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Objective: To compare the effects of two different intraoperative CO 2 pressures (8 and 15 mmHg) during laparoscopic hysterectomy for benign uterine pathologies in terms of postoperative abdominal and shoulder pain, laparoscopy-mediated vegetative alterations, pain medication requirement, arterial CO 2 pressure (pCO 2 ), surgical parameters, and safety., Design: Prospective randomised controlled study., Setting: German university hospital., Population: Female patients undergoing laparoscopic hysterectomy for benign uterine pathologies., Methods: Patients were randomised to a standard pressure (SP; 15 mmHg, control) or low-pressure (LP; 8 mmHg, experimental) group., Main Outcome Measures: Primary outcomes were postoperative abdominal and shoulder pain intensities, measured via numeric rating scale (NRS) and vegetative parameters (fatigue, nausea, vomiting, bloating) at 3, 24, and 48 hours postoperatively. Secondary outcomes were pain medication requirement (mg) and arterial pCO 2 (mmHg). Surgical parameters and intra- and postoperative complications were also recorded., Results: In total, 178 patients were included. Patients in the LP group (n = 91) showed significantly lower postoperative abdominal and shoulder pain scores, fewer vegetative alterations, lower pain medication requirements, a shorter postoperative hospitalization, and lower intra- and postoperative arterial pCO 2 values compared with the SP group (n = 87; P ≤ 0.01). No differences in intra- and postoperative complications were observed between groups., Conclusions: Low-pressure laparoscopy seems to be an effective and safe technique for the reduction of postoperative pain and laparoscopy-induced metabolic and vegetative alterations following laparoscopic hysterectomy for benign indications., Tweetable Abstract: Low-pressure laparoscopy seems to be an effective and safe technique for reduction of pain following laparoscopic hysterectomy., (© 2019 Royal College of Obstetricians and Gynaecologists.)

The purpose of this study was to investigate the impact of current cigarette smoking on sperm DNA methylation patterns. A total of 108 males (51 current smokers and 57 never smoked males) were included in the study. Using 450 BeadChip Arrays, the differentially methylated CpGs between current smokers (n=15) and never smoked males (n=15) were identified. Out of significantly 11 CpGs identified, 2 CpGs namely cg07869343 and cg19169023, which are located in the MAPK8IP3 and TKR genes were selected for further analysis. Using deep bisulfite sequencing in an independent cohort of current smokers (n=36) and never smoked males (n=42), 6 and 1 CpGs showed a significant difference in the MAPK8IP (CpG3, CpG5, CpG6, CpG7, CpG8, and CpG21) and in the TKR (CpG4) were identified, respectively (P≤0.05). Our results indicate that cigarette smoking causes biochemical changes in the sperm DNA methylation in many regions and could adversely affect semen parameters., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction Minimally invasive operative techniques are being used increasingly in gynaecological surgery. The expansion of the laparoscopic operation spectrum is in part the result of improved imaging. This study investigates the practical advantages of using 3D cameras in routine surgical practice. Materials and Methods Two different 3-dimensional camera systems were compared with a 2-dimensional HD system; the operating surgeon's experiences were documented immediately postoperatively using a questionnaire. Results Significant advantages were reported for suturing and cutting of anatomical structures when using the 3D compared to 2D camera systems. There was only a slight advantage for coagulating. The use of 3D cameras significantly improved the general operative visibility and in particular the representation of spacial depth compared to 2-dimensional images. There was not a significant advantage for image width. Depiction of adhesions and retroperitoneal neural structures was significantly improved by the stereoscopic cameras, though this did not apply to blood vessels, ureter, uterus or ovaries. Conclusion 3-dimensional cameras were particularly advantageous for the depiction of fine anatomical structures due to improved spacial depth representation compared to 2D systems. 3D cameras provide the operating surgeon with a monitor image that more closely resembles actual anatomy, thus simplifying laparoscopic procedures.

