J. Schmolling

Cross-linked type I collagen C- and N-telopeptides in women with bone metastases from breast cancer

Abstract This study documents values of biochemical markers of bone remodeling in 106 patients with breast cancer. Based on scintigraphic and radiological findings, patients were divided into 3 groups: 19 patients with bone metastases, 65 patients without bone metastases and normal bone scintigrams, and 22 patients with pathological, non-malignant findings on scintigraphy without proof of bone metastases. Urinary cross-linked type I collagen N-telopeptides (NTx) and serum cross-linked type I collagen C-telopeptides (ICTP) were assessed as markers of bone resorption. Bone alkaline phosphatase (BAP) was assessed as a marker of bone formation. All three markers were significantly higher in patients with bone metastases compared to both patients without skeletal recurrence and those with pathological, non-malignant scintigraphic findings (p < 0.01). There were no statistically significant differences between the latter two groups. The clinical sensitivity for diagnosing bone metastases was 44% for NTx, 65% for ICTP, and 26% for BAP, respectively. The clinical specificitiy for discriminating patients with bone disease from those without were 79%, 91%, and 92% for NTx, ICTP, and BAP, respectively. In conclusion, markers of bone remodeling are increased in patients with breast cancer metastatic to the skeleton. The sensitivity of the markers presented in this paper did not seem to be sufficient enough for early identification of patients with subclinical bone recurrence in a clinical practice setting.

Paraneoplastic neurological syndrome: patient with anti-Yo antibody and breast cancer: a case report

Abstract. Presented here is the case of a paraneoplastic cerebral degeneration (PCD) in a female patient with breast cancer and the indication of anti-Yo antibodies in the cerebrospina fluid (CSF) and serum. The patients primary indications were dizziness and a severe gait ataxia. The indication of anti-Yo antibodies led to the conclusion of the existence of a paraneoplastic cerebral degeneration. The antibodies in question are anti-Purkinje-cell autoantibodies acting against the antigens common to tumor and Purkinje cells which occur in association with a certain percentage of breast or ovarian cancers. The diagnosis of the primary tumor, that is clinically undetectable with conventional imaging processes, is performed with the aid of positron emission tomography (PET) to detect the presence of axillary lymph node metastases. The micro-invasive mammary carcinoma was able to be localized with the aid of MR mammography and, after MR mammography marking, was removed. The patient subsequently received adjuvant treatment with epirubicine and cyclophosphamide. This treatment failed to influence the paraneoplastic neurological symptoms.

Clinical application of maternal serum cytokine determination in premature rupture of membranes - interleukin-6, an early predictor of neonatal infection?

BACKGROUND In cases of premature rupture of membranes (PROM), an early detection of fetal infection is necessary in order to weigh infectious complications against prematurity. As routine parameters (leukocytes, C-reactive protein (CRP), fever, and fetal tachycardia) lack satisfactory sensitivity and specificity, this study evaluates whether the determination of interleukin-6 (IL-6), interleukin-8 (IL-8) or soluble interleukin-2 receptor (IL-2R) in maternal serum could supplement or replace routine inflammation parameters. METHODS In this prospective study results of clinical and laboratory parameters were investigated with respect to neonatal infection in 71 patients with PROM. IL-6, IL-8 and IL-2R were determined by enzyme immunoassays. RESULTS Best specificity and sensitivity could be demonstrated for CRP and IL-6. Both elevation of CRP and IL-6 correlated significantly (p<0.01 and p<0.001, respectively) with the onset of neonatal infection. At a cutoff of 11 pg/ml, IL-6 reaches a sensitivity of 81% and a specificity of 76%; CRP a specificity of 76% (cutoff 1.2 mg/dl) and a sensitivity of 56%. In 4/16 (25%) cases developing neonatal infection, IL-6 increased earlier than CRP. IL-8 and IL-2R results showed a less significant correlation with fetal outcome. CONCLUSIONS Determination of IL-6 in maternal serum can significantly contribute to an earlier detection of fetal infection in patients with PROM.

Digoxin, flecainide, and amiodarone transfer across the placenta and the effects of an elevated umbilical venous pressure on the transfer rate.

