Impact of Single Center Treatment on Ewing Sarcoma 10-Year Long Term Survival Rates.

PURPOSE OF THE STUDY Ewing sarcomas (ES) are the second most common solid malignant bone tumors in both, children and adolescents, and systemic chemotherapy protocols were established during the last 3 decades which proved to be a successful approach in addition to local treatment. The purpose of the present study is (i) to provide survival rates and prognostic factors for patients with ES which received treatment in a single center and (ii) to compare data with results of multicenter studies. MATERIALS AND METHODS Patients (n = 38) were treated by the same surgeon whereas surgery was combined with radiotherapy in 55.3% of the patients (n = 21). Median age at diagnosis was 17.5 years (4.7-60) and the median follow-up time for all patients was 8.2 years (9.8 years for survivors, 3.2 years for non-survivors). RESULTS The survival rate for metastasis free sarcoma decreases from 90.5% to 50% for patients diagnosed with disseminated disease stage. Patients with a good response to chemotherapy survived in 83.3% of the cases. In addition, a higher OS was found for patients younger than 15 years (82.4%) when compared to patients older than 15 years (73.3%). In contrast, multicenter studies reported lower survival rates for metastasis free (~60%) and metastasis stages (< 40%). DISCUSSION The survival rates in the present single center study are higher than the rates reported from multi-center studies although same chemotherapy protocols were used and no substantially difference are apparent for patient population. CONCLUSIONS Based on the present data we re-emphasize that patients with Ewing sarcoma receive appropriate treatment in a large and qualified center particularly considering the survival rates. In addition, our data underline that a close collaboration between the oncological team and the experienced surgeon is crucial for patient's care. Key words: Ewing sarcoma, survival rate, single center, prognostic factors, chemotherapy, surgery, multi center, single center.

[Acetabuloplasty - The Dega and Pemberton technique]. / Beckenosteotomie nach Dega und Pemberton.

BACKGROUND: Hip dysplasia is the most common congenital deformity requiring surgical correction osteotomy in order to prevent early onset of secondary hip arthrosis. The shape of the acetabulum can be modified by Dega or Pemberton osteotomy and is indicated for hip dysplasia and luxation with irregularities of the socket for children aged between 2 and 12 when the y­physis is still open. METHOD: We will describe indication, contra-indication, preoperative planning as well as details of the Pemberton technique. In addition, we will provide practical advice based on our long-standing experience. RESULTS: We present long-term results from the literature and also from our department. In addition, we will explain and critically discuss our own experiences and the risks and complications of surgical techniques. Good long-term results are reported for acetabuloplasties and Salter osteotomy which are preferred for surgical treatment of hip dysplasia in early life. Advantages and disadvantages of both surgical techniques will be compared in the discussion section. CONCLUSION: Dega and Pemberton acetabuloplasty shows good long-term results regarding prevention of a secondary coxarthrosis. However, correct indication is crucial since this surgical technique is more difficult compared to Salter osteotomy but is also associated with a higher correction potential and a lower complication rate.

Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors.

BACKGROUND: Synovial sarcoma (SS) is a malignant soft tissue sarcoma with a poor prognosis because of late local recurrence and distant metastases. To our knowledge, no studies have minimum follow-up of 10 years that evaluate long-term outcomes for survivors. PATIENTS AND METHODS: Data on 62 patients who had been treated for SS from 1968 to 1999 were studied retrospectively in a multicenter study. Mean follow-up of living patients was 17.2 years and of dead patients 7.7 years. RESULTS: Mean age at diagnosis was 35.4 years (range 6-82 years). Overall survival was 38.7%. The 5-year survival was 74.2%; 10-year survival was 61.2%; and 15-year survival was 46.5%. Fifteen patients (24%) died of disease after 10 years of follow-up. Local recurrence occurred after a mean of 3.6 years (range 0.5-14.9 years) and metastases at a mean of 5.7 years (range 0.5-16.3 years). Only four patients were treated technically correctly with a planned biopsy followed by a wide resection or amputation. Factors associated with significantly worse prognosis included larger tumor size, metastases at the time of diagnosis, high-grade histology, trunk-related disease, and lack of wide resection as primary surgical treatment. CONCLUSIONS: In SS, metastases develop late with high mortality. Patients with SS should be followed for >10 years.

Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury.

The role of a local angiotensin system in the vascular response to arterial injury was investigated by administering the angiotensin-converting enzyme (CE) inhibitor cilazapril to normotensive rats in which the left carotid artery was subjected to endothelial denudation and injury by balloon catheterization. In control animals, by 14 days after balloon injury, the processes of smooth muscle cell (SMC) proliferation, migration of SMCs from the media to the intima, and synthesis of extracellular matrix produced marked thickening of the intima, with reduction of the cross-sectional area of the lumen. However, in animals that received continuous treatment with the CE inhibitor, neointima formation was decreased (by about 80 percent), and lumen integrity was preserved. Thus, the angiotensin-converting enzyme may participate in modulating the proliferative response of the vascular wall after arterial injury, and inhibition of this enzyme may have therapeutic applications to prevent the proliferative lesions that occur after coronary angioplasty and vascular surgery.

Distinct mechanism for antidepressant activity by blockade of central substance P receptors.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

Randomized, Placebo Controlled Trial of NPT088, A Phage-Derived, Amyloid-Targeted Treatment for Alzheimer's Disease.

The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer's disease. Previous studies showed that NPT088 treatment reduced ß-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer's disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in ß-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer's disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer's disease symptoms was observed.

Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons.

Homozygous Igf1-/- mice at 2 months of age had reduced brain weights, with reductions evenly affecting all major brain areas. The gross morphology of the CNS was normal, but the size of white matter structures in brain and spinal cord was strongly reduced, owing to decreased numbers of axons and oligodendrocytes. Myelinated axons were more strongly reduced in number than unmyelinated axons. The volume of the dentate gyrus granule cell layer was reduced in excess of the decrease in brain weight. Among populations of calcium-binding protein-containing neurons, there was a selective reduction in the number of striatal parvalbumin-containing cells. Numbers of mesencephalic dopaminergic neurons, striatal and basal forebrain cholinergic neurons, and spinal cord motoneurons were unaffected. Cerebellar morphology was unaltered. Our findings suggest cell type- and region-specific functions for IGF-I and emphasize prominent roles in axon growth and maturation in CNS myelination.

GDNF induces a dystonia-like state in neonatal rats and stimulates dopamine and serotonin synthesis.

To test whether glial cell line-derived neurotrophic factor (GDNF) regulates the development of nigral dopaminergic neurons in vivo, neonatal rats received bilateral injections of GDNF into the striatum. Injections at postnatal day 2 induced a unique transient behavioral pattern characterized by forelimb hyperflexure, clawed toes of all limbs, and a kinked tail. Parallel to the behavioral changes, the levels of striatal and ventral mesencephalic dopamine and serotonin were increased from 60% to 100% with a proportional increase of principal metabolite levels. GDNF increased tyrosine hydroxylase activity in the ventral mesencephalon, but did not affect striatal activity of choline acetyltransferase and GABA uptake. GDNF failed to induce sprouting of dopaminergic neurites. Our findings suggest that during development striatal GDNF regulates the capacity of dopaminergic and of serotonergic neurons for neurotransmitter production and release.

Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation.