Purpose: The aim of our study was to investigate the rate of secondary carcinomas in patients with endometrial carcinoma (EC). In particular, we wanted to describe the subset of patients with endometrial and simultaneous ovarian carcinoma (OC), including outcomes. The study also compared patients with EC and ovarian metastasis with patients with EC and simultaneous OC. Patients and Methods: Data from 251 patients with primary endometrial carcinoma who underwent surgery in the years 2005-2009 at the Department of Obstetrics and Gynaecology, University of Tübingen, were analysed retrospectively. Results: A total of 28 patients (11.1 %) had a secondary carcinoma: 18 patients (7.1 %) had OC; 9 (3.5 %) patients had a history of breast cancer, and one patient (0.4 %) respectively had simultaneous carcinoma of the vulva or bladder. 14 patients (5.5 %) had advanced stage EC with ovarian metastasis or, in one case, metastasis to the ovarian tube. Patients with ovarian metastasis had a mean age of 71.2 ± 9.2 years at primary diagnosis, making them significantly older compared to patients with EC and simultaneous OC (55.3 ± 11.8 years, p < 0.001). Moreover, patients with ovarian metastasis significantly more often had EC with a higher tumour grade (grade 1: 0, grade 2: 21.4 %, grade 3: 78.6 %) compared to patients with simultaneous EC and OC (grade 1: 11.1 %, grade 2: 77.8 %, grade 3: 11.1 %; p < 0.001). Conclusion: Almost one in 10 patients with EC had a secondary carcinoma. The most common secondary carcinoma was OC followed by breast cancer. This should be taken into account in the diagnosis and therapy of patients with EC. Patients with simultaneous EC and OC were significantly younger than patients with EC and ovarian metastasis. In addition, their tumour had better prognostic features: thus, the tumour grade of the EC was significantly lower. Overall, the prognosis for patients with synchronous EC and OC is better than that for patients with EC and ovarian metastasis.

Different metabolic bone parameters such as RANK (receptor activator of nuclear factor-κB), RANK ligand (receptor activator of nuclear factor-κB ligand) and OPG (osteoprotegerin) control physiological bone remodelling. The pathophysiology of these factors in bone diseases and osseous metastases is becoming clearer. In metastatic breast cancer, osteolytic bone metastases are the result of increased osteoclastic activity caused either by increased RANK ligand or decreased OPG expression of metastatic osseous tumour cells. These findings may lead to new therapeutic options for the treatment of breast cancer patients. The aim of this work is to provide an overview of physiological bone remodelling and of the interaction between tumour cells and bone environment. Current therapy approaches and the mechanisms of action of drugs are described.

In women, malignant breast tumours are among the most common malignant diseases in Europe. In advanced breast cancer, the risk of bone metastasis increases to 65-75 %. The discovery of the physiological bone metabolism parameters RANK (receptor activator of nuclear factor-κB), RANKL (receptor activator of nuclear factor-κB ligand) and OPG (osteoprotegerin) as well as their pathophysiological involvement in bone-related diseases is the subject of new therapeutic strategies. The formation of osteolytic bone metastasis requires increased osteoclast activity. Activation of osteoclasts by excessive direct RANKL or reduced OPG expression of osseous metastatic tumour cells remains to be elucidated. More than 50 % of primary breast cancer cells express OPG and RANK, while RANKL could be detected only in 14-60 %. Increased OPG concentrations in the serum of patients with bone metastases have been shown in several studies, whereas the RANKL results are described in an opposite manner. The use of OPG as a biomarker for the detection of osteolytic bone metastases is not consistent and needs to be proved in further studies. Increased RANKL activity was found in diseases characterised by excessive bone loss and formed the basis of new therapeutic options. In several studies, a human monoclonal antibody to RANKL (denosumab) was investigated for the treatment of bone diseases. Denosumab is a promising therapeutic option due to its bone-protective effects.

Background: Disseminated tumor cells (DTCs) in bone marrow (BM) occur in 30-40% of primary breast cancer patients. An impaired bone microenvironment may lead to reduced bone density and osteoporosis affecting the BM as a homing site for DTCs. The bone mineral density (BMD) and its correlation to DTC in BM was evaluated., Materials and Methods: One hundred and eighty-one women (70 premenopausal, 111 postmenopausal) underwent quantitative ultrasonometry before adjuvant chemotherapy. BM aspirates were analyzed by immunocytochemistry using the ACIS system (Chromavision) based on immunostaining., Results: DTCs were detected in 39% of the patients. Positive BM status correlated significantly with the nodal status. BMD was significantly reduced in the postmenopausal patients (p=0.003). Smaller tumors and higher BMD correlated significantly (p<0.014). Fifty percent of the patients with preclinical osteoporosis were BM positive, whereas 37% with normal or osteopenic BMD had DTCs., Conclusion: An impaired bone micro-environment as found in preclinical osteoporosis might be a homing site for DTCs.

