Effects of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German, 12-month, prospective, randomised substudy.

BACKGROUND: Adjuvant treatment of hormone receptor-positive breast cancer in postmenopausal women with aromatase inhibitors may be associated with increased bone loss. PATIENTS AND METHODS: Two hundred patients were randomised to receive exemestane or tamoxifen as adjuvant treatment of hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry at baseline and after 6 and 12 months treatment. RESULTS: One hundred and sixty-one patients were assessable. Tamoxifen treatment resulted in a 0.5% increase from baseline in BMD at the spine, which was maintained at 12 months. Exemestane-treated patients experienced a 2.6% decrease from baseline in BMD at the spine at 6 months and a further 0.2% decrease at 12 months. There were significant differences in the changes in BMD between tamoxifen and exemestane at 6 and 12 months (P = 0.0026 and P = 0.0008, respectively). The mean changes in BMD from baseline at the total hip were also significantly different between exemestane and tamoxifen at 6 and 12 months (P = 0.0009 and P = 0.04, respectively). There was no difference between tamoxifen and exemestane in mean changes in BMD from baseline at the femoral neck. CONCLUSIONS: Exemestane treatment resulted in an increase in bone loss at 6 months; bone loss stabilised after 6- to 12-month treatment.

Gemcitabine and carboplatin in intensively pretreated patients with metastatic breast cancer.

BACKGROUND: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. PATIENTS AND METHODS: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. RESULTS: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombocytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. CONCLUSION: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2).

[Investigation of a fetal heart-rate pattern that shows a reduced oscillation amplitude]. / Silentes CTG--Hypoxie oder Intoxikation?

A fetal heart-rate pattern that has a reduced oscillation amplitude may indicate a physiological fetal dormant period but could also be an indication of fetal hypoxemia. In some rare cases such a fetal heart rate-pattern can be an indicator of cerebral or cardial fetal malformation or of an intoxication caused by sedative drugs. Our patient is a 32-year-old Para III in the phase of 29 weeks and 3 days gestation. Upon admission to the clinic, the fetal heart-rate pattern showed a reduced oscillation amplitude, and there were no signs of fetal movement. The ultrasound examination gave us no reason to suspect fetal malformation, and the results of the Doppler ultrasonography were also normal. However, although the patient had denied taking any medication at all, the results of an toxicological blood test confirmed our suspicion of benzodiazepine intoxication. Throughout the night the fetal heart-rate pattern was continuously measured, and in the early hours of the morning, after breaking down of the oxazepam medication, a normalization of the fetal heart-rate pattern was observed. This case report definitively demonstrates that Doppler ultrasonography is a valuable method for assessing any uncertainty regarding a fetal heart-rate pattern.

[Family planning and pregnancy with thalassemia major]. / Kinderwunsch und Schwangerschaft bei Thalassaemia major.

We present the case of a young Italian woman with thalassemia major and describe a series of complications such as infertility, fetal growth restriction, difficult intubation, and cardiac decompensation that occurred in the course of family planning, pregnancy, and the puerperal period. By review of the literature and based on own experiences, we show how the preconceptional consultation and the care during a pregnancy, especially the individualized planning of delivery, can be optimized. The intensive and interdisciplinary care by obstetricians and internists is very important.

Is prenatal HLA typing of uncultured amniocytes before the collection of related allogenic cord blood helpful?

The collection of related allogenic cord blood is gaining increasing importance in families with one child affected by haematopoietic disease. Within a family, there is only a 25% chance of a full HLA match between siblings. 50% of all collected cord blood samples cannot be used because of poor quality. Because of this, the determination of HLA type is useful for planning the collection of related allogenic cord blood transplants. We studied whether HLA typing is possible during late pregnancy if amniocentesis has not been performed during the first trimester. HLA -A, -B and -DRB loci were detected in amniotic fluid, as well as in corresponding cord blood and maternal blood using PCR-SSP. For the first time, HLA typing was performed from uncultured amniocytes. Unambiguous results were obtained from all samples. Fetal HLA-genotype in amniotic fluid was confirmed by typing results from corresponding cord blood. HLA typing of uncultured amniocytes during late pregnancy is a reliable and fast method. For the first time, prenatal HLA typing by amniocentesis after week 38 of gestation is possible in less than 8 h and without fetal risk.

Adjuvant endocrine treatment with medroxyprogesterone acetate or tamoxifen in stage I and II endometrial cancer--a multicentre, open, controlled, prospectively randomised trial.

