Changes of serum HER2 status during clinical course of metastatic breast cancer patients.

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.

Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis.

Although metastasis is a frequent event in breast cancer patients, insight into the clinical course, prognosis and therapy with respect to the site of the first metastases has been poor and contradictory in former investigations. Follow-up data from 648 patients with metastatic breast cancer were statistically analyzed. Patients with bone metastases at first relapse had better overall survival (median 71 vs. 48 months; p < 0.001) and survival after first metastases (median 24 vs 12 months; p < 0.001) than patients with visceral metastases at first relapse. Bone was the site of first metastasis in 46%, and 71% of patients with metastatic breast cancer developed bone metastases. The localization of the second metastatic site was of prognostic relevance in patients with first visceral metastases, but not in patients with first bone metastases. The presence of osseous metastases correlated significantly with estrogen and progesterone receptor positivity, tumor grading I/II and S-phase fraction <5%. The better prognosis of patients with bone metastases is not determined exclusively by hormone receptor status. The disease is significantly more stable in patients with first bone metastases than in those with first visceral metastases.

Does the measurement of four fetal arteries provide more information than the measurement of just two arteries in prenatal Doppler sonography?

OBJECTIVE: The objective of this study was to evaluate whether the measurement of two or more fetal arteries provides more information and leads to a selection of fetuses at higher risk. DESIGN: In 244 pregnancies Doppler examinations in four fetal arteries (fetal aorta, common carotid artery, middle cerebral artery, umbilical artery) were performed. The evaluation of the results was made by means of a Doppler score for standardization and systematization. The results were divided into four groups (normal, pre-pathological, pathological, highly pathological) and the individual correlations with fetal outcome parameters were investigated. The results from measuring only two fetal arteries (the fetal aorta and middle cerebral artery) were then compared with those from all four arteries. RESULTS: Increasing pathology of the Doppler score correlated with fetal outcome parameters. The results showed that if the Doppler result in the two-vessel measurement was normal (n = 180), pre-pathological (n = 29) or highly pathological (n = 12) then measuring four vessels generally brought no additional information. However, the four-vessel measurement was of advantage in the pathological group (n = 23) because it selected the high-risk fetuses (30.4%), as categorized by outcome. CONCLUSIONS: Differentiating between several degrees of pathology is important for the estimation of fetal risk. In cases of pathological Doppler findings, the measurement of more than two vessels is important in order to select fetuses at increased risk.

Prognostic relevance of cathepsin D detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.

Patients with an elevated level of cathepsin D in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of cathepsin D detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both anterior iliac crests in 290 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: BM2, which detects tumour-associated glycoprotein TAG 12, which is typically expressed by almost all breast cancer cells, and the anti-cathepsin D antibody. 67 of 149 BM2-positive women (45%) developed metastatic disease (median follow-up time: 69 months). Of these, 15 were cathepsin D-positive (22%). Patients with cathepsin D-positive cells in bone marrow (n = 26; 9%) had a significantly shorter metastasis-free interval (38 months) compared with women who were cathepsin D-negative (64.5 months). The worst prognosis was seen in patients positive for both markers (30.5 months), followed by those who were cathepsin D-negative and BM2-positive (48 months). The detection of cathepsin D on disseminated tumour cells characterises a subgroup of patients with a poorer prognosis who should undergo more aggressive adjuvant systemic therapy.

[Complete remission after salvage chemotherapy in metastatic breast carcinoma after failure of induction cycles of planned high dosage chemotherapy with stem cell support]. / Komplette Remission auf eine Salvage Chemotherapie beim metastasierten Mammakarzinom nach Versagen der Induktionszyklen bei geplanter Hochdosischemotherapie mit Stammzellsupport.

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.

Results of iliac crest biopsies taken from 1465 patients with primary breast cancer.

This study was performed to analyze the relevance of iliac crest biopsy in patients with primary breast cancer with regard to metastases of the primary tumor and osteogenic disease. We performed intraoperative bilateral biopsy of the anterior iliac crests in 1465 patients with primary breast cancer. The bone specimens were histologically evaluated with regard to quality of the biopsy, tumor involvement, and osteogenic and hematogenic disease. Accurate and clear evaluation of the iliac crest biopsies was possible in 1365 patients (93%). Osteopenia was diagnosed in 48 patients (3.5%); 24 patients (1.7%) showed histological evidence of tumor involvement of the skeletal system. All these 24 patients received systemic (adjuvant) therapy after surgery. Ten patients had micrometastases, although in 5 of them both the postoperative bone scan and X-rays showed no pathological results. In 10 women with histologically negative bone biopsies, metastases to the bone were diagnosed by bone scan and radiological methods. Random perioperative iliac bone biopsy cannot be recommended in patients with primary breast cancer. Iliac crest biopsy is relevant in certain scenarios (e.g. suspected recurrence, doubtful bone scan).