Purpose: The objective of the study was to determine whether the various breast biopsy procedures specified in the S 3 guidelines are sensibly represented within the current German health system as considered from a cost evaluation perspective., Materials and Methods: This prospectively designed multicenter study analyzed 221 breast biopsies at 7 institutions from 04/2006 to 01/2007. Core needle biopsies, vacuum-assisted biopsies and surgical open biopsies under sonographic or mammographic guidance were evaluated. During an analysis of process costs, the individual process steps were recorded in diagrammatic form and assigned to the true consumption of resources. The actual resource consumption costs were entered. A process-related breakeven analysis was conducted to check whether the reimbursement of individual biopsy types covers the costs., Results: Only sonographically guided core needle biopsy and surgical open biopsy are adequately reimbursed in the current German health system. All other breast biopsies indicate a negative profit margin. The principal reasons for under-funding are found in the area of reimbursement of investment and non-personnel costs., Conclusion: The reimbursement of breast biopsies must be improved in order to guarantee nationwide care of the population using the breast biopsy methods recommended in the S 3 guidelines and to avoid disincentives with respect to breast biopsy indications., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Primary carcinoma of the Bartholin's gland is rare, consequently standard management is not clear. Although the sentinel concept has gained popularity for other malignancies of the female reproductive tract, the literature lacks reports of this approach for carcinomas of the Bartholin's gland., Case: We present a patient with stage I adenocarcinoma of the Bartholin's gland. She was managed with wide excision and inguinal and laparoscopic pelvic sentinel lymphadenectomy followed by complete pelvic lymphadenectomy. We discuss the rationale for the sentinel concept., Conclusion: As for other gynaecological malignancies the sentinel lymphadenectomy seems to be an appropriate and feasible surgical approach for early stage carcinomas of the Bartholin's gland.

Objective: Since 2003, multiple cases of bisphosphonate-induced osteonecrosis of the jaw (ONJ) were reported. The aim of this study was to describe the incidence and risk factors of ONJ in patients with breast cancer or gynecological malignancies receiving bisphosphonates (BP)., Methods: ONJ was recorded for all patients with breast cancer or gynecological malignancies treated with intravenous bisphosphonates at the Department of Gynecology and Obstetrics, University Hospital Tuebingen during April, 1999 and May, 2006., Results: 10 of 345 (2.9%) patients with breast cancer or gynecological malignancies developed ONJ while receiving bisphosphonate therapy. Six patients with ONJ had a history of recent dental procedures. All patients had received zoledronic acid as part of their bisphosphonate regimen. Time of exposure to bisphosphonates and the number of treatment cycles were significant risk factors for the development of ONJ (p<0.001). In patients diagnosed with ONJ the mean number of treatment cycles was 27+/-18 cycles. However, the mean number of treatment cycles in patients without manifestation of ONJ was 12+/-12 cycles., Conclusion: Length of exposure to BPs and the cumulative dose of given BPs seem to be the most important risk factors for the development of ONJ followed by dental procedures.

Background: Several studies have supported the hypothesis that the concept of immuno-surveillance would not be effective in cancer patients. One reason for suppression of antitumor immunity may be attributed to immune impairment of T-lymphocytes, which extends beyond the tumor-microenvironment and might effect the peripheral blood. Therefore the aim of this study was to investigate the expression of immunoregulatory antigens in peripheral blood lymphocytes of primary breast cancer patients in comparison with healthy donors., Materials and Methods: The peripheral blood immune status of 61 patients with primary breast cancer was analysed by FACS-analysis. The different lymphocytic subpopulations were identified by intracellular/extracellular monoclonal antibodies in three-color flow cytometry. The distribution was compared to age-matched healthy female donors (n = 29)., Results: The expression of TCR zeta-chain, an important signal complex for T-cell activation and functional integrity of specific immune response, was significantly reduced in the cytotoxic specific T-cell population. Cytotoxic T-cells (CD3+/CD8+) also showed a down-regulation of CD28, the important ligand to the co-stimulatory molecule CD80 (B7.1) on antigen-presenting cells. Moreover, breast cancer patients had significantly more CD95 (FAS) expressing cytotoxic T-cells than their healthy counterparts (p < 0.05)., Conclusion: The significant up-regulation of CD95 and down-regulation of TCR zeta and CD28 in peripheral cytotoxic T-cells of breast cancer patients leads to the hypothesis of systemic immunosuppression, which could open the door for tumor cell dissemination via the blood stream and which is the subject of ongoing studies.

