[Cerebral MR imaging of malignant melanoma]. / Zerebrale MR-Bildgebung beim malignen Melanom.

CLINICAL/METHODICAL ISSUE: Melanoma is the third leading cancer entity to metastasize to the central nervous system (CNS) after lung and breast cancer. This is often an early event in the disease course and limits survival. Metastasis in the CNS is the cause of death in 10-40 % of melanoma patients and the incidence of brain metastasis is even higher (50-75 %). Cerebral metastases are commonly found in the subcortical white matter. The signal characteristics can vary substantially and may change over time due to hemorrhages or the accumulation of melanin and paramagnetic ions. It is not yet clear whether novel targeted therapies (e.g. immunotherapy and kinase inhibitors) alter imaging characteristics. Also immune-related side effects, such as hypophysitis (in approximately 5 % of patients receiving ipilimumab therapy) or granulomatous disease (neurosarcoid) can occur. STANDARD RADIOLOGICAL METHODS: Melanoma metastases are usually hyperdense in computed tomography (CT). In magnetic resonance imaging (MRI) T2-weighted (T2-w) fluid-attentuated inversion recovery (FLAIR) and T1-w sequences (with and without i.v. contrast) should be obtained. Coronal and axial imaging planes should be scanned to cross-correlate findings. METHODICAL INNOVATIONS: Susceptibility-weighted imaging is a new sensitive method to detect melanoma metastases. Approximately 66 % of melanoma metastases show intratumoral susceptibility signals (ITSS). This sets them apart from other metastases (e.g. lung and breast cancer show less ITSSs, specificity approximately 81-96 %). Diffusion imaging plays no major role in melanoma brain imaging. PERFORMANCE: Susceptibility-weighted imaging increases the sensitivity to detect metastases but lacks specificity. Differentiating metastases, microbleeding or calcification can be impossible. It is controversial how to interpret susceptibility signals without correlative signs on other sequences (differential diagnosis: metastasis, microbleeding and calcification). PRACTICAL RECOMMENDATIONS: CNS metastases are common in melanoma. MRI screening starting in stage IIc should be considered even in asymptomatic patients. Stage IV requires quarterly MRI examinations. Melanotic and amelanotic metastases show different MRI characteristics. The differentiation between metastasis and microbleeding can be impossible and might require a follow-up scan. Susceptibility-weighted imaging increases the sensitivity of metastases detection but lacks specificity. It can help to differentiate between different metastatic entities.

Material-Specific Roadmap Modes Can Improve the Visibility of Liquid Embolic Agents for Endovascular Embolization: A Systematic In Vitro Study.

BACKGROUND AND PURPOSE: Endovascular embolization using liquid embolic agents is a safe and effective treatment option for AVMs and fistulas. Because reliable visibility of these liquid embolic agents is essential for intraprocedural visual control to prevent complications, novel angiographic systems are equipped with material-specific roadmap modes. The aim of this study was the systematic in vitro comparison of conventional and material-specific roadmap modes regarding the visibility of the most used liquid embolic agents. MATERIALS AND METHODS: A recently introduced in vitro model, resembling cerebral vessels, was embolized with Onyx 18, Squid 18, PHIL 25%, and n-BCA mixed with iodized oil (n = 4 for each liquid embolic agent), as well as with contrast medium and saline, both serving as a reference. Imaging was performed in conventional and material-specific roadmap modes. The visibility of the liquid embolic agents in both modes was compared quantitatively and qualitatively. RESULTS: Significant differences between conventional and material-specific roadmap modes regarding the visibility of the liquid embolic agents were observed for all study groups. All liquid embolic agents were better visible in the material-specific roadmap modes compared with the conventional mode in qualitative and quantitative analyses (eg, Onyx in conventional-versus-material-specific modes along the 1.0-mm sector: mean contrast-to-noise ratio, 5.69 [SD, 0.85] versus 47.18 [SD, 5.72]; P < .001, respectively). CONCLUSIONS: In this in vitro study, we demonstrated a better visibility of all investigated liquid embolic agents by using material-specific roadmap modes compared with the conventional roadmap technique. Especially in complex anatomic situations, these novel roadmap modes could improve the visual control and thus the safety and efficacy of embolization procedures in clinical practice.

Vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) expression in luteinized human granulosa cells in vitro.

