[Emergencies in gynecology--what must I not forget?]. / Notfälle in der Gynäkologie--was darf ich nicht vergessen?

Emergency consultations happen frequently in gynaecology and may be due to abdominal pain, itching, utero-vaginal bleeding, rape, emergency contraception, insertion of foreign bodies, prolapse and urinary tract infection. Considering pregnancy in patients with child bearing potential is essential. Vaginal bleeding may be due to atrophy, infection, carcinoma or pregnancy. In the latter it is crucial to differentiate between ectopic, pathologic or physiologic pregnancy. In postmenopausal women further investigations by the gynaecologist are mandatory to exclude malignancy. Patients who have been raped need psychological, forensic and gynaecological support. Sexually transmitted disease including HIV must be considered and prophylactic drugs should be administered. If unprotected intercourse has occurred the "morning after pill" can be considered within 72 hours after intercourse or an IUD up to five days. Prolapse occurs rarely as an acute problem but may induce urinary retention. Urinary tract infection is a common complaint and should be treated with antibiotics.

Umbilical endometriosis.

We report two women who presented with a recurrent, mildly painful, bluish nodule in the umbilicus. Both patients complained of local tenderness and occasional bleeding that increased during menstruation. Neither patient had had previous pelvic surgery. Excision of the lesions revealed a primary umbilical endometriosis; in one case, a simultaneous laparoscopy showed a pelvic endometriosis. We review the current literature and discuss the possible etiopathogenesis and when a laparoscopy is indicated to diagnose a concomitant pelvic endometriosis. Umbilical endometriosis is a very rare disease but should be considered in the differential diagnosis of umbilical lesions.

Activation of the receptor protein tyrosine kinase EphB4 in endometrial hyperplasia and endometrial carcinoma.

BACKGROUND: Members of the Eph family of tyrosine kinases have been implicated in embryonic pattern formation and vascular development; however, little is known about their role in the adult organism. We have observed estrogen-dependent EphB4 expression in the normal breast suggesting its implication in the hormone-controlled homeostasis of this organ. Since the endometrium is a similarly hormone dependent organ and endometrial carcinoma is thought to result from estrogenic stimulation, we have investigated EphB4 expression in normal human endometrium and during its carcinogenesis. PATIENTS AND METHODS: EphB4 expression was analyzed immunohistochemically in 26 normal endometrium specimens, 15 hyperplasias and 102 endometrioid adenocarcinomas and correlated with clinical and prognostic tumor characteristics. RESULTS: In normal endometrial tissue no EphB4 protein was detected. Strikingly, we observed a drastic increase (P <0.0001) in the number of EphB4 protein-expressing glandular epithelial cells in the majority of hyperplasias and carcinomas. Moreover, we found a statistically highly significant positive correlation between EphB4 expression and post-menopausal stage of the patient (P = 0.007). CONCLUSIONS: These findings indicate that in the endometrium, EphB4 is an early indicator of malignant development and, thus, EphB4 may represent a potent tool for diagnosis and therapeutic intervention.

EGFR dependent expression of STAT3 (but not STAT1) in breast cancer.

STAT proteins constitute a family of transcription factors whose activation by cytokine and non-cytokine receptors leads to tyrosine phosphorylation, dimerization and translocation from the cytoplasm to the nucleus. In the nucleus they activate the transcription of specific genes by binding to consensus DNA elements. STATs 1 and 3 can be activated by both cytokine and non-cytokine receptors, and bind as homodimers or heterodimers to viral simian sarcoma virus (sis)-inducible elements such as that found in the c-fos promoter. Activation of c-Src and EGF receptor tyrosine kinases is associated with progression of breast cancer. Both these events lead to activation of STAT proteins, Src kinases activate STAT3 dependent transcription in mammary epithelial cells and EGF receptor activation can lead to activation of STATs 1 and 3. STAT3 activation has been demonstrated to have a role in oncogenesis and increasingly, activated STAT proteins are found to be activated in human cancer. In this study we describe detailed immunohistochemical analysis of nuclear and cytoplasmic STATs 1 and 3 expression in primary breast carcinomas and correlate this with EGFR, HER2, p53, ER, PR, p21/waf1, Bcl-XL and Ki-67 expression. We also compared expression between normal and tumor tissue. We report here a highly significant correlation between nuclear STAT3 expression and breast cancers compared to normal tissue. We also report a very strong correlation between nuclear STAT3 and EGFR expression in breast cancers. These data clearly demonstrate a strong association between STAT3 activation and breast tumorigenesis and strengthen the assertion that STAT3 activation may play an important role in the tumorigenic conversion of breast tissue mediated by tyrosine kinase signaling pathways.