Objectives: The presence of disseminated tumor cells (DTC) in breast cancer patients is associated with poor prognosis. However, there are limited data about the prevalence and prognostic impact of DTC in patients with gynecological tumors. The aim of this study was to evaluate the presence of DTC in the bone marrow (BM) of patients with gynecological cancers and to correlate their presence with established prognostic factors., Methods: BM aspirates of 201 patients with primary ovarian (n=69), cervical (n=54) and endometrial cancer (n=78), undergoing surgery at the Department of Gynecology and Obstetrics, University Hospital, Tuebingen, Germany between 1/2002 and 01/2006, were included into the study. Cytokeratin (CK)-positive cells were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3., Results: The bone marrow positivity rate was 36% in ovarian, 26% in cervical and 17% in endometrial cancer, respectively. Presence of DTC was significantly correlated with FIGO (International Federation of Gynecology and Obstetrics) tumor stage (p<0.05). The recurrence rate was 14% in patients with CK-positive cells compared to 8% in CK-negative patients (p=0.2). There was no correlation between DTC and other established prognostic factors including nodal status or grading except for cervical cancer. Patients with positive lymph node status were more likely to be bone marrow positive compared to those with negative lymph node status (p<0.05)., Conclusions: Disseminated tumor cells seem to be a general phenomenon in epithelial tumors even though their clinical impact remains to be evaluated. The hypothesis that bone marrow is the homing site of disseminated tumor cells is further supported by these data since gynecological tumors only rarely metastasize to the skeletal system.

Background: Serum HER2 testing allows the determination of the real-time HER2 status of breast cancer patients. The aim of this investigation was to study (i) whether changes of serum HER2 status occur during the clinical course of breast cancer and (ii) to evaluate the prognostic significance of serum HER2 status, at the time of first diagnosis of primary breast cancer and at the onset of metastatic disease, for survival after relapse (SAR)., Materials and Methods: HER2 serum levels were retrospectively measured in 152 breast cancer patients at the time of first diagnosis of breast cancer and at the onset of metastatic disease by enzyme immunoassay., Results: Twenty-seven out of 152 (18%) patients had elevated HER2 serum levels at the time of first diagnosis of breast cancer. In contrast, 56 out of 152 (37%) patients showed elevated serum HER2 levels when metastases were diagnosed. A change of serum HER2 status during clinical course was observed in 43 out of 152 (28%) patients. Serum HER2 status at the time of first diagnosis of breast cancer had no impact on survival after relapse (SAR) (p = 0.4). However, the median SAR for serum HER2-positive patients at the onset of metastatic disease was significantly shorter (8 months, 95% CI: 3-12) compared to patients serum HER2-negative at this time (18 months, 95% CI: 14-22) (p < 0.01)., Conclusion: Serum HER2 status can change during the course of disease. Therefore, the serum HER2 status should be re-evaluated at the time of diagnosis of metastatic disease to optimize treatment decisions.

Purpose: Tumor cell detection (TCD) in bone marrow is an outstanding prognostic factor in breast cancer. There is only one other study that has investigated more than 300 patients with a median follow-up of more than 5 years (J. L. Mansi et al., Lancet, 354:197-202, 1999). We report data from 727 patients with a median follow-up period of 6.5 years., Experimental Design: In a prospective study, intraoperatively aspirated bone marrow was screened for micrometastatic cancer cells. We used an immunocytological method (monoclonal mucin antibody 2E11; the avidin-biotin complex method)., Results: Forty-three percent of the patients were TCD positive. Sixty percent of the patients with distant metastases were tumor cell positive (155 of 258 patients). Forty-nine percent of the patients with positive TCD developed distant metastases (155 of 315 patients). TCD was an independent prognostic factor for clinical outcome after a median follow-up time of 6.5 years. The prognostic impact of TCD and tumor size remains constant with the time, whereas the impact of grading and progesterone receptor on risk seems to decrease with longer follow-up time., Conclusions: TCD remains an independent prognostic factor The impact of TCD does not change with longer follow-up time. TCD is a reliable prognostic factor and provides important information about the process of metastasis.