Vascularization is a prerequisit for corpus luteum formation. Angiogenesis is supposed to be regulated by vascular growth factors. Vascular endothelial growth factor (VEGF) induces specifically endothelial cell proliferation as well as angiogenesis and increases capillary permeability. With this study we demonstrate for the first time the presence of VEGF-mRNA in human luteinized granulosa cells by Northern blot technique. Granulosa cells were obtained from 11 individual patients undergoing ovarian stimulation for in vitro fertilization procedure. Two transcripts of VEGF-mRNA at 3.9Kb and at 4.3Kb could be detected in each case. Specific transcripts were expressed in different amounts. These results indicate that VEGF may promote at least in part vascularization of the human corpus luteum.

Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: importance in ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) is a severe complication arising from controlled ovarian stimulation treatment. This iatrogenic condition is potentially lethal and occurs in 0.3-5% of stimulated ovarian cycles. hCG exacerbates OHSS. The pathophysiology of OHSS is still unknown; therefore, treatment regimens are aimed at ameliorating symptoms. Prominent features of OHSS are an elevated risk of thromboembolism due to enhanced production of von Willebrand factor by endothelial cells and ascites, or pulmonary edema due to increased vascular permeability followed by third space fluid accumulation. Both of these sequelae can be evoked by vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF). High concentrations of VEGF/VPF have been demonstrated in ascitic fluid from patients with OHSS, but the source of VEGF/VPF in these patients remained unidentified. Here we report that the messenger ribonucleic acid expression of VEGF/VPF in human luteinized granulosa cells (GCs) is dose and time dependently enhanced by hCG in vitro. Furthermore, VEGF/VPF proteins are produced by GCs. Our results suggest that the effects of hCG on the development and course of OHSS may be mediated by the production of VEGF/VPF by GCs.

Immunohistochemical localization of thromboxane synthase in human intrauterine tissues.

Uterine tissues are known to be able to synthesize thromboxane A2 (TXA2), but there is little information about the nature of cells actually responsible for its production. In this study human placenta, fetal membranes, umbilical cord and pregnant myometrium were investigated immunohistochemically. The avidin-biotin method for a monoclonal antibody against human thromboxane synthase (Tü 300) was applied on frozen tissue sections. In placenta, fetal membranes and umbilical cord, staining was positive for Hofbauer cells and fibroblasts. Further, in sections of placenta, capillary endothelium showed antigenicity for TX synthase. Leiomyocytes in the umbilical cord vessels contained the enzyme as well. Preparations of pregnant myometrium were shown to express TX synthase in leiomyocytes, endothelial cells and connective tissue cells. Amnion, trophoblast and decidua did not possess antigenicity for this enzyme. Since TXA2 plays an important role for the regulation of vascular tone and aggregation of platelets and may stimulate myometrial contractions during parturition, the abundance of TX synthase in pregnancy-specific tissues confirms previous in vivo and in vitro observations. Further, TXA2 synthesized by Hofbauer cells may be involved in immunological reactions during pregnancy, and the number and level of activation of Hofbauer cells may be closely related to the initiation of labour. Thromboxane production by the endothelium lining the fetal vessels points to its regulatory role for the blood flow in the fetoplacental unit.

Arachidonate metabolism in human placenta, fetal membranes, decidua and myometrium: lipoxygenase and cytochrome P450 metabolites as main products in HPLC profiles.

Eicosanoids play a key role in pregnancy maintenance and parturition. We investigated the metabolism of arachidonic acid (AA) in short-term tissue cultures of placenta, fetal membranes, decidua and myometrium. Tissues were obtained from caesarean sections before the onset of labour after uncomplicated pregnancies. The released metabolites were analysed by high performance liquid chromatography (HPLC) and specific immunoassays. In radiotracer experiments tissues were labelled with [3H]-AA and metabolites released after incubation with calcium ionophore A23187 were profiled by HPLC. Decidua was more active in metabolizing AA (turnover 34 per cent) than myometrium (28 per cent), placenta (21 per cent) and fetal membranes (17 per cent). Main product in placenta, decidua and myometrium was 12-hydroxyeicosatetraeinoic (12-HETE) (decidua: 19 per cent of released radioactivity, myometrium 14 per cent, placenta 7 per cent). Fetal membranes formed 5-HETE as main product. Another major metabolite in placenta, fetal membranes and decidua was characterized by HPLC as 5(6)-epoxyeicosatrienoic acid. Only myometrium released appreciable amounts of prostaglandins in form of 6-keto-prostaglandin F1 alpha. In non-radioactive experiments formation of eicosanoids from endogenous AA was investigated by HPLC (fluorescence- and UV-detection) and immunoassays. These experiments confirmed the high production of 12-HETE and the low formation of prostaglandins. Our results suggest that the biological role of AA-metabolites, other than prostaglandins, have as yet been underestimated.