REK7 is an Eph-related tyrosine kinase receptor expressed exclusively in the nervous system, predominantly in hippocampus and cortex. A soluble REK7-IgG fusion protein, produced to analyze the biological role of REK7, prevents axon bundling in cocultures of cortical neurons with astrocytes, a model of late stage nervous system development and differentiation. Using REK7-IgG as an affinity reagent, we purified and cloned a novel REK7 ligand called AL-1, a GPI-linked protein homologous to other members of an emerging ligand family. Membrane attachment of AL-1 appears necessary for receptor activation, since REK7 on cortical neurons is efficiently activated by transfected cells expressing GPI-linked AL-1, but not by soluble AL-1. Consistent with this, soluble AL-1 blocks axon bundling. Our findings, together with the observation that both molecules are expressed in the brain, suggest a role in the formation of neuronal pathways, a crucial feature of nervous system development and regeneration.

BDNF mRNA expression in the developing rat brain following kainic acid-induced seizure activity.

Brain-derived neurotrophic factor (BDNF) mRNA expression was studied in the hippocampus at various developmental stages in normal rats and following kainic acid (KA)-induced seizure activity. Systemic administration of KA strongly elevated BDNF mRNA levels in all hippocampal subregions after postnatal day 21. In contrast, even though KA induced intense behavioral seizure activity at postnatal day 8, the seizures were not associated with elevations of BDNF mRNA levels, indicating a clear dissociation between behavioral seizures and increases in BDNF mRNA levels and contradicting the view that BDNF mRNA expression is principally regulated by neuronal activity. In the dentate gyrus at postnatal day 13, intense BDNF mRNA expression was limited to a defined area at the border between granule cell and molecular layers, suggesting the possibility that segregation of BDNF mRNA into defined subcellular compartments may play a role in establishing the well-delineated patterns of innervation in the hippocampus.

Reconstruction with non-vascularised fibular grafts after resection of bone tumours.

We evaluated 31 patients who were treated with a non-vascularised fibular graft after resection of primary musculoskeletal tumours, with a median follow-up of 5.6 years (3 to 26.7 years). Primary union was achieved in 89% (41 of 46) of the grafts in a median period of 24 weeks. All 25 grafts in 18 patients without additional chemotherapy and/or radiotherapy achieved primary union, compared with 16 of the 21 grafts (76%; 13 patients) with additional therapy (p=0.017). Radiographs showed an increase in diameter in 70% (59) of the grafts. There were seven fatigue fractures in six patients, but only two needed treatment. Non-vascularised fibular transfer is a simpler, less expensive and a shorter procedure than the use of vascularised grafts and allows remodelling of the fibula at the donor site. It is a biological reconstruction with good long-term results, and a relatively low donor site complication rate of 16%.

Treatment of shepherd's crook deformity in patients with polyostotic fibrous dysplasia using a new type of custom made retrograde intramedullary nail: a technical note.

AIMS: The severe form of coxa vara, the 'shepherd's crook deformity', is always a consequence of a locally extensive form of polyostotic fibrous dysplasia (or McCune-Albright syndrome). Treatment of this deformity is a challenge. The soft bone does not tolerate any implant that depends on the stability of the cortical bone (like plates or external fixators). Intramedullary nails are the most appropriate implants for stabilisation, but if they are inserted from the greater trochanter, they cannot correct the varus deformity enough. PATIENTS AND METHODS: We have developed a special intramedullary nail that can be inserted from the osteotomy site and can be driven retrograde into the femoral neck in an appropriate valgus position. We have operated 15 legs in 13 patients. The average age at surgery was 14 years and 5 months (6 to 28.9). In all, 11 femora had been operated before (unsuccessfully) with various implants. RESULTS: The average follow-up was 54.2 months (7 to 132). The average correction of the neck/(distal) shaft angle was 57.5° (10° to 80°) ( = 72.8%). While pre-operatively none of the patients was able to walk without aid, at follow-up only one patient was unable to walk, three used the aid of crutches because of tibial lesions and one patient had an increased external rotation of the leg. At follow-up, most patients were free of pain. One implant broke and had to be replaced. CONCLUSION: This new operative method offers the possibility of efficient correction and stabilisation of this severe and difficult deformation.

Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats.

