[Acardius or "twin-reversed arterial prefusion" sequence. Report of four cases and review of current therapeutic possibilities]. / Akardius oder "Twin-Reversed-Arterial-Perfusion"-Sequenz. Bericht über 4 Geminigraviditäten und Ubersicht über den aktuellen Stand der therapeutischen Möglichkeiten.

We describe four cases of acardius (one of hemiacardius, two of holoacardius acephalus, and one of the holacardius amorphus) and present the current range of therapeutic possibilities: control of amniotic fluid by repeated amniocentesis or indomethacin therapy, administration of digoxin to the mother, selective preterm delivery of the acardiac twin by hysterotomy, interruption of the anastomoses by injection of thrombogenic coils, sclerosing agents, umbilical cord ligation, fetoscopic laser coagulation, and thermocoagulation.

Association between histomorphometry and biochemical markers of bone turnover in a longitudinal rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis.

Advanced tumor osteopathy is characterized by abnormal bone turnover. Using a rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis, the aim of the present study was to define the sequential changes in, and the association between, biochemical and histomorphometric indices of bone metabolism during the early stages of developing tumor osteopathy. Eight-month-old Wistar rats (n = 48) were subcutaneously inoculated with either 2 x 10(6) cells of the Walker carcinosarcoma 256, or saline on day 0, and treated with either saline or the bisphosphonate ibandronate until killing on day 8. Serum calcium (sCa), alkaline phosphatase (sTAP), and osteocalcin (sOC) and urinary calcium (uCa), deoxypyridinoline (uDPD), and pyridinoline (uPYD) were measured daily. In a second semilongitudinal experiment (n = 70), the number of osteoclasts and osteoblasts (N.Oc, N.Ob), trabecular bone volume (BV/TV), and osteoid volume (O.Ar) were assessed by histomorphometry. In untreated tumor-bearing animals, osteoclast numbers increased by 74% on day 3 (5.4 +/- 2.4 vs. 3.1 +/- 1.5/mm(2), p < 0.05), and trabecular bone volume fell by 24% on day 4 (12.5 +/- 2.0 vs. 15.8 +/- 1.2%, p < 0.05). Both time course and magnitude of these changes were closely reflected by an increase in uDPD (0.46 +/- 0.14 vs. 0. 31 +/- 0.15 nmol/12 h, p < 0.05) and uPYD on day 4 (1.44 +/- 0.25 vs. 1.03 +/- 0.3 nmol/12 h, p < 0.05), sCa (3.8 +/- 0.52 vs. 3.0 +/- 0. 13 mmol/L, p < 0.01), and uCa (0.13 +/- 0.08 vs. 0.03 +/- 0.01 mmol/12 h, p < 0.001) on day 6, and sTAP (254 +/- 127 vs. 120 +/- 40 U/L, p < 0.001) on day 7 (mean +/- SD), whereas sOC remained unchanged until day 8. When combining the results of the two experiments, a high correlation was found between the number of osteoclasts and the urinary excretion of PYD (r = 0.91) and DPD (r = 0.89). Treatment with ibandronate delayed hypercalcemia, abolished hypercalciuria, and accelerated bone resorption. We conclude that osteoclast activation is an early event in PTHrP-mediated osteolysis, which is closely reflected by the renal excretion of pyridinium cross-links of type I collagen. Therefore, specific biochemical markers of collagen breakdown may be useful as early indicators of developing tumor osteopathy.

Age-related changes in insulin-like growth factor I and II in human femoral cortical bone: lack of correlation with bone mass.

