Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease.

Gains of chromosomes 7p and 8q are associated with poor prognosis among oestrogen receptor-positive (ER+) stage I/II breast cancer. To identify transcriptional changes associated with this breast cancer subtype, we applied suppression subtractive hybridisation method to analyse differentially expressed genes among six breast tumours with and without chromosomal 7p and 8q gains. Identified mRNAs were validated by real-time RT-PCR in tissue samples obtained from 186 patients with stage I/II breast cancer. Advanced statistical methods were applied to identify associations of mRNA expression with distant metastasis-free survival (DMFS). mRNA expression of the key enzyme of cholesterol biosynthesis, squalene epoxidase (SQLE, chromosomal location 8q24.1), was associated with ER+ 7p+/8q+ breast cancer. Distant metastasis-free survival in stage I/II breast cancer cases was significantly inversely related to SQLE mRNA in multivariate Cox analysis (P<0.001) in two independent patient cohorts of 160 patients each. The clinically favourable group associated with a low SQLE mRNA expression could be further divided by mRNA expression levels of the oestrogen-regulated zinc transporter LIV-1. The data strongly support that SQLE mRNA expression might indicate high-risk ER+ stage I/II breast cancers. Further studies on tumour tissue from standardised treated patients, for example with tamoxifen, may validate the role of SQLE as a novel diagnostic parameter for ER+ early stage breast cancers.

Whole genome expression analysis for biologic rational pathway modeling: application in cancer prognosis and therapy prediction.

Using semi-quantitative microarray technology, almost every one of the approximately 30 000 human genes can be analyzed simultaneously with a low rate of false-positives, a high specificity, and a high quantification accuracy. This is supported by data from comparative studies of microarrays and reverse-transcription PCR for established cancer genes including those for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2/ERBB2), estrogen receptor (ESR1), progesterone receptor (PGR), urokinase-type plasminogen activator (PLAU), and plasminogen activator inhibitor-1 (SERPINE1). As such, semi-quantitative expression data provide an almost completely comprehensive background of biological knowledge that can be applied to cancer diagnostics. In clinical terms, expression profiling may be able to provide significant information regarding (i) the identification of high-risk patients requiring aggressive chemotherapy; (ii) the pathway control of therapy predictive parameters (e.g. ESR1 and HER2); (iii) the discovery of targets for biologically rational therapeutics (e.g. capecitabine and trastuzumab); (iv) additional support for decisions about switching therapy; (v) target discovery; and (vi) the prediction of the course of new therapies in clinical trials. In conclusion, whole genome expression analysis might be able to determine important genes related to cancer progression and adjuvant chemotherapy resistance, especially in the context of new approaches involving primary systemic chemotherapy. In this review, we will survey the current progress in whole genome expression analyses for cancer prognosis and prediction. Special emphasis is given to the approach of combining biostatistical analysis of expression data with knowledge of biochemical and genetic pathways.

[Impact of DNA image cytometry (ICM) parameter and established prognostic factors on disease free survival (DFS) and overall survival (OS) of node-negative breast cancer (NNBC) patients]. / Bedeutung DNA-Bild-zytometrischer Parameter und etablierter Prognosefaktoren für krankheitsfreies Uberleben (DFS) und Gesamtüberleben (OS) nodal-negativer Mammakarzinompatientinnen.

OBJECTIVE: DNA ICM allows measurement of nuclear DNA content and genotypical grading of malignancy. The aim of this study was to prove the prognostic value of DNA parameter in comparison to established prognostic factors for DFS and OS. PATIENTS AND METHODS: Cytological imprints of 177 unselected primary NNBC patients were subjected to ICM. ICM parameter 2cDI, 5cEE, 9cEE, DNA mean value, proliferation fraction (SG2M) and ploidy were investigated together with established parameter like pT-stages, histology, grading, hormone receptor status and patient age regarding DFS and OS. Univariate and multivariate analysis were performed. RESULTS: Univariate analysis revealed that except ploidy all ICM parameter and pT-stages, histology as well as grading were significant prognostic factors for DFS. However, only 2cDI and pT-stages were proved independent prognostic factors in multivariate analysis. Regarding OS 9cEE, histology and pT-stages were significant factors in univariate analysis. However, only 9cEE and pT-stages were found to be independent prognostic factors in multivariate analysis. CONCLUSIONS: DNA - ICM parameter 2cDI and 9cEE together with pT-stages were proved independent prognostic factors in NNBC patients.