Benefits and risks of hormone replacement therapy (HRT).

In western countries more than 30% of the female population are postmenopausal. Approximately 30% of postmenopausal women suffer from clinical symptoms of the climacteric such as vasomotor symptoms, associated with hot flushes, night sweat, insomnia and depressive mood. Sufficient hormonal replacement therapy (HRT) will abolish specific menopausal symptoms in over 90% of patients, unspecific symptoms such as headache respond to placebo and HRT equally well. The question of cancer risk related to HRT will be addressed in this review. In combination with progestins, estrogens are obviously protective regarding ovarian and endometrial cancer. The association between HRT and breast cancer risk is presently unclear. Epidemiological data available so far do not provide compelling evidence as to a cause and effect relationship between HRT and breast cancer risk. There seems to be an overall trend towards a slightly increased risk with increasing duration of HRT use. Guidelines for HRT use in women with a history of endometrial and breast cancer are provided in this article.

Serum prolactin levels in patients with fibrocystic breast disease.

In 193 patients suffering from fibrocystic breast disease, basal serum prolactin concentrations were determined and compared to serum prolactin levels in 193 healthy women. In 45 additional patients and 23 healthy control subjects, a thyrotropin-releasing hormone (TRH) stimulation test was performed. The response to TRH in seven healthy female volunteers and in one patient with fibrocystic breast disease, was correlated with the mean serum prolactin levels over 24 hours. Serum prolactin levels were above normal in 45.6% of the patients and in 21.2% of the control subjects. Mean values of the two groups were significantly different (P less than .001). The maximum prolactin response to TRH stimulation was significantly higher in the study patients than in the control subjects (P less than .001). The TRH-stimulated prolactin response correlated positively with the mean 24-hour level (P less than .01, r = 0.8705). These results indicate that a high proportion of patients with fibrocystic breast disease exhibit increased daily prolactin secretion.

Inhibition of lactation by a long-acting bromocriptine.

A long-acting form of bromocriptine, a prolactin (PRL) secretion inhibitor, was administered to 122 postpartum women in single intramuscular injections of 20 (N = 24), 30 (N = 22), 40 (N = 46), and 50 mg (N = 30). In 91 women the substance was administered immediately after delivery to prevent galactopoiesis and in the remaining 31 women to inhibit established lactation. Effectiveness was estimated by the absence of breast engorgement and of milk secretion. Successful prevention or inhibition of lactation was highest among women receiving 50 mg bromocriptine (97%), and comparison between dosages revealed a close linear dose-response relationship (r = 0.98). Persistent and significant (P less than .001) PRL inhibition could be recorded for up to 22 days in successfully treated puerperas in comparison with 12 normally breast-feeding women who served as control subjects. No significant side effects or local reactions were recorded. Eleven of 46 postpartum women receiving 20 or 30 mg bromocriptine experienced onset of milk secretion or lactation rebound, and responded to oral administration of the drug. The presence of milk was associated with plasma PRL concentrations persistently above 25 ng/mL in all of them, whereas nine women in the same dosage range in whom lactation suppression was effective exhibited values below this limit. Dose-response data allow the establishment of a putative PRL threshold for induction of milk secretion of about 25 ng/mL. Maintenance of plasma PRL values below this limit prevents lactogenesis and inhibits lactopoiesis.

The effect of clomiphene on the synthesis of prostaglandins (PGF2 alpha, PGE2, PGI2) in human endometrial cells in vitro with and without addition of estradiol-17 beta or progesterone.

The production of prostaglandin F2 alpha in monolayer stromal cell cultures of proliferative human endometrium is enhanced by 10(-7) mol/l estradiol-17 beta or 10(-4) mol/l progesterone. Progesterone in high concentration (10(-4) mol/l) also enhanced the synthesis of prostaglandin E2. Clomiphene citrate reduced this increased prostaglandin production dose dependently. The synthesis of prostaglandin I2 was not influenced either by sex steroids or by clomiphene citrate.