The concentration of insulin-like growth factor-I (IGF-I) in human cortical bone declines with age, but the relevance of this decline for cortical bone turnover and bone mass is unknown. In the present study, we simultaneously assessed the concentration of IGF-I and -II in cortical bone matrix and histomorphometric parameters of bone mass and bone turnover in 125 samples from the proximal human femur shaft. Bone width decreased by 27% and porosity increased by 100% in female cortical bone between the fourth and the ninth decade. Similar, but weaker, changes tended to occur in male cortical bone. The concentrations of both IGF species were correlated with the percentage of osteons undergoing bone remodeling. However, despite age-related decreases in both IGF species in men and in IGF-I in women, neither of the IGFs accounted for age-related or age-independent variability in cortical porosity or bone width. In conclusion, these data suggest that the local concentrations of IGF-I and -II are related to cortical bone turnover. In contrast, our study provides no evidence for a major role of bone matrix IGF-I and -II as determinants of cortical bone mass in elderly individuals. Whether other components of the IGF system may be stronger determinants of cortical bone loss remains to be determined.

[Resting cartilage and the growth plate in dystrophic dysplasia: case report and clinicopathologic characteristics as compared to pseudodystrophic dysplasia and type II atelosteogenesis]. / Ruhender Knorpel und Epiphysenfuge bei diastrophischer Dysplasie. Kasuistik und klinisch-pathologische Charakteristika im Vergleich zur pseudodiastrophischen Dysplasie und zur Atelosteogenese Typ II.

The authors describe the histopathology of the resting cartilage and the growth plate in a case of diastrophic dysplasia and review the differential diagnosis with pseudo-diastrophic dysplasia and atelosteogenesis type II.

Concentration of insulin-like growth factor (IGF)-I and -II in iliac crest bone matrix from pre- and postmenopausal women: relationship to age, menopause, bone turnover, bone volume, and circulating IGFs.

Insulin-like growth factor-I (IGF-I) and -II are important local regulators of bone metabolism, but their role as determinants of human bone mass is still unclear. In the present study, we analyzed the concentration of IGF-I and -II in the bone matrix of 533 human biopsies from the iliac crest that were obtained during surgery for early breast cancer. There was an inverse association of bone matrix IGF-I concentration with age that was unaffected by menopause. Bone matrix IGF-I was positively associated with histomorphometric and biochemical parameters of bone formation and bone resorption and with cancellous bone volume. Based on the estimates of the linear regression analysis, women with a bone matrix IGF-I concentration 2 SD above the mean had a 20% higher bone volume than women with a bone matrix IGF-I concentration 2 SD below the mean. In contrast, serum IGF-I was neither correlated with bone turnover nor with bone volume and was only weakly associated with bone matrix IGF-I when adjusted for the serum concentration of IGF binding protein-3. Bone matrix IGF-II was positively associated with the osteoblast surface, but in contrast to IGF-I, tended to be positively associated with age and was unrelated to cancellous bone volume. In summary, our study suggests the following. 1) The concentration of IGF-I in cancellous bone undergoes age-related decreases that are similar to those of circulating IGF-I. 2) Menopause has no effect on this age-related decline. 3) Physiological differences in bone matrix IGF-I are associated with differences in iliac crest cancellous bone volume. 4) Bone matrix IGF-I is a better predictor of cancellous bone volume than circulating IGF-I. 5) The role of IGF-II in human bone tissue is clearly distinct from that of IGF-I.

Concentration of transforming growth factor beta in human bone tissue: relationship to age, menopause, bone turnover, and bone volume.

Transforming growth factor beta (TGF-beta) is thought to play an important role in bone metabolism, but its relationship to human bone turnover and bone mass has not been examined yet. In this study, we measured the concentration of TGF-beta in 811 samples of male and female bone from four representative sites of the human skeleton and in the supernatants of 72 short-term human bone marrow cultures from the iliac crest. The concentrations of TGF-beta1 and TGF-beta2 in the bone matrix were positively correlated with histomorphometric indices of bone resorption and bone formation and with serum levels of osteocalcin and bone-specific alkaline phosphatase. We also observed a positive association between the release of TGF-beta in the bone marrow cultures and serum osteocalcin. Changes in the rate of cancellous or cortical bone remodeling with age or menopause were accompanied by corresponding changes in skeletal TGF-beta. In contrast, there was no significant relationship between the concentration of TGF-beta and bone volume at any skeletal site. In conclusion, our study supports the hypothesis that TGF-beta plays an important role in human bone remodeling, but fails to demonstrate an association between the skeletal concentration of TGF-beta and human bone mass.