The function of the endothelium is impaired in hypertension. In spontaneously hypertensive rats (SHR), acetylcholine-induced relaxation is decreased and serotonin-induced constriction is increased. The goal of our study was to evaluate the effect of a long-term treatment with cilazapril, a new angiotensin converting enzyme inhibitor, or hydralazine, a vasodilator, on the endothelium-dependent responses in aorta of SHR. Wistar-Kyoto rats were used as normotensive reference. Isolated aortic rings with or without endothelium were suspended in organ chambers. The rings with intact endothelium were contracted with norepinephrine. Acetylcholine-induced relaxation was markedly enhanced by cilazapril treatment. The tension achieved at maximal relaxation was 8 +/- 4% of norepinephrine contraction in the cilazapril-treated SHR versus 55 +/- 5% in the untreated SHR (p less than 0.001). Hydralazine had no significant effect. The effect of serotonin was also markedly modified by cilazapril. In untreated SHR, serotonin induced the release of a vasoconstrictor substance by the endothelium as assessed by the ratio of maximal tension induced by serotonin in rings with endothelium over maximal tension in rings without endothelium, which was greater than 1. This ratio was reversed in cilazapril-treated SHR but not in hydralazine-treated SHR. Captopril had effects similar to cilazapril. Finally, evaluation of carotid arteries showed that cilazapril also prevented morphological changes of the intima in SHR (i.e., infiltration by mononuclear cells). We conclude that angiotensin converting enzyme inhibitors prevent the functional and morphological alterations in endothelium that are found in hypertension and speculate that this action might participate in their antihypertensive effect.

Effects of cilazapril on the cerebral circulation in spontaneously hypertensive rats.

Chronic hypertension is associated with a lower cerebral vascular reserve due to thickening of the media of cerebral vessels. The goal of the present study was to determine if long-term inhibition of angiotensin converting enzyme with cilazapril, a new long-acting angiotensin converting enzyme inhibitor, could improve cerebral vascular reserve. For this purpose, two groups of 12 spontaneously hypertensive rats were compared. One group was treated with 10 mg/kg/day cilazapril from 14 weeks to 33 weeks of age and was compared with a group treated with placebo. A third group of 12 Wistar-Kyoto rats treated with placebo was used as reference. At the end of the treatment period, cerebral vascular reserve was evaluated by measuring cerebral blood flow (radioactive microspheres) at rest and during maximal vasodilation induced by seizures provoked by bicuculline. Then, the rats were perfusion-fixed, and morphometry of the cerebral vasculature was performed. Cerebral vascular reserve was severely impaired in the spontaneously hypertensive rats since their maximal cerebral blood flow was decreased by 52% compared with the Wistar-Kyoto rats. Cilazapril normalized cerebral blood flow reserve. This normalization was associated with a decreased thickness of the medial layer in the carotid artery, the middle cerebral artery, and in the pial arteries larger than 100 microns. Further studies are required to determine whether this decreased medial thickness is due to the normalization of blood pressure induced by cilazapril or to the reduction of trophic factors such as angiotensin II.

Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition.

Hypertension is associated with an impairment of endothelium-dependent relaxation. The angiotensin converting enzyme inhibitors captopril and cilazapril can prevent this endothelial dysfunction. We recently observed that long-term treatment with cilazapril could also prevent subendothelial infiltration by mononuclear cells in spontaneously hypertensive rats. This prompted us to examine whether, in spontaneously hypertensive rats, endothelial dysfunction and subendothelial infiltration by mononuclear cells are associated. These cells were characterized as monocyte macrophages. Infiltration by monocyte macrophages was quantified by morphometry. Endothelial function was estimated by calculating serotonin ratio (maximal contraction to serotonin on isolated arterial rings with endothelium over maximal contraction on paired rings without endothelium). The regional distribution of endothelial dysfunction and subendothelial monocyte macrophages was similar. Both were maximal in the carotid artery, less in the aorta, and nonexistent in the renal artery. A 2-week treatment with cilazapril decreased both endothelial dysfunction (serotonin ratio decreased by 32%) and the number of subendothelial monocyte macrophages in the aorta, which decreased by 38%. We conclude that in spontaneously hypertensive rats, endothelial dysfunction and subendothelial monocyte macrophage infiltration are associated and that cilazapril can decrease both. The observation that angiotensin converting enzyme inhibitors affect subendothelial accumulation of monocyte macrophage may lead to a better understanding of the mechanism of action of this class of drugs.

