Randomised phase III trial of FEC120 vs EC-docetaxel in patients with high-risk node-positive primary breast cancer: final survival analysis of the ADEBAR study.

BACKGROUND: Taxane-containing adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. This study compared efficacy and tolerability of epirubicin (E)/cyclophosphamide (C) followed by docetaxel (Doc) with a dose-dense 5-fluorouracil (F)+E+ C regimen. METHODS: The ADEBAR study was a randomised phase III trial for women with primary invasive breast cancer and ⩾4 metastatic axillary lymph nodes (n=1364). Treatment consisted of four 21-day cycles of E plus C, followed by four 21-day cycles of Doc (EC-Doc), or six 28-day cycles of E plus F plus C (FEC120). RESULTS: Disease-free survival (DFS) was similar in the two treatment arms as shown by multivariate Cox regression adjusted for other prognostic factors (EC-Doc vs FEC120, hazard ratio (HR): 1.087; 95% confidence interval (CI): 0.878-1.346, P=0.444). In addition, there was no significant difference in overall survival (OS) between the two groups (HR: 0.974; 95% CI: 0.750-1.264, P=0.841). Haematologic toxicity was more common in FEC120 recipients; non-haematologic toxicities occurred more frequently in the EC-Doc arm. The serious adverse event rate was significantly higher in the FEC120 group (29.7% vs 22.5%). CONCLUSIONS: EC-Doc provides a feasible and effective alternative therapy option to FEC120 with a different safety profile in this high-risk breast cancer cohort.

[Influence of the injection technique on the false negative rate of SLNE in multifocal breast cancer]. / Einfluss der Injektionstechnik auf die Falsch-negativ-Rate bei der SLNE des mehrherdigen Mammakarzinoms.

AIM: We investigated the influence of the injection technique on the false negative rate in identifying the sentinel lymph node in multifocal breast cancer. PATIENTS, METHODS: 958 consecutive patients were divided into unifocal and multifocal breast cancer patients. The scintigrafic and intraoperative detection rate as well as the false negatives were calculated in relation to peritumoral or subareolar injection. RESULTS: In all patients the scintigrafic and intraoperative detection rate exceeded 99%, except in patients with multifocal cancer, who were injected peritumorally. In this group the intraoperative detection rate declined to 96%. In patients with unifocal breast cancer the false negative rate was below 5%, independent of the injection technique. Multifocal breast cancer patients showed a significant dependence on the injection technique. The false negative rate was 26.3% in patients with peritumoral injection and 5.6% in those with subareolar injection. CONCLUSION: The results clearly demonstrate that in multifocal breast cancer a reliable detection of a SLN is impossible with the peritumoral injection technique. Subareolar injection seems to be a way to operate on multifocal breast cancer with SLNE, but the number of investigated patients is too low for statistic approval. So, prospective studies should be performed to validate these preliminary results before SLNE becomes routine in multifocal breast cancer.

Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer.

BACKGROUND: Cytokeratins are specific markers of epithelial cancer cells in bone marrow. We assessed the influence of cytokeratin-positive micrometastases in the bone marrow on the prognosis of women with breast cancer. METHODS: We obtained bone marrow aspirates from both upper iliac crests of 552 patients with stage I, II, or III breast cancer who underwent complete resection of the tumor and 191 patients with nonmalignant disease. The specimens were stained with the monoclonal antibody A45-B/B3, which binds to an antigen on cytokeratins. The median follow-up was 38 months (range, 10 to 70). The primary end point was survival. RESULTS: Cytokeratin-positive cells were detected in the bone marrow specimens of 2 of the 191 control patients with nonmalignant conditions (1 percent) and 199 of the 552 patients with breast cancer (36 percent). The presence of occult metastatic cells in bone marrow was unrelated to the presence or absence of lymph-node metastasis (P=0.13). After four years of follow-up, the presence of micrometastases in bone marrow was associated with the occurrence of clinically overt distant metastasis and death from cancer-related causes (P<0.001), but not with locoregional relapse (P=0.77). Of 199 patients with occult metastatic cells, 49 died of cancer, whereas of 353 patients without such cells, 22 died of cancer-related causes (P<0.001). Among the 301 women without lymph-node metastases, 14 of the 100 with bone marrow micrometastases died of cancer-related causes, as did 2 of the 201 without bone marrow micrometastases (P<0.001). The presence of occult metastatic cells in bone marrow, as compared with their absence, was an independent prognostic indicator of the risk of death from cancer (relative risk, 4.17; 95 percent confidence interval, 2.51 to 6.94; P<0.001), after adjustment for the use of systemic adjuvant chemotherapy. CONCLUSIONS: The presence of occult cytokeratin-positive metastatic cells in bone marrow increases the risk of relapse in patients with stage I, II, or III breast cancer.