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).

In vitro and in vivo effects of tetrakisphosphonates on bone resorption, tumor osteolysis, ectopic calcification, and macrophages.

The biological effects of bisphosphonates in calcium-related disorders are attributed to the incorporation of the bisphosphonates in bone, enabling direct interaction with osteoclasts and/or osteoblasts. The high accumulation of bisphosphonates in bone, due to their high affinity to hydroxyapatite (HAP), is essential for mediating in vitro and in vivo activity. In this study we examined the activity of tetrakisphosphonates, molecules containing two P-C-P type bisphosphonate moieties connected by a carbon chain. The novel compounds were examined in a battery of in vitro and in vivo models including HAP formation and dissolution, ectopic calcification, bone resorption, tumor osteolysis, and of macrophage-like cells (anti- or pro-inflammatory properties). The inhibition of ectopic calcification was ranked as follows: geminal bisphosphonates > bisacylphosphonates > tetrakisphosphonates. Pamidronate, but not the tetrakisphosphonates, was an effective antiosteolytic agent. Neither DNTP (tetrasodium 1,9-dihydroxynonane 1,1,9,9-tetrakisphosphonate) nor the bisacylphosphonate, PiBP (pimeloylbisphosphonate) seem to possess strong macrophage suppressive or inductive effects and can be considered to be relatively inactive in terms of anti- or pro-inflammatory action. A significant anticalcification effect was caused by various phosphonates, such as the tetrakisphosphonates, but DNTP, a tetrakisphosphonate, was found toxic as it impeded somatic growth and bone development.

Bronchopneumonia disguising lung metastases of a painless central chondrosarcoma of pubis.

Chondrosarcoma is a generally locally malignant chondroid-forming bone tumor with a low potential for distant metastases. A small and completely painless central chondrosarcoma of pubis metastasizing to the lungs in a 63-year-old woman with bronchopneumonia is reported. Here we emphasize the mimicry and low growth of the chondrosarcoma and the easiness with which the diagnosis in completely asymptomatic patients can be missed. Although painless chondrosarcoma metastasizing to lung is rather rare, this tumor should be always included in the differential diagnosis of malignancies in this age category.

[Pathogenesis of bone metastasis and tumor osteopathies]. / Zur Pathogenese von Knochenmetastasen und Tumorosteopathien.

The development of bone metastases is a selective process in which the hematogenous dissemination of tumor cells into the bone marrow does not play a decisive role. In addition to the peculiarities of blood flow within the marrow sinuses, leading to an accumulation of circulating tumor cells, host organ specific factors (adhesion molecules, chemotactic signals, cytokines and growth factors) are pathogenetically involved. These factors are liberated from the bone matrix by osteoclasts, which are activated by a variety of osteotropic tumor factors. Thereby a tumor osteopathy develops, which by osteolytic bone destruction and tumor-enhanced remodelling may cause bone pain, pathological fractures and hypercalcemia of malignancy. So far only the late stage of macrometastases and the concomitant osteopathy can be diagnosed. Using immunocytological methods, tumor cells can now be detected in bone marrow aspirates during the early subclinical stage of tumor cell shedding. Tumor cell-positive bone marrow aspirates in general mean a worsening of the prognosis and may in breast cancer indicate those patients who are threatened by the development of bone metastases.

[Tumor-associated hypophosphatemic osteomalacia: case report and literature review]. / Tumorassoziierte, hypophosphatämische Osteomalazie: Fallpräsentation und Literaturübersicht.

Despite the great number of neoplastic entities, which are able to cause this disease, "oncogenous osteomalacia" is hardly known as a paraneoplastic phenomenon. Without removing the not constantly malignant tumor as the underlying cause recovery is not possible. Until now pathogenesis is unknown. Together with a review of the literature a case report is presented, in which a malignant fibrous histiocytoma of soft tissue caused an untreatable osteomalacia. Because of failure of local tumor control prognosis in this case must be considered fatal.