Previous studies with animal tumors showed that bone marrow (BM) is a privileged site where potentially lethal tumor cells are controlled in a dormant state by the immune system. Here, we investigated BM of breast cancer patients with respect to tumor cell content, immune activation status and memory T-cell content. BM-derived cells from primary operated breast cancer patients (n = 90) were compared with those from healthy donors (n = 10) and also with cells from respective blood samples. Cytokeratin 19-positive tumor cells were detected by nested polymerase chain reaction. Three-color flow cytometry was used to identify numbers and activation state of T cells, natural killer (NK) cells, monocytes/macrophages and subsets by a panel of monoclonal antibodies (mAbs). The proportion of memory T cells among the CD4 and CD8 T cells was much higher in BM of cancer patients than in healthy donors (p < 0.001). The extent of memory T-cell increase was related to the size of the primary tumor. Patient-derived BM memory CD8 T cells could be shown to contain specific HLA-A2/Her-2/neu(369-377) tetramer binding cells. Patients with disseminated tumor cells in their BM had more memory CD4 T cells and more CD56(+) CD8(+) cells than patients with tumor cell-negative BM. Only some of the immunological changes seen in BM samples of cancer patients were also detectable in peripheral blood samples. Our hypothesis that BM is a special compartment for immunological memory and tumor dormancy is supported by the above findings. The overall results reveal that BM is a valuable additional compartment for immune diagnosis in pathological conditions and possibly for follow-up treatment strategies., (Copyright 2001 Wiley-Liss, Inc.)

In an analysis of 84 primary-operated breast cancer patients and 11 healthy donors, we found that the bone marrow of most patients contained memory T cells with specificity for tumor-associated antigens. Patients' bone marrow and peripheral blood contained CD8+ T cells that specifically bound HLA/peptide tetramers. In short-term culture with autologous dendritic cells pre-pulsed with tumor lysates, patients' memory T cells from bone marrow (but not peripheral blood) could be specifically reactivated to interferon-gamma-producing and cytotoxic effector cells. A single transfer of restimulated bone-marrow T cells into NOD/SCID mice caused regression of autologous tumor xenotransplants associated with infiltration by human T cells and tumor-cell apoptosis and necrosis. T cells from peripheral blood showed much lower anti-tumor reactivity. Our findings reveal an innate, specific recognition of breast cancer antigens and point to a possible novel cancer therapy using patients' bone-marrow-derived memory T cells.

Like other metastases, bone metastases in breast cancer patients are not only a sign of the incurable nature of the underlying disease, but are also associated with specific complications. In particular, bone pain and pathological fractures impair the quality of life of those affected. Any treatment concept must, therefore, place the highest priority on preventing or reducing skeletal complications. There are two treatment options--local and systemic. Local therapy includes radiotherapy as well as surgical and orthopedic measures. The four pillars of systemic treatment are hormone therapy, chemotherapy, antiresorptive therapy with bisphosphonates, and treatment with centrally and/or peripherally acting analgesics. A precondition for successful treatment is close cooperation between medical/clinical oncologists, radiotherapists, surgeons/orthopedists, gynecologists, pain specialists, and endocrinologists (in the presence of a hypercalcemic syndrome). Patients with breast cancer associated solely with osseous metastasis may live for a number of years. It is, therefore, all the more important to start appropriate therapeutic measures early. Bisphosphonates play a particularly valuable role, since their main effect lies in the prevention of skeletal complications. Rather than replacing antineoplastic therapy, this class of substances supplements other treatments. Once started, bisphosphonate therapy should be given for the remainder of the patient's life, even in the event of osseous progression.