Clinical observations suggest that flecainide might pass the placenta more easily than digoxin, and that its transfer is less disturbed in case of hydrops fetalis than that of digoxin. The purpose of the study was to compare the materno-fetal transplacental transfer of digoxin, flecainide, and amiodarone, another antiarrhythmic agent used in the treatment of fetal tachyarrhythmia, and to assess the effect of an elevated umbilical venous pressure (UVP) on the transfer rate. Isolated lobules of 16 human placentas were dually perfused after spontaneous delivery or caesarean section. The transplacental transfer (area under the curve in the maternal compartment [maternal AUC], area under the curve in the fetal compartment [fetal AUC], kinetic parameters) of digoxin, flecainide, and amiodarone was calculated after these drugs were added to the maternal circuit. In five experiments, the effect of increased UVP on the transplacental transfer rate was assessed by elevating the UVP by 10 cm H2O. Flecainide efflux out of the maternal compartment was significantly greater than that of digoxin (maternal AUC 57.4% ± 5.1%/min vs 73.9% ± 1.5%/min), whereas the flecainide influx into the fetal circulation was smaller (fetal AUC 9.3% ± 4.1%/min vs 11.5% ± 2.0%/min). Only in 50% of the experiments were the smallest amounts of amiodarone detectable in the fetal compartment. An elevation of the UVP reduced the influx of digoxin and flecainide into the fetal compartment (fetal AUC) from 11.5% ± 2.0%/min to 7.4% ± 1.9%/min and from 9.3% ± 4.1% to 4.7% ± 1.4%/min, respectively. Materno-fetal transplacental transfer of digoxin, flecainide, and amiodarone decreases in this sequence. Fetal cardiac insufficiency accompanied by an elevation of the UVP might reduce the transplacental transfer of these drugs, although no significant difference could be found between the reduction of transfer of digoxin and flecainide.

Adhesion molecules, activin and inhibin—candidates for the biochemical prediction of hypertensive diseases in pregnancy?

BackgroundThe aim of the prospective study was to compare standard parameters as Doppler ultrasound and 24-h blood pressure measurement with possible maternal serological markers regarding their prognostic value in predicting hypertensive diseases in pregnancy.MaterialsTwenty-four-hour blood pressure measurement was performed before and after 32+0 gestational week in 57 pregnant women with either chronic hypertension (n=13), preeclampsia (n=21), pregnancy-induced hypertension (PIH; n=12) or normotension (n=11). Blood samples were taken and the concentrations of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), activin A and inhibin A were determined as well as serum uric acid, creatinine, total serum protein and serum albumin. Doppler ultrasound of the uterine arteries was examined before 32+0 gestational week in the same patients. For the statistical evaluation Kruskal-Wallis-Test and Mann-Whitney-U-Test were performed. Differences in the predictive value were evaluated by receiver-operating characteristics.ResultsVCAM-1 was significantly elevated in women developing hypertensive diseases as compared to normotensive women (preeclampsia: p<0.001; PIH: p<0.05; chronic hypertension: p<0.001). In early pregnancy activin A and inhibin A were significantly higher in preeclamptic patients than in the other groups (activin A: normotension: p<0.005; PIH: p<0.001; chronic hypertension: p<0.005) (inhibin A: normotension: p<0.005; PIH: p<0.001; chronic hypertension: p<0.01), thus suggesting them to be specific markers for the development of preeclampsia. Mean arterial pressure was significantly elevated in preeclampsia (p<0.001) and chronic hypertension (p<0.005) as compared to normotensives.ConclusionTwenty-four-hour blood pressure monitoring with determination of mean arterial pressure and measurement of VCAM-1, activin A and inhibin A as serum parameters can be suggested as useful tests in the specific prediction of different types of hypertensive diseases in pregnancy.

A Simple and Sensitive Assay for Determination of Human Anti-idiotypic Anti-B72.3 Antibodies, which Is not Affected by the Presence of Tumour-Associated Glycoprotein 72

An immunoradiometric assay is described for the determination of human anti-idiotypic anti-B72.3 IgG. The latter is formed in ovarian cancer patients after treatment with the murine monoclonal antibody B72.3, which is directed against the tumour-associated glycoprotein 72 (TAG-72). A gel coupled with Fc-specific anti-human IgG antibodies is used as a solid phase for the extraction of serum IgG. The anti-B72.3 IgG is then specifically detected by incubation with radiolabelled B72.3 detector antibodies. Calibration standards were prepared from serum obtained from a patient repeatedly treated with B72.3 antibodies. The concentration of anti-idiotypic anti-B72.3 antibodies was expressed as TAG-72-like arb.units/1. The assay performed with two 60-minute incubation steps is characterized by a high sensitivity (detection limit: 3 x 10(3) arb.units/1) and precision (coefficients of variation: intra-assay = 6.4% and 5.8% at 80 x 10(3) arb. units/1 and 217 x 10(3) arb.units/1, inter-assay = 8.7% and 7.1% at 91 x 10(3) arb.units/1 and 212 x 10(3) arb.units/1) and a good linearity of dilution (recovery after dilution between 99% and 107%). The assay is more specific than previously described methods; no interference was observed by TAG-72 up to 3.3 x 10(7) arb.units/1. Also, non-specific human anti-mouse antibodies did not cross-react up to 34.8 mg/l. The test may be modified for detection of anti-idiotypic antibodies, which are formed after treatment with other monoclonal antibodies.

Photoradiation of perfused placental tissue – a suitable in vitro model for photodynamic therapy?