Effects of 5-aminolaevulinic acid on human ovarian cancer cells and human vascular endothelial cells in vitro.

Results are reported on the cellular effects and the sensitivity of cultured tumor epithelial cells (TEC) derived from human ovarian cystadenocarcinoma and human umbilical vein-derived endothelial cells (HUVEC) to exogenous 5-aminolaevulinic acid (ALA) and ALA-induced photodynamic therapy (PDT). Cellular alterations and PDT efficiency were evaluated using colorimetric thiazolyl blue (MTT) assay, trypan blue exclusion assay, electron microscopy, and gel electrophoresis. ALA-induced protoporphyrin IX (PpIX) accumulation in TEC was associated with a concentration and time-dependent significant decrease in mitochondrial activity, increase in cell membrane permeability, and dark toxicity. Maximum PpIX loaded TEC demonstrated a high sensitivity to PDT. Neither cellular alterations nor PDT effects were observed in HUVEC under identical experimental conditions. These results indicate a potential clinical value for the use of ALA-mediated PDT to treat minimal residual disease in mucinous ovarian carcinoma. In addition, the ALA-induced PpIX cytotoxicity may be exported to a new chemotherapeutic regimen via a conventionally viewed photochemotherapeutic agent.

Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast.

BACKGROUND: Axl, a member of a family of receptor tyrosine kinases characterized by an extracellular domain resembling cell adhesion molecules and an intracellular conserved tyrosine kinase domain has been reported to induce cell proliferation and transformation. In mice, axl is expressed in the normal mammary gland and over-expressed in aggressive mammary tumors. PATIENTS AND METHODS: We have investigated the expression of axl immunohistochemically in 23 normal human breast samples and in 111 consecutive breast carcinomas. Expression of axl was correlated with tumour characteristics (lymph node involvement, stage, grade) and immunohistochemical expression of ER, PR, Ki-67 and c-erbB-2. RESULTS: In normal tissue, axl localizes to the membrane of breast epithelial cells. Axl protein shows membrane associated staining in high correlation (P = 0.004) with the expression of the estrogen receptor (ER). Axl expression was found in a subset of breast carcinomas and was also correlated with high significance (P < 0.0001) with the presence of ER. CONCLUSION: Our results suggest that axl may serve as a mediator of estrogen stimulation preventing the completion of the breast epithelial life cycle and that estrogen induced axl expression may give a survival signal to cancerous cells, preventing them from dying through apoptosis.

Tubal sterilization by means of endoluminal coagulation: an in vivo study in rabbits.

This study was conducted to investigate the effectiveness and safety of endoluminal tubal coagulation in obliterating the tubal lumen in rabbits. Forty female rabbits were subjected to laparotomy and hysterotomy. Endoluminal tubal coagulation was induced over a length of 3 cm in the proximal, extramural fallopian tube by using a heated stainless steel cannula or a cylindrical diffusing tip emitting argon laser radiation for one to 5 minutes. Tubal patency was evaluated by observing patterns of injected methylene blue and/or breeding success rates. Postoperative recovery was uneventful in all animals. A negative methylene blue test indicated occlusion in 51 of 52 tubes (tubal occlusion rate 98.1%), and a contraception rate of 100% in all 17 uteri in which the tube had been treated. The described endoluminal tubal coagulation method proved suitable for safe and effective sterilization in rabbits and has potential as a new transcervical tubal sterilization method for humans.

Clear cell adenocarcinoma of the cervix associated with a rare genitourinary malformation.

