Zusammenfassung Untersucht werden Rehaprozesse bei ambulanten und stationären Patienten nach radikaler Prostatovesikulektomie. Insgesamt wurden zu Rehabeginn Motivation und Erwartungen von 119 ambulanten und 719 stationären Patienten (≤64 Jahre) erfasst sowie am Ende Zufriedenheit und therapeutische Leistungen. Ambulante Patienten weisen einen höheren sozio-ökonomischen Status und eine bessere körperliche Verfassung auf. Bezüglich Motivation, Erwartungen und Zufriedenheit bestehen kaum Unterschiede. Beide Gruppen unterscheiden sich nicht in der Menge an erhaltenen Leistungen. Allerdings liegen z.T. Unterschiede in der Art der Maßnahmen vor. Ambulante und stationäre Reha sind hinsichtlich der Menge an therapeutischen Leistungen vergleichbar. Diskrepanzen in der Art der Leistungen sind auf das unterschiedliche Patientenklientel zurückzuführen. Die Studie gibt Hinweise auf settingspezifische Patientenmerkmale, was in größeren Stichproben zu verifizieren ist.

We evaluated processes in in- and outpatient rehabilitation after radical prostatectomy. Overall, we analyzed motivation and expectations of 119 in- and 719 outpatients (aged≤64) at the beginning of rehabilitation as well as satisfaction and the amount of interventions at the end. Compared to inpatients outpatients had a higher socio-economic status and better physical condition. Both groups reported similar outcomes regarding motivation, expectation and satisfaction. Furthermore in- and outpatients got a comparable amount of interventions, but both groups differed to some extent in regard to the kind of interventions. In- and outpatients are comparable in regard to their received amount of interventions. Discrepancies concerning the kind of interventions are due to differences between in- and outpatients. The results indicate specific patients' characteristics in both settings, but more research is needed to verify these findings.

15127 Background: Postoperative nutritional status is a major factor determining the outcome after gastrectomy for gastric cancer. However, weight loss is a regular consequence after gastrectomy for gastric cancer. This weight reduction occurs during the first months, after which the weight curve seems to stabilize. Aim of this study was to determine the effect of maltodextrin supplemented diet on postgastrectomy weight loss. Methods: In 2005 we introduced a liquid supplementation of maltodextrin to the conventional solid dietary schedule of patients who had underwent gastrectomy for gastric cancer. Between 01/2005 and 6/2006 87 consecutive patients with gastric cancer were included in the study. They were admitted to our hospital for a 3–4 weeks period of oncological rehabilitation, median age was 70 years, gastrectomy had been carried out up to 8 months before study inclusion. Oral nutrition followed the recommended dietary guidelines to avoid postgastrectomy dumping syndrome. This diet was supplemented with 150 g of maltodextrin, dissolved in 1 litre of tea (600 kcal). Weight changes in this study population were compared to a control population of 65 consecutive patients with gastric cancer who had been admitted to our hospital between 01/1992 and 12/1993, matching the same inclusion criteria as the study population but fed without the supplementation of maltrodextrin. Results: During the 3–4 weeks rehabilitation period patients from the maltodextrin study group were able to reach an average weight gain of 407g while patients from the control group lost in average 352 g during the same time span. We observed that weight gain substantially improved the psychological condition of the patients. Postgastrectomy dumping syndrome was similar in both groups depending on strict control of the dietary schedule. Conclusions: We conclude that a maltodextrin supplemented diet can effectively prevent postoperative weight loss during the first months after gastrectomy for gastric cancer. No significant financial relationships to disclose.

3076 Background: DPD represents the initial and rate-limiting enzyme in the catabolism of 5-FU. Deficiency of DPD has been linked to toxic side effects of 5-FU. The most common mutation of the DPD gene resulting in severe DPD deficiency is a G to A mutation in the GT 5’-splice recognition site of intron 14 (exon 14 skipping mutation). The corresponding mRNA lacks exon 14 and the enzymatic activity of the translated DPD protein is virtually absent. In a clinical setting heterozygous and homozygous carriers are being observed. Methods: We developed an RT-PCR based assay suitable for routine identification of the exon 14 skipping mutation. From February 2001 to October 2004 we performed an open, uncontrolled, prospective multicenter study to evaluate the prevalence and genotype/phenotype correlation of the exon 14 skipping mutation in patients treated with 5-FU chemotherapy. 1455 patients from 70 clinical centers in Germany were included in the study. Results: We identified 15 heterozygous carriers confirming a prevalence of 1% in the Caucasian population. For the analysis of 5-FU related toxicity WHO grades were ranked with a toxicity index revealing a significant higher toxicity in heterozygous compared to wildtype patients (p<0.0001). 50% of the heterozygote patients subsequently were treated with reduced doses of 5-FU. Nonetheless the positive predictive value of the screening test was still 50% indicating a strong correlation between genotype and phenotype. To identify patients in risk of severe 5-FU related toxicity we performed 5-FU pharmacokinetics in 12 heterozygous patients and 8 wildtype patients. All heterozygous patients showed a pathological 5-FU half-life with broad variations after intravenous bolus application of 450 mg/m2 5-FU while 75% of the wildtype controls had physiological results. Conclusions: We conclude that routine testing for the exon 14 skipping mutation and additional 5-FU pharmacokinetics for heterozygous patients prior to 5-FU treatment is an important step towards individually tailored therapy in cancer patients. [Table: see text]