[Evaluating the pregnant cervix uteri by ultrasound with computer-assisted texture analysis]. / Zur Beurteilung der graviden Cervix uteri im Sonogramm mittels computergestützter Texturanalyse.

BACKGROUND: Cervical ripening during pregnancy is associated with ultrastructural alterations, presumably correlated with structural changes of the ultrasonographic image. Analysing these changes might allow conclusions on cervical consistence without necessarily performing manual examination. PATIENTS AND METHODS: Ultrasound findings of 112 patients with normal pregnancy (14th to 41st week of pregnancy) have been compared to those of 57 patients admitted because of cervical insufficiency (20th to 35th week). A representative region of interest was analysed using a computer based texture analysing system ("Ultra" written in "Interactive Data Language"). 125 parameters derive from various texture algorithms: 1st order gray scale statistics, row, slit and area statistics, gradient statistics, cooccurrence statistics. By means of factor and multiple regression analysis those parameters could be determined, which contribute significantly to the clinical assessment of cervical consistence. Weighting these parameters a so called texture score (TS) and--implementing the other parameters of the Bishop-Score (BS)--a texture based cervical score (TBCS) could be established. RESULTS: Manual assessment of cervical consistence could be reproduced excellently by noninvasive texture analysis. TBCS was highly correlated to BS, correlation to remaining duration of pregnancy (RDOP) was highly significant for TBCS but insignificant for BS. CONCLUSIONS: Manual assessment of cervical consistence may be replaced by noninvasive texture analysis. Using RDOP as target parameter TS and TBCS turn out to be superior to manual assessment and BS respectively. DISCUSSION: Computer aided texture analysis of cervical ultrasound imaging provides a useful information, which can be obtained easily and might help to reduce palpatory controls and increase the accuracy of prediction of pregnancy prolongation.

Tumor cell contamination of peripheral blood stem cell transplants and bone marrow in high-risk breast cancer patients.

Twenty-one high-risk patients with primary stage II/III breast cancer were treated with high-dose chemotherapy comprising etoposide, ifosfamide, carboplatin and epirubicin (VIC-E). Tumor cells of epithelial origin were analyzed using the monoclonal antibodies CK2 (IgG1) and A45-B/B3 (IgG1) against cytokeratin (CK) components in bone marrow (BM) aspirates prior to chemotherapy, and in peripheral blood stem cell transplants (PBSCT). They were separated after the first (21/21 patients) and the second cycle (16/21 patients) of induction chemotherapy with VIP-E (etoposide, ifosfamide, cisplatin, epirubicin). Preliminary results showed CK positive tumor cells in 40% (14/35) of the analyzed transplants. In 7/12 (58.3%) patients, CK positive tumor cells were detectable in BM prior to treatment. Sixteen patients were separated after the 1st and 2nd cycle of VIP-E. PBSCT of 14/16 patients were assessable for presence of CK positive tumor cells. Our preliminary results demonstrate a lower tumor cell contamination of PBSCT separated after the 2nd cycle of induction therapy (14.3%) compared to contamination after the first induction therapy (64.3%). To date, 4/21 patients have experienced a relapse, and three of these patients had tumor cell positive transplants. Due to the small patient number only a trend towards a superior relapse-free survival in the patient group with CK negative transplants can be shown by Kaplan-Meier analysis.

[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.

[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.

[Torsion of the pregnant uterus]. / Torsion des schwangeren Uterus.