BACKGROUND: Cervical adenocarcinoma and genitourinary malformations are relatively common disorders, yet their coexistence is rare. CASE: A 49-year-old woman developed clear cell adenocarcinoma in the atretic hemicervix of a communicating uterus type 7 and had ipsilateral renal agenesis. Compared with the unaffected right hemicervix, only the tumor-involved glands of the atretic left hemicervix contained ciliated tuboendometrial cells. Four and a half years after radical hysterectomy and pelvic radiation, she showed no evidence of recurrence. CONCLUSION: In contrast to current opinion, communicating uteri type 7 are associated with ipsilateral renal agenesis. Our histologic findings support the hypothesis that tuboendometrial cells are the cells of origin for cervical clear-cell adenocarcinoma.

Ovarian cancer. an institutional review of patterns of care, health insurance and prognosis.

The purpose of this study was to investigate the prognostic importance of the health insurance status in 145 consecutive patients with ovarian cancer diagnosed between 1984 and 1996. All patients had basic (Type III) insurance to cover outpatient treatment and hospital expenses for a per diem flat fee; some patients had one of two types of supplemental private insurance (Type I and Type II) to cover the treatment by physicians of their choice and fee-for-service hospital treatment. The prognostic impact of health insurance was evaluated by multivariate statistical methods. The median follow-up was 81.9 months (range: 21-181); the 5-year probability of survival was 72% (standard error of the mean (SEM) 9.8%) for stage I, 53% (SEM 16.2%) for stage II, 17% (SEM 5. 9%) for stage III and 11% (SEM 5.5%) for stage IV cancer. Age, stage, histological grade and debulking surgery were independent predictors of survival in multivariate proportional hazards regression analysis. Patients with private insurance were younger and received more chemotherapy than patients with basic insurance. In multivariate analysis, insurance was an independent predictor of survival: patients with Type II insurance had a hazard ratio of 2.31 (95% confidence interval (CI): 1.05-5.04), and patients with Type III insurance had a hazard ratio of 3.30 (95% CI 1.52-7.17) compared with the reference group of Type I insured patients. Health insurance status was an independent predictor of survival in ovarian cancer. Research is needed to devise strategies to improve the medical care of patients with basic insurance.

[Guideline for the diagnosis of postmenopausal bleeding. PMPB Working Group of the SGGG]. / Leitlinie zur Abklärung von postmenopausalen Blutungen. Arbeitsgruppe PMPB der SGGG.

2.1. History and clinical-gynecological investigation including a Pap smear are the first step in the clarification. The history should make sure if there is in fact bleeding from the genital and not from the urological or the intestinal region. Drug intake should be recorded, and risk factors for the development of endometrial carcinoma should be considered. This will not affect further investigation. The clinical-gynecological investigation should prove the source of postmenopausal bleeding according to the anatomical site--uterine, infra-, or suprauterine. The causes of infrauterine bleeding may easily be diagnosed by means of inspection of the external genitalia and further by using a speculum. The causes of uterine bleeding are of major importance. Cytology and colposcopy, supported by bimanual investigation, exclude cervical carcinoma as a cause of bleeding. Atypical endometrial cells on the cytological smear arouse suspicion of endometrial carcinoma. 2.2. Transvaginal sonography (TVS) is the next step if the above-mentioned investigations are negative. Both adnexa should always be investigated and the findings sonographically documented, so that solid cystic masses in the adnexal area can be better identified as suprauterine causes of postmenopausal bleeding. Then the uterus should be investigated. Further procedures are decided from the results of measurement of the longitudinal section of the endometrium at the level of maximum endometrial thickness. If the endometrial thickness is _<4 mm, an observant attitude can be assumed. After 3 months the patient should be controlled against using TVS. If bleeding recurs or the endometrial thickness is >4 mm on TVS, the procedure given in subparagraph 2.3 should be followed. In case the endometrial thickness is >4mm or not measurable, a histomorphological investigation according to subparagraph 2.3 should be performed. In such cases, saline infusion sonohysterography(SIS) is useful as a simple method to supplement TVS. It can aid in the decision making as to which further, more invasive measures should be taken (endometrial biopsy/hysteroscopic resection). Computerized tomography or magnetic resonance imaging are, as a rule, not indicated in patients with postmenopausal bleeding. 2.3. A definite diagnosis is possible only on the basis of a histological investigation. If TVS or SS show evidence of a polypoid state, removal under hysteroscopic control is the diagnostic method of choice. In cases of symmetrical or asymmetrical thickening of the endometrium on SIS, a less invasive biopsy may be sufficient. If the biopsy specimen does not yield representative diagnostic material, one should proceed as described above. A fractionated curettage should as a rule not be performed solely, but in combination with hysteroscopy.

