds ratio [OR], 0.995). Likewise, a trend was shown for higher t-PA concentrations in the FF of women with fallopian-tube pathology (geometrical mean, 18.5 pg t-PA/mg protein; 25th-75th percentiles, 11.4-25.7) or endometriosis (geometrical mean, 18.8; 25th-75th percentiles, 11.4-27.1), compared to fertile women (geometrical mean, 14.3; 25th-75th percentiles, 10.3-17.6) and idiopathic subfertile women (geometrical mean, 13.9; 25th-75th percentiles, 9.5-17.8). Also, t-PA in FF is associated with the proportion of cleaved embryos (regression coefficient, 0.16). The concentrations of u-PA, PAI-1, and t-PA-PAI-1 complex were comparable between diagnostic subgroups in both men and women. CONCLUSION(S): The t-PA concentrations in spermatozoa and FF tend to be higher in human subfertility, and seem to be associated with some fertility outcome parameters.

C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration.

OBJECTIVE: To determine the frequency of C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism in fertile and subfertile males, and the MTHFR-dependent response of sperm concentration after folic acid and/or zinc sulfate intervention. DESIGN: Double-blind, placebo-controlled intervention study. Two outpatient fertility clinics and nine midwifery practices in The Netherlands. PATIENT(S): One hundred thirteen fertile and 77 subfertile males. Daily capsules of folic acid (5 mg) and/or zinc sulfate (66 mg), or placebo for 26 weeks. MAIN OUTCOME MEASURE(S): Prevalence of C677T MTHFR polymorphism and the response of sperm concentration related to MTHFR carriership after intervention treatment. RESULT(S): The C677T methylenetetrahydrofolate reductase genotypes were comparable in fertile and subfertile males. Independent of fertility state, sperm concentration significantly increased in wild-types after folic acid and zinc sulfate treatment only. Heterozygotes and homozygotes did not significantly benefit from either treatment. CONCLUSION(S): C677T methylenetetrahydrofolate reductase polymorphism is not a risk factor for male factor subfertility. In contrast to heterozygotes and homozygotes for C677T MTHFR polymorphism, sperm concentration in wild-types significantly improved after folic acid and zinc sulfate intervention. A stronger role of other folate genes on spermatogenesis is suggested.