Pathological version of the pregnant uterus is a rare complication. A case of 180 degrees sinistrotorsion of the uterus in the 39th gestational week is reported. The case was asymptomatic with the exception of preterm labor in the 30th week of pregnancy and was discovered during a cesarean section carried out because of myoma obstructing the birth canal. Mother and child were discharged in perfect health.

The prevention of mechanical birth trauma by means of computer aided simulation of delivery by means of nuclear magnetic resonance imaging and finite element analysis.

Anatomic disproportion gains an increasing interest in obstetrics. Imaging procedures (radiologic pelvimetry, computed or magnetic resonance imaging (MRI) fail to reflect the dynamics of delivery including deformations of the birth channel as well as of fetal structures. To validate findings of imaging procedures in this respect a method has been developed to perform a dynamic, biomechanical postprocessing of the static informations obtained from MRI. Using an especially developed software MRI pixel matrices of maternal pelvis and fetal head were color-codef1p4d--according to the principle of same density--line data were created. After sectional attribution of the resulting polygones a three-dimensional mesh of so called Finite elements (FE) was created, which then can be used for deformation analysis. Fetal head was then moved through the birth channel by means of computed simulation. This allows not only ongoing deformations to be visualized but also resulting forces to be calculated for at any time of the delivery process for any point of the anatomical model. Performing these simulations assuming various anatomic and physiologic conditions an obstetrical-biomechanical data basis could be obtained, that was implemented in a PC-based expert system. This allows interpretation of pelvimetric data with regard to birth dynamics.

[Uterine rupture without predisposing factors after a single vaginal PgE2 administration in prolonged pregnancy]. / Uterusruptur ohne prädisponierende Faktoren nach einmaliger vaginaler PgE2-Applikation bei Terminüberschreitung.

The case of a 38-year old 3/1 gravida with prolonged pregnancy is discussed. Labour was induced with a prostaglandin (PgE2-) vaginal tablet 4 days after an oxytocin stress test had failed. After rapid labour development, imminent fetal asphyxia suddenly occurred, leading to an emergency cesarean section. A rupture of the left uterus wall rupture with laceration of uterine vessels was demonstrated. This is the first case report of a uterus rupture that happened in prolonged pregnancy without predisposing risk factors after a single PgE2 dose that was correctly placed into the posterior fornix.

[Coping with illness/quality of life and immunologic parameters of patients with breast carcinoma and benign tumors]. / Krankheitsbewältigung/Lebensqualität und immunologische Parameter bei Patientinnen mit Mammakarzinom und benignen Tumoren.

OBJECTIVE: Maladaptive coping of the cancer illness leads to considerable psychosocial burden which can-as a chronic stress factor-impair various immune functions, e.g. cellular immunity. PATIENTS AND METHODS: In a collective of 118 patients suffering from mammary carcinoma and 48 patients suffering from benign mammary tumors Coping was measured with the EORTC-MAC-scale and Quality of life with three questionnaires. Out of the immunologic variables the lymphocyte subpopulations were determined with flow cytometry. Immunglobulines, neopterin, C-reactive protein, and herpes serology were determined using standard methods. RESULTS: At follow up a slight increase of the mean vales of sum-scores is observed for the adverse coping mechanisms, like helplessness/despair and fear. On the other hand, the values for the coping styles fatalism and denial decrease. Significant correlations are seen between anxious attitude and number of natural killer cells (CD16 and CD56). It must be pointed out that area of social contact show an inverse correlation in patients with mammary cancers: a strong improvement correlates with diminished natural killer cells as well as reduced activated killer cells. CONCLUSIONS: The aim of this study is to determine whether a high risk group can be defined using these parameters and if these parameter can be influenced by psychotherapeutic interventions such as establishing "Coping-support-groups".

[Pelvimetry using various magnetic resonance tomography techniques vs. digital image enhancement radiography: accuracy, time requirement and energy exposure]. / Pelvimetrie mittels verschiedener kernspintomographischer Techniken vs. digitale Bildverstärkerradiographie: Genauigkeit, Zeitbedarf und Energiebelastung.