Endometrial cancer is a hormone-dependent disease and therefore an adjuvant hormonal therapy might improve the outcome in the early stages of the disease. Between 1983 and 1989, we conducted a randomised trial of 388 patients who received either medroxyprogesterone acetate (MPA) (n=133) or tamoxifen (n=121) orally for 2 years, or were observed only (n=134) after surgical therapy. The aim was to evaluate whether an adjuvant treatment can improve disease-free and overall survival rates. After a median follow-up period of 56 months (range 3-199 months), we observed no differences in the disease-free and overall survival rates for the tamoxifen group compared with the control or the MPA group. Side-effects were more frequent and severe in the MPA-group than in the tamoxifen group. In patients with early endometrial cancer, adjuvant endocrine treatment did not significantly improve the outcome. However, tamoxifen did have some beneficial effects on coexisting morbidity.

Distinct expression of endothelin receptor subtypes A and B in luteinized human granulosa cells.

Endothelins (ET) are potent vasoconstrictive peptides originally isolated from vascular endothelial cells. Their biological effects are mediated through two different receptors, the endothelin-1 (ET-1)-selective endothelin receptor subtype ETA and the non-selective receptor subtype ETB. ET-1 protein has been found in human ovarian follicular fluid and ET-1 mRNA expression has been demonstrated in ovarian tissue. These findings indicate that the endothelin-system participates in the modulation of ovarian function, probably acting in an autocrine/paracrine manner. In the current study we used freshly aspirated, luteinized human granulosa cells (hGC) representing an in vitro model of the early corpus luteum. By means of RT-PCR and immunocytochemistry we investigated whether luteinized human granulosa cells express ETA and ETB receptors. Specific amplification products of ETA transcripts were detected in all samples investigated. In contrast, only after using a three-fold amount of ETB reverse transcripts we were able to demonstrate specific, but weak amplification products. In addition, immunocytochemical staining for ETA but not for ETB was found in granulosa cell preparations. The present study provides clear evidence that human granulosa cells predominantly express ETA receptor subtype mRNA and protein hinting to its possible role in follicle maturation and corpus luteum formation.

[Clinical use of the birth simulation program "Anapelvis 2.0" for prediction of feto-maternal disproportion]. / Klinische Anwendung des Geburtssimulationprogrammes "Anapelvis 2.0" zur Vorhersage eines Missverhältnisses.

INTRODUCTION: The birth simulation program Anapelvis 2.0 was developed to predict feto-maternal disproportion in order to avoid the unfavourable accompanying phenomena of a secondary caesarean section. - PATIENTS AND METHODS: The system was used in 71 patients of the Women's Hospital of the University of Mannheim during the period 01. 01. 1999 to 28. 02. 2001. These women were prone to feto-maternal disproportion according to their obstetrical history or to clinical findings. They were informed about the possibility of a computed birth simulation which was carried out in accordance with a standardized scheme. - RESULTS: 87.3 % of all patients followed the suggestion of the birth simulation in their decision concerning birth planning. In 76.1 % of the evaluated cases the delivery process was correctly predicted. - DISCUSSION: Even though the computed birth simulation has not yet been finally evaluated, it represents a source of important information for birth planning which numerous patients appreciate. It is essential for the acceptance and validity of the procedure to inform the patient comprehensively and to generate exact pelvimetric and fetometric data.

Modulation of tumor-induced lethality after pneumoperitoneum in a mouse model.

BACKGROUND: To the authors' knowledge, a generally accepted approach to prevent increased intraabdominal tumor implantation after laparoscopic cancer surgery does not exist. METHODS: One week after establishing an ovarian carcinoma cell line in black mice intraabdominally (n = 156), a carbon dioxide pneumoperitoneum (Group 1: n = 78) was administered. The effect of this procedure on tumor-induced lethality and the therapeutic effect of mitoxantrone and taurolidin mixed with heparin and sodium chloride was investigated. The different drugs were added immediately after the release of the pneumoperitoneum and after 48 hours. The 78 control animals received the drugs at the same time without preexisting pneumoperitoneum. Survival time was registered. RESULTS: The survival time was reduced significantly in all pneumoperitoneum groups compared with the corresponding control group without pneumoperitoneum. The effect of mitoxantrone on survival time (mean, 62.08 days) was diminished significantly by the application of a pneumoperitoneum (mean, 34.27 days). Taurolidine/heparin appeared to have a positive effect on survival time only in the case of a previous pneumoperitoneum (mean of 21.12 days vs. mean of 16.04 days in the pneumoperitoneum control group; P < 0.001). CONCLUSIONS: The induction of a pneumoperitoneum appears to decrease survival time by increasing tumor cell growth and decreases the efficacy of intraperitoneal chemotherapy. The effects of pneumoperitoneum appear to be reduced by the use of heparin/taurolidine, which theoretically blocks extracellular matrix binding domains and inhibits the production of interleukin-1.