Eicosanoid production by frozen tissue in vitro is markedly changed.

The influence of storing deep frozen human tissue specimens on their eicosanoid production in tissue culture was evaluated. Pieces of placenta and fetal membranes (n = 6) were divided and part processed immediately after obtaining the tissues, part after being kept at -20 degrees C for some days. Eicosanoid production was studied in tissue culture with incubation in oxygenated Hank's balanced salt solution (HBSS) at 37 degrees C for 1 h. Prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane A2 (TXA2) and leukotriene B4 (LTB4) production were significantly different in the tissues frozen prior to the incubation. This should be considered when interpreting eicosanoid synthesis in tissue cultures for their significance in vivo.

Management of multiple conceptions after gonadotropin-releasing hormone analog/human menopausal gonadotropin/human chorionic gonadotropin therapy.

The treatment course of a 31-year-old infertility patient due to PCO disease is presented. Because the patient failed to conceive after various treatment cycles with CC, she was subjected to a combined GnRHa/hMG/hCG therapy. After plasma E2 levels had reached 2400 pg/ml, three leading follicles, with diameters of 20 to 24 mm, were detected. Induction of ovulation was achieved by 10,000 IU hCG. The patient conceived and developed ovarian hyperstimulation. At 8 weeks of gestation, seven cystic structures were detected within the uterine cavity, five containing single embryos, and two with twin embryos. All nine embryos were vital, as evidenced by their heart beats. Embryo reduction was achieved by transabdominal puncture on three occasions. The three surviving fetuses were carried to the 34th week of gestation. After delivery by cesarean section, three healthy babies developed normally. This communication illustrates the complications that can be associated with ovulation induction in PCO disease: ovarian hyperstimulation, polyovulation, multiple conceptions, and their clinical management.

Ultrasonographic and hormonal studies in physiologic and insufficient menstrual cycles.

Intraovarian morphologic alterations in 6 physiologic menstrual cycles were studied by sonography and compared with 13 inadequate cycles with a short or missing luteal phase. In addition, basal body temperature, 17 beta-estradiol, luteinizing hormone, progesterone, testosterone, and dehydroepiandrosterone sulfate levels in serum were measured. The maximal follicle was significantly smaller in insufficient cycles (17.7 +/- 2.9 mm) than in physiologic cycles (23.0 +/- 2.3 mm). Corpus luteum structure was visualized in five of the six physiologic cycles but was not detected in insufficient cycles. Persistent polyfollicular reaction (greater than 3 follicles per ovary) without a dominant follicle larger than 10 mm was detected in the ovaries of three patients with clinical and hormonal signs of polycystic ovarian disease. Ultrasonography can be regarded as a useful additional tool in the evaluation and management of insufficient ovarian cycles.

Tamoxifen for breast cancer prevention.

Tamoxifen is of proven efficacy in the treatment of breast cancer. New data indicate that it might be able to reduce the occurrence of receptor positive breast cancer when taken as a preventative. However trade-offs for this reduction are an increased incidence of endometrial carcinomas and thromboembolic events. Therefore the use of tamoxifen as preventative ought to be restricted to clinical studies or a well defined high risk situation. Whether raloxifen is superior to tamoxifen remains to be shown.

Effects of 17beta-estradiol and progesterone on interleukin-6 production and proliferation of human umbilical vein endothelial cells.

The present investigation was performed to study the effects of steroids on interleukin-6 (IL-6) production and on proliferation of human umbilical vein endothelial cells (HUVEC). HUVEC were isolated and cultured in 24-well dishes until confluency was achieved. Afterwards cells were stimulated with either 17beta-estradiol or progesterone at concentrations of 10(-12)-10(-6) mol/l. IL-6 concentrations in cell supernatants were measured by ELISA and cell proliferation was determined by flow-cytometric assessment of S-phase-cells. 17Beta-estradiol significantly inhibited basal IL-6 secretion at doses of 10(-12)-10(-6) mol/l whereas progesterone had no measurable effects. Neither 17beta-estradiol nor progesterone affected the proliferation rate of endothelial cells. The results of our study suggest that 17beta-estradiol at non-proliferative doses regulates IL-6 secretion of endothelial cells and thereby modulates processes of vascular physiology.

A surprisingly ameliorating effect of high doses of estradiol in primary osteomyelofibrosis: a case report.