Hormone-dependent nuclear localization of the tyrosine kinase iyk in the normal human breast epithelium and loss of expression during carcinogenesis.

iyk, a member of the frk family of non-receptor tyrosine kinases, was originally isolated from normal mouse mammary glands and is characterized by a nuclear localizing signal within the SH2 domain. We have investigated the expression and subcellular localization of iyk in the normal human breast and in malignant breast diseases. Immuno-histochemical analyses revealed that in normal tissue iyk localizes to both cytoplasmic and nuclear compartments of breast epithelial cells. The subcellular distribution was dependent on the hormonal state, being mostly cytoplasmic during the follicular, proliferative phase of the menstrual cycle, whereas frequent nuclear staining was observed in the resting stages during the luteal phase and, most prominently, after menopause. Strikingly, invasive carcinomas, irrespective of tumor type or hormonal status of the patient, exhibited almost complete loss of iyk expression in both the cytoplasm and the nucleus. In contrast, in situ breast carcinomas from post-menopausal patients showed a clear reduction of the nuclear iyk localization while retaining cytoplasmic staining. Our results indicate that iyk expression is gradually lost during carcinogenesis; thus, iyk may be classified as a tumor-suppressor gene.

[Continuous peridural analgesia vs patient - controlled intravenous analgesia for pain therapy after thoracotomy]. / Kontinuierliche Periduralanalgesie versus patientenkontrollierte intravenöse Analgesie.Schmerztherapie nach Thorakotomien.

OBJECTIVES: Continuous epidural analgesia (EA) and patient-controlled intravenous analgesia (PCA) are widely used for postoperative pain control. Studies indicate that both analgesic regimens provide good analgesia after major surgery. However, because of the following reasons it is still unclear whether one of the two modes of application is superior. First, there are conflicting data regarding the differences in pain relief and drug use between epidural and intravenous administration of opioids. Second, in many studies epidural analgesia is performed by a combination of local anaesthetics and opioids. Third, reduced morbidity was observed only in some of the studies, in which epidural analgesia provided better pain relief than systemic opioid supply. Despite these conflicting results, EA with local anaesthetics and fentanyl as well as PCA with piritramid, a highly potent mu-agonist, are routinely used in Germany. The purpose of this study was to compare these two treatments for analgesic efficacy, pulmonary function, incidence of side effects and complications in patients undergoing thoracotomy. METHODS: In this prospective randomized trial 50 patients were included. For postoperative pain control 25 patients (EA group) received thoracic epidural infusion of local anaesthetics (bupivacaine 0.125% or ropivacaine 0,2%) and fentanyl 4,5 microg/ml with a flow rate of 4-10 ml/h. 25 patients received intravenous PCA with piritramid (bolus 2, 5 mg, lock out 15 minutes, maximum of 25 mg/4 h, no background infusion). RESULTS: Analgesia at rest and while coughing, as evaluated by visual analogue scale, was significantly better in the EA group. EA also resulted in superior values of pulmonary function tests, general condition and a lower incidence of sedation and nausea. In contrast, patients with EA reported distinctly more pruritus than patients with PCA. Duration of hospital stay was shorter in the EA group, but this difference did not reach statistical significance. There was one atelectasis in the EA group. No major complications related to EA or PCA were observed. CONCLUSION: In this study EA with local anaesthetics and fentanyl provided superior postoperative pain control and a lower incidence of sedation and nausea compared to intravenous PCA with piritramid, but there was no superiority as to pulmonary complications and duration of hospital stay.

Three-dimensional laparoscopy. Gadget or progress? A randomized trial on the efficacy of three-dimensional laparoscopy.