[Comparability of obstetric and perinatal data from England and Germany using standard-primip-groups - maternal and neonatal outcome]. / Vergleichbarkeit geburtshilflicher und perinataler Daten aus England und Deutschland durch Verwendung von Standard-Primip-Gruppen - Befinden von Mutter und Kind.

OBJECTIVE: Aim of the study was to assess whether different birth management of an english and german department can influence the maternal and neonatal outcome. MATERIAL AND METHODS: The database consisted of routinely published data from 1986-95 for two clinical units in Solihull (England) and Ibbenbueren (Germany) comprising 34 820 and 9 053 deliveries respectively. In order to standardise the obstetric risk profiles the heterogeneous primary groups were subdivided into "standard primip groups". A statistical comparison using the "binomial confidence interval method" was carried out. RESULTS: In the standardised comparison induction of labour, duration of labour 1-6 hours, vaginal delivery from cephalic presentation, elective caesarean section, both for cephalic and breech presentation, transfer to the childrens hospital were less frequent in Solihull. On the other hand, Solihull showed more frequent oxytocin administration, fetal blood analysis, epidural anaesthesia, episiotomies, duration of labour > 13 hours, forceps, ventouse and emergency caesarean section deliveries from cephalic presentation, vaginal deliveries or emergency caesarean sections from breech presentation, resuscitation of the newborn using mask and/or drugs, maternal blood loss > 1 000 ml as well as abnormalities of placental separation. Despite the different management of the departments being compared no significant differences in the incidence of perinatal hypoxia as determined by Apgar scores at 5 minutes nor in the fetal mortality rate between the units could be identified. CONCLUSION: Using standardised data the quality of obstetric and perinatal care in England and Germany can be reliably compared. Different birth management does not significantly influence the neonatal outcome.

Human papillomavirus genotypes in cervical cancer with different histological features.

We report the case of a 32-year-old woman having developed two cervical cancers synchronously, an adenocarcinoma and a squamous cell carcinoma. Polymerase chain reaction with the general primers GP5/GP6 and a subsequent enzyme-linked immunosorbent assay to detect human papillomaviruses (HPV) resulted in isolation of HPV 33 in the squamous cell carcinoma and HPV 18 in the adenocarcinoma. This is the first reported case of two histologically different synchronous cervical cancers with this distinct HPV expression pattern, and further confirms the association of certain 'high-risk' HPV genotypes to different histological features of carcinoma. Furthermore, the important role of microdissection for gaining tumor tissue of different areas in molecular diagnostics is supported.

c-myc oncogene gene dosage, serum CEA and CA-15.3 antigen levels, and cellular DNA values in relation to ex vivo chemosensitivity of primary human breast cancer.

A pilot study on relationships of selected molecular factors (c-myc oncogene average gene copy numbers (AGCN); serum CEA and CA 15.3 antigen levels; tumor cells' DNA values), to the ex vivo chemosensitivity of primary female human breast cancer in a modified adenosine triphosphate cell viability chemosensitivity assay (ATP-CVA), was performed. Four drug combinations were tested. A group of 75 cases of female primary breast cancer was assessed. Numerous correlations were found among molecular factors tested but none, with the exception of tumor grading, of these reflected ex vivo chemosensitivity of tumors tested. The results suggest that the parameters tested may not be important factors related to adjuvant chemoresponsiveness of primary human breast cancer to tested drug combinations.

Relationship of c-myc and erbB oncogene family gene aberrations and other selected factors to ex vivo chemosensitivity of ovarian cancer in the modified ATP-chemosensitivity assay.

A pilot study on relationships of selected molecular factors [erbB-1, erbB-2, erbB-3, and c-myc oncogene average gene copy numbers (AGCN); steroid receptors and pS2 gene expression; tumor cells' DNA values] to the ex vivo chemosensitivity of ovarian cancer in a modified adenosine triphosphate cell viability chemosensitivity assay (ATP-CVA), was performed. Despite the relatively small number of patients, numerous correlations among the factors tested were found. Nevertheless, only c-myc gene dosage positively affected ex vivo chemosensitivity of tumors tested.