OBJECTIVES: To report a case of a postmenopausal woman with primary (idiopathic) osteomyelofibrosis who showed a considerable improvement under the effect of high doses of estradiol given for the control of severe intractable menopausal symptoms. METHODS: This study was carried out by a case report. RESULTS: Astonishingly, under the effect of high doses of estradiol, both clinical and laboratory indices of the disease were not only kept stable but also showed a noticeable improvement. Hemoglobin increased from a value of 8.4 gm/dl in 1989 to 10.7 gm/dl in 1996. Blood transfusion was no longer necessary, the patient had had no infections whatsoever and was only afraid of not being allowed to continue using these high estrogen doses, which seemed indispensable and central to her well-being. CONCLUSIONS: High doses of estrogens could possibly be given the credit for ameliorating the natural sinister course of primary osteomyelofibrosis.

Cyclic administration of an LHRH analogue and of progesterone in risk patients to oral contraceptives.

Fifty-five cycles of 9 patients with normogonadotropic ovarian function having risks against oral contraceptives (OCs) and intrauterine devices (IUDs) were treated for contraception with buserelin in a dosage of 300 to 450 micrograms per day i.n. from day 5 to day 26 of the cycles. Additionally, progesterone (P) in a dosage of 75 mg per day was given by intravaginal suppositories from day 20 to day 26 of the cycle followed by a 7-day drug-free interval. Serum levels of LH, FSH and estradiol-17 beta (E2) showed a wide variability. However, most E2 levels were in the early or middle follicular phase range. Mean serum P levels monitored during P replacement were found to be in the secretory phase range. Pattern of menstrual cycles was regular in all patients except one whose menstrual bleedings were already disturbed prior to treatment. This mode of contraception was well accepted, no side effects were observed, no pregnancy occurred. In conclusion, contraception by low-dose intranasal application of buserelin combined with transvaginal P replacement seems to be a useful approach for contraception in patients at risk for both OCs and IUDs.

Ultrasonographic and endocrinological studies of ovarian function.

Ovarian morphological alterations in 6 physiological menstrual cycles were studied by sonography and compared to 13 inadequate cycles with a short or missing luteal phase. In addition, basal body temperature (BBT) and 17-beta-estradiol (E2), luteinizing hormone (LH), progesterone (P), testosterone (T) and dehydro-epiandrosterone-sulfate (DHEA-S) levels in serum were measured. Maximal follicle were significantly smaller in insufficient cycles (17.7 +/- 2.9 mm) than in physiological cycles (23 +/- 2.3 mm). Corpus luteum (CL) structure was visualized in 5 of the 6 physiological cycles but was not detected in insufficient cycles. Persistent poly-follicular reaction (greater than 3 follicles/ovary) without a dominant follicle larger than 10 mm was detected in the ovaries of 3 patients with clinical and hormonal signs of polycystic ovarian disease (PCOD).

Intrauterine insemination as first line treatment of unexplained and male factor infertility.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of intrauterine inseminations (IUI) as first line treatment of unexplained or male factor infertility. STUDY DESIGN: Retrospective analysis of 414 consecutive IUI treatment cycles in 124 couples with unexplained or male factor infertility. RESULTS: In 414 cycles 25 pregnancies were achieved (6% pregnancy rate per cycle and 20% per couple respectively). 24 healthy babies were born (20 singletons and 2 twins) as a result of our treatment. There was no significant difference in ejaculate parameters of patients who achieved a pregnancy compared with patients who failed to do so. Lowest values at which pregnancies were achieved were 0.8 mill sperm/ml and 11% progressive motility after sperm processing and 8% normal morphology before semen preparation. CONCLUSION: There is still a place for IUI as first line treatment for couples with unexplained or male factor infertility. Even in patients with moderate impairment of semen quality pregnancy rates up to 20% per couple can be achieved.

Doppler measurement of breast vascularity in women under pharmacologic treatment of benign breast disease.

Breast vascularization was measured with an 8-MHz continuous wave Doppler pencil probe. Flow values were low in asymptomatic women and high in patients with severe pain or dysplastic changes. Mild treatment with a plant extract produced only a small decrease in breast vascularization. Treatment with norethisterone acetate showed a dose-dependent decrease in blood flow. A good response was seen with a dosage of 5 mg/d, and a dramatic decrease was seen when 10 mg/d was taken. These results showed a good correlation with the patients' symptoms.