BACKGROUND: This study was designed to compare conventional laparoscopy with three-dimensional (3-D) laparoscopy. METHOD: Thirty candidates, 20 inexperienced and 10 experienced in operative laparoscopy, executed standardized exercises on a pelvitrainer. The candidates were randomized to two groups. Group A executed the exercises first with the conventional and then with the three-dimensional system. Group B accomplished the exercises in the reverse sequence. At the end of the exercises, the candidates answered specific questions about the two systems. RESULTS: A total of 21 h 6 min 6 sec of laparoscopic exercises were analyzed-10 h 8 min 1 sec with the conventional and 10 h 58 min 5 sec with the three-dimensional system (p = 0.38). Group A required 12 h 26 min 56 sec to perform all the exercises. There was no statistically significant difference from group B, where the candidates needed 8 h 39 min 10 sec (p = 0.14). Neither were there any differences in the number of failed attempts between the two groups. There were also no statistical difference when the results obtained from the candidates without experience in laparoscopy and the participants experienced in operative laparoscopy were analyzed separately. Both the inexperienced and the experienced candidates became tired earlier, had more headaches, and needed extra time to adapt to the 3-D system. CONCLUSION: When analyzed in a standardized fashion, 3-D laparoscopy does not have any significant advantages over conventional laparoscopy.

Lymphadenectomy in high risk endometrial carcinoma stage I and II: no more morbidity and no need for external pelvic radiation.

The objectives of this retrospective study were to analyze the morbidity of surgical staging and to evaluate the omission of external radiotherapy in high-risk patients with stage I and II endometrial carcinoma when the lymph nodes were negative. From 1988 to 1996, 63 of 117 patients underwent a pelvic and periaortic lymphadenectomy. The decision to perform lymphadenectomy was influenced by patient general health. Patients with lymphadenectomy had a better physical status (P < 0.0001). Lymphadenectomy increased mean operative time (P < 0.0001) and blood loss (P < 0.01), but there was no increase in postoperative complications. At a median follow-up of 54 months, there was one cuff recurrence in 56 patients. Nineteen high-risk patients without external pelvic radiation had the same disease-free survival rate as 37 low-risk patients (P = 0.1). In the group without lymphadenectomy, the disease-free survival for 18 high-risk patients and 32 low-risk patients was similar (P = 0.21). Surgical staging in properly selected patients does not increase postoperative complications and brachytherapy without external radiotherapy is associated with excellent disease-free survival when the lymph nodes are negative.

[Sentinel lymphadenectomy: an alternative to axillary lymphadenectomy in breast carcinoma]. / Sentinel-Lymphadenektomie: eine Alternative zur axillären Lymphadenektomie beim Mammakarzinom.

BACKGROUND: Axillary lymph node status is an important determinant of prognosis in breast cancer. However, lymphadenectomy does not benefit half of the patients in whom axillary nodes are free of disease. Sentinel lymph node biopsy is a new technique which allows accurate staging of breast carcinoma without performing total axillary dissection. We describe our experience with the introduction of sentinel lymphadenectomy. METHODS: Thirty-seven sentinel lymphadenectomies were performed in 35 patients referred to the Department of Obstetrics and Gynaecology of the University of Berne between December 1997 and June 1998. Mapping procedures were performed using a combination of vital blue dye with preoperative lymphscintigraphy with 99mTechnetium-labelled colloidal albumin and intraoperative use of a gamma probe. Complete axillary lymphadenectomy was then performed in 34 patients. RESULTS: One or more lymph nodes were identified in 33 of 37 procedures (89%). With the combination of both localisation techniques the sentinel nodes were identified in all (100%) of the last 19 patients. Sentinel and non-sentinel lymph nodes were always concordant. In this series the negative predictive value is 100% (95% confidence interval: 87.7%-100%). Metastases were found in the sentinel node in 11 of 30 patients (37%). From these 11 patients, 3 (27%) had micrometastases. CONCLUSIONS: Histopathologic examination of the sentinel lymph node accurately predicts the axillary lymph-node status. Patients with sentinel nodes free of metastases could avoid the unnecessary peri- and postoperative complications of complete axillary dissection. Further studies are needed to assess whether the improved diagnosis of micrometastases by sentinel lymphadenectomy influences the long-term prognosis of breast cancer.

Is laparoscopic oophorectomy rational in patients with breast cancer?