In recent studies, we and others have demonstrated that bone morphogenetic protein-2 (BMP-2) promotes vascularization, inhibits hypoxic cell death of cancer cells and may be involved in tumor angiogenesis. The activation of circulating endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) represents a crucial factor in the process of postnatal neovascularization. BMP-2 protein expression has been detected in several tumor tissues and BMP receptors are expressed in EPCs and MSCs. We therefore analysed the influence of recombinant human (rh) BMP-2 on the function of human EPCs and human bone marrow derived MSCs. Treatment of EPCs isolated from peripheral blood with rhBMP-2 did not induce any significant changes in EPC viability but induced a dose-dependent activation of chemotaxis. Incubation of human MSCs isolated from bone marrow aspirates with rhBMP-2 revealed no significant effect on MSC proliferation. Incubation of EPCs with supernatants of MSCs significantly increased the cell viability compared to controls cultivated with endothelial cell medium. Protein and mRNA expression of the vascular endothelial growth factor (VEGF) family member, placental growth factor (PlGF), which is known to be involved in the expansion and recruitment of EPCs, was induced in MSCs after treatment with rhBMP-2. We conclude that tumor- associated BMP-2 secretion might promote tumor angiogenesis by chemotactic effects on EPCs circulating in the peripheral blood and by increased secretion of paracrine angiogenic growth factors including PlGF in MSCs of the tumor stroma.

Tumor hypoxia leads to adaptive responses in cancer cells, including an induction of vasculogenesis initiated by circulating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs). The aim of the present study was to correlate the number of EPCs and CECs with the oxygenation of cervical cancer. Blood concentrations of EPCs were detected by FACS analysis with antibodies for CD34 and vascular endothelial growth factor receptor 2 (VEGFR2). CECs were evaluated by double staining for 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled acetylated low density lipoprotein (Di-LDL) and lectin in a cell culture assay. Ten patients with cervical cancer were compared with ten healthy volunteers. Intratumoral oxygen tension was assessed polarographically with the computerized Eppendorf histography system. Analysis of CEC numbers revealed no difference between patients and controls. However, patients had lower concentrations of CD34-positive hematopoietic stem cells (HSCs) but a significantly higher fraction of EPCs related to the number of HSCs (1.09% versus 0.53%). This fraction was significantly inversely correlated to the median oxygen tension (r = -0.74, p = 0.015). Our study shows for the first time a significant inverse correlation between the fraction of EPCs and intratumoral oxygen tension. We conclude that the fraction of EPCs should be further evaluated as a useful and convenient marker in the prediction of tumor tissue oxygenation.

Solid tumors often have an inadequate blood supply, which results in large regions that are subjected to hypoxic or anoxic stress. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates much of the transcriptional response of cells to hypoxia. Activating transcription factor 3 (ATF3) is another transcription factor that responds to a variety of stresses and is often upregulated in cancer. We investigated the regulation of ATF3 by oxygen deprivation. ATF3 induction occurred most robustly under anoxia, is common, and it is not dependent on presence of HIF-1 or p53, but is sensitive to the inhibition of c-Jun NH2-terminal kinase activation and the antioxidant N-acetylcystein. ATF3 could also be induced by desferrioxamine but not by the mitochondrial poison cyanide or the nonspecific 2-oxoglutarate dioxygenase inhibitor dimethyloxalylglycine. We also show that anoxic ATF3 mRNA is more stable than normoxic mRNA providing a mechanism for this induction. Thus, this study demonstrates that the regulation of ATF3 under anoxia is independent of 2-oxoglutarate dioxygenase, HIF-1 and p53, presumably involving multiple regulatory pathways.

