From the Cover: Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling

Cerebral cavernous malformations (CCM) are frequent vascular abnormalities caused by mutations in one of the CCM genes. CCM1 (also known as KRIT1) stabilizes endothelial junctions and is essential for vascular morphogenesis in mouse embryos. However, cellular functions of CCM1 during the early steps of the CCM pathogenesis remain unknown. We show here that CCM1 represents an antiangiogenic protein to keep the human endothelium quiescent. CCM1 inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary human endothelial cells. CCM1 strongly induces DLL4-NOTCH signaling, which promotes AKT phosphorylation but reduces phosphorylation of the mitogen-activated protein kinase ERK. Consistently, blocking of NOTCH activity alleviates CCM1 effects. ERK phosphorylation is increased in human CCM lesions. Transplantation of CCM1-silenced human endothelial cells into SCID mice recapitulates hallmarks of the CCM pathology and serves as a unique CCM model system. In this setting, the multikinase inhibitor Sorafenib can ameliorate loss of CCM1-induced excessive microvascular growth, reducing the microvessel density to levels of normal wild-type endothelial cells. Collectively, our data suggest that the origin of CCM lesions is caused by perturbed Notch signaling-induced excessive capillary sprouting, which can be therapeutically targeted.     

Die Bedeutung der Hypophyse für die Erkrankung der Niere

Ohne Zusammenfassung     

Global quality of life and its potential predictors in breast cancer patients: an exploratory study

Goals of work This study reflects variables being depicted as predictors of global quality of life in current research. The evaluation was conducted at the Division of Clinical Oncology at the Medical University in Graz, Austria. Patients and methods A sample of 210 breast cancer patients between ages 30 and 80 years was assessed 1−5 years after initial diagnosis in a tumor-free stage. Besides the socio-demographic and medical variables, the Brief Symptom Inventory (BSI), Impact of Event Scale (IES), Mental Adjustment to Cancer (MAC), and the Perceived Family Support (PFS) were used. To identify variables related to quality of life, stepwise multiple regression analyses were calculated. Main results In a regression analysis, the general severity index (BSI) was identified as the most important and helplessness/hopelessness (MAC) as the second important variable related to QoL. Including the BSI-subscales as predictors, the depression-subscale (BSI) explained 25% of the variance; in addition, somatization (BSI), helplessness/hopelessness (MAC), and having financial problems (semi-structured interview) were significantly related to global quality of life, but the medical variables showed no associations to the measured quality of life. Depression itself is associated with negative the impact of cancer, the number of stressful life events, being uncomfortable with the body, having financial problems and anxious preoccupation (MAC). Conclusions The awareness of the role of multi-factorial and associated variables could provide patients, family, and medical staff with appropriate and adequate tools to treat specific symptoms.     

Weekly 5-fluorouracil and high-dose folinic acid in combination with epidoxorubicin as first-line therapy in advanced breast cancer: a phase II study

A total of 25 patients with advanced breast cancer were treated weekly with i.v. 5-fluorouracil at 350 mg/m², folinic acid at 500 mg/m², and epidoxorubicin at 35 mg/m² as first-line chemotherapy for a maximum of 18 cycles. In all, 24 patients were evaluable for response. Overall, 1 patient achieved a complete response and 11 patients showed a partial response, for an objective response rate of 50%; the median duration of response was 18.3+ months and median survival amounted to 18.8+ months. Side effects were generally mild, with grade II leukopenia occurring in 10 patients and grade III leukopenia, in 1 patient. Other toxicity included nausea and vomiting (82%), diarrhea (48%), stomatitis (48%), and alopecia (92%), all of which were mainly restricted to WHO grades I and II. Our results suggest that leucovorin modulation of 5-fluorouracil can safely be incorporated into combination chemotherapy with epidoxorubicin on the investigated schedule. The observed response rate appears comparable with the obtained with other first-line regimens.     