In 50 patients with suspected or proven cephalo-pelvine disproportion pelvimetry was performed with MR-tomography using a gradient-echo-sequence (FLASH 2D) before or after labour. Results were compared with measurements using digital radiography. In principle, both methods are exchangeable. The sagittal pelvic in- and outlet bispinous diameters are well reproducible. On the other hand, the transverse pelvic inlet and the distance between the ischiatic tubera are not so reliably reproduced. The accuracy of measurement does not depend on individual pelvic distances. Critical statistical analysis demonstrates, that in the worst case differences between the two methods might become unacceptable. Our results indicate two major reasons: 1. there are interobserver problems which cannot be neglected, and 2. the anatomical definition of referential landmarks for the measurements is unsafe. In 10 volunteers, a comparison was made between a T1-weighted spin-echo sequence (SE), a fast gradient echo sequence (FLASH-2D) and an ultrafast gradient echo technique (Turbo-FLASH). For the examination techniques presented here, the high-frequency exposure load or specific absorption rate (SAR loc and SAR total) is below the values permitted by the German Federal Health Bureau (Bundesgesundheitsamt). Whereas the exposure load in case of spin-echo takes (SE) is 22fold higher than with the gradient echo technique (GHE), the load values of ultra-fast GE (usGE) are only about 16% of the 2D-FLASH sequence or about 0.007% of SE. The difference in image quality does not affect the accuracy of measurement.

[Labor induction with prostaglandin E2 in post-term pregnancy-- results of a multicenter study]. / Zur Geburtseinleitung mit Prostaglandin E2 bei Terminüberschreitung--Ergebnisse einer Multizenterstudie.

Post-term pregnancy has been the indication for induction of delivery in 542 patients from a multicenter study with 1472 patients undergoing induction with prostaglandin E2 given as vaginal tablet (3 mg) or as intracervical gel (0.5 mg), according to cervical ripeness. The obstetric characteristics of these 542 patients were compared to the data of the Baden-Wuerttemberg obstetrical trial as controls. Although cervical ripeness parameters differed significantly from those of the controls, birth intervals were significantly shorter in the study group. Fetal outcome parameters (umbilical artery pH, Apgar values, frequency of admission to pediatric ward) turned out to be more favorable in the study group. Frequency of operative vaginal deliveries (12.7%) and of Cesarean sections (15.5%) was significantly higher in the study group as compared to the reference group (operative vaginal deliveries 8.1%, secondary Cesarean sections 7.3%). If we relate these frequencies to data from prospective, randomized studies comparing active management of post-term pregnancies, it can be demonstrated that active management in general is associated with lower frequencies of operative deliveries. Additionally, the data from our study with active management of post-term pregnancy revealed even lower frequencies for operative deliveries as seen from actively managed post-term deliveries in the literature reviewed. Hence, the induction protocol adapted to cervical ripeness reported in this study is an efficient and safe management for post-term pregnancy minimizing the rate of operative deliveries.

Oxygenation of mammary tumors as evaluated by ultrasound-guided computerized-pO2-histography.

The average pO2 in breast carcinomas in situ is significantly lower than that in the normal breast tissue. The mean pO2 value for benign breast tumors is significantly higher than that of the breast cancers but lies significantly lower than the corresponding normal breast. No significant differences are found in the mean pO2 values when comparing cancers of different stages and histology. A decrease in the mean pO2 value is measured from the periphery to the center of the breast tumors investigated. The average pO2 values for pre- and postmenopausal patients differ significantly. The described method provides a reliable assessment of tissue pO2 in situ with a minimum of discomfort. Due to extensive inter tumor heterogeneity, prediction of pO2 values for tumors of same stage and same histology is not possible, so that measurement of individual tumor is mandatory for determining therapy response.

[A knowledge-based system for the interpretation of pelvimetric findings]. / Ein wissensbasiertes System zur Interpretation pelvimetrischer Befunde.

