Fanconi anemia (FA) is a rare recessive DNA repair disorder that is clinically characterized by congenital malformations, progressive bone marrow failure, and increased incidence of malignancies, especially acute myeloid leukemia and squamous cell carcinomas of the head and neck (HNSCCs) and the anogenital regions. On a cellular level, typical features of the disorder are a high degree of genomic instability and an increased sensitivity to bi-functionally alkylating agents. So far, germ-line defects in 15 different FA genes have been identified. Some of these FA genes are also established as tumor susceptibility genes for familiar cancers.In recent years, the prevention and therapy of HNSCCs in FA patients has become more important as the percentage of patients surviving into adulthood is rising. HNSCCs appear in very young FA patients without common risk factors. Since cisplatin-based chemotherapy in combination with radiotherapy, essential parts of the standard treatment approach for sporadic HNSCCs, cannot be used in FA patients due to therapy-associated toxicities and mortalities even with reduced dosing, surgery is the most important treatment option for HNSCCs, in FA patients and requires an early and efficient detection of malignant lesions. So far, no uniform treatment protocol for the management of HNSCCs in FA patients exists. Therefore, we propose that the information on affected FA patients should be collected worldwide, practical therapeutic guidelines developed and national treatment centers established.

Published results on treatment of relapsed adult acute lymphoblastic leukemia (ALL) are poor, despite improvements in first-line therapies. The aim of this retrospective analysis of the German Multicenter Study Group for Adult ALL was to identify prognostic factors and options for improvement. Five hundred forty-seven patients experiencing their first relapse (406 vs 141 <> 18 months from diagnosis) were evaluated. Median age was 33 (15-55) years. The aim of salvage therapy was to achieve a complete remission (CR) with subsequent a stem cell transplantation (SCT). The CR rate (assessed in Ph/BCR-ABL-negative ALL without CNS involvement) after the first salvage in relapse after chemotherapy (N=224) was 42%. After failure of first salvage (N=82), the CR rate after second salvage was 33%. In relapse after SCT (N=48) the CR rate after first salvage was 23%. The median overall survival after relapse was 8.4 months, and survival was 24% at 3 years. Prognostic factors for survival were relapse localization, response to salvage, performance of SCT and age. Overall survival appeared superior compared to previously published studies. This is likely due to the high rate of SCT (75%). Further improvement may be achieved with earlier relapse detection and experimental approaches in early relapse. These studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.

Quantification of minimal residual disease (MRD) by real-time polymerase chain reaction directed to T-cell-receptor and immunoglobulin gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytological complete response (CR) rate was 89% after induction phase I and II. At this time-point the molecular CR rate was 70% in 580 patients with cytological CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR)(74% vs. 35%; p<0.0001) and of overall survival (80% vs. 42%; p=0.0001) compared to patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study endpoint. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.

INTRODUCTION: The basis of disc degeneration is still unknown, but is believed to be a cell-mediated process. Apoptosis might play a major role in degenerative disc disease (DDD). The aim of this study was to correlate the viability of disc cells with the radiological degeneration grades (rDG) in disc herniation. MATERIALS AND METHODS: Forty anterior IVD's (C4-C7) from 39 patients with DDD were studied histologically and ultrastructurally to quantify healthy,"balloon", chondroptotic, apoptotic and necrotic cells. Patients were classified to their rDG, as having either prolapse (P: DGII + III) and/or osteochondrosis (O: DGIV + V). Similar studies were undertaken on eight control discs. RESULTS: Cell death by necrosis (mean 35%) was common but differed not significantly in both groups. All patients with a disc prolapse DGII + III revealed balloon cells (iAF: mean 32%). All appeared alive and sometimes were hypertrophic. However, significantly less balloon cells were found in the O-Group. Control samples revealed no evidence of "balloon" cells in DGII and only a minor rate in DGIII. CONCLUSION: According to the different rDG, quantitative changes were obvious in healthy and "balloon" cells, but not for cell death. At the moment it can only be hypothesized if "balloon" cells are part of a repair strategy and/or cause of disc herniation.

Apart from the well-known biologically active angiotensin II, other biologically active angiotensins have been discovered, including angiotensin IV and angiotensin-(1-7). Some years ago, we and others discovered that the Mas proto-oncogene encodes a receptor that is essential for angiotensin-(1-7) signaling. Angiotensin-(1-7) is not only expressed in the periphery but also within the brain. Based on that, we examined the distribution of Mas within the murine brain, using an antibody directed against the 3(rd) cytoplasmic loop of the receptor protein. Strongest Mas protein expression was detected in the dentate gyrus of the hippocampus and within the piriform cortex. However, Mas protein expression is not restricted to these areas, since Mas immunopositive neurons were also seen in different parts of the cortex, hippocampus, amygdala, basal ganglia, thalamus and hypothalamus. Based on the expression of Mas protein in the cortex and the limbic system, angiotensin-(1-7) signaling may play a role in synaptic plasticity, learning, memory and emotion, as has been described for angiotensin II and IV.