[Clinical importance of histology, grading and ploidies in primary breast cancer]. / Zur klinischen Wertigkeit von Histologie, Grading und Ploidie primärer Mammakarzinome.

OBJECTIVE: In order to characterise carcinoma of the breast the determination of ploidy can be used in addition to established prognostic factors such as histology and grading. The aim of the investigation was to establish the association between histology, grading and ploidy and to indicate the prognostic and predictive value of these parameters in relation to disease free survival (DFS) and overall survival (OS). MATERIAL AND METHODS: 125 consecutive cases of primary breast carcinoma occurring between the years 1992-1995 were surveyed. The median follow up time lasted 45 months. Correlation analyses were carried out using the Chi-square test, Kaplan-Meier (univariate) and Cox (multivariate) methods. RESULTS: Histology and grading showed no correlation to ploidy but seems to be of importance for DFS in node-negative breast carcinoma. Ploidy did not influence neither DFS nor OS. Ductal histology appeared to be a useful factor in predicting the response of cases treated with an anti-oestrogen (Tamoxifen) since in this group a higher relapse rate of 25% occurred. CONCLUSIONS: Ploidy appears not to be of clinical importance.

Amplification of erbB-4 oncogene occurs less frequently than that of erbB-2 in primary human breast cancer.

ErbB-4 protein is a recently discovered member of the ErbB family. The role of ErbB-4 protein in mammary-gland tissue has not been definitively established. To date, the expression of erbB-4 in breast tissue has been determined in only a few cases and, to the best of our knowledge, its amplification has not been examined. We therefore used the double differential polymerase chain reaction (ddPCR) for determination of the amplification profile of erbB-4 and erbB-2, another gene from the ErbB family, in human primary breast cancer specimens. We examined the amplification of the genes in 20 normal breasts and 176 invasive breast cancer samples. Amplification of erbB-2 was detected in 19% and erbB-4 in 13% of the samples studied. Co-amplification of the two oncogenes was found in only five out of 176 samples. Human breast cancer-derived cell lines in most cases overexpress both erbB-2 and erbB-4 (Beerli et al., 1995. Mol. Cell Biol. 15, 6496-6505; Han et al., 1995. Proc. Natl. Acad. Sci. USA 92, 9747-9751), but data on separate erbB-2 overexpression, without overexpression of erbB-4, were also reported (Wosikowski et al., 1997. Clin. Cancer Res. 3, 2405-2414). At the gene level, we found that co-amplification of the genes in the case of human breast cancer is rare. Moreover, an inverse association of the erbB-4 amplification with estrogen receptor activity and direct correlation with the tumor size were found. Due to these correlations, erbB-4 oncogene amplification can be assumed to be of prognostic or predictive value in the diagnosis of breast cancer.

[Pre-pathologic-pathologic cardiotocographic pattern in second stage of labor. Analysis of the incidence of acidosis and recommendations for fetal blood gas analysis]. / Präpathologisch-pathologische kardiotokographische Muster in der Austreibungsperiode. Analyse der Azidosefrequenz und Empfehlungen zur Fetalblutanalyse.

Fetal heart rate (FHR) patterns from 746 consecutive, documented vaginal deliveries within a 1 year period were reported on using the Hammacher Score. Characteristic FHR patterns were described and the frequency of acidosis calculated. FHR score, the single FHR parameters, baseline (BL), floatingline (FL) and oscillation type (OT) and the acid-base balance of the neonate were submitted to a correlation analysis according to Spearman. FHR patterns reported as ominous (FHR score > or = 5) were observed in 25.9% and were associated with a frequency of acidosis (pHUA < or = 7.20) of 38.1% Suspicious fetal heart rate patterns (FHR score 3-4) were seen in 60%, here the frequency of acidosis was 8.5%. With the inclusion of decelerations by the parameter FL an increased frequency of acidosis of 29% was registered only when 4 points were allocated. Total FHR score and the score parameter baseline (BL) correlated closest with the pH changes at the end of birth. Tachycardic FHR patterns showed the highest frequency of acidosis (55%) and ominous tracings (83%). The commonest FHR pattern, normocardia with decelerations (48%) exhibited only a low frequency of acidosis (8%) and ominous tracings (15%) with an average pH value of 7.27 +/- 0.08. To prevent an unnecessary operative delivery in the presence of an ominous FHR finding, whether in the late first stage or early second stage when birth is not imminent, a fetal blood analysis should be carried out. With a suspiciously assessed fetal heart rate pattern the fetal blood analysis will only rarely reveal a severe acidosis (pHUA < or = 7.10).