[Tumor simulating manifestations of renal osteopathy: differential diagnosis and follow-up clinical examples]. / Tumorvortüschende Manifestationen der renalen Osteopathie: Differentialdiagnose und exemplarische Verlaufsbeobachtungen.

The course of renal osteodystrophy possibly includes changes, which can mistakenly considered malignant. Especially dialysis-associated tumoral calcinosis may mislead to an inadequate aggressive surgical procedure. Spontaneous involution of these lesions takes place after subtotal parathyroidectomy. Brown tumors subsequent secondary hyperparathyroidism are extremely rare. During maintenance hemodialysis frequently appearing intraosseous cysts develop secondary to beta-2-microglobulin-amyloidosis. Surgery only should be performed in case of occurring pathologic fractures. Other cases are treated conservatively under continuous nephrologic supervision.

Prophylactic treatment of skeletal metastases, tumor-induced osteolysis, and hypercalcemia in rats with the bisphosphonate Cl2MBP.

BACKGROUND: The purpose of this study was to investigate the influence of a prophylactic bone protective treatment with the bisphosphonate dichloromethane/diphosphonic acid (Cl2MBP) in an experimental model of osteolysis with intraosseous implantation of the Walker carcinosarcoma 256 B. METHODS: The biphosphonate was given as a high-dose, short-term treatment (30 mg/5 days sc) followed by a treatment-free interval (1-7 weeks) or as a low-dose, long-term prophylactic treatment (2.5 or 5.0 mg/day/3 weeks sc). Osteolysis was measured with a radiographic and histologic grading system. RESULTS: The high-dose short-term prophylactic treatment was shown clearly to inhibit tumor osteolysis. The osteoprotective effect decreases with increasing length of the treatment-free interval. A similar positive result could be achieved following the low-dose long-term prophylactic treatment. Dosage could not be shown to influence the inhibition of tumor osteolysis in the long-term bone protective treatment. A possible direct influence of the treatment on tumor growth could be ruled out. The prophylactic treatment does not inhibit body weight increase. Animals treated prophylactically showed less weight loss than the controls after tumor implantation. CONCLUSIONS: These results show that a prophylactic treatment with Cl2MBPs protects the skeleton effectively against tumor osteolysis.

24R,25-dihydroxyvitamin D3 prevents aluminum-induced alteration of brain gangliosides in uremic rats by keeping the metal within perivascular astrocytes of the blood-brain barrier.

The administration of aluminum (Al) to uremic rats leads to Al accumulation in different brain regions with subsequent alteration of brain gangliosides. Addition of 24R,25-dihydroxyvitamin D3[24R,25-(OH)2D3] did not influence the brain Al content determined by plasma argon emission spectrometry, but prevented the decrease in brain gangliosides. By using electron microscopy and laser microprobe mass analysis, it was demonstrated that in rats given 24R,25-(OH)2D3 together with Al, the metal was mainly kept within perivascular astrocytes of the blood-brain barrier. On the contrary, in rats given Al only, the metal was evenly distributed throughout the brain areas causing extensive demyelination, chromatolysis of nerve cells in some brain regions (hippocampus) and brain edema. Our results could find application in the prevention of Al-induced encephalopathy in patients on hemodialysis.

[Sonography in therapy-oriented diagnosis and after-care of primary bone and soft tissue tumors]. / Die Sonographie in der therapieorientierten Diagnostik und Nachsorge von primären Knochen- und Weichteiltumoren.

Based on the results of 150 patients with primary tumors or the suspicion of malignant lesions of the locomotor system the perspectives and limits of the sonographic diagnosis under the therapeutic aspects of interdisciplinary oncologic cooperation is demonstrated. As the ideal adjunct to conventional roentgenograms, ultrasound is the first-line imaging procedure in the fields of primary diagnosis, follow-up, post-therapeutic care as well as tumor exclusion for methodic, patient-related and economic/logistic reasons. Its consequent application will markedly reduce the number of more invasive and expensive methods.