[Prenatal care of a HIV-1-positive pregnancy and birth]. / Die Betreuung der HIV-1-positiven Schwangerschaft und Geburt.

Mother-to-child (vertical) transmission of the human immunodeficiency virus type-1 (HIV-1) is now the main route of infection in HIV-positive children. Without any medical measures and avoiding breastfeeding the rate of vertical HIV-1-transmission is 15-20% in Europe. The rate of vertical HIV-transmission in the German centers is today approximately 2%. This low risk is the result of interdisciplinary prenatal care, antiretroviral therapy according to the individual risk profile as well as cesarean section before onset of labor, and antiretroviral treatment of neonates in the centers.

Urokinase and plasminogen activator-inhibitor (PAI-1) status in primary ovarian carcinomas and ovarian metastases compared to benign ovarian tumors as a function of histopathological parameters.

Ninety-eight patients with histologically confirmed ovarian tumors (77 primary ovarian carcinomas of stages T1 to T3 according to the postoperative histopathological classification pTNM classification, 14 ovarian metastases of various origins and seven benign ovarian tumors) were investigated with regard to the concentration of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) in membrane extracts of tumors. The results were correlated with the clinical course and with histopathological findings. With more advanced stage of primary ovarian carcinomas, there was a highly significant rise in the membrane concentrations of both uPA and PAI-1. However, increasing dedifferentiation of the tumors correlated only with uPA, but not with PAI-1. There was no correlation between the number of steroid receptors for estradiol and progesterone and the content of uPA or PAI-1 in the primary ovarian carcinomas. In the 14 ovarian metastases of different origins incluced in the study, the contents of uPA and PAI-1 were comparable to those of primary ovarian carcinomas. Compared with the malignant ovarian tumors, the median uPA and PAI-1 concentrations in the membrane fraction were 2.5-6 fold lower (highly significant) in the group of seven benign tumors. A cut-off value of 4.8ng/mg pellet protein for a prognostically favorable (< 4.8) or unfavorable course (> 4.8) could be determined for uPA (p = 0.0392) but not for PAI-1 on the basis of the Kaplan and Meier survival curves in the malignant primary ovarian carcinomas.

[Effect of CO2 pneumoperitoneum on intraperitoneal tumor growth in the animal model]. / Der Einfluss eines CO2-Pneumoperitoneums auf das intraperitoneale Tumorwachstum im Tiermodell.

Clinical observations during recent years describe the increased occurrence of rapid intraperitoneal metastases and an impairment of prognosis if a malignant tumour was operated laparoscopically. It is not known whether the observed induction of intraabdominal metastases after laparoscopic surgery in the result of an inadequate surgical procedure with spillage of tumour cells into the abdominal cavity or whether pneumoperitoneum-induced changes of the peritoneal milieu promote tumour growth. An animal model was established to examine the effect of a CO2-pneumoperitoneum on the intraperitoneal growth of tumour cells. Six week old nude mice were divided into 4 groups of 15 animals each. A CO2-pneumoperitoneum was induced by a micro-hysteroflator with an intraperitoneal pressure of 6 mmHg for 90 minutes in groups 2 and 4. Two different tumour cell lines, suspended in 2 ml of Ringer's solution for homogeneous spread of the cells, were injected i.p.. The control groups 1 and 3 received the tumour cells without pneumoperitoneum induction of a CO2-pneumoperitoneum resulted in an increasing seeding rate of tumour cells and provoked a significant increase in the number and size of intraabdominal metastases. Laparoscopic surgery of malignancies is therefore contraindicated.

[Indications for 3 D laparoscopy in gynecology]. / Zur Indikation der 3 D-Laparoskopie in der Gynäkologie.

In a prospective randomised study we investigated the possibilities of a 3 D-video system in comparison to a 2 D-video system in operative laparoscopy. On 76 patients the following operations were performed: enucleation of fibroids, extirpation of ovarian cysts, fimbrioplasty, tubo-tubal anastomosis and Burch's procedure via preperitoneal access. For microsurgical procedures of the adnexae the new 3 D-technology shows advantages in compared to the standard 2 D-laparoscopy. In these operations the operating area is naturally limited, and hence the disadvantages of the 3 D-technology like limited depth of focus are not important. The 3 D-system allows a very good visualisation even of small structures and safe and exact handling. For surgery of the uterus or larger tumours of the adnexae, the new technology is unsuited.

[Quality of life of over 60-year-old patients with breast and uterine carcinoma, 5 years after primary operation]. / Lebensqualität von über 60jährigen Patientinnen mit Mamma- bzw. Korpuskarzinom, 5 Jahre nach Primäroperation.