Prognostic relevance of aberrations in the erbB oncogenes from breast, ovarian, oral and lung cancers: double-differential polymerase chain reaction (ddPCR) for clinical diagnosis.

We have determined the average gene copy numbers (AGCN) of the erbB-1 gene, encoding the epidermal growth factor receptor (EGF-R), the erbB-2 and the erbB-3 genes in breast, ovarian, oral, and lung cancer tissue by using double-differential PCR (ddPCR). The ddPCR method comprises the co-amplification of the single-copy gene HBB, the erbB-1, erbB-2 and erbB-3 oncogenes and the second single-copy reference gene SOD2 under equal reaction conditions. In a retrospective study the AGCN of the erbB genes and the time up to the appearance of metastases were subjected to life-table analysis in 128 women with primary breast cancer. Patients whose breast cancer tissue showed an AGCN for erbB-1 of less than 0.4 and greater then 1.6, as expected from the literature, for erbB-2 of greater than 2.0 and for erbB-3 of less than 1.75 had decreased disease-free survival (DFS). The quotient of erbB-1 and erbB-2 AGCN was the most significant in multivariate Cox analysis followed by nodal status and progesterone receptor status. In extensive studies a similar association between erbB AGCN and metastasis was seen in ovarian cancer and oral cancer, though erbB oncogene aberrations in those entities were not as frequent as in breast cancer. The AGCN of erbB oncogenes may not be of prognostic value in untreated lung cancer patients.

[Exposure of the fetoplacental unit, breast milk and cow's milk to radionuclides 1 year after Chernobyl]. / Belastung der fetoplazentaren Einheit, der Muttermilch und Kuhmilch durch Radionuklide ein Jahr nach Tschernobyl.

Placenta, umbilical cord with membranes, amniotic fluid, foetal blood (from the umbilical vein), maternal urine and breast milk were examined for the non-natural radioisotopes 131iodine, 103ruthenium, 134caesium, 137caesium originating mainly from the nuclear power plant accident in Chernobyl compared with 40potassium existent in the natural environment. Apart from amniotic fluid, all samples contained considerable traces of caesium-radioisotopes. 131iodine and 103ruthenium could not be identified at the time of our survey due to their short half-life. The radioisotope load of placenta was found to be increased tenfold compared to studies before the Chernobyl catastrophe. Breast milk radioisotope load was found to be lower than that in cow's milk in a corresponding geographical region in the same period of time.

[Difficulties in interpreting the cardiotocogram in atrioventricular arrhythmia of the fetal heart]. / Interpretationsschwierigkeiten des Kardiotokogramms bei atrio-ventrikulärer Erregungsleitungsstörung des fetalen Herzens.

During a routine screening examination of a pregnancy during the 28th gestational week, a pericardial effusion and ascites were recognized in the fetus. Ultrasound B- and M-mode evaluation (echocardiography) revealed an atrio-ventricular block grade III with commencing cardiac insufficiency. Cardiac monitoring (CTG) by ultrasound (HP 8040A Fetal Monitor) documented primarily the fetal atrial activity when the logic switch was turned off, but after it was turned on there was no continuous recording. When fetal heart action was recorded by abdominal electrocardiogram (AFEKG) the cardiotocography showed simultaneously a ventricular frequency of 50/min. and a maternal frequency of 70-80/min. This case confirms that the registration of fetal heart action without real-time imaging is only of limited value in cases of cardiac-conduction anomalies. It is important that during ultrasound screening examination, the cardiac heart action is carefully evaluated.

[Acceleration behavior in the antepartum cardiotocogram and the condition of the newborn infant]. / Akzelerationsverhalten im antepartalen Kardiotokogramm und Neugeborenenzustand.