Bone sialoprotein (BSP) is a noncoflagenous bone matrix protein that is important for both mineralization and cell-cell interactions. Tissue studies in primary breast cancers have shown that immunohistochemical expression of BSP is associated with a high incidence of bone metastases in the course of the disease. We used a RIA to investigate the importance of serum BSP as a marker for subsequent bone metastases. Between 1994 and 1996, preoperative blood samples were collected from 388 consecutive patients with nonmetastatic breast cancer and from 30 control patients with benign breast disease. Serum BSP concentrations were measured in a blinded fashion by RIA. The cutoff for elevated serum BSP values was 24 ng/ml, ie., two SDs above the normal mean value. Serum BSP was correlated with the risk of metastasis and analyzed with regard to its prognostic value. After a median follow-up period of only 20 months, 28 patients had developed metastases. Fourteen patients had bone metastases only, 9 visceral metastases only, and 5 a combination of osseous and visceral metastases. Of the 19 women with skeletal metastases, 17 had preoperative serum BSP values in excess of 24 ng/ml (median BSP values: 48.3 ng/ml for isolated metastatic bone disease, 30.6 ng/ml for combined metastases), whereas none of the women with visceral metastases only had elevated serum BSP concentrations (median BSP value: 12.3 ng/ml). The median serum BSP value in the control group (benign breast disease) was 8.8 ng/ml serum BSP; levels correlated with the size of the primary tumor, but not with any other prognostic factors. Using a multivariate regression analysis, serum BSP was found to be the most important independent prognostic factor for the development of skeletal metastasis (P < 0.001; relative risk, 94); its specificity was 96.7%, and its sensitivity was 89.5%. Our study shows that patients with preoperatively elevated serum BSP levels are at high risk of subsequent bone metastases in the first years after primary surgery. The mechanism of BSP in the pathogenesis of skeletal metastases is unclear. Because BSP contains an integrin recognition sequence, its expression in tumor cells may facilitate their adhesion to the bone surface. However, it is possible that a proportion of circulation BSP is derived from normal or tumor-induced bone turnover. Breast cancer patients with elevated serum BSP levels may benefit from osteoprotective adjuvant therapy with bisphosphonates.

Background: Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer. We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer., Methods: Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received standard surgical treatment and customary hormonal therapy or chemotherapy., Results: Distant metastases were detected in 21 patients in the clodronate group and in 42 patients in the control group (P<0.001). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than in the control group (P=0.003 for both osseous and visceral metastases). Six patients in the clodronate group died, as did 22 in the control group (P=0.001). The mean number of bony metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs. 6.3)., Conclusions: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases.

We report on a patient with metastatic breast cancer confined to visceral (lung and pleura) site. A high-dose chemotherapy with peripheral progenitor blood cell transplantation was indicated. In contrast to other 24 patients two induction cycle chemotherapies (intensive dosis of Epirubicin/Ifosfamid/GCSF) didn't show any remission of metastases. Therefore a high dose chemotherapy with peripheral progenitor blood cell transplantation was not indicated any more. This patient had lung and pleura metastases and showed a complete remission after the following conventional chemotherapy (Carboplatin/Toxol) persisting more than 7 months. Non-responder after induction therapies have a poor prognosis but salvage therapy may be successful anyway. Mammary neoplasms can be sensible on special chemotherapy drugs only.

Doppler sonography now has a definite place in the surveillance of risk pregnancies. Uniform clinical management is sometimes difficult especially in borderline cases. The following study demonstrates the possibility of standardizing and systematizing Doppler results using a score. In a collective of 253 pregnant women we performed Doppler examinations in the fetal aorta, umbilical artery, middle cerebral artery, internal carotid artery. The results were divided into 4 groups and correlated to the fetal outcome. There was a highly significant worsening in prognosis regarding duration of pregnancy, birth weight and rate of cesarean sections with increasing Doppler score. In the event of pathological and highly pathological scores, the average duration of pregnancy was 23 and 48 days shorter than normal. As a result, there was a highly significant reduction in the average birth weight compared to fetuses with normal Doppler scores: by 1060.7 g in the case of a pathological score and by 1633.5 g in the case of a highly pathological score. There was a highly significant correlation concerning the rate of cesarean sections and the indication "fetal distress". The average interval between diagnosis and birth was 6.3 days in the case of pathological Doppler findings and 2.3 days in the case of highly pathological findings. The difference was highly significant. In the case of highly pathological scores all fetuses were delivered after at least 5 days, compared with after at least more than 10 days in those with only pathological Doppler findings. This reflects the fact that there is none room for discretion in case of a highly pathological flow. In summary the Doppler score allows better estimation of fetal risk and can improve fetal prognosis by special monitoring and earlier obstetric intervention.