Validation of the Korean version of the Syndrom Kurztest (SKT): a short test for the assessment of memory and attention

The Syndrom Kurztest SKT is a brief neuropsychological test battery that consists of nine subtests and defines two independent factors of memory and attention deficit. The aim of this study was to validate the Korean version of the SKT. The reliability of each subtest among three parallel Forms (A, B and C) of the Korean version was high (r = 0.46-0.95). The SKT had good concurrent validity with the Mini-Mental State Examination (r = -0.83, p < 0.001). Factor analysis confirmed the presence of two primary factors, memory and attention. The overall similarities of the factor structures for the Korean data and those for the data from Germany and the USA provide evidence of the transcultural stability of the SKT.     

Incidence of anaemia in breast cancer patients receiving adjuvant chemotherapy

Anaemia is frequent in breast cancer patients but often remains undiagnosed and untreated. To determine the incidence of anaemia a prospective survey of primary non-metastatic breast cancer patients who received at least four cycles of adjuvant, non-platinum multi-agent chemotherapy was conducted at 47 centres in Austria. Two hundred and forty seven patients were prospectively included between October 1999 and December 1999. Haemoglobin (Hb) levels were determined after surgery and prior to each cycle of chemotherapy. Treatment of anaemia (blood transfusion or epoetin alfa) during the observation period was at the physician's discretion. For the purpose of this study, patients were considered to be anaemic if their Hb was below 12 g/dl. At baseline (after surgery and before the first cycle of chemotherapy), 28.7% of all patients were anaemic. The only significant differentiating factor was the type of surgery. 37.9% of patients who underwent mastectomy were anaemic, whereas only 22.8% of patients who underwent breast conserving surgery were anaemic. Forty two percent of 176 patients with a Hb level of 12 g/dl at baseline developed anaemia during adjuvant chemotherapy. The only factor that significantly influenced the development of anaemia during chemotherapy was the Hb level at baseline. The total incidence of anaemia in patients with primary breast cancer who underwent surgery followed by adjuvant multi-agent chemotherapy was 58.7%. Forty nine patients (20.2%), 48 patients (19.2%) and 48 patients (19.2%) showed a decrease in Hb levels by 1 g/dl, 1–2 g/dl and >2 g/dl, respectively. Only 18.6% of the patients who were found to be anaemic received anaemia treatment. The two most important factors for developing anaemia are the kind of surgery and the Hb level prior to chemotherapy.     

The 870G>A Polymorphism of the Cyclin D1 Gene is not Associated with Breast Cancer

A common 870G > A polymorphism in the gene for cyclin D1, CCND1, has been linked to alternative splicing and cancer susceptibility. To analyze its role for breast cancer, we determined the CCND1 genotype in 500 breast cancer patients and 500 controls. CCND1 genotype frequencies were similar among patients and controls. The CCND1 genotype was furthermore not associated with tumor characteristics. We conclude that the CCND1 870G > A polymorphism is not associated with breast cancer.     

Magnetic resonance angiography unmasks reliable target vessels for pedal bypass grafting in patients with diabetes mellitus

OBJECTIVE: The purpose of this study was to evaluate the performance of pedal bypass grafts to foot vessels detected by magnetic resonance angiography (MRA) that were occult in conventional angiography in patients with diabetes mellitus and severe arterial occlusive disease. METHODS: Vascular surgery and radiology registries were reviewed for patients with pedal bypass grafts to arteries that were not detected with digital subtraction angiography but unmasked with MRA. From December 1997 to March 1999, 15 patients (mean age, 73 +/- 8 years) were identified and analyzed retrospectively. All the patients were diabetic, with 60% being insulin-dependent. Advanced tissue loss was the operative indication in all the cases. Distal anastomosis was performed to the dorsalis pedis artery in 10 cases and to the plantar artery in five cases, with ipsilateral greater saphenous vein as graft material in all the cases. RESULTS: The perioperative mortality rate was 7% (1 of 15 cases). One graft occlusion resulted in a secondary patency rate of 93.1%. During a mean follow-up examination period of 22 months, no graft occlusions and one major amputation were noted, which resulted in a secondary patency rate of 93.1% and a limb salvage rate of 89.5% at 36 months. CONCLUSION: Foot vessels that were occult in conventional angiography but could be detected with MRA were shown to be suitable target vessels for pedal bypass grafting with promising results.