[The prognostic significance of tumor cell detection in bone marrow of patients with breast cancer]. / Prognostische Bedeutung des Tumorzellnachweises im Knochenmark von Patientinnen mit Mammakarzinom.

In 95% of patients with primary breast cancer, the extent of metastases cannot be proven by conventional methods. Nevertheless, more than 50% of these patients have a relapse within five years. To improve the predictive value for recurrency, we examined bone marrow aspirates of 128 patients with primary breast cancer. Bone marrow aspirates from 2-6 sites of the skeleton (iliac crest and sternum) were taken as well as biopsies for histological examination. The immunohistochemical studies were carried out on interphase smears and stained with cytoceratin antibodies (PKK 1) and antibodies against tumor-specific antigen TAG 12 (12 H 12). All patients were screened for distant metastases (X-ray, ultrasound, bone scan). Tumor cells and micrometastases in bone marrow were detected in 41 patients (32%). Their presence was correlated to other prognostic factors (tumor size, lymph node status, oestrogen/progesterone receptors). The median duration of follow-up was 39.5 months. 14 patients (45%) in the tumor cell positive group relapsed, compared to only 4 out of 36 patients in the tumor cell negative group. In 29% we found bone metastases. The relapse free interval was shorter for patients with micrometastases (8 vs. 15.8 months). The presence of tumor cells in bone marrow aspirates detected at the time of primary surgery, is a useful prognostic factor and a good predictor of metastases and may help in selecting patients for systemic adjuvant treatment.

Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies?

Bisphosphonates are compounds with a high affinity for bone and other calcified tissues. They inhibit tumor-induced bone destruction and the associated hypercalcemia by hindering the activity of the osteoclasts. Owing to a long biological half-life of bisphosphonates in the bone, a treatment using a prophylactic regimen seems possible. This paper summarizes preclinical studies with the bisphosphonate 3-amino-1-hydroxypropylidene-1,1-diphosphonic acid and two methyl derivatives; 3-N,N-dimethylamino-1-hydroxypropylidene-1,1-diphosphonic acid and 4-N,N-dimetyhlamino-1-hydroxybutylidene-1,1-diphosphonic acid with respect to their bone-protecting activity in therapy as well as in prophylaxis. To find substances that are useful for the treatment of primary tumor, as well as bone metastasis, we synthesized and tested cis-diammine[nitrilotris(methylphosphonato)(2-)-O1,N1]platin um(II) and cis-diammine[( bis-(phosphonatomethyl)amino]acetato(2-)-O1,N1)platinum(II), which contain both an osteotropic and an antineoplastic moiety. Experiments were carried out: (a) in the intratibial transplanted Walker carcinosarcoma 256B of the rat, which mimics osteolytic bone metastasis, and (b) in the transplantable osteosarcoma of the rat, which shows a histology and metastatic pattern similar to that found in man. These investigations indicate that it is possible to effect adjuvant therapy of bone metastases by combination of two compounds with different properties into one structure without losing the therapeutic characteristics of the parent compounds. They thus provide evidence that it may be possible to design compounds well suited for the therapeutic or prophylactic treatment of bone-related malignancies.

Effects of parathyroidectomy on tissue calcium, phosphorus, magnesium, and copper concentrations in aluminum-loaded uremic rats.

Rats were subjected to a two-stage 5/6 nephrectomy and treated with Al for 2 and 4 wk with a cumulative dose of 4.2 and 8.4 mg of Al, respectively. Other animals were parathyrectomized (PTx) and loaded with 8.4 mg of Al for 4 wk. Total Al, Ca, P, Mg, and Cu contents were analyzed in the liver, kidney, and bone by inductively coupled plasma atomic emission spectrometry (ICP-AES). The results showed that Al given to growing uremic rats significantly increased the content of Al in the liver, kidney, and bone. Moreover, Al treatment increased the liver and kidney Ca levels and decreased the Ca and P values in bone. Previous parathyroidectomy significantly reduced Al accumulation within organs and changes in the Ca and P levels in the bone, liver, and kidney. The result was not influenced by different degrees of renal failure.