BACKGROUND Detection of risk factors for an air embolism in the left atrium, left ventricle, or systemic circulation (systemic air embolism, SAE) during a percutaneous core needle biopsy (PCNB) of the thorax. METHODS In a retrospective observational study, all PCNBs of the thorax in 610 patients between 2007 and 2009 were analyzed. The SmartStep™ technique (General Electric) was used for the biopsy, with which the examiner can prepare a batch of three 1.25-mm or 2.5-mm collimated slices within a second using a foot switch in the CT room to check the needle position. The image data thus generated and the control CT scans that followed were examined retrospectively for the presence of intravascular air. Intravascular air was defined as two or more adjacent voxels with absorption values of <-200 HU in the left atrium, left ventricle, aorta, or arteries during or after the procedure. The univariate statistical analysis of categorical variables was made using 2 by 2 tables and the Fisher test. The groups were compared using the Mann-Whitney test. Finally, a multivariate logistic regression analysis was used to identify independent risk factors for the occurrence of an SAE. RESULTS The radiological incidence of an SAE during a PCNB was 3.8%(23/610 patients), whereas the clinically apparent incidence was 0.49%. Two patients developed clinical symptoms consisting of transient hemiplegia or transient amaurosis; one died due to a fatal SAE of the coronary arteries. The mortality was thus 0.16%. The depth of the needle in the lesion (Wald: 6.859), endotracheal anesthesia (Wald: 5.721), location of the lesion above the level of the left atrium (Wald: 5.159), and prone position of the patients (Wald: 4.317) were independent risk factors for the incidence of an SAE (p < 0.05 each). Using explorative criteria, the acute angle of the needle to the tumor surface, and the transition of ventilated lung were independent factors. The frequency of biopsies, needle penetration depth, and tumor location near the diaphragm or in the lower lobe also played a subordinate role, not however, the needle penetration depth through the lung. CONCLUSION If possible, the PCNB should be performed under local anesthesia. We recommend avoiding endotracheal anesthesia and prone position. Whenever possible, patients should be positioned on the back in such a way that the tumor is lower than the left atrium. The tip of the needle should be within the tumor during the biopsy procedure.

BACKGROUND Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches. MATERIALS AND METHODS ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa). RESULTS NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G(0)/G(1) arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells. CONCLUSION NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL.

In 2 double-blind studies, ambulatory patients with objectively proven, disseminated metastatic breast carcinoma (TOPIC-1) or stage III/IV non-small-cell lung carcinoma (TOPIC-2) were randomized to certoparin 3000 IU or placebo subcutaneously once daily, for 6 months. Primary efficacy outcome was objectively confirmed symptomatic or asymptomatic venous thromboembolism (VTE). Safety outcomes included bleeding (major and minor), and thrombocytopenia. TOPIC-1 was halted after an interim analysis. Venous thromboembolism occurrence was not different between treatment groups in TOPIC-1 (4% treated with certoparin, 7 of 174 vs 4% receiving placebo, 7 of 177, odds ratio [OR] 1.02; 95% confidence interval [CI] 0.30-3.48) and in TOPIC-2 (4.5%, 12 of 268) vs 8.3%, 22 of 264, respectively, OR 0.52; CI 0.23-1.12). Mortality was not different between groups. A post hoc analysis showed certoparin significantly reduced VTE in stage IV lung carcinoma (3.5% vs 10.2%; P =.032) without increased bleeding. In conclusion, thrombosis risk and prophylactic benefit was highest in stage IV lung carcinoma patients.

GPVI has been proposed as a promising anti-platelet target since its blockade prevents experimental thrombosis without impairing hemostasis. The objective of this study was to develop a preclinical tool to evaluate the role of human GPVI in various models of thrombosis and to screen anti-GPVI compounds. A genetically modified mouse strain expressing human GPVI (hgp6) has been developed using a knock-in strategy. The mice were viable and fertile and did not present any hematological defect. About 3,700 copies of human GPVI were detected at the platelet surface. Platelet aggregation, fibrinogen binding and P-selectin exposure were normal in response to various agonists. The 9O12.2 Fab fragment directed against human GPVI bound to hgp6 platelets in vitro and ex vivo and markedly reduced collagen- and CRP-induced responses. Injection of 9O12.2 into hgp6 animals did not prolong the tail bleeding time but provided protection against lethal thromboembolism induced by a collagen/adrenaline mixture. In addition, 9O12.2 reduced arterial thrombus growth by 44% after superficial laser injury, by 43% after deep laser injury in mice pretreated with hirudin and by 48% after mechanical injury. In conclusion, we have developed a humanized mouse model which could be used in preclinical studies to evaluate the effects of anti-GPVI compounds.

ABSTRACT: BACKGROUND: The primary behavioural risks for the most common causes of mortality and morbidity in developed countries are tobacco smoking, poor nutrition, risky alcohol use, and physical inactivity. Evidence, guidelines and policies support routine clinician delivery of care to prevent these risks within primary care settings. Despite the potential afforded by community health services for the delivery of such preventive care, the limited evidence available suggests it is provided at suboptimal levels. This study aims to assess the effectiveness of a multi-strategic practice change intervention in increasing clinician's routine provision of preventive care across a network of community health services. METHODS: A multiple baseline study will be conducted involving all 56 community health facilities in a single health district in New South Wales, Australia. The facilities will be allocated to one of three administratively-defined groups. A 12 month practice change intervention will be implemented in all facilities in each group to facilitate clinician risk assessment of eligible clients, and clinician provision of brief advice and referral to those identified as being 'at risk'. The intervention will be implemented in a non-random sequence across the three facility groups. Repeated, cross-sectional measurement of clinician provision of preventive care for four individual risks (smoking, poor nutrition, risky alcohol use, and physical inactivity) will occur continuously for all three facility groups for 54 months via telephone interviews. The interviews will be conducted with randomly selected clients who have visited a community health facility in the last two weeks. Data collection will commence 12 months prior to the implementation of the intervention in the first group, and continue for six months following the completion of the intervention in the last group. As a secondary source of data, telephone interviews will be undertaken prior to and following the intervention with randomly selected samples of clinicians from each facility group to assess the reported provision of preventive care, and the acceptability of the practice change intervention and implementation. DISCUSSION: The study will provide novel evidence regarding the ability to increase clinician's routine provision of preventive care across a network of community health facilities. Trial registration: Australian Clinical Trials Registry ACTRN12611001284954 Universal Trial Number (UTN): U1111-1126-3465.