Role of angiotensin II in injury-induced neointima formation in rats.

Angiotensin converting enzyme inhibition markedly suppresses neointima formation in response to balloon catheter-induced vascular injury of the rat carotid artery. To determine whether this effect was mediated through the vasoactive peptide angiotensin II (Ang II), two approaches were followed. First, the balloon model was used to compare the effects of continuous infusion of Ang II, with and without concurrent converting enzyme inhibition by cilazapril; second, the effects of the orally active nonpeptidic Ang II receptor antagonist DuP 753 were analyzed. Morphometric analysis was performed at 14 days after balloon injury. Animals that received continuous infusion of Ang II (0.3 micrograms/min/rat) were found to have significantly greater neointima formation in response to balloon injury than controls. Animals treated with cilazapril (10 mg/kg/day) had markedly reduced neointima formation, but in animals receiving infusion of Ang II, treatment with cilazapril did not suppress development of neointimal lesions. In the second group of experiments, DuP 753 (10 mg/kg twice daily) was as effective to prevent neointima formation as cilazapril. These data support the conclusions that converting enzyme inhibition prevents neointima formation after vascular injury through inhibition of Ang II generation.

Heparin and cilazapril together inhibit injury-induced intimal hyperplasia.

Both heparin and the angiotensin converting enzyme inhibitor cilazapril inhibit intimal thickening in rat carotid arteries injured by the passage of a balloon catheter. The purpose of this study was to determine if combinations of the two drugs were more effective than either drug alone and whether the effect could be accounted for by inhibition of smooth muscle cell proliferation. Heparin (0.1-0.3 mg/kg/hr) administered by continuous intravenous infusion with or without cilazapril (0-25 mg/kg/day p.o.) produced a dose-dependent inhibition of smooth muscle accumulation at 14 days after rat carotid ballooning. At the lower doses, the inhibitory effects of heparin and cilazapril were additive when the drugs were used together. This overall effect on growth was reflected in decreased smooth muscle cell proliferation at 2 and 7 days. A 7-day course of heparin combined with cilazapril, a regimen that might be applicable in the clinical setting, produced an 80% inhibition of intimal thickening at 28 days. These results provide evidence that heparin and cilazapril together might prove to be more effective than either drug alone in the control of intimal hyperplasia after arterial injury.

Development of effective therapy for Alzheimer's disease based on neurotrophic factors.

Neurotrophic factors play a major role in brain development and function. Because administration of these factors can attenuate degeneration of neurons and behavioral deficits in animals, such molecules may become useful in the treatment of AD. At the present time, a solid rationale can be made for clinical trials with NGF, given the pronounced trophic effect of NGF on forebrain cholinergic neurons and the cholinergic atrophy occurring in AD. Future research in the following areas will be crucial toward development of successful neurotrophic factor therapy: (a) New research should focus on identifying new neurotrophic factors, which protect other vulnerable neurons in AD, in particular hippocampal and cortical neurons; (b) Multiple available strategies should be pursued to find ways to deliver neurotrophic proteins across the blood-brain barrier. In addition, a broadly based effort to establish a small-molecule pharmacology of neurotrophic factors is likely to lead to clinically useful drugs; (c) Regulatory guidance is necessary to establish ethically acceptable designs for clinical trials to unequivocally establish efficacy of drugs that attenuate the progression of AD.