Rare cancer-specific mutations in PIK3CA show gain of function

Fifteen rare cancer-derived mutants of PIK3CA, the gene coding for the catalytic subunit p110alpha of phosphatidylinositol 3-kinase (PI3K), were examined for their biological and biochemical properties. Fourteen of these mutants show a gain of function: they induce rapamycin-sensitive oncogenic transformation of chicken embryo fibroblasts, constitutively activate Akt and TOR-mediated signaling, and show enhanced lipid kinase activity. Mapping of these mutants on a partial structural model of p110alpha suggests three groups of mutants, defined by their location in distinct functional domains of the protein. We hypothesize that each of these three groups induces a gain of PI3K function by a different molecular mechanism. Mutants in the C2 domain increase the positive surface charge of this domain and therefore may enhance the recruitment of p110alpha to cellular membranes. Mutants in the helical domain map to a contiguous surface of the protein and may affect the interaction with other protein(s). Mutants in the kinase domain are located near the hinge of the activation loop. They may alter the position and mobility of the activation loop. Arbitrarily introduced mutations that have no detectable phenotype map either to the interior of the protein or are positioned on a surface region that lies opposite to the exposed surfaces containing gain-of-function mutants. Engineered mutants that exchange acidic or neutral residues for basic residues on the critical surfaces show a gain of function.     

Stereotactic Body Radiation Therapy for Abdominal Oligometastases: A biological and clinical review

ABSTRACT: Advances in imaging and biological targeting have led to the development of stereotactic body radiation therapy (SBRT) as an alternative treatment of extracranial oligometastases. New radiobiological concepts, such as ceramide-induced endothelial apoptosis after hypofractionated high-dose SBRT, and the identification of patients with oligometastatic disease by microRNA expression may yet lead to further developments. Key factors in SBRT are delivery of a high dose per fraction, proper patient positioning, target localisation, and management of breathing-related motion. Our review addresses the radiation doses and schedules used to treat liver, abdominal lymph node (LN) and adrenal gland oligometastases and treatment outcomes. Reported local control (LC) rates for liver and abdominal LN oligometastases are high (median 2-year actuarial LC: 61 -100% for liver oligometastases; 4-year actuarial LC: 68% in a study of abdominal LN oligometastases). Early toxicity is low-to-moderate; late adverse effects are rare. SBRT of adrenal gland oligometastases shows promising results in the case of isolated lesions. In conclusion, properly conducted SBRT procedures are a safe and effective treatment option for abdominal oligometastases.     

Contrast-enhanced Ultrasound in Dermatomyositis- and Polymyositis

Objective To evaluate prospectively contrast-enhanced ultrasound (CEUS) in patients suspected of having dermatomyositis or polymyositis. Methods In 35 patients (23 women, 12 men; mean age, 51 years ± 16 years) who were suspected of having dermatomyositis or polymyositis, perfusion in clinically affected skeletal muscles was quantified with contrast-enhanced intermittent power Doppler ultrasound. By applying a modified model that analyzed the replenishment kinetics of microbubbles, the perfusion-related parameters blood flow, local blood volume and blood flow velocity were measured. Findings were compared with muscle biopsy appearances and with the results of MRI that was performed with a 1.5-Tesla unit. Receiver operating characteristic analysis was performed and optimum thresholds for diagnosis of myositis were determined. Results Eleven patients had histologically confirmed dermatomyositis or polymyositis and showed significantly higher blood flow velocity (P = .01 for dermato- and P < .001 for polymyositis), blood flow (P < .001 for dermato- and polymyositis), and blood volume (P = .007 for dermato- and P < .001 for polymyositis) on contrast-enhanced ultrasound than those who did not have myositis. An increase in signal intensity on T2-weighted MR images was found in all patients with myositis. MRI had a sensitivity, specificity, positive (PPV), and negative predicting values (NPV) of 100%, 88%, 77%, and 100% for diagnosis of myositis, respectively. CEUS blood flow was the best ultrasound measure for diagnosis of dermato- or polymyositis with sensitivity, specificity, PPV, and NPV of 73%, 91%, 80%, and 88%, respectively. Conclusions Increased skeletal muscle perfusion measured by CEUS could serve as an additional measurer for the diagnosis of an inflammatory myopathy. Received in revised form: 6 June 2006 An erratum to this article is available at .     