[Doppler score for evaluating perinatal risk]. / Doppler-Score zur Beurteilung des perinatalen Risikos.

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.

Prognostic relevance of urokinase plasminogen activator detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.

Patients with an elevated level of urokinase plasminogen activator (uPA) in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of uPA detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both iliac crests in 280 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: 2E11, which detects TAG 12--a tumour-associated glycoprotein typically expressed by almost all breast cancer cells--and the anti-uPA antibody HD-UK9. Thirty-five of the 2E11-positive women (n = 132, 47%) developed metastatic disease (median follow-up time 44 months). Of these, most were uPA positive (n = 23, 65%) and only 12 were uPA negative. Patients with uPA-positive cells in bone marrow (n = 98, 35%) had a significantly shorter metastasis-free interval (36 months) than women who were uPA negative (44.5 months). The worst prognosis was seen in patients positive for both markers (29.5 months), followed by those who were uPA negative and 2E11 positive (37 months). The detection of uPA on disseminated tumour cells characterizes a subgroup of patients with an even worse prognosis, who should undergo more aggressive adjuvant systemic therapy. For the first time, it was possible to evaluate an important qualitative parameter involved in the process of breast cancer metastases.

[The clinical value of Doppler ultrasound in obstetrics]. / Klinische Wertigkeit der Dopplersonographie in der Geburtshilfe.

Doppler sonography now has many indications in obstetrical diagnosis. Its wide and often uncritical application was the reason for our study group to confirm its importance. Moreover, we wanted to prove our own procedure. We made 950 Doppler examinations in a group of 449 pregnant women and correlated the results to the fetal outcome. Children with pathological Doppler findings showed a significantly lower birth weight of 599 g, a significantly lower duration of pregnancy of 6 days, a significantly higher rate of Caesarean sections and a significantly higher death rate compared to children with normal Doppler findings. Concerning Apgar- and pH-values there was not any significant difference between the two collectives. These results show that fetuses with pathological Doppler values or growth retardation can have the same prognosis as fetuses with normal Doppler findings if they are recognized and monitored at an early stage. The morbidity by acidosis can thus be reduced.

[Does measurement of absolute velocity by Doppler examination of pregnant patients contribute additional valuable information?]. / Liefert die Messung von Absolutgeschwindigkeiten bei der Doppleruntersuchung von Schwangeren wichtige Zusatzinformationen?

Ultrasonics is very important for the control of risk pregnancies. Routinely, Doppler-ratios are used to assess fetal danger. The aim of the presented study was to clarify whether measurement of absolute blood flow velocity is useful for the assessment of fetal development as well. For this purpose we examined the fetal aorta in 149 patients: 90 patients with fetal growth retarded fetuses and 59 patients with normally developed fetuses. Systolic and diastolic peak velocities and the resistance index (RI) were measured. The absolute velocities did not show any correlation to the fetal growth. Moreover, there was no correlation between systolic peak velocity and resistance index, independent of degree of pathology. The diastolic peak velocity however correlated with high significance to the RI thus being directly dependent.

[Initial experiences with a new color technique: ultrasound angiography]. / Erste Erfahrungen mit einer neuen Farbtechnik: die Ultraschall-Angiographie.

The sonographic diagnosis can be expanded by Color Doppler. Nevertheless something is missing, especially concerning the demonstration of the very slow velocities as it can be found in neovascularized malignant tumors. A recently developed new color technique--the Angio-Color of the Diasonics Corporation, Sonotron (other companies have prototypes of this color)--promises to improve the detection of very low flow velocities. Due to a method very different to the conventional Doppler technique the registered signal is coded in the color image of the blood flow: that means that the amplitude and not the frequency shift is coded in color. Therefore there is less noise in the color mode with the possibility of showing the lower flow in comparison to the conventional Doppler. In Gynaecology and Obstetrics the advantages in the demonstration of the placental blood flow were obvious. In eutrophic fetuses the blood flow could be registered over the whole breadth of placenta, while in dystrophic fetuses this was possible only at the margin of the placenta with some color pixels in the middle of the organ. The conventional Color Doppler was not able to show the flow in the placenta even in eutrophic fetuses. Also the flow in fetal organs produced different results using both methods. So the angio-technique showed more color pixels in the periphery. In 8 malignant breast tumors both methods were able to show blood flow, but the Angio-Color showed more color pixels as the conventional color did.(ABSTRACT TRUNCATED AT 250 WORDS)

[Blood supply of malignant and benign tumors of the internal genitals]. / Die Durchblutung maligner und benigner Tumoren des inneren Genitale.