Background: Approximately 30% of the patients with primary breast cancer who have no axillary lymph node involvement (i.e., lymph node negative) at the time of surgery will relapse within 10 years; 10%-20% of the patients with distant metastases will be lymph node negative at surgery. Axillary lymph node dissection, as a surgical procedure, is associated with frequent complications. A possible alternative to nodal dissection in terms of prognosis may be the immunocytochemical detection of tumor cells in bone marrow., Purpose: In a prospective study, the value of tumor cell detection (TCD) in bone marrow was compared with axillary lymph node dissection in the prognosis of primary breast cancer after surgery., Methods: Data from 727 patients with primary, operable breast cancer were included in the analysis. All patients had surgery, including axillary lymph node dissection, from May 1985 through July 1994 at the Women's Hospital of the University of Heidelberg (Federal Republic of Germany). Bone marrow aspiration at two sites on each anterior iliac crest was performed immediately after surgery while the patients were under general anesthesia. Most patients received some type of systemic adjuvant therapy. The monoclonal antibody 2E11, directed against the polymorphic epithelial mucin TAG12, was used to detect tumor cells in bone marrow samples. The association of TCD with recognized prognostic indicators was evaluated by means of chi-squared tests. Survival without the development of distant metastases (i.e., distant disease-free survival) and overall survival were estimated by use of the Kaplan-Meier method; the logrank test was used to compare survival curves. A multivariate Cox regression analysis with stratification according to adjuvant treatment type was used to assess the independent prognostic value of TCD in bone marrow in relation to other variables. Reported P values are two-sided., Results: Tumor cells were detected in the bone marrow of 203 (55%) of 367 lymph node-positive patients and in 112 (31%) of 360 lymph node-negative patients. TCD was associated with larger tumors (P < .001), lymph node involvement (P = .001), and higher tumor grade (i.e., more undifferentiated) (P = .002). After a median follow-up of 36 months, patients with tumor cells in their bone marrow experienced reduced distant disease-free survival and overall survival (both P values < .001). TCD was an independent prognostic indicator for both distant disease-free survival and overall survival that was superior to axillary lymph node status, tumor stage, and tumor grade. Among patients with tumors less than 2 cm in diameter, TCD was the most powerful predictor of outcome., Conclusions and Implications: TCD in the bone marrow of patients with breast cancer is a valuable prognostic tool associated with negligible morbidity. Prospective randomized studies should be performed to determine whether TCD might replace axillary lymph node dissection in a defined subgroup of patients with small tumors.

Recently, the breast cancer susceptibility gene BRCA2 has been identified in chromosome 13q, a region that also contains the retinoblastoma gene RB1. To elucidate a possible role of BRCA2 and RB1 in sporadic breast tumorigenesis, allelic imbalance (AI) at 13q loci was examined in 78 primary sporadic breast tumors. AI was found in 52-63% of tumors. Nine tumors showed AI only in the BRCA2 region but not at RB1. Six tumors showed AI at RB1 but not in the BRCA2 region. AI in the BRCA2 region correlated significantly with aneuploidy (P = 0.032) and AI at RB1 with small tumor size (P = 0.025). Our data suggest that BRCA2 and RB1 may be both distinct target loci for AI on chromosome 13 in sporadic breast cancer.

Bisposphonates are pyrophosphate analogues and in the human organism are similarly bound to hydroxlapatite. By various mechanisms, bisphosponates inhibit the activity of the osteoclasts. Due to this characteristic feature they are exceptionally well suited to prevent bone destruction. Breast cancer is often complicated by skeletal metastases, associated with such typical complications as pain, pathologic fractures, hypercalcemia, aso. Bisphosphonates, in an adequate dose, reduce the rate of skeletal complications. The present publication is an overview on pharmacological aspects and therapeutic indications of bisphosphonates. Therapeutic guidelines on dosage and duration of therapy are given for individual indications. The palliative character of these substances is underlined and antiosteolytic treatment is described as the third pillar (beside hormone and chemotherapy) of systemic therapy of breast cancer with bone metastases. Subsequently, the most common side effects and complications are described. Bisphosphonates have osteoprotective characteristics and, possibly, could play a role in prophylaxis of ossary metastases.