Abstract Our aim was to evaluate the isolated placental lobule as a model to study the cytotoxic effects of photodynamic therapy (PDT) in vitro. Ten human placental lobules were dually perfused with a modified medium 199 for a 4-hour period. Photosan III was added to the fetal perfusate at a dose of 5 mg/kg tissue, and laser light (630 nm wavelength) provided by an argon-pumped dye laser was applied at 50 J/cm2 in the experimental group (n=5). Potassium and lactate dehydrogenase (LDH) release into the perfusate as well as the transplacental creatinine passage from PDT-treated placentas and control placentas (n=5) were compared, and light microscopic examinations of the placental tissue were performed after the experiments. Potassium release into the fetal perfusate was higher in the PDT-treated placental lobules (p<0.05), and weight gain during the artificial perfusion suggests the development of edema only in the photoradiated lobules (p<0.01). The release of the bigger molecules of the LDH however was comparable in the two experimental groups, and transplacental creatinine passage was not affected by photoradiation. Light microscopic examinations demonstrated lesions at the cytotrophoblast, the syncytiotrophoblast and the endothelium of the fetal vessels of the photoradiated placentas, although they were not specific and could also be found in the control tissue. We conclude that the isolated placenta may be used to study cytotoxic effects of photoradiation in vitro, but better specifity and sensitivity might be achieved if a. The perfusion time is prolonged to make the difference between the experimental and the control group clearer and b. Electron microscopic investigations are made to demonstrate intracellular lesions of the mitochondria and the endoplasmic reticulum.

Schwangerschaft und aplastische Anämie

The occurrence of aplastic anaemia (AA) in pregnancy is very rare and in severe cases accompanied by maternal mortaly due to haemorrhage and by poor fetal outcome. Since little is known about the relationship between AA and pregnancy according to numerous authors, induced abortion is supposed to be the only curative therapy concept. On the other hand, bone marrow transplantation (BMT), antilymphocyte globulin (ALG) therapy, corticosteroids and Ciclosporin A (CSA) have considerably improved the outcome of these mothers and their offspring. We now report about a fourth gravide patient who acquired severe AA in her second pregnancy and in whom therapeutic abortion was induced early in the third pregnancy because of bleeding complications. In the meantime there was no improvement in her peripheral blood counts and she became dependent on red cell and platelet transfusions. An additional combined immunosuppressive therapy with AG (0.75 mg/kg/bw over 8 days), methylprednisolone (5 mg/kg/bw over 8 days) and CSA (initial dose: 2 x 2.5 mg/kg/ bw, then 2 x 125 mg/day) did not show a significant improving effect. As unfortunately her only brother is HIV-positive and she became pregnant once again the search for a HLA-compatible bone marrow donor was shelved for the moment. Being aware of all maternal and fetal risks from AA and its therapy the patient decided to continue the pregnancy. In the first trimenon every two to four weeks erythrocyte and thrombocyte transfusions were necessary to keep haemoglobin around 10 gm/dl and platelet counts over 10 x 10 3 /μl to avoid bleeding complications. Furthermore, we carried on to treat with 2 x 125 mg CSA/ day. In the second and third trimenon the supportive care increased up to weekly erythrocyte and thrombocyte transfusions boosted temporarily by immunoglobulin infusions until delivery. At the end of the 36 th week the gravidity was terminated by elective Caesarian section and the healthy newborn had a birth weight of 2310 gm. According to recent clinical studies demonstrating the usefulness of human umbilical cord blood as an alternate source for haematopoietic bone marrow cells, the cord blood from her own placenta was collected for stem cell separation and autologous transplantation. Currently the patient is well but still dependent on erythrocyte and thrombocyte transfusions accompanied by treatment with CSA. Although the concentration of haematopoietic stem and progenitor cells in the cord blood of this case was low there are acceptable circumstances to reconstitute her haematopoiesis by stem cell transplantation.

Dynamik der Bildung anti-idiotypischer Antikörper und Auswirkungen auf den CA125-Spiegel nach Idiotypen-Vakzination mit dem MAb OC125 beim Ovarialkarzinom

Die Immunisierung von Patientinnen mit Ovarialkarzinomen durch eine Stimulierung des Idiotypen-Netzwerk-Systems (1) stellt moglicherweise eine effektive Form der Immuntherapie dar. Dabei werden F(Ab)2-Fragmente des gegen das tumor-assoziierteAntigen (TAA) CA 125 gerichteten Antikorpers OC125 wiederholt zur Induktion von Anti-Antikorpern infundiert (3). Im Rahmen dieser Untersuchung wurde auf die Dynamik der Bildung anti-idiotypischer Antikorper, den Verlauf des TAA CA 125 und den moglichen Bezug zwischen der Intensitat der Immunreaktion und dem klinischen Verlauf eingegangen.

Idiotypen-Netzwerk-Aktivierung durch Behandlung mit dem monoklonalen Antikörper OC125 als Immuntherapie des Ovarialkarzinom

Die Aktivierung des Idiotypen-Netzwerk-Systems stellt einen moglichen Einflusweg in das Immunsystem von Patientinnen mit Ovarialkarzinom dar. Dabei werden gegen ein tumor-assoziiertes Antigen (TAA) gerichtete Antikorper (MAb-OC125) zur Induktion von Folgeantikorpern (Ab2) eingesetzt, die Id + (Ab 1+)B-Zellen oder Id + T-Helferzellen aktivieren konnen (s. Abb. 1) (1).