9572 Background: Tumor expansion is characterized by an inability of the local vasculature to supply enough oxygen to the extensively proliferating tumor cells. Evidence is growing that hypoxia has a profound impact on malignant progression and on responsiveness to therapy. Hypoxia leads to adaptive responses that will help the cells survive including an induction of vasculogenesis initiated by circulating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs). The aim of the present study was to correlate the number of EPCs and/or CECs with the oxygenation status of locally advanced cervical carcinoma. Methods: Blood concentrations of EPCs were analysed by FACS with antibodies for the hematopoietic stem cell (HSC) marker CD34 and the endothelial marker vascular endothelial growth factor receptor 2 (VEGFR2, KDR). CECs were detected by double staining of DiLDL-uptake and lectin binding with laser scanning cytometry (LSC). A study population of 10 patients with cervical cancer was compared with 10 healthy volunteers. Oxygen tension in the tumor tissue of the patients with cervical cancer was assessed polarographically with the computerized Eppendorf histography system. Within the tumor tissue pO2 measurements were taken in each electrode track starting at a tissue depth of 5 mm. Results: Analysis of the CEC numbers neither revealed any difference between patients and controls nor did it show a correlation to the intratumoral oxygen tension. However, cervical cancer patients had a significantly higher fraction of EPCs related to total number of HSCs (1.09% versus 0.53%). This fraction was significantly inversely correlated to intratumoral oxygen tension (r=-0.76, p=0.011). Conclusions: Our study shows for the first time a significant inverse correlation between the fraction of EPCs and the median oxygen tension in cancer tissue. The fraction of EPCs might therefore be a useful marker in the prediction of the responsiveness to radiotherapy or other antitumoral strategies that rely on a certain tissue oxygenation. No significant financial relationships to disclose.

The majority of patients with acute leukemia enter complete remission following induction therapy, but relapse despite consolidation and maintenance chemotherapy. Allogeneic hematopoietic cell transplantation (HCT) is the most effective consolidation therapy but unfortunately associated with high transplant-related mortality (TRM). In order to decrease TRM but still apply a graft-versus-tumor effect, allogeneic HCT protocols with reduced-intensity conditioning were developed and more than 5000 HCT, of which 1500 for acute leukemia, performed. Detailed information is available on more than 400 patients with acute leukemia. The results, summarized in this article, confirm that reduced-intensity preparative regimens lead to full donor chimerism and to generation of graft-versus-leukemia (GvL) effects with curative potential in older patients (>60 years). Prospective-controlled clinical trials are needed in younger patients to compare results of HCT after reduced-intensity conditioning to those of HCT with conventional conditioning.

BMP-2 is involved in the fetal and postnatal development of the mammary gland but has also been detected in breast cancer cells. To clarify the biological role of BMP-2 in breast cancer, we used the human breast cancer cell line MCF-7. Incubation with BMP-2 under serum-free conditions induced activation of the mitogen activated protein kinases (MAPKs) ERK1/2 and the basic helix-loop-helix transcription factors Id-1, proteins that can protect from apoptosis. Stably transfected MCF-7 cells overexpressing BMP-2 revealed significantly increased resistance to hypoxia-induced apoptosis compared to empty vector controls. Cytoplasmic BMP-2/4 protein expression was detected in carcinoma cells of 81 samples of invasive breast cancer in contrast to adjacent normal mammary epithelial cells. BMP-2/4 expression did not correlate with common prognostic parameters and was not associated with relapse-free or overall survival. We conclude that BMP-2/4 expression is reactivated in invasive breast cancer and part of an autocrine/paracrine mechanism rescuing malignant cells from hypoxic cell death via activation of the MAPK and Id-1 pathway.

Breast cancer cell lines migrated towards a BMP-2 source depending on BMP-2 concentration. After a short exposure to BMP-2, the cells were able to migrate through matrigel. MCF-7 cells transfected with the BMP-2 gene also showed enhanced migratory properties and high expression of the metastasis-related gene BCSG1. In a xenograft model without estrogen supplementation MCF-7/BMP-2 cells formed tumors. These tumors were characterised by an enhanced vasculature and the formation of chondroid and osseous structures. In conclusion elevated levels of BMP-2 enhance the tumorigenic properties of breast carcinoma cells and drive the cells towards a more aggressive phenotype with estrogen independent growth.

With increasing donor age, the potential of transmitting diseases from donor to recipient reaches new dimensions. Potentially transmittable diseases from donors include infections, congenital disorders, and acquired illnesses like autoimmune diseases or malignancies of hematological or nonhematological origin. While established nonmalignant or malignant diseases might be easy to discover, early-stage hematological diseases like CML, light-chain multiple myelomas, aleukemic leukemias, occult myelodysplastic syndromes and other malignant and nonmalignant diseases might not be detectable by routine screening but only by invasive, new and/or expensive diagnostic tests. In the following article, we propose recommendations for donor work-up, taking into consideration the age of the donors. In contrast to blood transfusions, stem cells from donors with abnormal findings might still be acceptable for HCT, when no other options are available and life expectancy is limited. This issue is discussed in detail in relation to the available donor and stem cell source. Finally, the recommendations presented here aim at harmonized worldwide work-up for donors to insure high standard quality.