In the 5-year follow-up period, we studied the quality of life of 145 patients who were at least 60 years old at the time of primary operation. Of the patients, 70 women had breast cancer and 75 endometrium cancer. We used the questionnaire "short form health survey: medical outcomes study". The areas which were analyzed were stress due to therapy, body image/femininity and social contacts. The Karnofsky-Index was determined by the physician. In both groups, most stress was felt due to the operation and at the first knowledge of the diagnosis. In the area of emotional stress 1/3 of the patients of both groups declared continuous stress due to feelings of fear, helplessness and passivity. In the area of body image/femininity half the patients with breast cancer and 2/3 with endometrial cancer felt stress. In the area of social contact 2/3 of the patients felt uncertainty in contact with others and this led to social retreat in 1/3 of the women. The Karnofsky-Index of all patients was between 50-100%. Our study supports the view that older patients with cancer should also be offered psychosocial counseling.

Pathophysiologic features of a pneumoperitoneum at laparoscopy: a swine model.

OBJECTIVE: The aim of this study was to examine local and systemic reactions of the body to a pneumoperitoneum to elucidate potential dangers and risks of laparoscopic procedures. STUDY DESIGN: Laparoscopy was performed on 25 pigs. The pigs were divided into five groups by level of intraabdominal pressure (14 and 18 mm Hg) and gas used (carbon dioxide and air). The effects of the pneumoperitoneum on cardiopulmonary condition and the peritoneal milieu were observed. These effects should be the result of various changes as the mechanical, ventilatory, cellular, hormonal, and immunologic levels. RESULTS: In this animal study marked changes in the peritoneal milieu were observed, and we demonstrated that these changes were dependent on the gas used, intraabdominal pressure, and duration of application. Locally these changes are manifest in the development of severe peritoneal acidosis, hypercapnia, and the release of various mediators. Systemic changes, in particular cardiopulmonary changes, also depend on the intraabdominal pressure and the gas used. CONCLUSION: During conventional pneumoperitoneum the peritoneum might change to a large extent so that the development of new risks are possibly encouraged. A reduction in intraabdominal pressure with the use of carbon dioxide as the insufflation gas should result in normal acid-base balance.

[Uterine rupture during induced abortion with prostaglandins in the second trimester]. / Uterusruptur bei Abortinduktion mit Prostaglandinen im zweiten Trimenon.

Based on our own experiences and on the literature of the past 14 years the variety of the presenting symptoms in patients suffering from ruptured uterus during the second trimenon are discussed. focussing especially on the first symptoms of a so-called "silent" uterus rupture. A 41-year old second gravida, first para--the healthy full-term child was delivered by Caesarean section--suffered a "silent" uterus rupture after termination of pregnancy at 20th/21st weeks' gestation. As more than 50 per cent of patients with "silent" uterus rupture are diagnosed with considerable delay, early and repeated ultrasound examinations should be performed in all patients with unexplained symptoms or if despite abortion induction for several days no progression of birth occurs. In an artificially induced abortion, prostaglandins should be topically applied to enhance cervix ripening, preferably as a biphasic treatment (first for cervix ripening, later induction of contractions). It is not yet clear whether a single or total dose reduction of prostaglandins used in labour induction in the second trimenon may help to prevent uterus rupture in patients at risk. Predisposing risk factors must be taken into account before applying prostaglandins. Uterus rupture should always be considered as differential diagnosis if problems occur in patients after induced abortion in the second trimenon.

Measuring the thickness--is that all we have to do for sonographic assessment of endometrium in postmenopausal women?

For sonographic assessment of the endometrium in postmenopausal women, measurement of the maximum thickness is used in many cases as the sole criterion. The cut-off values stated in the literature, however, vary considerably. This prospective study examined 200 female patients in order to ascertain the value of echomorphology in addition to endometrial biometry. Up to an overall endometrial thickness of 3 mm, we observed only histologies without any pathological findings, whereas from an endometrial thickness of 10 mm upwards, only polyps, hyperplasias and carcinomas were found. In more than a third of our patients, the endometrial thickness was between 3 and 10 mm where the structure of the endometrium could reflect the possible histological finding: homogeneity, low echo and a sonographically depictable central echo between symmetrical endometrial leaves were an indication for absence of pathological findings, whereas heterogeneity and high echogenicity were pointers for pathological changes. In contrast to the sole measurement of endometrial thickness in the postmenopause, the combined metric and morphological parameters improve not only the predictability of pathological findings but, above all, the selectivity of the vaginosonographic assessment of the endometrium in postmenopausal women.