BACKGROUND: Unsuspected malignancy remains a problem for the laparoscopic surgeon. The aim of this study was to evaluate the risk of ovarian micrometastasis in patients with breast cancer who undergo laparoscopic oophorectomy. METHODS: We analyzed 25 premenopausal women with breast cancer who underwent therapeutic laparoscopic oophorectomy. The patients were subdivided into the following two groups according to ovarian pathology: group A with and group B without breast carcinoma micrometastasis. We then reviewed the follow-up data for both groups, with special attention to metastasis of the abdominal wall. RESULTS: Twelve of 44 ovaries removed by laparoscopy showed ovarian breast carcinoma micrometastasis. There were no predictive factors of micrometastasis. After a mean follow-up of 38.1 months (95% CI: 29.2-46.9 months), none of the patients with proven micrometastasis developed metastasis of the abdominal wall, and the 21 puncture sites were inconspicuous. CONCLUSIONS: Although 32% of patients may have unexpected ovarian micrometastasis, laparoscopic oophorectomy in patients with breast cancer remains a safe procedure.

[Breast carcinoma--when is mastectomy still appropriate?]. / Mammakarzinom--wann noch Ablatio mammae?

Conservative therapy is now an established treatment for early-stage breast cancer when the extent of breast resection is sufficient and when adequate radiotherapy can be given. Ten-year local recurrence rates ranging from 3% to 20%, approximately 0.8% per year have been reported. At the Department of Gynecology of the University of Berne we changed our approach to the local treatment and the frequency of breast conserving surgery rose in one year to 61% for tumors 2 cm or less (T1) and 31% for T2. Our aim is now to limit axillary dissection to patients with nodal involvement. We have therefore started to identify those patients by removing the sentinel node.

[Cervix cytology: Cervex Brush versus conventional cotton swab]. / Zervix-Zytologie: Cervex-Brush versus konventioneller Watteträger.

Cervical smears should contain endocervical cells to be accepted as representative for a cytologic diagnosis. In this prospective study with 200 women we compared cytologic specimens obtained by Cervex-Brush (100 women) or by conventional cotton-swab (100 women) technique. The incidence of smears containing cylindrical and metaplastic cells was 85% in the Cervex-Brush group and only 58% in the cotton-swab group. We believe that the application of the Cervex-Brush or a similar instrument should result in fewer repeat smears and fewer false-negative smears and thus in an improvement of the cervical cytology.

Expression of the receptor protein tyrosine kinase myk-1/htk in normal and malignant mammary epithelium.

We have recently reported the molecular characterization of a novel murine receptor PTK (myk-1), belonging to the eph-related family, whose expression was differentially regulated during mammary gland development and elevated in invasive mouse mammary tumours. In this communication we have investigated the cellular origin of myk-1 expression by in situ hybridisation and RNase protection. Murine antisense myk-1 probe specifically recognised ductal and alveolar epithelium in the resting mouse mammary gland. In normal human breast, the expression of htk, the human homologue, was also confined to the secretory luminal epithelial cells. RNase protection analysis of enriched luminal and myoepithelial cells prepared from human reduction mammoplasty tissue confirmed the luminal specificity. Elevated expression of htk was found in several human breast carcinoma cell lines as well as in primary, high grade, infiltrating, ductal carcinomas of the breast. The specific epithelial expression of the myk-1/htk receptor PTK suggest a specialised role of this eph-related PTK in the differentiation and/or maintenance of secretory epithelium in the adult.

A mathematical model for the estimation of human embryonic and fetal age.

Precise determination of donor age in human embryonic and fetal tissue is crucial for cell transplantation due to the existence of distinct time windows within which successful grafting is possible. This study demonstrates that between 4-12 wk postconception embryonic and fetal age can be estimated based on various morphometric parameters measured on a routine basis in suction abortion material. The greatest length, the neck-rump length, the foot length, and the proximal and distal arm and leg length were correlated with the anamnestic and ultrasonographically estimated age. Multivariate regression analyses showed a linear correlation between age and the logarithmic value of the various morphometric parameters. The best correlation was found for a mathematical model combining the limb parameters (r = 0.904; p < 0.001; n = 37). A prospective follow-up study (n = 40) was carried out to test the validity of the mathematical model. A high correlation was found between the calculated age and the estimated age based on anamnestic data (r = 0.749, p < 0.001). Outliers due to errors in the anamnestic data were readily identified by comparing anamnestic with calculated age. This method allows determination of embryonic and fetal age within and beyond the age group of the Carnegie classification and may, therefore, be useful for the needs of experimental and clinical cell transplantation.