Digital Image Intensifier Radiography (DIR) as well as Nuclear Magnetic Resonance Tomography (NMR) using an especially developed imaging routine for pelvimetry are suitable tools for the assessment of the anatomical conditions when mechanical problems are supposed to occur during birth (cephalopelvic disproportion, breech presentation). A concept for an optimised evaluation procedure of these imaging techniques has been developed, including: a more elaborate measuring protocol, easily and precisely executable due to appropriate software packages being implemented in the diagnostic units, calculation of obstetrically relevant parameters not deriving immediately from the imaging procedures. This is possible by means of multiple regression analysis of a data base from 467 evaluated female pelvis computed tomograms, calculation of intrapelvic soft tissue place requirements by means of correlative analysis of female computed tomograms and weight-/height-index, empirical determination of cut off values in borderline pelvi-fetometric constellations evaluating 190 births by means of logistic regression of the according pelvic-fetometric data. The calculations necessary to obtain all these parameters are implemented in a software package which also contains an algorithm for the general characterisation of an individual pelvis. Thus, a rather sophisticated knowledge base for pelvic assessment becomes easily accessible.

[Pelviscopic sacropexy in treatment of vaginal prolapse]. / Die pelviskopische Sakropexie zur Therapie des Vaginalprolapses.

Although transabdominal sacropexy to correct vaginal prolapse is technically simple and yields good results, a minimal invasive procedure is desirable in the treatment of this benign condition. We therefore developed a laparoscopic sacropexy technique and were able to apply this operation successfully. Pelviscopic sacropexy does not differ greatly in principle from the intraabdominal approach; however, the techniques used in the individual steps must be adapted to pelviscopic methods.

[Marshall-Marchetti-Krantz operation or fasciaplasty in therapy of recurrent urinary incontinence in women]. / Marshall-Marchetti-Krantz-Operation oder Faszienzügelplastik zur Therapie der rezidivharninkontinenz der Frau.

In this study, a follow-up examination was carried out, comprising 59 female patients who were operated between the years 1985 and 1991 because of recurrent urinary incontinence. We distinguished two different operating methods: 34 women were treated following the Marshall-Marchetti-Krantz operation technique, whereas a fasciaplasty-suspension was employed om 25 patients. At the urodynamic follow-up examination, the patients had experienced an average history of 2 years' recurrent urinary incontinence. The patients' subjective observation of anamnestic urinary incontinence was objectified by a clinical cough test, cystotonometry and sonography of the small pelvis. Making extensive use of the urodynamic examination possibilities showed a 79.4% improvement following the Marshall-Marchetti-Krantz operation in comparison to a 52% improvement after the fasciaplasty operation. The operations success is assessed by evaluation of the depression quotient. Here the Marshall-Marchetti-Krantz operation resulted in a significant improvement. After the fasciaplasty operation, however, this was not found to be the case.

[Diagnosis of local panarteritis nodosa of the uterine cervix]. / Diagnose einer lokalen Panarteritis nodosa der Cervix uteri.

A 44-year old woman was referred because of metrorrhagia and asthenia. A diagnosis of uterine malignancy was suspected on the basis of the management of the Cervix uteri and an elevated erythrocyte sedimentation rate. Conisation and hysterectomy were performed, and histological examination revealed necrotising vasculitis affecting the Cervix uteri. Corpus uteri, muscle and fat biopsies showed no Periarteritis nodosa lesions. The incidental finding of necrotising arteritis in a surgical uterine specimen, involves further study to exclude systemic disease. The ability to involve any organ in the body makes it possible for specialists in every branch of medicine to be involved in the management and care of these patients.

[D-dimer and plasminogen activator of the urokinase type: personal experiences with breast cancer]. / D-Dimer und Plasminogen Aktivator vom Urokinasetyp: Eigene Erfahrungen bei Mammakarzinomen.

Plasma values of d-dimer, a stable end product of plasmin-induced fibrinolysis, were ascertained in 128 female patients with mammary carcinoma. These patients demonstrated significantly increased d-dimers in comparison with the control group with benign mammary disease (p < 0.01). The sensitivity and specificity of d-dimer were slightly higher than those of the established tumour marker CA 15-3 and CEA. There was no correlation between d-dimers in the plasma and increased expression of urokinase plasminogen activator (UPA) in the tissue. Increased d-dimers in the plasma of female patients with mammary carcinoma reflect multi-factoral interactions between carcinoma growth and the haemostatic-fibrinolytic system, and may be used as tumour markers.