Malignant tumours differ mostly from benign lesions in their blood supply. This fact can be used in the sonographic diagnosis of the tumour status. This, however, depends on the availability of ultrasound equipment, capable of demonstrating this difference, which can only be detected in smallest blood vessels, in which the blood flow is extremely slow. We employed the Sonolayer SSH 140A (Toshiba, Japan) and the Quantum 2000 (Siemens, Germany) for diagnosis of lesions of the female inner genital tract. Both instruments could visualize the slow blood flow velocities in the tissues examined. Diagnosis of blood circulation in tumours of the inner genital tract thus seems less dependent on the technology employed as is the case in examining the breasts. 41 patients with ovarian tumours, 31 with endometrial pathology, and 33 with cervical lesions were examined preoperatively. Findings were correlated to histology. The lowest resistance index (RI) measured was evaluated. The following RI values were found: Ovarian tumours: malignant 46%, benign 78% (49%). Tumours of the corpus uteri: malignant 54%, benign 65% (55%). Cervical lesions: malignant 55%, benign 79% (58%). Results in premenopausal women with non-malignant lesions are specified in brackets. Pre- and postmenopausal status proved essential. When compared to breast findings, the difference between benign and malignant tumours of the inner genital tract is less pronounced due to the fact, that, physiologically, these tissues are characterised by a higher blood supply. Differentiation was thus almost impossible in premenopausal women. However, in menopausal patients, a highly significant difference between benign and malignant tumours was found, which could serve as basis for tumour status prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of intracavitary irradiation on the venous system of the pelvis and leg]. / Einfluss der intrakavitären Bestrahlung auf das Becken-Beinvenensystem.

A late complication of combined radiotherapy for malignoma of the inner genital tract is leg edema, whether of venous or lymphatic origin, which is not always clear. To analyse the influence of radiotherapy upon the pelvic and leg venous system, we performed sonographic caliber, occlusion plethysmographic and light reflexion rheographic measurements of veins in 32 patients prior and subsequent to irradiation. No statistically significant difference was found between mean values measured with the different methods. A clear deterioration of venous function was detected after treatment. Sonographic examinations of pelvic vessels after radiotherapy showed veins much less clearly outlined and with thicker walls, thus pointing to a direct connection between irradiation and edema of the vein wall. Whereas deterioration of the other parameters may also be explained by, for example, long periods of lying. Since according to our own observations, an insufficiency of the leg venous valves occurs relatively often, sometimes even years later, there is a clear correlation between irradiation and edema of the venous wall, with a slight deterioration of venous function detectable directly after irradiation. In order to prevent vein damage, prophylaxis of thrombosis and vessel topography should therefore always be considered when planning radiotherapy.

[The value of Doppler imaging of the aorta, carotid artery and middle cerebral artery in obstetric diagnostics]. / Untersuchungen zur Wertigkeit der Dopplerbefunde von Aorta, A. carotis und A. cerebri media und der geburtshilflichen Diagnostik.

The relation of blood blow in the fetal aorta and carotis is a marker for the well being of the unborn child. Increase of cerebral vascularity associated with decrease of blood flow in the aorta is a sign for a fetal risk situation. It is, however, of disadvantage that the fetal carotis is often difficult to image with an wedge-shaped angle between doppler beam and vessel. We therefore included screening of an intracerebral vessel (a. cerebri media) in order to find out whether examination of this vessel, much more easier to perform, may have a similar diagnostic value or be an even more sensitive prognosticator of fetal risk than the carotis. In two hundred and forty patients in the 29th to 40th week of gestation all these three vessels were scanned with the duplex system AI 3200, Dornier company, Germany. The result was correlated to sonographic biometry, birth weight, and mode of delivery. It could be proven that when analyzing individual findings, pathology in the risk groups is much higher, whereas mean values showed less marked differences between risk and control groups. Our results suggest that the a. cerebri media is a slightly more sensitive indicator of fetal risk, since in this vessel retrograde resistance can be detected earlier and is more evident. A combination between assessment of the aorta and a cerebral vessel, is however, the method of choice in cases of pathological findings in diagnosis of fetal well being, since only examination of a peripheral and a central vessel results in an exact diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)