MRI for identification of progression in brain tumors: from morphology to function

For monitoring of brain tumors, it is crucial to identify progression or treatment failure early during follow-up to change treatment schemes and, thereby, optimize patient outcome. In the past years, several areas within the field of magnetic resonance (MR) have seen considerable advances: modern contrast media, advanced morphologic approaches and several functional techniques, for example, in the visualization of tumor perfusion or tumor cell metabolism. This review presents these recent advances by introducing the different techniques and outlining their benefit for identification of progression in brain tumors, with a focus on gliomas, metastases and meningiomas. After radiotherapy, MR spectroscopy helps to more accurately discriminate between radiation necrosis and glioma progression. In low-grade gliomas, perfusion MR techniques enable a more sensitive detection of anaplastic transformation than conventional MRI. Modern contrast media, as well as diffusion tensor imaging, allow for an improved tumor delineation and assessment of tumor extension. We will also highlight the biological background of these techniques, their applicability and current limitations. In conclusion, modern MRI techniques have been developed that are on the doorstep to be integrated in clinical routine.     

Quetiapine in patients with comorbid schizophrenia-spectrum and substance use disorders: an open-label trial

BACKGROUND: Preliminary evidence suggests that clozapine relieves the craving for psychoactive substances in schizophrenia patients. Quetiapine shares crucial pharmacological properties with clozapine. Promising results have been described with quetiapine therapy in patients with psychosis and substance use disorder. METHODS: Based on Diagnostic and Statistical Manual of Mental Disorders - fourth edition (DSM-IV) criteria, patients were diagnosed with comorbid schizophrenia-spectrum and substance use disorders. Patients were switched to quetiapine for a 12-week open-label trial. Craving, quantities used, days of consumption, and severity of substance abuse were assessed every 3 weeks. Alcohol and Drug Use Scales were administered on baseline and end-point. Psychiatric symptoms, depressive symptoms, extrapyramidal symptoms, and cognition were also assessed at baseline, week 6 and week 12. RESULTS: Twenty-four schizophrenia-spectrum patients were included in the last observation carried forward (LOCF) analyses, responding to one or more of the following substance use disorders: cannabis (15 patients), alcohol (10 patients), and other psychoactive substances (nine patients). Overall, severity of substance abuse improved during the study. Less weekly days were spent on drugs of abuse. A decrease in the weekly Canadian dollars spent on psychoactive substances was also observed. Cognition, psychiatric, depressive, and extrapyramidal symptoms also significantly improved (p < 0.05). CONCLUSIONS: In this open-label, uncontrolled trial, significant improvements were noted in substance abuse, psychiatric symptoms, extrapyramidal symptoms, and cognition during quetiapine therapy. The study suffered from three main limitations: (1) the open-label design of the study; (2) the patients' poor compliance; and (3) the small sample size involved. Controlled studies on the use of quetiapine in dual diagnosis schizophrenia are warranted to confirm that the effects are drug-related.     

Impact on delirium detection of using a sensitive instrument integrated into clinical practice

Early symptoms of delirium often go unnoticed. The Nursing Delirium Screening Scale (Nu-DESC) is a recently developed short, accurate and sensitive 24-h screening instrument. The Nu-DESC is more sensitive than the instrument from which it was derived, the Confusion Rating Scale (CRS). This study examined the impact on delirium detection of using the Nu-DESC over the CRS in 134 consecutive oncology patients. Expected false-negative rate (FNR) reductions at different delirium prevalence rates when using the Nu-DESC compared to the CRS and the number needed to screen (NNS) by the Nu-DESC were calculated. Kaplan-Meier survival analyses were used to study Nu-DESC-CRS divergences in delirium status and length of delirium-free survival. Ninety-nine patients were negative for delirium according to both tests. Of the remaining 35 patients, 16 had identical Nu-DESC-CRS delirium status and delirium-free survival, whereas 19 were detected later by the CRS (mean, 4.8 days). Among the 19 patients, 6 were still CRS negative upon hospital discharge. Integrating a continuous and sensitive delirium assessment instrument into usual care can facilitate its recognition, since more cases of delirium are diagnosed and patients are detected earlier.     

Vascular protectants for the treatment of atherosclerosis

AGI-1067, the monosuccinic acid ester of probucol, is a phenolic antioxidant member of a novel class of agents termed vascular protectants. It has strong antioxidant properties, equipotent to those of probucol, and anti-inflammatory properties. It inhibits gene expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 and has been effective at preventing atherosclerosis in all tested animal models. It also improved luminal dimensions of reference segments in the percutaneous coronary intervention (PCI) vessels in the CART-1 clinical trial, which suggests a direct anti-atherosclerosis effect. Two important trials that test the antioxidant/anti-inflammatory hypothesis are ongoing with AGI-1067: the Canadian Atherosclerosis and Restenosis Trial, which assesses its value for the reduction of both atherosclerosis progression in non-PCI vessels and post-PCI restenosis, and the Aggressive Reduction of Inflammation Stops Events trial, which is evaluating the effects of AGI-1067 on hard cardiovascular outcomes.