Hypoxia is a key factor in tumor development, contributing to angiogenesis and radiotherapy resistance. Hypoxia-inducible factor-1 (HIF-1) is a major transcription factor regulating the response of cancer cells to hypoxia. However, tumors also contain areas of more severe oxygen depletion, or anoxia. Mechanisms for survival under anoxia are HIF-1alpha independent in Caenorhabditis elegans and, thus, differ from the hypoxic response. Here we report a differential response of cancer cells to hypoxia and anoxia by demonstrating the induction of activating transcription factor-4 (ATF-4) and growth arrest DNA damage 153 (GADD153) protein specifically in anoxia and the lack of induction in hypoxia. By applying RNAi, ATF-4 induction in anoxia was shown to be independent of HIF-1alpha, and desferrioxamine mesylate (DFO) and cobalt chloride induced HIF-1alpha but not ATF-4 or GADD153. Furthermore, the inductive response of ATF-4 and GADD153 was not related to alterations in or arrest of mitochondrial respiration and was independent of von Hippel-Lindau (VHL) disease mutations. In reoxygenated anoxic cells, ATF-4 had a half-life of less than 5 minutes; adding the proteasome inhibitor to normoxic cells up-regulated ATF-4 protein. Extracts from primary human tumors demonstrated more ATF-4 expression in tumors near necrotic areas. Thus, this study demonstrates a novel HIF-1alpha-independent anoxic mechanism that regulates ATF-4 induction at the protein stability level in tumor cells.

Stichodactyla helianthus is a sea anemone relatively abundant along Cuban coasts appearing in two morphos with different colors in their tentacles: green or brownish, probably due to their association with algal symbionts. Traditionally, the brownish morpho has been used as a source of sticholysins I and II, the most characterized cytolysins from this anemone, but the green morpho is the most abundant along the western coasts of Havana. The present work is aimed to establish if the cytolysins purified from the green morpho (StIg and StIIg) are similar to those purified from brownish anemones (StI and StII). Following the same chromatographic procedure used to purify the toxins from morphos, the electrophoretic mobilities, amino acid compositions, amino terminal sequences and molecular masses were practically identical between analogal cytolysins. In conclusion, homologous sticholysins purified from the green and brownish variants of Stichodactyla helianthus are the same molecular entities.

Purpose: The activity of dihydropyrimidine dehydrogenase (DPD) - the rate-limiting enzyme in fluorouracil (5-FU) catabolism - has been reported to vary according to the time of day. On the basis of this data. so-called chronomodulated chemotherapy regimens with variable-rate infusions of 5-FU have been investigated in the treatment of advanced colorectal cancer. Recent results suggest lower toxicity of 5-FU by chronomodulated application. However, the pattern of circadian DPD activity levels have been shown to vary considerably. Methods: We. therefore. studied the circadian changes in mRNA expression of DPD in leukocytes of ten patients with advanced gastrointestinal carcinomas prior to chronomodulated 5-FU-based salvage therapy and in 5five healthy controls. Simultaneously. we measured serum cortisol levels (SCL) to evaluate the endogenous circadian hormone rhythm. Results: SCL displayed. a consistent circadian rhythm with the mean peak value of serum cortisol at 8 a.m. and the mean trough value at 11 p.m. both in patients and in controls. However. mean minimum-maximum serum cortisol differences of SCL were significantly lower in patients compared to controls. In the 5fivehealthy controls, a trend towards a circadian rhythm of DPD mRNA expression was observed with the peak of expression at 5 a.m. which was significantly different from the trough at 2 p.m. (P < 0.005 Mann-Whitney-Wilcoxon test). When each control was Studied separately, only two individuals showed circadian variations that could be fitted to a cosine wave (P=0.001, P=0.014, Cosinor analysis). In contrast, DPD mRNA expression in patients with advanced gastrointestinal carcinomas did not demonstrate any consistent circadian rhythm. Pairwise comparisons of groups of DPD mRNA levels at different times of the day did not show significant differences. Conclusions: In conclusion, our analysis of DPD mRNA expression in leukocytes from healthy controls demonstrates first evidence for a circadian DPD mRNA expression periodicity. In patients with advanced gastrointestinal carcinomas, however, this rhythm seems to be disturbed although circadian endogenous cortisol secretion pattern is maintained.

Raida et al . [(1)][1] , in the September 2001 issue of Clinical Cancer Research, investigated the genetic basis of dihydropyrimidine dehydrogenase deficiency in cancer patients who developed grade 3–4 toxicity after 5-FU[2][2] -containing regimens. Twenty-five patients were genotyped for the exon