The prognostic value of fetal heart accelerations in the antepartal cardiotocogram (CTG) is analyzed with regard to fetal outcome. A total of 560 CTGs made one week before delivery were divided into five groups: newborns with cord around the neck, newborns with acidosis, newborns with fetal growth retardation, newborns with low Apgar scores at 1 and 5 minutes (Apgar-7), normal newborns as control group. In contrast to other publications, the present authors did not find accelerations in the antepartal CTG to be a definite positive prognostic sign. These observations indicate that fetal heart acceleration evaluation should not be included in a fetal heart score in the antepartal CTG.

[Prenatal ultrasonic diagnosis of achondroplasia]. / Pränatale Ultraschalldiagnostik bei Achondroplasie.

The pregnancy of a woman with achondroplasia was monitored by ultrasound from the 29th to the 38th week of gestation. Starting with the 29th week of gestation, there was a suspicion of the foetus having the same skeletal dysplasia. The following measurements were in the pathological range: the length of the upper arm, the humerus, the lower arm, the thigh, the femur, the leg, the tibia, as well as the maximal thigh diameter, the ratios of thigh diameter to crown-rump length and maximal thigh diameter to the biparietal diameter. Unsuspected head-rump measures associated with measurements, displayed an achondroplasia which had been discovered in the newborn.

[Uterus septus with adenocarcinoma of one half of the uterus]. / Uterus septus mit Adenokarzinom der einen Korpushälfte.

The authors demonstrate a rare case of an adenocarcinoma of the uterus associated with a uterus septus. The concomitance of carcinoma and congenital uterine anomalies is coincidental and has no causal connection. Congenital anomalies of the uterus which remain undetected can be responsible for serious delay in diagnosis of carcinoma and may adversely interfere with treatment efforts.

Evaluation of infants with acidosis using a perinatal "negative factor" score.

Using Prechtl's concept of optimal conditions as modified by Michaelis et al. [7] we analysed the case records of 50 acidotic newborn infants (umbilical artery pH of 7,250 or less) and of 34 controls. Acidotic infants had a significantly higher negative (or adverse) factor score. There was a correlation between the degree of acidosis and the negative factor score. There were, however, no relations between scores in isolated subgroups of negative factors and fetal acidosis though the same was not true for some combinations of subgroups (such as pre-eclampsia, operative delivery, fetal bradycardia in the second stage of labour).

[Experiences in the assessment of the subpartal cardiotocogram (author's transl)]. / Erfahrungen bei der Bewertung des subpartalen Kardiotokogramms.

750 cardiotocographic curves of the last 30 minutes prior to vaginal delivery were assessed retrospectively according to the CTG score after Hammacher et al. (6). The aim of this study was to examine the prognostic value of the CTG score with regard to the foetal acid-base stains. The results obtained showed a distinct interdependence between the CTG score and the risk of foetal acidosis. Correct interpretation of the CTG can be ensured only if all three different CTG parameters are considered. The most frequent and reliable pointers to the existence of foetal acidosis are the occurrence of severe variable or late decelerations which can be detected from an examination of the floating-line pattern.

["Antepartum noninvasive evaluation of persistant fetal cardiac arrhythmias" (author's transl)]. / "Antepartale nichtinvasive Abklärung persistierender Rhythmusstörungen des fetalen Herzens".

Fetal cardiac arrhythmias are increasingly more frequently discovered by cardiotocographic monitoring beginning at the 30th week of gestation. The computation of systolic time intervals represents a noninvasive technique to evaluate the cardiovascular performance of these fetuses. The pre-ejection period, ventricular ejection time and duration of systole of 41 healthy fetuses, two fetuses with supraventricular tachycardia and one with complete atrio-ventricular block were computed on the basis of abdominal fetal electrocardiogram and phonocardiogram. One fetus with supraventricular tachycardia had a pathologic prolonged pre-ejection period and duration of systole. This fetus became acidotic during delivery and died from persistent cardiac arrhythmia and congestive heart failure after 2 years. Further investigations should be done in order to prove, if a prolonged pre-ejection period and duration of systole have a significant value. According to the present experiences of the author a vaginal delivery can be recommended, if normal systolic time intervals exist in the arrhythmic fetus.